Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation

Publication date: Available online 10 August 2017
Source:Cell Stem Cell
Author(s): Charles A. Thomas, Leon Tejwani, Cleber A. Trujillo, Priscilla D. Negraes, Roberto H. Herai, Pinar Mesci, Angela Macia, Yanick J. Crow, Alysson R. Muotri
Three-prime repair exonuclease 1 (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1. We observed abundant extrachromosomal DNA in TREX1-deficient neural cells, of which endogenous Long Interspersed Element-1 retrotransposons were a major source. TREX1-deficient neurons also exhibited increased apoptosis and formed three-dimensional cortical organoids of reduced size. TREX1-deficient astrocytes further contributed to the observed neurotoxicity through increased type I interferon secretion. In this model, reverse-transcriptase inhibitors rescued the neurotoxicity of AGS neurons and organoids, highlighting their potential utility in therapeutic regimens for AGS and related disorders.

Graphical abstract

Teaser

Thomas et al. used human pluripotent stem cells to dissect the contribution of neurons and glia to the neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). They found that mutant cells accumulate retroviral-like extrachromosomal nucleic acids that trigger a neurotoxic response, and they suggest that anti-retrovirals could potentially provide therapy for this disease.


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Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes

Publication date: Available online 10 August 2017
Source:Cell Stem Cell
Author(s): Catherine C. Coombs, Ahmet Zehir, Sean M. Devlin, Ashwin Kishtagari, Aijazuddin Syed, Philip Jonsson, David M. Hyman, David B. Solit, Mark E. Robson, José Baselga, Maria E. Arcila, Marc Ladanyi, Martin S. Tallman, Ross L. Levine, Michael F. Berger
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.

Graphical abstract

Teaser

Coombs et al. examined a large cohort of solid tumor patients who underwent deep-coverage, paired tumor/blood sequencing and demonstrated that clonal hematopoiesis is common and associated with increasing age, tobacco use, and prior radiation therapy and that it predicts an increased risk of hematologic cancers and shorter survival.


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Open Chromatin Profiling in hiPSC-Derived Neurons Prioritizes Functional Noncoding Psychiatric Risk Variants and Highlights Neurodevelopmental Loci

Publication date: Available online 10 August 2017
Source:Cell Stem Cell
Author(s): Marc P. Forrest, Hanwen Zhang, Winton Moy, Heather McGowan, Catherine Leites, Leonardo E. Dionisio, Zihui Xu, Jianxin Shi, Alan R. Sanders, William J. Greenleaf, Chad A. Cowan, Zhiping P. Pang, Pablo V. Gejman, Peter Penzes, Jubao Duan
Most disease variants lie within noncoding genomic regions, making their functional interpretation challenging. Because chromatin openness strongly influences transcriptional activity, we hypothesized that cell-type-specific open chromatin regions (OCRs) might highlight disease-relevant noncoding sequences. To investigate, we mapped global OCRs in neurons differentiating from hiPSCs, a cellular model for studying neurodevelopmental disorders such as schizophrenia (SZ). We found that the OCRs are highly dynamic and can stratify GWAS-implicated SZ risk variants. Of the more than 3,500 SZ-associated variants analyzed, we prioritized ∼100 putatively functional ones located in neuronal OCRs, including rs1198588, at a leading risk locus flanking MIR137. Excitatory neurons derived from hiPSCs with CRISPR/Cas9-edited rs1198588 or a rare proximally located SZ risk variant showed altered MIR137 expression, dendrite arborization, and synapse maturation. Our study shows that noncoding disease variants in OCRs can affect neurodevelopment, and that analysis of open chromatin regions can help prioritize functionally relevant noncoding variants identified by GWAS.

Graphical abstract

Teaser

Forrest et al. outline an approach for prioritizing noncoding GWAS risk variants using open chromatin analysis in differentiating hiPSCs. They further show that CRISPR/Cas9 editing of prioritized schizophrenia risk SNPs near MIR137 alters gene expression, open chromatin, and neurodevelopment in hiPSC-derived neurons.


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Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars

Abstract

Colorectal cancer (CRC) is a leading cause of tumor-related morbidity and mortality worldwide, with mortality most often attributable to metastatic disease. Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, has a significant role in the treatment of metastatic CRC (mCRC). However, patient access to bevacizumab may be limited in some regions or circumstances, owing to factors related to insurance coverage, reimbursement, patient out-of-pocket costs, or availability. As a result, outcomes for patients with mCRC may be worsened. Additionally, counterfeit bevacizumab has infiltrated legitimate supply chains, exposing patients to risk. Oncologists may also be affected detrimentally, since resolving access issues can be time-consuming and demoralizing. The imminent expiry of patents protecting bevacizumab provides other manufacturers with the opportunity to produce highly similar versions known as biosimilars. High-quality, safe, and effective biosimilars have the potential to expand access to bevacizumab. Most of the bevacizumab biosimilars currently in development are in clinical trials in patients with non-small-cell lung cancer, and future authorization for mCRC indications will, therefore, be based on extrapolation. This article reviews the current role of bevacizumab in the management of mCRC, the possible barriers associated with diminished access to bevacizumab, and the potential bevacizumab biosimilars in development. How biosimilars may impact the treatment of mCRC is also discussed.

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Anticancer efficacy of the hypoxia-activated prodrug evofosfamide is enhanced in combination with proapoptotic receptor agonists against osteosarcoma

Abstract

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia also leads to treatment opportunities as demonstrated by the development of compounds that target regions of hypoxia within tumors. Evofosfamide is a hypoxia-activated prodrug that is created by linking the hypoxia-seeking 2-nitroimidazole moiety to the cytotoxic bromo-isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions of tumors, the DNA cross-linking toxin, Br-IPM, is released leading to cell death. This study assessed the anticancer efficacy of evofosfamide in combination with the Proapoptotic Receptor Agonists (PARAs) dulanermin and drozitumab against human osteosarcoma in vitro and in an intratibial murine model of osteosarcoma. Under hypoxic conditions in vitro, evofosfamide cooperated with dulanermin and drozitumab, resulting in the potentiation of cytotoxicity to osteosarcoma cells. In contrast, under the same conditions, primary human osteoblasts were resistant to treatment. Animals transplanted with osteosarcoma cells directly into their tibiae developed mixed osteosclerotic/osteolytic bone lesions and consequently developed lung metastases 3 weeks post cancer cell transplantation. Tumor burden in the bone was reduced by evofosfamide treatment alone and in combination with drozitumab and prevented osteosarcoma-induced bone destruction while also reducing the growth of pulmonary metastases. These results suggest that evofosfamide may be an attractive therapeutic agent, with strong anticancer activity alone or in combination with either drozitumab or dulanermin against osteosarcoma.

In this study, we investigated the cytotoxic activity of the hypoxia-activated prodrug evofosfamide against human osteosarcoma cells in vitro as a single agent and in combination with proapoptotic receptor agonist's dulanermin and drozitumab. We then assessed the anticancer activity of evofosfamide alone and in combination with drozitumab using a clinically relevant orthotopic mouse model of osteosarcoma and on subsequent pulmonary metastases. Evofosfamide as a single agent reduced tumor burden in bone and cooperated with drozitumab to protect bone from osteosarcoma-induced bone destruction while also reducing the incidence of pulmonary metastases and importantly, evofosfamide alone and in combination with drozitumab was not toxic to normal bone metabolism in vivo.

http://ift.tt/2vK6afr

Impact of depression treatment on health-related quality of life among adults with cancer and depression: a population-level analysis

Abstract

Purpose

Cancer diagnosis in adults is often accompanied by negative impacts, which increase the risk of depression thereby lowering health-related quality of life (HRQoL). We examined the association between depression treatment and HRQoL among US adults with cancer and depression.

Methods

Patients age 18 and above, with self-reported cancer and depression diagnoses were identified from Medical Expenditure Panel Survey database for 2006–2013. Baseline depression treatment was categorized as antidepressants only, psychotherapy with or without antidepressant use, and no reported use of antidepressants or psychotherapy. HRQoL was measured using SF-12 physical component summary (PCS) and mental component summary (MCS) scores. Adjusted ordinary least squares regressions estimated the association between type of depression treatment and HRQoL.

Results

Out of 450 (weighted per calendar year: 2.1 million) cancer adults included in the study, 51% received antidepressants only, while 16% received psychotherapy with or without antidepressants. In bivariate analyses, the mean MCS score was lowest among those who received psychotherapy with or without antidepressants compared to those receiving antidepressants only and those with no reported use of either modality, p < 0.05. In multivariate analyses, there was no significant difference in HRQoL by type of depression treatment.

Conclusion

Despite treatment for depression, HRQoL did not improve during the measurement timeframe. Quality of life is a priority health outcome in cancer treatment, yet our findings suggest that current clinical approaches to ameliorate depression in cancer patients appear to be suboptimal.

