Cancers, Vol. 10, Pages 165: CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Cancers, Vol. 10, Pages 165: CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Cancers doi: 10.3390/cancers10060165

Authors: Hoda Kardooni Estela Gonzalez-Gualda Emmanouil Stylianakis Sina Saffaran Jonathan Waxman Robert M. Kypta

The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-β/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-β. TGF-β signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-β found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-β signaling.

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Evaluation of external reference levels for central venous pressure measurements of severely obese patients in the supine position

Abstract

Purpose

A proper reference level is important for measuring intracardiac pressures, especially for parameters with small normal values such as central venous pressure (CVP). Although several external zero reference levels (eZRLs) have been proposed for non-obese patients, none has been reported for severely obese patients. The aim of this study was to investigate an appropriate eZRL for CVP measurements of severely obese patients.

Methods

Chest computed tomography images of 65 patients with body mass index (BMI) ≥ 35 kg/m² were retrospectively reviewed. The anteroposterior thoracic diameter and height of the mid-right atrium (RA) were measured. Four reported eZRLs for CVP measurements (midthoracic level, two-thirds and four-fifths of the thoracic diameter above table level, and 5 cm below the anterior thorax) were examined for error when predicting the midpoint of the RA.

Results

The median BMI was 36.9 kg/m² [interquartile range (IQR), 36.0–39.2]. There was a significant difference in the calculated errors for the midpoint of the RA among the four eZRLs (Kruskal–Wallis test, P < 0.001). Two-thirds of the thoracic diameter above table level was the most accurate reference level for CVP measurement (Steel–Dwass post hoc analysis, P < 0.001). The Bland–Altman plot showed acceptable agreement for clinical use (mean difference, − 7 mm; 95% limit of agreement, − 23 to 9 mm).

Conclusion

The most accurate eZRL for CVP measurements of severely obese patients in the supine position was two-thirds of the thoracic diameter above table level. This result is consistent with that of a previous report of non-obese patients.

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Cancers, Vol. 10, Pages 164: Development of an Experimental Model for Analyzing Drug Resistance in Colorectal Cancer

Cancers, Vol. 10, Pages 164: Development of an Experimental Model for Analyzing Drug Resistance in Colorectal Cancer

Cancers doi: 10.3390/cancers10060164

Authors: Mohamed Elbadawy Tatsuya Usui Hideyuki Yamawaki Kazuaki Sasaki

Colorectal cancer (CRC) is one of the most common cancers, for which combination treatment of chemotherapy is employed. However, most patients develop drug resistance during the course of treatment. To clarify the mechanisms of drug resistance, various research models have been developed. Recently, we established a human CRC patients-derived three-dimensional (3D) culture system using an air-liquid interface organoid method. It contained numerous cancer stem cells and showed resistance to 5-fluorouracil and Irinotecan. In this review, we introduce conventional and our established models for studying drug resistance in CRC.

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Editorial Board

Publication date: June 2018
Source:Cancer Treatment Reviews, Volume 67





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Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up†

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Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up†

Soft tissue sarcomas (STSs) gather over 80 histological entities, with even more molecular subsets, characterised by a low to very low incidence in all populations. The majority of sarcomas arise from the soft tissue (close to 75%), with ∼15% gastrointestinal stromal tumours (GISTs) and 10% bone sarcomas. These ESMO–EURACAN (European Society for Medical Oncology–European Reference Network for rare adult solid cancers) Clinical Practice Guidelines cover STSs, while GISTs are covered by dedicated ESMO–EURACAN Clinical Practice Guidelines [1]. Kaposi's sarcoma is not considered in the present document. Extraskeletal Ewing and Ewing-like sarcoma is covered by ESMO Clinical Practice Guidelines on bone sarcomas [2]. In general, the same principles for these tumours in children apply to adults. This is also the case for embryonal and alveolar rhabdomyosarcomas, which are exceedingly rare in adults. On the other hand, pleomorphic rhabdomyosarcoma is viewed as a high-grade, adult-type STS. Extraskeletal osteosarcoma is also a high-grade STS, whose clinical resemblance with osteosarcoma of bone is doubtful (prospective collection of data is encouraged to generate evidence on the therapeutic implications of such a diagnosis). Adult STS pathological subtypes occurring in adolescents should be managed the same way as in adult patients, though the same histotype might display clinical peculiarities when occurring at different ages.

