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Biomedicines Jan 2024Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with... (Review)
Review
Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on developing targeted therapies that may allow for improved antileukemic effects while reducing toxicity significantly. Gemtuzumab ozogamicin (GO) is one of the most thoroughly studied molecularly targeted therapies in adults. GO is a monoclonal antibody against CD33 IgG4 linked to the cytotoxic drug calicheamicin DMH. The use of GO as a chemotherapeutic agent is not generalized for all patients who suffer from AML, particularly for those whose health prevents them from using intensive conventional chemotherapy, in which case it can be used on its own, and those who have suffered a first relapse, where its combination with other chemotherapeutic agents is possible. This systematic review aimed to comprehensively evaluate GO, focusing on its molecular structure, mode of action, pharmacokinetics, recommended dosage, resistance mechanisms, and associated toxicities to provide valuable information on the potential benefits and risks associated with its clinical use. A systematic review of eight scientific articles from 2018 to 2023 was conducted using PRISMA analysis. The results showed that GO treatment activates proapoptotic pathways and induces double-strand breaks, initiating DNA repair mechanisms. Cells defective in DNA repair pathways are susceptible to GO cytotoxicity. GO has recommended doses for newly diagnosed CD33+ AML in combination or as a single agent. Depending on the treatment regimen and patient status, GO doses vary for induction, consolidation, and continuation cycles. Multidrug resistance (MDR) involving P-glycoprotein (P-gp) is associated with GO resistance. The overexpression of P-gp reduces GO cytotoxicity; inhibitors of P-gp can restore sensitivity. Mitochondrial pathway activation and survival signaling pathways are linked to GO resistance. Other resistance mechanisms include altered pharmacokinetics, reduced binding ability, and anti-apoptotic mechanisms. GO has limited extramedullary toxicity compared to other AML treatments and may cause hepatic veno-occlusive disease (HVOD). The incidence of hepatic HVOD after GO therapy is higher in patients with high tumor burden. Hematological side effects and hepatotoxicity are prominent, with thrombocytopenia and neutropenia observed. In conclusion, GO's reintroduction in 2017 followed a thorough FDA review considering its altered dose, dosing schedule, and target population. The drug's mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity.
PubMed: 38255313
DOI: 10.3390/biomedicines12010208 -
NPJ Microgravity Jan 2024With increasing possibilities of multi-year missions in deep space, colonizing other planets, and space tourism, it is important to investigate the effects of space... (Review)
Review
With increasing possibilities of multi-year missions in deep space, colonizing other planets, and space tourism, it is important to investigate the effects of space travel on human reproduction. This study aimed to systematically review and summarize the results of available literature on space travel, microgravity, and space radiation, or Earth-based spaceflight analogues impact on female and male reproductive functions in humans. This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Space Biomedicine Systematic Review methods. The search was performed using three databases: PubMed, Web of Science, and Medline Complete. During the database search, 364 studies were identified. After the study selection process, 16 studies were included in the review. Five studies included female participants, and the findings show an increased risk of thromboembolism in combined oral contraceptive users, decreased decidualization, functional insufficiency of corpus luteum, and decreased progesterone and LH levels related to space travel or its simulation. Male participants were included in 13 studies. In males, reproductive health considerations focused on the decrease in testosterone and sex hormone-binding globulin levels, the ratio of male offspring, sperm motility, sperm vitality, and the increase in sperm DNA fragmentation related to space travel or its simulation. Results of this systematic review highlight the need to focus more on the astronaut's reproductive health in future research, as only 16 studies were found during the literature search, and many more research questions related to reproductive health in astronauts still need to be answered.
PubMed: 38238348
DOI: 10.1038/s41526-024-00351-1 -
The Lancet. Microbe Feb 2024Clinical bedaquiline resistance predominantly involves mutations in mmpR5 (Rv0678). However, mmpR5 resistance-associated variants (RAVs) have a variable relationship... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Clinical bedaquiline resistance predominantly involves mutations in mmpR5 (Rv0678). However, mmpR5 resistance-associated variants (RAVs) have a variable relationship with phenotypic Mycobacterium tuberculosis resistance. We did a systematic review to assess the maximal sensitivity of sequencing bedaquiline resistance-associated genes and evaluate the association between RAVs and phenotypic resistance, using traditional and machine-based learning techniques.
METHODS
We screened public databases for articles published from database inception until Oct 31, 2022. Eligible studies performed sequencing of at least mmpR5 and atpE on clinically sourced M tuberculosis isolates and measured bedaquiline minimum inhibitory concentrations (MICs). A bias risk scoring tool was used to identify bias. Individual genetic mutations and corresponding MICs were aggregated, and odds ratios calculated to determine association of mutations with resistance. Machine-based learning methods were used to define test characteristics of parsimonious sets of diagnostic RAVs, and mmpR5 mutations were mapped to the protein structure to highlight mechanisms of resistance. This study was registered in the PROSPERO database (CRD42022346547).
