Mutant KRAS Copy-Number Gain Drives Metabolic Reprogramming [Metabolism]

Homozygous and heterozygous KRAS mutant cancer cells have distinct metabolic phenotypes.

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Noted [News in Brief]

A collection of recently published news items.

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Tracking Tumor Evolution through Mathematics [News in Brief]

A recent study suggests that many cancers undergo neutral evolution, with all key mutations present at the start of malignancy. New mutations acquired along the way don't confer any advantages on tumor cells.

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Mutant CALR Requires Its C-terminus and MPL to Transform [Research Articles]

Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK–STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN.

Significance: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL. Cancer Discov; 6(4); 368–81. ©2016 AACR.

See related commentary by Stanley and Steidl, p. 344.

This article is highlighted in the In This Issue feature, p. 331

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Illumina Spin-off to Develop Early-Detection Test [News in Brief]

DNA-sequencing giant Illumina has formed a new company, called Grail, to develop liquid biopsies capable of spotting cancer before symptoms arise. The start-up is working on a low-cost "pan-cancer" test that can detect multiple cancer types early, which it hopes to introduce by 2019.

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TGF{beta} Mediates Tumor Suppression via Induction of EMT-Linked Apoptosis [Pancreatic Cancer]

TGFβ induces a SMAD4-dependent EMT in the pancreas that promotes apoptosis.

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Expanding the Scope of ENCODE [News in Brief]

The National Human Genome Research Institute has earmarked up to $38 million in grant funding for five new initiatives aimed at expanding ENCODE, its database of functional elements in human and mouse genomes. For the first time, grantees will focus on diseased tissue samples in an effort to understand how these functional elements influence the development of cancer and other diseases.

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Molecular Mechanism of Mutant CALR-Mediated Transformation [In the Spotlight]

Summary: Elf and colleagues used an elegant series of functional and biochemical assays to investigate the molecular mechanism of mutant calreticulin (CALR)–driven cellular transformation in myeloproliferative neoplasms (MPN). Mutant CALR is sufficient to induce MPN in mouse transplantation experiments, and transformation is dependent upon physical interaction mediated by the positive electrostatic charge of the mutant CALR C-terminal domain and the thrombopoietin receptor MPL. Cancer Discov; 6(4); 344–6. ©2016 AACR.

See related article by Elf et al., p. 368.

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Accelerating Lead Compound Optimization [News in Brief]

Chemists at The Scripps Research Institute in La Jolla, CA, and Pfizer's La Jolla Laboratories have devised a new way to rapidly synthesize strained-ring structures, which are increasingly favored to optimize potential drugs. With this method, strain-release amination, Pfizer researchers were able to produce sufficient quantities of a particular structure they needed to evaluate a promising cancer drug candidate.

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Targeting p300 Addiction in CBP-Deficient Cancers [Research Articles]

Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300. Ablation of p300 in CBP-knockout and CBP-deficient cancer cells induced G₁–S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP-deficient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifically suppressed the growth of CBP-deficient lung and hematopoietic cancer cells in vitro and in vivo; thus p300 is a promising therapeutic target for treatment of CBP-deficient cancers.

Significance: Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a "synthetic lethal–based therapeutic strategy" for CBP-deficient cancers by inhibition of the p300 HAT activity. Patients with CBP-deficient cancers could benefit from therapy using p300-HAT inhibitors. Cancer Discov; 6(4); 430–45. ©2015 AACR.

See related commentary by Kadoch, p. 350.

This article is highlighted in the In This Issue feature, p. 331

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NUDT15 Variants Alter Thiopurine-Associated Hematopoietic Toxicity [Drug Response]

Inactivating NUDT15 polymorphisms are associated with thiopurine intolerance.

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Exercise Reduces Tumor Initiation and Progression in Mouse Models [Tumorigenesis]

Running suppresses tumor growth in mouse tumor models by increasing natural killer cell infiltration.

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Metastatic Prostate Tumors Exhibit Limited Intraindividual Heterogeneity [Genomics]

Metastatic prostate tumors exhibit high heterogeneity among and not within individuals.

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Rps14 Haploinsufficiency Promotes Erythroid Differentiation Defects [Myelodysplastic Syndrome]

Rps14 haploinsufficiency promotes an S100A8-mediated p53-dependent erythroid differentiation block.

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Circulating Neoantigen-Specific T Cells Can Be Prospectively Identified [Immunotherapy]

PD-1 is a biomarker for circulating neoantigen-specific lymphocytes in patients with melanoma.

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Plasmacytoid Variant Bladder Cancers Harbor CDH1 Mutations [Bladder Cancer]

CDH1 mutations are specific to, and occur in the majority of, plasmacytoid variant bladder cancers.

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Inhibition of p38 or MK2 Increases SMAC-Mimetic Efficacy against AML [Leukemia]

The loss of p38 or MK2 enhances SMAC-mimetic–mediated TNF production and cytotoxicity.

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Lifting Up the HAT: Synthetic Lethal Screening Reveals a Novel Vulnerability at the CBP-p300 Axis [In the Spotlight]

Summary: Cancer genotype–specific synthetic lethal vulnerabilities represent promising therapeutic targets. In this issue of Cancer Discovery, Ogiwara and colleagues uncover a synthetic lethal relationship between two histone acetyl transferase paralogs, CBP and p300, highlighting that cancer cells deficient in CBP are uniquely sensitized to genetic and chemical inhibition of p300. Cancer Discov; 6(4); 350–2. ©2016 AACR.

See related article by Ogiwara et al., p. 430.

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The Effects of Dietary Omega-3s on Muscle Composition and Quality in Older Adults

Abstract

This review will focus on findings from the few studies performed to date in humans to examine changes in muscle protein turnover, lean or muscle mass, and physical function following fish oil-derived omega-3 fatty acid treatment. Although considerable gaps in our current knowledge exist, hypertrophic responses (e.g., improvements in the rate of muscle protein synthesis and mTOR signaling during increased amino acid availability and an increase in muscle volume) have been reported in older adults following prolonged (8 to 24 weeks) of omega-3 fatty acid supplementation. There is also accumulating evidence that increased omega-3 fatty acid levels in red blood cells are positively related to strength and measures of physical function. As a result, increased omega-3 fatty acid consumption may prove to be a promising low-cost dietary approach to attenuate or prevent aging-associated declines in muscle mass and function.

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Is regorafenib providing clinically meaningful benefits to pretreated patients with metastatic colorectal cancer?

