The tumor suppressor p53, often referred to as the “guardian of the genome,” is mutated in more than half of human cancers. These mutations have a significant impact on cancer biology and response to therapy. p53 mutations involve a range of changes that interfere with DNA binding, eliminate tumor suppressor functions, and, in many cases, confer dominant-negative or gain-of-function characteristics that actively promote oncogenesis. These mutations are closely linked to poor clinical outcomes and resistance to standard treatments. This review examines the impact of p53 mutations on cancer therapy in various ways. In chemotherapy and radiotherapy, loss of wild-type p53 impairs DNA damage responses, whereas mutant forms often contribute to treatment resistance. Additionally, p53 status influences responses to targeted therapies and immunotherapies, thereby affecting patient outcomes and prognoses. Importantly, ongoing clinical trials are beginning to integrate p53 mutational status as a predictive biomarker for therapy selection. Strategies aimed at restoring p53 activity are gaining increasing popularity in the development of treatments. These approaches include gene therapy to reintroduce the wild-type gene, targeted degradation of mutant p53 proteins, and small molecules designed to refold or reactivate mutant p53. In addition, synthetic lethality frameworks are being utilized to exploit vulnerabilities specific to tumors with p53 mutations, as well as interventions that target downstream effectors of p53 pathway. Together, these strategies represent a significant shift in precision oncology.

In 2001, two enzyme-encoding genes were recognized in the fruit fly Drosophila melanogaster. The genetic material, labeled Dicer-1 and Dicer-2, encodes ribonuclease-type enzymes with slightly diverse target substrates. The human orthologue is DICER1. It is a gene, which has been positioned on chromosome 14q32.13. It contains 27 exons, which are linking the two enzyme domains. DICER1 is found in all organ systems. It has been proved that it is paramount in human development. The protein determined by DICER1 is a ribonuclease (RNase). This RNase belongs to the RNase III superfamily, formally known as ’endoribonuclease’. It has been determined that the function of RNase III proteins is set to identify and degrade double-stranded molecules of RNA. DICER1 is a vital “housekeeping” gene. The multi-domain enzyme is key for small RNA processing. This enzyme functions in numerous pathways, including RNA interference paths, DNA damage renovation, and response to viruses. At the protein level, DICER is also involved in several human diseases, of which the pleuro-pulmonary blastoma is probably the most egregious entity. Numerous studies have determined the full range of DICER1 functions and the corresponding relationship to tumorigenic and non-neoplastic diseases. In fact, genetic mutations (somatic and germline) have been detected in DICER1 and are genetically associated with at least two clinical syndromes: DICER1 syndrome and GLOW syndrome. The ubiquity of this enzyme in the human body makes it an exquisite target for nanotechnology-supported therapies and repurposing drug approaches.

Hepatic fibrinogen storage disease is an uncommon autosomal dominant hereditary illness marked by hypofibrinogenemia and the accumulation of variant fibrinogen in the hepatic endoplasmic reticulum. We present an asymptomatic 15-month-old male with elevated liver enzymes. Test results indicate hypofibrinogenemia. The liver biopsy revealed circular eosinophilic inclusion bodies within the hepatocyte cytoplasm. After diastase pretreatment, the inclusion bodies did not stain using the periodic acid - Schiff procedure. Ultrastructural examination revealed the characteristic fibrinogen storage curvilinear inclusions. Sequence analysis using the Blueprint Genetics (BpG) FLEX Bleeding Disorder/Coagulopathy Panel identified a heterozygous missense variant FGG c.1075 G>C, p. (Gly359Arg). Thus, the patient was diagnosed with hepatic fibrinogen storage disease. Our findings suggest that in patients with asymptomatic elevated liver enzymes presenting with unanticipated hypofibrinogenemia, hepatic fibrinogen storage disorder must be included in the differential diagnosis. Furthermore, our results underscore the significance of molecular diagnosis in patients diagnosed with cryptogenic liver disease.

