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Biomolecules & Biomedicine Sep 2023Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African... (Review)
Review
Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Androgens; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Antineoplastic Agents
PubMed: 37021836
DOI: 10.17305/bb.2023.8782 -
JAMA Aug 2023Intravenous magnesium sulfate administered to pregnant individuals before birth at less than 30 weeks' gestation reduces the risk of death and cerebral palsy in their... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Intravenous magnesium sulfate administered to pregnant individuals before birth at less than 30 weeks' gestation reduces the risk of death and cerebral palsy in their children. The effects at later gestational ages are unclear.
OBJECTIVE
To determine whether administration of magnesium sulfate at 30 to 34 weeks' gestation reduces death or cerebral palsy at 2 years.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial enrolled pregnant individuals expected to deliver at 30 to 34 weeks' gestation and was conducted at 24 Australian and New Zealand hospitals between January 2012 and April 2018.
INTERVENTION
Intravenous magnesium sulfate (4 g) was compared with placebo.
MAIN OUTCOMES AND MEASURES
The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years' corrected age) or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a pediatrician) at 2 years' corrected age. There were 36 secondary outcomes that assessed the health of the pregnant individual, infant, and child.
RESULTS
Of the 1433 pregnant individuals enrolled (mean age, 30.6 [SD, 6.6] years; 46 [3.2%] self-identified as Aboriginal or Torres Strait Islander, 237 [16.5%] as Asian, 82 [5.7%] as Māori, 61 [4.3%] as Pacific, and 966 [67.4%] as White) and their 1679 infants, 1365 (81%) offspring (691 in the magnesium group and 674 in the placebo group) were included in the primary outcome analysis. Death or cerebral palsy at 2 years' corrected age was not significantly different between the magnesium and placebo groups (3.3% [23 of 691 children] vs 2.7% [18 of 674 children], respectively; risk difference, 0.61% [95% CI, -1.27% to 2.50%]; adjusted relative risk [RR], 1.19 [95% CI, 0.65 to 2.18]). Components of the primary outcome did not differ between groups. Neonates in the magnesium group were less likely to have respiratory distress syndrome vs the placebo group (34% [294 of 858] vs 41% [334 of 821], respectively; adjusted RR, 0.85 [95% CI, 0.76 to 0.95]) and chronic lung disease (5.6% [48 of 858] vs 8.2% [67 of 821]; adjusted RR, 0.69 [95% CI, 0.48 to 0.99]) during the birth hospitalization. No serious adverse events occurred; however, adverse events were more likely in pregnant individuals who received magnesium vs placebo (77% [531 of 690] vs 20% [136 of 667], respectively; adjusted RR, 3.76 [95% CI, 3.22 to 4.39]). Fewer pregnant individuals in the magnesium group had a cesarean delivery vs the placebo group (56% [406 of 729] vs 61% [427 of 704], respectively; adjusted RR, 0.91 [95% CI, 0.84 to 0.99]), although more in the magnesium group had a major postpartum hemorrhage (3.4% [25 of 729] vs 1.7% [12 of 704] in the placebo group; adjusted RR, 1.98 [95% CI, 1.01 to 3.91]).
CONCLUSIONS AND RELEVANCE
Administration of intravenous magnesium sulfate prior to preterm birth at 30 to 34 weeks' gestation did not improve child survival free of cerebral palsy at 2 years, although the study had limited power to detect small between-group differences.
TRIAL REGISTRATION
anzctr.org.au Identifier: ACTRN12611000491965.
Topics: Adult; Female; Humans; Infant; Infant, Newborn; Pregnancy; Australia; Cerebral Palsy; Gestational Age; Infant Mortality; Magnesium Sulfate; Maori People; Premature Birth; Prenatal Care; Pregnancy Outcome; Administration, Intravenous; New Zealand; Child, Preschool; Young Adult; Pacific Island People; Asian; Australian Aboriginal and Torres Strait Islander Peoples; White
PubMed: 37581672
DOI: 10.1001/jama.2023.12357 -
Cancers Jun 2023Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the... (Review)
Review
Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the older population. As described herein, we reviewed the available literature to summarize the current landscape of early-onset colorectal cancer, including risk factors, clinicopathological presentation, genetic makeup of patients, and management. Currently, early-onset colorectal cancer is treated similarly as late-onset colorectal cancer, yet the available literature shows that early-onset colorectal cancer is more aggressive and different, and this remains a significant unmet need. A detailed understanding of early-onset colorectal cancer is needed to identify risk factors for the increased incidence and tailor treatments accordingly.
PubMed: 37370811
DOI: 10.3390/cancers15123202 -
JAMA Neurology Sep 2023Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and...
IMPORTANCE
Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.
OBJECTIVE
To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations.
DESIGN, SETTING, AND PARTICIPANTS
This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control.
MAIN OUTCOMES AND MEASURES
The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed.
RESULTS
In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families.
CONCLUSIONS AND RELEVANCE
This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.
Topics: Humans; Polymicrogyria; Exome Sequencing; Retrospective Studies; Mutation, Missense; Siblings; Nerve Tissue Proteins; Connexins
PubMed: 37486637
DOI: 10.1001/jamaneurol.2023.2363