Abstract

Treatment with regorafenib has demonstrated statistically significant improvements in terms of overall survival, progression-free survival and disease control when compared with placebo in pretreated patients with metastatic colorectal cancer in two placebo-controlled, randomized, phase III trials (CORRECT and CONCUR). Similar results were observed in two open-label, single-arm studies (REBECCA and CONSIGN) performed in the real-world setting. But several authors have suggested that the benefit provided by regorafenib may not be clinically meaningful for these patients. Moreover, it has been suggested that not all subgroups of patients might benefit from regorafenib. The intention of this review is to provide an overview of the existing evidence for regorafenib in terms of efficacy, tolerability and quality of life in different subpopulations according to clinical and biological characteristics. Additionally, the magnitude of the clinical benefit provided by regorafenib to these patients has been explored and whether there are poorer outcomes in certain subpopulations.

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Clinical Significance of Serum Galectin-3 Levels in Gastric Cancer Patients

Abstract

Purpose

Galectin-3, a member of the galectin family, is an endogenous β-galactoside-binding lectin. It plays an important role in the pathogenesis of multiple malignancies and its expression strongly also affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of galectin-3 in gastric cancer patients.

Material and methods

A total of 58 patients with diagnosis of gastric cancer were enrolled into this study. Serum galectin-3 concentrations were determined by the solid-phase sandwich ELISA method. Age- and sex-matched 30 healthy controls were included in the analysis.

Results

The median age at diagnosis was 59.5 years, range 32 to 82 years. There was no significant difference in the baseline serum galectin-3 levels between gastric cancer patients and healthy controls (p = 0.357). The older patients had elevated galectin-3 levels compared with younger ones (p = 0.02). The other known clinical variables including gender, site of lesion, histopathology, tumor size, lymph node involvement, and stage of disease were not correlated with serum galectin-3 concentrations (p > 0.05). Moreover, no relationship was shown between serum galectin-3 level and chemotherapy responsiveness (p = 0.36). Likewise, serum galectin-3 concentrations were not associated with prognosis on survival (p = 0.54).

Conclusion

Serum levels of galectin-3 have no diagnostic, predictive and prognostic roles in gastric cancer patients.

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Rhabdomyosarcoma masquerading as lymphadenopathy in a patient with newly diagnosed Hodgkin’s lymphoma

Abstract

Background

Hodgkin's lymphoma (HL) is a rare malignancy which often presents with lymphadenopathy and classic "B symptoms" of weight loss, fever, and night sweats. Additional masses or nodes could easily be presumed to be a result of the initial diagnosis. On the other hand, adult rhabdomyosarcoma is a rare malignancy presenting with a new mass in a patient with previous diagnosis of Hodgkin's lymphoma. In both cases, a tissue diagnosis should be obtained to appropriately confirm the diagnosis.

Case presentation

We present a case of a 64-year-old male who presents with right axillary lymphadenopathy, diagnosed as Hodgkin's lymphoma. He subsequently developed left inguinal lymphadenopathy without the classic B symptoms of HL. Excisional biopsy revealed rhabdomyosarcoma. Stage III Hodgkin's lymphoma (lymph node involvement on both sides of the diaphragm) is not commonly seen without typical B symptoms. Once the diagnosis of two primary malignancies is made, the dilemma becomes determining the treatment course. In the case of Hodgkin's lymphoma and rhabdomyosarcoma, there is some overlap in the chemotherapeutic regimen and use of radiation.

Conclusions

This case illustrates the importance of careful examination of Hodgkin's lymphoma patients and consideration of additional tissue diagnoses in atypical presentations of new masses or lymphadenopathy on the opposite side of the diaphragm.

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Porta hepatic schwannoma: case report and a 30-year review of the literature yielding 15 cases

Abstract

Background

Schwannomas located in the periportal region are extremely rare. Only 14 cases have been reported in the medical literature worldwide. Cases of porta hepatic schwannomas reported in the literature worldwide were reviewed. As a result, it is very challenging for surgeons to make a preoperative diagnosis due to its rarity and nonspecific imaging manifestations.

Case Presentation

A 57-year-old Chinese female was admitted to our institution with complaint of upper abdominal distension and the abdominal CT in the local hospital revealed a hypodense mass in the porta hepatis. A fine needle aspiration (FNA) was made to confirm the diagnosis, but the result was just suggestive of spindle cell neoplasia. Eventually, the patient underwent surgery and postoperative pathology confirmed schwannoma in porta hepatis. The patient recovered uneventfully with no evidence of recurrence after a follow-up period of 41 months.

Conclusions

It is essential for the final diagnosis of porta hepatic schwannomas to combine histological examination with immunohistochemistry after surgery. The main treatment of porta hepatic schwannomas is complete excision with free margins and no lymph node dissection. In some cases, biliary reconstruction or the proper hepatic and the gastroduodenal artery resection was performed because the tumor was inseparably attached to the extrahepatic bile duct or the proper hepatic and the gastroduodenal artery. Malignant transformation of schwannomas is very rare and the overall prognosis is satisfactory.

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The association between the duration of fluoropyrimidine-based adjuvant chemotherapy and survival in stage II or III gastric cancer

Abstract

Background

This study was conducted to propose the optimal duration of fluoropyrimidine-based adjuvant chemotherapy consisting of fluoropyrimidine derivatives alone or combined with intravenous platinum for stage II or III gastric cancer (GC).

Methods

We analyzed retrospectively the data from 2219 patients with histologically confirmed adenocarcinoma in the stomach, who underwent a curative gastrectomy with lymphadenectomy from 2005 to 2012. Five-year overall survival (OS) and 3-year relapse-free survival (RFS) were analyzed according to the duration of fluoropyrimidine-based adjuvant chemotherapy.

Results

Data from 617 patients with stage II or III GC were analyzable; 187 patients (30.3 %) were treated with surgery alone, while 430 patients (69.7 %) were treated with postoperative adjuvant chemotherapy. The duration of adjuvant chemotherapy was less than 6 months [group 1] in 147 patients (34.2 %), 6 months to less than 12 months [group 2] in 94 patients (21.9 %), 1 year to less than 2 years [group 3] in 139 patients (32.3 %), and over 2 years [group 4] in 50 patients (11.6 %). The 5-year OS in groups 1, 2, 3, and 4 was 75.7, 87, 90.3, and 93.4 %, respectively, while 3-year RFS was 52.5, 58.8, 81.4, and 94.0 %, respectively.

Conclusions

In this retrospective study, we did not demonstrate any significant improvement in OS and RFS by longer periods of fluoropyrimidine-based adjuvant chemotherapy in stage II or III GCs. Further prospective randomized studies are needed.

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Clinical efficacy of postoperative adjuvant transcatheter arterial chemoembolization on hepatocellular carcinoma

Abstract

Background

The aim of this study was to evaluate the clinical efficacy of postoperative adjuvant transcatheter arterial chemoembolization (TACE) on hepatocellular carcinoma (HCC).

Methods

Data from 117 patients with HCC who underwent hepatectomy between December 2010 and February 2014 were retrospectively reviewed. In total, 55 patients underwent surgical resection only (group A), and 62 patients underwent surgical resection with adjuvant TACE (group B). The perioperative clinical indicators, postoperative sequential treatment, and follow-up were compared between the two groups of patients. The Kaplan-Meier method was used to compare survival between the groups, and prognostic factors were evaluated by a Cox proportional hazard model.

