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BMJ (Clinical Research Ed.) Oct 2023Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an... (Review)
Review
Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.
Topics: Humans; Amyotrophic Lateral Sclerosis; Pathology, Molecular; Disease Progression
PubMed: 37890889
DOI: 10.1136/bmj-2023-075037 -
International Journal of Molecular... Sep 2023Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by... (Review)
Review
Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by changes in bone homeostasis, which lead to reduced bone mass, impaired bone quality, and an increased risk of fractures. The pathophysiology of osteoporosis is complex and multifactorial, involving imbalances in hormones, cytokines, and growth factors. Understanding the cellular and molecular mechanisms underlying osteoporosis is essential for appropriate diagnosis and management of the condition. This paper provides a comprehensive review of the normal cellular and molecular mechanisms of bone homeostasis, followed by an in-depth discussion of the proposed pathophysiology of osteoporosis through the osteoimmunological, gut microbiome, and cellular senescence models. Furthermore, the diagnostic tools used to assess osteoporosis, including bone mineral density measurements, biochemical markers of bone turnover, and diagnostic imaging modalities, are also discussed. Finally, both the current pharmacological and non-pharmacological treatment algorithms and management options for osteoporosis, including an exploration of the management of osteoporotic fragility fractures, are highlighted. This review reveals the need for further research to fully elucidate the molecular mechanisms underlying the condition and to develop more effective therapeutic strategies.
Topics: Humans; Pathology, Molecular; Osteoporosis; Osteoporotic Fractures; Bone Density; Bone and Bones
PubMed: 37834025
DOI: 10.3390/ijms241914583 -
Gut Jul 2023IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less...
OBJECTIVE
IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.
DESIGN
Transcriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn's disease, n=421 UC and 243 controls) in the Mount Sinai Crohn's and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.
RESULTS
bMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.
CONCLUSION
Transcriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.
Topics: Humans; Colitis, Ulcerative; Inflammation; Crohn Disease; Biopsy; Biomarkers; Intestinal Mucosa
PubMed: 36109152
DOI: 10.1136/gutjnl-2021-326451 -
Nature Sep 2023Abnormal assembly of tau, α-synuclein, TDP-43 and amyloid-β proteins into amyloid filaments defines most human neurodegenerative diseases. Genetics provides a direct... (Review)
Review
Abnormal assembly of tau, α-synuclein, TDP-43 and amyloid-β proteins into amyloid filaments defines most human neurodegenerative diseases. Genetics provides a direct link between filament formation and the causes of disease. Developments in cryo-electron microscopy (cryo-EM) have made it possible to determine the atomic structures of amyloids from postmortem human brains. Here we review the structures of brain-derived amyloid filaments that have been determined so far and discuss their impact on research into neurodegeneration. Whereas a given protein can adopt many different filament structures, specific amyloid folds define distinct diseases. Amyloid structures thus provide a description of neuropathology at the atomic level and a basis for studying disease. Future research should focus on model systems that replicate the structures observed in disease to better understand the molecular mechanisms of disease and develop improved diagnostics and therapies.
Topics: Humans; alpha-Synuclein; Amyloid; Amyloid beta-Peptides; Cryoelectron Microscopy; Neurodegenerative Diseases; Pathology, Molecular; Protein Folding
PubMed: 37758888
DOI: 10.1038/s41586-023-06437-2 -
Diagnostic Pathology Oct 2023Digital pathology (DP) is being increasingly employed in cancer diagnostics, providing additional tools for faster, higher-quality, accurate diagnosis. The practice of... (Review)
Review
Digital pathology (DP) is being increasingly employed in cancer diagnostics, providing additional tools for faster, higher-quality, accurate diagnosis. The practice of diagnostic pathology has gone through a staggering transformation wherein new tools such as digital imaging, advanced artificial intelligence (AI) algorithms, and computer-aided diagnostic techniques are being used for assisting, augmenting and empowering the computational histopathology and AI-enabled diagnostics. This is paving the way for advancement in precision medicine in cancer. Automated whole slide imaging (WSI) scanners are now rendering diagnostic quality, high-resolution images of entire glass slides and combining these images with innovative digital pathology tools is making it possible to integrate imaging into all aspects of pathology reporting including anatomical, clinical, and molecular pathology. The recent approvals of WSI scanners for primary diagnosis by the FDA as well as the approval of prostate AI algorithm has paved the way for starting to incorporate this exciting technology for use in primary diagnosis. AI tools can provide a unique platform for innovations and advances in anatomical and clinical pathology workflows. In this review, we describe the milestones and landmark trials in the use of AI in clinical pathology with emphasis on future directions.
Topics: Male; Humans; Artificial Intelligence; Diagnostic Imaging; Pathology, Clinical; Prostate; Neoplasms
PubMed: 37784122
DOI: 10.1186/s13000-023-01375-z -
The Journal of Molecular Diagnostics :... Sep 2023The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of... (Review)
Review
CYP3A4 and CYP3A5 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European...
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document will focus on clinical CYP3A4 and CYP3A5 PGx testing that may be applied to all CYP3A4- and CYP3A5-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide.
Topics: Humans; Pharmacogenetics; Cytochrome P-450 CYP3A; Genotype; Consensus; Pathology, Molecular; Pharmacists; Pathologists
PubMed: 37419245
DOI: 10.1016/j.jmoldx.2023.06.008 -
Molecular Cell Sep 2023Cohesin connects CTCF-binding sites and other genomic loci in cis to form chromatin loops and replicated DNA molecules in trans to mediate sister chromatid cohesion....
Cohesin connects CTCF-binding sites and other genomic loci in cis to form chromatin loops and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here, we describe a cohesin hinge mutant that can extrude DNA into loops but is unable to mediate cohesion in human cells. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesin's cohesion and loop extrusion activities can be partially separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wild-type cohesin. This suggests that cohesion establishment and cohesin's interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.
Topics: Humans; Chromatids; Binding Sites; Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Cohesins
PubMed: 37591243
DOI: 10.1016/j.molcel.2023.07.024 -
International Journal of Molecular... Jul 2023This Special Issue aims to highlight the advances made regarding the molecular profile of digestive system tumors in experimental and clinical studies [...].
This Special Issue aims to highlight the advances made regarding the molecular profile of digestive system tumors in experimental and clinical studies [...].
Topics: Humans; Pathology, Molecular; Gastrointestinal Neoplasms; Digestive System Neoplasms; Biomarkers, Tumor; Neoplasms
PubMed: 37446314
DOI: 10.3390/ijms241311136 -
Cell Mar 2024The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of... (Review)
Review
The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes.
Topics: Humans; Biomarkers, Tumor; Medical Oncology; Neoplasms; Precision Medicine; Tumor Microenvironment
PubMed: 38552610
DOI: 10.1016/j.cell.2024.02.041 -
Taiwanese Journal of Obstetrics &... Nov 2023
Topics: Female; Humans; Pathology, Molecular; Endometrial Neoplasms; Endometrium; Endometrial Hyperplasia
PubMed: 38008493
DOI: 10.1016/j.tjog.2023.09.013