CXCR4 antagonism ameliorates leukocyte abnormalities in a preclinical model of WHIM syndrome.

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.

Cysteamine dioxygenase (ADO) governs cancer cell mitochondrial redox homeostasis through proline metabolism.

2-Aminoethanethiol dioxygenase (ADO) is a thiol dioxygenase that sulfinylates cysteamine and amino-terminal cysteines in polypeptides. The pathophysiological roles of ADO remain largely unknown. Here, we demonstrate that ADO expression represents a vulnerability in cancer cells, as ADO depletion led to loss of proliferative capacity and survival in cancer cells and reduced xenograft growth.

Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.

Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry-based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs.

Sample Size Estimation Using a Partially Clustered Frailty Model for Biomarker-Strategy Designs With Multiple Treatments.

Biomarker-guided therapy is a growing area of research in medicine. To optimize the use of biomarkers, several study designs including the biomarker-strategy design (BSD) have been proposed. Unlike traditional designs, the emphasis here is on comparing treatment strategies and not on treatment molecules as such.

A joint frailty model for recurrent and competing terminal events: Application to delirium in the ICU.

Joint models linking longitudinal biomarkers or recurrent event processes with a terminal event, for example, mortality, have been studied extensively. Motivated by studies of recurrent delirium events in patients receiving care in an intensive care unit (ICU), we devise a joint model for a recurrent event process and multiple terminal events. Being discharged alive from the ICU or experiencing mortality may be associated with a patient's hazard of delirium, violating the assumption of independent censoring.

Sample size estimation for recurrent event data using multifrailty and multilevel survival models.

In epidemiology and clinical research, recurrent events refer to individuals who are likely to experience transient clinical events repeatedly over an observation period. Examples include hospitalizations in patients with heart failure, fractures in osteoporosis studies and the occurrence of new lesions in oncology. We provided an in-depth analysis of the sample size required for the analysis of recurrent time-to-event data using multifrailty or multilevel survival models.

A marginalized two-part joint model for a longitudinal biomarker and a terminal event with application to advanced head and neck cancers.

The sum of the longest diameter (SLD) of the target lesions is a longitudinal biomarker used to assess tumor response in cancer clinical trials, which can inform about early treatment effect. This biomarker is semicontinuous, often characterized by an excess of zeros and right skewness. Conditional two-part joint models were introduced to account for the excess of zeros in the longitudinal biomarker distribution and link it to a time-to-event outcome.

Trends in epidemiology and risk factors of opportunistic infections in kidney transplant recipients between 2004 and 2017.

Background: While opportunistic infections are a frequent and challenging problem in kidney transplant recipients, their long-term epidemiology remains hardly known.

Methods: Opportunistic infections were recorded in 1144 recipients transplanted in our center between 2004 and 2015. Incidence rates and baseline risk factors were determined using joint frailty models.

Association between pre-diagnosis geriatric syndromes and overall survival in older adults with cancer (the INCAPAC study).

Introduction: Several population-based studies have reported disparities in overall survival (OS) among older patients with cancer. However, geriatric syndromes, known to be associated with OS in the geriatric population, were rarely studied. Thus, our aim was to identify the determinants of OS among French older adults with cancer, including geriatric syndromes before cancer diagnosis.

WHIM Syndrome-linked CXCR4 mutations drive osteoporosis.

WHIM Syndrome is a rare immunodeficiency caused by gain-of-function CXCR4 mutations. Here we report a decrease in bone mineral density in 25% of WHIM patients and bone defects leading to osteoporosis in a WHIM mouse model. Imbalanced bone tissue is observed in mutant mice combining reduced osteoprogenitor cells and increased osteoclast numbers.

On the Choice of Longitudinal Models for the Analysis of Antitumor Efficacy in Mouse Clinical Trials of Patient-derived Xenograft Models.

Unlabelled: In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms.

Bayesian estimation of two-part joint models for a longitudinal semicontinuous biomarker and a terminal event with INLA: Interests for cancer clinical trial evaluation.

