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The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: We performed a meta-analysis investigating the efficacy and adverse effects of sacubitril-valsartan in various types of heart failure including more recent studies and a larger sample size. We conducted an electronic search through Cochrane, Web of Science, PubMed, and Embase. Included studies were randomized controlled trials analyzing the efficacy of sacubitril-valsartan compared with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) in patients with heart failure. Fourteen trials were included. Pooled estimates were analyzed using RevMan 5.4.1. The odds ratio (OR) of hospitalization from worsening heart failure that compared sacubitril-valsartan with control was 0.70 (95% CI, 0.51-0.97; P = 0.03) in patients with heart failure with reduced ejection fraction (HFrEF) with a relative risk reduction (RRR) of 24.3% and absolute risk reduction (ARR) of 3.4%. In patients with heart failure with midrange (HFmEF) and preserved (HFpEF) ejection fraction, the OR was 0.80 (95% CI, 0.71-0.90; P = 0.0001) with RRR of 14.5% and ARR of 3.3%. There was a significant reduction in cardiovascular deaths (OR = 0.79; 95% CI, 0.70-0.89; P = <0.0001) and all-cause mortality (OR = 0.84; 95% CI, 0.75-0.94; P = 0.002) in patients with HFrEF, with no significant differences in patients with HFmEF and HFpEF. Hospitalization rate was significantly reduced in patients taking sacubitril-valsartan across all analyzed cohorts. Sacubitril-valsartan significantly reduced the risk of all-cause mortality and cardiovascular death in patients with HFrEF but not in patients with HFmEF/HFpEF. These findings support sacubitril-valsartan use in reducing hospitalization of patients with HFmEF and HFpEF. More studies should be performed to further analyze the efficacy of sacubitril-valsartan in patients with HFmEF/HFpEF., Competing Interests: HZ, ATH, and EAR have no conflict of interest to report. JSA serves as an advisor to Merck, Viiv Healthcare, and Theratechnologies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gemtuzumab ozogamicin (GO) improves outcomes when added to intensive AML chemotherapy. A meta-analysis suggested the greatest benefit when combining fractionated doses of GO (GO3) with 7 + 3. To test whether GO3 can be safely used with high intensity chemotherapy, we conducted a phase 1/2 study of cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M) in adults with newly diagnosed AML or other high-grade myeloid neoplasm (NCT03531918). Sixty-six patients with a median age of 65 (range: 19-80) years were enrolled. Cohorts of six and twelve patients were treated in phase 1 with one dose of GO or three doses of GO (GO3) at 3 mg/m 2 per dose. Since a maximum-tolerated dose was not reached, the recommended phase 2 dose (RP2D) was declared to be GO3. At RP2D, 52/60 (87%) patients achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease (MRD). Eight-week mortality was 0%. Six- and twelve-month event-free survival (EFS) were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease (EFS: p = 0.007; OS: p = 0.030). These data indicate that CLAG-M/GO3 is safe and leads to superior outcomes than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.

With increased longevity related to the advent of antiretroviral therapy, there are increasing proportions of older persons with HIV (PWH). Prior studies have demonstrated increased prevalence of geriatric syndromes in older PWH and recommended the Comprehensive Geriatric Assessment (CGA) in this population. However, there is currently no peer-reviewed literature that outlines how to perform the CGA in PWH in the clinical setting. In this article, we offer a review on how to perform the CGA in PWH, outline domains of the CGA and their importance in PWH, and describe screening tools for each domain focusing on tools that have been validated in PWH, are easy to administer, and/or are already commonly used in the field of geriatrics., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The internal medicine (IM) subinternship has been a long-established clinical experience in the final phase of medical school deemed by key stakeholders as a crucial rotation to prepare senior medical students for internship. Medical education has changed greatly since the first national curriculum for this course was developed in 2002 by the Clerkship Directors in Internal Medicine (CDIM). Most notably, competency-based medical education (CBME) has become a fixture in graduate medical education and has gradually expanded into medical school curricula. Still, residency program directors and empirical studies have identified gaps and inconsistencies in knowledge and skills among new interns. Recognizing these gaps, the Association of Program Directors in Internal Medicine (APDIM) surveyed its members in 2010 and identified four core skills essential for intern readiness. The Association of American Medical Colleges (AAMC) also published 13 core entrustable professional activities (EPAs) for entering residency to be expected of all medical school graduates. Results from the APDIM survey along with the widespread adoption of CBME informed this redesign of the IM subinternship curriculum. The authors provide an overview of this new guide developed by the Alliance for Academic Internal Medicine (AAIM) Medical Student-to-Resident Interface Committee (MSRIC).

