Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer.

Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.

Who Benefits Most? A Multisite Study of Coaching and Resident Well-being.

BACKGROUND: Coaching has been shown to improve resident well-being; however, not all benefit equally. OBJECTIVE: Assess predictors of changes in resident physician well-being and burnout in a multisite implementation of a Professional Development Coaching Program. DESIGN: Pre- and post-implementation surveys administered to participant cohorts at implementation sites in their intern year. Effect size was calculated comparing pre- and post-intervention paired data. PARTICIPANTS: In total, 272 residents in their intern year at five internal medicine residency programs (Boston Medical Center, University Hospitals Cleveland Medical Center, Duke University, Emory University, Massachusetts General Hospital). Analyses included 129 residents with paired data. INTERVENTIONS: Interns were paired with a faculty coach trained in positive psychology and coaching skills and asked to meet quarterly with coaches. MAIN MEASURES: Primary outcomes included Maslach Burnout Inventory depersonalization (DP) and emotional exhaustion (EE) subscales, and the PERMA well-being scale. Key predictors included site, demographics, intolerance of uncertainty, hardiness-resilience, gratitude, and coping. Program moderators included were reflection, goal setting, and feedback. KEY RESULTS: Well-being (PERMA) changed from baseline to follow-up in all participants; females showed a decline and males an increase (-1.41 vs. .83, p = 0.04). Self-reflection was associated with positive change in PERMA (mean positive change 1.93, p = 0.009). Burnout (EE) declined in non-Hispanic white residents vs. Black/Asian/Hispanic/other residents (-1.86, p = 0.021). Burnout improved with increased goal setting. CONCLUSION: Coaching programs should consider tailored approaches to support residents whose well-being is impacted by gender and/or race, and who have higher intolerance of uncertainty and lower resilience at baseline. Coaching skills of goal setting and reflection may positively affect interns and teach coping skills.

Evaluating and Managing the Patient with Back Pain.

A review of the literature, including recent guidelines and original studies, has informed this detailed description of best clinic practices used to evaluate, diagnose, treat, and manage adult patients who present to the outpatient clinic with complaints of low back pain. A case-based format helps guide the reader through clinical decision making and the key learning objectives.

LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors.

PURPOSE: Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254. EXPERIMENTAL DESIGN: LXH254 was profiled in biochemical, in vitro, and in vivo assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of in vivo models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF. RESULTS: We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive. CONCLUSIONS: LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.

Delivering on the Promise: Exploring Training Characteristics and Graduate Career Pursuits of Primary Care Internal Medicine Residency Programs and Tracks.

BACKGROUND: Specialized primary care internal medicine (PC IM) residency programs and tracks aim to provide dedicated PC training. How programs deliver this is unclear. OBJECTIVE: We explored how PC IM programs and tracks provide ambulatory training. METHODS: We conducted a cross-sectional survey from 2012 to 2013 of PC IM program and track leaders via a search of national databases and program websites. We reported PC IM curricular content, clinical experiences, and graduate career pursuits, and assessed correlation between career pursuits and curricular content and clinical experiences. RESULTS: Forty-five of 70 (64%) identified PC IM programs and tracks completed the survey. PC IM programs provide a breadth of curricular content and clinical experiences, including a mean 22.8 weeks ambulatory training and a mean 69.4 continuity clinics per year. Of PC IM graduates within 5 years, 55.8% pursue PC or general internal medicine (GIM) careers and 23.1% pursue traditional subspecialty fellowship training. Curricular content and clinical experiences correlate weakly with career choices. PC IM graduates pursuing PC or GIM careers correlated with ambulatory rotation in women's health (correlation coefficient [rho] = 0.36, P = .034) and mental health (rho = 0.38, P = .023) and curricular content in teaching and medical education (rho = 0.35, P = .035). PC IM graduates pursuing subspecialty fellowship negatively correlated with curricular content in leadership and teams (rho = -0.48, P = .003) and ambulatory training time (rho = -0.38, P = .024). CONCLUSIONS: PC IM programs and tracks largely deliver on the promise to provide PC training and education and produce graduates engaged in PC and GIM.

