Alternative splicing of modulatory immune receptors in T lymphocytes: a newly identified and targetable mechanism for anticancer immunotherapy.

Alternative splicing (AS) is a mechanism that generates translational diversity within a genome. Equally important is the dynamic adaptability of the splicing machinery, which can give preference to one isoform over others encoded by a single gene. These isoform preferences change in response to the cell's state and function.

Monobloc vs. Modular Radial-Head Arthroplasty for Complex Elbow Trauma: Long-Term Follow-Up and Comparative Evaluation.

Mason Type 3 radial-head fractures are typically treated with open reduction and internal fixation (ORIF) or radial-head arthroplasty (RHA). Prosthetic options include traditional monobloc implants and newer modular implants designed to match patient anatomy. While short- and medium-term outcomes of metallic RHA are generally favorable, this study aims to compare the long-term outcomes of patients treated with monobloc versus modular implants.

Volar Locking Plating of Extra-articular Distal Radius Fracture: A Retrospective Clinical Study Comparing Locking Screws versus Smooth Locking Pegs.

 Open reduction and internal fixation of distal radius fractures is one of the most common procedures performed in wrist surgery. The use of volar locking plate has gained increasing interest in the past decade. Epiphyseal fixation can be done either with locking screws or smooth locking pegs, with no evidence supporting the use of one rather than the other.

A novel pulsed electromagnetic field device as an adjunct therapy to surgical treatment of distal radius fractures: a prospective, double-blind, sham-controlled, randomized pilot study.

Introduction: The purpose of this study is to evaluate whether using a Fracture Healing Patch (FHP) device that generates pulsed electromagnetic fields (PEMF), applied at the fracture site immediately after open reduction and internal fixation surgery, can accelerate healing of acute distal radius fractures.

Methods: In a prospective, double-blind, randomized, and sham-controlled study, thirty-two patients with DRFs treated with ORIF were included. Patients were allocated to a PEMF (active) group (n = 15) or a control (sham) group (n = 17).

The future of affordable cancer immunotherapy.

The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval.

Preventing skin toxicities induced by EGFR inhibitors by topically blocking drug-receptor interactions.

Epidermal growth factor receptor (EGFR) inhibitors are used to treat many advanced-stage epithelial cancers but induce severe skin toxicities in most treated patients. These side effects lead to a deterioration in the quality of life of the patients and compromise the anticancer treatment. Current treatment strategies for these skin toxicities focus on symptom reduction rather than preventing the initial trigger that causes the toxicity.

The Effects of Novel Pulsed Electromagnetic Field Therapy Device on Acute Distal Radius Fractures: A Prospective, Double-Blind, Sham-Controlled, Randomized Pilot Study.

Background: this pilot study aimed at determining whether the application of a novel new method of generating pulsed electromagnetic field (PEMF), the Fracture Healing Patch (FHP), accelerates the healing of acute distal radius fractures (DRF) when compared to a sham treatment.

Methods: 41 patients with DRFs treated with cast immobilization were included. Patients were allocated to a PEMF group ( = 20) or a control (sham) group ( = 21).

Conserved allosteric inhibition mechanism in SLC1 transporters.

Excitatory amino acid transporter 1 (EAAT1) is a glutamate transporter belonging to the SLC1 family of solute carriers. It plays a key role in the regulation of the extracellular glutamate concentration in the mammalian brain. The structure of EAAT1 was determined in complex with UCPH-101, apotent, non-competitive inhibitor of EAAT1.

Rethinking Conservative Treatment of Humeral Diaphyseal Fractures in Elderly Patients With Dementia.

Objectives: To assess outcomes and complications of conservatively managed humeral diaphyseal fractures in elderly patients, with an emphasis on the subgroup diagnosed with dementia.

Design: Retrospective.

Setting: Upper extremity surgery unit at an academic Level I trauma center.

The role of immune checkpoint receptors in the malignant phenotype of cutaneous T cell lymphoma.

Immune checkpoint receptors (ICR) modulate the immune response and are critical hubs for immunotherapy. However, data on their role in T lymphoid malignancies, such as cutaneous T cell lymphoma (CTCL), is sparse. We aimed to explore the role of ICR in the malignant features of transformed T lymphocytes and evaluate the effect of ICR-targeting monoclonal antibodies, often used as immunotherapy for solid tumors.

PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR.

Cancer immunotherapy focuses on inhibitors of checkpoint proteins, such as programmed death ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have a generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, intrinsic and microenvironmental factors may be involved.

Early postoperative dressing removal in hand surgery: Novel concepts for individualized surgical dressing management.

Postoperative dressing protocols after clean surgery without implant vary widely. The purpose of this study was to elucidate whether early postoperative dressing removal is a valid option, as compared to untouched dressing or twice-weekly dressing change approach. A prospective randomized study was conducted on patients who underwent carpal tunnel release (CTR) or trigger finger release (TFR) between January and November 2020.

Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions.

SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6 had a strong agonistic effect.

Performance of the Roche cobas MTB Assay for the Molecular Diagnosis of Pulmonary Tuberculosis in a High HIV Burden Setting.

Increased access to and improved sensitivities of methods for diagnosing Mycobacterium tuberculosis infection and detecting rifampicin and isoniazid resistance are needed. Herein, the performance of the new cobas MTB assay for use on cobas 6800/8800 Systems (Roche) was assessed and compared with two other commercial assays: RealTime MTB (Abbott), and Xpert MTB/RIF (Cepheid). Molecular PCR-based assays were conducted on sputum specimens from individuals with presumptive and confirmed tuberculosis (n = 294) from two clinical facilities in South Africa between December 2016 and October 2017.

Multiple ipsilateral femoral stress fractures in a patient taking denosumab for osteoporosis-a case report.

Unlabelled: This is the first report describing three ipsilateral femoral stress fractures in a patient taking denosumab.

Introduction: Multiple reports of atypical femur fractures (AFF) in patients receiving denosumab have emerged recently. Denosumab is an anti-resorptive agent approved for treatment of osteoporosis.

SLAMF6​ deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint.

SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a exhaustion marker. By breeding Pmel-1 mice with SLAMF6 -/- mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen.

Immunotherapy Potentiates the Effect of Chemotherapy in Metastatic Melanoma-A Retrospective Study.

Melanoma survival increased with targeted- and immunotherapy agents, yet most patients ultimately progress and require salvage therapy. In our experience, some progressive disease patients on immune-checkpoint inhibitors (ICIs) demonstrate deep and sustained responses to chemotherapy. We hypothesized that ICIs improve the response to subsequent chemotherapy in metastatic melanoma.

Clinical Outcomes of Limited Open Intramedullary Headless Screw Fixation of Metacarpal Fractures in 91 Consecutive Patients.

The objective of the study is to evaluate clinical and radiographic outcomes in patients treated with limited-open retrograde intramedullary headless screw (IMHS) fixation for metacarpal neck and shaft fractures. Retrospective review of 91 consecutive patients (79 men; 12 women), mean age 28 (range =15-69) years, treated with IMHS fixation for acute displaced metacarpal neck (N = 56) and shaft (N = 35) fractures at a single institution. Mean follow-up was 10 (range = 1-71, median = 3) months.

Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor.

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.

Combined Expression of Genetic Adjuvants Via mRNA Electroporation Exerts Multiple Immunostimulatory Effects on Antitumor T Cells.

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or gene-modified T cells expressing antitumor TCRs or chimeric antigen receptors often yields a high rate of clinical response in several types of cancer. New approaches for enhancing the functional properties of antitumor T cells could improve the clinical outcome of these treatments. To this end, we created 3 classes of genes, each designed to operate autonomously upon expression in T cells.

The Focused Musculoskeletal Factory.

Rheumatology has evolved rapidly over the past 20 years. The availability of numerous treatment interventions has dramatically altered patient outcomes and revitalized the specialty. At the same time, the economics of medical practice is challenging the practicing rheumatologist to seek more efficient and more attractive models of care delivery.

Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40.

New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto-oligomerizing CD40 derivatives to induce strong activation of APCs in a ligand-independent manner.

Efficacy of intratympanic corticosteroid as a salvage treatment in idiopathic sudden sensorineural hearing loss.

Introduction: Idiopathic sudden sensorineural hearing loss (ISSHL) is defined as an abrupt hearing loss of at least 30dB of unknown cause. The hearing response obtained after intratympanic steroid injection as a salvage treatment after a prior failure of initial systemic steroid treatment was analysed.

Material And Method: An observational study was performed on 125 cases of ISSHL who were diagnosed from 2006 to 2014.

Clinical assessment of Eustachian tube dysfunction through the Eustachian tube dysfunction questionnaire (ETDQ-7) and tubomanometry.

Objective: Evaluation of the severity of Eustachian tube dysfunction using the Spanish validation of the Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) and tubomanometry (TMM).

Materials And Methods: Spanish validation of the ETDQ-7.

Patients: Prospective study with 125 patients, 75 of whom reported symptoms compatible with Eustachian tube dysfunction.

Subspinal impingement: clinical outcomes of arthroscopic decompression with one year minimum follow up.

Purpose: This study was designed to (1) evaluate the clinical outcomes after arthroscopic subspinal decompression in patients with hip impingement symptoms and low AIIS, and to (2) assess the presence of low anterior inferior iliac spine on the pre-operative radiographs of patients with established subspinal impingement diagnosed intra-operatively.

Methods: Retrospective analysis of patients who underwent arthroscopic subspinal decompression has been performed. The indications for surgery were femoroacetabular impingement (FAI), or subspinal impingement.