Results

The two groups showed no significant difference in age, gender, preoperative A-fetoprotein (AFP) values, preoperative Child-Pugh score, hepatitis B virus(HBV) DNA levels, duration of surgery, hepatectomy technique, albumin values 1-week postoperative, postoperative complications, duration of postoperative hospital stay, cirrhosis, tumor size, tumor differentiation, tumor encapsulation, satellite nodules, or microvascular infiltration. Cox regression analysis revealed that tumor size, satellite nodules, and microvascular infiltration were significantly independent prognostic factors (P = 0.001, 0.002, and 0.001). Of the 117 patients, the 1-, 2-, and 3-year disease-free survival rates were 64.5, 50.0, and 41.9 %, respectively, for group B (62 patients) and 45.5, 36.4, and 30.9 %, respectively, for group A (55 patients). Although improving trends of disease-free survival were observed in the adjuvant TACE group, there was a significant difference in postoperative 1-year survival between the two groups (P = 0.04) but no significant difference in postoperative 2- and 3-year survival. In patients with tumor size >5 cm, the 1-, 2-, and 3-year disease-free survival rates were 41.7, 25.0, and 12.5 %, respectively, for group B and 11.8, 0, and 0 %, respectively, for group A. There was a significant difference in postoperative 1- and 2-year survival between the two groups (P = 0.04 and 0.03, respectively) but no significant difference in postoperative 3-year survival. In patients with microvascular infiltration, the 1-, 2-, and 3-year disease-free survival rates were 42.3, 26.9, and 15.4 %, respectively, for group B and 12.5, 4.2, and 0 %, respectively, for group A. There was a significant difference between the two groups (P = 0.02, 0.03, and 0.045, respectively). In patients with satellite nodules, the 1-, 2-, and 3-year disease-free survival rates were 50.0, 50, and 40 %, respectively, for group B and 17.6, 0, and 0 %, respectively, for group A. There was a significant difference between the two groups (P = 0.04, 0.01, and 0.03, respectively). In patients with tumor size ≤5 cm, without satellite nodules, or without microvascular infiltration, there was no significant difference between the two groups in the 1-, 2-, or 3-year disease-free survival rates. Of 117 patients overall, 18 (15.4 %) developed hepatitis B virus reactivation: 2 (3.6 %) patients in group A and 16 (25.8 %) patients in group B. There was a significant difference between the two groups (P = 0.000). Of these patients, one (1.8 %) patient in group A and five (8.1 %) patients in group B developed hepatitis due to hepatitis B virus reactivation. There was a significant difference between the two groups (P = 0.000).

Conclusions

Postoperative adjuvant TACE can improve the 1-year disease-free survival rate of HCC patients. Postoperative adjuvant TACE may improve 2- and 3-year disease-free survival rates, but no statistical significance was found. For patients with tumor size >5 cm, postoperative adjuvant TACE can improve 1- and 2-year disease-free survival rates, and postoperative adjuvant TACE may improve the 3-year disease-free survival rate. For HCC patients with tumor size ≤5 cm, postoperative adjuvant TACE may improve the 1-, 2-, and 3-year disease-free survival rates, but no statistical significance was found. For patients with microvascular infiltration or satellite nodules, postoperative adjuvant TACE can improve the 1-, 2-, and 3-year disease-free survival rates. For patients without microvascular infiltration or without satellite nodules, postoperative adjuvant TACE cannot improve 1-, 2-, or 3-year disease-free survival rates. For patients with tumor size >5 cm with microvascular infiltration or with satellite nodules, postoperative adjuvant TACE was suggested. Hepatitis B virus reactivation can occur in patients with postoperative adjuvant TACE; thus, antiviral treatment was suggested for these patients.

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Nuances in the Management of Older People With Multiple Myeloma

Abstract

Multiple myeloma is a disease of the elderly, with about a third of patients at diagnosis older than 75 years of age. Yet, the population of elderly patients is heterogeneous: older patients are more likely to have comorbidities and frailties complicating both their initial diagnosis and subsequent management, but these are not consistent across the group. Furthermore, patients with comorbidities and frailty are generally underrepresented in clinical trials. Despite the survival of myeloma patients increasing following the introduction of novel agents, older patients continue to have worse outcomes with increased treatment-related toxicity. Treatment tolerability is not defined by age alone, rather a combination of age, physical function, cognitive function, and comorbidities. These factors all influence patients' tolerability of treatment and therefore treatment efficacy and should also be considered when reviewing the results of clinical trials. It is the nuances of determining how these factors interact that should influence initial treatment and ongoing management decisions and these will be discussed here.

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Overweight in mice, induced by perinatal programming, exacerbates doxorubicin and trastuzumab cardiotoxicity

Abstract

Purpose

Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardiotoxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ.

Methods

Immediately after birth, litters of C57BL/6 mice were either maintained at 9 pups (normal litter, NL) or reduced to 3 (small litter, SL) in order to induce programming of ~15 % overweight through postnatal overfeeding. At 4 months, NL and SL mice received a single intra-peritoneal injection of either saline, DOX (6 mg/kg), TRZ (10 mg/kg) or both (DOX–TRZ). Transthoracic echocardiography was performed 24 h before as well as 10 and 20 days after treatments.

Results

Twenty days after DOX administration, systolic dysfunction was observed only in the overweight SL group, while NL mice group had a normal left ventricular ejection fraction. However, in the NL group, functional impairment appeared when TRZ was co-administered. Forty-eight hours after drug administration, gene expression of natriuretic peptides (ANP, BNP) appeared to be potentiated in DOX–TRZ mice of both the NL and SL group, whereas the expression of β-MHC increased significantly in overweight SL mice only.

Conclusions

In an acute model of DOX cardiotoxicity, moderately overweight adult mice were more sensitive to cardiac systolic impairment. Moreover, our results confirm the potentiating action of TRZ on DOX-induced cardiotoxicity in lean mice.

