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Transplantation Proceedings Nov 2023Studies examining outcomes of genitourinary malignancy (GU) in the solid organ transplant (SOT) population predominantly focus on renal transplant recipients and consist...
BACKGROUND
Studies examining outcomes of genitourinary malignancy (GU) in the solid organ transplant (SOT) population predominantly focus on renal transplant recipients and consist of relatively small cohorts. We aimed to expand knowledge of the characteristics and outcomes of de novo GU malignancies in all patients with SOT at a large tertiary center.
METHODS
The SOT database was queried for recipients with de novo bladder, renal cell, and prostate malignancy, and a retrospective chart review was performed. Descriptive statistics and Kaplan-Meier survival estimates were calculated. Cox proportional hazards regression was used for multivariate modeling of predictive factors in the development of GU malignancy.
RESULTS
Solid organ transplant recipients with de novo bladder malignancy comprised 64.3% with high grade and 38.1% with advanced stage (≥T2) disease at initial diagnosis. Only 3.7% of patients with de novo renal cell carcinoma presented with metastatic disease, and 13.6% with localized disease developed recurrences. The most common stage in de novo prostate cancer patients was pT3 (52.2%). Kaplan-Meier estimates (95% CI) for 5-year overall (OS) and cancer-specific survival (CSS) were 44.12% (31.13-62.52) and 80.80% (68.85-94.81) for bladder, 78.90% (68.93-90.30) and 96.61% (92.10-100.00) for renal cell, and 81.18% (72.01-91.51) and 96.16% (90.95-100.00) for prostate cancer, respectively. Age at transplant and time from transplant to cancer diagnosis were predictive of de novo bladder cancer OS (P = .042 and .021, respectively).
CONCLUSION
To our knowledge, this is the largest single-center cohort examined for GU malignancy after SOT. Bladder and renal cell cancer had worse OS but similar CSS as historical rates for nontransplant patients. De novo prostate cancer had similar CSS.
Topics: Male; Humans; Retrospective Studies; Neoplasms; Organ Transplantation; Urogenital Neoplasms; Prostatic Neoplasms; Transplant Recipients; Incidence
PubMed: 37775402
DOI: 10.1016/j.transproceed.2023.07.023 -
Human Genetics Aug 2023Neurodevelopmental disorders (NDDs) and congenital anomalies (CAs) are rare disorders with complex etiology. In this study, we investigated the less understood genomic...
Neurodevelopmental disorders (NDDs) and congenital anomalies (CAs) are rare disorders with complex etiology. In this study, we investigated the less understood genomic overlap of copy number variants (CNVs) in two large cohorts of NDD and CA patients to identify de novo CNVs and candidate genes associated with both phenotypes. We analyzed clinical microarray CNV data from 10,620 NDD and 3176 CA cases annotated using Horizon platform of GenomeArc Analytics and applied rigorous downstream analysis to evaluate overlapping genes from NDD and CA CNVs. Out of 13,796 patients, only 195 cases contained 218 validated de novo CNVs. Eighteen percent (31/170) de novo CNVs in NDD cases and 40% (19/48) de novo CNVs in CA cases contained genomic overlaps impacting developmentally constraint genes. Seventy-nine constraint genes (10.1% non-OMIM entries) were found to have significantly enriched genomic overlap within rare de novo pathogenic deletions (P value = 0.01, OR = 1.58) and 45 constraint genes (13.3% non-OMIM entries) within rare de novo pathogenic duplications (P value = 0.01, OR = 1.97). Analysis of spatiotemporal transcriptome demonstrated both pathogenic deletion and duplication genes to be highly expressed during the prenatal stage in human developmental brain (P value = 4.95 X 10). From the list of overlapping genes, EHMT1, an interesting known NDD gene encompassed pathogenic deletion CNVs from both NDD and CA patients, whereas FAM189A1, and FSTL5 are new candidate genes from non-OMIM entries. In summary, we have identified constraint overlapping genes from CNVs (including de novo) in NDD and CA patients that have the potential to play a vital role in common disease etiology.