Implications for cancer survivors

Adults with cancer and comorbid depression should receive appropriate depression care in order to improve their HRQoL.

http://ift.tt/2wyCJL7

Risk adapted dose-intensified postoperative radiation therapy in prostate cancer patients using a simultaneous integrated boost technique applied with helical Tomotherapy

Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose-intensi...

http://ift.tt/2wylAkN

Relationship between radiation dose and microbleed formation in patients with malignant glioma

Cranial irradiation is associated with long-term cognitive changes. Cerebral microbleeds (CMBs) have been identified on susceptibility-weighted MRI (SWI) in patients who have received prior cranial radiation, ...

http://ift.tt/2vn9uwc

A278C mutation of dihydropteridine reductase decreases autophagy via mTOR signaling

Abstract

Dihydropteridine reductase (QDPR) plays an important role in the recycling of BH4 and is closely related to oxidative stress. We have previously reported that the overexpression of QDPR in human kidney HEK293T cells significantly protected against oxidative stress, and these beneficial effects were abolished by A278C mutation. To evaluate the effect of wild-type and mutant QDPR on autophagy and its mechanism in HEK293T cells, we constructed the wild-type and mutant QDPR expression plasmids and transfected them into HEK293T cells. Three days later, cells were collected to observe the expression of fusion protein and the intracellular production of reactive oxygen species (ROS). Western blot analysis was employed to evaluate the change of mTOR and ribosomal protein S6 kinase B1 (S6K1) signaling and the expression of LC-I, LC-II, Bcl-1, Bcl-2, p62, and p53. The results showed that the exogenous wild-type QDPR significantly decreased the expression of mTOR and phosphorylation of the mTOR and S6K1. Mutation of QDPR inhibited the regulation of mTOR, suggesting that QDPR is a positive regulator of autophagy via suppressing mTOR signaling. The expressions of p62, LC3-II and Beclin 1 were dramatically enhanced in wild-type QDPR group, which were reversed after QDPR mutation. Additionally, mutation of QDPR altered the upregulation of QDPR on Beclin 2. It is therefore concluded that QDPR appears to play an important role in enhancing autophagy, and its mutation contributes to dysregulation of autophagy.

http://ift.tt/2wN0pL8

Ctenopharyngodon idella IKKβ interacts with PKR and IκBα

Abstract

Inhibitor of nuclear factor kappa-B kinase β (IKKβ) is a subunit of the IKK complex. It can activate the NF-κB pathway through phosphorylating IκB in response to a wide range of stimuli. In the present study, an IKKβ gene from grass carp (Ctenopharyngodon idella; KT282114) was cloned and identified by homologous cloning and rapid-amplification of cDNA ends (RACE) technique. The complete CiIKKβ cDNA is 3428 bp in length, with the longest open reading frame (ORF) of 2337 bp encoding a polypeptide of 778 amino acids. The deduced amino acid sequence of CiIKKβ has similar domain distribution to those of mammalian. For example, CiIKKβ consists of a serine/threonine kinase domain at the N-terminal, a basic region leucin zipper (BRLZ) domain in the middle, a homeobox associated leucin zipper (HALZ) domain and an IKKβ NEMO (NF-κB essential modulator) binding domain at the C-terminal. Phylogenetic tree analysis also showed that CiIKKβ is highly homologous to zebrafish IKKβ (DrIKKβ) and clearly distinct from the mammalian and amphibian counterparts. The expression of CiIKKβ was ubiquitously found in the liver, intestine, kidney, gill, spleen, heart, and brain tissues of grass carp and significantly up-regulated in CIK cells under the stimulation with Poly I:C and UV-inactivated grass carp hemorrhagic virus. To investigate the activation mechanism of NF-κB pathway in fish and the role of CiIKKβ in the pathway, we explored the protein interactions of protein kinase R (PKR) with IKKβ and IKKβ with IκBα by co-immunoprecipitation and GST-pull down assays. The interaction between each pair was confirmed. The results suggest that CiIKKβ may be a primary member in the activation of NF-κB pathway in fish.

http://ift.tt/2wN6V4s

mTOR signaling pathway differently regulates central and peripheral axon regeneration

Abstract

Numerous studies have shown that the intrinsic axonal regenerative capacity of neurons differs between the peripheral and central nervous systems (CNSs). However, the molecular mechanisms controlling intrinsic axonal regenerative capacity are unclear. A better understanding of these mechanisms should aid in the development of effective therapeutic strategies for traumatic nervous system injury, including spinal cord injury. Here, we found that blocking mammalian target of rapamycin (mTOR) activity dramatically diminished axonal regrowth from embryonic cortical neurons. However, mTOR activity was not required for axonal regrowth from adult peripheral sensory neurons. By analyzing the levels of phospho-S6, a downstream target of mTOR, we found that embryonic cortical neurons had a much higher mTOR activity compared with adult peripheral sensory neurons. Our findings suggest that, in the CNS, the mTOR pathway plays a critical role in regulating the regenerative capacity of neurons, in contrast to the peripheral nervous system.

http://ift.tt/2vTzJM5

Effects of trigonelline inhibition of the Nrf2 transcription factor in vitro on Echinococcus granulosus

Abstract

The aim of this study was to investigate the impact of trigonelline (TRG) on Echinococcus granulosus, and to explore the inhibition impact of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway on E. granulosus protoscoleces. Echinococcus granulosus protoscoleces were incubated with various concentrations of TRG, and then Nrf2 protein expression and its localization in protoscoleces were detected by western blot analysis and immunofluorescence assay, respectively. Reactive oxygen species (ROS) level in protoscoleces was measured using ROS detection kit. Caspase-3 activity was measured using a caspase-3 activity assay kit, and NAD(P)H quinone oxidoreductase (NQO)-1 and heme oxygenase (HO)-1 activities in protoscoleces were measured by ELISA. The effect of TRG on protoscoleces viability was investigated using 0.1% eosin staining, and ultrastructural alterations in protoscoleces were examined by scanning electron microscopy (SEM). Immunolocalization experiment clearly showed that Nrf2 protein was predominantly present in cells of protoscoleces. TRG treatment reduced NQO-1 and HO-1 activities in protoscoleces, but could increase ROS level at early time. Protoscoleces could not survive when treated with 250 μM TRG for 12 days. SEM results showed that TRG-treated protoscoleces presented damage in the protoscoleces region, including hook deformation, lesions, and digitiform protuberance. Nrf2 protein expression was significantly decreased and caspase-3 activity was clearly increased in protoscoleces treated with TRG for 24 and 48 h, respectively, when compared with that in controls (P < 0.05). Our results demonstrated that TRG had scolicidal activity against E. granulosus protoscoleces. Nrf2 protein was mainly expressed in the cells and TRG could efficiently inhibit the Nrf2 signaling pathway in E. granulosus.

http://ift.tt/2wMROIj

Up-regulation of carcinoembryonic antigen-related cell adhesion molecule 1 in gastrointestinal cancer and its clinical relevance

Abstract

Serum carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is dysregulated in various malignant tumors and has been associated with tumor progression. However, the expression and regulatory mechanisms of serum CEACAM1 in gastrointestinal cancer are still unclear. The expression ratio of the CEACAM1-L and CEACAM1-S isoforms has seldom been investigated in gastrointestinal cancer. In this study, we intended to explore the expression and diagnostic value of CEACAM1 in gastrointestinal cancer. Serum CEACAM1 levels were measured by enzyme-linked immunosorbent assay. The protein expression and distribution of CEACAM1 in tumors were examined by immunohistochemical staining. The expression patterns and ratio of CEACAM1-L/S were analyzed by reverse transcription-polymerase chain reaction. The results showed that serum CEACAM1 levels were significantly higher in cancer patients than in healthy controls. CEACAM1 was found in secreted forms within the neoplastic glands, and its expression was more intense at the tumor invasion front. The CEACAM1-L/S (L:S) ratios were up-regulated during tumorigenesis. Our data suggest that the serum level of CEACAM1 may be used to discriminate gastrointestinal cancer patients from health controls.

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Ginseng saponin Rb1 enhances hematopoietic function and dendritic cells differentiation

http://ift.tt/2wMFebN

Local knockdown of Nav1.6 relieves pain behaviors induced by BmK I

Abstract

Voltage-gated sodium channels (VGSCs) in peripheral nociceptive sensory neurons are critical to transmit pain signals. BmK I purified from the venom of scorpion Buthus martensi Karsch (BmK) has been demonstrated to be the primary contributor of envenomation-associated pain. However, the role of distinct VGSCs such as Nav1.6 in the induction and maintenance of pain behaviors induced by BmK I was ambiguous. Herein, using molecular and behavioral approaches we investigated the mRNA and protein expression profiles of Nav1.6 in rat DRG after intraplantar injection of BmK I and tested the pain behaviors after knockdown of Nav1.6 in BmK I-treated rats. It was shown that during induction and maintenance of pain responses induced by BmK I, the expression of Nav1.6 in DRG was found to be significantly increased at both mRNA and protein levels. The percentage of co-localization of Nav1.6 and Isolectin B4, a molecular marker of small diameter non-peptidergic DRG neurons, was increased at the maintenance phase of pain responses. Furthermore, spontaneous pain and mechanical allodynia, but not thermal hyperalgesia induced by BmK I, were significantly alleviated after knockdown of Nav1.6. These data strongly suggest that Nav1.6 plays an indispensable role in the peripheral pain hypersensitivity induced by BmK I.

http://ift.tt/2vThjv5

The potential role of retinoic acid receptor α on glomerulosclerosis in rats and podocytes injury is associated with the induction of MMP2 and MMP9

Abstract

Retinoic acid receptor α (RARα) plays a crucial role in kidney disease. However, the underlying mechanisms in glomerulosclerosis (GS) is still not clear. The roles of RARα in an adriamycin (ADR)-induced GS rat model and in ADR-induced podocyte injury in vitro were investigated. RARα was over-expressed in GS rats, and serum, urine and kidney samples were collected to detect the induction of the expression of the receptor. RARα expression was inhibited and/or over-expressed in cultured podocytes following injury, as demonstrated by morphometric assays, cell toxicity, and matrix metalloproteinase (MMP) enzymatic activity. RARα displayed a renoprotective role in GS rats, resulting in a lower GS index, podocyte foot process fusion, and proteinuria, reduced serum creatinine and blood urea nitrogen. Further experiments indicated that RARα inhibited the accumulation of TGF-β1, α-smooth muscle actin, collagen IV, and fibronectin, while it induced MMP2 and MMP9 excessive expression in podocytes in vitro. RARα improved the renal function and attenuated the progression of GS that was associated with the over-expression of MMP2 and MMP9.

http://ift.tt/2wN0u1o

Tetramethylpyrazine reverses intracerebroventricular streptozotocin-induced memory deficits by inhibiting GSK-3β

