A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer.

Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution-the selection of mutant clones in response to drug treatment-non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.

Sepsis among Patients Admitted to the Intensive Care Unit of a Tertiary Care Centre.

Introduction: Sepsis is a life-threatening dysfunction and is one of the common causes of admission in intensive care units. Early diagnosis and management improves the outcome of patients. The aim of this study was to find out the prevalence of sepsis among patients admitted to the intensive care unit of a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among patients admitted to the intensive care unit of a tertiary care centre after obtaining ethical approval from the Institutional Review Committee. Data of patients admitted from 1 February 2022 to 31 January 2023 was collected between 6 April 2023 to 27 April 2023. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Results: Among 1001 patients, the prevalence of sepsis was 278 (27.77%) (25-30.54, 95% Confidence Interval). Among them, 209 (75.17%) developed septic shock. The mean age was 56.6±19.34 years. Pneumonia 43 (15.46%) and genitourinary infection 43 (15.46%) were the most common sources of infection and the source was unknown in 124 (44.60%) of patients. Hypertension 75 (26.97%) was the most common comorbidity. Acute kidney injury 166 (59.71%) was the most common complication followed by thrombocytopenia 165 (59.35%) and transaminitis 79 (28.41%). Conclusions: The prevalence of sepsis among patients admitted to the intensive care unit was higher than other studies done in similar settings. Keywords: infection; intensive care unit; sepsis; tertiary care centre.

Addressing Drug Resistance in Cancer: A Team Medicine Approach.

Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. We then discuss how a 'Team Medicine' approach, involving an interdisciplinary team of basic scientists working together with clinicians, has uncovered new therapeutic strategies. These strategies, referred to as intermittent or 'adaptive' therapy, which are based on eco-evolutionary principles, have met with remarkable success in potentially precluding or delaying the emergence of drug resistance in several cancers. Incorporating such treatment strategies into clinical protocols could potentially enhance the precision of delivering personalized medicine to patients. Furthermore, reaching out to patients in the network of hospitals affiliated with leading academic centers could help them benefit from such innovative treatment options. Finally, lowering the dose of the drug and its frequency (because of intermittent rather than continuous therapy) can also have a significant impact on lowering the toxicity and undesirable side effects of the drugs while lowering the financial burden carried by the patient and insurance providers.

Preparations for and practices of online education during the Covid-19 pandemic: A study of Bangladesh and Nepal.

Online education has been adopted widely to address the educational chaos created by the Covid-19 pandemic. Reports on its constraints and challenges appear daily in the global media. However, accounts of teachers' and students' experiences of this abrupt shift in pedagogical modality are conspicuously absent in the available literature. This article reports the findings of a study that explored teachers' and students' experiences of online education during the pandemic in the context of higher education in Bangladesh and Nepal. The online survey with 147 students and 76 teachers and interviews with a sub-sample of 17 participants indicate that they adapt the action potentials of the digital artifacts to local contexts and use them in the best possible ways to facilitate their communication and enhance student learning in difficult circumstances. The major challenges and constraints they experience in transitioning to online education include poor network, lack of digital skills, lack of technological support from institutions among others. The study findings indicate some pressing policy, pedagogical and research implications, which are discussed in the final section.

Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.