RATIONALE:Collagenous gastritis is an uncommon condition initially identified in 1989 by Colletti and Trainer, characterized by a subepithelial collagen band exceeding 10 μm in thickness. Two patient subgroups have been identified: children and young adults exhibiting severe anemia with illness confined to the gastric mucosa and no colonic involvement, and older individuals presenting with watery diarrhea and collagenous gastritis linked to collagenous colitis. A combination of hyperplastic polyps and Marsh I duodenal lymphocytosis has not been fully reported yet. PATIENT CONCERNS:A 15-year-old boy exhibited a prolonged history of fatigue, lethargy, weight reduction, and poor development. He exhibited iron deficiency anemia. Previous oral iron supplementation had been ineffective, necessitating the use of intravenous iron infusions. An endoscopy revealed a nodular, polypoid stomach with small polyps located in the antrum. DIAGNOSES:Biopsies revealed characteristics of collagenous gastritis, characterized by a thickened subepithelial band. A polyp exhibited elongated, architecturally distorted pits with outpouchings, cystic dilation, and papillary formation but without dysplasia. Intraepithelial lymphocytes exceeding 30 per 100 epithelial cells were seen in the small intestine. In our patient, pericryptal fibroblasts, inflammatory cells, and a distinctive subepithelial band made of randomly oriented collagen fibers were shown histologically and ultrastructurally. INTERVENTIONS:The patient was treated with lansoprazole 30 mg twice daily and famotidine 40 mg once daily, as well as oral iron supplementation. OUTCOMES:Clinical improvement was noted, and hemoglobin and ferritin levels were 123 g/L and 9 µg/L, respectively, at 12 months following therapy. LESSONS:In consideration of a colon-rectal cancer diagnosis of his father at the age of 45 years, we carried out a Search Tool for the Retrieval of Interacting Genes/Proteins and Pymol-based Protein Data Bank study and found that interleukin-4 may be the key factor supporting the occurrence of hyperplastic polyps in collagenous gastritis.

p53, often referred to as the "guardian of the genome," is a critical regulator of cellular responses to stress. p53 plays a dual role in tumor suppression and immune regulation. In addition to its well-known functions of maintaining genomic stability and inducing apoptosis, p53 orchestrates a complex interaction between innate and adaptive immune responses. This involvement contributes to pathogen clearance, immune surveillance, and immunogenic cell death (ICD). This review explores the influence of p53 on immune dynamics, detailing its effects on macrophages, dendritic cells, natural killer cells (NK), T cells, and B cells. This review explains how mutations in p53 disrupt immune responses, promoting tumor immune evasion, and highlights its regulation of inflammatory cytokines and pattern recognition receptors. Furthermore, p53's role in ICD marks it as a key player in antitumor immunity, which has significant implications for cancer immunotherapy. The review also discusses the role of p53 in inflammation, autoimmune diseases, and chronic infections, revealing its dual function in promoting and suppressing inflammation through interactions with NF-κB signaling. Therapeutically, approaches that target p53, including wild-type p53 reactivation and combination therapies with immune checkpoint inhibitors, show considerable promise. Advances in high-throughput technologies, such as single-cell RNA sequencing and CRISPR screens, provide new insights into the immunological functions of p53, including its role in microbiome-immune interactions and immune senescence. This comprehensive review highlights the importance of incorporating immunological insights from p53 into innovative therapeutic strategies, addressing existing knowledge gaps, and paving the way for personalized medicine.

Nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated steatotic liver disease (MASLD), is a liver condition that is linked to overweight, obesity, diabetes mellitus, and metabolic syndrome. Nonalcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a form of NAFLD/MASLD that progresses over time. While steatosis is a prominent histological characteristic and recognizable grossly and microscopically, liver biopsies of individuals with NASH/MASH may exhibit several other abnormalities, such as mononuclear inflammation in the portal and lobular regions, hepatocellular damage characterized by ballooning and programmed cell death (apoptosis), misfolded hepatocytic protein inclusions (Mallory–Denk bodies, MDBs), megamitochondria as hyaline inclusions, and fibrosis. Ballooning hepatocellular damage remains the defining feature of NASH/MASH. The fibrosis pattern is characterized by the initial expression of perisinusoidal fibrosis (“chicken wire”) and fibrosis surrounding the central veins. Children may have an alternative form of progressive NAFLD/MASLD characterized by steatosis, inflammation, and fibrosis, mainly in Rappaport zone 1 of the liver acinus. To identify, synthesize, and analyze the scientific knowledge produced regarding the implications of using a score for evaluating NAFLD/MASLD in a comprehensive narrative review. The search for articles was conducted between 1 January 2000 and 31 December 2023, on the PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases. This search was complemented by a gray search, including internet browsers (e.g., Google) and textbooks. The following research question guided the study: “What are the basic data on using a score for evaluating NAFLD/MASLD?” All stages of the selection process were carried out by the single author. Of the 1783 articles found, 75 were included in the sample for analysis, which was implemented with an additional 25 articles from references and gray literature. The studies analyzed indicated the beneficial effects of scoring liver biopsies. Although similarity between alcoholic steatohepatitis (ASH) and NASH/MASH occurs, some patterns of hepatocellular damage seen in alcoholic disease of the liver do not happen in NASH/MASH, including cholestatic featuring steatohepatitis, alcoholic foamy degeneration, and sclerosing predominant hyaline necrosis. Generally, neutrophilic-rich cellular infiltrates, prominent hyaline inclusions and MDBs, cholestasis, and obvious pericellular sinusoidal fibrosis should favor the diagnosis of alcohol-induced hepatocellular injury over NASH/MASH. Multiple grading and staging methods are available for implementation in investigations and clinical trials, each possessing merits and drawbacks. The systems primarily used are the Brunt, the NASH CRN (NASH Clinical Research Network), and the SAF (steatosis, activity, and fibrosis) systems. Clinical investigations have utilized several approaches to link laboratory and demographic observations with histology findings with optimal platforms for clinical trials of rapidly commercialized drugs. It is promising that machine learning procedures (artificial intelligence) may be critical for developing new platforms to evaluate the benefits of current and future drug formulations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts between the host and virus and govern induction, resulting in multiorgan impacts. Its pathophysiology involves the followings: 1) the angiotensin-converting enzyme (ACE2) and Toll-like receptor (TLR) pathways: 2) the neuropilin (NRP) pathway: 3) the spike protein pathway. Therefore, it is necessary to block the pathological course with modulating innate lymphoid cells against diverse corona variants in the future.

Background:Eosinophilic esophagitis is a chronic inflammatory disorder, often relapsing. There is an increasing need to develop new alternative diagnostic and monitoring methods on a critical basis, which will provide samples through none or minimally invasive procedures. This study aims to identify and document the types and roles of potential biomarkers in eosinophilic esophagitis released by eosinophils as well as the potential relationship to the peak eosinophilic count and the degree of degranulation of in situ eosinophils (DGE/DGE + NDGE: degranulated eosinophils/degranulated eosinophils and non-degranulated eosinophils).Methods:This is the first in-depth systematic review study using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) parameters involving a literature search of academic databases (PubMed, Scopus, Medline, Google Scholar, and Cochrane Database, 2011-2022) targeting specifically the eosinophilic counts and ratio, and the eosinophilic degranulation products as potential biomarkers. Data were extracted from ten selected studies and presented on a spreadsheet.Results:The studies show the ability to detect eosinophilic and non-eosinophilic degranulation products, and absolute eosinophilic count in samples, including blood and urine, thereby serving as potential surrogates in making the diagnosis or monitoring disease progression in the future. There is an obvious paucity of studies that correlate potential biomarkers to the degree of degranulation of in situ eosinophils.Conclusions:A few minimally invasive methods and biomarkers may be suggested as alternative tools in diagnosing and monitoring eosinophilic esophagitis. While there is no consensus on the clinical usefulness of these biomarkers, our critical evaluation may suggest that the eosinophilic degranulation ratio (DGE/DGE + NDGE: degranulated eosinophils/degranulated eosinophils and non-degranulated eosinophils) in the esophagus may be critical for evaluating properly these biomarkers. An increasing trend may culminate in the potential clinical use of these biomarkers evaluated not only with the peak eosinophilic count, but also with the degranulation score upon regulatory bodies' approval to monitor eosinophilic esophagitis in the future. We strongly advocate for the necessity to score the esophageal biopsies with both a peak eosinophilic count and a score of the degranulated eosinophils.

