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1.
Sci Rep ; 12(1): 10998, 2022 06 29.
Article in English | MEDLINE | ID: mdl-35768447

ABSTRACT

Molecular pathology services for colorectal cancer (CRC) in Sudan represent a significant unmet clinical need. In a retrospective cohort study involving 50 patients diagnosed with CRC at three major medical settings in Sudan, we aimed to outline the introduction of a molecular genetic service for CRC in Sudan, and to explore the CRC molecular features and their relationship to patient survival and clinicopathological characteristics. Mismatch repair (MMR) and BRAF (V600E) mutation status were determined by immunohistochemistry. A mismatch repair deficient (dMMR) subtype was demonstrated in 16% of cases, and a presumptive Lynch Syndrome (LS) diagnosis was made in up to 14% of patients. dMMR CRC in Sudan is characterized by younger age at diagnosis and a higher incidence of right-sided tumours. We report a high mortality in Sudanese CRC patients, which correlates with advanced disease stage, and MMR status. Routine MMR immunohistochemistry (with sequential BRAF mutation analysis) is a feasible CRC prognostic and predictive molecular biomarker, as well as a screening tool for LS in low-middle-income countries (LMICs).


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Colorectal Neoplasms , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Mismatch Repair/genetics , Feasibility Studies , Humans , Microsatellite Instability , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies
2.
Nat Commun ; 11(1): 4734, 2020 09 18.
Article in English | MEDLINE | ID: mdl-32948759

ABSTRACT

A primary reason for the intense interest in structural biology is the fact that knowledge of structure can elucidate macromolecular functions in living organisms. Sustained effort has resulted in an impressive arsenal of tools for determining the static structures. But under physiological conditions, macromolecules undergo continuous conformational changes, a subset of which are functionally important. Techniques for capturing the continuous conformational changes underlying function are essential for further progress. Here, we present chemically-detailed conformational movies of biological function, extracted data-analytically from experimental single-particle cryo-electron microscopy (cryo-EM) snapshots of ryanodine receptor type 1 (RyR1), a calcium-activated calcium channel engaged in the binding of ligands. The functional motions differ substantially from those inferred from static structures in the nature of conformationally active structural domains, the sequence and extent of conformational motions, and the way allosteric signals are transduced within and between domains. Our approach highlights the importance of combining experiment, advanced data analysis, and molecular simulations.


Subject(s)
Calcium Channel Agonists/chemistry , Macromolecular Substances/chemistry , Ryanodine Receptor Calcium Release Channel/chemistry , Binding Sites , Cryoelectron Microscopy , Ligands , Molecular Conformation , Molecular Dynamics Simulation , Ryanodine Receptor Calcium Release Channel/metabolism
3.
Sci Rep ; 7(1): 16702, 2017 12 01.
Article in English | MEDLINE | ID: mdl-29196616

ABSTRACT

Estrogen replacement therapy increases the risk of human ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. This study uses primary cultures of mouse ovarian surface epithelium (OSE) to demonstrate that one possible mechanism by which estrogen accelerates the initiation of ovarian cancer is by up-regulation of microRNA-378 via the ESR1 pathway to result in the down-regulation of a tumour suppressor called Disabled-2 (Dab2). Estrogen suppression of Dab2 was reproducible in vivo and across many cell types including mouse oviductal epithelium and primary cultures of human ovarian cancer cells. Suppression of Dab2 resulted in increased proliferation, loss of contact inhibition, morphological dysplasia, and resistance to oncogene-induced senescence - all factors that can sensitize OSE to transformation. Given that DAB2 is highly expressed in healthy human OSE and is absent in the majority of ovarian tumours, this study has taken the first steps to provide a mechanistic explanation for how estrogen therapy may play a role in the initiation of ovarian cancer.


Subject(s)
Adaptor Proteins, Vesicular Transport/biosynthesis , Carcinoma, Ovarian Epithelial/metabolism , Cell Transformation, Neoplastic , Epithelial Cells/metabolism , Estradiol/adverse effects , Ovarian Neoplasms/metabolism , Ovary/metabolism , Tumor Suppressor Proteins/biosynthesis , Adaptor Proteins, Signal Transducing , Adaptor Proteins, Vesicular Transport/genetics , Animals , Apoptosis Regulatory Proteins , Carcinoma, Ovarian Epithelial/chemically induced , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/pathology , Cell Transformation, Neoplastic/chemically induced , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Epithelial Cells/pathology , Epithelium/metabolism , Epithelium/pathology , Estradiol/pharmacology , Female , Humans , Mice , Mice, Knockout , Ovarian Neoplasms/chemically induced , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Ovary/pathology , Tumor Suppressor Proteins/genetics
4.
Nat Chem Biol ; 13(5): 494-500, 2017 05.
Article in English | MEDLINE | ID: mdl-28263965

ABSTRACT

The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via 'promiscuous' reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.


Subject(s)
Biocatalysis , Glutarates/metabolism , L-Lactate Dehydrogenase/metabolism , Malate Dehydrogenase/metabolism , Gas Chromatography-Mass Spectrometry , Humans , Hydrogen-Ion Concentration , Ketoglutaric Acids/chemistry , Ketoglutaric Acids/metabolism , Molecular Structure , Stereoisomerism
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