Abstract

Brain dysfunction, especially cognitive impairment, is one of the main complications in Alzheimer's disease (AD), which threatens the health of 46.8 million people worldwide. At present, the pathogenesis of cognitive dysfunction is only partially understood, and effective therapies for memory loss in AD remain elusive. Tetramethylpyrazine (TMP) is one of the major bioactive compounds purified from Chuanxiong, a Chinese herb used for the treatment of neurovascular and cardiovascular diseases. The neuroprotective properties of TMP are evident in some neurodegenerative diseases, including Parkinson's disease. However, whether TMP plays a neuroprotective role in AD is still unknown. Here, we report that 2-week treatment with TMP rescued both short-term and long-term fear memory impairment induced by intracerebroventricular injection of streptozotocin in a well-known AD rat model. Administration of TMP also restored spatial learning and memory retention abilities in streptozotocin-injected rats. Furthermore, TMP inhibited the activity of GSK-3β, an important kinase that mediates hippocampal synaptic and memory disorders in diabetes mellitus. Finally, we found that TMP treatment restored the function of cholinergic neurons. Our data suggest that dietary uptake of TMP can provide protection against memory loss in AD, and the inhibition of GSK-3β may play an important role in this protective effect.

http://ift.tt/2vTnoYm

Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion

Abstract

OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) is a deubiquitinating enzyme (DUB) that belongs to the ovarian tumor (OTU) domain protease superfamily. Although it has been demonstrated to play important roles in the development of many kinds of cancer, the mechanism of OTUB1 in hepatocellular carcinoma (HCC) is not clear. The aim of this study was to explore the roles of OTUB1 in HCC progression using cell lines and 115 archived HCC samples. In addition, the clinical outcomes were also analyzed with a special focus on OTUB1 expression in HCC samples. In the immunohistochemical study, OTUB1 showed high expression in 60 of the 115 cases (52.2%). The OTUB1 expression level was significantly correlated with many clinicopathological parameters, including TNM stage (P = 0.002), histology stage (P = 0.002), and metastasis/recurrence (P = 0.016). Survival analysis showed that the group with OTUB1 overexpression had significantly shorter overall survival time than the group with OTUB1 downregulation (hazard ratio [HR] = 0.482; confidence interval [CI]: 0.311–0.748; P = 0.001). Multivariate analysis indicated that OTUB1 expression was a significant and independent prognostic parameter (HR = 0.214; CI: 0.126–0.364; P < 0.001) for HCC patients. The ability of HCC cells to undergo proliferation, migration, and invasion was suppressed by disruption of endogenous OTUB1 using short hairpin RNA (shRNA). OTUB1 expression appears to be a new and independent predictor for the prognosis of HCC patients. Overexpression of OTUB1 in HCC could be a novel, effective, and supplementary biomarker for HCC because it plays a vital role in the progression of HCC.

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A novel telomerase-interacting OTU protein of Eimeria tenella and its telomerase-regulating activity

http://ift.tt/2wMWTQN

Prohibitin 2/PHB2 in Parkin-mediated mitophagy: a potential therapeutic target for mitochondrial diseases

http://ift.tt/2vTF865

Cell cycle-dependent control of homologous recombination

Abstract

DNA double-strand breaks (DSBs) are among the most deleterious type of DNA lesions threatening genome integrity. Homologous recombination (HR) and non-homologous end joining (NHEJ) are two major pathways to repair DSBs. HR requires a homologous template to direct DNA repair, and is generally recognized as a high-fidelity pathway. In contrast, NHEJ directly seals broken ends, but the repair product is often accompanied by sequence alterations. The choice of repair pathways is strictly controlled by the cell cycle. The occurrence of HR is restricted to late S to G2 phases while NHEJ operates predominantly in G1 phase, although it can act throughout most of the cell cycle. Deregulation of repair pathway choice can result in genotoxic consequences associated with cancers. How the cell cycle regulates the choice of HR and NHEJ has been extensively studied in the past decade. In this review, we will focus on the current progresses on how HR is controlled by the cell cycle in both Saccharomyces cerevisiae and mammals. Particular attention will be given to how cyclin-dependent kinases modulate DSB end resection, DNA damage checkpoint signaling, repair and processing of recombination intermediates. In addition, we will discuss recent findings on how HR is repressed in G1 and M phases by the cell cycle.

http://ift.tt/2wMEGD2

Dermatofibrosarcoma Protuberans of the Breast—a Rare Entity

Abstract

Dermatofibrosarcoma protuberans (DFSP) represents about 1% of soft-tissue sarcomas with an estimated incidence of 0.8 to 5.0 cases per million per year. This lesion may occur anywhere in the body but more than 50% occur on the trunk, 20% on the head and neck and 30% on the extremities. DFSP of the breast is an extremely uncommon site of presentation. Data regarding DFSP of the breast is limited and mostly in the form of case reports. Clinical presentation is not uniform and may mimic benign skin lesions [1]. However, it typically presents as a nodular cutaneous mass in early or mid-adult life. We herein report a case of DFSP of the breast in a 33-year-old lady who was managed successfully in our institute and review the literature associated with it.

http://ift.tt/2wMpMwn

Endometriosis and the risk of skin cancer: a prospective cohort study

Abstract

Purpose

Endometriosis has been associated with an increased risk of skin melanoma. However, associations with other skin cancer types and how they compare with melanoma are unclear. Our objective was to prospectively investigate the relationships between endometriosis and risk of non-melanoma and melanoma skin cancers.

Methods

E3N is a prospective cohort of 98,995 French women aged 40–65 years in 1990. Data on surgically confirmed endometriosis and skin cancer diagnoses were collected every 2–3 years through self-report, with skin cancer cases confirmed through pathology reports. Hazard Ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox regression models.

Results

Between 1990 and 2008, 535 melanoma, 247 squamous-cell carcinoma (SCC), and 1,712 basal-cell carcinoma (BCC) cases were ascertained. Endometriosis was associated with an increased overall risk of skin cancer (HR 1.28, 95% CI 1.05–1.55). When considering skin cancer type, endometriosis was associated with melanoma risk (HR 1.64, 95% CI 1.15–2.35), but not with SCC (HR 1.21, 95% CI 0.62–2.36) or BCC (HR 1.16, 95% CI 0.91–1.48) (non-melanoma skin cancers combined: HR 1.17, 95% CI 0.93–1.46), although no heterogeneity was detected across skin cancer types (Phomogeneity = 0.13).

Conclusion

These data support an association between a personal history of endometriosis and the risk of skin cancer and suggest that the association is strongest for melanoma.

http://ift.tt/2utTXIh

Long Non-coding RNAs and Prostate Cancer

Abstract

Long non-coding RNAs (lncRNAs) are RNA transcripts larger than 200 nucleotides that do not code for proteins whose aberrant expression has been documented in various types of cancer, including prostate cancer. The lack of appropriate sensitive and specific biomarkers for prostate cancer has led to over-diagnosis and overtreatment, making lncRNAs promising novel biomarkers as well as therapeutic targets for the disease. This review attempts to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer, which contribute to carcinogenesis. Especially, we focused on lncRNAs regulated by androgen receptor and expressed in castration-resistant prostate cancer.

This article is protected by copyright. All rights reserved.

http://ift.tt/2uuw9DY

Modeling phenotypes of malignant gliomas

Abstract

Malignant gliomas are primary tumors of the central nervous system characterized by diffuse infiltration into the brain and a high recurrence rate. Advances in comprehensive genomic studies have provided unprecedented insight into the genetic and molecular heterogeneity of these tumors and refined our understanding of their evolution from low to high grade. However, similar levels of phenotypic characterization are indispensable to understanding the complexity of malignant gliomas. Experimental glioma models have also achieved great progress in recent years. Advances in transgenic technologies and cell culture have allowed the establishment of mouse models that mirror the human disease with increasing fidelity and which support single-cell resolution for phenotypic analyses. Here we review the major types of preclinical glioma models, with an emphasis on how recent developments in experimental modeling have shed new light on two fundamental aspects of glioma phenotype, their cell of origin and their invasive potential.

This article is protected by copyright. All rights reserved.

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Strategy for the treatment and follow-up of sinonasal solitary extramedullary plasmacytoma: a case series

Extramedullary plasmacytoma is a rare neoplasm characterized by monoclonal proliferation of plasma cells outside bone marrow. It accounts for 4% of all non-epithelial sinonasal tumors. According to the literat...

http://ift.tt/2vT5Yu0

A rare case of pediatric lipoma with t(9;12)(p22;q14) and evidence of HMGA2-NFIB gene fusion

Publication date: Available online 9 August 2017
Source:Cancer Genetics
Author(s): Melanie Lacaria, Dina El Demellawy, Jean McGowan-Jordan
Lipoma is a benign tumor, typically of adulthood, with characteristic cytogenetic findings, including rearrangement of 12q13-15; these rearrangements often lead to the fusion of the HMGA2 gene at this locus to the transcriptional regulatory domain of its fusion partner, resulting in neomorphic activity that presumably facilitates the neoplastic process. Herein, we report a rare case of pediatric lipoma with t(9;12)(p22;q14) and evidence of HMGA2-NFIB gene fusion in a 9 year-old boy. This case provides further evidence of the link between NFIB rearrangement and early-onset, deep-seated lipomatous tumors.



http://ift.tt/2wy47sr

Regulatory mechanisms of long noncoding RNAs on gene expression in cancers

Publication date: Available online 9 August 2017
Source:Cancer Genetics
Author(s): Weiliang Sun, Yunben Yang, Chunjing Xu, Junming Guo
Long non-coding RNAs (lncRNAs) are a heterogeneous class of RNAs that are non-protein coding transcripts longer than 200 nucleotides. In this review, we introduce the mechanisms by which lncRNAs regulate gene expression in four parts, epigenetic regulation (genetic imprinting and chromatin remodeling), transcriptional regulation (molecular decoy), post-transcriptional regulation (splicing and mRNA decay), and translational regulation. H19, Xist, and others are involved in genomic imprinting. HOTAIR and ANRIL function in chromatin remodeling. GAS5 is degraded through an RNA decay pathway. NEAT1 and MALAT1 function not only in the regulation of transcription but also in splicing.



http://ift.tt/2vn4hoc

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment

Abstract

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε⁺Vα7.2⁺CD161⁺⁺ or CD3ε⁺MR1 tetramer⁺ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

http://ift.tt/2fvyTyk

Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2)

Abstract

Background

Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer.