FINDINGS
18 eligible studies were identified, comprising 975 M tuberculosis isolates containing at least one potential RAV (mutation in mmpR5, atpE, atpB, or pepQ), with 201 (20·6%) showing phenotypic bedaquiline resistance. 84 (29·5%) of 285 resistant isolates had no candidate gene mutation. Sensitivity and positive predictive value of taking an any mutation approach was 69% and 14%, respectively. 13 mutations, all in mmpR5, had a significant association with a resistant MIC (adjusted p<0·05). Gradient-boosted machine classifier models for predicting intermediate or resistant and resistant phenotypes both had receiver operator characteristic c statistic of 0·73 (95% CI 0·70-0·76). Frameshift mutations clustered in the α1 helix DNA-binding domain, and substitutions in the α2 and α3 helix hinge region and in the α4 helix-binding domain.
INTERPRETATION
Sequencing candidate genes is insufficiently sensitive to diagnose clinical bedaquiline resistance, but where identified, some mutations should be assumed to be associated with resistance. Genomic tools are most likely to be effective in combination with rapid phenotypic diagnostics. This study was limited by selective sampling in contributing studies and only considering single genetic loci as causative of resistance.
FUNDING
Francis Crick Institute and National Institute of Allergy and Infectious Diseases at the National Institutes of Health.
Topics: United States; Humans; Antitubercular Agents; Diarylquinolines; Tuberculosis; Mycobacterium tuberculosis; Genomics
PubMed: 38215766
DOI: 10.1016/S2666-5247(23)00317-8 -
International Journal of Antimicrobial... Mar 2024Peptide nucleic acids (PNAs) are synthetic molecules that are like DNA/RNA, but with different building blocks. PNAs target and bind to mRNAs and disrupt the function of... (Review)
Review
Peptide nucleic acids (PNAs) are synthetic molecules that are like DNA/RNA, but with different building blocks. PNAs target and bind to mRNAs and disrupt the function of a targeted gene, hence they have been studied as potential antibacterials. The aim of this systematic review was to provide an in-depth analysis of the current status of PNAs as antibacterial agents, define the characteristics of the effective PNA constructs, and address the gap in advancing PNAs to become clinically competent agents. Following the PRISMA model, four electronic databases were searched: Web of Science, PubMed, SciFinder and Scopus. A total of 627 articles published between 1994 and 2023 were found. After screening and a rigorous selection process using explicit inclusion and exclusion criteria, 65 scientific articles were selected, containing 656 minimum inhibitory concentration (MIC) data. The antibacterial activity of PNAs was assessed against 20 bacterial species. The most studied Gram-negative and Gram-positive bacteria were Escherichia coli (n=266) and Staphylococcus aureus (n=53), respectively. In addition, the effect of PNA design, including construct length, binding location, and carrier agents, on antibacterial activity was shown. Finally, antibacterial test models to assess the inhibitory effects of PNAs were examined, emphasising gaps and prospects. This systematic review provides a comprehensive assessment of the potential of PNAs as antibacterial agents and offers valuable insights for researchers and clinicians seeking novel therapeutic strategies in the context of increasing rates of antibiotic-resistant bacteria.
Topics: Anti-Bacterial Agents; Bacteria; Peptide Nucleic Acids; Staphylococcus aureus
PubMed: 38185398
DOI: 10.1016/j.ijantimicag.2024.107083 -
Critical Reviews in Food Science and... Dec 2023NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), a member of the nucleotide-binding domain (NOD) and leucine-rich repeat sequence (LRR) protein (NLR) family,... (Review)
Review
NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), a member of the nucleotide-binding domain (NOD) and leucine-rich repeat sequence (LRR) protein (NLR) family, plays an essential role in the inflammation initiation and inflammatory mediator secretion, and thus is also associated with many disease progressions. Food-derived bioactive peptides (FDBP) exhibit excellent anti-inflammatory activity in both and models. They are encrypted in plant, meat, and milk proteins and can be released under enzymatic hydrolysis or fermentation conditions, thereby hindering the progression of hyperuricemia, inflammatory bowel disease, chronic liver disease, neurological disorders, lung injury and periodontitis by inactivating the NLRP3. However, there is a lack of systematic review around FDBP, NLRP3, and NLRP3-related diseases. Therefore, this review summarized FDBP that exert inhibiting effects on NLRP3 inflammasome from different protein sources and detailed their preparation and purification methods. Additionally, this paper also compiled the possible inhibitory mechanisms of FDBP on NLRP3 inflammasomes and its regulatory role in NLRP3 inflammasome-related diseases. Finally, the progress of cutting-edge technologies, including nanoparticle, computer-aided screening strategy and recombinant DNA technology, in the acquisition or encapsulation of NLRP3 inhibitory FDBP was discussed. This review provides a scientific basis for understanding the anti-inflammatory mechanism of FDBP through the regulation of the NLRP3 inflammasome and also provides guidance for the development of therapeutic adjuvants or functional foods enriched with these FDBP.