Purpose of Review: Cellular therapy using T cells modified to express chimeric antigen receptors (CAR-T cells) has had striking success in patients that have failed previous treatment for CD19 + B cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or acute lymphoblastic leukemia (ALL). Curative therapy for this group of diseases has previously been limited to allogeneic hematopoietic cell transplantation HCT (alloHCT). The recent results of CAR-T cell therapy raise the question of how best to integrate CAR-T cell therapy and alloHCT in the care of these patients., Recent Findings: Within the past 2 years, results from larger trials and increased follow-up of patients treated with CD19 CAR-T cell therapy suggest that some may achieve durable remission without transplant. The balance of efficacy and toxicity for CAR-T cell therapy and alloHCT vary by disease type, disease status at the time of treatment, patient characteristics, and the specific therapy employed. There are early signals that subsequent transplantation of patients who have achieved remission with CAR-T may be a potentially viable (though expensive) strategy.

People aging with HIV present a unique challenge for providers. HIV-infected patients experience accentuated aging and multimorbidity, but are typically disconnected from geriatric care, which is limited by a shortage of geriatric providers worldwide. Consequently, HIV providers are tasked with managing multiple age-related illnesses, within service networks that are historically not designed to care for aging patients. While comfortable with the management of antiretroviral therapy, HIV providers may have limited training on how to recognize or manage geriatric syndromes, especially in the context of multimorbidity. The result is an emerging, vulnerable population, and the question is how to best care for them. As part of the answer, we offer examples of how providers can use geriatric principles to improve the care of aging HIV-infected patients. We begin by describing basic geriatric concepts and examples of care models, and subsequently use a patient case to illustrate their applications at the patient level. At the system level, we discuss how HIV service networks can use components of geriatric care models to meet the needs of aging HIV-infected patients. Lastly, we identify aging-specific guidelines and service integration as important areas for future endeavors., (© 2017 S. Karger AG, Basel.)

Increasing proportions of older adults are living with the human immunodeficiency virus (HIV). It is estimated that more than 50% of individuals with HIV in the United States are aged 50 and older. Part of this group consists of individuals who have aged with chronic HIV infection, but a large proportion also results from new HIV diagnosis, with approximately 17% of new HIV diagnoses in 2013 occurring in individuals aged 50 and older. Although many of the recommendations on management of HIV infection are not age-specific, individuals with HIV aged 50 and older differ from their younger counterparts in many aspects, including immune response to antiretroviral therapy, multimorbidity, antiretroviral toxicities, and diagnostic considerations. This article outline these differences, offers a strategy on how to care for this unique population, and provides special considerations for problem-based management of individuals with HIV aged 50 and older., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Background and Objectives: Functional and cognitive impairment correlates with medical outcomes in older persons, yet documentation in the medical record is often inadequate. The purpose of this pilot study was to evaluate fourth year (M4) medical students' charting performance of cognition and functional status in older persons during non-geriatric clerkships using an audit tool., Methods: The research assistants used a chart abstracting tool to retrospectively review patients' charts. The abstracting tool contained keywords and phrases to prompt the research assistants to look for any documentation of patient status in four domains: (1) delirium or acute confusional state, (2) chronic cognitive impairment, (3) activities of daily living, and (4) instrumental activities of daily living. The threshold was any mention of keywords in these domains., Results: On non-geriatrics M4 clerkships in the hospital, students documented acute cognitive status (ACS) and presence or absence of chronic cognitive impairment (CCI) in 57% and 68% of cases respectively, with physicians and/or nurses doing it more often at 63% and 84%. Both students and other care providers documented ACS and CCI in the same charts 41% and 59% of the time, respectively. Students documented activities of daily living (ADLs) and instrumental activities of daily living (IADLs) 31% and 3% respectively, physicians and/or nurses 59% and 0%., Conclusions: Documentation of cognitive status in hospital charts for students and physicians was somewhat higher than in the literature. This may be because geriatrics is integrated into our 4-year curriculum. Documentation by both students and physicians was better for ADLs than IADLs and poor for IADLs overall.

For decades, the internal medicine (IM) subinternship has served as a critical interface between undergraduate and graduate medical education. As such, the vast majority of U.S. medical schools offer this rotation to help students prepare for post-graduate training. Historically an experiential rotation, a formal curriculum with specific learning objectives was eventually developed for this course in 2002. Since then, graduate medical education (GME) has changed significantly with the regulation of duty hours, adoption of competency-based education, and development of training milestones and entrustable professional activities. In response to these and many other changes to residency training and medical practice, in 2010, the Association of Program Directors in Internal Medicine (APDIM) surveyed its members-with input from the Clerkship Directors in Internal Medicine (CDIM) Subinternship Task Force-to determine which core skills program directors expected from new medical school graduates. The results of that survey helped to inform a joint CDIM-APDIM committee's decision to re-evaluate the goals of the IM subinternship in an effort to enhance the transition from medical school to residency. This joint committee defined the minimum expectations of what constitutes an IM subinternship rotation, proposed recommended skills for IM subinterns, and discussed challenges and future directions for this crucial course.

