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Background: Estrogen receptors occur in about two-thirds of breast tumors and endocrine therapy is probably the most important systemic therapy for hormone receptor positive breast cancer. However, after an initial response to hormonal therapy, most tumors develop resistance leading to disease progression. Central mechanisms thought to be involved in this process include: 1) alterations in tumor cell physiology causing insensitivity to drug-induced apoptosis or induction of drug-detoxifying mechanisms; 2) expression of energy-dependent transporters that eject anti-cancer drugs from cells and 3) the emergence of cancer stem-like cell clones that are estrogen-independent and/or antiestrogen resistant. We and others have shown that Notch signaling mediates survival signals in ER+ breast cancer cells; induces expression of drug transporter ABCG2 (BCRP), activates ERa in the absence of estrogen and mediates survival of breast cancer stem-like cells. Previously, we demonstrated a crosstalk between ERa and Notch signaling whereby estrogen inhibits Notch activation and estrogen withdrawal ortamoxifen re-activate Notch, a possible mechanism of resistance. The mechanism of these effects has remained elusive. Methods: we used sub-cellular fractionation and immunofluorescence staining to investigate the total expression and cellular distribution of Notch signaling components in MCF-7 cells treated with 17-p-estradiol, or estrogen-free medium. Results: Our data shows that in cells treated with estrogen-free medium, Notchi is located in the Lipid Rafts (LR) in the plasma membrane, along with Notch signaling components such as presenilin 1 (the catalytic subunit of γ-secretase), ADAM10 and Notch negative regulator NUMB. There is published evidence that γ-secretase is most active in lipid rafts. 17-p-Estradiol modifies the membrane lipid composition and change the localization of Notch and Notch regulators (such as ADAM10, presenilin-1 and NUMB) at the plasma membrane, thereby altering the activation of Notch. These observations are consistent with a model in which the lipid composition of the plasma membrane is a critical factor in regulating the rate of Notch activation. FDA-approved cholesterol lowering drugs affect Notch signaling in ways consistent with this model. Conclusions: Our findings indicate that endocrine therapy affects Notch signaling at least in part through alterations in membrane composition and lipid raft localization of Notch signaling components. [ABSTRACT FROM AUTHOR]

Background: Development of a screening assay for the clinical use of broadly neutralizing antibodies (bnAbs) is a priority for HIV therapy and cure initiatives., Methods: We assessed the PhenoSense Monoclonal Antibody (mAb) Assay (Labcorp-Monogram Biosciences) which is CLIA-validated and has been used prospectively and retrospectively in multiple recent bnAb clinical trials., Results: When performed on pre-ART plasma and on-ART longitudinal PBMC samples sourced from a recent clinical trial, the PhenoSense mAb Assay produced robust reproducibility, concordance across sample types, and expected ranges in the susceptibility measures of bnAbs in clinical development. PhenoSense mAb applied retrospectively to baseline samples from three recent studies correlated with published laboratory-based study evaluations, but baseline bnAb susceptibility was not consistently predictive of durable virus suppression. Assessment of the feasibility of the assay in four recent clinical studies provides estimates of assay success rate and processing time., Conclusions: The PhenoSense mAb Assay provides reproducible bnAb susceptibility measurements across relevant sample types yet was not consistently predictive of virus suppression. Logistical and operational assay requirements can impact timely clinical trial conduct. These results inform bnAb studies in development., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000× less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion., (© 2024 Teixeira et al.)

