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Clinical Proteomics Jun 2024The development of breast cancer has been mainly reported in women who have reached the post-menopausal stage; therefore, it is the primary factor responsible for death... (Review)
Review
The development of breast cancer has been mainly reported in women who have reached the post-menopausal stage; therefore, it is the primary factor responsible for death amongst postmenopausal women. However, if treated on time it has shown a survival rate of 20 years in about two-thirds of women. Cases of breast cancer have also been reported in younger women and the leading cause in them is their lifestyle pattern or they may be carriers of high penetrance mutated genes. Premenopausal women who have breast cancer have been diagnosed with aggressive build-up of tumors and are therefore at more risk of loss of life. Mammography is an effective way to test for breast cancer in women after menopause but is not so effective for premenopausal women or younger females. Imaging techniques like contrast-enhanced MRI can up to some extent indicate the presence of a tumor but it cannot adequately differentiate between benign and malignant tumors. Although the 'omics' strategies continuing for the last 20 years have been helpful at the molecular level in enabling the characteristics and proper understanding of such tumors over long-term longitudinal monitoring. Classification, diagnosis, and prediction of the outcomes have been made through tissue and serum biomarkers but these also fail to diagnose the disease at an early stage. Considerably there is no adequate detection technique present globally that can help early detection and provide adequate specificity, safety, sensitivity, and convenience for the younger and premenopausal women, thereby it becomes necessary to take early measures and build efficient tools and techniques for the same. Through biopsies of nipple aspirate fluid (NAF) biomarker profiling can be performed. It is a naturally secreted fluid from the cells of epithelium found in the breast. Nowadays, home-based liquid biopsy collection kits are also available through which a routine check on breast health can be performed with the help of NAF. Herein, we will review the biomarker screening liquid biopsy, and the new emerging technologies for the examination of cancer at an early stage, especially in premenopausal women.
PubMed: 38943056
DOI: 10.1186/s12014-024-09495-4 -
JACC. Advances Oct 2023Little evidence is available on the disease expression in relatives of index patients with hypertrophic cardiomyopathy (HCM). This information has important implications...
BACKGROUND
Little evidence is available on the disease expression in relatives of index patients with hypertrophic cardiomyopathy (HCM). This information has important implications for family screening programs, genetic counseling, and management of affected families.
OBJECTIVES
The purpose of this study was to investigate the disease expression and penetrance in relatives of index patients carrying pathogenic/likely pathogenic (P/LP) variants in recognized HCM genes.
METHODS
A total of 453 consecutive and unrelated HCM index patients underwent clinical and genetic investigations. A total of 903 relatives of genotype-positive index patients were invited for clinical investigations and genetic testing. Penetrance, disease expression, and incidence rates of major adverse cardiac events (MACEs) were investigated in individuals carrying P/LP variants.
RESULTS
Forty percent (183/453) of index patients carried a P/LP variant. Eighty-four percent (757/903) of all relatives of index patients with P/LP variants were available for the investigation, of whom 54% (407/757) carried a P/LP variant. The penetrance of HCM among relatives was 39% (160/407). Relatives with HCM and index patients were diagnosed at a similar age (43 ± 18 years vs 46 ± 15 years; = 0.11). There were no differences in clinical characteristics or incidence rates of MACE during 8 years of follow-up.
CONCLUSIONS
The disease expression of HCM among index patients and affected relatives carrying P/LP variants in recognized disease genes was similar, with an equal risk of experiencing MACE. These findings provide evidence to support family screening and follow-up of genotype-positive HCM families to improve management and diminish the number of adverse disease complications among relatives.
PubMed: 38938358
DOI: 10.1016/j.jacadv.2023.100604 -
European Journal of Cancer (Oxford,... Jun 2024Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric... (Review)
Review
Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.
PubMed: 38936103
DOI: 10.1016/j.ejca.2024.114145 -
Molecular Therapy. Methods & Clinical... Jun 2024Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using...
Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic mice at a dose of 1e12 vg per mouse resulted in expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.
PubMed: 38934011
DOI: 10.1016/j.omtm.2024.101269 -
BioRxiv : the Preprint Server For... Jun 2024Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying...
Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants (pLoF) in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. We identified explanations for the presumed lack of disease manifestation in 701 of the variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders rarely occur, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.
