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Background: RAS/BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported., Materials and Methods: A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/BRAF p.V600E mutated (BRAF mut ), MMRd/BRAF mut , and MMRd/BRAF wild type (BRAF wt ). MLH1 promoter (pMLH1) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit., Results: The MMRd/BRAF mut group showed a higher pMLH1 methylation rate compared to both the MMRd/BRAF wt and the MMRp/BRAF mut groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF (p-value <0.0001). The MMRd/BRAF mut group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were pMLH1 methylated. Instead, the MMRd/BRAF wt group presented 50.0 % of CIMP-H adenocarcinomas., Conclusions: Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAF mut and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest regarding the publishing paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Objectives: Evaluation of pulmonary capillary wedge pressure (PCWP) through right heart catheterization can indirectly provide an estimation of the filling pressure of the left ventricle. Echocardiography can estimate left ventricular compliance using mitral annular tissue Doppler imaging (TDI). The E/e' ratio refers to the correlation between the peak mitral inflow (E-wave) velocity and early diastolic tissue Doppler mitral annular velocity (e'). The main purpose of this systematic review was to establish the correlation between echocardiographic E/e' ratio and PCWP. The correlation between E/e' and left ventricular end-diastolic pressure (LVEDP) was evaluated as a secondary objective., Design: A systematic review and meta-analysis of observational studies was conducted. The search was based on Medline (PubMed), Scopus, and Web of Science., Setting: Intensive care unit or cardiac intensive care unit., Participants: Adult patients., Interventions: Any study comparing the left ventricular filling pressure obtained by cardiac catheterization (reference) and echocardiographic evaluation, in particular TDI analysis (intervention), were included., Measurements and Main Results: The pooled analysis included 94 studies from the initially identified 7,304 records. The correlation was 0.48 (95% CI 0.42-0.54, Q = 420.52, I 2 = 84.8%) for PCWP and 0.50 (95% CI 0.38-0.60, Q = 210.91, I 2 = 89.1%) for LVEDP., Conclusions: The E/e' ratio moderately correlated with PCWP/LVEDP. The correlation was stable irrespective of the sites where e' was measured, but each site has its own limitations for specific patient subpopulations. The correlation was weak in patients with heart failure with a preserved ejection fraction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although hypercoagulability is commonly associated with malignancies, whether coagulation factors directly affect tumor cell proliferation remains unclear. Herein, by performing single-cell RNA sequencing (scRNA-seq) of the prostate tumor microenvironment (TME) of mouse models of castration-resistant prostate cancer (CRPC), we report that immunosuppressive neutrophils (PMN-MDSCs) are a key extra-hepatic source of coagulation factor X (FX). FX activation within the TME enhances androgen-independent tumor growth by activating the protease-activated receptor 2 (PAR2) and the phosphorylation of ERK1/2 in tumor cells. Genetic and pharmacological inhibition of factor Xa (FXa) antagonizes the oncogenic activity of PMN-MDSCs, reduces tumor progression, and synergizes with enzalutamide therapy. Intriguingly, F10 high PMN-MDSCs express the surface marker CD84 and CD84 ligation enhances F10 expression. Elevated levels of FX, CD84, and PAR2 in prostate tumors associate with worse survival in CRPC patients. This study provides evidence that FXa directly promotes cancer and highlights additional targets for PMN-MDSCs for cancer therapies., Competing Interests: Declaration of interests Authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16 LUC reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin-the most concentrated flavonoid in HK-as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16-CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16-CDK6 interaction., (© 2024. The Author(s).)

