Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Reducing sexual risk and promoting acceptance of men who have sex with men living with HIV in India: Outcomes and process evaluation of a pilot randomised multi-level intervention

ABSTRACT

HIV-positive men who have sex with men (HIV+MSM) in India need culturally-relevant interventions to promote safer sex. We tested a multi-level intervention among HIV+MSM that targeted individual, interpersonal, and community factors, based on the Social-Personal and Social Ecological Models. We conducted a 2?×?2 factorial RCT with 119 HIV+MSM randomised to receive either an individual-level intervention (ILI) using motivational interviewing to promote safer sex, a community-level intervention (CLI) to strengthen community norms toward safer sex and reduce stigma among MSM communities, a multi-level intervention combining the individual- and community-level interventions (ILI?+?CLI), or standard-of-care control. Participants completed pre- and post-intervention assessments of a composite sexual risk score and a process evaluation to assess fidelity and satisfaction. Out of the 119 HIV+MSM, 106 (89.0%) completed pre- and post-intervention assessments. Generalised Estimating Equation models showed that both CLI (Incidence Rate Ratio [IRR]?=?.67, 95% CI .47 to .96) and ILI?+?CLI (IRR?=?.66, 95% CI .48 to .91) groups had a statistically significant decrease in sexual risk compared to the standard-of-care. The interventions had high levels of fidelity and satisfaction. This pilot RCT demonstrated feasibility and potential effectiveness of a multi-level intervention that addresses individual, interpersonal and community-level contributors of sexual risk among HIV+MSM.     

PAHs and PM2.5 emissions and female breast cancer incidence in metro Atlanta and rural Georgia

Environmental chemical exposure could be an important etiologic factor for geographic differences in breast cancer incidence. In this study, we examined emissions of polycyclic aromatic hydrocarbons (PAHs) and PM_2.5 in relation to breast cancer incidence in metro Atlanta and rural Georgia by analyzing data from the Surveillance, Epidemiology, and End Results Program and the Environmental Protection Agency. The results showed that metro Atlanta had a significantly higher age-adjusted annual incidence rate of female breast cancer than rural Georgia (132.6 vs. 113.7 per 100,000) for 1992–2011. Emissions of both PAHs [adjusted β = 0.568 (95 % CI: 0.209, 0.927); p = 0.004] and PM_2.5 [adjusted β = 2.964 (95 % CI: 0.468, 5.459); p = 0.023] were significantly associated with breast cancer incidence in metro Atlanta area. This study suggests that ambient air pollution, especially PAHs and PM_2.5, could have a significant impact on the increased incidence of female breast cancer in urban areas.     

Impact of the COVID-19 lockdown on digital device-related ocular health

Purpose:Since the declaration of the lockdown due to COVID-19, the usage of digital devices has gone up across the globe, resulting in a challenge for the visual systems of all ages. The purpose of this study is to assess the impact of the lockdown on digital device usage, and consequently, the ocular surface health implications and circadian rhythm abnormalities related to digital eye strain.Methods:An open online survey was sent through various social media platforms and was open for a period of 2 weeks.Results:A total of 407 usable responses were obtained; the average age of respondents was 27.4 years. Typically, 93.6% of respondents reported an increase in their screen time since the lockdown was declared. The average increase in digital device usage was calculated at about 4.8 ± 2.8 h per day. The total usage per day was found to be 8.65 ± 3.74 hours. Sleep disturbances have been reported by 62.4% of people. Typically, 95.8% of respondents had experienced at least one symptom related to digital device usage, and 56.5% said that the frequency and intensity of these symptoms increased since the lockdown was declared.Conclusion:The study highlighted the drastic increase in use of digital devices after the initiation of the COVID-19 lockdown, and along with it, the slow deterioration of ocular health across all age groups. Awareness about prevention of digital eye strain should be stressed, and going forward, measures to bring these adverse effects to a minimum should be explored.     

Drug discovery strategies for acute radiation syndrome

Introduction: There are at the minimum two major, quite different approaches to advance drug discovery. The first being the target-based drug discovery (TBDD) approach that is commonly referred to as the molecular approach. The second approach is the phenotype-based drug discovery (PBDD), also known as physiology-based drug discovery or empirical approach.

Area covered: The authors discuss, herein, the need for developing radiation countermeasure agents for various sub-syndromes of acute radiation syndromes (ARS) following TBDD and PBDD approaches. With time and continuous advances in radiation countermeasure drug development research, the expectation is to have multiple radiation countermeasure agents for each sub-syndrome made available to radiation exposed victims.

Expert opinion: The majority of the countermeasures currently being developed for ARS employ the PBDD approach, while the TBDD approach is clearly under-utilized. In the future, an improved drug development strategy might be a ‘hybrid’ strategy that is more reliant on TBDD for the initial drug discovery via large-scale screening of potential candidate agents, while utilizing PBDD for secondary screening of those candidates, followed by tertiary analytics phase in order to pinpoint efficacious candidates that target the specific sub-syndromes of ARS.     

Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells

CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.