Aberrant BLM cytoplasmic expressionassociates with DNA damage stress and hypersensitivity to DNA-damaging agents in colorectal cancer

Background Bloom syndrome is a rare and recessive disorder characterized by loss-of-function mutations of the BLM gene, which encodes a RecQ 30–50 DNA helicase. Despite its putative tumor suppressor function, the contribution of BLM to human sporadic colorectal cancer (CRC) remains poorly understood. Methods The transcriptional regulation mechanism underlying BLM and related DNA damage response regulation in independent CRC subsets and a panel of derived cell lines was investigated by bioinformatics analysis, the transcriptomic profile, a CpG island promoter methylation assay, Western blot, and an immunolocalization assay. Results In silico analysis of gene expression data sets revealed that BLM is overexpressed in poorly differentiated CRC and exhibits a close connection with shorter relapsefree survival even after adjustment for prognostic factors and pathways that respond to DNA damage response through ataxia telangiectasia mutated (ATM) signaling. Functional characterization demonstrated that CpG island promoter hypomethylation increases BLM expression and associates with cytoplasmic BLM mislocalization and increased DNA damage response both in clinical CRC samples and in derived cancer cell lines. The DNA-damaging agent S-adenosylmethionine suppresses BLM expression, leading to the inhibition of cell growth following accumulation of DNA damage. In tumor specimens, cytoplasmic accumulation of BLM correlates with DNA damage and cH2AX and phosphorylated ATM foci and predicts long-term progression-free survival in metastatic patients treated with irinotecan. Conclusions Taken together, the findings of this study provide the first evidence that cancer-linked DNA hypomethylation and cytosolic BLM mislocalization might reflect compromised levels of DNA-repair activity and enhanced hypersensitivity to DNA-damaging agents in CRC patients

Early Sex Work Initiation and Condom Use among Alcohol-Using Female Sex Workers in Mombasa, Kenya: A Cross-Sectional Analysis

Objectives Early initiation of sex work is prevalent among female sex workers (FSWs) worldwide. The objectives of this study were to investigate if early initiation of sex work was associated with: (1) consistent condom use, (2) condom negotiation self-efficacy or (3) condom use norms among alcohol-using FSWs in Mombasa, Kenya. Methods In-person interviews were conducted with 816 FSWs in Mombasa, Kenya. Sample participants were: recruited from HIV prevention drop-in centres, 18 years or older and moderate risk drinkers. Early initiation was defined as first engaging in sex work at 17 years or younger. Logistic regression modelled outcomes as a function of early initiation, adjusting for drop-in centre, years in sex work, supporting others and HIV status. Results FSWs who initiated sex work early were significantly less likely to report consistent condom use with paying sex partners compared with those who initiated sex work in adulthood. There was no significant difference between groups in consistent condom use with non-paying sex partners. FSWs who initiated sex work early endorsed less condom negotiation self-efficacy with paying sex partners compared with FSWs who did not initiate sex work early. Conclusions Findings highlight a need for early intervention for at-risk youth and adolescent FSWs, particularly in relation to HIV sexual risk behaviours. Evidence-based interventions for adolescent FSWs or adult FSWs who began sex work in adolescence should be developed, implemented and evaluated

Physical and sexual violence, childhood sexual abuse and HIV/STI risk behaviour among alcohol-using women engaged in sex work in Mongolia

Although the prevalence of human immunodeficiency virus (HIV) in Mongolia is low, it could increase without strategic prevention strategies. Female sex workers (FSWs) often experience barriers to prevention, including interpersonal violence. This study investigated if childhood sexual abuse (CSA) or recent physical or sexual violence was associated with HIV sexual risk behaviours and if CSA modified associations between recent violence and HIV sexual risk behaviours. Two-hundred twenty-two women who (1) were at least 18 years old and clients at the National AIDS Foundation; (2) reported vaginal or anal sex in the past 90 days in exchange for money or goods and (3) met criteria for harmful alcohol use in the past year were enrolled. In-person interviews assessed sexual risk behaviours and violence in childhood and adulthood. Negative binomial regression, ordinary least squares regression and modified Poisson regression were performed. Sexual risk with paying partners was associated with penetrative CSA and sexual violence by paying partners. CSA and recent violence were not associated with sexual risk behaviours with intimate partners. CSA modified the association between recent sexual violence and unprotected sex with intimate partners. Findings highlight the need for integrated violence and sexual risk reduction services to ensure safe and effective prevention for FSWs

JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer

Background: Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically "cold" tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear. Methods: We used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies. Results: We identified the lymphocyte antigen 6 complex, locus G6D (LY6G6D) as significantly overexpressed (around 15-fold) in CRC when compared with its relatively low expression in other human solid tumours. LY6G6D up-regulation was predominant in MSS CRCs characterized by an enrichment of immune suppressive regulatory T-cells and a limited repertoire of PD-1/PD-L1 immune checkpoint receptors. Coexpression of LY6G6D and CD15 increases the risk of metastatic relapse in response to therapy. Both JAK-STAT5 and RAS-MEK-ERK cascades act in concert as key regulators of LY6G6D and Fucosyltransferase 4 (FUT4), which direct CD15-mediated immune-resistance. Momelotinib, an inhibitor of JAK1/JAK2, consistently abrogated the STAT5/LY6G6D axis in vitro, sensitizing MSS cancer cells with an intact JAK-STAT signaling, to efficiently respond to trametinib, a MEK inhibitor used in clinical setting. Notably, colon cancer cells can evade JAK2/JAK1-targeted therapy by a reversible shift of the RAS-MEK-ERK pathway activity, which explains the treatment failure of JAK1/2 inhibitors in refractory CRC. Conclusions: Combined targeting of STAT5 and MAPK pathways has superior therapeutic effects on immune resistance. In addition, the new identified LY6G6D antigen is a promising molecular target for human MSS CRC

Urothelial bladder carcinoma metastasizing to the eye: A systematic review and case report

The eye is a rare site for disseminated malignancies; nevertheless, several tumors may metastasize to ocular structures. Few cases of urothelial and bladder cancer with eye involvement have been described in the literature thus far. The rarity of metastatic ocular localization implies an accurate differential diagnosis among the possible primary tumor sites. However, a specific diagnostic algorithm is not currently available, nor a defined therapeutic approach. Eye metastases are associated with advanced disease and poor prognosis. Physicians should be made aware of the possibility of eye involvement in patients with a past medical history of urothelial bladder cancer associated with ocular symptoms. The present case reports discusses the first documented case, to the best of our knowledge, of an urothelial bladder cancer metastasizing to the retro bulbar region that infiltrates the lacrimal gland. Furthermore, the report provides a systematic qualitative review of the current literature on eye metastases from urothelial bladder cancer using the Preferred Reporting Items for Systematic Reviews and Meta Analyses

Variations of perceived exertion in relation to heart rate responses in an international level race walkers before a 50-km race

Introduction. The ability to accurately control and monitor exercise intensity (EI) during training sessions plays a key role in planning the athletic season. This can be achieved by means of rating of perceived exertion (RPE) (Borg, 1998) and heart rate (HR) (Achten and Jeukendrup, 2003). Over the years several RPE- and HR-based methods have been proposed to quantify global EI. However, to date no study has been conducted with regards to race walking (RW). Thus, this case study aimed to investigate the typical RPE and HR seasonal variations of an international level race walker training for a 50-km race and to examine the relationship between RPE and HR to further confirm the use of RPE to assess EI during RW-specific training. Methods. Training data were collected during the competitive season 2009 (127 training sessions) consisting of four macrocycles of intense training interspersed by one week of tapering before the Italian 50-km championship. The Borg\u2019s 6-20 RPE scale (Borg, 1998) was used to measure the athlete perception of effort referred to the whole training session. HR was recorded using a short-range telemetry system and expressed relative to the maximum value (%HRmax) of the athlete determined during an incremental maximal test. The relationships between RPE and %HRmax were analysed using Pearson\u2019s product moment correlation. Statistical significance was set at P < 0.05. Results. The athlete completed the event in 4h 14min 02s (personal best time, 39min 48s slower than the World Record). The mean RPE was 11.1 (1.6), 13.1 (1.3), 13.2 (1.5), 12.4 (1.3) and 11.4 (1.0), 13.5 (0.8), 12.7 (0.4), 12.0 (1.5) for the training and tapering period, respectively. The mean %HRmax was 83.7 (2.0), 85.3 (4.6), 84.8 (4.1), 85.7 (3.8) and 83.0 (0.7), 85.7 (4.5), 84.8 (1.6), 85.4 (2.5) % for the training and tapering period, respectively. The correlation between the mean RPE and %HRmax showed a very large significant relationship (r = 0.74, P = 0.04). Discussion. The result found indicates that a very large and significant relation exists between RPE and HR. This finding is in line with previous studies which showed how RPE is correlated with many physiological variables, such as HR (Chen et al., 2002), and provides evidence which confirms that RPE can be considered a simple and valid method for quantifying the global EI during RW-specific training. References Achten J, Jeukendrup AE. (2003). Sports Med, 33, 517-538 Borg G. (1998). Borg\u2019s perceived exertion and pain scale. Human Kinetics, Champaign, IL Chen MJ, Fan X, Moe ST (2002). J Sports Sci, 20, 873-899