>Dear Editor,OnMarch8–15,2022,aboardofinternationalscientists assembled in Lyon to evaluate the carcinogenicity of cobalt metal,cobalt(Ⅱ)salts,antimonytrioxide,andweaponsgradetungstenalloyharboringnickelandcobalt[1].The131st International Agency for Research on Cancer (IARC)Monograph is the result of a 6–9-month work of perusing the literature, slide evaluation, data interpretation, and interim meetings. The assessment of cobalt, antimony, and nickelcontaining alloys will have tremendous consequences for the industry, health, and defense departments[1].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The pathophysiology of COVID-19 uses the following three mechanisms: (1) inflammasome activation mechanism; (2) cGAS–STING signaling mechanism; and (3) SAMHD1 tetramerization mechanism, which leads to IFN-I production. Interactions between the host and virus govern induction, resulting in multiorgan impacts. The NLRP3 with cGAS–STING constitutes the primary immune response. The expression of SARS-CoV-2 ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication by targeting the RIG-I/MDA5, TRIF, and cGAS–STING signaling. SAMHD1 has a target motif for CDK1 to protect virion assembly, threonine 592 to modulate a catalytically active tetramer, and antiviral IFN responses to block retroviral infection. Plastic and allosteric nucleic acid binding of SAMHD1 modulates the antiretroviral activity of SAMHD1. Therefore, inflammasome activation, cGAS–STING signaling, and SAMHD1 tetramerization explain acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury of COVID-19. It might be necessary to effectively block the pathological courses of diverse diseases. 1. DNA-driven immune response connects with NLRP3 and controls its inflammasome activity, which leads to IFN-I production via STING. The NLRP3 with cGAS-STING constitutes the primary immune response. 2. The expression of SARS-CoV-2 ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication by targeting the RIG-I/MDA5, TRIF, and cGAS-STING signaling. 3. Plastic and allosteric nucleic acid binding of SAMHD1 reduces the magnitude of IFN and induction of virus-specific cytotoxic T cells. SAMHD1-deficient cells detect and activate IFN-I-mediated self ISG gene expression via cGAS–STING. 4. SAMHD1 autonomously controls viral infection through innate and adaptive immunity at the level of the infected cell.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan malignancy defined by the WHO as affection fewer than 65 per 100,000 people and by the U.S. FDA as affecting less than 200,000 people in the U.S.. The BPDCN international registry was launched in July 2022 with the aim to create a large database for this rare disease, to generate data-driven diagnostic and treatment recommendations, and provide real-world evidence. Aim:The aim of this abstract is to evaluate the outcomes of BPDCN patients treated with tagraxofusp, an immunotoxin targeting CD123 that was approved by the U.S. FDA in December 2018 and the European EMA in January 2021 for the treatment of BPDCN. Methods: The registry collects retrospective and prospective data of patients diagnosed with BPDCN after January 1st, 2010. We assessed baseline characteristics, response to treatment and outcomes of BPDCN patients who received tagraxofusp. Results: As of June 2024, 70 patients from 13 countries (USA, Egypt, Canada, Italy, Georgia, Turkey, UK, India, Armenia, Iraq, Kuwait, Cyprus and Romania) were included in the registry. Among those, 22 patients (from USA, UK and Italy) have received treatment with tagraxofusp. Seventeen patients were treated with tagraxofusp as a first line therapy and 5 patients as a second line. The median age was 76years (range 40-87) with only one female patient. Fifteen patients had received tagraxofusp before the U.S. FDA approval in the setting of clinical trials. In the first line therapy setting, the overall response rate was 82% (14/17 patients) where 9 patients had a complete response (CR), 5 pts partial response (PR), 2 stable disease (SD), and one patient was not evaluable(no information was available). Of the 9 CR patients, 2 passed away from other reasons besides BPDCN, one was lost to follow up, the other 6 relapsed. Median time to relapse was 3 months. Among the relapsed patients, 4 experienced progressive or stable disease on subsequent chemotherapy regimens, 2 were treated with HyperCVAD followed allogeneic stem cell transplantation (allo-SCT) and were alive at last follow-up. Of the 7 patients with PR and SD as first line therapy, 6 experienced progressive disease, 1 patient who was treated with HyperCVAD followed by allo-SCT was alive at last follow-up. None of 5 patients treated with tagraxofusp as a second line therapy experienced CR, two patients experienced short SD, the other three progressive disease. At the last follow-up information was available for 19 of 22 patients of which 4 were alive. Conclusion: Tagraxofusp yields high response rates with more than 50% CR in the upfront setting; however, the relapse rates without allo-SCT remains high. This therapy is currently only available in selected countries and only 3 out of the 13 countries participating in this registry reported its use. The treatment strategy of BPDCN should be a total therapy approach incorporating novel agents like tagraxofusp with intrathecal chemotherapy and allo-SCT to prevent the relapse.