Introduction: To assess the effectiveness of novel HIV curative strategies, "cure" trials require periods of closely monitored antiretroviral therapy (ART) analytical treatment interruptions (ATIs). We performed a systematic review and meta-analysis to identify the impact of ATI with or without novel therapeutics in cure-related studies on the time to viral re-suppression following ART restart., Methods: Medline, Embase and Web of Science databases were searched for human studies involving ATIs from 1 January 2015 till 22 April 2024. The primary outcome was time to first viral re-suppression (plasma HIV viral load [VL] <50 copies/ml) stratified by receipt of interventional drug with ATI (IA) or ATI-only groups. Random-effects proportional meta-analysis and multivariable Cox proportional hazards analysis were performed using R., Results: Of 1073 studies screened, 13 were included that met the inclusion criteria with VL data available after restarting ART (n = 213 participants). There was no difference between time to viral suppression in IA or ATI-only cohorts (p = 0.22). For 87% of participants, viral suppression within 12 weeks of ART restart was achieved, and all eventually had at least one VL <50 copies/ml during follow-up. After adjusting for covariables, while participants in the IA cohort were associated with less rapid suppression (adjusted hazard ratio [aHR] 0.61, 95% CI 0.40-0.94, p = 0.026), other factors include greater log VL at ART restart (aHR 0.56, 95% CI 0.46-0.68, p<0.001), duration since HIV diagnosis (aHR 0.93, 95% CI 0.89-0.96) and longer intervals between HIV VL monitoring (aHR 0.66, 95% CI 0.59-0.74, p<0.001). However, the use of integrase inhibitors was associated with more rapid viral suppression (aHR 1.74, 95% CI 1.16-2.59)., Discussion: When designing studies involving ATIs, information on time to viral re-suppression after restarting ART is important to share with participants, and should be regularly monitored and reported, to assess the impact and safety of specific trial interventions in ATI studies., Conclusions: The majority of participants achieved viral suppression after restarting ART in ATI studies. ART regimens containing integrase inhibitors and frequent VL monitoring should be offered for people restarting ART after ATI studies to ensure rapid re-suppression., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Study Objectives: Fever following immunizations is a common presenting chiefcomplaint among infants. The 2021 American Academy of Pediatrics (AAP) febrile infant clinical practice guidelines exclude recently immunized (RI) infants. This is a challenge for clinicians in the management of the febrile RI young infant. The objective of this study was to assess the prevalence of SBI in RI febrile young infants between 6 and 12 weeks of age., Methods: This was a retrospective chart review of infants 6-12 weeks who presented with a fever ≥38 °C to two U.S. military academic Emergency Departments over a four-year period. Infants were considered recently immunized (RI) if they had received immunizations in the preceding 72 h prior to evaluation and not recently immunized (NRI) if they had not received immunizations during this time period. The primary outcome was prevalence of serious bacterial infection (SBI) further delineated into invasive-bacterial infection (IBI) and non-invasive bacterial infection (non-IBI) based on culture and/or radiograph reports., Results: Of the 508 febrile infants identified, 114 had received recent immunizations in the preceding 72 h. The overall prevalence of SBI was 11.4% (95% CI = 8.9-14.6) in our study population. The prevalence of SBI in NRI infants was 13.7% (95% CI = 10.6-17.6) compared to 3.5% (95% CI = 1.1-9.3) in RI infants. The relative risk of SBI in the setting of recent immunizations was 0.3 (95% CI = 0.1-0.7). There were no cases of invasive-bacterial infections (IBI) in the RI group with all but one of the SBI being urinary tract infections (UTI). The single non-UTI was a case of pneumonia in an infant who presented with respiratory symptoms within 24 h of immunizations., Conclusion: The risk of IBI (meningitis or bacteremia) in RI infants aged 6 to 12 weeks is low. Non-IBI within the first 24 h following immunization was significantly lower than in febrile NRI infants. UTIs remain a risk in the RI population and investigation with urinalysis and urine culture should be encouraged. Shared decision making with