Cancer-Associated Immune Resistance and Evasion of Immune Surveillance in Colorectal Cancer

Data from molecular profiles of tumors and tumor associated cells provide a model in which cancer cells can acquire the capability of avoiding immune surveillance by expressing an immune-like phenotype. Recent works reveal that expression of immune antigens (PDL1, CD47, CD73, CD14, CD68, MAC387, CD163, DAP12, and CD15) by tumor cells "immune resistance," combined with prometastatic function of nonmalignant infiltrating cells, may represent a strategy to overcome the rate-limiting steps of metastatic cascade through (a) enhanced interactions with protumorigenic myeloid cells and escape from T-dependent immune response mediated by CD8+ and natural killer (NK) cells; (b) production of immune mediators that establish a local and systemic tumor-supportive environment (premetastatic niche); (c) ability to survive either in the peripheral blood as circulating tumor cells (CTCs) or at the metastatic site forming a cooperative prometastatic loop with foreign "myeloid" cells, macrophages, and neutrophils, respectively. The development of cancer-specific "immune resistance" can be orchestrated either by cooperation with tumor microenvironment or by successive rounds of genetic/epigenetic changes. Recognition of the applicability of this model may provide effective therapeutic avenues for complete elimination of immune-resistant metastatic cells and for enhanced antitumor immunity as part of a combinatorial strategy

Crosstalk between the tumor microenvironment and immune system in pancreatic ductal adenocarcinoma: Potential targets for new therapeutic approaches

Pancreatic ductal adenocarcinoma is a lethal disease for which radical surgery and chemotherapy represent the only curative options for a small proportion of patients. Recently, FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of metastatic patients but prognosis remains poor. A pancreatic tumor microenvironment is a dynamic milieu of cellular and acellular elements, and it represents one of the major limitations to chemotherapy efficacy. The continued crosstalk between cancer cells and the surrounding microenvironment causes immunosuppression within pancreatic immune infiltrate increasing tumor aggressiveness. Several potential targets have been identified among tumor microenvironment components, and different therapeutic approaches are under investigation. In this article, we provide a qualitative literature review about the crosstalk between the tumor microenvironment components and immune system in pancreatic cancer. Finally, we discuss potential therapeutic strategies targeting the tumor microenvironment and we show the ongoing trials

CD71 in Gestational Pathology: A Versatile Immunohistochemical Marker With New Possible Applications

Transferrin receptor/CD71 is a membrane protein expressed on nucleated red blood cells (NRBCs) and trophoblasts. Here, we propose the first study to evaluate the usefulness of CD71 immunolabeling in the main fields of gestational pathology. To this aim, formalin-fixed, paraffin-embedded samples of 45 orthotopic (23 spontaneous abortive and 22 molar pregnancies) and 11 ectopic pregnancies were immunostained for CD71. NRBCs were morphologically evident in 23 cases: 12/23 abortive, 4/11 ectopic, and 7/10 partial molar pregnancies. CD71 immunolabeling detected NRBCs in all 23 previous cases and in 8 new cases: 2 partial moles and 6 spontaneous abortive pregnancies. No NRBCs were detected in complete moles by means of either morphology or immunohistochemistry (IHC). In 4 cases with extensive necrotic changes, CD71 marked NRBCs and a few ghost villi, which were not certainly identifiable with standard histological evaluation. Furthermore, there was an inversely proportional relationship between total percentage of CD71-positive NRBCs and gestational age (R=0.69; P<0.0001). We conclude that CD71 is a robust IHC marker for the detection of NRBCs and chorionic villi, especially in the presence of necrosis. The demonstration of NRBCs can be important in molar pathology, helping to exclude a complete mole. The application of CD71 could improve the diagnosis of this pathology in selected cases in which diffuse necrotic or hemorrhagic aspects may hinder the interpretation of the conventional approach with histology, IHC for p57, and ploidy analysis. Finally, the inverse correlation between the total percentage of CD71-positive NRBCs and gestational age suggests that this analysis may help in pregnancy dating