An Experiential Resident Module for Understanding Social Determinants of Health at an Academic Safety-Net Hospital.

Introduction: Half of the U.S. population has chronic illness. Many disparities exist in health care for management of chronic disease among poorer individuals, including decreased access to healthy foods, homelessness, and difficulty navigating large hospital systems due to low health literacy. A survey of resident physicians found significant gaps in preparedness to provide cross-cultural care. Education is needed to promote consideration of patients' social and cultural barriers in managing disease and navigating the health care system. This module was created as an introduction to social determinants of health, and highlights disparities in access to healthy food, water, shelter, and medical care in a sample of the residents' own continuity clinic patient panel. Methods: We designed this experiential module to help internal medicine residents at an urban institution better understand how social constructs might hinder patient health. Activities were chosen by learners from a list of options, and carried out in small groups during a half day of protected time. We used reflective writing exercises to elicit resident thoughts about the module. Results: Thirty-nine second-year residents participated in the module. Following the course, 41% of residents submitted reflective statements about their experience. Reflective responses suggest an enhanced appreciation for social determinants of health, a sense of empowerment to advocate for better patient resources, and an appreciation for systems-level factors that play a role in social determinants of health. Discussion: Our results demonstrate that a short, experience-based module can impact resident attitudes about social determinants and improve advocacy around identifying community resources.

Does patient gender impact resident physicians' approach to the cardiac exam?

BACKGROUND: Physical examination remains an important part of the initial evaluation of patients presenting with chest pain but little is known about the effect of patient gender on physician performance of the cardiovascular exam. OBJECTIVE: To determine if resident physicians are less likely to perform five key components of the cardiovascular exam on female versus male standardized patients (SPs) presenting with acute chest pain. DESIGN: Videotape review of SP encounters during Objective Structured Clinical Examinations (OSCEs) administered by the Emory University Internal Medicine Residency Program in 2006 and 2007. Encounters were reviewed to assess residents' performance of five cardiac exam skills: auscultation of the aortic, pulmonic, tricuspid, and mitral valve areas and palpation for the apical impulse. PARTICIPANTS: One hundred forty-nine incoming residents. MAIN MEASURES: Residents' performance for each skill was classified as correct, incorrect, or unknown. KEY RESULTS: One hundred ten of 149 (74 %) of encounters were available for review. Residents were less likely to correctly perform each of the five skills on female versus male SPs. This difference was statistically significant for auscultation of the tricuspid (p = 0.004, RR = 0.62, 95 % CI 0.46-0.83) and mitral (p = 0.007, RR = 0.58, 95 % CI = 0.41-0.83) valve regions and palpation for the apical impulse (p < 0.001, RR = 0.27, 95 % CI = 0.16-0.47). Male residents were less likely than female residents to correctly perform each maneuver on female versus male SPs. The interaction of SP gender and resident gender was statistically significant for auscultation of the mitral valve region (p = 0.006) and palpation for the apical impulse (p = 0.01). CONCLUSIONS: We observed significant differences in the performance of key elements of the cardiac exam for female versus male SPs presenting with chest pain. This observation represents a previously unidentified but potentially important source of gender bias in the evaluation of patients presenting with cardiovascular complaints.

Quality improvement of tuberculosis screening in foreign-born patients.

In the United States, a disproportionate percentage of tuberculosis (TB) cases occur in foreign-born persons. We implemented a performance improvement project to improve rates of screening for latent tuberculosis infection in a medical clinic. A questionnaire was developed to identify patients for tuberculosis screening, which was performed as a Tuberculin Skin Test (TST). Patients with positive skin tests underwent further testing. One hundred and sixty-five patients were screened, with 58 TSTs ordered and 36 placed. Twenty-seven patients returned to have the TST read with 12 positive. Eleven of these patients had chest X-rays, 2 revealing findings suggestive of active TB. This project identifies the importance of a standardized TB screening process for high-risk patients and identifies barriers to such a process.

