Antitumor effect of anti-PD-1 antibody in NOG-MHC dKO mice

Purpose:Humanized mouse models using NOD/Shi-scid-IL2r gammanull (NOG) and NOD/LtSz-scid IL2r gamma null (NSG) mouse are associated with several limitations, such as long incubation time for stem cell engraftment and the development of xeno-graft versus host disease (xeno-GVHD) in mice injected with peripheral blood mononuclear cells (PBMCs). To solve problems, we used humanized major histocompatibility (MHC) class I and class II-deficient NOG mice (referred to as NOG-dKO) to evaluate the anti-tumor effect of anti-programmed death-1 (PD-1) antibody. Experimental Design: Humanized NOG-dKO mice, in which human PBMCs and human lymphoma cell line SCC-3 or glioblastoma cell line U87 were transplanted, were used as an immunotherapy model to investigate the effect of anti-PD-1 antibody. A biosimilar anti-PD-1 monoclonal antibody generated in our lab was administered to humanized NOG-dKO mice transplanted with tumors. Results:Within 4 weeks after transplantation, human CD45+ cells in antibody-treated mice constituted approximately 70% of spleen cells. The injection of anti-PD-1 antibody reduced by more 50% the size of SCC-3 and U87 tumors. In addition, induction of cytotoxic T lymphocytes (CTL) against SCC-3 cells and upregulation of natural killer (NK) cell activity was observed in the antibody-treated group. Tumor-infiltrating lymphocyte (TIL) profiling showed that more exhausted marker (PD1+TIM3+LAG3+) positive T cells maintained in anti-PD-1 antibody-treated tumor. A greater number of CD8+ and granzyme-producing T cells infiltrated the tumor in mice treated with the anti-PD-1 antibody. Conclusions:These results suggest that NOG-dKO mice might serve as a good humanized immunotherapy model to evaluate the efficacy of anti-PD-1 antibody prior to the clinical treatment.

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GRM1 Expression and PCa progression in Pre-Clinical Models

Purpose:We recently demonstrated that glutamate receptor GRM1 was expressed at high levels in castration-resistant prostate cancer (CR-PCa) tissues and cells. Herein, we determined the relationship between GRM1 and AR, PSA, and tumor growth, remission, and recurrence in preclinical PCa models. The effect of alterations in GRM1 expression was also investigated on PCa cell growth, migration and invasion. Experimental Design:We used quantitative gene expression and immunohistochemistry to define the temporal association between GRM1 expression and AR, PSA, and tumor growth during CR progression in CWR22 (n = 59) and LuCaP 35 (n = 12) PCa xenografts. The effect of alterations in GRM1 expression levels on growth, migration, and invasion was investigated in GRM1-overexpressed or -silenced PCa cell lines. The effect of DHT on GRM1 expression was determined in the presence or absence of the antiandrogen bicalutamide. Results:We found that GRM1 transcript and tissue expression directly correlated with growth and AR and PSA expression in hormone-sensitive (HS), castrated, and CR tumor xenografts. GRM1 overexpression or silencing directly correlated with PCa cell proliferation, migration, and invasion. DHT increased GRM1 expression via an AR-dependent manner in HS- and CR-PCa cell lines. Conclusions:This is a first report of GRM1 as an androgen and AR-target gene. GRM1 expression directly correlated with tumor growth, regression, and recurrence and may contribute to CR-progression of PCa in preclinical models. Further studies are needed to define the utility of GRM1 as a druggable target or biomarker for PCa.

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Bystander and Abscopal Effects of Radiotherapy

Siva and colleagues have demonstrated that localized thoracic radiation resulted in DNA damage at out-of-field sites. Though these interesting findings require validation, we discuss the important clinical implications of this data, especially in the era of immune therapies.

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CADBOSS: A computer-aided diagnosis system for whole-body bone scintigraphy scans

Ali Aslantas, Emre Dandil, Semahat Saǧlam, Murat Çakiroǧlu

Journal of Cancer Research and Therapeutics 2016 12(2):787-792

Aims: The aim of this study is to develop a computer-aided diagnosis system for bone scintigraphy scans. (CADBOSS). CADBOSS can detect metastases with a high success rates. The primary purpose of CADBOSS is as supplementary software to facilitate physician's decision making. Materials and Methods: CADBOSS consists of various elements, such as hotspot segmentation, feature extraction/selection and classification. A level set active contour segmentation algorithm was used for the detection of hotspots. Moreover, a novel image gridding method was proposed for feature extraction of metastatic regions. An artificial neural network classifier was used to determine whether metastases were present. Performance evaluation of CADBOSS was performed with the help of an image database which included 130 images. (30 non-metastases and 100 metastases) collected from 60 volunteers. All images were obtained within approximately 3 hours after injecting a small amount of radioactive material 99mTc-MDP into the patients and then carrying out scanning with a gamma camera. The 10-fold cross-validation technique was used for all tests. Results: CADBOSS could correctly identify in 120 out of 130 images. Thus, the accuracy, sensitivity, and specificity of CADBOSS were 92.30%, 94%, and 86.67%, respectively. Moreover, CADBOSS increased physician's success in detecting metastases from 95.38% to 96.9%. Conclusions: Detailed experiments showed that CADBOSS outperforms state-of-the-art computer-aided diagnosis. (CAD) systems and reasonably improves physician' diagnostic success.

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Dosimetric comparison of different treatment planning techniques with International Commission on Radiation Units and Measurements Report-83 recommendations in adjuvant pelvic radiotherapy of gynecological malignancies

Evrim Duman, Aysun Inal, Aycan Sengul, Timur Koca, Yigit Cecen, Melek Nur Yavuz

Journal of Cancer Research and Therapeutics 2016 12(2):975-980

Aim: The study evaluates the different treatment planning techniques according to three recommendation levels of the International Commission on Radiation Units and Measurements Report-83 in gynecologic cancer patients treated with adjuvant pelvic radiotherapy (APR). Materials and Methods: Computerized tomography images of ten endometrial and cervical cancer patients who were treated with APR were assessed. For each patient, five different treatment plans were created. One homogeneity index and four different conformity indexes (CIs) were calculated for three-dimensional conformal radiotherapy (3D-CRT), field-in-field (FIF), seven-field intensity modulated radiotherapy (7-IMRT) with two different degrees beginning (7A-IMRT, 7B-IMRT) and 9-IMRT treatment plans. Dose volume histogram parameters and normal tissue complication probability (NTCP) were compared for organs at risk (OAR). Results: The CI values of the IMRT were closer to 1 with respect to other plans (P < 0.05). The rectum and the bladder volumes which received more than 40 Gy were decreased with IMRT compared to 3D-CRT (P < 0.05). Doses received by the 195 cc volume of the small intestine and NTCP values were significantly decreased with IMRT (P < 0.05). Conclusion: IMRT provided more protection than FIF plans at high dose volumes of the OAR; however, it did not show any superiority at low-dose volumes. The NTCP results supported IMRT for only small intestine protection. Because IMRT is increasingly used clinically, the comparison of NTCP will become more common in the near future. Therefore, new prospective studies with sufficient number of patients and appropriate NTCP models are needed for this treatment modality.

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Oxidative stress marker in oral cancer: A review

Payal Katakwar, Rashmi Metgud, Smitha Naik, Rashu Mittal

Journal of Cancer Research and Therapeutics 2016 12(2):438-446

Oxygen derived species such as hydrogen peroxide, superoxide anion radical, hydroxyl radical (OH-), and singlet oxygen are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer. Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS) during their metabolism. Oxidative damage to cellular DNA can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. ROS influences central cellular processes such as proliferation, apoptosis, and senescence which are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention.

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Irinotecan compared with etoposide in combination with platinum in previously untreated extensive stage small cell lung cancer: An updated systemic review

Qinyong Hu, Qi Wang, Hengbo Zhu, Yi Yao, Qibin Song

Journal of Cancer Research and Therapeutics 2016 12(2):881-887

Objective: To compare the therapeutic effect of irinotecan/platinum (IP) and etoposide/platinum (EP) in treatment-naïve extensive small cell lung cancer patients. Methods: Systematic computerized searches of PubMed database and Chinese National Knowledge Infrastructure were performed. Summary odds ratio (OR) or hazard ratio (HR), and 95% confidence intervals (95% CI) were used to compare IP with EP in previously untreated small cell lung cancer patients. Results: A total of 10 randomized trials were included in the analyses. The result showed the patients treated with irinotecan combinations experienced longer overall survival than epotoside, the pooled HR was 0.85 (95% CI = 0.78-0.92). The pooled OR revealed that IP stated better objective overall response than EP regimens (OR = 1.10, 95% CI = 0.92-1.32). Treatment-related deaths were similar between the two groups. Conclusion: IP regimens could be used as first-line treatment for extensive stage small cell lung cancer patients.