Topics: Humans; DNA Copy Number Variations; Neurodevelopmental Disorders; Phenotype
PubMed: 36383254
DOI: 10.1007/s00439-022-02482-5 -
American Journal of Cancer Research 2023This large population-based study determined the epidemiology and outcomes of secondary acute myeloid leukemia (sAML) in multiple myeloma (MM) survivors using the...
This large population-based study determined the epidemiology and outcomes of secondary acute myeloid leukemia (sAML) in multiple myeloma (MM) survivors using the Surveillance Epidemiology and End Results (SEER) Research Plus 9 database. To identify 64,753 cases of MM which included 136 cases with sAML; these patients were juxtaposed with patients with AML from the same database. Younger MM patients who received chemotherapy (ChT) had a higher sAML risk. The novel agent era saw a decreased sAML incidence (0.15% vs. 0.26%) and shorter latency period (median: 56 vs. 66 months, =0.031). Compared to AML, sAML patients were older (median age 69 vs. 68 years, =0.027), less likely to receive ChT (51.9% vs. 67.4%, <0.001), and had inferior overall survival (OS) (median OS: 2 vs. 5 months, <0.001). Multivariate Cox regression revealed that younger diagnosis age, diagnosis after 2003, and ChT were associated with prolonged OS in sAML patients. Clinicians should be aware of the sAML risk in younger, intensively-treated MM patients. Given the poor sAML prognosis compared to AML, clinical trials of novel therapies based on age, geriatric assessment, and cytogenetic features are warranted.
PubMed: 37970345
DOI: No ID Found -
International Journal of Molecular... Jan 2024The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing worldwide at an alarming pace, due to an increase in obesity,... (Review)
Review
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing worldwide at an alarming pace, due to an increase in obesity, sedentary and unhealthy lifestyles, and unbalanced dietary habits. MASLD is a unique, multi-factorial condition with several phases of progression including steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Sterol element binding protein 1c (SREBP1c) is the main transcription factor involved in regulating hepatic de novo lipogenesis. This transcription factor is synthesized as an inactive precursor, and its proteolytic maturation is initiated in the membrane of the endoplasmic reticulum upon stimulation by insulin. SREBP cleavage activating protein (SCAP) is required as a chaperon protein to escort SREBP from the endoplasmic reticulum and to facilitate the proteolytic release of the N-terminal domain of SREBP into the Golgi. SCAP inhibition prevents activation of SREBP and inhibits the expression of genes involved in triglyceride and fatty acid synthesis, resulting in the inhibition of de novo lipogenesis. In line, previous studies have shown that SCAP inhibition can resolve hepatic steatosis in animal models and intensive research is going on to understand the effects of SCAP in the pathogenesis of human disease. This review focuses on the versatile roles of SCAP/SREBP regulation in de novo lipogenesis and the structure and molecular features of SCAP/SREBP in the progression of hepatic steatosis. In addition, recent studies that attempt to target the SCAP/SREBP axis as a therapeutic option to interfere with MASLD are discussed.
Topics: Animals; Humans; Fatty Liver; Lipid Metabolism; Lipogenesis; Liver Neoplasms; Sterol Regulatory Element Binding Protein 1; Intracellular Signaling Peptides and Proteins; Membrane Proteins
PubMed: 38256181
DOI: 10.3390/ijms25021109 -
Biomolecules Jan 2024Cholesterol (CHOL) is a multifaceted lipid molecule. It is an essential structural component of cell membranes, where it cooperates in regulating the intracellular... (Review)
Review
Cholesterol (CHOL) is a multifaceted lipid molecule. It is an essential structural component of cell membranes, where it cooperates in regulating the intracellular trafficking and signaling pathways. Additionally, it serves as a precursor for vital biomolecules, including steroid hormones, isoprenoids, vitamin D, and bile acids. Although CHOL is normally uptaken from the bloodstream, cells can synthesize it de novo in response to an increased requirement due to physiological tissue remodeling or abnormal proliferation, such as in cancer. Cumulating evidence indicated that increased CHOL biosynthesis is a common feature of breast cancer and is associated with the neoplastic transformation of normal mammary epithelial cells. After an overview of the multiple biological activities of CHOL and its derivatives, this review will address the impact of de novo CHOL production on the promotion of breast cancer with a focus on mammary stem cells. The review will also discuss the effect of de novo CHOL production on in situ and invasive carcinoma and its impact on the response to adjuvant treatment. Finally, the review will discuss the present and future therapeutic strategies to normalize CHOL biosynthesis.