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Anterior disc derangement with reduction of the temporomandibular joint: a case report

Temporomandibular dysfunction involving anterior disc derangement with or without reduction, secondary to posterior ligament insufficiency is typically managed conservatively with success in a majority of pati...

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Breast and cervical cancer incidence and mortality trends in Russia 1980–2013

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Anton Barchuk, Alexander Bespalov, Heini Huhtala, Tuvshinjargal Chimed, Irina Laricheva, Alexey Belyaev, Freddie Bray, Ahti Anttila, Anssi Auvinen
BackgroundBreast and cervical cancer are among the leading causes of preventable cancer deaths in women in Russia. The aim of this study is to analyze changes in breast and cervical cancer incidence and mortality trends using data from the Russian State Cancer Registry.MethodsThe age-standardized rates of cervical cancer incidence (1993–2013) and mortality (1980–2013) were analyzed using piecewise linear regression. Age-period-cohort models were used to estimate the temporal effects and provide future predictions.ResultsBreast and cervical cancer incidence rates uniformly increased over two decades from 33.0 to 47.0 per 100,000 and from 10.6 to 14.2 per 100,000, respectively. Breast cancer mortality rates however declined from 17.6 to 15.7 in 2013, while cervical cancer mortality increased steadily from 5.6 to 6.7. Breakpoints in the risk occurred in cohorts born 1937–1953, indicating a recent generational decrease in breast cancer mortality, but a concomitant increase in cervical cancer. Cervical cancer has already surpassed breast cancer in terms of years of life lost (YLL) (23.4 per death vs 18.5 in 2009–2013), while future projections suggest that the annual YLL could reach 1.2 million for cervical cancer and (decline to) 1.8 million for breast cancer by the year 2030.ConclusionThe temporal patterns of breast cancer incidence and mortality in Russia are in line with other countries in Europe, although cervical cancer rates and the risk of occurrence in recent generations is rapidly increasing; these trends underscore the need to place immediate priority in national cervical vaccination and screening programs.



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Problems and solutions in IGRT for cervical cancer

Publication date: Available online 26 May 2018
Source:Reports of Practical Oncology & Radiotherapy
Author(s): Iván Ríos, Ilse Vásquez, Elsa Cuervo, Óscar Garzón, Johnny Burbano
The contribution of Image-guided Radiotherapy (IGRT) to modern radiotherapy is undeniable, being the way to bring into daily practice the dosimetric benefits of Intensity-Modulated Radiotherapy (IMRT). Organ and target motion is constant and unpredictable at the pelvis, thus posing a challenge to the safe execution of IMRT. There are potential benefits of IMRT in the radical treatment of cervical cancer patients, both in terms of dose escalation and decrease of toxicity. But it is essential to find IGRT solutions to control the aspects that can lead to geographic miss targeting or organs at risk (OAR) overdose. This review seeks to describe the problems and possible solutions in the clinical implementation of IMRT/IGRT protocols to treat intact cervical cancer patients.



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Definitive Local Therapy is Associated with Improved Overall Survival in Metastatic Cervical Cancer