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Hypoxia regulates stemness of breast cancer MDA-MB-231 cells

Abstract

Human breast cancers include cancer stem cell populations as well as non-tumorigenic cancer cells. Breast cancer stem cells possess self-renewal capability and thus are the root cause of recurrence and metastasis of malignant tumors. Hypoxia is a fundamental pathological feature of solid tumor tissues and exerts a wide range of effects on the biological behavior of cancer cells. However, there is little information on the role of hypoxia in modulating the stemness of breast cancer cells. In the present study, we cultured MDA-MB-231 cells in a hypoxic gas mixture to simulate the hypoxic environment in tissues and to determine how hypoxia conditions could affect the cell proliferation, apoptosis, cytotoxicity, and colony-forming ability. Expression of the stem cell phenotype CD24⁻CD44⁺ESA⁺ was analyzed to assess the effects of hypoxia on stemness transformation in MDA-MB-231 cells. Our results found that the cell toxicity of MDA-MB-231 cells was not affected by hypoxia. Hypoxia could slightly inhibit the growth of MDA-MB-231 cells, but the inhibitory effect is not significant when compared with normoxic control. Moreover, hypoxia significantly blocked the apoptosis in MDA-MB-231 cells (P < 0.05). The proportion of CD24⁻CD44⁺ESA⁺ cells in MDA-MB-231 cells was increased greatly after they were treated with hypoxia, and cell colony-formation rate of MDA-MB-231 cells also increased significantly in hypoxia-treated cells. These results encourage the exploration of hypoxia as a mechanism which might not be underestimated in chemo-resistant breast cancer treatment.

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Multi-kinase inhibitors, AURKs and cancer

Abstract

Inhibitors that impact function of kinases are valuable both for the biological research as well as therapy of kinase-associated diseases, such as different cancers. There are quite a number of inhibitors, which are quite specific for certain kinases and several of them are either already approved for the cancer therapy or are in clinical studies of various phases. However, that does not mean that each single kinase inhibitor is suitable for targeted therapy. Some of them are not effective others might be toxic or fail some other criteria for the use in vivo. On the other hand, even in case of successful therapy, many responders eventually develop resistance to the inhibitors. The limitations of various single kinase inhibitors can be fought using compounds which target multiple kinases. This tactics can increase effectiveness of the inhibitors by the synergistic effect or help to diminish the likelihood of drug resistance. To date, several families of kinases are quite popular targets of the inhibition in cancers, such as tyrosine kinases, cycle-dependent kinases, mitogen-activated protein kinases, phosphoinositide 3-kinases as well as their pathway "players" and aurora kinases. Aurora kinases play an important role in the control of the mitosis and are often altered in diverse human cancers. Here, we will describe the most interesting multi-kinase inhibitors which inhibit aurora kinases among other targets and their use in preclinical and clinical cancer studies.

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Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy

Abstract

Background

The Hippo signaling acts as a tumor-suppressor pathway that negatively regulates TAZ and YAP. Increasing evidence supports the activation of TAZ and YAP in breast cancer. Moreover, the Hippo pathway is involved in the biology of non-neoplastic cells residing in the tumor microenvironment. On this basis, we herein assessed TAZ and YAP in triple-negative breast cancer and its surrounding microenvironemnt in order to investigate their impact on pathological complete response (pCR) and tumor recurrence.

Methods

Sixty-one triple-negative breast cancer patients treated with neoadjuvant chemotherapy were retrospectively evaluated. TAZ and YAP were assessed by immunohistochemistry and classified as positive or negative according to the percentage of tumor-expressing cells, cellular localization, and staining intensity. TAZ and YAP expression was also evaluated in non-lymphocytic stromal cells, tumor-infiltrating lymphocytes (TILs) and endothelial cells. The Pearson's Chi-squared test of independence was used to test the association between TAZ/YAP and clinical-molecular factors. A multivariate logistic regression model was generated to identify variables impacting pCR. The Kaplan-Meier method and the log-rank test were used for estimating and comparing survival curves. Cox proportional regression models were built to evaluate the risk of recurrence for the variables considered. Internal validation was carried out with a re-sampling without replacement method.

Results

We did not observe any impact on pCR rate when TAZ and YAP were addressed singularly. Conversely, the combined expression of YAP in tumor cells and non-lymphocytic stromal cells was an independent predictor of reduced pCR rate in the multivariate model (OR 7.13, 95 % CI: 1.23–41.41, p = 0.029). Next, the combined expression of TAZ and YAP was associated with shorter disease-free survival (DFS) in multivariate analysis (HR 3.07, 95 % CI: 1.24–7.61, p = 0.016). The robustness of these findings were internally validated.

Conclusions

The combined expression of YAP in TNBC cells and in the surrounding stroma seems to be associated with a decreased likelihood to achieve pCR. Conversely, the combined expression of TAZ and YAP in tumor cells conferred poor survival outcomes.

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Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway

Abstract

Background

Sonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH pathway has not been described in gastric cancer. The aim of this study was to explore molecular mechanisms underlying autocrine SHH signaling in gastric cancer cells.

Methods

SHH expression was assessed using immunohistochemistry and the results were compared with clinicopathologic parameters, including survival. Using gastric cancer cell lines, we measured SHH mRNA and protein expression, and studied the effects of SHH signaling on cell proliferation and SHH secretion. We also studied the effects of an inhibitor of PLC-γ1 on phosphorylation of phospholipase Cγ1 and extracellular signal-regulated kinases (ERK)1/2.

Results

SHH protein expression in gastric cancer tissue was significantly higher compared with that in normal gastric tissue (P < 0.001), and the increased expression was significantly associated with pT staging (P = 0.004), pN staging (P = 0.018), pM staging (P = 0.006), and pTNM staging (P < 0.001). In multivariate analyses, overall survival in gastric cancer was significantly shorter in cases with high SHH expression (HR = 1.734, 95 % CI: 1.109–2.713, P = 0.016). The AGS and SGC-7901 gastric cancer cell lines expressed SHH mRNA and protein. In these cell lines, SHH promoted carcinogenesis through activation of the PLCγ1-ERK1/2 pathway, resulting in increased cell proliferation and survival.

Conclusions

Increased SHH expression is associated with shorter survival in gastric cancer patients, and SHH could represent a useful biomarker or therapeutic target for this disease.

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Quercetin sensitizes glioblastoma to t-AUCB by dual inhibition of Hsp27 and COX-2 in vitro and in vivo

Abstract

Background

Evidences indicate that inflammatory process plays pivotal role in tumor disease. Soluble epoxide hydrolase inhibitors (sEHIs) have been shown to participate in anti-inflammation and tumorigenesis by protecting epoxyeicosatrienoic acids (EETs). Although we have previously revealed some effects of t-AUCB on glioma in vitro, further investigations are needed to demonstrate its effects on glioblastoma growth in vivo and how to strengthen its antitumor effect.

Methods

CCK-8 kit was used to test cell growth. Cell migration capacity was performed by wound healing assays. Transwell assay was used to test cell invasion potency. Cell-cycle analysis and cell apoptosis was performed by flow cytometry. The activity of caspase-3 in cells was measured using caspase-3 activity assay kits. Total RNA was extracted from cells lysated by TRIzol reagent. qRT-PCR was performed by ABI 7500 fast RT- PCR system. Lipofectamine RNAiMAX Transfection Reagent (Invitrogen) was used for siRNA transfection. Western blootting was used to test protein expression. Tumor cell xenograft mouse models were used for in vivo study. The SPSS version 17.0 software was applied for statistical analysis.