Proteins and other macromolecules that cross biological membranes have great potential as tools for research and next-generation therapeutics. Here, we describe two assays that effectively quantify the cytosolic localization of a number of previously reported peptides and protein domains. One assay, which we call GIGI (glucocorticoid-induced eGFP induction), is an amplified assay that informs on relative cytosolic access without the need for sophisticated imaging equipment or adherent cells. The second, GIGT (glucocorticoid-induced eGFP translocation), is a nonamplified assay that informs on relative cytosolic access and exploits sophisticated imaging equipment to facilitate high-content screens in live cells. Each assay was employed to quantify the cytosolic delivery of several canonical "cell permeable peptides," as well as more recently reported minimally cationic miniature proteins and zinc finger nuclease domains. Our results show definitively that both overall charge as well as charge distribution influence cytosolic access and that small protein domains containing a discrete, helical, penta-Arg motif can dramatically improve the cytosolic delivery of small folded proteins such as zinc finger domains. We anticipate that the assays described herein will prove useful to explore and discover the fundamental physicochemical and genetic properties that influence both the uptake and endosomal release of peptidic molecules and their mimetics.

Previous work has shown that certain β(3)-peptides can effectively mimic the side chain display of an α-helix and inhibit interactions between proteins, both in vitro and in cultured cells. Here we describe a β(3)-peptide analog of GLP-1, CC-3(Act), that interacts with the GLP-1R extracellular domain (nGLP-1R) in vitro in a manner that competes with exendin-4 and induces GLP-1R-dependent cAMP signaling in cultured CHO-K1 cells expressing GLP-1R.

Aberrant activation of the epidermal growth factor receptor (EGFR), a prototypic receptor tyrosine kinase, is critical to the biology of many common cancers. The molecular events that define how EGFR transmits an extracellular ligand binding event through the membrane are not understood. Here we use a chemical tool, bipartite tetracysteine display, to report on ligand-specific conformational changes that link ligand binding and kinase activation for full-length EGFR on the mammalian cell surface. We discover that EGF binding is communicated to the cytosol through formation of an antiparallel coiled coil within the intracellular juxtamembrane (JM) domain. This conformational transition is functionally coupled to receptor activation by EGF. In contrast, TGFα binding is communicated to the cytosol through formation of a discrete, alternative helical interface. These findings suggest that the JM region can differentially decode extracellular signals and transmit them to the cell interior. Our results provide new insight into how EGFR communicates ligand-specific information across the membrane.

Proteins represent an expanding class of therapeutics, but their actions are limited primarily to extracellular targets because most peptidic molecules fail to enter cells. Here we identified two small proteins, miniature protein 5.3 and zinc finger module ZF5.3, that enter cells to reach the cytosol through rapid internalization and escape from Rab5+ endosomes. The trafficking pathway mapped for these molecules differs from that of Tat and Arg(8), which require transport beyond Rab5+ endosomes to gain cytosolic access. Our results suggest that the ability of 5.3 and ZF5.3 to escape from early endosomes is a unique feature and imply the existence of distinct signals, encodable within short sequences, that favor early versus late endosomal release. Identifying these signals and understanding their mechanistic basis will illustrate how cells control the movement of endocytic cargo and may allow researchers to engineer molecules to follow a desired delivery pathway for rapid cytosolic access., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In recent years, scientists have expanded their focus from cataloging genes to characterizing the multiple states of their translated products. One anticipated result is a dynamic map of the protein association networks and activities that occur within the cellular environment. While in vitro-derived network maps can illustrate which of a multitude of possible protein-protein associations could exist, they supply a falsely static picture lacking the subtleties of subcellular location (where) or cellular state (when). Generating protein association network maps that are informed by both subcellular location and cell state requires novel approaches that accurately characterize the state of protein associations in living cells and provide precise spatiotemporal resolution. In this review, we highlight recent advances in visualizing protein associations and networks under increasingly native conditions. These advances include second generation protein complementation assays (PCAs), chemical and photo-crosslinking techniques, and proximity-induced ligation approaches. The advances described focus on background reduction, signal optimization, rapid and reversible reporter assembly, decreased cytotoxicity, and minimal functional perturbation. Key breakthroughs have addressed many challenges and should expand the repertoire of tools useful for generating maps of protein interactions resolved in both time and space., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Etravirine, a nonnucleoside reverse transcriptase inhibitor, was provided through an international early access program (EAP) prior to regulatory approval., Methods: The Phase III, nonrandomized, open-label EAP investigated etravirine 200 mg twice daily plus a background regimen (BR) in patients who had failed multiple antiretroviral regimens. Efficacy and safety are reported for HIV-infected adults from the United States through week 48, including subgroups receiving etravirine +/- darunavir/ritonavir and/or raltegravir., Results: The intent-to-treat population included 2578 patients; 62.4% and 56.7% of patients received darunavir/ritonavir and raltegravir, respectively, in their BR. At week 48, 62.3% of patients achieved viral loads <75 copies per milliliter; responses across subgroups were similar. Median CD4 count increase from baseline was >100 cells per cubic millimeter. No unexpected safety concerns emerged; serious AEs and deaths due to AEs, considered possibly related to etravirine, occurred in 2.0% and 0.3% of patients, respectively. Discontinuations due to AEs were low overall (4.4%) and comparable across subgroups., Conclusions: Etravirine combined with a BR, often including other new antiretrovirals, such as darunavir/ritonavir and/or raltegravir, provided an effective treatment option in treatment-experienced patients with HIV-1.