Two-part joint models for a longitudinal semicontinuous biomarker and a terminal event have been recently introduced based on frequentist estimation. The biomarker distribution is decomposed into a probability of positive value and the expected value among positive values. Shared random effects can represent the association structure between the biomarker and the terminal event.

A flexible class of generalized joint frailty models for the analysis of survival endpoints.

This article focuses on shared frailty models for correlated failure times, as well as joint frailty models for the simultaneous analysis of recurrent events (eg, appearance of new cancerous lesions or hospital readmissions) and a major terminal event (typically, death). As extensions of the Cox model, these joint models usually assume a frailty proportional hazards model for each of the recurrent and terminal event processes. In order to extend these models beyond the proportional hazards assumption, our proposal is to replace these proportional hazards models with generalized survival models, for which the survival function is modeled as a linear predictor through a link function.

Effects of air pollution on clinical pregnancy rates after in vitro fertilisation (IVF): a retrospective cohort study.

Objective: To evaluate the effect of air pollution, from oocyte retrieval to embryo transfer, on the results of in vitro fertilisation (IVF) in terms of clinical pregnancy rates, at two fertility centres, from 2013 to 2019.

Design: Exploratory retrospective cohort study.

Setting: This retrospective cohort study was performed in the Reproductive Biology Department of Bordeaux University Hospital localised in Bordeaux, France and the Jean Villar Fertility Center localised in Bruges, France.

Time-to-event surrogate endpoint validation using mediation analysis and meta-analytic data.

With the ongoing development of treatments and the resulting increase in survival in oncology, clinical trials based on endpoints such as overall survival may require long follow-up periods to observe sufficient events and ensure adequate statistical power. This increase in follow-up time may compromise the feasibility of the study. The use of surrogate endpoints instead of final endpoints may be attractive for these studies.

Socioeconomic status and its relation with breast cancer recurrence and survival in young women in the Netherlands.

Background: Associations between socioeconomic status (SES) and breast cancer survival are most pronounced in young patients. We further investigated the relation between SES, subsequent recurrent events and mortality in breast cancer patients < 40 years. Using detailed data on all recurrences that occur between date of diagnosis of the primary tumor and last observation, we provide a unique insight in the prognosis of young breast cancer patients according to SES.

Fine-tuning of MEK signaling is pivotal for limiting B and T cell activation.

MEK1 and MEK2, the only known activators of ERK, are attractive therapeutic candidates for both cancer and autoimmune diseases. However, how MEK signaling finely regulates immune cell activation is only partially understood. To address this question, we specifically delete Mek1 in hematopoietic cells in the Mek2 null background.

Time to next treatment or death as a candidate surrogate endpoint for overall survival in advanced melanoma patients treated with immune checkpoint inhibitors: an insight from the phase III CheckMate 067 trial.

Background: Time to next treatment or death (TNT-D) may be a patient-relevant endpoint in patients treated with immune checkpoint inhibitors. This study investigated TNT-D as a surrogate endpoint (SE) for overall survival (OS) in previously untreated advanced melanoma patients.

Methods: Patient-level data from the 60-month results of the CheckMate 067 randomised, controlled trial were used.

Conditional copula models for correlated survival endpoints: Individual patient data meta-analysis of randomized controlled trials.

Correlations among survival endpoints are important for exploring of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms.

and Functional Redundancy in Erythropoiesis.

Several studies have established the crucial role of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway in hematopoietic cell proliferation and differentiation. MEK1 and MEK2 phosphorylate and activate ERK1 and ERK2. However, whether MEK1 and MEK2 differentially regulate these processes is unknown.

Sample size estimation for cancer randomized trials in the presence of heterogeneous populations.

A key issue when designing clinical trials is the estimation of the number of subjects required. Assuming for multicenter trials or biomarker-stratified designs that the effect size between treatment arms is the same among the whole study population might be inappropriate. Limited work is available for properly determining the sample size for such trials.