Results

Our data shown that t-AUCB inhibits cell proliferation, migration and invasion and induces cell cycle G1 phase arrest in vitro but induces no cell apoptosis; increased Hsp27 activation and following COX-2 overexpression confer resistance to t-AUCB treatment in glioblastoma both in vitro and in vivo; quercetin sensitizes glioblastoma to t-AUCB by dual inhibition of Hsp27 and COX-2 in vitro and in vivo.

Conclusions

These results indicate that combination of t-AUCB and quercetin may be a potential approach to treating glioblastoma.

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Topographic expression of the Hippo transducers TAZ and YAP in triple-negative breast cancer treated with neoadjuvant chemotherapy

The Hippo signaling acts as a tumor-suppressor pathway that negatively regulates TAZ and YAP. Increasing evidence supports the activation of TAZ and YAP in breast cancer. Moreover, the Hippo pathway is involve...

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Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway

Sonic hedgehog (SHH) plays critical roles in cell growth and development. Tumor cells express SHH, which can promote cell proliferation and epithelial-to-mesenchymal transition. However, the autocrine SHH path...

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Quercetin sensitizes glioblastoma to t-AUCB by dual inhibition of Hsp27 and COX-2 in vitro and in vivo

Evidences indicate that inflammatory process plays pivotal role in tumor disease. Soluble epoxide hydrolase inhibitors (sEHIs) have been shown to participate in anti-inflammation and tumorigenesis by protectin...

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Effects of paclitaxel on permanent head and neck squamous cell carcinoma cell lines and identification of anti-apoptotic caspase 9b

Abstract

Purpose

Paclitaxel is an effective chemotherapeutic agent against various human tumors inducing apoptosis via binding to β-tubulin of microtubules and arresting cells mainly in the G2/M phase of the cell cycle. However, the underlying specific molecular mechanisms of paclitaxel on head and neck squamous cell carcinoma (HNSCC) have not been identified yet.

Methods

The apoptotic effects and mechanisms of paclitaxel on different permanent HPV-negative HNSCC cell lines (UT-SCC-24A, UT-SCC-24B, UT-SCC-60A and UT-SCC-60B) were determined by flow cytometry assays, polymerase chain reaction analysis, immunofluorescence-based assays and sequencing studies.

Results

Paclitaxel induced a G2/M arrest in HNSCC cell lines followed by an increased amount of apoptotic cells. Moreover, the activation of caspase 8, caspase 10 and caspase 3, and the loss of the mitochondrial outer membrane potential could be observed, whereas an activation of caspase 9 could barely be detected. The efficient activation of caspase 9 was not affected by altered methylation patterns. Our results can show that the promoter region of apoptotic protease activating factor 1 (Apaf-1) was not methylated in the HNSCC cell lines. By sequencing analysis two isoforms of caspase 9, the pro-apoptotic caspase 9 and the anti-apoptotic caspase 9b were identified. The anti-apoptotic caspase 9b is missing the catalytic site and acts as an endogenous inhibitor of apoptosis by blocking the binding of caspase 9 to Apaf-1 to form the apoptosome.

Conclusion

Our data indicate the presence of anti-apoptotic caspase 9b in HNSCC, which may serve as a promising target to increase chemotherapeutic apoptosis induction.

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Intensity modulated arc therapy implementation in a three phase adaptive 18F-FDG-PET voxel intensity-based planning strategy for head-and-neck cancer

This study investigates the implementation of a new intensity modulated arc therapy (IMAT) class solution in comparison to a 6-static beam step-and-shoot intensity modulated radiotherapy (s-IMRT) for three-pha...

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Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas

Glioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for suppleme...

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Verification of microRNA expression in human endometrial adenocarcinoma

Abstract

Background

MicroRNAs are small non-coding RNAs that have been implicated in tumor initiation and progression. In a previous study we identified 138 miRNAs as differentially expressed in endometrial adenocarcinoma compared to normal tissues. One of these miRNAs was miRNA-34a, which regulates several genes involved in the Notch pathway, which is frequently altered in endometrial cancer. The aims of this study were to verify the differential expression of a subset of miRNAs and to scrutinize the regulatory role of mir-34a on the target genes NOTCH1 and DLL1.

Methods

Twenty-five miRNAs that were previously identified as differentially expressed were subjected to further analysis using qPCR. To investigate the regulation of NOTCH1 and DLL1 by mir-34a, we designed gain- and loss-of-function experiments in Ishikawa and HEK293 cell lines by transfection with a synthetic mir-34a mimic and a mir-34a inhibitor.

Results

Of the 25 validated miRNAs, seven were down-regulated and 18 were up-regulated compared to normal endometrium, which was fully consistent with our previous findings. In addition, the up-regulation of mir-34a led to a significant decrease in mRNA levels of NOTCH1 and DLL1, while down-regulation led to a significant increase in mRNA levels of these two genes.

Conclusions

We verified both up-regulated and down-regulated miRNAs in the tumor samples, indicating various roles of microRNAs during tumor development. Mir-34a functions as a regulator by decreasing the expression of NOTCH1 and DLL1. Our study is the first to identify a correlation between mir-34a and its target genes NOTCH1 and DLL1 in endometrial adenocarcinoma.

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25-methoxyl-dammarane-3β, 12β, 20-triol and artemisinin synergistically inhibit MDA-MB-231 cell proliferation through downregulation of testes-specific protease 50 (TSP50) expression

Abstract

While the incidence of cancer continues to increase, the current therapeutic options remain imperfect. Therefore, there is an urgent need to discover new targeted anti-cancer therapies. Testes-specific protease 50 (TSP50) is abnormally expressed in most cancer tissues and downregulation of TSP50 expression can reduce cell proliferation and induce cell apoptosis, which makes it a potential target for cancer therapy. In this study, we constructed a firefly luciferase reporter pGL3-TSP50-3′-UTR as a drug screening model to screen potential candidate compounds that target TSP50 mRNA. We identified the compound 7P3A, which consists of 70 % 25-methoxyl-dammarane-3β, 12β, 20-triol and 30 % artemisinin, as being capable of inhibiting the TSP50-3′-UTR reporter activity, as well as the expression of TSP50. Further investigation revealed that 7P3A could inhibit MDA-MB-231 cell proliferation and induce cell cycle arrest, and over-expression of TSP50 partially reversed the effect of 7P3A. In vivo investigation showed that 7P3A could inhibit tumor growth in a xenograft model of breast cancer. These results suggest that 7P3A exhibits anti-cancer effects, in part, through downregulation of TSP50 expression.

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The role of microRNA-26a in human cancer progression and clinical application

Abstract

MicroRNAs, a class of endogenous, small (18–25 nucleotides) noncoding RNAs, regulate gene expression by directly binding to the 3′-untranslated regions of target messenger RNAs. Evidence has shown that alteration of microRNAs is involved in cancer initial and progression. MicroRNA-26a is commonly dysregulated in diverse cancers and is involved in various biological processes, including proliferation, migration, invasion, angiogenesis, and metabolism by targeting multiple mRNAs. This review summarizes current research on the physiology and pathological functions of miR-26a and its applications for clinical therapy.

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Sorghum stem extract modulates Na + /K + -ATPase, ecto-5′-nucleotidase, and acetylcholinesterase activities

Abstract

Sorghum stem (Sorghum bicolor) has been in use in traditional medicine systems for the management of neurodegenerative conditions. However, there is dearth of information on the scientific basis for its use in the treatment of such conditions. This study sought to assess the antioxidant activity and effects of phenolic extract from sorghum stem (Sorghum bicolor) on some cholinergic (acetylcholinesterase (AChE)) and purinergic (Na⁺/K⁺-ATPase and ecto-5′-nucleotidase) enzymes associated with neurological conditions. Phenolic-rich extract was prepared using methanol: 1 N HCl (1:1, v/v) mixture and characterized using high-performance liquid chromatography-diode array detector (HPLC-DAD). In vitro tests were used to investigate the effects of the phenolic extract on AChE, Na⁺/K⁺-ATPase, and ecto-5′-nucleotidase activities. Furthermore, the hydroxyl (OH) radical scavenging and Fe²⁺-chelating abilities of the extract were investigated. HPLC-DAD analysis revealed the presence of some phenolic acids such as caffeic acid (120.58 mg/g), ferulic acid (76.45 mg/g), gallic acid (17.48 mg/g), chlorogenic acid (16.25 mg/g), and flavonoids such as kaempferol (15.98 mg/g), rutin (51.07 mg/g), quercetin (263.16 mg/g), and quercitrin (89.21 mg/g) in the phenolic extract. The extract significantly inhibited AChE and ecto-5′-nucleotidase activities in a dose dependent manner with IC₅₀ = 24.88 μg/ml and IC₅₀ = 37.49 μg/ml, respectively, and increased Na⁺/K⁺-ATPase activity in a dose dependent manner. Furthermore, the phenolic extract also scavenged OH radicals and was able to chelate Fe²⁺ in a dose dependent manner with IC₅₀ = 54.27 μg/ml and 18.47 μg/ml, respectively. This study revealed the antioxidant and modulatory effects of phenolic extracts from sorghum stem on some cholinergic and purinergic enzymes.

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Jimson weed ( Datura stramonium L.) alkaloid extracts modulate cholinesterase and monoamine oxidase activities in vitro: possible modulatory effect on neuronal function

Abstract

Despite the well-established medicinal values of Jimson weed (Datura stramonium L.), this medicinal plant has been associated with neurological effects such as hallucination and anxiety in folklore. This study examined the effect of alkaloid extracts from the leaf and fruit of Jimson weed on critical enzymes of the monoaminergic [monoamine oxidase (MAO)] and cholinergic [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] systems of neurotransmission. Alkaloid extracts were prepared by solvent extraction method and their interaction with the activities of MAO, AChE, and BChE were assessed (in vitro). Gas chromatography coupled with mass spectroscopic (GC-MS) characterization of the extracts was also carried out. The results revealed that the extracts inhibited the activity of the enzymes assayed for in a concentration-dependent manner. Considering the IC₅₀ values, the fruit extract had more potent (P < 0.05) inhibitory effect on the enzymes' activities, compared to the leaf extract. GC-MS characterization revealed the presence of atropine, scopolamine, amphetamine, 3-methoxyamphetamine, 3-ethoxyamhetamine cathine, spermine, phenylephrine, and 3-piperidinemethanol, among others in the extracts. The alteration of activities of these critical enzymes of the cholinergic and monoaminergic signaling may be responsible for the reported neurological effects of this medicinal plant in folklore; nevertheless, the fruit extract exhibited more neuromodulatory effect than the leaf.

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Gastro esophageal reflux disease (GERD) prevalence and related risk factors in north of Iran

Abstract

Background

Gastroesophageal reflux disease (GERD) is one of the most frequent disorders in daily clinical practice with numerous associated consequences. A large number of studies were conducted to determine the prevalence of GERD and its associated risk factors which led to inconsistent results. The present study was performed to evaluate the prevalence of GERD and its related risk factors in north of Iran.

Methods

Nine hundred and thirty-three educated participants aged 18–77 years who had at least a High School Diploma were enrolled in the present study. Validated Persian version of Gastroesopahageal reflux questionnaire was used to collect the data. To determine the GERD associated risk factors, logistic regression was performed.

Results

The prevalence of GERD was 53.5 % (frequent GERD: 12.1 %). Among seven potential risk factors, the positive history of reflux in first relatives (OR = 2.37, CI = 1.76–3.20, p value < 0.001) and asthma (OR = 2.605, CI = 1.553–4.368, p < 0.001) were significantly associated with GERD. Spouse history of GERD in interaction with first relatives history of GERD and smoking was significantly associated with GERD too.

Conclusion

The prevalence of GERD is increasing in our country compared to previus studies, which may lead to serious increment of malignant conditions such as esophagus adenocarcinoma.

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Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study

Summary

Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p < 0.05). Dose–response relationships indicated a favorable benefit/risk ratio at 3 mg and 4 mg weekly, which are below the maximum tolerated dose of 5.5 mg. At 3 mg, the model predicted that: 37 % of patients will achieve clinical benefit; incidence of grade ≥ 3 neutropenia and thrombocytopenia will be 10 % and 23 %, respectively; and incidence of grade ≥ 2 rash, fatigue, and diarrhea will be 8 %, 19 %, and 19 %, respectively. Conclusions Based on the findings, patients in the phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3 mg, increasing to 4 mg if acceptable tolerability after 4 cycles, to provide maximum clinical benefit balanced with adequate tolerability.

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Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas

Abstract

Background

Glioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for supplementary biomarkers that could provide reliable and early assessment of treatment efficacy. Analysis of alterations in the metabolome may be a source for identification of new biomarker patterns harboring predictive information. Ideally, the biomarkers should be found within an easily accessible compartment such as the blood.

Method

Using gas-chromatographic- time-of-flight-mass spectroscopy we have analyzed serum samples from 11 patients with glioblastoma during the initial phase of radiotherapy. Fasting serum samples were collected at admittance, on the same day as, but before first treatment and in the morning after the second and fifth dose of radiation. The acquired data was analyzed and evaluated by chemometrics based bioinformatics methods. Our findings were compared and discussed in relation to previous data from microdialysis in tumor tissue, i.e. the extracellular compartment, from the same patients.