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Clinical significance of inflammatory mediators in the pathogenesis of oral cancer

Jayendrakumar B Patel, Franky D Shah, Geeta M Joshi, Prabhudas S Patel

Journal of Cancer Research and Therapeutics 2016 12(2):447-457

Oral cancer has become a grave problem in many parts of the globe with two.thirds of the cases occurring in developing countries. Chronic inflammation plays a prominent role in the development of oral cancer. The rationale for molecular targeted prevention of oral cancer is promising. Therefore, there are continued improvements to our understanding of the molecular connections between inflammation and oral cancer. The inflammatory mediators including nuclear factor kappa B, vascular endothelial growth factor, inflammatory cytokines, prostaglandin pathways, p53, reactive oxygen and nitrogen species, and microRNAs are major key players in the pathogenesis of oral cancer. Currently, visual cytology.based techniques and biopsy are used to detect dysplasia and early stage of oral squamous cell carcinoma. These approaches are limited in their ability to judge the severities of oral lesions and are useful only after the appearance of visual changes. Thus, traditional cytological and biopsy assays combined with testing of inflammatory biomarkers would be beneficial for the efficient early detection of oral dysplastic lesions and early stages of oral squamous cell carcinoma.

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Evaluation of anaplastic lymphoma kinase expression in nonsmall cell lung cancer;a tissue microarray analysis

Raheleh Roudi, Gholamreza Haji, Zahra Madjd, Ahmad Shariftabrizi, Mitra Mehrazma

Journal of Cancer Research and Therapeutics 2016 12(2):1065-1069

Introduction: The oncogenic form of anaplastic lymphoma kinase (ALK) gene is an attractive candidate marker for diagnostic and therapeutic purposes in several malignancies, including nonsmall cell lung cancer (NSCLC). This study aimed to examine the expression levels and clinical significance of ALK in a series of NSCLC tumors. Material and Methods: We retrospectively reviewed 140 samples of NSCLC, including 64 (46%) squamous cell carcinoma (SCC), 62 (44%) adenocarcinoma (ADC), and 14 (10%) large cell carcinoma (LCC) for expression of ALK using immunohistochemistry; and immunostaining patterns were correlated with clinicopathological parameters. Results: Expression of ALK was significantly different between SCC with ADC (P < 0.001) and LCC samples (P < 0.001). The highest level of ALK expression was found in ADC cases with poor differentiation and high nuclear grade (P = 0.005 and P = 0.005, respectively). Furthermore, high level of ALK expression was more often observed in ADC cases with poor prognosis features (P = 0.013). Conclusions: These findings suggested that ALK can be considered as a promising target in the targeted therapy in patients with lung ADC.

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Oral cancer: Etiology and risk factors: A review

Malay Kumar, Ronak Nanavati, Tapan G Modi, Chintan Dobariya

Journal of Cancer Research and Therapeutics 2016 12(2):458-463

Oral cancer is the sixth most common malignancy in the world. Oral cancer is of major concern in Southeast Asia primarily because of the prevalent oral habits of betel quid chewing, smoking, and alcohol consumption. Despite recent advances in cancer diagnoses and therapies, the 5.year survival rate of oral cancer patients has remained at a dismal 50% in the last few decades. This paper is an overview of the various etiological agents and risk factors implicated in the development of oral cancer.

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Characterization and localization of c-kit and epidermal growth factor receptor in different patterns of adenoid cystic carcinoma

Anshi Jain, Devi Charan Shetty, Ajit Singh Rathore, Kiran Kumar

Journal of Cancer Research and Therapeutics 2016 12(2):834-839

Introduction: Adenoid cystic carcinoma (ACC) is malignant neoplasm of the salivary glands. It accounts for most cases of minor salivary gland malignancies and a substantial proportion of parotid and submandibular gland malignancies. ACC is associated with a high mortality rate, and it often recurs after prolonged periods of time, and this occurs even when radical excision has been performed. Aims: The present study was aimed to determine the localization of dual cell population and to analyze the potency of using a system of dual markers (c-kit and epidermal growth factor receptor [EGFR]) in enhancing the characterization of ACC. Subject and Method: Three micrometer thin sections of adenoid cystic carcinoma were obtained. One set of slides was stained by hematoxylin and eosin for reconfirmation of histological diagnosis while the other two sets were stained for c-kit and EGFR using immunohistochemical method. Statistical Analysis Used and Results: Show c-kit expression to be limited to the inner ductal epithelial cells and the EGFR expression mainly to the outer myoepithelial cells in the majority of tubular and cribriform patterns. In solid ACC, c-kit was uniformly positive while EGFR was consistently negative. Conclusions: C-kit and EGFR biomarkers can be used to enhance the characterization of ACC and to determine the localization of dual cell population which could suggest the dual origin of ACC and provides evidence for the new therapeutic strategy in ACC.

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Anesthetics impact on cancer recurrence: What do we know?

Sachidanand Jee Bharati, Tumul Chowdhury, Sergio D Bergese, Subhamay Ghosh

Journal of Cancer Research and Therapeutics 2016 12(2):464-468

Surgery is an important component of treatment in cancer patients. However, surgical stress, anesthesia, and perioperative analgesia interfere with the host immune defense mechanisms and may contribute to metastatic dissemination of malignant tumors and cancer progression. Little is known about the effects of anesthesia on tumor recurrence. In vivo studies and clinical data show some evidence that regional anesthesia is beneficial for cancer patients as it may decrease the risk of metastasis. This short review summarizes the clinical data on the possible association between anesthesia, perioperative analgesia, and the risk of cancer recurrence. Most of the clinical reports are based on retrospective studies, and properly designed prospective trials including a sufficient number of patients is required to reveal the interaction of various anesthetic drugs and methods and cancer progression.

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Comparison of clinical outcomes after thoracoscopic sublobectomy versus lobectomy for Stage I nonsmall cell lung cancer: A meta-analysis

Quanxing Liu, Hongmei Wang, Dong Zhou, Xufeng Deng, Jiaxin Min, Jigang Dai

Journal of Cancer Research and Therapeutics 2016 12(2):926-931

Background: Although lobectomy has long been considered the standard procedure for Stage I nonsmall cell lung cancer (NSCLC), the selection of sublobectomy for Stage I NSCLC remains controversial. Amidst growing enthusiasm for minimally invasive surgery, the comparison of clinical outcomes after thoracoscopic sublobectomy versus thoracoscopic lobectomy may be of immense value. Objective: The present study aimed to compare the overall survival (OS) and disease-free survival (DFS) outcomes of patients who underwent thoracoscopic sublobectomy with those who underwent thoracoscopic lobectomy for Stage I NSCLC. Methods: An electronic search was conducted using five online databases from their dates of inception to February 2014. Hazard ratio (HR) was used in this meta-analysis, calculated from the published survival data. Results: Eight studies met the selection criteria, including a total of 1613 patients (463 patients underwent thoracoscopic sublobectomy, and 1150 patients underwent thoracoscopic lobectomy). From the available data, compared with thoracoscopic sublobectomy, there was a significant benefit of thoracoscopic lobectomy on OS (HR: 1.45; 95% confidence interval [CI]: 1.11–1.90; P = 0.007). However, in subgroup analysis of thoracoscopic segmentectomy and thoracoscopic lobectomy, there was no significant difference in OS (HR: 1.03; 95% CI: 0.76–1.39; P = 0.85) or DFS (HR: 1.19; 95% CI: 0.67–2.10; P = 0.56) between the two groups. In addition, compared with thoracoscopic wedge resection, there was a significant benefit of thoracoscopic lobectomy on OS (HR: 4.19; 95% CI: 2.19–8.03, P < 0.0001). Conclusion: For Stage I patients, thoracoscopic segmentectomy leads to survival rates comparable to thoracoscopic lobectomy. However, the overall several of thoracoscopic lobectomy is superior to that of wedge resection.

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Proliferative verrucous leukoplakia: An update

Anita Munde, Ravindra Karle

Journal of Cancer Research and Therapeutics 2016 12(2):469-473

Proliferative verrucous leukoplakia (PVL) is a rare form of oral leukoplakia, which was first described in 1985 by Hansen et al. Since then, various published case series have presented PVL as a disease with aggressive biological behavior due to its high probability of recurrence and a high rate of malignant transformation, usually higher than 70%. PVL is a long-term progressive condition, which is observed more frequently in elderly women, over 60 years at the time of diagnosis. The buccal mucosa and tongue are the most frequently involved sites. It develops initially as a white plaque of hyperkeratosis that eventually becomes a multifocal disease with confluent, exophytic and proliferative features with a progressive deterioration of the lesions, making it more and more difficult to control. Tobacco use does not seem to have a significant influence on the appearance or progression of PVL and may occur both in smokers and nonsmokers. Prognosis is poor for this seemingly harmless-appearing white lesion of the oral mucosa. At present, the etiology of PVL remains unclear as well as its management and diagnosis, which is still retrospective, late and poorly defined, lacking consensus criteria. This short review discusses the clinical and histopathological features, diagnosis, traditional treatment and the current management of the disease.