Topics: Humans; Cognition; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Bile Acids and Salts; Carcinoma
PubMed: 38254664
DOI: 10.3390/biom14010064 -
Oral Oncology May 2024De novo metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) constitutes 10% of recurrent/metastatic (RM) cases. Radiotherapy (RT) has a crucial role in the... (Review)
Review
De novo metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) constitutes 10% of recurrent/metastatic (RM) cases. Radiotherapy (RT) has a crucial role in the treatment of locally advanced HNSCC, however its application on RM diseases is still limited. The advent of immune checkpoint inhibitors (ICIs) improves the survival of RM HNSCC, however median overall survival is still limited. Integration of locoregional RT with ICIs in de novo metastatic HNSCC represents a promising treatment option. This perspective aims to explore the role of the combination of locoregional and systemic treatment in improving outcomes for synchronous de novo metastatic HNSCC patients and highlights the principal crucial point in decision making.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Neoplasm Metastasis; Immune Checkpoint Inhibitors; Neoplasm Recurrence, Local
PubMed: 38552469
DOI: 10.1016/j.oraloncology.2024.106768 -
Xenobiotica; the Fate of Foreign... Aug 2023In the early 2000s pharmaceutical drug discovery was beginning to use computational approaches for absorption, distribution, metabolism, excretion and toxicity... (Review)
Review
In the early 2000s pharmaceutical drug discovery was beginning to use computational approaches for absorption, distribution, metabolism, excretion and toxicity (ADME/Tox, also known as ADMET) prediction. This emphasis on prediction was an effort to reduce the risk of later stage failures from ADME/Tox.Much has been written in the intervening twenty plus years and significant expenditure has occurred in companies developing these capabilities which can be gleaned from publications. It is therefore an appropriate time to briefly reflect on what was proposed then and what the reality is today.20 years ago, we tended to optimise bioactivity and perhaps one ADME/Tox property at a time. Previously pharmaceutical companies needed a whole infrastructure for models - and experts, IT, champions on a project team, educators and management support. Now we are in the age of generative design where bioactivity and many ADME/Tox properties can be optimised and large language model technologies are available.There are also some challenges such as the focus on very large molecules which may be outside of current ADME/Tox models.We provide an opportunity to look forward with the increasing public data for ADME/Tox as well as expanded types of algorithms available.
PubMed: 37539466
DOI: 10.1080/00498254.2023.2245049 -
Canadian Journal of Kidney Health and... 2023transplant amyloidosis denotes the condition when a patient develops amyloidosis after transplantation but had not been diagnosed with the disease prior to...
RATIONALE
transplant amyloidosis denotes the condition when a patient develops amyloidosis after transplantation but had not been diagnosed with the disease prior to transplantation. The incidence of amyloidosis in kidney transplants is rare, but few published case reports have described the occurrence of Amyloid A protein (AA) and Light Chain (AL) amyloidosis. However, hereditary fibrinogen A alpha chain (AFib) has not been previously reported.
PATIENT PRESENTATION
We present a 72-year-old man, a kidney transplant recipient, who developed progressive rise in his creatinine about 3 years after transplantation. He has long-standing diabetes mellitus type 2, obesity, and hypertension, so he did not have a kidney biopsy of his native kidneys prior to transplantation.
DIAGNOSIS
A kidney transplant biopsy was done that showed amyloidosis. Mass spectrophotometry confirmed it as AFib amyloidosis. Genetic testing of the patient revealed that he has fibrinogen A alpha gene (FGA) point mutation with a p.E545V variant.
INTERVENTIONS
Cardiac evaluation showed normal transthoracic echocardiogram. Cardiac magnetic resonance imaging (MRI) showed no involvement by amyloidosis. A peripheral nerve biopsy showed diabetic neuropathy. Thus, the kidney was the only organ involved by the disease. The kidney transplant was managed conservatively with blood pressure and diabetes control in addition to his usual immunosuppression regimen which was not altered. He is being treated with diuretics, angiotensin receptor inhibitors, and sodium glucose transport 2 inhibitors.
