MLH1 gene promoter methylation status partially overlaps with CpG methylator phenotype (CIMP) in colorectal adenocarcinoma.

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.

Advancing therapeutic frontiers: a pipeline of novel drugs for luminal and perianal Crohn's disease management.

Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria.

Post mortem validation and mechanistic study of UCB-J in progressive supranuclear palsy patients' brains.

Introduction: Progressive supranuclear palsy (PSP) is a devastating 4R tauopathy affecting motor functions and is often misdiagnosed/underdiagnosed due to a lack of specific biomarkers. Synaptic loss is an eminent feature of tauopathies including PSP. Novel synaptic positron emission tomography tracer UCB-J holds great potential for early diagnosis; however, there is a substantial knowledge gap in terms of the mechanism and the extent and nature of synaptic loss in PSP.

IMMUNOREACT 9 metachronous rectal cancers have high HLA-ABC expression on healthy epithelium but a lower infiltration of CD3+ T cells than primary lesions.

Lynch syndrome is rarely associated with rectal cancer (RC) and thus, metachronous RC has been scarcely investigated. This study aimed to analyze the mucosal immune microenvironment in sporadic and metachronous RC. We analyzed the mucosal immune microenvironment in the 25 metachronous RCs present in the IMMUNOREACT 1 and 2 multicentre observational studies (624 patients).

CRIPTO's multifaceted role in driving aggressive prostate cancer unveiled by in vivo, organoid, and patient data.

CRIPTO (or CR-1 or TDGF1) is a protein that plays an active role in tumor initiation and progression. We have confirmed that increased expression of CRIPTO is associated with clinical and prostate-specific antigen (PSA) progression in human prostate tissues. Our approach involved gaining insight into the role of CRIPTO signaling in castration-resistant Nkx3.

Development of a novel tool for individual treatment trials in mucopolysaccharidosis.

Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication.

IMMUNOREACT 8: Immune markers of local tumor spread in patients undergoing transanal excision for clinically N0 rectal cancer.

Background: Transanal excision of rectal cancer can be considered the definitive surgical treatment if the depth spread is T1 or lower, and the lesion is completely included within the resection margin. This study aims to analyze the immune microenvironment in healthy rectal mucosa as a possible predictor of tumor infiltration depth, lateral tumor spread, and recurrence of rectal cancer after transanal local excision.

Methods: This study is a subanalysis of data from the IMMUNOREACT 1 and 2 trials (NCT04915326 and NCT04917263, respectively) including all the patients who underwent transanal excision of rectal cancer.

Liquid biopsy to identify Barrett's oesophagus, dysplasia and oesophageal adenocarcinoma: the multicentre study.

Background: There is no clinically relevant serological marker for the early detection of oesophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's oesophagus (BE).

Objective: To develop and test a blood-based assay for EAC and BE.

Design: Oesophageal MicroRNAs of BaRRett, Adenocarcinoma and Dysplasia () was a large, international, multicentre biomarker cohort study involving 792 patient samples from 4 countries (NCT06381583) to develop and validate a circulating miRNA signature for the early detection of EAC and high-risk BE.

1-Piperidine Propionic Acid Protects from Septic Shock Through Protease Receptor 2 Inhibition.

Sepsis is a complex disorder caused by a dysregulated host response to infection, with high levels of morbidity and mortality. Treatment aimed to modulate immune response and maintain vascular function is still one of the major clinical challenges. This study was designed to test the effect of the small molecule 1-Piperidine Propionic Acid (1-PPA) as molecular targeted agent to block protease-activated receptor 2 (PAR2), one of the major modulators of inflammatory response in LPS-induced experimental endotoxemia.

DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency.

In mammals, 5-methylcytosine (5mC) and Polycomb repressive complex 2 (PRC2)-deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naive pluripotent state, there is massive gain of 5mC concomitantly with restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naive and differentiated cells in the presence and absence of the DNA methylation machinery.

Refractory Crohn's Disease: Perspectives, Unmet Needs and Innovations.

Crohn's disease (CD) is a complex, chronic inflammatory bowel disease characterized by unpredictable flare-ups and periods of remission. Despite advances in treatment, CD remains a significant health burden, leading to substantial direct healthcare costs and out-of-pocket expenses for patients, especially in the first-year post-diagnosis. The impact of CD on patients' quality of life is profound, with significant reductions in physical, emotional, and social well-being.