Publication date: Available online 26 May 2018
Source:Practical Radiation Oncology
Author(s): Sriram Venigalla, David M. Guttmann, Zachary D. Horne, Ruben Carmona, Jacob E. Shabason, Sushil Beriwal
PurposeDefinitive local therapy is often used in metastatic cervical cancer to reduce morbidity associated with local tumor progression. However, the potential benefit of this therapeutic approach has not been rigorously investigated. We hypothesized that definitive local therapy would be associated with improved overall survival (OS) in metastatic cervical cancer.Methods and MaterialsPatients ≥18 years with newly diagnosed metastatic cervical cancer treated with chemotherapy were identified from the National Cancer Database. Patients were dichotomized into the following cohorts¹: definitive local therapy, defined as either concurrent chemoradiotherapy or definitive surgery, or² conservative therapy, defined as systemic therapy with or without palliative radiotherapy. The association between definitive local therapy and OS was assessed using propensity score-weighted Cox proportional hazards models. Potential unmeasured confounding was assessed through sensitivity analyses. Factors associated with receipt of definitive local therapy were identified with multivariable logistic regression.ResultsOf 2,838 total patients, 1,194 (42%) and 1,644 (58%) were treated with definitive local therapy and conservative therapy, respectively. Receipt of definitive local therapy was statistically significantly associated with less comorbidity, lower clinical T stage, and node negative disease. Compared to conservative therapy, definitive local therapy was associated with improved OS (HR=0.57, 95% CI: 0.52-0.62, p ≤ 0.001). Median OS was 19.2 months in the definitive local therapy cohort and 10.1 months in the conservative therapy cohort. These findings were robust to potential unmeasured confounding in sensitivity analyses and on landmark analyses of patients surviving at least 12 months (HR=0.71, 95% CI: 0.62 – 0.82, p ≤ 0.001).ConclusionsDefinitive local therapy is associated with improved OS in patients with metastatic cervical cancer. These findings suggest a novel setting for the use of definitive local therapy in the metastatic setting.



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Androgen blockade based clinical trials landscape in triple negative breast cancer

Publication date: Available online 25 May 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Yaqin Shi, Fang Yang, Doudou Huang, Xiaoxiang Guan
Androgen receptor (AR) targeted treatment has shown promising preliminary results in triple negative breast cancer (TNBC). Identification of AR-associated signaling pathways is of great significance for in-depth understanding of their roles in pathogenesis of TNBC. To meet this objective, preclinical and clinical studies were conducted to clarify the biological interactions of AR signaling and combination strategies based on AR-targeted therapy. Biologically, AR signaling in TNBC which not only interacts with a network of key pathways, involving PI3K/AKT/mTOR, cell cycle, and DNA damage repair pathways, but mediates pivotal processes of tumor initiation and immunogenic modulation, may present an opportunity to overcome the insensitivity of single AR-targeted therapy. Research in investigating androgen-blockade based combination therapy in this aggressive tumor has demonstrated promising benefit in preclinical studies, and comparable clinical trials of combined strategies with CDK4/6 inhibitors, PI3K inhibition, chemotherapy, and immunotherapy, are ongoing. Accordingly, clinical interpretation of AR-related biological interactions, aiming at combined blockade of the signaling pathways may pave a new way for endocrine-based therapy in the treatment of TNBC.



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Mitochondria in Cancer metabolism, an organelle whose time has come?

Publication date: Available online 26 May 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Rebecca G. Anderson, Lais P. Ghiraldeli, Timothy S. Pardee
Mitochondria have long been controversial organelles in cancer. Early discoveries in cancer metabolism placed much emphasis on cytosolic contributions. Initial debate focused on if mitochondria had a role in cancer formation and progression at all. More recently the contributions of mitochondria to cancer development and progression have become firmly established. This has led to the identification of novel targets and inhibitors being studied as new therapeutic approaches. This review will summarize the role of mitochondria in cancer and highlight several agents under development.



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Isolated Knee Arthritis as Early and Only Symptom of Whipple’s Disease

We report a case of isolated Whipple's disease involving the knee of a 64-year-old female patient who presented recurrent monoarthritis whose origin was not clear. Initially, the cause of the gradually invalidating symptoms was related to a meniscal lesion and a diffuse minor grade chondropathy, but pain and functional impairment suggested that more exams were needed. Biopsies were performed during arthroscopy. The histology showed highly inflammatory infiltrates with PAS staining negative for Tropheryma while PCR revealed the infection with Tropheryma whipplei. This, following the recommendation of a rheumatologist and infectious disease specialist, led to biopsies of the gastrointestinal tract and analysis of the cerebrospinal fluid that showed no other organ involvement. This confirms the scientific literature that an isolated monoarthritis without involvement of the gastrointestinal tract caused by this bacterium is rare but can occur as an early manifestation of potentially fatal systemic disease. Moreover, a review of the scientific literature showed the uncertainty about epidemiology of this rare disease, suggesting that more and specific data are required.

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