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Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials.

Background In response to the opioid epidemic, naloxone distribution programs aim to prevent overdose death by making naloxone available and training people to use it. Peers of individuals at risk of opioid overdose are well-positioned to administer naloxone and prevent overdose death. Methods We conducted key informant interviews with 18 individuals with past or current opioid and heroin drug use who had administered naloxone to a peer during an overdose emergency. Interviews explored individuals’ experiences with administration and their recommendations for program and policy improvement. Data were systematically coded and analyzed for themes. Results Participants sought naloxone rescue kits because they perceived high risk of overdose. They described high satisfaction with training and felt prepared to administer naloxone during overdose incidents. Overwhelmingly, participants perceived naloxone to be effective and emphasized the need to make it widely available. Findings suggest that engagement in overdose prevention strategies other than naloxone differs by gender, with females more likely than males to use multiple different strategies. Participants described that overdose experiences do not have a lasting impact on drug use behaviors. Conclusions Findings support the feasibility of naloxone distribution to peer opioid and heroin users and provide recommendations for policy improvement, including effective and well-advertised Good Samaritan laws and links to treatment for opioid use disorder.

This article is rooted in the narratives of four disabled people with obvious impairments within higher education institutions (HEI). Their lived experiences highlight how the adoption of the neoliberal agenda by HEIs has ensured the continued exclusion of disabled academics. This article shares how the implementation of mainstream business structures, and the business ethos, has been experienced by disabled academics seeking equality of education and professional academic opportunities. It demonstrates the personal impacts that can occur when institutions vehemently value income over inclusion and when academic staff adhere to these standards. If the doors to academia were closed to disabled people in the past, neoliberalism has surely locked them.

Military children don't exist in a vacuum; rather, they are embedded in and deeply influenced by their families, neighborhoods, schools, the military itself, and many other interacting systems. To minimize the risks that military children face and maximize their resilience, write Harold Kudler and Colonel Rebecca Porter, we must go beyond clinical models that focus on military children as individuals and develop a public health approach that harnesses the strengths of the communities that surround them. In short, we must build communities of care. One obstacle to building communities of care is that at many times and in many places, military children and their families are essentially invisible. Most schools, for example, do not routinely assess the military status of new students' parents. Thus Kudler and Porter's strongest recommendation is that public and private institutions of all sorts—from schools to clinics to religious institutions to law enforcement—should determine which children and families they serve are connected to the military as a first step toward meeting military children's unique needs. Next, they say, we need policies that help teachers, doctors, pastors, and others who work with children learn more about military culture and the hardships, such as a parent's deployment, that military children often face. Kudler and Porter review a broad spectrum of programs that may help build communities of care, developed by the military, by nonprofits, and by academia. Many of these appear promising, but the authors emphasize that almost none are backed by strong scientific evidence of their effectiveness. They also describe new initiatives at the state and federal levels that aim to break down barriers among agencies and promote collaboration in the service of military children and families.

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression - and its correlation with EMT and anticorrelation with IFN-response genes - was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.

Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE) and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear beta-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis.

Immune checkpoint inhibitors (ICI) synergize preclinically with antibody drug conjugates (ADC), harboring anti-tubulin maytansinoid payloads. We conducted an investigator-initiated, single-arm, phase 2 trial of mirvetuximab soravtansine (MIRV), a folate receptor alpha (FOLR1/FRα)-targeting ADC with the maytansinoid payload, DM4, combined with pembrolizumab in female patients with recurrent FOLR1-expressing serous endometrial cancer (EC, NCT03835819). Co-primary objectives include objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6); secondary objectives include PFS, overall survival, duration of response and safety. Exploratory objectives include correlation of tumor genomics and immunoprofiling with clinical activity. Eighteen patients initiated protocol therapy [MIRV 6 mg/kg adjusted ideal body weight IV and pembrolizumab 200 mg IV every 3 weeks]. Confirmed ORR is 28% (1 complete and 4 partial responses, 95% CI:10-53%), Kaplan Meier estimate of PFS6 is 24.4% (95% CI:7.7-46.1%) with 4 patients progression free at 6 months; trial was closed early for feasibility (planned sample size of 35 patients not reached) and hence these results are considered preliminary. G3 treatment-related adverse effects were rare with no grade ≥4 toxicities. We report a population of high FOLR1-expressing tumor-associated macrophages (CD163 + FOLR1 + ), suggesting potential on-target, off-tumor immune editing by MIRV. A composite biomarker score derived in this cohort correlates with objective response to MIRV and pembrolizumab.

Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non-randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). Primary objectives include objective response rate (ORR) and rate of progression-free survival (PFS) at 6 months (PFS6) while secondary objectives include PFS, overall survival, duration of response and toxicity. Twenty-five patients initiate protocol therapy [letrozole 2.5 mg orally (PO) once a day (qd), abemaciclib 150 mg PO twice a day (bid) and metformin 500 mg PO qd]. ORR is 32% (3 complete and 5 partial responses, 95% CI 14.9%-53.5%), Kaplan Meier estimate of PFS6 is 69.8% (95% CI 46.9%-84.3%) and median PFS is 19.4 months (95% CI 5.7 months–not estimable). No patients discontinue therapy because of toxicity. There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3-fold increase in metformin exposure. Combined hormonal therapy and CDK4/6 inhibition face resistance challenges in endometrial cancer. Here, the authors present a phase 2, one-arm clinical trial, where metformin is combined with letrozole (hormonal therapy) and abemaciclib (a CDK4/6 inhibitor) reporting safety and efficacy in patients with endometrial cancer.

Pervasive transcription of eukaryotic genomes generates a plethora of noncoding RNAs. In fission yeast, the heterochromatin factor Clr4/Suv39 methyltransferase facilitates RNA interference (RNAi)—mediated processing of centromeric transcripts into small interfering RNAs (siRNAs). Clr4 also mediates degradation of antisense RNAs at euchromatic loci, but the underlying mechanisms has remained elusive. We show that Clr4 and the RNAi effector RITS (RNA-induced transcriptional silencing) interact with Mlo3, a protein related to mRNA quality control and export factors. Loss of Clr4 impairs RITs interaction with Mlo3, which is required for centromeric siRNA production and antisense suppression. Mlo3 also interacts with the RNA surveillance factor TRAMP, which suppresses antisense RNAs targeted by Clr4 and RNAi. These findings link Clr4 to RNA quality control machinery and suggest a pathway for processing potentially deleterious RNAs through the coordinated actions of RNAi and other RNA processing activities.

Purpose: This study aimed to address the knowledge gap between implementing and sustaining evidence-based fall prevention practices for hospitalized patients by exploring perspectives of the interprofessional health care team. Design: A qualitative design was used to capture insights from clinicians across disciplines in a large midwestern academic medical center. Methods: Four homogenous semistructured focus groups and three individual interviews involving a total of 20 clinicians were conducted between October 2013 and March 2014. Audio-recorded data were transcribed and analyzed using inductive qualitative analysis. Findings: Two primary themes emerged from participants regarding the sustainability of an evidence-based fall prevention program: communication patterns within the interprofessional health care team and influences of hospital organizational practices and elements. Several subthemes also emerged. Participants gave nursing staff primary responsibility for fall risk assessment and prevention. Conclusions: Individual professional perceptions and practices, as well as organizational characteristics, affect the sustainability of evidence-based fall prevention practices. While all team members recognized patient falls as a significant quality and safety issue, most believed that direct care nurses hold primary responsibility for leading fall prevention efforts. The data support the importance of effective interprofessional team communication and organizational practices in sustaining an evidence-based fall prevention program across inpatient units. Furthermore, the data call into question the wisdom in labeling quality indicators as “nursing sensitive”; the evidence indicates that a team approach is best.