Impact of neoadjuvant chemoradiotherapy on pathologic response in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis.

Background: The impact of chemoradiotherapy on pathologic response, resection margin, and survival benefit is still debated. The aim of this study was to compare the rate of pathologic complete response (pCR) in surgical resection following neoadjuvant chemotherapy vs. chemoradiotherapy, and secondarily, to compare the rate of R0 resection and Overall Survival (OS).

Genotype-phenotype findings in patients with mucopolysaccharidosis II from the Hunter Outcome Survey.

Purpose: This study investigated the relationship between mucopolysaccharidosis II (MPS II) iduronate-2-sulfatase gene (IDS) variants and phenotypic characteristics, particularly cognitive impairment, using data from the Hunter Outcome Survey (HOS) registry.

Methods: HOS data for male patients (n = 650) aged ≥5 years at latest cognitive assessment with available genetic data were analyzed. Predefined genotype categories were used to classify IDS variants and report phenotypic characteristics by genotype.

The impact of the embryonic DNA methylation program on CTCF-mediated genome regulation.

During mammalian embryogenesis, both the 5-cytosine DNA methylation (5meC) landscape and three dimensional (3D) chromatin architecture are profoundly remodeled during a process known as 'epigenetic reprogramming.' An understudied aspect of epigenetic reprogramming is how the 5meC flux, per se, affects the 3D genome. This is pertinent given the 5meC-sensitivity of DNA binding for a key regulator of chromosome folding: CTCF.

Towards needed improvements in inherited metabolic medicine in adulthood: The SIMMESN adult metabolic working group and MetabERN Joint Position Statement.

Inherited metabolic disorders (IMDs), previously considered as a paediatric sub-specialisation are more and more prevalent in adults, thanks to improved survival, and the expansion of diagnostic tools detecting attenuated-late onset forms in adulthood. Italy is one of the countries with the highest number of IMDs screened by dry blood spots in neonates, allowing them to receive early treatments and to reach adult age. Despite this, awareness of IMDs is still low by the adult medical community, with difficulties in transition and transfer of patients to adult services and unmet patient needs.

Bioprospecting, Synergistic Antifungal and Toxicological Aspects of the Hydroxychalcones and Their Association with Azole Derivates against spp. for Treating Vulvovaginal Candidiasis.

Vulvovaginal candidiasis (VVC) remains a prevalent fungal disease, characterized by challenges, such as increased fungal resistance, side effects of current treatments, and the rising prevalence of non- spp. naturally more resistant. This study aimed to propose a novel therapeutic approach by investigating the antifungal properties and toxicity of 2-hydroxychalcone (2-HC) and 3'-hydroxychalcone (3'-HC), both alone and in combination with fluconazole (FCZ) and clotrimazole (CTZ).

Monitoring and integrated care coordination of patients with alpha-mannosidosis: A global Delphi consensus study.

Introduction: Current literature lacks consensus on initial assessments and routine follow-up care of patients with alpha-mannosidosis (AM). A Delphi panel was conducted to generate and validate recommendations on best practices for initial assessment, routine follow-up care, and integrated care coordination of patients with AM.

Methods: A modified Delphi method involving 3 rounds of online surveys was used.

Challenges and opportunities in neurometabolic disease treatment with enzyme delivery.

Introduction: Neurometabolic disorders remain challenging to treat, largely due to the limited availability of drugs that can cross the blood-brain barrier (BBB) and effectively target brain impairment. Key reasons for inadequate treatment include a lack of coordinated knowledge, few studies on BBB status in these diseases, and poorly designed therapies.

Areas Covered: This paper provides an overview of current research on neurometabolic disorders and therapeutic options, focusing on the treatment of neurological involvement.

Proton CT on biological phantoms for x-ray CT calibration in proton treatment planning.

To present and characterize a novel method for x-ray computed tomography (xCT) calibration in proton treatment planning, based on proton CT (pCT) measurements on biological phantoms.A pCT apparatus was used to perform direct measurements of 3D stopping power relative to water (SPR) maps on stabilized, biological phantoms. Two single-energy xCT calibration curves-i.