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Even with the medicalization of HIV/AIDS, bringing programs and services into communities requires effective programs and service delivery systems. Developing and maintaining the capacities of these programs are critical. Because capacity building has become such an important part of HIV prevention work, greater attention must be given to the best practices in this area. In this article, the best practices and lessons learned from one national capacity building initiative are presented. Using a nonexperimental approach, the authors present 4 years of capacity building assistance service provision in the field of HIV prevention. [ABSTRACT FROM AUTHOR]

, , 603-607. Twenty-five patients in the National Heart Hospital have had aortic valve replacement with unsupported autologous fascia lata and have been followed for two to three and a half years. Three patients died before leaving hospital. Nine of the 22 survivors required re-operation for severe aortic regurgitation and the other 13 developed aortic incompetence. In 11, regurgitation dated from the operation and progressed; and in 11 it appeared later and progressed. In view of the disappointing results which were obvious within six months unsupported autologous fascia lata valves have not been used for aortic valve replacement since December 1970. [ABSTRACT FROM PUBLISHER]

Background: In 2018, the U.S. Army Surgeon General created the Army Medical Department Military-Civilian Trauma Team Training (AMCT3) program to enhance the clinical proficiency of medical personnel serving on Army trauma teams called forward resuscitative surgical detachments (FRSDs). FRSDs provide resuscitative and surgical care to wounded patients in the deployed environment until they can be medically evacuated to a higher level of care. Through AMCT3, FRSD personnel work at civilian trauma centers while not deployed in order to maintain their combat casualty care competency., Purpose: This article describes an innovative nursing-specific AMCT3 program model in which Army nurses serving on an FRSD are embedded within a level 1 trauma center for a 3-year assignment. The goal of the program, which was established at Vanderbilt University Medical Center (VUMC) in Nashville, Tennessee, is to improve participants' clinical proficiency and skills in preparation for the next major military conflict, with the aim of reducing preventable battlefield deaths., Methods: The VUMC Military Affairs Committee, in consultation with Army medical leaders, developed a unique 3-part model for a nursing partnership program at VUMC. This model includes separate tracks for critical care and emergency nurses. The nurses receive training in their specialty, cross-training in the opposite track, and other professional development opportunities. A critical care nurse and an emergency nurse were assigned to the program in January 2022 and September 2022, respectively., Results: Between January 2022 and June 2023, the critical care nurse completed all the required individual critical task lists-specialty-specific clinical skills Army medical personnel must be competent in before deployment-except for 1, obtaining intra-abdominal pressure., Conclusion: The VUMC AMCT3 nursing partnership training model ensures that Army nurses are highly prepared to function as part of the FRSD and to provide superior combat casualty care in a resource-limited environment., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A Provincial PPE Safety Coach Program was introduced to support appropriate use of personal protective equipment by health care workers. The objective was to understand barriers and facilitators to implementation., Methods: A qualitative study was conducted mid-2021. Participants were recruited using a purposive sampling strategy. Interviews were conducted using a guide informed by the Theoretical Domains Framework and Consolidated Framework for Implementation Research. Analysis was conducted using the Theoretical Domains Framework., Results: Prominent domains identified by staff were "social influences and skills", "environmental context and resources", "social/professional role and identity", "emotion", and "belief of consequences". Prominent domains identified by safety coaches were "knowledge", "social/professional role and identity", "environmental context and resources", and "memory". Only "environmental context and resources" and "social/professional role and identity" were similar. The main facilitators were fear of COVID-19 and leadership commitment, while the main barriers were lack of clarity and balancing the role., Discussion: Understanding the local context of a health care environment influenced the success of safety coaches. The role allowed individuals to develop leadership skills and help staff improve their perceived competence in using personal protective equipment., Conclusions: Safety coaches were well received. Influencing factors provide a basis for strategies to embed this approach throughout a health care system., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in the USA. Several studies have demonstrated the antitumor properties of saffron in different types of cancers, including prostate cancer. The oral administration of saffron extract has been reported to have antitumor effects on aggressive prostate-cancer-cell-line-derived xenografts in nude male mice. The objective of this study was to carry out in vitro studies of saffron-treated prostate cancer cells to ascertain the effects of saffron on key intermediates in prostate carcinogenesis. Our studies demonstrated the significant inhibition of cell proliferation for androgen-sensitive prostate cancer cell lines via apoptotic pathways. We also demonstrate the statistically significant down-regulation of DNA methyltransferases (COMT, MGMT, EHMT2, and SIRT1 deacetylase) in saffron-treated prostate cancer cells. In addition, saffron-treated prostate cancer cells displayed a statistically significant dysregulation of DNA repair intermediates (WRN, p53, RECQ5, MST1R, and WDR70) in a time-dependent manner. Furthermore, Western blot analysis demonstrated that saffron treatment induced changes in the expression of other key genes (DNMT1, DNMT3b, MBD2, CD44, HDAC3, c-Myc, NF-kB, TNFα, AR, N-RAS, and PTEN) in prostate cancer cells. Collectively, our findings demonstrate the important mechanisms by which saffron mediates anti-tumor properties in prostate cancer. These findings suggest that the use of saffron supplements alongside standard treatment protocols may yield beneficial effects for individuals with prostate cancer.