Patients with autoimmune gastritis (AIG) have a 13-fold risk of developing type-1 neuroendocrine tumors, whereas the risk for gastric adenocarcinoma is still uncertain. Here we describe the clinicopathologic and molecular features of a series of gastric carcinomas (GC) arising in the context of AIG. A total of 26 AIG-associated GC specimens were collected from 4 Italian Institutions. Immunohistochemistry for MUC1, MUC2, MUC5AC, MUC6, CDX2, HER2, PD-L1, CLDN18, mismatch repair (MMR) proteins, and p53 and EBV-encoded RNA (EBER) in situ hybridization were performed. Histologic and immunohistochemical features were jointly reviewed by 5 expert gastrointestinal pathologists. Next-generation sequencing analysis (TrueSight Oncology 500, Illumina) of 523 cancer-related genes was performed on 19 cases. Most tumors were diagnosed as pT1 (52%) and they were located in the corpus/fundus (58%) and associated with operative link for gastritis assessment stage II gastritis (80.8%), absence of parietal cells, complete intestinal metaplasia, and enterochromaffin-like-cell micronodular hyperplasia. Only 4 (15.4%) GCs were diagnosed during follow-up for AIG. The following histotypes were identified: 20 (77%) adenocarcinomas; 3 (11%) mixed neuroendocrine-non-neuroendocrine neoplasms, and 2 (8%) high-grade solid adenocarcinomas with focal neuroendocrine component, 1 (4%) adenocarcinoma with an amphicrine component. Overall, 7 cases (27%) showed MMR deficiency, 3 (12%) were positive (score 3+) for HER2, 6 (23%) were CLDN18 positive, and 11 (42%) had PD-L1 combined positive score ≥ 10. EBER was negative in all cases. Molecular analysis revealed 5/19 (26%) microsatellite instability (MSI) cases and 7 (37%) tumor mutational burden (TMB) high. The most frequently altered genes were TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [2 amplified and 5 mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with longstanding misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB high., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Cancer is highly infiltrated by myeloid-derived suppressor cells (MDSCs). Currently available immunotherapies do not completely eradicate MDSCs. Through a genome-wide analysis of the translatome of prostate cancers driven by different genetic alterations, we demonstrate that prostate cancer rewires its secretome at the translational level to recruit MDSCs. Among different secreted proteins released by prostate tumor cells, we identified Hgf, Spp1 and Bgn as the key factors that regulate MDSC migration. Mechanistically, we found that the coordinated loss of Pdcd4 and activation of the MNK/eIF4E pathways regulate the mRNAs translation of Hgf, Spp1 and Bgn. MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Approximately 15 % of colorectal adenocarcinomas (CRCs) are characterized by an altered expression of DNA mismatch repair (MMR) proteins (i.e. MMR deficiency [MMRd]). Lymph node ratio (LNR) represents one of the most important prognostic markers in non-advanced CRCs. No significant data are available regarding LNR distribution depending on MMR status., Purpose of the Study: The aim of the present work was to compare pathological and clinical characteristics of MMRd tumors versus MMR proficient (MMRp) cases. Particular attention was paid to how these molecular sub-groups relate to the LNR., Materials and Methods: A mono-Institutional series of 1037 consecutive surgically treated stage I-IV CRCs were retrospectively selected and data were obtained from pathological reports. Cases were characterized for MMR/MSI status by means of immunohistochemistry or for microsatellite instability (MSI) analysis., Results: MMRd/MSI tumors (n = 194; 18.7 %) showed significant differences in comparison to MMRp lesions for sex (female prevalence 50.5 % vs 40.7 %; p = 0.013), age (74.2 vs 69.2; p < 0.001), location (right side; p < 0.001), diameter (larger than MMRp; p < 0.001), growth pattern (expansive pattern of growth; p < 0.001), peri- (p = 0.0002) and intra-neoplastic (p = 0.0018) inflammatory infiltrate, presence of perineural invasion (p < 0.001), stage (lower stage at presentation; p < 0.001), grade (higher prevalence of high-grade tumors; p < 0.001), and LNR (lower; p < 0.001)., Conclusions: MMRd/MSI tumors are a distinct molecular CRC subtype characterized by a significantly lower LNR in comparison to MMRp lesions. These data further support the prognostic impact of MMRd/MSI status in early-stage CRCs., Competing Interests: Declaration of Competing Interest None related to the current work., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

In sessile serrated lesions (SSLs) with adenomatous dysplasia, the dysplastic component and the serrated component without dysplasia should be considered as part of the same lesion, classified as SSL with dysplasia. However, some of these lesions may actually represent collisions between a serrated polyp and a conventional adenoma. Further supporting the "collision theory", conventional adenomatous dysplasia may be found in association with hyperplastic polyps (HPs). In order to determine the molecular and biological landscape of conventional type dysplasia in serrated lesions, we collected 17 cases of colorectal serrated lesions with adenomatous dysplasia, classifying them as SSL with dysplasia (n = 10) or as mixed lesions comprising a HP component and a conventional adenomatous component (n = 7). We characterized the dysplastic and the non-dysplastic component of each lesion, after microdissection, through the targeted mutational analysis of 11 commonly altered genes in colorectal cancer (AKT1, APC, BRAF, CTNNB1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, PTEN and TP53). We also characterized MMR and p53 status by immunohistochemistry. Overall, 14/17 (82.4 %) cases harbored a mutation in at least one of the two components. The most altered genes were BRAF in 10/17 (58.8 %) cases, APC in 2/17 (11.8 %) and TP53 in 4/17 (23.5 %). Among the SSL with dysplasia, the mutational profile was concordant between the two components in 7/10 (70 %) cases, while among the mixed lesions, the mutational profile was concordant in 1/7 (14.3 %). In all but two cases of SSL with dysplasia, MMR status was concordant between the two components of the serrated lesions. Our findings suggest that adenomatous dysplasia may develop in SSL as part of the serrated lesion, even if some SSL with dysplasia may actually be collision lesions. On the other hand, the polyps that are morphologically classifiable as mixed lesions composed of a HP and a conventional adenomatous component are more likely to be collision lesions., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