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The effect of curcumin on low-passage glioblastoma cells in vitro

Oana Alexandru, Ada M Georgescu, Laurentiu Ene, Stefana O Purcaru, Florentina Serban, Alisa Popescu, Corina Brindusa, Ligia G Tataranu, Vasile Ciubotaru, Anica Dricu

Journal of Cancer Research and Therapeutics 2016 12(2):1025-1032

Background: Plant extract therapy has been the cornerstone of cancer treatment for many years. The natural component curcumin demonstrated antineoplastic effects on different type of tumor cells. In this study, we explored the effectiveness of curcumin against low-passage human primary glioblastoma (GB) cell cultures. Materials and Methods: Early passage GB cell cultures (GB3B, GB4B, and GB5B) were established from fresh samples tissue obtained from GB patients. Growth rate (GR) and doubling time (DT) was determined for each cell line. The cytotoxic effect of curcumin was quantified by hemocytometer cell counting, using trypan blue. To study the changes in cell shape, GB cells exposed to a concentration corresponding to inhibitory concentration 50 (IC50) of curcumin were studied by phase-contrast microscopy by capturing images during the treatment. Results: Our results showed that GB cells proliferate with a GR of 0.2872 and a DT of 2.41 days for GB3B, a GR of 0.2787 and a DT of 2.49 days for GB4B, and a GR of 0.2787 and a DT of 2.49 days for GB5B. Curcumin induced cell death in GB cells in a time- and dose-dependent manner. The IC50 for GB3B was 46.4 µM, for GB4B was 78,3 µM, and for GB5B was 47.7 µM. Phase contrast microscopy showed that cultures treated with curcumin in a concentration corresponding to IC50 contained rounded cells and cell fragments, 72 h after the treatment. Conclusions: The results of the present investigation proved that curcumin is a natural compound potentially useful in the fight against GB.

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Electronic game: A key effective technology to promote behavioral change in cancer patients

Reza Safdari, Marjan Ghazisaeidi, Azadeh Goodini, Mahboobeh Mirzaee, Jebraeil Farzi

Journal of Cancer Research and Therapeutics 2016 12(2):474-480

Cancer diagnosis is a very unpleasant and unbelievable experience. Appropriate management and treatment of these diseases require a high degree of patient engagement. Interactive health electronic games are engaging, fun, challenging, and experiential and have the potential to change the attitude and behavior, which can improve the player's health. The use of these digital tools, as one of the most attractive and entertaining modern technologies, canem power patients, provide suitable palliative care, promote health behavior change strategies, increase patient engagement, enhance healthy lifestyle habits, improve self.management, and finally improve the quality of life of the patients. Finally, the aim of this article was to describe electronic games and their effects on the promotion of behavior change in cancer patients. In addition, this article describes categories, characteristic features, and benefits of this digital media in the lifestyle modification of cancer patients.

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Multimodality management of primary diaphragmatic synovial sarcoma: First report

Preyas J Vaidya, Anil Heroor, Sitaram Prasad, Rajat Bhargava, Nanadan Arulvannan, Jay Mehta, Boman N Dhabhar, Prashant N Chhajed

Journal of Cancer Research and Therapeutics 2016 12(2):1098-1101

Synovial cell sarcoma is an extremely rare tumor of mesenchymal origin. It commonly affects the soft tissues of the extremities but could possibly origin from the head and neck, heart, lung, pleura, mediastinum, esophagus, abdominal wall and the mesentery, and retroperitoneum. Primary synovial sarcoma of pleura, mediastinum, and lung have been reported. Primary synovial sarcoma of the diaphragm has not been reported to the best of our knowledge. We report a case of primary synovial cell sarcoma of the diaphragm presenting as a recurrent pleural effusion and pain in the left hypochondrium managed with multimodality approach.

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Tele-cytology: An innovative approach for cervical cancer screening in resource-poor settings

Sandeep Singh, Sorabh Badaya

Journal of Cancer Research and Therapeutics 2016 12(2):481-485

Carcinoma cervix remains a leading cause of cancer mortality among women in countries lacking any screening program. The existing screening policy and approach via conventional cytology centered mainly in Tertiary Care Center, is totally unaffordable to Indian women, especially in the remote areas. This suggests the need of depolarizing the resources via generating the near real time modalities which could be used at the door step of the needy ones. For any screening modality to be effective it should be adequately sensitive, specific, reproducible, cheap, simple, affordable, and the most important is should be real time to ensure wide coverage and curtail loss to follow-up. Incorporating telecytology as a screening tool could make the dream come true. Telecytology is the interpretation of cytology material at a distance using digital images. Use of mobile telecytology unit housed in a van carrying satellite equipment and the automated image capturing systems is the central theme behind this idea. The imaging equipment would be carrying out the imaging of Papanicolaou smears prepared at the screening site and sending the images to the central laboratories situated at some tertiary care level. This concept could overcome the hindrance of trained cytology infrastructure in the resource poor settings and could provide an efficient and economical way of screening patients. There is possibility that the designed approach may not detect the entire women positive for the disease but if the desired objective was to diagnose as many cases as possible in resource poor setting, then this process offers an advantage over no screening at all.

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Flavopiridol's antiproliferative effects in glioblastoma multiforme

Gozde Cobanoglu, Irem Dogan Turacli, Ayla Cihan Ozkan, Abdullah Ekmekci

Journal of Cancer Research and Therapeutics 2016 12(2):811-817

Aim of Study: Glioblastoma multiforme (GBM) is largely refractory to surgical operation, radiotherapy, and chemotherapy in use today. Remaining lifetime accounting for the GBM-affected patients varies between 12 and 16 months generally. The most frequently altered genes in GBM are p53, epidermal growth factor receptor, PTEN, and cyclin-dependent kinase inhibitor 2A. Our aim is to investigate the antiproliferative and apoptotic effects of flavopiridol, a cyclin-dependent kinases and specific phosphokinase inhibitor, on glioblastoma cell lines having different genetic profiles: U87MG, U118MG, and T98G. Materials and Methods: Cell viability and IC50 values were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, protein expressions were determined by Western blot and caspase activities were analyzed by activity kit. Results: Western blot analysis showed down-regulation of the cyclin D1, c-Myc, and p53 protein activities, and up-regulation of p27KIP1 activity after flavopiridol treatment. Additionally, flavopiridol diminished p-Akt protein levels generally which induces inhibition of proliferation. Conclusion: The present study demonstrated that flavopiridol did not induce caspase-3/7 activation, BIM, and BAX pro-apoptotic proteins but it leads to the expression changes of various proteins that inhibit proliferation and eternity in glioblastoma cell lines which have different genetic alterations.

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A review on oral cancer biomarkers: Understanding the past and learning from the present

Arvind Babu Rajendra Santosh, Thaon Jones, John Harvey

Journal of Cancer Research and Therapeutics 2016 12(2):486-492

Biomarkers are broadly classified as genomic, proteomic, or metabolomic. Molecular biology and oncology research studies on oral cancer biomarkers focus on identifying key biological molecules or markers that could be linked to cancer development, risk assessment, screening, recurrence prediction, indicating prognosis, indicating invasion/metastasis and monitoring therapeutic responses of cancer. Cluster of differentiation factor 34 is a salivary biomarker that can identify recurrence potential of oral squamous cell carcinoma (OSCC). Integrin α3 and integrin β4 are genomic biomarkers that are helpful in estimating the risk of regional and hematogenous dissemination of malignant oral squamous cells. Other examples are vascular endothelial growth factor, B-cell lymphoma-2, claudin 4, yes-associated protein 1 and MET proto-oncogene, and receptor tyrosine kinase, which are genomic biomarkers that are used to predict radio-resistance in OSCC tissue. The present article reviews the clinical application, methodologies and steps in developing candidate biomarkers, protocols in reporting, evaluating candidate biomarkers, and challenges in biomarker research with a focus OSCC.

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Human herpesvirus multiplex ddPCR detection in brain tissue from low- and high-grade astrocytoma cases and controls

Abstract

Background

Glioblastoma (GBM) is a fatal CNS malignancy, representing 50 % of all gliomas with approximately 12–18 months survival time after initial diagnosis. Recently, the human herpesvirus cytomegalovirus (CMV) has been suggested to have an oncogenic role, yet this association remains controversial. In addition, human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have also been associated with low-grade gliomas, but few studies have examined HHV-6 and EBV in glioblastomas. Droplet digital PCR (ddPCR) is a highly precise diagnostic tool that enables the absolute quantification of target DNA. This study examines the association between multiple human herpesviruses and astrocytomas.

Methods

This study analyzed 112 brain tissue specimens, including 45 glioblastoma, 12 astrocytoma grade III, 2 astrocytoma grade II, 4 astrocytoma grade I, and 49 controls. All brain tissue samples were de-identified and pathologically confirmed. Each tissue block was sectioned for DNA extraction and CMV, EBV, HHV-6A and HHV-6B, and a cellular housekeeping gene were amplified by ddPCR.

Results

Neither CMV nor HHV-6A were detected in any of the astrocytoma samples. However, HHV-6B (p = 0.147) and EBV (p = 0.049) had a higher positivity frequency in the GBM compared to the controls.

Conclusion

The undetectable CMV DNA in the astrocytoma cohort does not support the observation of an increased prevalence of CMV DNA in GBM, as reported in other studies. EBV has a significantly higher positivity in the GBM cohort compared to the controls, while HHV-6B has a higher but not statistically significant positivity in the case cohort. Whether these viruses play an oncogenic role in GBM remains to be further investigated.

