Twist-Induced Epithelial-to-Mesenchymal Transition Confers Specific Metabolic and Mitochondrial Alterations.

Cells undergo significant epigenetic and phenotypic change during the epithelial-to-mesenchymal transition (EMT), a process observed in development, wound healing, and cancer metastasis. EMT confers several advantageous characteristics, including enhanced migration and invasion, resistance to cell death, and altered metabolism. In disease, these adaptations could be leveraged as therapeutic targets.

Society for Immunotherapy of Cancer: updates and best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) image analysis and data sharing.

Objectives: Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force.

Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial.

Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy.

The Discovery of Head Direction Cells: A Personal Account.

This article is my recollection of events surrounding the discovery of head direction (HD) cells by Jim Ranck in 1984 and the first journal publications 6 years later. Ranck first described the fundamental properties of HD cells qualitatively in a Society for Neuroscience abstract (1984) and in the proceedings to a conference. Ranck, however, was convinced by Bob Muller, a faculty colleague in the lab, to delay writing up Jim's discovery until they developed a two-spot video tracking system, which would enable proper quantitative analyses.

Concordance of Whole-Slide Imaging and Conventional Light Microscopy for Assessment of Pathologic Response Following Neoadjuvant Therapy for Lung Cancer.

Pathologic response is an endpoint in many ongoing clinical trials for neoadjuvant regimens, including immune checkpoint blockade and chemotherapy. Whole-slide scanning of glass slides generates high-resolution digital images and allows for remote review and potential measurement with image analysis tools, but concordance of pathologic response assessment on digital scans compared with that on glass slides has yet to be evaluated. Such a validation goes beyond previous concordance studies, which focused on establishing surgical pathology diagnoses, as it requires quantitative assessment of tumor, necrosis, and regression.

Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma.

Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here we show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, we identify a noncanonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions and increased expression of T cell memory markers.

Interictal blood-brain barrier dysfunction in piriform cortex of people with epilepsy.

Objective: The piriform cortex is considered to be highly epileptogenic. Its resection during epilepsy surgery is a predictor for postoperative seizure freedom in temporal lobe epilepsy. Epilepsy is associated with a dysfunction of the blood-brain barrier.

Differences in Protein Capture by SP3 and SP4 Demonstrate Mechanistic Insights of Proteomics Cleanup Techniques.

The goal of proteomics experiments is to identify proteins to observe changes in cellular processes and diseases. One challenge in proteomics is the removal of contaminants following protein extraction, which can limit protein identifications. Single-pot, solid-phase-enhanced sample preparation (SP3) is a cleanup technique in which proteins are captured on carboxylate-modified particles through a proposed hydrophilic-interaction-liquid-chromatography (HILIC)-like mechanism.

Biomarker development for PD-(L)1 axis inhibition: a consensus view from the SITC Biomarkers Committee.

Therapies targeting the programmed cell death protein-1/programmed death-ligand 1 (PD-L1) (abbreviated as PD-(L)1) axis are a significant advancement in the treatment of many tumor types. However, many patients receiving these agents fail to respond or have an initial response followed by cancer progression. For these patients, while subsequent immunotherapies that either target a different axis of immune biology or non-immune combination therapies are reasonable treatment options, the lack of predictive biomarkers to follow-on agents is impeding progress in the field.

Characterizing US contact patterns relevant to respiratory transmission from a pandemic to baseline: Analysis of a large cross-sectional survey.

Background: Contact plays a critical role in infectious disease transmission. Characterizing heterogeneity in contact patterns across individuals, time, and space is necessary to inform accurate estimates of transmission risk, particularly to explain superspreading, predict age differences in vulnerability, and inform social distancing policies. Current respiratory disease models often rely on data from the 2008 POLYMOD study conducted in Europe, which is now outdated and potentially unrepresentative of behavior in the US.

Differences in Protein Capture by SP3 and SP4 Demonstrate Mechanistic Insights of Proteomics Clean-up Techniques.

The goal of proteomics experiments is to identify proteins to observe changes in cellular processes and diseases. One challenge in proteomics is the removal of contaminants following protein extraction, which can limit protein identification. Single-pot, solid-phase-enhanced sample preparation (SP3) is a clean-up technique in which proteins are captured on carboxylate-modified particles through a proposed hydrophilic-interaction-liquid-chromatography (HILIC)-like mechanism.

Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade.

Background: Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity.

Methods: Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy.

The Anterior Thalamus Preferentially Drives Allocentric But Not Egocentric Orientation Tuning in Postrhinal Cortex.

Navigating a complex world requires integration of multiple spatial reference frames, including information about one's orientation in both allocentric and egocentric coordinates. Combining these two information sources can provide additional information about one's spatial location. Previous studies have demonstrated that both egocentric and allocentric spatial signals are reflected by the firing of neurons in the rat postrhinal cortex (POR), an area that may serve as a hub for integrating allocentric head direction (HD) cell information with egocentric information from center-bearing and center-distance cells.

Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers.

Purpose: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers.

Methods: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible.

Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.

Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response.

Comparison of head direction cell firing characteristics across thalamo-parahippocampal circuitry.

Head direction (HD) cells, which fire persistently when an animal's head is pointed in a particular direction, are widely thought to underlie an animal's sense of spatial orientation and have been identified in several limbic brain regions. Robust HD cell firing is observed throughout the thalamo-parahippocampal system, although recent studies report that parahippocampal HD cells exhibit distinct firing properties, including conjunctive aspects with other spatial parameters, which suggest they play a specialized role in spatial processing. Few studies, however, have quantified these apparent differences.

Immune microenvironment of basal cell carcinoma and tumor regression following combined PD-1/LAG-3 blockade.

Systemic treatment options for patients with locally advanced or metastatic basal cell carcinoma (BCC) are limited, particularly when tumors are refractory to anti-programmed cell death protein-1 (PD-1). A better understanding of immune checkpoint expression within the BCC tumor microenvironment may inform combinatorial treatment strategies to optimize response rates. CD3, PD-1, programmed death ligand-1 (PD-L1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3)+ cell densities within the tumor microenvironment of 34 archival, histologically aggressive BCCs were assessed.

Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study.

Background: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival.

Methods: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1.

Angular Head Velocity Cells within Brainstem Nuclei Projecting to the Head Direction Circuit.

The sense of orientation of an animal is derived from the head direction (HD) system found in several limbic structures and depends on an intact vestibular labyrinth. However, how the vestibular system influences the generation and updating of the HD signal remains poorly understood. Anatomical and lesion studies point toward three key brainstem nuclei as key components for generating the HD signal-nucleus prepositus hypoglossi, supragenual nucleus, and dorsal paragigantocellularis reticular nuclei.