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We described a copper(I)‐catalyzed atom economic and selective hydroamination‐cyclization of alkynyl‐tethered quinazolinones to prepare a variety of indole‐fused pyrazino[1,2‐a]quinazolinones in good to excellent yields ranging from 39 %–99 % under mild reaction conditions. Control experiments revealed that coordination‐directed method of quinazolinone moiety with copper(I) was important for the selective hydroamination‐cyclization of alkynes at the N1‐atom instead of N3‐atom of quinazolinone. The reaction could be easily performed at gram scales and some prepared indole‐fused pyrazino[1,2‐a]quinazolinones with donating groups on the indole moiety showed a distinct fluorescence emission wavelength with blue shift under the acid conditions. [ABSTRACT FROM AUTHOR]

Survival of Medulloblastoma (MB) depends on various factors, including the gene expression profiles of MB tumor tissues. In this study, we identified 967 MB survival-related genes (SRGs) using a gene expression dataset and the Cox proportional hazards regression model. Notably, the SRGs were over-represented on chromosomes 6 and 17, known for the abnormalities monosomy 6 and isochromosome 17 in MB. The most significant SRG was HMGA1 (high mobility group AT-hook 1) on chromosome 6, which is a known oncogene and a histone H1 competitor. High expression of HMGA1 was associated with worse survival, primarily in the Group 3γ subtype. The high expression of HMGA1 was unrelated to any known somatic copy number alteration. Most SRGs on chromosome 17p were associated with low expression in Group 4β, the MB subtype, with 93% deletion of 17p and 98% copy gain of 17q. GO enrichment analysis showed that both chromosomes 6 and 17 included SRGs related to telomere maintenance and provided a rationale for testing telomerase inhibitors in Group 3 MBs. We conclude that HMGA1, along with other SRGs on chromosomes 6 and 17, warrant further investigation as potential therapeutic targets in selected subgroups or subtypes of MB. [ABSTRACT FROM AUTHOR]

After over 3 decades of research, an effective anti-HIV vaccine remains elusive. The recently halted HVTN702 clinical trial not only further stresses the challenge to develop an effective HIV vaccine but also emphasizes that unconventional and novel vaccine strategies are urgently needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provided greater than 80% protection to Mauritian cynomolgus macaques against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses correlated with vaccine efficacy. The PCS vaccine did not induce immune activation or inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune microenvironment generated by the PCS vaccine was predictive of vaccine efficacy. Our study demonstrates, for the first time to our knowledge, that a vaccine which targets only viral maturation, but lacks full-length Env and Gag immunogens, can prevent intravaginal infection in a stringent macaque/SIV challenge model. Targeting HIV maturation thus offers a potentially novel approach to developing an effective HIV vaccine., Introduction HIV mutates rapidly and preferentially infects activated [CD4.sup.+] T cells. Inflammation activates and attracts HIV target cells, thereby enhancing the risk of infection (1-3). These inherent characteristics of HIV [...]

Genetic assistant positions are now widely integrated in genetic services to address genetic counselor shortages and ultimately improve efficiency. While over 40% of genetic counselors report working with a genetic assistant ("NSGC Professional Status Survey: Work Environment," 2022), there is limited information about the genetic assistant workforce. The present study surveyed 164 genetic assistants and 139 individuals with experience working with genetic assistants (specifically genetic counselors, residents, geneticists, and administrative staff). Information was collected about genetic assistant demographics, positions, roles and responsibilities, and career paths. The data revealed that the genetic assistant workforce is demographically similar to the genetic counselor workforce and that most genetic assistants intend to pursue a career in genetic counseling. The genetic assistant positions were heterogeneous in terms of the roles and responsibilities assigned, even when separated by work setting. Lastly, participants reported that there were at least 144 genetic assistants across their institutions, a number that has likely grown since the time of the survey. The findings from this study highlight important opportunities for future research and focus, especially development of a scope of practice and competencies for genetic assistants, as well as the potential to use genetic assistant positions as an avenue to improve diversity within the genetic counseling workforce. [ABSTRACT FROM AUTHOR]

Supramolecular nanocarriers (NCs) that are capable of responding to stimuli and actively targeting specific cells have garnered significant interest in recent years. However, designing multi-stimuli responsive nanocarriers with active targeting capabilities remains a challenge. To address this issue, we developed a temperature/enzyme dual-stimuli responsive supramolecular nanocarrier (AβCD/HA NC) through the electrostatic interaction between a cationic heptakis-(6-amino-6-deoxy)-β-cyclodextrin (AβCD) and anionic hyaluronic acid (HA). The AβCD/HA NC exhibited temperature/enzyme co-triggered assembly/disassembly behavior, which facilitated the loading, delivery, and release of the first-line anti-liver cancer drug doxorubicin (DOX). The release rate of DOX from the DOX-loaded AβCD/HA NC was found to be 82.4% at T = 45 °C and with the addition of hyaluronidase (HAase). During the uptake studies conducted on SMMC-7721 liver cancer cells, it was observed that the AβCD/HA NC significantly enhances the intracellular uptake of DOX, and the DOX present in the NC can efficiently be delivered to the cell nucleus. The cellular viability assay (MTS) demonstrated that the DOX-loaded NC not only provided a better inhibitory effect on SMMC-7721 liver cancer cells than free DOX and cisplatin, but also exhibited only one-tenth of the cytotoxicity of free DOX in BEAS-2B normal human epithelial cells. Our findings suggest that the AβCD/HA NC holds great promise for the targeted treatment of liver cancer cells. [ABSTRACT FROM AUTHOR]