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Physical Activity as a Nonpharmacological Symptom Management Approach in Myeloproliferative Neoplasms: Recommendations for Future Research

Purpose: Essential thrombocythemia, polycythemia vera, and myelofibrosis are rare chronic hematological malignancies known as myeloproliferative neoplasms (MPNs) and are characterized by deregulated myeloid lineage cell production, splenomegaly, and heterogeneous symptom profiles. MPN patients suffer from a significant symptom burden (eg, fatigue, depressive symptoms, early satiety) and an impaired overall quality of life (QoL). Current treatments typically include pharmacological approaches, which may come with additional side effects and may be limited by treatment-associated toxicities (ie, cytopenias). Nonpharmacological approaches such as physical activity may be beneficial for reducing symptom burden and improving QoL. To date, no studies have examined physical activity as a nonpharmacological approach in MPN patients despite preliminary evidence supporting its benefit in other hematological cancers. The purpose of this article is to (1) review the literature related to physical activity and specific hematological cancer subtypes and to (2) make suggestions for future research involving physical activity in MPN patients as a symptom management strategy. Methods: A brief review of studies examining physical activity in leukemias, lymphomas, and myelomas (excluding stem-cell transplant patients) was conducted. Results: There is preliminary evidence to suggest that physical activity may be an effective approach to improve patient-reported outcomes (fatigue, depression, anxiety, sleep), physical fitness (cardiovascular fitness, balance, body composition), and overall QoL in other hematological cancers. Conclusions: Based on encouraging findings in other hematological cancers, future research should examine the feasibility and effectiveness of physical activity in MPN patients.

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Gene Expression Analysis Reveals the Concurrent Activation of Proapoptotic and Antioxidant-Defensive Mechanisms in Flavokawain B-Treated Cervical Cancer HeLa Cells

Flavokawain B (FKB) is known to possess promising anticancer abilities. This is demonstrated in various cancer cell lines including HeLa cells. Cervical cancer is among the most widely diagnosed cancer among women today. Though FKB has been shown to be effective in treating cancer cells, the exact molecular mechanism is still unknown. This study is aimed at understanding the effects of FKB on HeLa cells using a microarray-based mRNA expression profiling and proteome profiling of stress-related proteins. The results of this study suggest that FKB induced cell death through p21-mediated cell cycle arrest and activation of p38. However, concurrent activation of antioxidant-related pathways and iron sequestration pathway followed by activation of ER-resident stress proteins clearly indicate that FKB failed to induce apoptosis in HeLa cells via oxidative stress. This effect implies that the protection of HeLa cells by FKB from H₂O₂–induced cell death is via neutralization of reactive oxygen species.

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Best practice guidelines in the psychosocial management of HPV-related head and neck cancer. Recommendations from the European Head and Neck Cancer Society's Make Sense Campaign

This article summarises best practices for supporting patients from initial HPV-related cancer diagnosis, with recommendations on the integration of counselling, psychological assessment, sexual impact discussion, patient education, and referrals into head and neck cancer treatment plans. It is hoped that raising awareness through the Make Sense Campaign will ultimately improve patient outcomes.

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A randomized trial on chlorhexidine dressings for the prevention of catheter-related bloodstream infections in neutropenic patients

Chlorhexidine dressings reduced the incidence of definite and probable catheter-related bloodstream infections in neutropenic patients. In contrast to previous studies, tolerance to chlorhexidine and control dressings was similar.

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"Saving the best treatment for last?"

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Chemotherapy remains an essential element of personalized care for persons with lung cancers

Chemotherapy works. Chemotherapy can enhance the effectiveness of all other modalities and improve the curability of patients with locoregional spread of their lung cancers. While tremendous advances in molecularly targeted and immunotherapies are changing the landscape of treatment options, chemotherapy remains an essential component of personalized care for persons with lung cancers.

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Genomic Studies of Multiple Myeloma Reveal an Association between X Chromosome Alterations and Genomic Profile Complexity

Abstract

The genomic profile of multiple myeloma (MM) has prognostic value by dividing patients into a good prognosis hyperdiploid group and a bad prognosis non-hyperdiploid group with a higher incidence of IgH translocations. This classification, however, is inadequate and many other parameters like mutations, epigenetic modifications and genomic heterogeneity may influence the prognosis. We performed a genomic study by array-based comparative genomic hybridization (aCGH) on a cohort of 162 patients to evaluate the frequency of genomic gains and losses. We identified a high frequency of X chromosome alterations leading to partial Xq duplication, often associated with Xi deletion in female patients. This partial X duplication could be a cytogenetic marker of aneuploidy as it is correlated with a high number of chromosomal breakages. Patient with high level of chromosomal breakage had reduced survival regardless the region implicated. A higher transcriptional level was shown for genes with potential implication in cancer and located in this altered region. Among these genes, IKBKG and IRAK1 are members of the NFKB pathway which plays an important role in MM and is a target for specific treatments. This article is protected by copyright. All rights reserved.

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A cure is possible: a study of 10-year survivors of brain metastases

Abstract

Little is known on the natural history, recurrence patterns, neurocognitive outcomes and prognostic factors associated with survival in long-term survivors (≥10 years) from brain metastasis (BM). In this study, the records of 1953 patients who underwent treatment for BM with a potential for ≥10 years of follow-up were reviewed. Cox regression analysis identified factors predictive for overall survival (OS). The median age at brain metastasis diagnosis was 60 years and the median OS was 6.4 months. The 1-year OS rate was 29.9, 12.1 % at 2 years, 3.0 % at 5 years, and 1.3 % at 10 years. On multivariable analysis, factors associated with worse OS included gender (males, HR 1.2), multiple brain metastases (HR 1.3), no surgery (HR 1.8), and no stereotactic radiosurgery (HR 1.8) (p < 0.0001 each). Fifty-six patients (2.9 %) survived ≥5 years; 23 patients (1.2 %) survived ≥10 years and the median survival for ≥10 year survivors was 18.5 years. Six of the 10-year survivors had an intracranial recurrence, five occurred within 11 years from the first treatment. Presence of a solitary lesion or single lesion at the time of brain metastasis diagnosis was associated with improved survival. Eight of the ≥10 year survivors (34.8 %) had no neurological symptoms at last follow-up; none of the 10-year survivors were documented to have a neurologic death. Our study demonstrates that patients with favorable prognostic features should undergo multimodality treatment. Albeit rare, patients who are alive 10 years after treatment for their brain metastases may be considered cured from their intracranial disease.

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A cure is possible: a study of 10-year survivors of brain metastases

Abstract

Little is known on the natural history, recurrence patterns, neurocognitive outcomes and prognostic factors associated with survival in long-term survivors (≥10 years) from brain metastasis (BM). In this study, the records of 1953 patients who underwent treatment for BM with a potential for ≥10 years of follow-up were reviewed. Cox regression analysis identified factors predictive for overall survival (OS). The median age at brain metastasis diagnosis was 60 years and the median OS was 6.4 months. The 1-year OS rate was 29.9, 12.1 % at 2 years, 3.0 % at 5 years, and 1.3 % at 10 years. On multivariable analysis, factors associated with worse OS included gender (males, HR 1.2), multiple brain metastases (HR 1.3), no surgery (HR 1.8), and no stereotactic radiosurgery (HR 1.8) (p < 0.0001 each). Fifty-six patients (2.9 %) survived ≥5 years; 23 patients (1.2 %) survived ≥10 years and the median survival for ≥10 year survivors was 18.5 years. Six of the 10-year survivors had an intracranial recurrence, five occurred within 11 years from the first treatment. Presence of a solitary lesion or single lesion at the time of brain metastasis diagnosis was associated with improved survival. Eight of the ≥10 year survivors (34.8 %) had no neurological symptoms at last follow-up; none of the 10-year survivors were documented to have a neurologic death. Our study demonstrates that patients with favorable prognostic features should undergo multimodality treatment. Albeit rare, patients who are alive 10 years after treatment for their brain metastases may be considered cured from their intracranial disease.

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New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies

Abstract

The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.

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Phase 1 Study of CEP-37250/KHK2804, a Tumor-specific Anti-glycoconjugate Monoclonal Antibody, in Patients with Advanced Solid Tumors

Abstract

Background

CEP-37250/KHK2804 is a recombinant, humanized, non-fucosylated, monoclonal antibody directed to sialic acid-containing glycoconjugates frequently found on certain tumor cell types.

Objective

The objective was to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, potential immunogenicity, and preliminary clinical efficacy of CEP-37250/KHK2804 monotherapy in patients with advanced cancer in a first-in-human, phase 1 study.

Materials and Methods

In phase 1a, patients (n = 31) with solid tumors received increasing doses of CEP-37250/KHK2804 (0.03–1.0 mg/kg) intravenously once weekly using a standard 3 + 3 dose-escalation design. In phase 1b, two dose-expansion cohorts of patients with colorectal (n = 15) and pancreatic (n = 16) cancer, respectively, received the maximum tolerated dose (MTD).

Results

The MTD of CEP-37250/KHK2804 was 0.3 mg/kg weekly. Dose-limiting toxicities were infusion-related reactions and increased serum transaminases. In the overall population (N = 62), the most frequent treatment-related adverse event (AE) was an infusion-related reaction (45.2 %). Positive post-baseline CEP-37250/KHK2804 neutralizing antibodies were reported in 14 patients (22.6 %), almost exclusively in patients who developed infusion-related reactions. The most frequent treatment-related AE grade ≥3 was increased AST or ALT in six patients (9.7 %). Three patients experienced treatment-related serious cardiac events (grade 4 ECG abnormality, grade 4 atrial fibrillation, and grade 3 acute myocardial infarction, respectively). Pharmacokinetic exposure to CEP-37250/KHK2804 increased proportionally to dose, with accumulation up to two fold with repeated administration. Mean elimination half-life was 34.1 to 70.3 hours over the dose range from 0.03 to 1.0 mg/kg. No patient had a complete or partial best response. Thirteen of 40 (32.5 %) evaluable patients had unconfirmed stable disease, four of which were confirmed (10.0 %).

