Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.

Background: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

Methods: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe.

Autologous T cell therapy for MAGE-A4 solid cancers in HLA-A*02 patients: a phase 1 trial.

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ).

Polypharmacy in Hospice and Palliative Care.

In patients with limited life expectancy, or if the clinician would not be surprised if the patient were to die within a year, reconsidering the treatment targets and engaging in an open discussion with the patient on their goals of care would be appropriate. When a desire to deprescribe has been reached by both clinician and patient, a stepwise and guided approach to deprescribing with regular follow-ups is recommended. This article discusses common medications that can be deprescribed in the palliative/hospice patients and provides toolkits for future reference.

Potentiating adoptive cell therapy using synthetic IL-9 receptors.

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γ) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γ cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells.

Newly developed pseudogout arthritis after therapy with MAGE-A4 directed TCR T cells responded to treatment with tocilizumab.

With durable cancer responses, genetically modified cell therapies are being implemented in various cancers. However, these immune effector cell therapies can cause toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Pseudogout arthritis is an inflammatory arthritis induced by deposition of calcium pyrophosphate dihydrate crystals.

Trajectories of Unsecured Debt across the Life Course and Mental Health at Midlife.

In this paper, we contribute to a growing literature on debt and mental health and ask whether patterns of unsecured debt accumulation and repayment over two decades are associated with depressive symptoms at age 50. Using data from the National Longitudinal Study of Youth 1979 Cohort and group trajectory models, we have three key findings. First, we find substantial heterogeneity in debt trajectories across the life course.

Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes.

Multidrug resistance-1 (MDR1) acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiological functions remain enigmatic. Using a recently developed MDR1-knockin reporter allele (Abcb1aAME), we found that constitutive MDR1 expression among hematopoietic cells was observed in cytolytic lymphocytes-including CD8+ cytotoxic T lymphocytes (CTLs) and natural killer cells-and regulated by Runt-related (Runx) transcription factors. Whereas MDR1 was dispensable for naive CD8+ T cell development, it was required for both the normal accumulation of effector CTLs following acute viral infection and the protective function of memory CTLs following challenge with an intracellular bacterium.

Identifying Patients with Rare Disease Using Electronic Health Record Data: The Kaiser Permanente Southern California Membranous Nephropathy Cohort.

Introduction: Developing a reliable means to identify and study real-world populations of patients with membranous nephropathy (MN) using electronic health records (EHRs) would help advance glomerular disease research. Identifying MN cases using EHRs is limited by the need for manual reviews of biopsy reports.

Objective: To evaluate the accuracy of identifying patients with biopsy-proven MN using the EHR in a large, diverse population of an integrated health system.

Late-Stage Failures of Monoclonal Antibody Drugs: A Retrospective Case Study Analysis.

Aim: To analyze the late-stage failures of monoclonal antibody drugs. The later a drug fails in development, the more time and expense is incurred by the sponsor.

Methods: We review the late stage, Phase III, failures of 21 monoclonal antibody drugs between 2014 and 2019 using published and publicly available information to characterize the reasons for these failures.

Distinct Requirements of CHD4 during B Cell Development and Antibody Response.

The immunoglobulin heavy chain (Igh) locus features a dynamic chromatin landscape to promote class switch recombination (CSR), yet the mechanisms that regulate this landscape remain poorly understood. CHD4, a component of the chromatin remodeling NuRD complex, directly binds H3K9me3, an epigenetic mark present at the Igh locus during CSR. We find that CHD4 is essential for early B cell development but is dispensable for the homeostatic maintenance of mature, naive B cells.

The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids.

CD4 T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4 T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1 hosts.

Role of Dysregulated Cytokine Signaling and Bacterial Triggers in the Pathogenesis of Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic, and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome showed a highly heterogeneous landscape of genetic perturbations, and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease.

Patients and caregivers costs for colonoscopy-based colorectal cancer screening: Experience of low-income individuals undergoing free colonoscopies.

Many studies have documented barriers to colorectal cancer screenings. However, there is lack of comprehensive information on the time and costs borne by low-income patients and the persons accompanying the patient (caregiver) for colonoscopies in the United States. We surveyed patients in three health clinics in Philadelphia retrospectively who had undergone free colonoscopies in the previous 18-month period.