families guide a less invasive approach to the care of these children. Future research utilizing a large prospective multi-center data registry would aid in further defining the risk of both IBI and non-IBI among RI infants., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration., Methods: ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days., Results: A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P =0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Background: Long-acting treatment for HIV has potential to improve adherence, provide durable viral suppression, and have long-term individual and public health benefits. We evaluated treatment with two antibodies that broadly and potently neutralise HIV (broadly neutralising antibodies; bNAbs), combined with lenacapavir, a long-acting capsid inhibitor, as a long-acting regimen., Methods: This ongoing, randomised, blind, phase 1b proof-of-concept study conducted at 11 HIV treatment centres in the USA included adults with a plasma HIV-1 RNA concentration below 50 copies per mL who had at least 18 months on oral antiretroviral therapy (ART), CD4 counts of at least 500 cells per μL, and protocol-defined susceptibility to bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS). Participants stopped oral ART and were randomly assigned (1:1) to one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. Investigational site personnel and participants were masked to treatment assignment throughout the randomised period. The primary endpoint was incidence of serious adverse events until week 26 in all randomly assigned participants who received one dose or more of any study drug. This study is registered with ClinicalTrials.gov, NCT04811040., Findings: Between June 29 and Dec 8, 2021, 21 participants were randomly assigned, ten in each group received the complete study regimen and one withdrew before completing the regimen on day 1. 18 (86%) of 21 participants were male; participants ranged in age from 25 years to 61 years and had a median CD4 cell count of 909 (IQR 687-1270) cells per μL at study entry. No serious adverse events occurred. Two grade 3 adverse events occurred (lenacapavir injection-site erythaema and injection-site cellulitis), which had both resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir; 12 (60%) of 20 were grade 1. One (10%; 95% CI 0-45) participant had viral rebound (confirmed HIV-1 RNA concentration of ≥50 copies per mL) in the zinlirvimab 10 mg/kg group, which was resuppressed on ART, and one participant in the zinlirvimab 30 mg/kg group withdrew at week 12 with HIV RNA <50 copies per mL., Interpretation: Lenacapavir with teropavimab and zinlirvimab 10 mg/kg or 30 mg/kg was generally well tolerated with no serious adverse events. HIV-1 suppression for at least 26 weeks is feasible with this regimen at either zinlirvimab dose in selected people with HIV-1., Funding: Gilead Sciences., Competing Interests: Declaration of interests JJE reports grants or contract payments made to their institution from ViiV Healthcare, Janssen Pharmaceuticals, and Gilead Sciences and consulting fees from ViiV Healthcare, Merck, and Gilead Sciences. SJL declares no competing interests. GC reports grants or contract payments from ViiV Healthcare, Merck, AbbVie, Janssen Pharmaceuticals, and Gilead Sciences and support for attending meetings from Gilead Sciences. PC reports grants or contract payments from Lilly, Seres Therapeutics, National Institutes of Health, Merck, ViiV Healthcare, Janssen Pharmaceuticals, and Gilead Sciences and data safety monitoring or advisory board participation from Westat. PJR reports grants or contract payments from ViiV Healthcare, Merck, AbbVie, Theratechnology, and Gilead Sciences; honoraria from ViiV Healthcare and Gilead Sciences; and support for attending meetings from Gilead Sciences. DJ reports grants or contract payments made to his institution from Janssen Pharmaceuticals, Gilead Sciences, and NeuroRx; honoraria from Clinical Care Options; and advisory board participation for CITI and Theratechnologies. ED reports grants or contract payments from ViiV Healthcare, Merck, AbbVie, TeroTechnology/Taimed Biologic, and Gilead Sciences. AM reports grants or contract payments from Gilead Sciences, ViiV Healthcare, Merck, Taimed Biologic, Janssen Pharmaceuticals, and GSK and advisory board participation for Gilead Sciences, Merck, and ViiV Healthcare. SEW reports grants or contract payments from