The introduction of immunotherapy has revolutionized the oncological targeted therapy paradigm. Microsatellite instability (MSI) identifies a subgroup of colorectal cancers (CRCs) which respond to treatment with immune checkpoint inhibitors. Tissue biopsy is currently the gold standard for the assessment of MSI/Mismatch Repair deficiency (MMRd) by means immunohistochemistry or molecular assays. However, the application of liquid biopsy in the clinic may help to overcome several limitations of tissue analysis and may provide great benefit to the diagnostic scenario and therapeutic decision-making process. In the context of MSI/MMRd CRC, the use of liquid biopsy may allow to establish MSI/MMR status if tissue sampling cannot be performed or in case of discordant tissue biopsies. Liquid biopsy may also become a powerful tool to monitor treatment response and the onset resistance to immunotherapy over time and to stratify of MSI/MMRd patients according to their risk of relapse and metastases. The aim of this review is to summarize the main technical aspects and clinical applications, the benefits, and limitations of the use of liquid biopsy in MSI/MMRd colorectal cancer patients., Competing Interests: UM has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, ThermoFisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck, and AstraZeneca, Jannseen unrelated to the current work. SL has received personal fees for consulting or advisory role from Amgen, Merck Serono, Lilly, Astra Zeneca, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Servier, MSD, Roche, Pierre-Fabre, and GSK, and receiving research grants from Amgen, Merck Serono, Bayer, Roche, Lilly, Astra Zeneca, and Bristol-Myers Squibb, unrelated to the current work. Matteo Fassan received research funding from Astellas Pharma, Macrophage Pharma and QED Therapeutics and had roles as consultant or advisor for Astellas Pharma, Roche, Astra Zeneca, MSD and GSK-Tesaro, unrelated to the current work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ceccon, Angerilli, Rasola, Procaccio, Sabbadin, Bergamo, Malapelle, Lonardi and Fassan.)

The introduction of next-generation sequencing (NGS) in the molecular diagnostic armamentarium is deeply changing pathology practice and laboratory frameworks. NGS allows for the comprehensive molecular characterization of neoplasms, in order to provide the best treatment to oncologic patients. On the other hand, NGS raises technical issues and poses several challenges in terms of education, infrastructures and costs. The aim of this review is to give an overview of the main NGS sequencing platforms that can be used in current molecular diagnostics and gain insights into the clinical applications of NGS in precision oncology. Hence, we also focus on the preanalytical, analytical and interpretative issues raised by the incorporation of NGS in routine pathology diagnostics.

The problem of detecting and identifying sensor faults is critical for efficient, safe, regulatory-compliant, and sustainable operations of modern industrial processing systems. The increasing complexity of such systems brings, however, new challenges for sensor fault detection and sensor fault isolation (SFD-SFI). One of the key enablers for any SFD-SFI method is analytical redundancy, which is provided by an analytical model of sensor observations derived from first principles or identified from historical data. As defective sensors generate measurements that are inconsistent with their expected behavior as defined by the model, SFD amounts to the generation and monitoring of residuals between sensor observations and model predictions. In this article, we introduce a disentangled recurrent neural network (RNN) with the objective to cope with the smearing-out effect, i.e., where the propagation of a sensor fault to nonfaulty sensor results in large and misleading residuals. The introduction of a probabilistic model for the residual generation allows us to develop a novel procedure for the identification of the faulty sensors. The computational complexity of the proposed algorithm is linear in the number of sensors as opposed to the combinatorial nature of the SFI problem. Finally, we empirically verify the performance of the proposed SFD-SFI architecture using a real data set collected at a petrochemical plant.

MicroRNAs (miRNAs) are small non-coding RNAs that play a pivotal role in many aspects of cell biology, including cancer development. Within esophageal cancer, miRNAs have been proved to be involved in all phases of carcinogenesis, from initiation to metastatic spread. Several miRNAs have been found to be dysregulated in esophageal premalignant lesions, namely Barrett's esophagus, Barrett's dysplasia, and squamous dysplasia. Furthermore, numerous studies have investigated the alteration in the expression levels of many oncomiRNAs and tumor suppressor miRNAs in esophageal squamous cell carcinoma and esophageal adenocarcinoma, thus proving how miRNAs are able modulate crucial regulatory pathways of cancer development. Considering these findings, miRNAs may have a role not only as a diagnostic and prognostic tool, but also as predictive biomarker of response to anti-cancer therapies and as potential therapeutic targets. This review aims to summarize several studies on the matter, focusing on the possible diagnostic-therapeutic implications.