OUTCOMES
Kidney transplant function exhibited only slow progression over 18 months since the diagnosis was confirmed. This slow progression is likely because the p.E545V point mutation variant is less aggressive than other gene deletion mutations and because our patient was judged to have been diagnosed early in the course of his disease.
TEACHING POINTS
In this case report, we illustrate the findings and testing that confirmed the diagnosis of AFib amyloidosis. We summarize the clinical aspects, outcomes of the disease, and treatment options. We believe this case report is interesting because it is the first reported case of AFib amyloidosis in a kidney transplant recipient who was not known to have the disease prior to kidney transplantation.
PubMed: 37920778
DOI: 10.1177/20543581231209207 -
Journal of Molecular Modeling Aug 2023Modulation of disease progression is frequently started by identifying biochemical pathway catalyzed by biomolecule that is prone to inhibition by small molecular weight...
CONTEXT
Modulation of disease progression is frequently started by identifying biochemical pathway catalyzed by biomolecule that is prone to inhibition by small molecular weight ligands. Such ligands (leads) can be obtained from natural resources or synthetic libraries. However, de novo design based on fragments assembly and optimization is showing increasing success. Plasmodium falciparum parasite depends on glutathione-S-transferase (PfGST) in buffering oxidative heme as an approach to resist some antimalarials. Therefore, PfGST is considered an attractive target for drug development. In this research, fragment-based approaches were used to design molecules that can fit to glutathione (GSH) binding site (G-site) of PfGST.
METHODS
The involved approaches build molecules from fragments that are either isosteric to GSH sub-moieties (ligand-based) or successfully docked to GSH binding sub-pockets (structure-based). Compared to reference GST inhibitor of S-hexyl GSH, ligands with improved rigidity, synthetic accessibility, and affinity to receptor were successfully designed. The method involves joining fragments to create ligands. The ligands were then explored using molecular docking, Cartesian coordinate's optimization, and simplified free energy determination as well as MD simulation and MMPBSA calculations. Several tools were used which include OPENEYE toolkit, Open Babel, Autodock Vina, Gromacs, and SwissParam server, and molecular mechanics force field of MMFF94 for optimization and CHARMM27 for MD simulation. In addition, in-house scripts written in Matlab were used to control fragments connection and automation of the tools.
Topics: Plasmodium falciparum; Molecular Docking Simulation; Ligands; Antimalarials; Glutathione
PubMed: 37584781
DOI: 10.1007/s00894-023-05650-0 -
Frontiers in Genome Editing 2023Genome editing (GE) is one of the most efficient and useful molecular approaches to correct the effects of gene mutations in hereditary monogenetic diseases, including... (Review)
Review
Combined approaches for increasing fetal hemoglobin (HbF) and production of adult hemoglobin (HbA) in erythroid cells from β-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing.
Genome editing (GE) is one of the most efficient and useful molecular approaches to correct the effects of gene mutations in hereditary monogenetic diseases, including β-thalassemia. CRISPR-Cas9 gene editing has been proposed for effective correction of the β-thalassemia mutation, obtaining high-level "" production of adult hemoglobin (HbA). In addition to the correction of the primary gene mutations causing β-thalassemia, several reports demonstrate that gene editing can be employed to increase fetal hemoglobin (HbF), obtaining important clinical benefits in treated β-thalassemia patients. This important objective can be achieved through CRISPR-Cas9 disruption of genes encoding transcriptional repressors of γ-globin gene expression (such as ) or their binding sites in the HBG promoter, mimicking non-deletional and deletional HPFH mutations. These two approaches (β-globin gene correction and genome editing of the genes encoding repressors of γ-globin gene transcription) can be, at least in theory, combined. However, since multiplex CRISPR-Cas9 gene editing is associated with documented evidence concerning possible genotoxicity, this review is focused on the possibility to combine pharmacologically-mediated HbF induction protocols with the "" production of HbA using CRISPR-Cas9 gene editing.
PubMed: 37529398
DOI: 10.3389/fgeed.2023.1204536