Carney syndrome is an autosomal dominant complex involving endocrinopathy, mucocutaneous hyperpigmentation, and different tumors, including cardiac myxomas. We report on a single family with several members affected with Carney syndrome. Family and individual medical histories were investigated in several Canadian provinces. The histology slides were also reviewed. Four family members (two young women, both sisters, their mother, and maternal grandmother) were found to harbor Carney syndrome. Everyone was presented with multiple and recurrent atrial myxomas of the heart, requiring multiple open cardiac surgeries. Breast myxomas and cutaneous hyperpigmentation were also revealed in one of the sisters and their mother. Interestingly, genetic testing was positive for the female family members and negative for the father and brother. We cannot rule out that the brother may have had a new mutation or harboring a mosaic. The young woman's brother did not have cardiac myxoma but developed a unilateral Sertoli cell tumor of testis. Carney syndrome is a rare complex multisystemic genetic disorder, including multiple and recurrent cardiac myxomas. We strongly suggest that reporting familial Carney syndrome is still critical in the 21st century to augment the awareness of this situation among clinicians and pathologists.

Abstract Pediatric cancer remains the leading cause of disease-related death among children aged 1–14 years. A few risk factors have been conclusively identified, including exposure to pesticides, high-dose radiation, and specific genetic syndromes, but the etiology underlying most events remains unknown. The tumor microenvironment (TME) includes stromal cells, vasculature, fibroblasts, adipocytes, and different subsets of immunological cells. TME plays a crucial role in carcinogenesis, cancer formation, progression, dissemination, and resistance to therapy. Moreover, autophagy seems to be a vital regulator of the TME and controls tumor immunity. Autophagy is an evolutionarily conserved intracellular process. It enables the degradation and recycling of long-lived large molecules or damaged organelles using the lysosomal-mediated pathway. The multifaceted role of autophagy in the complicated neoplastic TME may depend on a specific context. Autophagy may function as a tumor-suppressive mechanism during early tumorigenesis by eliminating unhealthy intracellular components and proteins, regulating antigen presentation to and by immune cells, and supporting anti-cancer immune response. On the other hand, dysregulation of autophagy may contribute to tumor progression by promoting genome damage and instability. This perspective provides an assortment of regulatory substances that influence the features of the TME and the metastasis process. Mesenchymal cells in bone and soft-tissue sarcomas and their signaling pathways play a more critical role than epithelial cells in childhood and youth. The investigation of the TME in pediatric malignancies remains uncharted primarily, and this unique collection may help to include novel advances in this setting.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are closely related liver conditions that have become more prevalent globally. This review examines the intricate interplay between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH. The combination of these two factors creates a synergistic situation referred to as "double trouble", which promotes the accumulation of lipids in the liver and the subsequent progression from simple steatosis (NAFLD) to inflammation (NASH). Microbiome dysbiosis, characterized by changes in the composition of gut microbes and increased intestinal permeability, contributes to the movement of bacterial products into the liver. It triggers metabolic disturbances and has anti-inflammatory effects. Understanding the complex relationship between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH is crucial for advancing innovative therapeutic approaches that target these underlying mechanisms.

