Early infantile-onset epileptic encephalopathy 28 due to a homozygous microdeletion involving the WWOX gene in a region of uniparental disomy.

The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year-old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile-onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities, and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22.

Ofatumumab plus high dose methylprednisolone followed by ofatumumab plus alemtuzumab to achieve maximal cytoreduction prior to allogeneic transplantation for 17p deleted or TP53 mutated chronic lymphocytic leukemia.

We hypothesized that ofatumumab with sequential methylprednisolone - alemtuzumab would be an effective and tolerable regimen for patients with high-risk chronic lymphocytic leukemia (CLL) with TP53 dysfunction. Thirty CLL patients with TP53 dysfunction (15 treatment naive (TN), 15 relapsed/refractory (R/R)) were enrolled in this phase II study. Therapy included ofatumumab with methylprednisolone for 2-4 monthly cycles, then ofatumumab with alemtuzumab for 4-24 weeks, then allogeneic transplantation or maintenance.

Does the use of adjunct urine lipopolysaccharide lipoarabinomannan in HIV-infected hospitalized patients reduce the utilization of healthcare resources? A post hoc analysis of the LAM multi-country randomized controlled trial.

Background: The World Health Organization (WHO) recommends the use of adjunctive urine lipopolysaccharide lipoarabinomannan (LAM) testing in hospitalized HIV-infected persons with suspected tuberculosis (TB) and a CD4 count <100cells/ml. However, the recommendation is conditional, and uptake by individual treatment programmes depends on perceived additional benefit. The aim of this study was to determine whether adjunctive LAM testing has additional clinical benefits including a reduction in healthcare-related use of resources.

A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation.

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.

The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients.

An autologous dendritic cell vaccine polarizes a Th-1 response which is tumoricidal to patient-derived breast cancer cells.

Breast cancer remains one of the leading causes of cancer-associated death worldwide. Conventional treatment is associated with substantial toxicity and suboptimal efficacy. We, therefore, developed and evaluated the in vitro efficacy of an autologous dendritic cell (DC) vaccine to treat breast cancer.

Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies.

The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells.

Prediction of peripheral nerve stimulation thresholds of MRI gradient coils using coupled electromagnetic and neurodynamic simulations.

Purpose: As gradient performance increases, peripheral nerve stimulation (PNS) is becoming a significant constraint for fast MRI. Despite its impact, PNS is not directly included in the coil design process. Instead, the PNS characteristics of a gradient are assessed on healthy subjects after prototype construction.

Evaluation of stacked resonators to enhance the performance of a surface receive-only array for prostate MRI at 3 Tesla.

Prostate MRI is an important tool to diagnose and characterize cancer. High local sensitivity and good parallel imaging performance are of paramount importance for diagnostic quality and efficiency. The purpose of this work was to evaluate stacked resonators as part of a surface receiver array for prostate MRI at 3 Tesla.

The rise of apoptosis: targeting apoptosis in hematologic malignancies.

Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma-extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development.

Evaluating the effects of receive-only arrays in specific absorption rate simulations at 3 and 7 T.

Specific absorption rate (SAR) simulations are performed for most clinical and research transmit coil configurations. Such simulations allow the determination of limits in transmit power for patient safety. Different human models and coil configurations have been previously investigated using these simulations.

Statins enhance efficacy of venetoclax in blood cancers.

Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells.

Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia.

The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors. We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies. Median age was 66 years and 60% had del(17p).

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial.

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort.

Review of targeted therapy in chronic lymphocytic leukemia: what a radiologist needs to know about CT interpretation.

The last 5 years have been marked by profound innovation in the targeted treatment of chronic lymphocytic leukemia (CLL) and indolent lymphomas. Using CLL as a case study, we present a timeline and overview of the current treatment landscape for the radiologist, including an overview of clinical and radiological features of CLL, discussion of the targeted agents themselves, and the role of imaging in response and toxicity assessment. The goal is to familiarize the radiologist with multiple Food and Drug Administration (FDA)-approved targeted agents used in this setting and associated adverse events which are commonly observed in this patient population.

Metatranscriptome analysis of the microbial fermentation of dietary milk proteins in the murine gut.

Undigestible food ingredients are converted by the microbiota into a large range of metabolites, predominated by short chain fatty acids (SCFA). These microbial metabolites are subsequently available for absorption by the host mucosa and can serve as an energy source. Amino acids fermentation by the microbiota expands the spectrum of fermentation end-products beyond acetate, propionate and butyrate, to include in particular branched-SCFA.

Regulatory T Cells Subvert Mycobacterial Containment in Patients Failing Extensively Drug-Resistant Tuberculosis Treatment.

Rationale: The advent of extensively drug-resistant (XDR) tuberculosis (TB) and totally drug-resistant TB, with limited or no treatment options, has facilitated renewed interest in host-directed immunotherapy, particularly for therapeutically destitute patients. However, the selection and utility of such approaches depend on understanding the host immune response in XDR-TB, which hitherto remains unexplored.

Objectives: To determine the host immunological profile in patients with XDR-TB, compared with drug-sensitive TB (DS-TB), using peripheral blood and explanted lung tissue.

Reasons for initiation of treatment and predictors of response for patients with Rai stage 0/1 chronic lymphocytic leukemia (CLL) receiving first-line therapy: an analysis of the Connect CLL cohort study.

A 'watch-and-wait' strategy is recommended for most patients with early-stage chronic lymphocytic leukemia (CLL) prior to treatment initiation. In the Connect CLL registry, a prospective observational cohort study of 1494 patients treated in 199 US centers, median time to first-line treatment initiation was 3.8, 1.

Tyrosine kinase inhibitors and immune checkpoint blockade in allogeneic hematopoietic cell transplantation.

Advances in the prevention of graft-versus-host disease (GVHD) and opportunistic infection have improved survival after allogeneic hematopoietic cell transplantation (allo-HCT) in the past decade. However, few inroads have been made into the treatment or prevention of relapse of the underlying malignancy for which allo-HCT is being performed. The introduction of US Food and Drug Administration-approved agents with significant activity in a variety of hematologic malignancies provides an opportunity to evaluate these interventions in the allo-HCT setting.

Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenetics: A Real-world Clinical Experience in the Connect CLL Registry.

Introduction: Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy.

Patients And Methods: In the present analysis of the Connect CLL Registry (ClinicalTrials.

Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy.

B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment.