GrB-Fc-KS49, an anti-EMP2 granzyme B fusion protein therapeutic alters immune cell infiltration and suppresses breast cancer growth.

Background: Granzyme B (GrB) is a key effector molecule, delivered by cytotoxic T lymphocytes and natural killer cells during immune surveillance to induce cell death. Fusion proteins and immunoconjugates represent an innovative therapeutic approach to specifically deliver a deadly payload to target cells. Epithelial membrane protein-2 (EMP2) is highly expressed in invasive breast cancer (BC), including triple-negative BC (TNBC), and represents an attractive therapeutic target.

Micronutrient dose response (MiNDR) study among women of reproductive age and pregnant women in rural Bangladesh: study protocol for double-blind, randomised, controlled trials.

Introduction: Optimising the micronutrient status of women before and during reproduction confers benefits to them and their offspring. Antenatal multiple micronutrient supplements (MMS), given as a daily tablet with nutrients at ~1 recommended dietary allowance (RDA) or adequate intake (AI) reduces adverse birth outcomes. However, at this dosage, MMS may not fully address micronutrient deficiencies in settings with chronically inadequate diets and infection.

Application of Causal Forest Model to Examine Treatment Effect Heterogeneity in Substance Use Disorder Psychosocial Treatments.

Objectives: Heterogeneity of treatment effect (HTE) is a concern in substance use disorder (SUD) treatments but has not been rigorously examined. This exploratory study applied a causal forest approach to examine HTE in psychosocial SUD treatments, considering multiple covariates simultaneously.

Methods: Data from 12 randomized controlled trials of nine psychosocial treatments were obtained from the National Institute on Drug Abuse Clinical Trials Network.

CD4 T Cells Occupy Perivascular and Perifollicular Niches in Healthy Human Skin.

Regulatory T cells (Tregs) are specialised T lymphocytes that sit at the nexus of immune regulation and tissue repair. While it is appreciated that a substantial number of Tregs are present in healthy human skin, less is known about their microanatomic spatial localisation. Knowledge about the specialised niches that Tregs occupy may aid in rational drug development to treat dermatologic diseases.

Phase II trial of pembrolizumab, ipilimumab, and aspirin in melanoma: clinical outcomes and translational predictors of response.

Objective: Many patients with melanoma treated with immune checkpoint inhibitors (ICIs) do not derive response. Preclinical and retrospective studies identified that inhibition of the cyclooxygenase (COX) pathway may improve response to ICI treatment.

Methods: This prospective single site phase II trial accrued patients with advanced/metastatic melanoma.

Expanding the clinicopathologic spectrum and genomic landscape of tumors with SMARCA2/4::CREM fusions.

CREB gene family (ATF1, CREB1, CREM) fusions with either EWSR1 or FUS gene partners drive the pathogenesis of a wide range of neoplasms, including various soft tissue tumors, intracranial myxoid mesenchymal tumors (IMMTs), hyalinizing clear cell carcinoma (HCCC), and rare mesotheliomas. Recently, a SMARCA2::CREM fusion was reported in one case each of IMMT and HCCC. In this study, we expand the clinicopathologic and molecular spectrum of these neoplasms by describing three additional cases with SMARCA2::CREM and one with a novel SMARCA4::CREM fusion, highlighting the recurrent potential of additional CREB gene fusion partners beyond FET family members.

Phase reduction explains chimera shape: When multibody interaction matters.

We present an extension of the Kuramoto-Sakaguchi model for networks, deriving the second-order phase approximation for a paradigmatic model of oscillatory networks-an ensemble of nonidentical Stuart-Landau oscillators coupled pairwisely via an arbitrary coupling matrix. We explicitly demonstrate how this matrix translates into the coupling structure in the phase equations. To illustrate the power of our approach and the crucial importance of high-order phase reduction, we tackle a trendy setup of nonlocally coupled oscillators exhibiting a chimera state.

A Novel Whole Tissue Explant Model of Hidradenitis Suppurativa.

Hidradenitis Suppurativa (HS) is a relatively common and highly morbid inflammatory skin disease. Due to our relatively limited understanding of HS's pathogenesis, there are currently insufficient treatment options available, and many patients' medical needs are not being met. This is partly due to a scarcity of ex vivo human assays and animal models that accurately recapitulate the disease.