Non-coding RNAs (ncRNAs) are RNA molecules that do not code for protein but play key roles in regulating cellular processes. NcRNAs globally affect gene expression in diverse physiological and pathological contexts. Functionally important ncRNAs act in chromatin modifications, in mRNA stabilization and translation, and in regulation of various signaling pathways. Non-alcoholic fatty liver disease (NAFLD) is a set of conditions caused by the accumulation of triacylglycerol in the liver. Studies of ncRNA in NAFLD are limited but have demonstrated that ncRNAs play a critical role in the pathogenesis of NAFLD. In this review, we summarize NAFLD’s pathogenesis and clinical features, discuss current treatment options, and review the involvement of ncRNAs as regulatory molecules in NAFLD and its progression to non-alcoholic steatohepatitis (NASH). In addition, we highlight signaling pathways dysregulated in NAFLD and review their crosstalk with ncRNAs. Having a thorough understanding of the disease process’s molecular mechanisms will facilitate development of highly effective diagnostic and therapeutic treatments. Such insights can also inform preventive strategies to minimize the disease’s future development.

MicroRNAs (miRNAs) are small RNA molecules that regulate more than 30% of genes in humans. Recent studies have revealed that miRNAs play a crucial role in tumorigenesis. Large sets of miRNAs in human tumors are under-expressed compared to normal tissues. Furthermore, experiments have shown that interference with miRNA processing enhances tumorigenesis. Multiple studies have documented the causal role of miRNAs in cancer, and miRNA-based anticancer therapies are currently being developed. This review primarily focuses on two key points: (1) miRNAs and their role in human cancer and (2) the regulation of tumor suppressors by miRNAs. The review discusses (a) the regulation of the tumor suppressor p53 by miRNA, (b) the critical role of the miR-144/451 cluster in regulating the Itch-p63-Ago2 pathway, and (c) the regulation of PTEN by miRNAs. Future research and the perspectives of miRNA in cancer are also discussed. Understanding these pathways will open avenues for therapeutic interventions targeting miRNA regulation.

BackgroundDysbiotic biliary bacterial profile is reported in cancer patients and is associated with survival and comorbidities, raising the question of its effect on the influence of anticancer drugs and, recently, the suggestion of perichemotherapy antibiotics in pancreatic cancer patients colonized by the Escherichia coli and Klebsiella pneumoniae.ObjectiveIn this study, we investigated the microbial communities that colonize tumours and which bacteria could aid in diagnosing pancreatic and biliary cancer and managing bile-colonized patients.MethodsA retrospective study on positive bile cultures of 145 Italian patients who underwent cholangiopancreatography with PC and EPC cancer hospitalized from January 2006 to December 2020 in a QA-certified academic surgical unit were investigated for aerobic/facultative-anaerobic bacteria and fungal organisms.ResultsWe found that among Gram-negative bacteria, Escherichia coli and Pseudomonas spp were the most frequent in the EPC group, while Escherichia coli, Klebsiella spp, and Pseudomonas spp were the most frequent in the PC group. Enterococcus spp was the most frequent Gram-positive bacteria in both groups. Comparing the EPC and PC, we found a significant presence of patients with greater age in the PC compared to the EPC group. Regarding Candida spp, we found no significant but greater rate in the PC group compared to the EPC group (11.7% vs 1.96%). We found that Alcaligenes faecalis was the most frequent bacteria in EPC than the PC group, among Gram-negative bacterial species.ConclusionsAge differences in gut microbiota composition may affect biliary habitats in our cancer population, especially in patients with pancreatic cancer. Alcaligenes faecalis isolated in the culture of bile samples could represent potential microbial markers for a restricted follow-up to early diagnosis of extra-pancreatic cancer. Finally, the prevalence of Candida spp in pancreatic cancer seems to trigger new aspects about debate about the role of fungal microbiota into their relationship with pancreatic cancer.