Methods

The effects of gambogic acid on cell viability, the cell cycle, and apoptosis were assessed using 4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and flow cytometry in pancreatic cancer cell lines. Protein expression was detected by western blot analysis and mRNA expression was detected using q-PCR. A xenograft tumor model of pancreatic cancer was used to investigate the synergistic effects of gambogic acid and gemcitabine.

Results

Gambogic acid effectively inhibited the growth of pancreatic cancer cell lines by inducing S-phase cell cycle arrest and apoptosis. Synergistic activity of gambogic acid combined with gemcitabine was observed in PANC-1 and BxPC-3 cells based on the results of MTT, colony formation, and apoptosis assays. Western blot results demonstrated that gambogic acid sensitized gemcitabine-induced apoptosis by enhancing the expression of cleaved caspase-3, cleaved caspase-9, cleaved-PARP, and Bax, and reducing the expression of Bcl-2. In particular, gambogic acid reduced the expression of the ribonucleotide reductase subunit-M2 (RRM2) protein and mRNA, a trend that correlated with resistance to gemcitabine through inhibition of the extracellular signal-regulated kinase (ERK)/E2F1 signaling pathway. Treatment with gambogic acid and gemcitabine significantly repressed tumor growth in the xenograft pancreatic cancer model. Immunohistochemistry results demonstrated a downregulation of p-ERK, E2F1, and RRM2 in mice receiving gambogic acid treatment and combination treatment.

Conclusions

These results demonstrate that gambogic acid sensitizes pancreatic cancer cells to gemcitabine in vitro and in vivo by inhibiting the activation of the ERK/E2F1/RRM2 signaling pathway. The results also indicate that gambogic acid treatment combined with gemcitabine might be a promising chemotherapy strategy for pancreatic cancer.

http://ift.tt/2wxH69m

Epulis-Like Presentation of Gingival Renal Cancer Metastasis

Mouth metastatic cancers are very rare and they usually represent the evidence of a widespread disease. Common primary tumors are lung carcinoma in men and breast carcinoma in women, followed by kidney cancer. In the oral soft tissues, the gingiva is the most common site, suggesting a possible role of inflammation in the attraction of circulating tumor cells. Oral metastasis has a serious prognosis. In this work, we describe the case of a 58-year-old man affected by renal cancer, who was brought to our attention for the appearance of a gingival swelling. Initially, the lesion was excised through a provisional clinical diagnosis of epulis. Subsequently, anatomopathological analysis showed a metastasis compatible with clear-cell carcinoma and specifically its renal origin was confirmed by immunohistochemical techniques.
Case Rep Oncol 2017;10:758–763

http://ift.tt/2wM3mvp

The Successful Treatment of Pulmonary Pleomorphic Carcinoma with Pembrolizumab: A Case Report

Pulmonary pleomorphic carcinomas are rare malignant tumors, and no standard treatments have been established. We herein report the successful treatment of a patient with pulmonary pleomorphic carcinoma with pembrolizumab. A 51-year-old man who was a current smoker presented to our hospital due to dyspnea and hemosputum. Chest X-ray showed right-sided pneumothorax with pleural effusion; chest tube drainage was therefore performed. Computed tomography after chest tube drainage showed a cavitary nodule in the right upper lobe and right hilar and bilateral mediastinal lymphadenopathy. Surgery was performed for the diagnosis and treatment. He was eventually diagnosed with pulmonary pleomorphic carcinoma corresponding to clinical stage IVB (cT2aN2M1c [PLE, ADR, HEP]). The giant cells strongly expressed programmed death ligand-1, and the tumor proportion score was more than 50%. Therefore, pembrolizumab was introduced as the first-line therapy. After 3 cycles of pembrolizumab, his right hilar and bilateral mediastinal lymphadenopathy and pleural dissemination notably decreased. Pembrolizumab might be an effective therapy for pulmonary pleomorphic carcinoma.
Case Rep Oncol 2017;10:752–757

http://ift.tt/2vSL3s6

Unmet Needs of Adult Survivors of Childhood Cancers: Associations with Developmental Stage at Diagnosis, Cognitive Impairment, and Time from Diagnosis

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2vqSQdE

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment

Abstract

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε⁺Vα7.2⁺CD161⁺⁺ or CD3ε⁺MR1 tetramer⁺ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

http://ift.tt/2fvyTyk

Oncological outcomes in an Australian cohort according to the new prostate cancer grading groupings

Abstract

Background

A new 5-tiered grading grouping system has recently been endorsed for reporting of prostate cancer (PCa) grade to better reflect escalating risk of progression and cancer death. While several validations of the new grade groupings have been undertaken, most have involved centralised pathological review by specialist urological pathologists.

Methods

Participants included 4268 men with non-metastatic PCa diagnosed between 2006 and 2013 from the multi-institutional South Australia Prostate Cancer Clinical Outcomes Collaborative registry. PCa-specific survival and biochemical recurrence-free survival were compared across the five grade groups using multivariable competing risk regression.

Results

For the entire cohort, risk of PCa death increased with increasing grade groups (at biopsy) Adjusted subdistribution-hazard ratios [sHR] and 95% confidence intervals [95%CI] were: 2.2 (1.5–3.6); 2.5 (1.6–4.2); 4.1 (2.6–6.7) and 8.7 (4.5–14.0) for grade groups II (pattern 3 + 4), III (pattern 4 + 3), IV (total score 8) and V (total score 9–10) respectively, relative to grade group I (total score < =6). Clear gradients in risk of PCa death were observed for radical prostatectomy (RP), but were less clear for those who had radiotherapy (RT) with curative intent and those who were managed conservatively. Likewise, risk of biochemical recurrence increased across grade groups, with a strong and clear gradient for men undergoing RP [sHR (95%CI): 2.0 (1.4–2.8); 3.8 (2.9–5.9); 5.3 (3.5–8.0); 11.2 (6.5–19.2) for grade groups II, III, IV and V respectively, relative to grade group I], and a less clear gradient for men undergoing RT.

Conclusion

In general, the new five-tiered grade groupings distinguished PCa survival and recurrence outcomes for men with PCa. The absence of a clear gradient for RT may be due to heterogeneity in this patient group.

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Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care

Abstract

Background

Hotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear.

Methods

The mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed.

Results

Mutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p < 0.001) and truncal localization of the culprit primary (p = 0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p = 0.013) and development of metastatic disease (p = 0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p = 0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02 – 3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15 – 6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06–0.48) were significant multivariate risk factors.

Conclusions

NRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.

http://ift.tt/2wLnWfo

A lowered 26S proteasome activity correlates with mantle lymphoma cell lines resistance to genotoxic stress

Abstract

Background

Mantle cell lymphoma (MCL) is a B-cell hemopathy characterized by the t(11;14) translocation and the aberrant overexpression of cyclin D1. This results in an unrestrained cell proliferation. Other genetic alterations are common in MCL cells such as SOX11 expression, mutations of ATM and/or TP53 genes, activation of the NF-κB signaling pathway and NOTCH receptors. These alterations lead to the deregulation of the apoptotic machinery and resistance to drugs. We observed that among a panel of MCL cell lines, REC1 cells were resistant towards genotoxic stress. We studied the molecular basis of this resistance.

Methods

We analyzed the cell response regarding apoptosis, senescence, cell cycle arrest, DNA damage response and finally the 26S proteasome activity following a genotoxic treatment that causes double strand DNA breaks.

Results

MCL cell lines displayed various sensitivity/resistance towards genotoxic stress and, in particular, REC1 cells did not enter apoptosis or senescence after an etoposide treatment. Moreover, the G2/M cell cycle checkpoint was deficient in REC1 cells. We observed that three main actors of apoptosis, senescence and cell cycle regulation (cyclin D1, MCL1 and CDC25A) failed to be degraded by the proteasome machinery in REC1 cells. We ruled out a default of the βTrCP E3-ubiquitine ligase but detected a lowered 26S proteasome activity in REC1 cells compared to other cell lines.

Conclusion

The resistance of MCL cells to genotoxic stress correlates with a low 26S proteasome activity. This could represent a relevant biomarker for a subtype of MCL patients with a poor response to therapies and a high risk of relapse.

http://ift.tt/2vSZQTr

The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells

Abstract

Background

Glioblastoma (GBM) is a highly migratory, invasive, and angiogenic brain tumor. Like vascular endothelial growth factor-A (VEGF-A), placental growth factor (PlGF) promotes GBM angiogenesis. VEGF-A is a ligand for both VEGF receptor-1 (VEGFR-1) and VEGFR-2, while PlGF interacts exclusively with VEGFR-1. We recently generated the novel anti-VEGFR-1 monoclonal antibody (mAb) D16F7 that diminishes VEGFR-1 homodimerization/activation without affecting VEGF-A and PlGF binding.

Methods

In the present study, we evaluated the expression of VEGFR-1 in human GBM tissue samples (n = 42) by immunohistochemistry, in cell lines (n = 6) and GBM stem cells (GSCs) (n = 18) by qRT-PCR and/or western blot analysis. In VEGFR-1 positive GBM or GSCs we also analyzed the ability of D16F7 to inhibit GBM invasiveness in response to VEGF-A and PlGF.

Results

Most of GBM specimens stained positively for VEGFR-1 and all but one GBM cell lines expressed VEGFR-1. On the other hand, in GSCs the expression of the receptor was heterogeneous. D16F7 reduced migration and invasion of VEGFR-1 positive GBM cell lines and patient-derived GSCs in response to VEGF-A and PlGF. Interestingly, this effect was also observed in VEGFR-1 positive GSCs transfected to over-express wild-type EGFR (EGFRwt⁺) or mutant EGFR (ligand binding domain-deficient EGFRvIII⁺). Furthermore, D16F7 suppressed intracellular signal transduction in VEGFR-1 over-expressing GBM cells by reducing receptor auto-phosphorylation at tyrosine 1213 and downstream Erk1/2 activation induced by receptor ligands.