Conclusions

The study was stopped early due to the lack of efficacy. Additionally, safety concerns (i.e., cardiac issues, hepatic toxicity, and infusion-related reactions) made the benefit-risk assessment unfavorable for continued development of CEP-37250/KHK2804, which was halted indefinitely. [Study registered at ClinicalTrials.gov #NCT01447732].

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Victor Despeignes, the forgotten pioneer of radiation oncology

Publication date: Available online 25 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Nicolas Foray
Radiotherapy is 120 years old and its birth can be set in the year 1896. That year, three novel concepts came together in the French city of Lyon: the discovery of X-rays; the hygienist notion of cancer etiology; and the invention of cinema. Lyon was the home town of the Lumière brothers who had developed cinematography but who had larger ideas in the world of imaging and therapy. They encouraged local scientists and physicians to investigate the biological effects of X-rays by providing, for this purpose, materials and notably X-rays tubes. At the same time, the bacterial theory of disease (hygienism or parasitism) was taking hold and its study was strongly encouraged by two successive mayors of Lyon. Victor Despeignes, a former student of University of Lyon, had been molded by Pasteur's ideas and, convinced by the parasitic theory of cancer, performed in July 1896 the first documented anti-cancer radiation treatment on his neighbor who probably suffered from a gastric lymphoma. He gave us the very first description of tumor regression following radiation. The historical and technological context is discussed.

Teaser

Radiotherapy is 120 years old. Victor Despeignes performed in July 1896 the first documented anti-cancer radiation treatment on his neighbor who probably suffered from a gastric lymphoma. He gave us the very first description of tumor regression following radiation.


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Quality of life and performance status from a sub-study conducted within a prospective phase III randomized trial of concurrent standard radiation vs. accelerated radiation plus cisplatin for locally advanced head and neck carcinoma: NRG Oncology RTOG 0129

Publication date: Available online 25 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Canhua Xiao, Qiang Zhang, Phuc Felix Nguyen-Tân, Marcie List, Randal S. Weber, K. Kian Ang, David Rosenthal, Edith J. Filion, Harold Kim, Craig Silverman, Adam Raben, Thomas Galloway, Andre Fortin, Elizabeth Gore, Eric Winquist, Christopher U. Jones, William Robinson, David Raben, Quynh-Thu Le, Deborah Bruner
Purpose/Objective(s)To analyze quality of life (QOL) and performance status (PS) for head and neck cancer (HNC) patients treated on NRG Oncology RTOG 0129 by treatment (secondary outcome) and p16 status, and to examine the association between QOL/PS and survival.Methods and MaterialsEligible patients were randomized into either accelerated-fractionation arm or standard-fractionation arm, and completed the Performance Status Scale for the HN (PSS-HN), the Head and Neck Radiotherapy Questionnaire (HNRQ), and the Spitzer Quality of Life Index (SQLI) at 8 time points from pre-treatment to 5-years post-treatment.ResultsResults from the analysis of area under the curve showed that QOL/PS was not significantly different between the two arms from baseline to one-year post-treatment (p ranged from 0.39 to 0.98).: Results from general linear mixed models further supported the non-significant treatment effects until 5 years post-treatment (p=0.95, 0.90, and 0.84 for PSS-HN Diet, Eating, and Speech, respectively).At pre-treatment and after one year post-treatment, p16-positive oropharyngeal cancer (OPC) patients had better QOL than p16-negative patients (p ranged from 0.0283 to <0.0001 for all questionnaires). However, QOL/PS decreased more significantly from pre-treatment to the last 2 weeks of treatment in the p16-positive group than the p16-negative group (p ranged from 0.0002 to <0.0001).Pre-treatment QOL/PS was a significant independent predictor of overall, progression-free, and locoregional failure but not distant metastasis (p ranged from 0.0063 to <0.0001).ConclusionsThe results indicated patients in both arms may have experienced similar QOL/PS. p16-positive patients had better QOL/PS at baseline and after one-year follow-up. Patients presenting with better baseline QOL/PS scores had better survival.

Teaser

This large international, multi-institutional phase III trial yielded three major findings related to quality of life (QOL)/performance status (PS). First, QOL/PS was similar in both accelerated and standard radiotherapy arms. Second, p16-positive oropharyngeal cancer patients experienced better QOL/PS than p16-negative patients. Finally, pre-treatment QOL/ PS was a significant independent prognostic factor for survival in locally advanced HNC patients.


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Prostate brachytherapy case volumes by academic and non-academic practices: Implications for future residency training

Publication date: Available online 25 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Peter F. Orio, Paul L. Nguyen, Ivan Buzurovic, Daniel W. Cail, Yu-Wei Chen
PurposeThe utilization of prostate brachytherapy continues to decline in the United States. We examined the national practice patterns of both academic and non-academic practices performing prostate brachytherapy by case volume per year to further characterize the decline and postulate the impact this trend may have on training the next generation of residents.Methods and MaterialsMen diagnosed with prostate cancer and treated with radiation therapy in 2004-2012 were identified. Annual brachytherapy case volume at each facility was determined and further categorized into ≤12 cases per year (i.e. on average ≤1 case per month), 13-52 cases per year, and ≥53 cases per year (i.e. on average ≥1 case per week) in academic practices versus non-academic practices.ResultsIn 2004-2012, academic practices performing on average ≤1 brachytherapy case per month increased from 56.4% to 73.7% and this percentage increased from 60.2% to 77.4% in non-academic practices (P-value both<.0001). Practices performing on average ≥ 1 case per week decreased among both academic practices (from 6.7% to 1.5%) and non-academic practices (from 4.5% to 2.7%).ConclusionsBoth academic and non-academic radiation oncology practices have demonstrated a significant reduction in the use of prostate brachytherapy from 2004-2012. As the case volume continues to decline it is unclear whether we are prepared to train the next generation of residents in this critical modality.

Teaser

With 73.7% of academic practices performing ≤12 brachytherapy implants per year, 24.8% performing 13-53 cases and only 1.5% performing ≥53 cases per year the question becomes the ability of academic training practices to adequately teach future residents to perform prostate brachytherapy. Given these concerning trends it must be determined how to fix this trend in order to ensure this treatment modality is not lost in the future.


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Dose and fractionation in radiotherapy of curative intent for non-small-cell lung cancer: Meta-analysis of randomized trials

Publication date: Available online 25 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Johanna C. Rankin, David J. Cutter, Sarah C. Darby, Geoff S. Higgins, Paul McGale, Mike Partridge, Carolyn W. Taylor
PurposeThe optimum dose and fractionation in radiotherapy of curative intent for non-small-cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiotherapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy.Methods and materialsEligible studies were randomized comparisons of two or more radiotherapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled.Results3,795 patients in 25 randomized comparisons of radiotherapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% CI 1.04-1.22) when radiotherapy was given alone, and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (p for difference=0.001).In comparisons of radiotherapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (p for trend=0.004). The benefit increased with increasing dose in the lower-dose arm (p for trend=0.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not.There was heterogeneity in the median survival ratio by geographical region (p<0.001), average age at randomization (p<0.001) and year trial started (p for trend=0.004), but not for proportion of patients with squamous cell carcinoma (p=0.2).ConclusionsIn trials with concurrent chemotherapy, higher radiotherapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiotherapy was given without chemotherapy, progressively higher radiotherapy doses resulted in progressively longer survival and no upper dose level was found above which there was no further benefit. These findings support consideration of further radiotherapy dose escalation trials, making use of modern treatment methods to reduce toxicity.

Teaser

We conducted a meta-analysis of overall survival in 3,795 patients with non-small-cell lung cancer who were randomized in 21 trials comparing higher versus lower radiotherapy doses of curative intent. In trials with chemotherapy, higher radiotherapy doses led to poorer survival but, in trials where chemotherapy was not given, higher time-corrected biologically equivalent doses resulted in longer survival. These findings support consideration of further trials of radiotherapy dose escalation within the context of toxicity reduction.


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Investigating Effects of Acidic pH on Proliferation, Invasion and Drug-Induced Apoptosis in Lymphoblastic Leukemia

Abstract

Some studies have shown that extracellular pH in tumors, which results in tumor progression, is less than that in normal tissues. The aim of this study was to investigate the effects of extracellular acidic pH on proliferation, invasion, and drug-induced apoptosis in acute lymphoblastic cells. The cells were cultured in different pH (pH 6.6 and pH 7.4) for 12 days. Cell proliferation was assessed by MTT assay and cell invasion was assayed by invasion assay and gene expression analysis of MMP-9. Drug-induced apoptosis was evaluated after exposure to doxorubicin for 24 hours by annexin V/PI staining and gene expression analysis of BAX pro-apoptotic protein. The results indicated the enhanced growth and invasion of leukemic cells at pH 6.6 (P ≤ 0.05). Furthermore, the cells at pH 6.6 were resistant to apoptosis by doxorubicin (P ≤ 0.05). It can be concluded that acidic pH increases the proliferation, invasion and reduces the drug-induced apoptosis in acute lymphoblastic leukemia. Extracellular acidity can influence the behavior of leukemic cells and therefore, the manipulation of extracellular liquid can be selected as a therapeutic strategy for leukemia, especially for acute lymphoblastic leukemia.

