Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73.

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers

A double whammy:the association between comorbidities and severe dengue among adult patients-a matched case-control study

BACKGROUND: Dengue infection is the most prevalent mosquito-borne viral infection globally. Concurrently, there has also been an upsurge of non-communicable comorbidities. We aimed to investigate the association between these comorbidities and the development of severe dengue. METHODS: We performed a retrospective, case-control study involving 117 cases with severe dengue and 351 controls with non-severe dengue; matched according to gender, age (+/- 5 years old), and admission date (+/- 2 weeks). We analyzed the data using conditional odds ratio (cOR) and adjusted conditional odds ratio (AcOR) using univariate and multivariable conditional logistic regression respectively. RESULTS: Six main comorbidities namely obesity, diabetes mellitus, hypertension, hyperlipidemia, chronic pulmonary disease, and ischemic heart disease were observed among cases and controls. Multivariable conditional logistic regression model found only hypertension to be independently associated with the development of severe dengue (ACOR 2.46; 95% CI:1.09–5.53). Among symptoms at presentation, lethargy, vomiting, bleeding manifestations, and abdominal pain were associated with increased odds of severe dengue, although the associations were not statistically significant. Headache (ACOR: 0:32; 95% CI: 0.21–0.51) and skin rash (ACOR: 0.42; 95% CI: 0.22–0.81) were associated with significantly lower odds of severe dengue. Severe dengue patients were also found to have significantly higher white cell count, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, creatine kinase, and lactate dehydrogenase on admission, while platelet and albumin were significantly lower compared to non-severe dengue patients. CONCLUSIONS: Our study found a significant association between hypertension and the development of severe dengue in adult patients. For clinical practice, this finding suggests that dengue patients with underlying hypertension warrant closer clinical monitoring for deterioration. The association between significant derangement in various laboratory parameters and severe dengue as shown in this study is in keeping with previous reports. While further substantiation by larger prospective studies will be desirable, this association may serve to inform the dengue triaging process

Baseline Characteristics of cases (severe dengue) and controls (non-severe dengue).

Baseline Characteristics of cases (severe dengue) and controls (non-severe dengue).</p

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(DOCX)</p

Conditional odds ratio (cOR) and adjusted conditional odds ratio (AcOR) for the association between comorbidities and severe dengue.

Conditional odds ratio (cOR) and adjusted conditional odds ratio (AcOR) for the association between comorbidities and severe dengue.</p

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(DOCX)</p

Admission laboratory parameters of cases (severe dengue) compared to controls (non-severe dengue).

Admission laboratory parameters of cases (severe dengue) compared to controls (non-severe dengue).</p

Clinical presentation on admission of cases (severe dengue) compared to controls (non-severe dengue).

Clinical presentation on admission of cases (severe dengue) compared to controls (non-severe dengue).</p

The impact of online education during the Covid-19 pandemic on the professional identity formation of medical students: A systematic scoping review.

Evolving individual, contextual, organizational, interactional and sociocultural factors have complicated efforts to shape the professional identity formation (PIF) of medical students or how they feel, act and think as professionals. However, an almost exclusive reliance on online learning during the COVID-19 pandemic offers a unique opportunity to study the elemental structures that shape PIF and the environmental factors nurturing it. We propose two independent Systematic Evidence-Based Approach guided systematic scoping reviews (SSR in SEBA)s to map accounts of online learning environment and netiquette that structure online programs. The data accrued was analysed using the clinically evidenced Krishna-Pisupati Model of Professional Identity Formation (KPM) to study the evolving concepts of professional identity. The results of each SSR in SEBA were evaluated separately with the themes and categories identified in the Split Approach combined to create richer and deeper 'themes/categories' using the Jigsaw Perspective. The 'themes/categories' from each review were combined using the Funnelling Process to create domains that guide the discussion. The 'themes/categories' identified from the 141 included full-text articles in the SSR in SEBA of online programs were the content and effects of online programs. The themes/categories identified from the 26 included articles in the SSR in SEBA of netiquette were guidelines, contributing factors, and implications. The Funnelling Process identified online programs (encapsulating the content, approach, structures and the support mechanisms); their effects; and PIF development that framed the domains guiding the discussion. This SSR in SEBA identifies the fundamental elements behind developing PIF including a structured program within a nurturing environment confined with netiquette-guided boundaries akin to a Community of Practice and the elemental aspect of a socialisation process within online programs. These findings ought to be applicable beyond online training and guide the design, support and assessment of efforts to nurture PIF

The role of mentoring, supervision, coaching, teaching and instruction on professional identity formation: a systematic scoping review

Abstract Background Mentoring’s pivotal role in nurturing professional identity formation (PIF) owes much to its combined use with supervision, coaching, tutoring, instruction, and teaching. However the effects of this combination called the ‘mentoring umbrella’ remains poorly understood. This systematic scoping review thus aims to map current understanding. Methods A Systematic Evidence-Based Approach guided systematic scoping review seeks to map current understanding of the ‘mentoring umbrella’ and its effects on PIF on medical students and physicians in training. It is hoped that insights provided will guide structuring, support and oversight of the ‘mentoring umbrella’ in nurturing PIF. Articles published between 2000 and 2021 in PubMed, Scopus, ERIC and the Cochrane databases were scrutinised. The included articles were concurrently summarised and tabulated and concurrently analysed using content and thematic analysis and tabulated. The themes and categories identified were compared with the summaries of the included articles to create accountable and reproducible domains that guide the discussion. Results A total of 12201 abstracts were reviewed, 657 full text articles evaluated, and 207 articles included. The three domains identified were definitions; impact on PIF; and enablers and barriers. The mentoring umbrella shapes PIF in 3 stages and builds a cognitive base of essential knowledge, skills and professional attitudes. The cognitive base informs thinking, conduct and opinions in early supervised clinical exposure in Communities of practice (COP). The COPs’ individualised approach to the inculcation of desired professional characteristics, goals, values, principles and beliefs reshapes the individual’s identity whilst the socialisation process sees to their integration into current identities. Conclusion The mentoring umbrella’s provides personalised longitudinal support in the COP and socialisation process. Understanding it is key to addressing difficulties faced and ensuring holistic and timely support. </jats:sec