Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC).

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potently immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and non-enzymatic functions. Pharmacological therapies targeting IDO1 enzyme activity have generally failed to improve the overall survival of patients with cancer. Developing new therapeutic agents that are capable of neutralizing both enzyme-and non-enzyme-derived immunosuppressive IDO1 effects is therefore of high interest.

Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment: A Systematic Review.

Purpose: A glioblastoma (GBM) is a primary brain tumor with significant unmet therapeutic needs. Immune checkpoint inhibitors (ICIs) have marked therapeutic benefits in many different cancers but have yet to show benefit for most GBM patients in phase III trials.

Methods: A systematic review querying ClinicalTrials.

Weak integration allows novel fin shapes and spurs locomotor diversity in reef fishes.

In complex functional systems composed of many traits, selection for specialized function can induce trait evolution by acting directly on individual components within the system, or indirectly through networks of trait integration. However, strong integration can also hinder diversification into regions of trait space that are not aligned with axes of covariation among traits. As a result, non-independence among traits may limit capacity for functional expansion.

Complexity and weak integration promote the diversity of reef fish oral jaws.

Major trade-offs often manifest as axes of diversity in organismal functional systems. Overarching trade-offs may result in high trait integration and restrict the trajectory of diversification to be along a single axis. Here, we explore the diversification of the feeding mechanism in coral reef fishes to establish the role of trade-offs and complexity in a spectacular ecological radiation.

NKG2C/ tumor cell expression enhances immunotherapeutic efficacy against glioblastoma.

Background: Activating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment.

Methods: We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by NKG2C, among bulk and single-cell RNA sequencing GBM data sets.

The Impact of Obesity on Success of Immediate Lymphatic Reconstruction for Prevention of Breast Cancer-Related Lymphedema.

Background: Breast cancer-related lymphedema (BRCL) is a potential sequela of high-risk breast cancer treatment. Preventive treatment with immediate lymphatic reconstruction (ILR) at the time of axillary lymph node dissection (ALND) has emerged as the standard of care; however, there is relatively little known about factors that may contribute to procedural failure.

Methods: A retrospectively maintained, institutional review board-approved study followed patients who underwent ILR at the time of ALND at our tertiary care center between May 2018 and May 2023.

Hydrodynamic Function of the Slimy and Scaly Surfaces of Teleost Fishes.

The scales and skin mucus of bony fishes are both proposed to have a role in beneficially modifying the hydrodynamics of water flow over the body surface. However, it has been challenging to provide direct experimental evidence that tests how mucus and fish scales change the boundary layer in part due to the difficulties in working with live animal tissue and difficulty directly imaging the boundary layer. In this manuscript, we use direct imaging and flow tracking within the boundary layer to compare boundary layer dynamics over surfaces of fish skin with mucus, without mucus, and a flat control surface.

Penile Revascularization for Erectile Dysfunction Secondary to Arterial Insufficiency: A Case Series.

Background: First described by Michal et al in 1972, penile revascularization for vasculogenic impotence and its outcomes has been scarcely reported in plastic surgery literature. Such injuries are often secondary to atherosclerosis of the distal internal pudendal, common penile or proximal cavernosal artery, or locoregional trauma. Various techniques have been described to restore blood flow to the cavernosal body.

Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation.

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging.

Anti-aquaporin-4 immunoglobulin G/anti-myelin oligodendrocyte glycoprotein immunoglobulin G double-positive paraneoplastic neurological syndrome in a patient with triple-negative breast cancer.

We report a rare case of paraneoplastic neurological syndrome with dual seropositivity of anti-aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in a 40 year-old woman with metastatic triple-negative breast cancer. She received multiple lines of anti-neoplastic treatment, including immunotherapy with pembrolizumab, as well as cytotoxic chemotherapy. Paraneoplastic meningoencephalomyelitis developed 2 years after diagnosis of breast cancer and 1 year after discontinuation of immunotherapy with pembrolizumab.

Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment.

CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells.

Clinical characteristics of people with intellectual disability admitted to hospital with constipation: identifying possible specific high-risk factors.

Background: People with intellectual disabilities (ID) die on an average 20 years earlier to the general population. They have higher rates of multimorbidity and polypharmacy. Around 25% of people with ID report chronic constipation.

High-resolution measurements of swordfish skin surface roughness.

The three-dimensional morphology of swordfish skin roughness remains poorly understood. Subsequently, its importance to the overall physiology and hydrodynamic performance of the swordfish is yet to be determined. This is at least partly attributable to the inherent difficulty in making the required measurements of these complex biological surfaces.

LDHA-regulated tumor-macrophage symbiosis promotes glioblastoma progression.

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase (LDH) inhibitor stiripentol (an FDA-approved anti-seizure drug for Dravet Syndrome) emerges as the top hit. Combined profiling and functional studies demonstrate that LDHA-directed ERK pathway activates YAP1/STAT3 transcriptional co-activators in glioblastoma cells to upregulate CCL2 and CCL7, which recruit macrophages into the tumor microenvironment.

'Making every contact count' with patients with musculoskeletal conditions: a qualitative exploration of acceptability to physiotherapists.

Aim: To qualitatively explore physiotherapists' experiences and acceptability of implementing 'Making Every Contact Count Healthy Conversation Skills' (MECC HCS) in routine practice with patients with musculoskeletal (MSK) conditions.

Methods: This article reports the second phase of a mixed method, sequential explanatory study. Physiotherapists trained in and delivering MECC HCS in their practice were invited to take part in semi-structured interviews.

Breastfeeding Ability After Breast Reductions: What does the Literature Tell us in 2023?

Introduction: Reduction mammaplasties are routinely performed on women of child-bearing age, yet there still exists some uncertainty regarding a patient's ability to breastfeed following the procedure. This is due to inconsistent definitions of "successful" breastfeeding, a variety of pedicles implemented, and inadequate follow-up in the published literature. Our aim was to summarize the current data and provide clear recommendations for counseling patients on expected breastfeeding outcomes following reduction mammaplasty.

Characteristics and Complication Rates of Mandibular Fractures Caused by Violent Mechanisms Versus Nonviolent Mechanisms.

Background: Mandibular fractures due to intentionally violent mechanisms represent a unique subset of facial fractures. The objective of our research is to identify how violence affects patterns of mandibular fractures and their outcomes.

Methods: In this institutional review board-approved, retrospective study, we examined our institution's records for adult patients >18 years of age who presented with ≥ 1 mandibular fractures from January 2011 to January 2022.

Immediate Lymphatic Reconstruction in 77 Consecutive Breast Cancer Patients: 2-year Follow-up.

Background:  Breast cancer-related lymphedema (BCRL) is a cyclical, progressive disease that begins at the time of axillary dissection and worsens in the setting of adjuvant oncologic therapies. The paradigm of lymphedema management in these patients is shifting from therapeutic surgeries and decongestive therapy to preventative surgery with immediate lymphatic reconstruction (ILR).

Methods:  After institutional review board approval, a prospective database was maintained of all patients undergoing ILR.