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MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression

Abstract

Background

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and frequently progresses from an actinic keratosis (AK), a sun-induced keratinocyte intraepithelial neoplasia (KIN). Epigenetic mechanisms involved in the phenomenon of progression from AK to cSCC remain to be elicited.

Methods

Expression of microRNAs in sun-exposed skin, AK and cSCC was analysed by Agilent microarrays. DNA methylation of miR-204 promoter was determined by bisulphite treatment and pyrosequencing. Identification of miR-204 targets and pathways was accomplished in HaCat cells. Immunofluorescence and immunohistochemistry were used to analyze STAT3 activation and PTPN11 expression in human biopsies.

Results

cSCCs display a marked downregulation of miR-204 expression when compared to AK. DNA methylation of miR-204 promoter was identified as one of the repressive mechanisms that accounts for miR-204 silencing in cSCC. In HaCaT cells miR-204 inhibits STAT3 and favours the MAPK signaling pathway, likely acting through PTPN11, a nuclear tyrosine phosphatase that is a direct miR-204 target. In non-peritumoral AK lesions, activated STAT3, as detected by pY705-STAT3 immunofluorescence, is retained in the membrane and cytoplasm compartments, whereas AK lesions adjacent to cSCCs display activated STAT3 in the nuclei.

Conclusions

Our data suggest that miR-204 may act as a "rheostat" that controls the signalling towards the MAPK pathway or the STAT3 pathway in the progression from AK to cSCC.

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Response to Schellekens et al.

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Sulik, Gayle A. Pink Ribbon Blues. New York: Oxford University Press, 2011. 402 pp. $33.95.

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Comments on ‘Psychological intervention targeting distress for cancer patients: a meta-analytic study investigating uptake and adherence’ by Brebach and colleagues (2016)

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Issue Information

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Neutrophil elastase and matrix metalloproteinase 12 in cystic fibrosis lung disease

Abstract

Chronic lung disease remains the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Recent studies in young children with CF diagnosed by newborn screening identified neutrophil elastase (NE), a major product released from neutrophils in inflamed airways, as a key risk factor for the onset and early progression of CF lung disease. However, the understanding of how NE and potentially other proteases contribute to the complex in vivo pathogenesis of CF lung disease remains limited. In this review, we summarize recent progress in this area based on studies in βENaC-overexpressing (βENaC-Tg) mice featuring CF-like lung disease and novel protease-specific Förster resonance energy transfer (FRET) sensors for localization and quantification of protease activity in the lung. These studies demonstrated that NE is implicated in several key features of CF lung disease such as neutrophilic airway inflammation, mucus hypersecretion, and structural lung damage in vivo. Furthermore, these studies identified macrophage elastase (matrix metalloproteinase 12 (MMP12)) as an additional protease contributing to early lung damage in βENaC-Tg mice. Collectively, these results suggest that NE and MMP12 released from activated neutrophils and macrophages in mucus-obstructed airways play important pathogenetic roles and may serve as potential therapeutic targets to prevent and/or delay irreversible structural lung damage in patients with CF.

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Long-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER Study

Abstract

Introduction

Latanoprostene bunod (LBN) is a novel nitric oxide (NO)-donating prostaglandin F2α analog. We evaluated the long-term safety and intraocular pressure (IOP)-lowering efficacy of LBN ophthalmic solution 0.024% over 1 year in Japanese subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT).

Methods

This was a single-arm, multicenter, open-label, clinical study. Subjects aged 20 years and older with a diagnosis of OAG or OHT instilled 1 drop of LBN ophthalmic solution 0.024% in the affected eye(s) once daily in the evening for 52 weeks and were evaluated every 4 weeks. Safety assessments included vital signs, comprehensive ophthalmic exams, and treatment-emergent adverse events (AEs). Absolute and percent reductions from baseline in IOP were also determined.

Results

Of 130 subjects enrolled, 121 (93.1%) completed the study. Mean age was 62.5 years, and mean (standard deviation) baseline IOP was 19.6 (2.9) and 18.7 (2.6) mmHg in study eyes and treated fellow eyes, respectively. Overall, 76/130 (58.5%) and 78/126 (61.9%) subjects experienced ≥1 AEs in study eyes and treated fellow eyes, respectively. In both study eyes and treated fellow eyes, the most common AEs were conjunctival hyperemia, growth of eyelashes, eye irritation, and eye pain. At 52 weeks, 9% of treated eyes had an increase in iris pigmentation compared with baseline based on iris photographs. No safety concerns emerged based on vital signs or other ocular assessments. Mean reductions from baseline in IOP of 22.0% and 19.5% were achieved by week 4 in study and treated fellow eyes, respectively. These reductions were maintained through week 52 (P < 0.001 vs. baseline at all visits).

Conclusion

Once daily LBN ophthalmic solution 0.024% was safe and well-tolerated in Japanese subjects with OAG or OHT when used for up to 1 year. Long-term treatment with LBN ophthalmic solution 0.024% provided significant and sustained IOP reduction.

Trial registration

ClinicalTrials.gov identifier, NCT01895972.

Funding

Bausch & Lomb, Inc. a division of Valeant Pharmaceuticals International Inc.

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The Cost-Effectiveness of Ranibizumab Treat and Extend Regimen Versus Aflibercept in the UK

Abstract

Introduction

Wet age-related macular degeneration (AMD) is a chronic eye condition that causes severe deterioration of vision and even blindness. Current wet AMD treatment in the UK involves the vascular endothelial growth factor inhibitors ranibizumab and aflibercept. Patients with wet AMD require frequent and long-term monitoring for treatment to be effective, contributing to a substantial resource burden at wet AMD centers. The European license for ranibizumab was recently updated with an individualized 'treat and extend' (T&E) regimen, comprising a structured monitoring and treatment protocol. This study evaluated the cost-effectiveness of ranibizumab T&E versus aflibercept within a UK setting.

Methods

An individual patient-level simulation model was developed utilizing treatment effects from a network meta-analysis of randomized controlled trials. The model was conducted from a UK National Health Service (NHS) perspective over a lifetime horizon and the base case utilized probabilistic sensitivity analysis to assess uncertainty in the model. Additional scenario analyses were conducted to assess the impact of changes to the model inputs.

Results

Ranibizumab T&E was found to be more effective and less costly than aflibercept, providing, on average, an additional 1.058 quality-adjusted life years (QALYs) and a cost-saving of £19,604 over a lifetime horizon. At list price, ranibizumab T&E was found to be cost-effective versus aflibercept in 100% of simulations at a willingness-to-pay threshold of £20,000 per QALY. The robustness of the results was tested in several scenario analyses; ranibizumab T&E was found to be more effective, and less costly, than aflibercept in the vast majority of cases.

Conclusion

This evaluation suggests that treating patients with ranibizumab according to the T&E regimen could be a better use of NHS resources than aflibercept, and could, therefore, be considered as a first-line regimen for patients with wet AMD in the UK.

Funding

Novartis Pharmaceuticals UK Limited.

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Impact of Warfarin on Atrial-Fibrillation Outcomes Related to Economic Consumption Patterns: Hospitalization, Cost, and Mortality may be Predictable and Modifiable at the Population Level

Abstract

Introduction

Warfarin reduces atrial fibrillation (AF)-related strokes and may impact mortality, hospitalizations, and costs. This study investigated the possibility that patterns of warfarin consumption are associated with the frequency of acute events.

Methods

Annual cost profiles of 9.2 million Medicare beneficiaries with AF were analyzed to identify patterns of benefits consumption from 2000 through 2010. Beneficiaries were divided into five consumption clusters based upon their annual cost profiles, ranging from crisis consumers at the high end to low consumers. Resource-utilization patterns and outcome differences were calculated between AF beneficiaries who received warfarin and those who did not. Propensity score-matched analysis was performed to reduce selection bias.

Results

The annual percentages of beneficiaries and expenditures that differentiated each cluster showed stable patterns. Warfarin use influenced consumption patterns and outcomes. The most important financial difference between higher and lower consumers was inpatient cost. AF beneficiaries on warfarin had lower annual cost profiles and had a higher propensity to persist in or migrate to consumption clusters with comparatively small reimbursement claims and lower hospitalization risks. AF beneficiaries not on warfarin had higher cost and mortality.

Conclusions

These data signal that a nontrivial portion of acute events (hospitalization and mortality) are amenable to medical intervention (warfarin). When acute events are amenable to medical intervention and occur at a higher frequency because guidelines have not been applied evenly across affected populations, it is appropriate to define those occurrences as disparities associated with systemic failure in evidence-based medicine. Quality-improvement initiatives that reduce therapeutic disparities may result in lower cost and improved outcomes.

Funding

No funding or sponsorship was received for this study or publication of this article.