Conclusion

The results from this study suggest that VEGFR-1 is a relevant target for GBM therapy and that D16F7-derived humanized mAbs warrant further investigation.

http://ift.tt/2wLkTDN

Relationship between radiation dose and microbleed formation in patients with malignant glioma

Abstract

Background

Cranial irradiation is associated with long-term cognitive changes. Cerebral microbleeds (CMBs) have been identified on susceptibility-weighted MRI (SWI) in patients who have received prior cranial radiation, and serve as radiographic markers for microvascular injury thought to contribute to late cognitive decline. The relationship between CMB formation and radiation dose has not previously been quantified.

Methods

SWI was performed on 13 patients with stable WHO grade III-IV gliomas between 2 and 4 years after chemoradiotherapy to 60 Gy. The median age at the time of treatment was 41 years (range 25 – 74 years). CMBs were identified as discrete foci of susceptibility on SWI that did not correspond to vessels. CMB density for low (<30 Gy), median (30–45 Gy), and high (>45 Gy) dose regions was computed.

Results

Twelve of 13 patients exhibited CMBs. The number of CMBs was significantly higher for late (>3 years from treatment) compared to early (<3 years) timepoints (early median 6 CMBs; late median 27 CMBs; p = 0.001), and there were proportionally more CMBs at lower doses for late scans (p = 0.006). 88% of all CMBs were observed in regions receiving at least 30 Gy, but the CMB density within medium and high dose regions was not significantly different (p = 0.33 and p = 0.9, respectively, for early and late time points).

Conclusions

CMBs predominantly form in regions receiving at least 30 Gy, but form in lower dose regions with longer follow-up. We do not observe a clear dose–response relationship at doses above 30 Gy. These findings provide important information to assess the risk of late microvascular sequelae from cranial irradiation.

http://ift.tt/2vmyqnL

Intraoperative imaging techniques for glioma surgery

Future Oncology, Ahead of Print.


http://ift.tt/2uJQjJp

Identification of key lncRNAs in colorectal cancer progression based on associated protein–protein interaction analysis

Abstract

Background

Colorectal cancer (CRC) was one of the most commonly diagnosed malignancies. The molecular mechanisms involved in the progression of CRC remain unclear. Accumulating evidences showed that long noncoding RNAs (lncRNAs) played key roles in tumorigenesis, cancer progression, and metastasis. Therefore, we aimed to explore the roles of lncRNAs in the progression of CRC.

Methods

In this study, we aimed to identify differentially expressed lncRNAs and messenger RNAs (mRNAs) in CRC by analyzing a cohort of previously published datasets: GSE64857. GO and KEGG pathway analyses were applied to give us insight in the functions of those lncRNAs and mRNAs in CRC.

Results

Totally, 46 lncRNAs were identified as differentially expressed between stage II and stage III CRC for the first time screening by microarray. GO and KEGG pathway analyses showed that differentially expressed lncRNAs were involved in regulating signal transduction, cell adhesion, cell differentiation, focal adhesion, and cell adhesion molecules.

Conclusions

We found three lncRNAs (LOC100129973, PGM5-AS1, and TTTY10) widely co-expressed with differentially expressed mRNAs. We also constructed lncRNA-associated PPI in CRC and found that these lncRNAs may be associated with CRC progression. Moreover, we found that high PGM5-AS1 expression levels were associated with worse overall survival in CRC cancer. We believe that this study would provide novel potential therapeutic and prognostic targets for CRC.

http://ift.tt/2vI1c36

HBO1 promotes cell proliferation in bladder cancer via activation of Wnt/β-catenin signaling

Abstract

Histone acetyltransferase binding to ORC1 (HBO1), a histone acetyltransferase, was recently identified as an oncoprotein; however, its role in bladder cancer remains unknown. In this study, we showed that HBO1 was highly expressed at both the mRNA and the protein levels in bladder cancer. HBO1 expression was associated with the clinical features of human bladder cancer, including tumor size (p = 0.018) and T (p = 0.007) classifications. Patients with higher HBO1 expression had shorter recurrence-free survival time, whereas patients with lower HBO1 expression had better survival time. Moreover, we found that ectopic overexpression of HBO1 promoted, whereas HBO1 silencing inhibited tumor growth in bladder cancer cells both in vitro and in vivo. We further demonstrated that upregulation of HBO1 activated the Wnt/β-catenin signaling pathway and led to nuclear localization of β-catenin and upregulation of downstream targets of of Wnt/β-catenin signaling. These findings suggest that HBO1 plays a key role in the progression of bladder cancer via the Wnt/β-catenin pathway, and may serve as a potential therapeutic target for the treatment of bladder cancer. This article is protected by copyright. All rights reserved

http://ift.tt/2wwMEAX

Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival

ABSTRACT

Metzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated in the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C > A, ADAMTS3 rs788935 T > C, TLL2 rs10882807 T > C and MMP9 rs3918251 A > G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (P_trend< 0.001). An improvement was observed in the prediction model [area under the curve (AUC) = 81.4% to 78.6%], when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS. This article is protected by copyright. All rights reserved

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Functional genetic variants of XRCC4 and ERCC1 predict survival of gastric cancer patients treated with chemotherapy by regulating the gene expression

Abstracts

DNA repair protects genomic integrity and may modulate chemotherapy efficacy. Few large-scale studies have evaluated predictive roles of genetic variants of DNA repair genes in survival of Chinese gastric cancer (GCa) patients treated with chemotherapy. Here, we assessed the roles of 35 single nucleotide polymorphisms (SNPs) in DNA repair genes in survival of 1,002 GCa patients, of whom 694 received chemotherapy and 308 did not. Among patients receiving chemotherapy, the ERCC1 rs2298881A allele was associated with a better survival [hazards ratio (HR) =0.82, 95% confidence interval (CI) =0.69-0.98; P = 0.03)], whereas two XRCC4 SNPs were associated with a worse survival (HR = 1.26, 95% CI = 1.03-1.54 for the rs10040363G allele, P = 0.02; and HR = 1.30, 95% CI = 1.06-1.59 for the rs2075685T allele, P = 0.01). These three SNPs were unique survival predictors for patients treated with chemotherapy (P < 0.05 for all) but not for patients without chemotherapy (P > 0.05 for all), suggesting that they modulated chemotherapy efficacy. Patients who received chemotherapy and had haplotypes with at least one death-risk allele in XRCC4 had a poor survival, and the trend for an increase in the number of death-risk alleles adversely affecting the survival was also observed in an allelic dose-dependent manner (P_trend = 0.001). Further functional analysis revealed that the death-risk alleles up-regulated the gene expression, leading to a worse survival as suggested by our meta-analysis pooling both mRNA microarray data from the GEO database and published data [ERCC1: HR = 1.31 (1.08-1.58); P = 0.006]. These functional genetic variants may independently or jointly affect survival in chemotherapy-treated GCa patients by modulating the gene expression in the tumors. This article is protected by copyright. All rights reserved

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Combination Cisplatin and Sulforaphane Treatment Reduces Proliferation, Invasion and Tumor Formation in Epidermal Squamous Cell Carcinoma

Abstract

Epidermal squamous cell carcinoma is an extremely common type of cancer. Early tumors can be successfully treated by surgery, but recurrent disease is aggressive and resistant to therapy. Cisplatin is often used as a treatment, but the outcome is rarely satisfactory. For this reason new strategies are required. Sulforaphane is a diet-derived cancer prevention agent that is effective in suppressing tumor growth in animal models of skin cancer. We monitored the efficacy of sulforaphane and cisplatin as a combined therapy for squamous cell carcinoma. Both agents suppress cell proliferation, growth of cancer stem cell spheroids, matrigel invasion and migration of SCC-13 and HaCaT cells and combination treatment is more efficient. In addition, SCC-13 cell derived cancer stem cells are more responsive to these agents than non-stem cancer cells. Both agents suppress tumor formation, but enhanced suppression is observed with combined treatment. Moreover, both agents reduce the number of tumor-resident cancer stem cells. SFN treatment of cultured cells or tumors increases apoptosis and p21^Cip1 level, and both agents increase tumor apoptosis. We suggest that combined therapy with sulforaphane and cisplatin is efficient in suppressing tumor formation and may be a treatment option for advanced epidermal squamous cell carcinoma. This article is protected by copyright. All rights reserved

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Mutation status of RAD51C, PALB2, and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

Summary

In addition to BRCA1 and BRCA2, RAD51C, PALB2, and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not been evaluated yet. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2, and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exon 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non-synonymous variants, c.89A>C, c.736A>G, and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second-degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

This article is protected by copyright. All rights reserved.

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Complex genetic control of lung tumorigenesis in resistant mice strains

Abstract

The SM/J mouse strain is resistant to chemically induced lung tumorigenesis despite having a haplotype, in the pulmonary adenoma susceptibility locus (Pas1) locus, that confers tumor susceptibility in other strains. To clarify this inconsistent genotype-phenotype correlation, we crossed SM/J mice with another resistant strain and did genome-wide linkage analysis in the (C57BL/6J x SM/J)F2 progeny exposed to urethane to induce lung tumors. Overall, >80% of F2 mice of both sexes developed from 1 to 20 lung tumors. Genotyping of 372 F2 mice for 744 informative non-redundant SNPs dispersed over all autosomal chromosomes revealed four quantitative trait loci (QTLs) affecting lung tumor multiplicity, on chromosome 3 (near rs13477379), 15 (rs6285067), 17 (rs33373629), and 18 (rs3706601), all with logarithm of the odds (LOD) scores >5. Four QTLs modulated total lung tumor volume, on chromosome 3 (rs13477379), 10 (rs13480702), 15 (rs6285067), and 17 (rs3682923), all with LOD scores >4. No QTL modulating lung tumor multiplicity or total volume was detected in Pas1 on chromosome 6. This study demonstrates that the SM/J strain carries, at the Pas1 locus, the resistance allele—a finding that will facilitate identification of the Pas1 causal element. More generally, it demonstrates that lung tumorigenesis is under complex polygenic control even in a pedigree with low susceptibility to this neoplasia, suggesting that the genetics of lung tumorigenesis is much more complex than evidenced by the pulmonary adenoma susceptibility and resistance loci that have, so far, been mapped in a small number of crosses between a few inbred strains.

