This second edition of A Charter School Principal's Story shares the impact of a leadership experience in a DC school within a greater context of education as told through the critical and creative ...lens of ten years of reflection.
While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is ...not known.
PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor.
Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24-0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10-0.31) and HER2
(HR = 0.32; 95% PI, 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19-0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27-0.54), with no significant difference between the two groups (
= 0.60).
Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2
breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response.
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Although asexual reproduction via clonal propagation has been proposed as the principal reproductive mechanism across parasitic protozoa of the Leishmania genus, sexual recombination has long been ...suspected, based on hybrid marker profiles detected in field isolates from different geographical locations. The recent experimental demonstration of a sexual cycle in Leishmania within sand flies has confirmed the occurrence of hybridisation, but knowledge of the parasite life cycle in the wild still remains limited. Here, we use whole genome sequencing to investigate the frequency of sexual reproduction in Leishmania, by sequencing the genomes of 11 Leishmania infantum isolates from sand flies and 1 patient isolate in a focus of cutaneous leishmaniasis in the Çukurova province of southeast Turkey. This is the first genome-wide examination of a vector-isolated population of Leishmania parasites. A genome-wide pattern of patchy heterozygosity and SNP density was observed both within individual strains and across the whole group. Comparisons with other Leishmania donovani complex genome sequences suggest that these isolates are derived from a single cross of two diverse strains with subsequent recombination within the population. This interpretation is supported by a statistical model of the genomic variability for each strain compared to the L. infantum reference genome strain as well as genome-wide scans for recombination within the population. Further analysis of these heterozygous blocks indicates that the two parents were phylogenetically distinct. Patterns of linkage disequilibrium indicate that this population reproduced primarily clonally following the original hybridisation event, but that some recombination also occurred. This observation allowed us to estimate the relative rates of sexual and asexual reproduction within this population, to our knowledge the first quantitative estimate of these events during the Leishmania life cycle.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adipose tissue is an essential regulator of metabolic homeostasis. In contrast with white adipose tissue, which stores excess energy in the form of triglycerides, brown adipose tissue is thermogenic, ...dissipating energy as heat via the unique expression of the mitochondrial uncoupling protein UCP1. A subset of UCP1+ adipocytes develops within white adipose tissue in response to physiological stimuli; however, the developmental origin of these “brite” or “beige” adipocytes is unclear. Here, we report the identification of a BMP7-ROCK signaling axis regulating beige adipocyte formation via control of the G-actin-regulated transcriptional coactivator myocardin-related transcription factor A, MRTFA. White adipose tissue from MRTFA–/– mice contains more multilocular adipocytes and expresses enhanced levels of brown-selective proteins, including UCP1. MRTFA–/– mice also show improved metabolic profiles and protection from diet-induced obesity and insulin resistance. Our study hence unravels a central pathway driving the development of physiologically functional beige adipocytes.
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•BMP7 induces brown adipogenesis in mesenchymal stem cells•BMP7 inhibits ROCK and promotes F- to G-actin conversion•Overexpression of MRTFA or SRF inhibits brown adipogenesis•Loss of MRTFA promotes browning and resistance to obesity
A signaling axis driven by ROCK and the transcription factor MRTFA regulates the conversion of mesenchymal stem cells (MSCs) to brown-like (beige) adipocytes. Small molecule inhibitors or loss of MRTFA in mice leads to beige adipocyte formation, enhanced energy expenditure, and protection against diet-induced obesity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some ...viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we show that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 lytic replication via this mechanism.
Caraco et al discuss the need to humanize psychiatric advance directives. The use of advance directives, wellness self-management, and supported decision making are commonplace in the US medical ...system. Primary and preventive medicine, cardiology, oncology, and palliative care provide education to aid patients in taking care of their own health and exercising their right to receive or decline treatment. Such guidance promotes bodily autonomy and preserves dignity. The principles behind these practices are key to ethical practice. However, during psychiatric treatment, these same principles frequently are not followed. Rather, the presumptive expertise and power lie within the treatment community and not with the patient. The expectation is treatment adherence, often with legal consequences for not doing so.
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