Through the looking glass: how reflective learning influences the development of young faculty members.

BACKGROUND: Faculty development is needed that will influence clinical teachers to better enable them to transmit humanistic values to their learners and colleagues. PURPOSE: We sought to understand the processes whereby reflective learning influenced professional growth in a convenience sample of young faculty members. METHODS: We analyzed appreciative inquiry narratives written over 4 years using the constant comparative method to identify major underlying themes and develop hypotheses concerning how reflective learning influenced participants in the faculty development program. Six of the participants and the facilitator were participant observers in the qualitative analysis. RESULTS: Group support, validation, and cohesion led to adoption of common values that informed the professional development of the participants over 4 years of the study. Common values influenced the group members as they progressed in their careers. CONCLUSIONS: Faculty development programs that focus on humanism and reflective learning can facilitate the growth of young faculty members by influencing their values and attitudes at crucial phases of their careers.

Changes in gene expression during pituitary morphogenesis and organogenesis in the chick embryo.

The anterior pituitary gland plays an important role in the regulation of many physiological processes. Formation of Rathke's pouch (RP), the precursor of the anterior pituitary, involves evagination of the oral ectoderm in a multi-step process regulated by cell interactions, signaling pathways, and transcription factors. Chickens are an excellent model to study development because of the availability of large sample sizes, accurate timing of development, and embryo accessibility. The aim of this study was to quantify mRNA expression patterns in the developing chicken anterior pituitary to evaluate the chicken embryo as a model for mammalian pituitary development. The expression profiles of 16 genes differentially expressed in RP and neuroectoderm were determined in this study. Among these, Pitx1, Pitx2, and Hesx1 mRNA levels were high on embryonic days (e) 2.5 to e3 in RP and decreased during development. Expression of Pit1 and Tbx19 mRNA in RP reached the highest levels by e7 and e6.5, respectively. Levels of glycoprotein subunit α mRNA increased beginning at e4. FGF8 mRNA showed the highest expression at e3 to e3.5 in neuroectoderm. BMP2 showed slight decreases in mRNA expression in both tissues during development, while Isl1 and Noggin mRNA expression increased in later development. Taken together, we present the first quantitative transcriptional profile of pituitary organogenesis. Our results will help further understanding of the functional development of this gland. Moreover, because of the high similarity in gene expression patterns observed between chicken and mouse, chickens could serve as an excellent model to study genetic and molecular mechanisms underlying pituitary development.

Inercia clínica: la dificultad de superarla / Clinical inertia: hard to move it forward

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Transcriptional and pathway analysis in the hypothalamus of newly hatched chicks during fasting and delayed feeding.