This article is protected by copyright. All rights reserved.

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Impact of body mass index on treatment outcome of neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Publication date: Available online 10 August 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Yanwu Sun, Zongbin Xu, Huiming Lin, Xingrong Lu, Ying Huang, Shenghui Huang, Xiaojie Wang, Pan Chi
AimTo determine the effect of obesity, measured by body mass index (BMI), on tumor response, surgical outcome in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (nCRT) and radical surgery.MethodLARC patients undergoing nCRT and radical surgery from 2008 to 2014 were included and divided into three groups: nonobese (BMI < 25.0 kg/m²), obese I (BMI 25.0-29.9 kg/m²), and obese II (BMI ≥ 30.0 kg/m²). Tumor response, surgical and oncological outcome were compared between groups. Multivariate analyses were performed to identify risk factors for local recurrence.ResultsA total of 522 LARC patients were analyzed (407 non-obese, 93 obese I, 22 obese II). Postoperative complications did not differ between groups. Increased BMI was associated with poorer T downstaging and Rectal Cancer Regression Grade (P = 0.116, P = 0.036). With a mean follow-up of 57 months, the 5-year overall survival and distant metastasis rates did not differ between groups (P = 0.861, P = 0.116). The 5-year local recurrence rate in obese II patients was 14.6%, higher than that in nonobese and obese I groups (P = 0.015). Cox regression analysis demonstrated that BMI ≥ 30 kg/m² (HR = 6.187, P = 0.010) was significantly associated with increased risk for local recurrence.ConclusionObesity was associated with poorer T downstaging and Rectal Cancer Regression Grade, and thus poor local control in LARC following nCRT in Asian patients. More effective treatment strategies to improve treatment outcome for obese patients with LARC is warranted.



http://ift.tt/2fvwe7A

Patterns of care and the survival of elderly patients with high-risk endometrial cancer: A Case-control study from the FRANCOGYN group

Publication date: Available online 9 August 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Aline Rousselin, Sofiane Bendifallah, Krystel Nyangoh Timoh, Lobna Ouldamer, Geoffroy Canlorbe, Emilie Raimond, Nina Hudry, Charles Coutant, Olivier Graesslin, Cyril Touboul, Pierre Collinet, Alexandre Bricou, Cyrille Huchon, Emile Daraï, Marcos Ballester, Jean Levêque, Vincent Lavoue
BACKGROUNDThe standard of care of endometrial cancer involves complex procedures such as pelvic and para-aortic lymphadenectomy and omentectomy, particularly for high-risk endometrial cancer. Few data are available about these complex surgical procedures and adjuvant therapy in elderly women. We aim to examine treatment and survival of elderly women diagnosed with high-risk endometrial cancer.STUDY DESIGNWe performed a case-control study of women diagnosed between 2001 and 2013 with high-risk endometrial cancers. Women older than 70 years (n=198) were compared with patients <70 years (n=198) after matching on high-risk for recurrence and LVSI status.RESULTSElderly patients had lymphadenectomies less frequently compared with younger patients (76% vs 96%, p<0.001) and no adjuvant treatment more frequently (17% vs 8%, p=0.005) due to less chemotherapy being administered (23% vs 46%, p<0.001). The 3-year DFS, CSS and OS of patients ≥ 70 years was 52% (43-61), 81% (74-88) and 61% (53-70), respectively. These were significantly lower than the 3-year DFS, CSS, and OS of younger patients, which was 75% (68-82) (p<0.001), 92% (87-96) (p<0.008) and 75% (69-82) (p=0.018), respectively. Cox proportional hazard models found that elderly women had 57% increased risk of recurrence (hazard ratio 1.57, 95% CI 1.04-2.39) compared with younger patients.CONCLUSIONAlthough we found an independently significant lower DFS in elderly patients with high-risk endometrial cancer when compared with young patients, elderly women are less likely to be treated with lymphadenectomy and chemotherapy. Specific guidelines for management of elderly patients with high-risk endometrial cancer are required to improve their prognosis.



http://ift.tt/2hN0CuY

Suprapubic approach for robotic complete mesocolic excision in right colectomy: oncologic safety and short-term outcomes of an original technique

Publication date: Available online 10 August 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Wanda Petz, Dario Ribero, Emilio Bertani, Simona Borin, Giampaolo Formisano, Sofia Esposito, Giuseppe Spinoglio, Paolo Pietro Bianchi
IntroductionRight–sided colon cancer has a worse prognosis than left-sided colon cancer. Complete mesocolic excision (CME) with central vessels ligation (CVL) reduces local recurrence, but is technically demanding, particularly with a laparoscopic approach.Aim of this study is to describe a new robotic approach to right colectomy with CME and CVL and to report oncologic safety and short term outcomes.MethodsTwenty consecutive patients were included. All patients had a right colon adenocarcinoma and underwent right colectomy with a suprapubic approach. Surgery was realized with the Da Vinci Xi® system and all trocars were placed along an horizontal line 3-6 cm above the pubis. CME with CVL was realized in all the patients.Data analysed were: duration of surgery, conversions to open surgery, intraoperative and postoperative complication by Clavien Dindo classification, margins of resections, length of specimen and number of lymph nodes retrieved.ResultsPatients median age was 69 years, median body mass index was 27 kg/m². Median operative time was 249 minutes, blood loss was negligible, no conversions to open or laparoscopic surgery occurred. Median hospital stay was six days; two postoperative grade IIIa Clavien-Dindo complications occurred, no 30-days postoperative death was registered. Resection margins were negative in all patients; median tumour diameter was 3.6 cm, median specimen length was 40 cm, median number of harvested lymph nodes was 40.ConclusionsRobotic right colectomy with CME using a suprapubic approach is a feasible and safe technique that allows for an extended lymphadenectomy and provides high quality surgical specimens.



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Fibrous sheath interacting protein 1 overexpression is associated with unfavorable prognosis in bladder cancer: a potential therapeutic target

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Fucosyltransferase VII promotes proliferation via the EGFR/AKT/mTOR pathway in A549 cells

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Efficacy and safety of apatinib treatment for advanced esophageal squamous cell carcinoma

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Therapies for acute myeloid leukemia: vosaroxin

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Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth

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Prostate and breast cancer in four Nordic countries: A comparison of incidence and mortality trends across countries and age groups 1975–2013

Abstract

In recent decades, management of prostate and breast cancer patients has changed considerably. The purpose of the present study is to interpret patterns of prostate and breast cancer incidence and mortality in four Nordic countries across age groups and time periods. Prostate and breast cancer incidence and mortality data (1975–2013) were obtained from the NORDCAN database. Joinpoint regression models were used to identify changes in the trends. A more prominent increase in prostate than breast cancer incidence was observed. From the mid-1990s, mortality rates in patients below 75 years of age have decreased for both cancers in all four countries. The relative decline in breast cancer mortality from 1985–89 to 2009–13 were largest in women under 50 years of age, with reductions in mortality rates ranging from 38% in Finland to 55% in Denmark. In the age group 55–74 years, mortality rates for prostate cancer declined more than for breast cancer in all countries except Denmark, ranging from 14% in Denmark to 39% in Norway. The substantial decrease in breast cancer mortality in women below regular screening age and the reductions in mortality from both cancers in Denmark from the mid-1990s are consistent with beneficial contributions from improved treatment besides mammography screening and increased PSA testing. Alongside similar mortality decreases, the larger increases in prostate cancer incidence as compared to breast cancer indicate that a higher proportion of prostate cancer cases are overdiagnosed. This article is protected by copyright. All rights reserved.

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Investigation of cross-contamination among human cell lines used in China

Abstract

Increasing attention has been paid to the hazard of cell line cross-contamination. More journals are requiring that cell lines be authenticated prior to manuscript submission. China Center for Type Culture Collection (CCTCC) has authenticated cell lines for publications in the International Journal of Cancer since 2009. Between 2010 and 2016, we authenticated 485 cell lines from 66 Chinese universities and research institutes. Almost 50% of cell lines were misidentified, most were completely replaced by other cell lines (mainly HeLa and its sublines). The number of cell lines we received for authentication increased dramatically after 2013, but the proportion of misidentified cell lines remained elevated (over 50%). We strongly recommend that researchers take authentication of cell lines seriously and routinely perform authentication of the cell lines used in their laboratories. This article is protected by copyright. All rights reserved.

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Meta-Analysis of the Association Between Dietary Inflammatory Index (DII) and Cancer Outcomes

Abstract

Pro-inflammatory dietary patterns have been associated with increased cancer risk and mortality. We present a systematic review and meta-analysis of the current published literature on a Dietary Inflammatory Index (DII) score and its association with cancer risk and mortality outcomes. Published articles from online databases (PubMed, Scopus, and Embase) examining the association between DII and any cancer risk, incidence, or mortality between 1980 and November 2016 were selected for review. Results of studies meeting inclusion criteria were summarized and meta-analyzed using STATA to generate summary measures of association across studies. Sixty-three published articles were identified from the search, and following title, abstract and full-text review, twenty-four studies met inclusion criteria. All articles calculated DII scores based on study-specific food-frequency questionnaires using methodology from the same paper. Of the twenty-four included studies, thirteen were case-control, six were prospective cohort, one was a retrospective cohort, three were RCTs, and one did not specify study design. The most common cancers examined were colorectal, breast, lung, and prostate. Individuals in the highest versus lowest DII categories had 25% increased risk of overall cancer incidence (RR: 1.24, 95% CI: 1.14-1.35), 75% higher odds of cancer (OR: 1.75, 95% CI: 1.43-2.16) and 67% increased risk of cancer mortality (RR: 1.67, 95% CI: 1.13-2.48). Upon stratification for cancer type, positive associations remained (RR_breast: RR: 1.12, 95% CI: 1.03-1.22) (RR_colorectal: 1.33, 95% CI: 1.22-1.46) (RR_lung: 1.30, 95% CI: 1.13-1.50). There were consistent and significant positive associations between higher DII and cancer incidence and mortality across cancer types, study populations, and study design. This article is protected by copyright. All rights reserved.