Results

We found a significant change in metabolite pattern in serum comparing samples taken before radiotherapy to samples taken during early radiotherapy. In all, 68 metabolites were lowered in concentration following treatment while 16 metabolites were elevated in concentration. All detected and identified amino acids and fatty acids together with myo-inositol, creatinine, and urea were among the metabolites that decreased in concentration during treatment, while citric acid was among the metabolites that increased in concentration. Furthermore, when comparing results from the serum analysis with findings in tumor extracellular fluid we found a common change in metabolite patterns in both compartments on an individual patient level. On an individual metabolite level similar changes in ornithine, tyrosine and urea were detected. However, in serum, glutamine and glutamate were lowered after treatment while being elevated in the tumor extracellular fluid.

Conclusion

Cross-validated multivariate statistical models verified that the serum metabolome was significantly changed in relation to radiation in a similar pattern to earlier findings in tumor tissue. However, all individual changes in tissue did not translate into changes in serum. Our study indicates that serum metabolomics could be of value to investigate as a potential marker for assessing early response to radiotherapy in malignant glioma.

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Intensity modulated arc therapy implementation in a three phase adaptive 18 F-FDG-PET voxel intensity-based planning strategy for head-and-neck cancer

Abstract

Background

This study investigates the implementation of a new intensity modulated arc therapy (IMAT) class solution in comparison to a 6-static beam step-and-shoot intensity modulated radiotherapy (s-IMRT) for three-phase adaptive ¹⁸F-FDG-PET-voxel-based dose-painting-by-numbers (DPBN) for head-and-neck cancer.

Methods

We developed ¹⁸F-FDG-PET-voxel intensity-based IMAT employing multiple arcs and compared it to clinically used s-IMRT DPBN. Three IMAT plans using ¹⁸F-FDG-PET/CT acquired before treatment (phase I), after 8 fractions (phase II) and CT acquired after 18 fractions (phase III) were generated for each of 10 patients treated with 3 s-IMRT plans based on the same image sets. Based on deformable image registration (ABAS, version 0.41, Elekta CMS Software, Maryland Heights, MO), doses of the 3 plans were summed on the pretreatment CT using validated in-house developed software. Dosimetric indices in targets and organs-at-risk (OARs), biologic conformity of treatment plans set at ≤5 %, treatment quality and efficiency were compared between IMAT and s-IMRT for the whole group and for individual patients.

Results

Doses to most organs-at-risk (OARs) were significantly better in IMAT plans, while target levels were similar for both types of plans. On average, IMAT ipsilateral and contralateral parotid mean doses were 14.0 % (p = 0.001) and 12.7 % (p < 0.001) lower, respectively. Pharyngeal constrictors D_50% levels were similar or reduced with up to 54.9 % for IMAT compared to s-IMRT for individual patient cases. IMAT significantly improved biologic conformity by 2.1 % for treatment phases I and II. 3D phantom measurements reported an agreement of ≥95 % for 3 % and 3 mm criteria for both treatment modalities. IMAT delivery time was significantly shortened on average by 41.1 %.

Conclusions

IMAT implementation significantly improved the biologic conformity as compared to s-IMRT in adaptive dose-escalated DPBN treatments. The better OAR sparing and faster delivery highly improved the treatment efficiency.

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Analytical Assessment of Bio- and Toxic Elements Distribution in Pu-erh and Fruit Teas in View of Chemometric Approach

Abstract

This study concerns application of flame atomic absorption spectrometry (FAAS) in assessment of macro- and microelement and toxic metal levels (Mg, Ca, K, Na, Mn, Cu, Fe, Zn, Cr, Ni, Co, Cd and Pb) in dark (Pu-erh) and fruit tea leaves and their infusions. Phosphorus was also determined in the form of phosphomolybdate by spectrophotometric method. The reliability of the method was checked using three certified reference materials. The results of analysis were in agreement with the certified values, with analytical recovery ranging from 86 to 113 %. Significant correlations (p < 0.001) were found between concentrations of P, Zn, K, Ni, Fe, Co, Cr, and Pb in Pu-erh tea, whereas in fruit tea, such interdependences were found between Mg, Fe, P, Ni, and Co. Kruskal-Wallis test results have related differences in Pu-erh tea quality as well as technological processing of fruit tea to their mineral composition. In order to characterize tea elemental content, chemometric techniques such as factor analysis (FA) and cluster analysis (CA) were used. Their application allowed on differentiation of samples in view of the fermentation type, technological processing, and overall quality.

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Cerium Oxide-Incorporated Calcium Silicate Coating Protects MC3T3-E1 Osteoblastic Cells from H 2 O 2 -Induced Oxidative Stress

Abstract

Oxidative stress regulates cellular functions in multiple pathological conditions, including bone formation by osteoblastic cells. In this work, the protective effects of cerium oxide (CeO₂)-incorporated calcium silicate (CeO₂-CS) coating on the response of osteoblasts to H₂O₂-induced oxidative stress and the related mechanism were examined. CeO₂ incorporation significantly improved osteoblast viability and reduced cell apoptosis caused by H₂O₂ when compared with the control. H₂O₂-induced reduction of differentiation marker alkaline phosphatase (ALP) was recovered in the presence of the CeO₂-CS coating. The above effects were mediated by the antioxidant effect of CeO₂. The CeO₂-CS coating immersed in 0.1 mM H₂O₂ aqueous solution was able to degrade 64 % of it in 1 week. In addition, CeO₂ incorporation decreased reactive oxygen species (ROS) production and suppressed malondialdehyde (MDA) formation in H₂O₂-treated osteoblasts. Taken together, CeO₂-CS biomedical coatings with antioxidant property would be promising for bone regeneration under oxidative stress.

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The Effects of Copper on Brain Microvascular Endothelial Cells and Claudin Via Apoptosis and Oxidative Stress

Abstract

Many neurodegenerative diseases are related to copper although the effects on brain microvascular endothelial cells (BMECs) are poorly understood. In the present study, a primary BMEC culture model was established to evaluate the effects of copper on brain microvascular endothelial cells and whether claudin-1, claudin-3, claudin-5, and claudin-12 isoforms contribute to apoptosis and intrinsic antioxidant activity. Our results showed that copper ions had dual effects on BMECs by regulating intracellular reactive oxygen species (ROS) levels. Copper levels between 30 and 120 μM could enhance viability and promote proliferation. On the other hand, copper cytotoxicity was a result of apoptosis indicating a redox-independent manner of cell death. Expression levels of claudins were also regulated by copper in a concentration-dependent manner. We identified four claudin isoforms (1, 3, 5, and 12) and showed that their expression levels were regulated as a group by copper. Antioxidant activity of BMECs was also copper regulated, and superoxide dismutase and catalase were the main contributors to BMEC antioxidant functions. Together, our results indicated that copper had dual effects on BMEC growth and intrinsic antioxidant activities played a crucial role in BMEC survival and tight junction.