PubMed: 38153262
DOI: 10.1080/10408398.2023.2294164 -
Reproductive Sciences (Thousand Oaks,... Apr 2024Routine semen analysis provides considerable information regarding sperm parameters; however, it is not solely adequate to predict male fertility potential. In the past... (Review)
Review
Routine semen analysis provides considerable information regarding sperm parameters; however, it is not solely adequate to predict male fertility potential. In the past two decades, several advance sperm function tests have been developed. The present systematic review intends to assess the clinical utility of available advance sperm function tests in predicting the male fertility potential. A systematic literature search was conducted as per PRISMA guidelines using PubMed, MEDLINE, Google Scholar, and Cochrane Library. Different keywords either singly or in combination were used to retrieve the relevant articles related to sperm function tests, male fertility, and pregnancy outcomes. A total of 5169 articles were obtained, out of which 110 meeting the selection criteria were included in this review. The majorly investigated sperm function tests are hypo-osmotic swelling test, acrosome reaction test, sperm capacitation test, hemizona binding assay, sperm DNA fragmentation test, seminal reactive oxygen species test, mitochondrial dysfunction tests, antisperm antibody test, nuclear chromatin de-condensation (NCD) test, etc. The different advance sperm function tests analyse different aspects of sperm function. Hence, any one test may not be helpful to appropriately predict the male fertility potential. Currently, the unavailability of high-quality clinical data, robust thresholds, complex protocols, high cost, etc., are the limiting factors and prohibiting current sperm function tests to reach the clinics. Further multi-centric research efforts are required to fulfil the existing lacunas and pave the way for these tests to be introduced into the clinics.
Topics: Pregnancy; Female; Male; Humans; Infertility, Male; Semen; Sperm Motility; Spermatozoa; Fertility
PubMed: 38012524
DOI: 10.1007/s43032-023-01405-7 -
European Journal of Surgical Oncology :... Jan 2024Practice is variable in the inclusion or exclusion of the thoracic duct (TD) as part of the resected specimen and associated lymphadenectomy in radical esophagectomy for... (Review)
Review
Practice is variable in the inclusion or exclusion of the thoracic duct (TD) as part of the resected specimen and associated lymphadenectomy in radical esophagectomy for esophageal cancer. While some surgeons believe that the removal of TD-associated nodes may improve radicality and survival, others suggest this represents systemic disease and resection may increase morbidity without survival benefit. A systematic review was performed up to March 2023 using the search terms 'esoph∗' AND 'thoracic duct' for relevant articles which compared thoracic duct preservation (TDP) to resection (TDR) in esophagectomy for esophageal cancer. Included studies were required to report relevant oncological outcomes including at least one of overall survival (OS), disease free survival (DFS) and nodal yield. Seven cohort studies were included in data synthesis, including data for 5926 patients. None of the reported studies were randomised controlled trials. All studies originated from Japan or South Korea with almost exclusively squamous cell-type cancer. Nodal yield was higher in TDR groups. TDR was equivalent or inferior to TDP with reference to clinical outcomes (length of stay, morbidity, mortality). A single study reported increased OS in the TDR group while the remaining studies reported no significant difference. Overall study quality was moderate to poor. While an increased nodal yield may be associated with TDR, this may also be associated with higher morbidity, and currently available data does not suggest any survival benefit.
Topics: Humans; Thoracic Duct; Esophagectomy; Retrospective Studies; Esophageal Neoplasms; Carcinoma, Squamous Cell; Lymph Node Excision; DNA-Binding Proteins
PubMed: 37979459
DOI: 10.1016/j.ejso.2023.107271 -
Minerva Endocrinology Mar 2024Nesfatin-1 is a satiety peptide secreted by central, peripheral nervous system and some peripheral tissues. This meta-analysis was conducted to explore the associations... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Nesfatin-1 is a satiety peptide secreted by central, peripheral nervous system and some peripheral tissues. This meta-analysis was conducted to explore the associations with diagnostic accuracy of circulatory nesfatin-1 in polycystic ovary syndrome (PCOS).
EVIDENCE ACQUISITION
Relevant studies were retrieved by online database and manual searching. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. The subgroup analysis based on the Body Mass Index (BMI), fasting insulin (F-INS), and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) was conducted. Meta-analysis of correlations and meta-regression were performed for the associations of nesfatin-1 with metabolic and hormonal covariates. The diagnostic test accuracy (DTA) meta-analysis was conducted for the utility of nesfatin-1 in PCOS. The publication bias was tested with Egger's and Begg's regression tests.