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High expression of BAG3 predicts a poor prognosis in human medulloblastoma

Abstract

Bcl2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock protein (Hsp) 70, regulates various physiological and pathological processes. However, its role in human medulloblastoma has not been clarified. First of all, the expression of BAG3 was examined in formalin-fixed, paraffin-embedded specimens by immunohistochemical staining. And then, the prognostic role of BAG3 was analyzed in 51 medulloblastoma samples. Finally, the roles of BAG3 in the proliferation, migration, and invasion of Daoy medulloblastoma cell were investigated using a specific short hairpin RNA (shRNA). The expression of BAG3 in medulloblastoma tissues was higher than nontumorous samples. Furthermore, BAG3 overexpression significantly correlated with poor prognosis of patients with medulloblastoma. The overall survival and tumor-free survival in patients with BAG3 low expression were higher than high expression. Univariate and multivariate analysis showed that BAG3 overexpression was an independent prognostic marker for medulloblastoma. After the BAG3 knockdown, the Daoy cells exhibited decreased the ability to proliferate and form neurosphere. The preliminary mechanism study showed that overexpression of BAG3 might facilitate the cell cycle transition from G1 to S phase by modulating the cyclin-dependent kinase 2 (CDK2) and cyclin E expression. Additionally, we found that BAG3 might enhance the medulloblastoma cell migratory and invasive ability. In summary, BAG3 overexpression may regulate the survival and invasive properties of medulloblastoma and may serve as a potential therapy target for medulloblastoma.

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MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen-related receptor alpha

Abstract

Metastasis has become the main challenge for treatment of estrogen receptor alpha (ERα) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERRα), a nuclear receptor overexpressed in ERα negative breast cancer. Targeted inhibition of ERRα by si-RNA increased miR-497 expression while overexpression of ERRα inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERRα by binding to the 3′UTR region of ERRα. Luciferase assay and ChIP assay confirmed that ERα directly regulated the transcription of miR-497, suggesting that loss of ERα lowered miR-497 level in ERα negative breast cancer. Further, overexpression of miR-497 not only inhibited ERRα expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ERα negative breast cancer. Taken together, our findings suggested that, in ERα negative breast cancer, the low level of ERα reduced miR-497 expression, which promoted ERRα expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity.

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Gene/protein expression of CAPN1/2-CAST system members is associated with ERK1/2 kinases activity as well as progression and clinical outcome in human laryngeal cancer

Abstract

Recent evidence indicates the involvement of calpains (CAPNs), a family of cysteine proteases, in cancer development and progression, as well as the insufficient response to cancer therapies. The contribution of CAPNs and regulatory calpastatin (CAST) and ERK1/2 kinases to aggressiveness, disease course, and outcome in laryngeal cancer remains elusive. This study was aimed to evaluate the CAPN1/2-CAST-ERK1/2 enzyme system mRNA/protein level and to investigate whether they can promote the dynamic of tumor growth and prognosis. The mRNA expression of marker genes was determined in 106 laryngeal cancer (SCLC) cases and 73 non-cancerous adjacent mucosa (NCLM) controls using quantitative real-time PCR. The level of corresponding proteins was analyzed by Western Blot. SLUG expression, as indicator of pathological advancement was determined using IHC staining. Significant increases of CAPN1/2-CAST-ERK1/2 levels of mRNA/protein were noted in SCLC compared to NCLM (p < 0.05). As a result, a higher level of CAPN1 and ERK1 genes was related to larger tumor size, more aggressive and deeper growth according to TFG scale and SLUG level (p < 0.05). There were also relationships of CAPN1/2 and ERK1 with incidences of local/nodal recurrences (p < 0.05). An inverse association for CAPN1/2, CAST, and ERK1/2 transcripts was determined with regard to overall survival (p < 0.05). In addition, a higher CAPN1 and phospho-ERK1 protein level was related to higher grade and stage (p < 0.05) and was found to promote worse prognosis. This is the first study to show that activity of CAPN1/2- CAST-ERK1/2 axis may be an indicator of tumor phenotype and unfavorable outcome in SCLC.

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Breed and seasonal variations in erythrocyte osmotic fragility of goat kids raised in semi-arid savannah

Abstract

The aim of this study was to evaluate the influence of sex, breed and season on erythrocyte osmotic fragility (EOF) as a biomarker of erythrocyte membrane integrity and oxidative stress in Red Sokoto (n = 60) and Sahel (n = 60) kids exposed to the peak of the three distinct seasons prevailing in the Northern Guinea Savannah Zone of Nigeria. The results revealed that irrespective of breed, thermal stress during the hot-dry season (HDS) had greater influence on EOF causing significant (P < 0.05) increase in EOF when compared with the cold-dry (CDS). The EOF of Red Sokoto kids was significantly (P < 0.05) higher during the HDS, but lower (P < 0.05) during the CDS when compared with that of Sahel kids. There was no significant (P > 0.05) sex difference in the EOF of both breeds. In conclusion, breed and season dramatically influence the susceptibility of erythrocytes of kids to hypotonic haemolysis with heat stress during the HDS causing decrease in membrane integrity in both breeds of goats. However, sexual immaturity may be responsible for lack of sexual dimorphism in EOF in both breeds. The use of mitigation techniques and prevention of additional stress factors such as weaning is recommended during the peak of the HDS.

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Erratum to: Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program

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Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer

Summary

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 monoclonal antibody, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open-label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non-life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies.

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Downregulation of HMGB1 by miR-34a is sufficient to suppress proliferation, migration and invasion of human cervical and colorectal cancer cells

Abstract

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein known to be highly expressed in human cervical (CaCx) and colorectal (CRC) cancers, and sustained high levels of HMGB1 contribute to tumourigenesis and metastasis. HMGB1-targeted cancer therapy is of recent interest, and there are not many studies on miRNA-mediated HMGB1 regulation in these cancers. Since miRNA-based therapeutics for cancer is gaining importance in recent years, it was of interest to predict miRNAs targeting HMGB1. Based on the identification of a potential miR-34a response element in HMGB1–3′ untranslated region (3′UTR) and an inverse correlation between HMGB1 and miR-34a expression levels in CaCx and CRC tissues, from a subset of the local population as well as a large sampling from TCGA database, experiments were performed to validate HMGB1 as a direct target of miR-34a in CaCx and CRC cells. Ectopic expression of miR-34a decreased the wild-type HMGB1–3′UTR luciferase activity but not that of its mutant in 3′UTR luciferase assays. While forced expression of miR-34a in CaCx and CRC cells inhibited HMGB1 mRNA and protein levels, proliferation, migration and invasion, inhibition of endogenous miR-34a enhanced these tumourigenic properties. siRNA-mediated HMGB1 suppression imitated miR-34a expression in reducing proliferation and metastasis-related events. Combined with the disparity in expression of miR-34a and HMGB1 in clinical specimens, the current findings would help in not only understanding the complexity of miRNA-target regulatory mechanisms but also in designing novel therapeutic interventions in CaCx and CRC.

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Knockdown of USP39 induces cell cycle arrest and apoptosis in melanoma

Abstract

The spliceosome machinery composed of multimeric protein complexes guides precursor messenger RNAs (mRNAs) (pre-mRNAs) splicing in eukaryotic cells. Spliceosome components have been shown to be downregulated in cancer and could be a promising molecular target for anticancer therapy. The ubiquitin-specific protease 39 (USP39) is essential for pre-mRNA splicing, and upregulated USP39 expression is noted in a variety of cancers. However, the role of USP39 in the development and progression of melanoma remains unclear. In the present study, USP39 expression was found to be increased in melanoma tissues compared with that in nevus tissues. USP39 silencing via lentivirus-mediated short hairpin RNA (shRNA) significantly suppressed melanoma cell proliferation, induced G0/G1 cell cycle phase arrest, and increased apoptosis in vitro. Moreover, USP39 knockdown suppressed melanoma tumor growth in a xenograft model. In addition, USP39 silencing was associated with the increased expressions of p21, p27, and Bax. Furthermore, the inhibition of USP39 expression decreased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, indicating that ERK signaling pathways might be involved in the regulation of melanoma cell proliferation by USP39. Our findings suggest that USP39 may play crucial roles in the development and pathogenesis of melanoma, and it may serve as a potential therapeutic target for melanoma.

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MicroRNA-497 downregulation contributes to cell proliferation, migration, and invasion of estrogen receptor alpha negative breast cancer by targeting estrogen-related receptor alpha

Abstract

Metastasis has become the main challenge for treatment of estrogen receptor alpha (ERα) negative breast cancer. Here, we found a negative correlation between miR-497 and estrogen-related receptor alpha (ERRα), a nuclear receptor overexpressed in ERα negative breast cancer. Targeted inhibition of ERRα by si-RNA increased miR-497 expression while overexpression of ERRα inhibited miR-497 expression. Further investigation showed that miR-497 targeted ERRα by binding to the 3′UTR region of ERRα. Luciferase assay and ChIP assay confirmed that ERα directly regulated the transcription of miR-497, suggesting that loss of ERα lowered miR-497 level in ERα negative breast cancer. Further, overexpression of miR-497 not only inhibited ERRα expression but also reduced MIF level and MMP9 activity, which led to significant decreases in cell proliferation, migration, and invasion of ERα negative breast cancer. Taken together, our findings suggested that, in ERα negative breast cancer, the low level of ERα reduced miR-497 expression, which promoted ERRα expression that enhanced cell proliferation, migration, and invasion by increasing MIF expression and MMP9 activity.

