LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses.

Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.

VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms.

Myeloid-derived suppressor cells (MDSCs) impair antitumor immune responses. Identifying regulatory circuits during MDSC development may bring new opportunities for therapeutic interventions. We report that the V-domain suppressor of T cell activation (VISTA) functions as a key enabler of MDSC differentiation. VISTA deficiency reduced STAT3 activation and STAT3-dependent production of polyamines, which causally impaired mitochondrial respiration and MDSC expansion. In both mixed bone marrow (BM) chimera mice and myeloid-specific VISTA conditional knockout mice, VISTA deficiency significantly reduced tumor-associated MDSCs but expanded monocyte-derived dendritic cells (DCs) and enhanced T cell-mediated tumor control. Correlated expression of VISTA and arginase-1 (ARG1), a key enzyme supporting polyamine biosynthesis, was observed in multiple human cancer types. In human endometrial cancer, co-expression of VISTA and ARG1 on tumor-associated myeloid cells is associated with poor survival. Taken together, these findings unveil the VISTA/polyamine axis as a central regulator of MDSC differentiation and warrant therapeutically targeting this axis for cancer immunotherapy.

The Impact of the Initial Clinical Presentation of Bladder Cancer on Histopathological and Morphological Tumor Characteristics.

This study investigated the impact of the initial clinical presentation of bladder cancer on tumor characteristics. A cross-sectional, retrospective study was performed, and it involved 515 patients who underwent transurethral bladder cancer resection at the University Hospital Center Split between April 2019 and April 2023, excluding recurrent cases. The association between symptomatic versus asymptomatic presentation and bladder cancer characteristics was analyzed. A subgroup analysis compared tumor characteristics between patients with gross and microscopic hematuria. Multiple regression analyses revealed a significant association between symptomatic presentation and the detection of high-grade bladder cancer (OR 3.43, 95% CI 2.22-5.29, p < 0.001), concomitant CIS (OR 3.41, 95% CI 1.31-8.88, p = 0.012), T2 stage bladder cancer (OR 5.79, 95% CI 2.45-13.71, p < 0.001), a higher number of tumors (IRR 1.24, 95% CI 1.07-1.45, p = 0.005), and larger tumor size (B 1.68, 95% CI 1.19-2.18, p < 0.001). In the subgroup analysis, gross hematuria was associated with the detection of high-grade bladder cancer (OR 2.07, 95% CI 1.12-3.84, p = 0.020), T2 stage bladder cancer (OR 6.03, 95% CI 1.42-25.49, p = 0.015), and larger tumor size (B 1.8, 95% CI 0.99-2.6, p < 0.001). The identified associations between symptomatic presentation and unfavorable bladder cancer characteristics, likely attributed to early detection in asymptomatic cases, underscore the importance of additional research in the development of bladder cancer screening strategies.

Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

Transcriptional network orchestrating regional patterning of cortical progenitors.

We uncovered a transcription factor (TF) network that regulates cortical regional patterning in radial glial stem cells. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1, and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer-gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning in the mouse.

Resilience and Quality of Life of Patients with Breast Cancer.

INTRODUCTION: Breast cancer is the most common malignancy in women. Modern research attempts to investigate the relationship between psychoemotional parameters and the length of survival of breast cancer patients. Understanding the factors which affect a higher level of resilience can have important clinical implications and can represent a guiding principle for designing psychological interventions that would accelerate recovery and improve the quality of life of cancer patients. To explore the relationship between resilience and quality of life of women with breast cancer. METHODS: The study was conducted at the Clinic of Oncology of the University Clinical Hospital Mostar, which included 60 subjects. Objective realization was achieved through using the socio-demographic questionnaire purposely made for this research, the quality of life questionnaire WHQOL-BREF and the psychological resilience questionnaire CD-RISC-25. RESULTS: Subjects treated with radiotherapy achieved statistically significantly higher scores on subscales of the quality of life: mental health, social relations, and the environment. No statistically significant correlations were found between the level of resilience and results in the domains of quality of life. CONCLUSION: There is not a statistically significant association between resilience levels and quality of life in patients with breast cancer.

Papillary thyroid carcinoma in a hyper-functional thyroid nodule.

The authors reported the case of 69 years old woman presented with subclinical hyperthyroidism. 99m-Tc pertechnetate scan showed the abnormal focus of hot uptake in the left lobe, suggestive of a hyperfunctioning toxic thyroid nodule. Surgical treatment was advised because of the size of the nodule as a more applicable solution. Histological findings showed papillary thyroid carcinoma.

Influence of the Interlayer Temperature on Structure and Properties of Wire and Arc Additive Manufactured Duplex Stainless Steel Product.

WAAM (wire and arc additive manufacturing) is becoming an increasingly popular method to produce components from metals, which are usually not so suitable for conventional production methods. One of the good examples is duplex stainless steels (DSSs), which are quite complex for welding and machining. Excessive ferrite amount is a common problem for them and controlling an interlayer temperature could offer a solution. However, using too low interlayer temperature will slow down the whole process and compromise one of the WAAM's main advantages-the high productivity. The aim of this study is to find the relationship between interlayer temperature and process duration and to determine the influence of the interlayer temperature on product structure and other properties. Three samples (walls) were made using different interlayer temperatures (50 °C, 100 °C and 150 °C) and they were tested to analyze their surface texture, chemical composition, ferrite amount, the appearance of porosity and the hardness. Ferrite amount was higher and there was more porosity on lower interlayer temperatures, while there is no significant difference between surface texture and chemical composition for the samples. Considering the fact that higher interlayer temperatures provide a faster process, they should be preferred to produce duplex stainless steel products.

An ultra high-throughput method for single-cell joint analysis of open chromatin and transcriptome.

Simultaneous profiling of transcriptome and chromatin accessibility within single cells is a powerful approach to dissect gene regulatory programs in complex tissues. However, current tools are limited by modest throughput. We now describe an ultra high-throughput method, Paired-seq, for parallel analysis of transcriptome and accessible chromatin in millions of single cells. We demonstrate the utility of Paired-seq for analyzing the dynamic and cell-type-specific gene regulatory programs in complex tissues by applying it to mouse adult cerebral cortex and fetal forebrain. The joint profiles of a large number of single cells allowed us to deconvolute the transcriptome and open chromatin landscapes in the major cell types within these brain tissues, infer putative target genes of candidate enhancers, and reconstruct the trajectory of cellular lineages within the developing forebrain.

Giant infrapatellar ganglion cyst of Hoffa's fat pad.

We present the case of a 36-year-old woman who works as a kindergarten teacher, often she is kneeling on her knees due to the nature of the job. Since a year ago, she noticed that her right knee was swelling. She had an orthopaedic examination when she could no longer bend her knee. Inspection and palpation revealed the swelling of the anterior and anterior-lateral aspect of the knee. MRI imaging revealed a large, sharply defined, lobulated lesion of the infrapatellar fat pad. After the surgical incision, a lobular lesion was found and surgically removed. Histological analysis confirmed a ganglion cyst.