Low CD1c + myeloid dendritic cell counts correlated with a high risk of rapid disease progression during early HIV-1 infection.

Background: During early HIV-1 infection (EHI), the interaction between the immune response and the virus determines disease progression. Although CD1c + myeloid dendritic cells (mDCs) can trigger the immune response, the relationship between CD1c + mDC alteration and disease progression has not yet been defined.

Methods: EHI changes in CD1c + mDC counts, surface marker (CD40, CD86, CD83) expression, and IL-12 secretion were assessed by flow cytometry in 29 patients.

PDK1 Activity Regulates Proliferation, Invasion and Growth of Hemangiomas.

Background: Hemangiomas are common vascular endothelial cell tumors. Abnormally activated PI3K/Akt signaling pathway is one of the most important biological characteristics of Hemangioma. 3-phosphoinositide-dependent kinase 1(PDK1), an upstream protein of Akt, regulates the activity of Akt and its downstream kinases.

VH replacement in primary immunoglobulin repertoire diversification.

The genes encoding the variable (V) region of the B-cell antigen receptor (BCR) are assembled from V, D (diversity), and J (joining) elements through a RAG-mediated recombination process that relies on the recognition of recombination signal sequences (RSSs) flanking the individual elements. Secondary V(D)J rearrangement modifies the original Ig rearrangement if a nonproductive original joint is formed, as a response to inappropriate signaling from a self-reactive BCR, or as part of a stochastic mechanism to further diversify the Ig repertoire. VH replacement represents a RAG-mediated secondary rearrangement in which an upstream VH element recombines with a rearranged VHDHJH joint to generate a new BCR specificity.

Increase of RT-related transmitted drug resistance in non-CRF01_AE among HIV type 1-infected men who have sex with men in the 7 cities of China.

Objectives: To elucidate new features in the prevalence of HIV-1 transmitted drug resistance (TDR) in men who have sex with men (MSM) in China.

Methods: A total of 441 HIV-1-positive subjects were recruited from high-risk MSM populations in 7 cities across China between 2012 and 2013. Nucleotide sequences of 1.

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells.

Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (VH)-encoded "elbow" between variable and constant domains. By sequencing 2.

T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia.

Th17 cells are a proinflammatory subset of effector T cells that have been implicated in the pathogenesis of asthma. Their production of the cytokine IL-17 is known to induce local recruitment of neutrophils, but the direct impact of IL-17 on the lung epithelium is poorly understood. In this study, we describe a novel mouse model of spontaneous IL-17-driven lung inflammation that exhibits many similarities to asthma in humans.

Level of phosphohistone H3 among various types of human cancers.

Objectives: Anti-phosphorylated histone H3 (pHH3) antibodies specifically detect the core protein histone H3 only when phosphorylated at serine 10 (Ser10) or serine 28 (Ser28). Measurement of pHH3 levels can be used for quantifying mitosis and the effectiveness of mitotic inhibitors in early drug development. However, data on the expression level of pHH3 (Ser10) and pHH3 (Ser28) among different cancers are limited.

Repeatability of edited lactate and other metabolites in astrocytoma at 3T.

Purpose: To assess the repeatability of measurement of lactate and other metabolites in tumors using magnetic resonance spectroscopy (MRS).

Materials And Methods: MRS with spectral editing for lactate was performed on 10 patients with astrocytoma (two Grade III, eight Grade IV) using an 8-channel receive coil at 3T. Lactate, lipid, choline, creatine, and N-acetyl aspartate (NAA) signals were measured in regions of tumor and contralateral white matter.

Firefly luciferase-based dynamic bioluminescence imaging: a noninvasive technique to assess tumor angiogenesis.

Objective: Bioluminescence imaging (BLI) is emerging as a cost-effective, high-throughput, noninvasive, and sensitive imaging modality to monitor cell growth and trafficking. We describe the use of dynamic BLI as a noninvasive method of assessing vessel permeability during brain tumor growth.

Methods: With the use of stereotactic technique, 10 firefly luciferase-transfected GL26 mouse glioblastoma multiforme cells were injected into the brains of C57BL/6 mice (n = 80).