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The ever-evolving role of pathologists in the management of breast cancer with neoadjuvant treatment: recommendations based on the Spanish clinical experience

Abstract

Purpose

To compare the current international standards for neoadjuvant systemic therapy (NAST) protocols, and establish consensus recommendations by Spanish breast pathologists; and to look into the Spanish reality of defining pathological complete response in daily practice.

Materials and methods

A modified Delphi technique was used to gain consensus among a panel of 46 experts with regard to important issues about NAST specimens, with the objective of standardize handling and analysis of these breast cancer specimens. In addition, a survey was conducted among 174 pathologists to explore the Spanish reality of post-NAST breast cancer specimens handling.

Results

Our survey shows that pathologists in Spain follow the same guidelines as their international colleagues and face the same problems and controversies. Among the experts, 94.1% agreed on the recommendation for a pre-treatment evaluation with a core needle biopsy, and 100% of experts agreed on the need of having properly indicated information for the post-NAST surgical specimens. However, only 82.7% of them receive properly labelled specimens and even less receive specimens where markers are identified and the degree of clinical/radiological response is mentioned. Among participants 59.9% were familiar with the residual cancer burden system for post-NAST response quantification, but only 16.1% used it regularly.

Conclusions

Active participation on breast cancer multidisciplinary teams, optimal usage of core needle biopsy for timely and standardized procedures for the diagnostic analysis, and accurate diagnosis of pathological complete response and complete evaluation of the response to NAST need to become the standard practice when handling breast cancer specimens in Spain.

http://ift.tt/2vpbkei

Picropodophyllin (PPP) is a potent rhabdomyosarcoma growth inhibitor both in vitro and in vivo

Abstract

Background

Insulin-like growth factors and insulin are important factors promoting cancer growth and metastasis. The molecules act through IGF1 (IGF1R) and insulin (InsR) receptors. Rhambodmyosarcomas (RMS) overproduce IGF2 – a potent ligand for IGF1R and, at the same time, highly express IGF1 receptor. The purpose of the study was to evaluate possible application of picropodophyllin (PPP) – a potent IGF1R inhibitor.

Methods

In our study we used a number of in vitro assays showing influence of IGF1R blockage on RMS cell lines (both ARMS and ERMS) proliferation, migration, adhesion, cell cycling and signal transduction pathways. Additionally, we tested possible concomitant application of PPP with commonly used chemotherapeutics (vincristine, actinomycin-D and cisplatin). Moreover, we performed an in vivo study where PPP was injected intraperitoneally into RMS tumor bearing SCID mice.

Results

We observed that PPP strongly inhibits RMS proliferation, chemotaxis and adhesion. What is more, application of the IGF1R inhibitor attenuates MAPK phosphorylation and cause cell cycle arrest in G2/M phase. PPP increases sensitivity of RMS cell lines to chemotherapy, specifically to vincristine and cisplatin. In our in vivo studies we noted that mice treated with PPP grew smaller tumors and displayed significantly decreased seeding into bone marrow.

Conclusions

The cyclolignan PPP effectively inhibits RMS tumor proliferation and metastasis in vitro and in an animal model.

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Case 24-2017: An 8-Month-Old Girl with Fever and an Abdominal Mass

Presentation of Case. Dr. Rajitha Venkatesh (Pediatrics): An 8-month-old girl was admitted to this hospital because of fever and an abdominal mass. The patient had been in her usual good health until approximately 6 days before admission, when she passed a large stool surrounded by clotted blood.…

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Diffuse cerebral oedema from sickle cell vaso-occlusive crisis

Description

A middle-aged African-American male with homozygous sickle cell disease presented with vaso-occlusive crisis and suffered a generalised tonic-clonic seizure while in the emergency department. He had been seizure-free for more than a decade, thus was not taking antiepileptic medications. CT head revealed diffuse cerebral oedema, effacement of the fourth ventricle and obstructive hydrocephalus (figure 1). An external ventricular drain was placed with improvement of hydrocephalus, and a repeat CT head revealed right parietal hypodensity (figure 1). MRI brain and conventional cerebral angiogram showed right parietal cerebral oedema, a large arteriovenous malformation, right internal carotid artery occlusion, moyamoya disease and basilar artery aneurysm (figure 2). The patient's cerebral oedema and neurological examination initially improved after exchange transfusion; however, he developed acute subarachnoid haemorrhage from basilar artery aneurysm rupture and brainstem strokes causing coma. He underwent palliative extubation after discussion with family and is now deceased.

...

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Persisting fatigue and myalgia as the presenting features in a case of hypokalaemic periodic paralysis

We report a case of a 9-year-old boy who developed hypokalaemic periodic paralysis (HypoPP) following a prodrome of persistent fatigue and muscle aches associated with mildly elevated creatine kinase (CK) levels.

HypoPP is usually associated with a sudden onset of weakness and hypokalaemia at presentation. A review of published cases failed to identify any other reports of individuals with a similar onset of symptoms and elevated CK levels prior to the development of frank HypoPP.

In the case described above, the association of these symptoms with elevated levels of CK may have been related to the underlying mutation in the skeletal muscle calcium channels that was subsequently identified.

In cases of persisting fatigue and myalgia associated with elevated CK levels it may be helpful to consider HypoPP in the differential diagnosis.

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Regadenoson cardiac stress test-induced stress cardiomyopathy

Takotsubo cardiomyopathy, also described as apical ballooning syndrome/stress-induced cardiomyopathy, imitates acute coronary syndrome and is usually related to a massive physiological or emotional stressor. We describe perhaps the first reported case to the best of our knowledge of a 55-year-old Caucasian woman who presented with congestive heart failure after having a regadenoson cardiac stress test a few hours prior to presentation to the hospital. Transthoracic echocardiogram revealed reduced heart function. She had normal coronaries on cardiac catheterisation, and left ventriculography confirmed apical ballooning syndrome. She underwent guideline-directed therapy, and heart function improved in the repeat echocardiogram along with clinical resolution of symptoms.

http://ift.tt/2ftSLBY

A rare urological presentation of appendicitis

A 17-year-old boy with no medical comorbidities, but a significant family history of malignancy, presented to Accident and Emergency following 3 days of increasing rectal pain, symptoms of bladder outflow obstruction (poor flow, intermittent stream and hesitancy) and dysuria. Notably he had no abdominal pain. Digital rectal examination revealed a tender, enlarged prostate. Inflammatory markers were significantly raised (white cell count 17.7, C reactive protein 191). He was diagnosed clinically as prostatitis and commenced on intravenous antibiotics. Despite this his pain and inflammatory markers deteriorated, necessitating a CT of his abdomen and pelvis. This demonstrated multiloculated large thick-walled abscesses in the pelvis closely related to the rectum, prostate and seminal vesicles with some bowel wall thickening. Laparoscopy demonstrated a large colonic mass adherent to surrounding structures. The procedure was converted to laparotomy to enable resection of the mass via a limited right haemicolectomy. He recovered well and was discharged. Histopathological analysis of the specimen revealed appendicitis.

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Sight preserving orbital decompression: a novel multidisciplinary approach to managing severe proptosis in neurofibromatosis type 2

We describe the importance of collaboration between multiple surgical specialties in managing a complex case of sight-threatening severe proptosis in a young woman with type 2 neurofibromatosis (NF2) complicated by pre-existing contralateral blindness. Trans-nasal and lateral orbital surgical approaches were aided by stereotactic navigation to debulk a large frontal/sphenoid wing meningioma, which had been exerting pressure onto the right globe and optic nerve. The patient made an excellent postoperative recovery along with preserved residual visual acuity, normal neurology and a good aesthetic outcome.

http://ift.tt/2fv5Drs

Bimaxillary concomitant hypohyperdontia in a 10-year-old child

Numerical anomalies, either addition or deletion, are quite a common findings in human dentition. However, it is extremely rare to find both hypodontia and hyperdontia simultaneously in the same individual. This condition is referred as concomitant hypohyperdontia (CHH). Aetiology of this condition is still obscure. The prevalence of CHH has been reported to be between 0.002% and 3.1%. This case report highlights a rare occurrence of bimaxillary CHH represented by the absence of both mandibular central incisors and presence of two supernumerary teeth in the maxillary anterior segment. The rarity of such condition of mixed hypodontia as well as hyperdontia in single human dentition prompted the author to report the case.

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Extramedullary haematopoiesis presenting with cardiac tamponade in a patient with polycythaemia vera

A 71-year-old man with a history of polycythaemia vera, diagnosed 4 years ago, presented to the emergency room with shortness of breath. A bedside echocardiogram revealed a large pericardial effusion with features concerning for pericardial tamponade. A left anterior thoracotomy and a pericardial window were emergently performed in the operating room and relieved the patient's symptoms. Histology evaluation of the pericardial fragments and pericardial fluid revealed the presence of trilineage haematopoietic elements without any increase in the blasts. A bone marrow core biopsy revealed an increase in reticulin fibre and increase in the number of blasts of 5%–10%, whereas peripheral blood testing was positive for JAK2 V617F mutation. This case report reviews the literature for cases of extramedullary haematopoiesis associated with myeloproliferative neoplasms.

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Atypical haemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN), different diseases or a spectrum of complement-mediated glomerular diseases?

Historically, patients with kidney diseases caused by genetic or acquired dysregulation of the complement alternative pathway have been grouped into clinical syndromes, C3 glomerulopathy (C3GN/DDD) and thrombotic microangiopathy (TMA), specifically atypical haemolytic uremic syndrome (aHUS). Recent data suggested that these diseases share a common pathophysiology and that patients can transition between glomerulopathies in this spectrum. Histopathologically, the main difference cited is the immunofluorescence (IF) findings, with C3 predominance in C3 glomerulopathy (compared with immunoglobulins and complements in immune complex-mediated membranoproliferative glomerulonephritis (MPGN)) and negative IF in TMA. We report a case in which a patient presented with hypertension, seizures, proteinuria, renal impairment and immune complex-mediated MPGN on kidney biopsy. Months later, she presented with classical TMA. She failed to respond to steroids and plasma exchange therapy but subsequently made a remarkable haematological and renal recovery after eculizumab treatment, thus supporting an underlying complement dysregulation and a diagnosis of aHUS.