BACKGROUND: The hypothalamus plays a central role in regulating appetite and metabolism. However, the gene networks within the hypothalamus that regulate feed intake and metabolism, and the effects of fasting on those pathways are not completely understood in any species. The present experiment evaluated global hypothalamic gene expression in newly hatched chicks using microarray analysis to elucidate genes and pathways regulated by feeding, fasting, and delayed feeding. Ten groups of chicks were sampled over four days post-hatch, including fed, fasted, and 48 h fasted followed by access to feed for 4 h, 24 h, and 48 h. Hypothalamic samples were collected for microarray analysis (n = 4). Expression patterns of selected genes were confirmed by quantitative real-time PCR. Pathway analysis of the microarray results predicted a network of genes involved in neuropeptide or neurotransmitter signaling. To confirm the functionality of this predicted gene network, hypothalamic neurons from fed and fasted chicks were isolated and cultured in the presence of neuropeptide Y, somatostatin, alpha-melanocyte stimulating hormone, norepinephrine, and L-phospho-serine. Results confirmed functional relationships among members of the predicted gene network. Moreover, the effects observed were dependent upon the nutritional state of the animals (fed vs. fasted). RESULTS: Differences in gene expression (> or = 1.6 fold) were detected in 1,272 genes between treatments, and of those, 119 genes were significantly (P < 0.05) different. Pathway Miner analysis revealed that six genes (SSTR5, NPY5R, POMC, ADRB2, GRM8, and RLN3) were associated within a gene network. In vitro experiments with primary hypothalamic neurons confirmed that receptor agonists involved in this network regulated expression of other genes in the predicted network, and this regulation within the network was influenced by the nutritional status and age of the chick. CONCLUSIONS: Microarray analysis of the hypothalamus during different nutritional states revealed that many genes are differentially regulated. We found that functional interactions exist among six differentially regulated genes associated within a putative gene network from this experiment. Considering that POMC, an important gene in controlling metabolism, was central to this network, this gene network may play an important role in regulation of feeding and metabolism in birds.

Effect of a selected Lactobacillus spp.-based probiotic on Salmonella enterica serovar enteritidis-infected broiler chicks.

The effect of a Lactobacillus spp.-based probiotic (FM-B11) on Salmonella enterica serovar Enteritidis (SE) recovery was evaluated in liquid (Expt. 1) and lyophilized (Expt. 2) forms in two separate experiments with two trials each. For each trial, 80 broiler chicks were randomly allocated into two treatments: control and probiotic culture. All chicks were challenged with SE (approximately 10(4) colony-forming units [cfu]) upon arrival at our laboratory. In both experiments, probiotic culture was administered in the drinking water for 3 consecutive days at a final concentration of approximately 10(6) cfu/ml, beginning 1 hr after SE challenge. Cecal tonsils were aseptically removed at 24 and 72 hr postchallenge, followed by enrichment and plating on xylose lactose deoxycholate (XLD) agar for the presence or absence of Salmonella-typical colonies. In Expt. 1, a significant reduction (P < 0.05) in SE-positive samples was observed in both trials at 24 and 72 hr postchallenge. Additionally, in Expt. 2, the lyophilized probiotic decreased (P < 0.05) SE recovery at both 24 and 72 hr postchallenge compared with the control group in trial 1. In trial 2, SE evaluation was performed only at 72 hr after challenge and fewer (P < 0.001) treated samples were positive for SE. Results showed that application of either liquid or lyophilized probiotic culture in the drinking water for 3 consecutive days can help to reduce SE recovery from young birds, although further research is needed to elucidate the mechanism of this response.

Repaving the road to academic success: the IMeRGE approach to peer mentoring.

In recent years, academic health centers have made a considerable effort to encourage medical students and physicians-in-training to consider academic medicine as a career choice. For physicians, selecting a career in academic medicine may be the first hurdle, but the challenge of successfully maintaining an academic career is perhaps a more formidable task. Mentoring is a much-needed response to this challenge. But the success of traditional mentoring programs at academic institutions is often limited by, among other things, the availability of senior faculty who can serve as mentors. The authors describe the formation and organization of the Internal Medicine Research Group at Emory (IMeRGE), an innovative peer mentoring group within the Division of General Medicine at Emory University. This group, born partially out of the mentoring needs of our women and minority faculty, shared the primary goal of fostering a collaborative atmosphere among junior faculty, while simultaneously acquiring experience through advanced faculty development. The authors present our methods of garnering division support for designated time and financial resources, defining member responsibilities, developing a curriculum, providing peer support, and seeking advisors with expertise in the areas on which we wished to focus. In addition to the development of IMeRGE, the authors provide an overview of the pros and cons of traditional mentoring versus peer mentoring; discuss the challenges faced by IMeRGE and strategies for addressing these issues; and present the paradigm of IMeRGE as a template for alternative forms of academic mentorship.