EVIDENCE SYNTHESIS
The combined effect size including a total of 14 studies showed a significantly higher nesfatin-1 level in PCOS as compared to controls (SMD=0.93, Z=2.17, P=0.03). The nesfatin-1 was found to be significantly higher in a subgroup of studies with mean BMI>25 kg/m (SMD=1.35, Z=2.06, P=0.04), F-INS <13 mIU/mL (SMD=2.74, Z=3.59, P=0.0003), and HOMA-IR >2.7 (SMD=1.58, Z=2.65, P=0.008). The DTA meta-analysis produced a pooled diagnostic odds ratio of 19.58 and area under curve were of 0.888 for nesfatin-1 in PCOS.
CONCLUSIONS
The results indicate a multifactorial involvement such as endocrine and metabolic alterations in the form of BMI, insulin and HOMA-IR status with the higher nesfatin-1 levels in PCOS. The promising results of DTA meta-analysis warrants further research into the clinical and prognostic utility of nesfatin-1 in PCOS.
Topics: Female; Humans; Biomarkers; Body Mass Index; Calcium-Binding Proteins; DNA-Binding Proteins; Insulin; Insulin Resistance; Nerve Tissue Proteins; Nucleobindins; Polycystic Ovary Syndrome
PubMed: 37943280
DOI: 10.23736/S2724-6507.23.04003-4 -
Clinical and Experimental Rheumatology Apr 2024To describe the phenotypic, genetic, and outcome characteristics of large-vessel vasculopathy (LVV) in childhood associated with genetic variants. Additionally, a...
OBJECTIVES
To describe the phenotypic, genetic, and outcome characteristics of large-vessel vasculopathy (LVV) in childhood associated with genetic variants. Additionally, a systematic literature review was conducted to delineate the differences between LVV with and without genetic variants.
METHODS
The medical records of all children with LVV seen between January 2000 and September 2022 at our institution were retrospectively reviewed for demographic, clinical and genetic data, and outcomes at the last follow-up visit. In addition, we systematically reviewed the literature for the clinical features and known variants of previously reported cases.
RESULTS
Eleven patients with childhood LVV were identified; five (three males) of them had proven genetic variants (two DOCK8variants, one FOXP3, one DiGeorge syndrome, and one ZNF469 variant), while six patients had sporadic childhood LVV. Remarkably, patients with genetic variants were younger and had early-onset disease. However, the diagnosis of LVV was delayed compared to those without genetic variants. All patients with genetic variants were treated with corticosteroids, and three patients required sequential immunosuppressive drugs. Four patients underwent surgical intervention, and one received a haematopoietic stem-cell transplant (HSCT). Three patients achieved clinical remission, and two died. Furthermore, data from 20 previously published cases was extracted from the literature. All patients had inherited disorders. Of those, 14 patients had a genetically proven diagnosis. Most of them are treated with corticosteroids and immunosuppressive drugs, with partial responses. Two patients underwent HSCT. There were four deaths.
CONCLUSIONS
This study demonstrates that a variety of inherited disorders may contribute to childhood LVV. Strong genetic evidence and the preponderance of autosomal-recessive inheritance may allow us to propose that monogenic LVV is a distinct entity.
Topics: Humans; Phenotype; Male; Child; Female; Child, Preschool; Genetic Predisposition to Disease; Adolescent; Immunosuppressive Agents; Genetic Variation; Retrospective Studies; Infant; Treatment Outcome; Risk Factors; Adrenal Cortex Hormones; Vascular Diseases; Age of Onset; Forkhead Transcription Factors; Hematopoietic Stem Cell Transplantation; Guanine Nucleotide Exchange Factors; DNA-Binding Proteins
PubMed: 37404170
DOI: 10.55563/clinexprheumatol/je8rq2 -
Circulation. Genomic and Precision... Aug 20231p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor . Early studies...
BACKGROUND
1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor . Early studies suggest that deletion of may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of loss is unknown.
METHODS
This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific knockout mouse ( conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis.
RESULTS
The retrospective cohort included 71 patients. Among individuals with deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with not deleted (=0.1). In the combined retrospective and systematic review cohort (n=134), deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, =0.03). deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (=0.04). Among those deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female conditional knockout mice. Further, female conditional knockout mice demonstrate significantly elevated risk of mortality (=0.0003).
CONCLUSIONS
deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with deletion should be assessed for cardiac disease.
Topics: Animals; Female; Humans; Male; Mice; Cardiomyopathies; DNA-Binding Proteins; Fibrosis; Mice, Knockout; Multicenter Studies as Topic; Retrospective Studies; Transcription Factors
PubMed: 37395136
DOI: 10.1161/CIRCGEN.122.003912