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Pathobiology : Journal of... 2024Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether... (Review)
Review
Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether referred to as myeloid neoplasms (MN), is a major source of mortality. Apart from transformation to acute myeloid leukemia, the clinical progression of MN is mostly due to the overgrowth of pre-existing hematopoiesis by the MN without an additional transforming event. Still, MN may evolve along other recurrent yet less well-known scenarios: (1) acquisition of MPN features in MDS or (2) MDS features in MPN, (3) progressive myelofibrosis (MF), (4) acquisition of chronic myelomonocytic leukemia (CMML)-like characteristics in MPN or MDS, (5) development of myeloid sarcoma (MS), (6) lymphoblastic (LB) transformation, (7) histiocytic/dendritic outgrowths. These MN-transformation types exhibit a propensity for extramedullary sites (e.g., skin, lymph nodes, liver), highlighting the importance of lesional biopsies in diagnosis. Gain of distinct mutations/mutational patterns seems to be causative or at least accompanying several of the above-mentioned scenarios. MDS developing MPN features often acquire MPN driver mutations (usually JAK2), and MF. Conversely, MPN gaining MDS features develop, e.g., ASXL1, IDH1/2, SF3B1, and/or SRSF2 mutations. Mutations of RAS-genes are often detected in CMML-like MPN progression. MS ex MN is characterized by complex karyotypes, FLT3 and/or NPM1 mutations, and often monoblastic phenotype. MN with LB transformation is associated with secondary genetic events linked to lineage reprogramming leading to the deregulation of ETV6, IKZF1, PAX5, PU.1, and RUNX1. Finally, the acquisition of MAPK-pathway gene mutations may shape MN toward histiocytic differentiation. Awareness of all these less well-known MN-progression types is important to guide optimal individual patient management.
Topics: Humans; Granulocyte Precursor Cells; Myeloproliferative Disorders; Myelodysplastic Syndromes; Mutation; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid, Acute
PubMed: 37232015
DOI: 10.1159/000530940 -
Pharmacological Reports : PR Aug 2023Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for the treatment of non-erosive reflux disease (NERD), ulcers associated with non-steroidal... (Review)
Review
Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for the treatment of non-erosive reflux disease (NERD), ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs), esophagitis, peptic ulcer disease (PUD), Zollinger-Ellison syndrome (ZES), gastroesophageal reflux disease (GERD), non-ulcer dyspepsia, and Helicobacter pylori eradication therapy. The drugs have the effect of inhibiting acid production in the stomach. According to research, PPIs can affect the composition of gut microbiota and modulate the immune response. Recently, there has been a problem with the over-prescription of such drugs. Although PPIs do not have many side effects, their long-term use can contribute to small intestinal bacterial overgrowth (SIBO) or C. difficile and other intestinal infections. Probiotic supplementation during PPIs therapy may provide some hope in the reduction of emerging therapy side effects. This review aims to present the most important effects of long-term PPI use and provides critical insights into the role of probiotic intervention in PPI therapy.
Topics: Humans; Proton Pump Inhibitors; Clostridioides difficile; Dysbiosis; Gastroesophageal Reflux; Probiotics; Immunity; Immunomodulation
PubMed: 37142877
DOI: 10.1007/s43440-023-00489-x -
Gastroenterologia Y Hepatologia Jun 2024The recognition and treatment of intestinal bacterial overgrowth syndrome are matters of controversy. The symptoms that have guided the search for the disorder suffer...
The recognition and treatment of intestinal bacterial overgrowth syndrome are matters of controversy. The symptoms that have guided the search for the disorder suffer from lack of specificity, especially in the absence of well-defined predisposing factors. The accuracy of diagnostic procedures has been questioned and the proposed therapies achieve generally low effectiveness figures, with large differences between available studies. It is also unknown whether the normalization of tests is really a guarantee of cure. Within this framework of uncertainty, and in order to contribute to the guidance and homogenization of medical practice, a group of experts from the AEG and ASENEM have formulated the key questions on the management of this pathology and have provided answers to them, in accordance with the available scientific evidence. In addition, they have drawn up statements based on the conclusions of the review and have voted on them individually to reflect the degree of consensus for each statement.
PubMed: 38852778
DOI: 10.1016/j.gastrohep.2024.502216 -
American Journal of Medical Genetics.... May 2024The Simpson-Golabi-Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X-linked semi-dominant trait,... (Review)
Review
The Simpson-Golabi-Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X-linked semi-dominant trait, with variable expressivity in males and reduced penetrance and expressivity in females. The clinical spectrum is broad, ranging from mild manifestations in both males and females to multiple malformations and neonatal death in the more severely affected cases. An increased risk of neoplasia is reported, requiring periodical surveillance. Intellectual development is normal in most cases. SGBS is caused by a loss-of-function mutation of the GPC3 gene, either deletions or point mutations, distributed all over the gene. Notably, GPC3 deletion/point mutations are not found in a significant proportion of clinically diagnosed SGBS cases. The protein product GPC3 is a glypican functioning as a receptor for Hh at the cell surface, involved in the Hh-Ptc-Smo signaling pathway, a regulator of cellular growth.
PubMed: 38766979
DOI: 10.1002/ajmg.c.32088 -
The Journal of Clinical Endocrinology... Jan 2024Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature,... (Review)
Review
Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged. Multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome, respectively, variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.
Topics: Humans; Autism Spectrum Disorder; Abnormalities, Multiple; Syndrome; Histone Methyltransferases; Intellectual Disability; Epigenesis, Genetic
PubMed: 37450557
DOI: 10.1210/clinem/dgad420 -
Gut Jul 2023In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death....
OBJECTIVE
In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the T/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.
DESIGN
AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (T) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed T activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.
RESULTS
The prophylactic Tdepletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8/γδTCR IELs. T depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa which associates with severe disease and infected necrosis was diminished in T depleted animals.
CONCLUSION
T play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, T-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting T in AP may help to ameliorate the disease course.
Topics: Mice; Humans; Animals; T-Lymphocytes, Regulatory; Pancreatitis, Acute Necrotizing; Acute Disease; Bacterial Translocation; RNA, Ribosomal, 16S; Mice, Inbred C57BL
PubMed: 36631247
DOI: 10.1136/gutjnl-2022-327448