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Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.

We estimate the demand for subsidized insurance in the Affordable Care Act marketplaces using administrative enrollment data for the 39 states that used Healthcare.gov between 2015 and 2017. Our results expand the existing literature on marketplace take-up, the extensive margin, in several important ways. First, we provide the first estimates of price elasticities based on administrative data from states with Federally Facilitated Marketplaces, which accounted for three-quarters of all marketplace enrollment and include states that did not expand Medicaid. Our estimates suggest that price elasticities may be lower in our sample of states than in states such as California (a major data source for other studies), which expanded Medicaid and pursued policies that may have increased price sensitivity. Our analysis also yields new evidence suggesting that many people in the coverage gap in non-expansion states obtain subsidies by reporting income just above the federal poverty line at the time of enrollment, especially in Florida. Finally, we update the existing literature describing higher demand for insurance coverage by women by estimating the difference in take-up rates by gender while controlling for eligibility for subsidies, finding that these gender differences persist among both young and older adults. [ABSTRACT FROM AUTHOR]

An interview with doctor Andrew Hopper, exploring his journey and insights into neonatology. Topics include essential qualities for excelling as a neonatologist, the evolving advancements and challenges in the field, and advice for aspiring neonatologists to enhance their training and career preparation.

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

Purpose of Review: Triple negative breast cancer remains a diagnosis that strikes fear into patients and providers alike due to its associated treatment challenges and natural history. The recent decades have seen significant advances in the field of breast cancer radiation oncology, and in this review we seek to highlight current standards of care, the historic basis for current recommendations, and future directions. Recent Findings: Advances in the field of breast radiation oncology have been numerous in the recent decades and include various hypofractionated regimens, new data and nuances in the administration of regional nodal radiation, new systemic agents and combinations with radiotherapy, and novel strategies that radically change current treatment paradigms. In this review, we will navigate the applicability of these data and approaches to the management of triple negative breast cancer. Summary: Triple negative breast cancer remains a challenging disease process, but one that we have seen considerable advancement in the management of in the recent decades. We are optimistic that patients will continue to benefit from treatment approaches that improve disease control and quality of life. [ABSTRACT FROM AUTHOR]

The article focuses on the alarming rise in congenital syphilis cases, which have increased by 740 percent over the past decade. Topics include the racial disparities in case rates, barriers to timely testing and treatment, and the Centers for Disease Control and Prevention's efforts to combat syphilis through guidelines and expanded testing options.

The article focuses on the declined interest in doing a pediatric residency. Topics discussed include residency characteristics that are important to pediatric residency applicants, factors that could explain why gender diversity and research emphasis are less valued during the pediatric residency application process, and reasons for the decreased interest in pediatric subspecialties in the length of training.

This article investigates the challenges of navigating the adoption of remote and hybrid working for large organizations with diverse functions. Focus groups with employees of the UK business of a multinational organization identify conceptual contributions to the sociology of work and employment and empirical findings in the context of the COVID-19 pandemic that inform future policy and practice. Location-based flexible working has a potential unintended 'ripple' effect wherein application of individual-level flexibility has wider-reaching consequences throughout the organization. Findings emphasize that organizations need to recognize and respond to new realities of location-based flexibility. Management must navigate potential 'ripples' in the development of flexible working policies and practice, shaped by various tensions, including an overarching autonomy–control paradox. This requires a coordinated approach centred on 'inclusive flexibility' and 'responsible autonomy' that involves moving away from one-size-fits-all strategies towards a tailored approach offering employees choice, agency and voice in decision-making, while accommodating different stakeholder needs. [ABSTRACT FROM AUTHOR]

The article focuses on neonatal bacterial meningitis, a life-threatening infection with high mortality and morbidity rates in neonates. Topics discussed include the leading causes of meningitis, particularly Group B Streptococcus, risk factors associated with infection, and the critical importance of early diagnosis and treatment.