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Curcumin inhibits cell growth and induces cell apoptosis through upregulation of miR-33b in gastric cancer

Abstract

In this work, the in vitro experiments about biological mechanisms of curcumin were conducted using the gastric cancer cell lines SGC-7901 and BGC-823. After 24-h exposure to curcumin at the concentrations of 5, 10, 15, 20, and 40 μmol/L, two cells showed the decreased proliferation and increased apoptosis abilities. Real-time PCR, Cell Counting Kit-8 (CCK-8) assay, western blotting, and cell apoptosis assay were used to further study the underlying mechanisms of curcumin. The first stage of our studies showed that curcumin affected the expression of miR-33b, which, in turn, affected the expression of the X-linked inhibitor of apoptosis protein (XIAP) messenger RNA (mRNA). Next, curcumin was also identified to regulate the proliferation and apoptosis of SGC-7901 and BGC-823 cells. Further bioinformatics analysis and luciferase reporter assays proved that XIAP was one of the target genes of miR-33b. In the next stage, SGC-7901 and BGC-823 cells were treated with 20 μL curcumin, miR-33b mimics, and small interfering RNA (siRNA) of XIAP, respectively. The results showed that curcumin had similar effects on cell growth and apoptosis as the upregulation of miR-33b and the upregulation of the siRNA of XIAP. The results that followed from the restore experiments showed that curcumin affected cell growth and apoptosis presumably by upregulating the XIAP targeting in gastric cancer. Collectively, our results indicate that curcumin-miR-33b-XIAP coupling might be an important mechanism by which curcumin induces the apoptosis of SGC-7901 and BGC-823 cells.

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Gene/protein expression of CAPN1/2-CAST system members is associated with ERK1/2 kinases activity as well as progression and clinical outcome in human laryngeal cancer

Abstract

Recent evidence indicates the involvement of calpains (CAPNs), a family of cysteine proteases, in cancer development and progression, as well as the insufficient response to cancer therapies. The contribution of CAPNs and regulatory calpastatin (CAST) and ERK1/2 kinases to aggressiveness, disease course, and outcome in laryngeal cancer remains elusive. This study was aimed to evaluate the CAPN1/2-CAST-ERK1/2 enzyme system mRNA/protein level and to investigate whether they can promote the dynamic of tumor growth and prognosis. The mRNA expression of marker genes was determined in 106 laryngeal cancer (SCLC) cases and 73 non-cancerous adjacent mucosa (NCLM) controls using quantitative real-time PCR. The level of corresponding proteins was analyzed by Western Blot. SLUG expression, as indicator of pathological advancement was determined using IHC staining. Significant increases of CAPN1/2-CAST-ERK1/2 levels of mRNA/protein were noted in SCLC compared to NCLM (p < 0.05). As a result, a higher level of CAPN1 and ERK1 genes was related to larger tumor size, more aggressive and deeper growth according to TFG scale and SLUG level (p < 0.05). There were also relationships of CAPN1/2 and ERK1 with incidences of local/nodal recurrences (p < 0.05). An inverse association for CAPN1/2, CAST, and ERK1/2 transcripts was determined with regard to overall survival (p < 0.05). In addition, a higher CAPN1 and phospho-ERK1 protein level was related to higher grade and stage (p < 0.05) and was found to promote worse prognosis. This is the first study to show that activity of CAPN1/2- CAST-ERK1/2 axis may be an indicator of tumor phenotype and unfavorable outcome in SCLC.

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Curcumin inhibits cell growth and induces cell apoptosis through upregulation of miR-33b in gastric cancer

Abstract

In this work, the in vitro experiments about biological mechanisms of curcumin were conducted using the gastric cancer cell lines SGC-7901 and BGC-823. After 24-h exposure to curcumin at the concentrations of 5, 10, 15, 20, and 40 μmol/L, two cells showed the decreased proliferation and increased apoptosis abilities. Real-time PCR, Cell Counting Kit-8 (CCK-8) assay, western blotting, and cell apoptosis assay were used to further study the underlying mechanisms of curcumin. The first stage of our studies showed that curcumin affected the expression of miR-33b, which, in turn, affected the expression of the X-linked inhibitor of apoptosis protein (XIAP) messenger RNA (mRNA). Next, curcumin was also identified to regulate the proliferation and apoptosis of SGC-7901 and BGC-823 cells. Further bioinformatics analysis and luciferase reporter assays proved that XIAP was one of the target genes of miR-33b. In the next stage, SGC-7901 and BGC-823 cells were treated with 20 μL curcumin, miR-33b mimics, and small interfering RNA (siRNA) of XIAP, respectively. The results showed that curcumin had similar effects on cell growth and apoptosis as the upregulation of miR-33b and the upregulation of the siRNA of XIAP. The results that followed from the restore experiments showed that curcumin affected cell growth and apoptosis presumably by upregulating the XIAP targeting in gastric cancer. Collectively, our results indicate that curcumin-miR-33b-XIAP coupling might be an important mechanism by which curcumin induces the apoptosis of SGC-7901 and BGC-823 cells.

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Downregulation of HMGB1 by miR-34a is sufficient to suppress proliferation, migration and invasion of human cervical and colorectal cancer cells

Abstract

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein known to be highly expressed in human cervical (CaCx) and colorectal (CRC) cancers, and sustained high levels of HMGB1 contribute to tumourigenesis and metastasis. HMGB1-targeted cancer therapy is of recent interest, and there are not many studies on miRNA-mediated HMGB1 regulation in these cancers. Since miRNA-based therapeutics for cancer is gaining importance in recent years, it was of interest to predict miRNAs targeting HMGB1. Based on the identification of a potential miR-34a response element in HMGB1–3′ untranslated region (3′UTR) and an inverse correlation between HMGB1 and miR-34a expression levels in CaCx and CRC tissues, from a subset of the local population as well as a large sampling from TCGA database, experiments were performed to validate HMGB1 as a direct target of miR-34a in CaCx and CRC cells. Ectopic expression of miR-34a decreased the wild-type HMGB1–3′UTR luciferase activity but not that of its mutant in 3′UTR luciferase assays. While forced expression of miR-34a in CaCx and CRC cells inhibited HMGB1 mRNA and protein levels, proliferation, migration and invasion, inhibition of endogenous miR-34a enhanced these tumourigenic properties. siRNA-mediated HMGB1 suppression imitated miR-34a expression in reducing proliferation and metastasis-related events. Combined with the disparity in expression of miR-34a and HMGB1 in clinical specimens, the current findings would help in not only understanding the complexity of miRNA-target regulatory mechanisms but also in designing novel therapeutic interventions in CaCx and CRC.

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Knockdown of USP39 induces cell cycle arrest and apoptosis in melanoma

Abstract

The spliceosome machinery composed of multimeric protein complexes guides precursor messenger RNAs (mRNAs) (pre-mRNAs) splicing in eukaryotic cells. Spliceosome components have been shown to be downregulated in cancer and could be a promising molecular target for anticancer therapy. The ubiquitin-specific protease 39 (USP39) is essential for pre-mRNA splicing, and upregulated USP39 expression is noted in a variety of cancers. However, the role of USP39 in the development and progression of melanoma remains unclear. In the present study, USP39 expression was found to be increased in melanoma tissues compared with that in nevus tissues. USP39 silencing via lentivirus-mediated short hairpin RNA (shRNA) significantly suppressed melanoma cell proliferation, induced G0/G1 cell cycle phase arrest, and increased apoptosis in vitro. Moreover, USP39 knockdown suppressed melanoma tumor growth in a xenograft model. In addition, USP39 silencing was associated with the increased expressions of p21, p27, and Bax. Furthermore, the inhibition of USP39 expression decreased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, indicating that ERK signaling pathways might be involved in the regulation of melanoma cell proliferation by USP39. Our findings suggest that USP39 may play crucial roles in the development and pathogenesis of melanoma, and it may serve as a potential therapeutic target for melanoma.

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Disparities in psychosocial cancer care: A report from the International Federation of Psycho-Oncology Societies

Abstract

Background

The aim of the study was to understand the characteristics of the International Federation of Psycho-Oncology Societies (FPOS) and possible disparities in providing psychosocial care in countries where psycho-oncology societies exist.

Method

A survey was conducted among 29 leaders of 28 countries represented within the FPOS by using a questionnaire covering (i) characteristics of the society; (ii) characteristics of the national health care system (NHS); (iii) level of implementation of psycho-oncology and (iv) main problems of psycho-oncology in the country.

Results

Twenty-six (90%) FPOS returned the questionnaires. One-third reported to have links with and support from their government, while almost all had links with other scientific societies. FPOS varied in their composition of members' professions. Psychosocial care provision was covered by state-funded health services in a minority of countries. Disparities between countries arose from different causes and were problematic in some parts of the world (e.g. Africa, SE Asia). Elsewhere (e.g. Southern Europe, Eastern Europe), austerity policies were reportedly responsible for resource shortages with negative consequences on psychosocial cancer care. Half of FPOS rated themselves to be integrated into mainstream provision of care, although lack of funding was the most common complain.

Conclusion

The development and implementation of psycho-oncology is fragmented and undeveloped, particularly in some parts of the world. More effort is needed at national level by strong coalitions with oncology societies, better national research initiatives, cancer plans and patient advocacy, as well as by stronger partnership with international organizations (e.g. WHO, UICC).

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