A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1 -altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1 - amplified Versus GLI1- rearranged Tumors.

GLI1 -altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1 -altered mesenchymal neoplasms to date, including 23 GLI1- amplified and 15 GLI1 -rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation.

Differentiating Low-Grade from High-Grade Intracranial Ependymomas: Comparison of Dynamic Contrast-Enhanced MRI and Diffusion-Weighted Imaging.

Background And Purpose: The aim of this study was to determine the diagnostic value of fractional plasma volume derived from dynamic contrast-enhanced perfusion MR imaging versus ADC, obtained from DWI in differentiating between grade 2 (low-grade) and grade 3 (high-grade) intracranial ependymomas.

Materials And Methods: A hospital database was created for the period from January 2013 through June 2022, including patients with histologically-proved ependymoma diagnosis with available dynamic contrast-enhanced MR imaging. Both dynamic contrast-enhanced perfusion and DWI were performed on each patient using 1.

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.

A unified quantification of synchrony in globally coupled populations with the Wiener order parameter.

We tackle the quantification of synchrony in globally coupled populations. Furthermore, we treat the problem of incomplete observations when the population mean field is unavailable, but only a small subset of units is observed. We introduce a new order parameter based on the integral of the squared autocorrelation function and demonstrate its efficiency for quantifying synchrony via monitoring general observables, regardless of whether the oscillations can be characterized in terms of the phases.

Development and prospective validation of an artificial intelligence-based smartphone app for rapid intraoperative pituitary adenoma identification.

Background: Intraoperative pathology consultation plays a crucial role in tumor surgery. The ability to accurately and rapidly distinguish tumor from normal tissue can greatly impact intraoperative surgical oncology management. However, this is dependent on the availability of a specialized pathologist for a reliable diagnosis.

Interleukin-2-induced skin inflammation.

Recombinant human IL-2 has been used to treat inflammatory diseases and cancer; however, side effects like skin rashes limit the use of this therapeutic. To identify key molecules and cells inducing this side effect, we characterized IL-2-induced cutaneous immune reactions and investigated the relevance of CD25 (IL-2 receptor α) in the process. We injected IL-2 intradermally into WT mice and observed increases in immune cell subsets in the skin with preferential increases in frequencies of IL-4- and IL-13-producing group 2 innate lymphoid cells and IL-17-producing dermal γδ T cells.

Feedback control of collective dynamics in an oscillator population with time-dependent connectivity.

We present a numerical study of pulsatile feedback-based control of synchrony level in a highly-interconnected oscillatory network. We focus on a nontrivial case when the system is close to the synchronization transition point and exhibits collective rhythm with strong amplitude modulation. We pay special attention to technical but essential steps like causal real-time extraction of the signal of interest from a noisy measurement and estimation of instantaneous phase and amplitude.

The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

Introduction: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD.

Methods: One hundred and sixty-four participants were randomized to placebo ( = 83) or AGB101 ( = 81), an extended-release formulation of low dose (220 mg) levetiracetam.

Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche.

Immune tolerance is maintained in lymphoid organs (LOs). Despite the presence of complex immune cell networks in non-LOs, it is unknown whether self-tolerance is maintained in these tissues. We developed a technique to restrict genetic recombination to regulatory T cells (T) only in skin.

Tertiary lymphoid structures sustain cutaneous B cell activity in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic skin condition affecting approximately 1% of the US population. HS skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu, the biology and the contribution of these cells in HS pathogenesis are unclear.

Inferring connectivity of an oscillatory network via the phase dynamics reconstruction.

We review an approach for reconstructing oscillatory networks' undirected and directed connectivity from data. The technique relies on inferring the phase dynamics model. The central assumption is that we observe the outputs of all network nodes.

High-order phase reduction for coupled 2D oscillators.

Phase reduction is a general approach to describe coupled oscillatory units in terms of their phases, assuming that the amplitudes are enslaved. The coupling should be small for such reduction, but one also expects the reduction to be valid for finite coupling. This paper presents a general framework, allowing us to obtain coupling terms in higher orders of the coupling parameter for generic two-dimensional oscillators and arbitrary coupling terms.