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Tetraparesia: an unusual presentation of disseminated tuberculosis

A 48-year-old man with a 4 months history of asthenia, anorexia, 10 kg weight loss and 1 month of hematuria and dysuria was admitted to another hospital for sudden muscular weakness. He was found to have areflexic tetraparesis and was referred to our hospital.

On admission, he was bradycardic, tachypneic, with flaccid tetraplegia. Laboratory results showed metabolic acidemia, severe hyperkalemia and hyponatremia, acute renal dysfunction and sterile pyuria. After hyperkalemia correction, the neurological symptoms resolved.

On the second day, he became febrile and chest radiograph and CT images showed a pulmonary bilateral reticulomicronodular pattern, left hydronephrosis and diffuse bladder wall thickening. Disseminated tuberculosis was considered as diagnosis by the coexistence of this imagiologic alterations and sterile pyuria. Acid-fast test for Mycobacteriumtuberculosis was negative, but the urine culture became positive after 2 weeks.

Antituberculosis treatment was started. One year later, he was asymptomatic and the structural urinary lesions had disappeared.

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Giant hydronephrosis in a case of ureterocele with duplex system: an entity yet not reported

Ureterocele, which is a cystic dilatation of the terminal ureter, is usually associated with the upper moiety in a case of the duplex system. Giant hydronephrosis, a rare entity, is usually due to pelviureteric junction obstruction and is usually diagnosed in infants and children. We report a unique case of a unilateral complete duplex system with ureterocele with giant hydronephrosis of the upper moiety in an adult woman presenting as an abdominal lump. To the best of our knowledge, this is the first case of giant hydronephrosis associated with ureterocele in an adult patient.

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A Phase II Multicentre, Open-Label, Proof-of-Concept Study of Tasquinimod in Hepatocellular, Ovarian, Renal Cell, and Gastric Cancers

Abstract

Background

Tasquinimod is a small molecule with immunomodulatory, anti-angiogenic, and anti-metastatic properties that targets the tumor microenvironment. This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors.

Patients and Methods

This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38), and gastric (n = 21) cancers. Tasquinimod was given orally every day (0.5 mg/day for at least 2 weeks, with dose increase to 1 mg/day) until radiological progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, intolerable toxicity, or patient withdrawal. The primary efficacy endpoint was progression-free survival (PFS) rate according to RECIST 1.1 by central assessment.

Results

Interim futility analyses at 8 weeks (6 weeks for the gastric cancer cohort) found adequate clinical activity of tasquinimod only in the hepatocellular cohort and recruitment to the other three cohorts was stopped. PFS rates were 26.9% at 16 weeks, 7.3% at 24 weeks, 13.2% at 16 weeks, and 9.5% at 12 weeks, respectively, in hepatocellular, ovarian, renal cell, and gastric cancer cohorts. The pre-defined PFS threshold was not reached in the hepatocellular cancer cohort at the second stage of the trial. The most common treatment-related adverse events were fatigue (48.5%), nausea (34.1%), decreased appetite (31.7%), and vomiting (24.6%).

Conclusions

This study failed to demonstrate clinical activity of tasquinimod in heavily pre-treated patients with advanced hepatocellular, ovarian, renal cell, and gastric cancer.

Trial registration

NCT01743469.

http://ift.tt/2vRvP6u

Salvage chemotherapy for adults with relapsed or refractory lymphoma in Malawi

Abstract

Background

Lymphoma is highly associated with HIV in sub-Saharan Africa (SSA), which contributes to worse outcomes relative to resource-rich settings, and frequent failure of first-line chemotherapy. However, there are no second-line treatment descriptions for adults with relapsed or refractory lymphoma (RRL) in SSA.

Methods

We describe HIV+ and HIV- patients with RRL receiving salvage chemotherapy in Malawi. Patients were prospectively treated at a national teaching hospital in Lilongwe, with the modified EPIC regimen (etoposide, prednisolone, ifosfamide, cisplatin) between June 2013 and May 2016, after failing prior first-line chemotherapy.

Results

Among 21 patients (18 relapsed, 3 refractory), median age was 40 years (range 16–78), 12 (57%) were male. Thirteen patients (62%) were HIV+, of whom 12 (92%) were on antiretroviral therapy (ART) at initiation of salvage chemotherapy, with median CD4 cell count 139 cells/μL (range 12–529) and 11 (85%) with suppressed HIV RNA. Median number of EPIC cycles was 3 (range 1–6), and the commonest toxicity was grade 3/4 neutropenia in 19 patients (90%). Fifteen patients responded (3 complete, 12 partial, overall response rate 71%), but durations were brief. Median overall survival was 4.5 months [95% confidence interval (CI) 2.4–5.6]. However, three patients, all HIV+, experienced sustained remissions. Tolerability, response, and survival did not differ by HIV status.

Conclusions

The appropriateness and cost-effectiveness of this approach in severely resource-limited environments is uncertain, and multifaceted efforts to improve first-line lymphoma treatment should be emphasized, to reduce frequency with which patients require salvage chemotherapy.

Trial registration

NCT02835911. Registered 19 January 2016.

http://ift.tt/2usf0uA

An Overview of the Current Management of Bilobar Colorectal Liver Metastases

Abstract

Bilobar colorectal liver metastases (BCRLM) present a challenging scenario for liver surgeons globally. The following article aims to provide an overview of the different strategies which may be utilised in order to successfully manage advanced BCRLM.

http://ift.tt/2urLCbP

The ever-evolving role of pathologists in the management of breast cancer with neoadjuvant treatment: recommendations based on the Spanish clinical experience

Abstract

Purpose

To compare the current international standards for neoadjuvant systemic therapy (NAST) protocols, and establish consensus recommendations by Spanish breast pathologists; and to look into the Spanish reality of defining pathological complete response in daily practice.

Materials and methods

A modified Delphi technique was used to gain consensus among a panel of 46 experts with regard to important issues about NAST specimens, with the objective of standardize handling and analysis of these breast cancer specimens. In addition, a survey was conducted among 174 pathologists to explore the Spanish reality of post-NAST breast cancer specimens handling.

Results

Our survey shows that pathologists in Spain follow the same guidelines as their international colleagues and face the same problems and controversies. Among the experts, 94.1% agreed on the recommendation for a pre-treatment evaluation with a core needle biopsy, and 100% of experts agreed on the need of having properly indicated information for the post-NAST surgical specimens. However, only 82.7% of them receive properly labelled specimens and even less receive specimens where markers are identified and the degree of clinical/radiological response is mentioned. Among participants 59.9% were familiar with the residual cancer burden system for post-NAST response quantification, but only 16.1% used it regularly.

Conclusions

Active participation on breast cancer multidisciplinary teams, optimal usage of core needle biopsy for timely and standardized procedures for the diagnostic analysis, and accurate diagnosis of pathological complete response and complete evaluation of the response to NAST need to become the standard practice when handling breast cancer specimens in Spain.

http://ift.tt/2vpbkei

Optimizing peripheral blood stem cells transplantation outcome through amend relapse and graft failure: a review of current literature

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been considered as a valuable approach in treatment of numerous malignant and none malignant hematologic disorders. However, relapse and poor graft function (PGF) after allo-SCT remain to be controversial issues which may affect the transplantation outcome. Relevant articles were searched in MEDLINE database (2000–2016) using keywords and phrases: donor lymphocyte infusions, allogeneic stem cells transplantation, relapsed hematologic malignancies, booster schedules, cell dose, laboratory monitoring protocols and technical aspects of apheresis. Relapse of disease and PGF could be reduced via noting some main points such as choosing the suitable time and patient for donor lymphocyte infusion (DLI) and also determination of patients who ought to candidate for second allogeneic HSCT or for the use of stem cell boost. DLI and stem cell booster are promising treatment strategies noted in this review. Finally, this paper discusses indications and technical aspects of DLI and stem cell booster in hematological malignancies and emphasizes their therapeutic or pre-emptive potentials.

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Analysis of Plasma Epstein–Barr Virus DNA to Screen for Nasopharyngeal Cancer

Analysis of circulating DNA derived from cancer cells, which is frequently known as a "liquid biopsy," is being evaluated as a tool in the care of patients with cancer. Although a wide range of cancer-associated changes, including point mutations, copy-number aberrations, and alterations in DNA…

http://ift.tt/2vRuFbm

Plasma Epstein–Barr Virus DNA for Screening

In this issue of the Journal, Chan et al. report on the monitoring of Epstein–Barr virus (EBV) DNA in plasma samples to screen a population that was at high risk for nasopharyngeal carcinoma. Although interest in monitoring circulating cell-free tumor DNA has surged, the application of this method…

http://ift.tt/2wKuLxL

Title page

Publication date: August 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1868, Issue 1





http://ift.tt/2vQIAxB

Analysis of Plasma Epstein–Barr Virus DNA to Screen for Nasopharyngeal Cancer

Analysis of circulating DNA derived from cancer cells, which is frequently known as a "liquid biopsy," is being evaluated as a tool in the care of patients with cancer. Although a wide range of cancer-associated changes, including point mutations, copy-number aberrations, and alterations in DNA…

http://ift.tt/2vRuFbm

Plasma Epstein–Barr Virus DNA for Screening

In this issue of the Journal, Chan et al. report on the monitoring of Epstein–Barr virus (EBV) DNA in plasma samples to screen a population that was at high risk for nasopharyngeal carcinoma. Although interest in monitoring circulating cell-free tumor DNA has surged, the application of this method…

http://ift.tt/2wKuLxL

Discharges with surgical procedures performed less often than once per month per hospital account for two-thirds of hospital costs of inpatient surgery

Most surgical discharges (54%) at the average hospital are for procedures performed no more often than once per month at that hospital. We hypothesized that such uncommon procedures would be associated with an even greater percentage of the total cost of performing all surgical procedures at that hospital.

http://ift.tt/2vQBB7Q