Gilead Sciences and Merck. MR reports consulting fees from Merck, Gilead Sciences, ViiV Healthcare, and Janssen Pharmaceuticals and honoraria from AbbVie, Gilead Sciences, ViiV Healthcare, and Janssen Pharmaceuticals. LG reports grants or contract payments made to their institution from Gilead Sciences and Merck; and honoraria from the AIDS Education and Training Center—South Central. LAV, YZ, HH, and SEC report employment with and stock in Gilead Sciences. JMB reports employment with and stock in Gilead Sciences; grants or contract payments and participation on a data monitoring committee from the US National Institutes of Health; and consulting fees from Gilead Sciences, Merck, and Janssen Pharmaceuticals. MC reports data safety monitoring or advisory board participation for Gilead Sciences., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Transcatheter aortic valve replacement (TAVR) provides an option for extreme-risk patients who underwent reoperation for a failed surgical aortic bioprosthesis. Long-term data on patients who underwent TAVR within a failed surgical aortic valve (TAV-in-SAV) are limited. The CoreValve Expanded Use Study evaluated patients at extreme surgical risk who underwent TAV-in-SAV. Outcomes at 5 years were analyzed by SAV failure mode (stenosis, regurgitation, or combined). Echocardiographic outcomes are site-reported. TAV-in-SAV was attempted in 226 patients with a mean age of 76.7 ± 10.8 years; 63.3% were male, the Society of Thoracic Surgeons predicted risk of mortality score was 9.0 ± 6.7%, and 87.5% had a New York Heart Association classification III or IV symptoms. Most of the failed surgical bioprostheses were stented (81.9%), with an average implant duration of 10.2 ± 4.3 years. The 5-year all-cause mortality or major stroke rate was 47.2% in all patients; 54.4% in the stenosis, 37.6% in the regurgitation, and 38.0% in the combined groups (p = 0.046). At 5 years, all-cause mortality was higher in patients with versus without 30-day severe prosthesis-patient mismatch (51.7% vs 38.3%, p = 0.026). The overall aortic valve reintervention rate was 5.9%; highest in the regurgitation group (12.6%). The mean aortic valve gradient was 14.1 ± 9.8 mm Hg and effective orifice area was 1.57 ± 0.70 at 5 years. Few patients had >mild paravalvular regurgitation at 5 years (5.5% moderate, 0.0% severe). TAV-in-SAV with supra-annular, self-expanding TAVR continues to represent a safe and lasting intermediate option for extreme-risk patients who have appropriate sizing of the preexisting failed surgical valve. Clinical and hemodynamic outcomes were stable through 5 years., Competing Interests: Declaration of competing interest Dr. Bajwa reports fees for consulting and proctoring from Medtronic; Dr. Laham has received research grants from Boston Scientific, Medtronic, Edwards Lifesciences, and Abbott Vascular; Dr. Dauerman is a consultant to Medtronic and Boston Scientific; Data Safety and Monitoring Board member for health care research institute, Recor Medical and Cardiovascular Research Foundation (multiple trials), research grants from Medtronic and Boston Scientific; Dr. Waksman is a member of the advisory board for Abbott Vascular, Amgen, Boston Scientific, Cardioset, Cardiovascular Systems Inc, Medtronic (Abbot), Philips Volcano, Pi-Cardia Ltd; as a Consultant for Abbott Vascular, Amgen, Biosensors, Biotronik, Boston Scientific, Cardioset, Cardiovascular Systems Inc, Medtronic, Philips Volcano, Pi-Cardia Ltd; receives grant support from Abbott Vascular, AstraZeneca, Biosensors, Biotronik, Boston Scientific, Chiesi; serves on the Speakers Bureau for AstraZeneca and Chiesi; and is an investor in Med Alliance; Dr. Allaqaband is a proctor and consultant for Medtronic; Dr. Caskey reports proctor fees from Medtronic; Dr. Byrne reports proctor fees and honoraria from Medtronic and proctor fees and honoraria from Abbott; Dr. Li is an employee and shareholder of Medtronic; Dr. Kleiman is a consultant for Medtronic and Boston Scientific and receives grant support from Medtronic; Dr. Reardon is a consultant for Medtronic, W.L. Gore and Associates and Boston Scientific; Dr. Chetcuti has received grant support and fees for proctoring from Medtronic and is a consultant for Jena valve; Dr. Deeb serves as on an advisory board and as a proctor for Medtronic; as a consultant and research investigator for Edwards Lifesciences; as a consultant and proctor for Terumo; and as a research investigator for Gore Medical with all fees paid to his institution. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The glycosylation of viral envelope proteins can play important roles in virus biology and immune evasion. The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) includes 22 N-linked glycosylation sequons and 17 O-linked glycosites. We investigated the effect of individual glycosylation sites on SARS-CoV-2 S function in pseudotyped virus infection assays and on sensitivity to monoclonal and polyclonal neutralizing antibodies. In most cases, the removal of individual glycosylation sites decreased the infectiousness of the pseudotyped virus. For glycosylation mutants in the N-terminal domain and the receptor-binding domain (RBD), reduction in pseudotype infectivity was predicted by a commensurate reduction in the level of virion-incorporated S protein and reduced S trafficking to the cell surface. Notably, the presence of a glycan at position N343 within the RBD had diverse effects on neutralization by RBD-specific monoclonal antibodies cloned from convalescent individuals. The N343 glycan reduced the overall sensitivity to polyclonal antibodies in plasma from COVID-19 convalescent individuals, suggesting a role for SARS-CoV-2 S glycosylation in immune evasion. However, vaccination of convalescent individuals produced neutralizing activity that was resilient to the inhibitory effect of the N343 glycan.IMPORTANCEThe attachment of glycans to the spike proteins of viruses during their synthesis and movement through the secretory pathway can affect their properties. This study shows that the glycans attached to the severe acute respiratory syndrome coronavirus-2 spike protein enable its movement to the cell surface and incorporation into virus particles. Certain glycans, including one that is attached to asparagine 343 in the receptor-binding domain of the spike protein, can also affect virus neutralization by antibodies. This glycan can increase or decrease sensitivity to individual antibodies, likely through direct effects on antibody epitopes and modulation of spike conformation. However, the overall effect of the glycan in the context of the polyclonal mixture of antibodies in convalescent serum is to reduce neutralization sensitivity. Overall, this study highlights the complex effects of glycosylation on spike protein function and immune evasion., Competing Interests: The authors declare no conflict of interest.

Objective: To test whether a neonatal intensive care unit-based language curriculum for families with preterm infants enhances the language environment and postdischarge Bayley Scales of Infant and Toddler Development (BSID)-III language and cognitive scores., Methods: A randomized controlled trial was conducted with infants born at ≤32 weeks assigned to a parent-driven language intervention or health-safety lessons (controls). Recordings of adult word counts (AWC), conversational turns, and child vocalizations were captured at 32, 34, and 36 weeks. Primary outcomes included 2-year BSID-III language and cognitive scores., Results: We randomized 95 infants; 45 of the 48 intervention patients (94%) and 43 of the 47 controls (91%) with ≥2 recordings were analyzed. The intervention group had higher AWCs (rate ratio, 1.52; 95% CI, 1.05-2.19; P = .03) at 36 weeks, increased their AWCs between all recordings, and had lower rates of 2-year receptive language scores <7 (10% vs 38%; P < .02). The intervention was associated with 80% decreased odds of a language composite score of <85 (aOR, 0.20; 95% CI, 0.05-0.78; P = .02), and 90% decreased odds of a receptive score of <7 (0.10; 95% CI, 0.02-0.46; P = .003); there was no association found with cognitive scores. Increases in AWC and conversational turns between 32 and 36 weeks were independently associated with improved 2-year BSID-III language scores for both study groups., Conclusions: Short-term parent-driven language enrichment in the neonatal intensive care unit contributes to increased AWCs at 36 weeks and improved 2-year language scores. In adjusted analyses, increases in conversational turns and AWCs at 36 weeks were independently associated with improved language scores. This low-cost, easily implemented intervention can potentially help to mitigate speech delays among preterm infants., Trial Registration: Registered with www., Clinicaltrials: gov, NCT02528227., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)