Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors
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Weak ties and the value of social connections for autistic people as revealed during the COVID-19 pandemic
A diverse portfolio of social relationships matters for people’s wellbeing, including both strong, secure relationships with others (‘close ties’) and casual interactions with acquaintances and strangers (‘weak ties’). Almost all of autism research has focused on Autistic people’s close ties with friends, family and intimate partners, resulting in a radically constrained understanding of Autistic sociality. Here, we sought to understand the potential power of weak-tie interactions by drawing on 95 semi-structured interviews with Autistic young people and adults conducted during the COVID-19 pandemic. We analysed the qualitative data using reflexive thematic analysis within an essentialist framework. During the COVID-19 lockdowns, Autistic people deeply missed not only their close personal relationships but also their “incidental social contact” with acquaintances and strangers. These weak-tie interactions appear to serve similar functions for Autistic people as they do for non-autistic people, including promoting wellbeing. These findings have important implications both for future research into Autistic sociality and for the design of practical services and supports to enhance Autistic people’s opportunities to flourish.
High baseline levels of PD-L1 reduce the heterogeneity of immune checkpoint signature and sensitize anti-PD1 therapy in lung and colorectal cancers
Immune checkpoint blockade (ICB) therapy only induces durable responses in a subset of cancer patients. The underlying mechanisms of such selective efficacy remain largely unknown. By analyzing the expression profiles of immune checkpoint molecules in different statuses of murine tumors, we found that tumor progression generally randomly upregulated multiple immune checkpoints, thus increased the Heterogeneity of Immune checkpoint Signature (HIS) and resulted in immunotherapeutic resistance. Interestingly, overexpressing one pivotal immune checkpoint in a tumor hindered the upregulation of a majority of other immune checkpoint genes during tumor progression via suppressing interferon γ, resulting in HIS-low. Indeed, PD-L1 high-expression sensitized baseline large tumors to anti-PD1 therapy without altering the sensitivity of baseline small tumors. In line with these preclinical results, a retrospective analysis of a phase III study involving patients with non-small cell lung cancer (NSCLC) revealed that PD-L1 tumor proportion score (TPS) ≥ 50% more reliably predicted therapeutic response in NSCLC patients with baseline tumor volume (BTV)-large compared to patients with BTV-small. Notably, TPS combined with BTV significantly improved the predictive accuracy. Collectively, the data suggest that HIS reflects the dynamic features of tumor immune evasion and dictates the selective efficacy of ICB in a tumor size-dependent manner, providing a potential novel strategy to improve precision ICB. These findings highlight the application of ICB to earlier stages of cancer patients. The integration of PD-L1 with BTV may immediately improve patient stratification and prediction performance in the clinic.
Neuroinflammatory fluid biomarkers in patients with Alzheimer’s disease: a systematic literature review
Neuroinflammation is associated with both early and late stages of the pathophysiology of Alzheimer’s disease (AD). Fluid biomarkers are gaining significance in clinical practice for diagnosis in presymptomatic stages, monitoring, and disease prognosis. This systematic literature review (SLR) aimed to identify fluid biomarkers for neuroinflammation related to clinical stages across the AD continuum and examined long-term outcomes associated with changes in biomarkers.
Targeting CDK4/6 in breast cancer
Dysregulation of the cell cycle machinery, particularly the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark of breast cancer pathogenesis. The introduction of CDK4/6 inhibitors has transformed the treatment landscape for hormone receptor-positive breast cancer by effectively targeting abnormal cell cycle progression. However, despite their initial clinical success, drug resistance remains a significant challenge, with no reliable biomarkers available to predict treatment response or guide strategies for managing resistant populations. Consequently, numerous studies have sought to investigate the mechanisms driving resistance to optimize the therapeutic use of CDK4/6 inhibitors and improve patient outcomes. Here we examine the molecular mechanisms regulating the cell cycle, current clinical applications of CDK4/6 inhibitors in breast cancer, and key mechanisms contributing to drug resistance. Furthermore, we discuss emerging predictive biomarkers and highlight potential directions for overcoming resistance and enhancing therapeutic efficacy.
Management practices and manufacturing firm responses to a randomized energy audit
Increasing the efficiency of industrial energy use is widely considered important for mitigating climate change. We randomize assignment of an energy audit intervention aimed at improving energy efficiency and reducing energy expenditures of small- and medium-sized metal processing firms in Shandong Province, China, and examine impacts on energy outcomes and interactions with firms’ management practices. We find that the intervention reduced firms’ unit cost of electricity by 8% on average. Firms with more developed structured management practices showed higher rates of recommendation adoption. However, the post-intervention electricity unit cost reduction is larger in firms with less developed practices, primarily driven by a single recommendation that corrected managers’ inaccurate reporting of transformer usage at baseline, lowering their electricity costs. By closing management-associated gaps in awareness of energy expenditures, energy audit programmes may reduce a firm’s unit cost of energy but have an ambiguous impact on energy use and climate change.
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