The synthesis and evaluation of a new anion receptor based on the 4-amido-1,8-naphthalimide scaffold is described. The findings indicate that the amide N-H is an enhanced H-bond donor but is otherwise restricted in its ability to participate in the binding of simple anions.

Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-κB (NF-κB) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-κB. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-κB activation in their bone marrow. Fifteen patients were treated, their median age was 71 (range 56-87), 33% were low and 67% int-1 by IPSS, median number of prior therapies was 2, all patients were transfusion dependent. Baseline median pp65 percentage was 31% and 11 patients had evidence of ring sideroblasts (RS). SC bortezomib was safe, well tolerated with no excess toxicity. Three patients out of the 15 (20%) had evidence of response with hematologic improvement (HI-E). Bortezomib caused a decrease in pp65 levels in 7 out of 13 evaluable patients (54%, P = .025). Of interest, unexpectedly, we observed a significant decrease in RS in 7 out of 10 (70%) evaluable patients during treatment. In conclusion, this study suggests that NF-κB activation, measured by pp65 levels, may be a useful biomarker in MDS. Bortezomib is safe in this patient population but has modest clinical activity. The role of the proteasome in the genesis of RS needs further study., (© 2017 Wiley Periodicals, Inc.)

XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.

Background: Tyrosine kinase inhibitors, such as crizotinib and erlotinib, are widely used to treat non-small-cell lung cancer, but after initial response, relapse is common because of the emergence of resistance through multiple mechanisms. Here, we investigated whether a frontline combination with an HSP90 inhibitor could delay the emergence of resistance to these inhibitors in preclinical lung cancer models., Methods: The HSP90 inhibitor, onalespib, was combined with either crizotinib or erlotinib in ALK- or EGFR-activated xenograft models respectively (H2228, HCC827)., Results: In both models, after initial response to the monotherapy kinase inhibitors, tumour relapse was observed. In contrast, tumour growth remained inhibited when treated with an onalespib/kinase inhibitor combination. Analysis of H2228 tumours, which had relapsed on crizotinib monotherapy, identified a number of clinically relevant crizotinib resistance mechanisms, suggesting that HSP90 inhibitor treatment was capable of suppressing multiple mechanisms of resistance. Resistant cell lines, derived from these tumours, retained sensitivity to onalespib (proliferation and signalling pathways were inhibited), indicating that, despite their resistance to crizotinib, they were still sensitive to HSP90 inhibition., Conclusions: Together, these preclinical data suggest that frontline combination with an HSP90 inhibitor may be a method for delaying the emergence of resistance to targeted therapies., Competing Interests: AC, TS, KH, HKS, NTT, JFL and NGW are employees of Astex Pharmaceuticals.

KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.

The Dispositional Hope Scale (DHS; Snyder et al., 1991) is composed of items assessing an individual's perception of his or her agency and pathways. This study examined support for the bifactor structure and relation of the factors in this model with depressive symptoms. It also examined cross-gender measurement invariance for the bifactor model. A community sample of 413 women and 257 men completed the DHS. Confirmatory factor analysis indicated more support for the bifactor model than the 1- and 2-factor models. Results also indicated full measurement invariance across gender for the bifactor and the 2-factor models. The general and the specific agency factors, but not the specific pathways factor, correlated with depressive symptoms. The better support for the bifactor model suggests that ideally hope has to be measured and examined by factors reflecting high covariance for agency and pathways, and also factors reflecting unique variances for agency and pathways. The support for full cross-gender measurement invariance indicated that there are no differences in measurement and scaling properties for the DHS across ratings provided by women and men, and therefore the DHS ratings can be scored in the same way for women and men.