Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

Short-Duration Prednisolone in Children with Nephrotic Syndrome Relapse: A Noninferiority Randomized Controlled Trial

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Technique of flap elevation for robot assisted selective neck dissection via retroauricular approach: a surgeon’s guide

Journal of Robotic Surgery - The retroauricular approach is being increasingly used in surgeries of head and neck in an attempt to avoid a disfiguring scar over the face or neck. The elevation of...     

An observational analysis of low-dose thalidomide in recalcitrant prurigo nodularis

Thalidomide has been used as an effective treatment for prurigo nodularis (PN) with a median dose of 200 mg, but the risk of peripheral neuropathy precludes long-term use. We analysed the efficacy of low-dose thalidomide (< 100 mg) in 17 patients with recalcitrant PN. Patients were initiated on thalidomide 50 mg on alternate days, and the dose was increased (doubled) in a stepwise manner, if needed, until a ≥ 50% reduction in score (partial response; PR) on a visual analogue scale (VAS) was achieved. Thalidomide then was continued at the same dose for 4 weeks to achieve ≥ 90% decrease in VAS score; if this was not achieved, the dose was increased to a maximum of 100 mg and continued until complete resolution of lesions (complete response; CR). Four patients discontinued thalidomide due to adverse effects. Four patients achieved PR, while 9 patients (n = 2 with 50 mg, n = 7 with 100 mg) achieved CR. No patient developed neuropathy. In addition, complete responders achieved an earlier ≥ 50% reduction in VAS score. Two patients relapsed after 12 months but responded to thalidomide 50 mg.     

PMP22 Gene–Associated Neuropathies: Phenotypic Spectrum in a Cohort from India

Journal of Molecular Neuroscience - Reports of spectrum of clinical manifestations in PMP22 gene–associated neuropathies (duplication/mutations) are scarce. To identify the frequency of PMP22...     

Male circumcision for HIV prevention in India: emerging viewpoints and practices of health care providers

A compelling case for promoting male circumcision (MC) as an intervention for reducing the risk of heterosexually acquired HIV infection was made by dissemination of the results of three studies in Africa. The WHO/UNAIDS recommendation for MC for countries like India, where the epidemic in concentrated in high-risk groups, advocates MC for specific population groups such as men at higher risk for HIV acquisition. A multicentre qualitative study was conducted in four geographically distinct districts (Belgaum, Kolkata, Meerut and Mumbai) in India during June 2009 to June 2011. Two categories of health care providers: Registered Healthcare Providers (RHCPs) and traditional circumcisers were interviewed by trained research staff who had received master's level education using interview guides with probes and open-ended questions. Respondents were selected using purposive sampling. A comparative analysis of the perspectives of the RHCP vs. traditional circumcisers is presented. Representatives of both categories of providers expressed the need for Indian data on MC. Providers feared that promoting circumcision might jeopardize/undermine the progress already made in the field of condom promotion. Reservation was expressed regarding its adoption by Hindus. Behavioural disinhibition was perceived as an important limitation. A contrast in the practice of circumcision was apparent between the traditional and the trained providers. MC should be mentioned as a part of comprehensive HIV prevention services in India that includes HIV counselling and testing, condom distribution and diagnosis and treatment of sexually transmitted infections. It should become an issue of informed personal choice rather than ethnic identity.