Beta-peptides possess several features that are desirable in peptidomimetics; they are easily synthesized, fold into stable secondary structures in physiologic buffers, and resist proteolysis. They can also bind to a diverse array of proteins to inhibit their interactions with alpha-helical ligands. beta-peptides are usually not cell-permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg(8) sequence to a beta-peptide improves uptake but adds considerable mass. We previously reported that embedding a small cationic patch within a PPII, alpha-, or beta-peptide helix improves uptake without the addition of significant mass. In another mass-neutral strategy, Verdine, Walensky, and others have reported that insertion of a hydrocarbon bridge between the i and i + 4 positions of an alpha-helix also increases cell uptake. Here we describe a series of beta-peptides containing diether and hydrocarbon bridges and compare them on the basis of cell uptake and localization, affinities for hDM2, and 14-helix structure. Our results highlight the relative merits of the cationic-patch and hydrophobic-bridge strategies for improving beta-peptide uptake and identify a surprising correlation between uptake efficiency and hDM2 affinity.

Survival of naive T cells is dependent upon IL-7, which is present in vivo in limiting amounts with the result that naive T cells must compete for IL-7-mediated survival signals. It would seem imperative during T cell homeostasis that limiting IL-7 be shared by the greatest possible number of T cells. We now describe a novel regulatory mechanism that specifically suppresses IL7Ralpha transcription in response to IL-7 and other prosurvival cytokines (IL-2, IL-4, IL-6, and IL-15). Consequently, IL7R expression is reduced on T cells that have received cytokine-mediated survival signals so they do not compete with unsignaled T cells for remaining IL-7. Interestingly, cytokine-mediated suppression of IL7Ralpha transcription involves different molecular mechanisms in CD4+ and CD8+ T cells, as CD8+ T cells utilize the transcriptional repressor GFI1 while CD4+ T cells do not. We suggest that this homeostatic regulatory mechanism promotes survival of the maximum possible number of T cells for the amount of IL-7 available.

Although there are varied inheritance patterns in motor neuron disease (MND), the phenotype of MND is reported to be constant within these families, ie, cases of amyotrophic lateral sclerosis or primary lateral sclerosis do not occur in pedigrees with cases of spinal muscular atrophy. We describe four pedigrees whose members diverged in the phenotype of MND expressed. The intrafamilial variation of phenotype suggests a similar pathogenesis for some of the varied types of familial MND and the need for careful inquiry of family history in all patients with MND.

A patient with Yersinia enterocolitica endocarditis was seen with bacteremia, valvular vegetation, new heart murmur, and septic embolism. To our knowledge, this is the first reported case of Y enterocolitica infectious endocarditis and is yet another clinical manifestation of disease produced by this organism.

An association between venous thrombosis and cancer was first suggested by Trousseau, and has been confirmed by multiple postmortem studies. Clinical studies have shown that thrombophlebitis migrans may occur before malignancies become clinically evident, and therefore serves as a clue to occult cancer. A relation between occult cancer and the commoner deep venous thrombosis and pulmonary embolism has not been established. We ascertained the incidence of cancer before and after pulmonary embolism was diagnosed by pulmonary angiography in 128 patients. The incidence of cancer before pulmonary embolism (12%) was essentially the same as that in a comparison group of patients without pulmonary embolism (10%). In the 2 years after pulmonary angiography, however, cancer was diagnosed in 13 patients with pulmonary embolism in contrast to no patients in the comparison group (p less than 0.001). The most frequent cancers involved the lung, gastrointestinal tract, breast, and uterus. The malignancies were nearly always occult when pulmonary embolism occurred. These findings indicate that pulmonary embolism with or without overt deep venous thrombosis should alert the clinician to consider occult cancer.