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Long-Term Supplementation with Chromium Malate Improves Short Chain Fatty Acid Content in Sprague-Dawley Rats

Abstract

Our previous study showed that chromium malate improved the composition of intestinal flora, glycometabolism, glycometabolism-related enzymes, and lipid metabolism in type 2 diabetes mellitus (T2DM) rats. The present study was designed to evaluate the effect of chromium malate with long-term supplementation on short chain fatty acid (SCFA) content in Sprague-Dawley rats. The samples were analyzed by gas chromatography with high linearity (R ² ≥ 0.9995), low quantification limit (0.011–0.070 mM), and satisfactory recoveries. The method was simple and environmentally friendly. The acetic content in cecum of 3-month control group was significantly higher than that of 1-year control group. When compared with 1-year control group, chromium malate (at a dose of 20.0 μg Cr/kg bw) could significantly increase acetic, propionic, i-butyric butyric, butyric, i-valeric, valeric, and n-caproic levels. The acetic, propionic, i-butyric, valeric, and n-caproic contents of 1-year chromium malate group (at a dose of 20.0 μg Cr/kg bw) had a significant improvement when compared with 1-year chromium picolinate group. Acetic, propionic, and butyric contained approximately 91.65 % of the total SCFAs in 1-year group. The results indicated that the improvement of chromium malate on short chain fatty acid content change was better than that of chromium picolinate.

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An Incredible Mentor: a Tribute to Dick Bakemeier

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Development of Plain Language Supplemental Materials for the Biobank Informed Consent Process

Abstract

The US Department of Health and Human Services addresses clear communication in the informed consent process as part of the Notice of Proposed Rulemaking for revisions to the Common Rule. However, prior research has shown that participants may not fully comprehend research studies despite completion of an informed consent process. Our main goal was to provide plain language information about donation processes to a cancer biobank to supplement an informed consent form. We developed and conducted cognitive testing with supplemental brochures that clearly communicated information about three different models for consent (notice, broad and study-specific) to future use of biospecimens. During the brochure development process, we conducted qualitative, semi-structured, individual, in-person cognitive interviews among 14 women to examine participants' perceptions of the brochures. Each participant provided feedback regarding the understandability, graphics and layout, and cultural appropriateness of the brochures. Our findings demonstrate that these methods may be used to tailor consent form brochures, such as the ones developed here, to other populations. This study therefore adds to our understanding of how best to present content to help women from two different racial groups make informed decisions about participation in a cancer biobank.

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ECG low QRS voltage and wide QRS complex predictive of centenarian 360-day mortality

Abstract

We examined the electrocardiographic (ECG) findings of centenarians and associated them with >360-day survival. Physical and functional assessment, resting electrocardiogram and laboratory tests were performed on 86 study participants 101.9 ± 1.2 years old (mean ± SD) (70 women, 16 men) and followed for at least 360 days. Centenarian ECGs were assessed for left ventricular hypertrophy (LVH) according to the Romhilt–Estes score, Sokolow–Lyon criteria and Cornell voltage criteria which were positive for 12.8, 6.98, and 10.5 % of participants, respectively. Fifty-two study participants (60 %) survived ≥360 days. Multivariate logistic regression analysis revealed a negative relationship between 360-day survival and the following: R II <0.45 mV adjusted for CRP (odds ratio (OR) = 0.108, 95 % confidence interval (CI) = 0.034–0.341, P < .001), R aVF < 0.35 mV adjusted for CRP (OR = 0.151, 95 % CI = 0.039–0.584, P < .006), Sokolow–Lyon voltage <1.45 mV adjusted for CRP (OR = 0.178, 95 % CI = 0.064–0.492, P = .001), QRS ≥90 ms adjusted for CRP (OR = 0.375, 95 % CI = 0.144–0.975, P = .044), and Romhilt–Estes score ≥5 points adjusted for sex and Barthel Index (OR = 0.459, 95 % CI = 0.212–0.993, P = .048) in single variable ECG models. QRS voltage correlated positively with systolic and pulse pressure, serum vitamin B12 level, sodium, calcium, phosphorous, TIMP-1, and eGFR. QRS voltage correlated negatively with BMI, WHR, serum leptin, IL-6, TNF-α, and PAI-1 levels. QRS complex duration correlated positively with CRP; QTc correlated positively with TNF-α. Results suggest that Romhilt–Estes LVH criteria scores ≥5 points, low ECG QRS voltages (Sokolow–Lyon voltage <1.45 mV), and QRS complexes ≥90 ms are predictive of centenarian 360-day mortality.

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TEN YEARS OF HPV VACCINES: STATE OF ART AND CONTROVERSIES

Publication date: Available online 2 April 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Roberto Angioli, Salvatore Lopez, Alessia Aloisi, Corrado Terranova, Carlo De Cicco, Giuseppe Scaletta, Stella Capriglione, Andrea Miranda, Daniela Luvero, Roberto Ricciardi, Roberto Montera, Francesco Plotti
The human papillomavirus (HPV) represents one of the most common sexually transmitted infections and it has been related to cervical cancer. The HPV vaccines prevent infection with certain species of HPV associated with the development of cervical cancer or genital warts. We carried out a PubMed search up to 2015 evaluating all randomized studies published in literature. This review discusses the current status of HPVs vaccines on the global market, efficacy, safety profiles, controversies and future vaccine developments. Three HPVs vaccines are currently on the global market: bivalent, quadrivalent and ninevalent. Bivalent and quadrivalent vaccines can protect against almost 70% of cervical HPV-related cancerous and precancerous conditions and the ninevalent vaccine, instead, provides a protection against almost 90%. The use of vaccinations raised several controversies in the last years and, currently, is not possible to establish which type of vaccine is most effective, however all of them are safe.



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Transarterial Radioembolization with Yttrium-90 for the Treatment of Hepatocellular Carcinoma

Abstract

Background

Hepatocellular carcinoma (HCC) is a common cause of worldwide mortality. Transarterial radioembolization (TARE) with yttrium-90 (Y90), a transcatheter intra-arterial procedure performed by interventional radiology, has become widely utilized in managing HCC.

Methods

The following is a focused review of TARE covering its commercially available products, clinical considerations of treatment, salient clinical trial data establishing its utility, and the current and future roles of TARE in the management of HCC.

Results

TARE is indicated for patients with unresectable, intermediate stage HCC. The two available products are glass and resin microspheres. All patients undergoing TARE must be assessed with a history, physical examination, clinical laboratory tests, imaging, and arteriography with macroaggregated albumin. TARE is safe and effective in the treatment of unresectable HCC, as it has a safer toxicity profile than chemoembolization, longer time-to-progression, greater ability to downsize and/or bridge patients to liver transplant, and utility in tumor complicated by portal vein thrombosis. TARE can also serve as an alternative to ablation and chemotherapy.

Conclusion

TARE assumes an integral role in the management of unresectable HCC and has been validated by numerous studies.

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