PubMed: 38915639
DOI: 10.1101/2024.06.12.593113 -
BioRxiv : the Preprint Server For... Jun 2024is a key genetic determinant of syndromic and non-syndromic cleft lip and palate. The ability to interrogate post-embryonic requirements of has been hindered, as...
is a key genetic determinant of syndromic and non-syndromic cleft lip and palate. The ability to interrogate post-embryonic requirements of has been hindered, as global ablation in the mouse causes neonatal lethality. Prior work analyzing in mouse models defined its role in the embryonic surface epithelium and periderm where it is required to regulate cell proliferation and differentiation. Several reports have also described gene expression in other cell types, such as muscle, and neuroectoderm. However, analysis of a functional role in non-epithelial cell lineages has been incomplete due to the severity and lethality of the knockout model and the paucity of work with a conditional allele. Here we describe the generation and characterization of a new floxed mouse model and analysis of ablation in periderm and neural crest lineages. This work found that loss of in periderm recapitulates a mild null phenotype, suggesting that -mediated signaling in periderm plays a crucial role in regulating embryonic development. Further, conditional ablation of in neural crest cells resulted in an anterior neural tube defect of variable penetrance. The generation of this conditional allele allows for new insights into craniofacial development and new exploration into the post-natal role of .
PubMed: 38915513
DOI: 10.1101/2024.06.11.598425 -
Clinical Immunology (Orlando, Fla.) Jun 2024OTULIN encodes an eponymous linear deubiquitinase (DUB) essential for controlling inflammation as a negative regulator of the canonical NF-κB signaling pathway via the...
OTULIN encodes an eponymous linear deubiquitinase (DUB) essential for controlling inflammation as a negative regulator of the canonical NF-κB signaling pathway via the regulation of M1-Ub dynamics. Biallelic loss-of-function (LOF) mutations in OTULIN cause an autosomal recessive condition named Otulin-Related Autoinflammatory Syndrome (ORAS), also known as Otulipenia or AutoInflammation, Panniculitis, and Dermatosis Syndrome (AIPDS). Monoallelic OTULIN LOF, also known as OTULIN Haploinsufficiency (OHI) or Immunodeficiency 107 (IMD107), has been linked to an incompletely penetrant, dominantly inherited susceptibility to invasive Staphylococcal infections. At the same time, a recent novel ORAS-like inflammatory syndrome was described in association with a heterozygous missense mutation that appears to exert dominant negative (DN) effects. In this manuscript, we report the identification of a novel homozygous missense mutation, c.595 T > A; p.(Trp199Arg), in a Moroccan infant with an ORAS phenotype and provide experimental evidence for its pathogenicity. We go on to systematically review the literature for OTULIN-associated conditions by using the GenIA database (www.geniadb.net) to collect, extract and harmonize all clinical, laboratory and functional data for published patients and variants. Our comprehensive synthesis of genotypic, phenotypic, and mechanistic data enables a more in-depth view of the diverse mechanisms and pathways by which the OTULIN pathogenic variants may lead to human immune disease. This review may help variant classification activities and inform future variant evaluation, as well as the development of diagnostic and management guidelines. It also identifies current knowledge gaps and raises additional questions warranting future investigation.
PubMed: 38914362
DOI: 10.1016/j.clim.2024.110292 -
Neurobiology of Disease Jun 2024CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's...
CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aβ) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.
PubMed: 38914170
DOI: 10.1016/j.nbd.2024.106575 -
American Journal of Ophthalmology Jun 2024The purpose of our study was to assess the phenotypic and genotypic spectrum in a large cohort of patients with PRPF31-associated retinal dystrophy.
PURPOSE
The purpose of our study was to assess the phenotypic and genotypic spectrum in a large cohort of patients with PRPF31-associated retinal dystrophy.
DESIGN
Retrospective cohort study METHODS: In this retrospective chart review study, we collected cross-sectional data on the phenotype and genotype of patients with PRPF31-associated retinal dystrophy from the clinics for inherited retinal dystrophies at the University of Tuebingen and the local RetDis database and biobank. Patients underwent thorough ophthalmological examinations and genetic testing.
RESULTS
Eighty-six patients from 61 families were available for clinical assessment, while genomic DNA was available for 111 individuals (index patients and family members). Fifty-three different disease-associated variants were observed in our cohort. Point mutations were the most common class. All but two patients exhibited features of a typical Retinitis pigmentosa (RP). One patient showed a cone-rod-dystrophy pattern. One mutation carrier revealed no signs of a retinal dystrophy. There was a statistically significant better visual acuity for patients with large deletions in the 20-39 age group. Cystoid macular edema was common in those with preserved central retina and showed an association with female sex.
CONCLUSION
Our study confirms high phenotypic variability in disease onset and age at which legal blindness is reached in PRPF31-linked RP. Non-penetrance is commonly documented in family history, although poorly represented in our study, possibly indicating that true asymptomatic mutation carriers are rare if followed-up over lifetime with thorough ophthalmologic workup.
PubMed: 38909744
DOI: 10.1016/j.ajo.2024.06.020 -
Reproductive Biology and Endocrinology... Jun 2024Premutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian...
BACKGROUND
Premutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian insufficiency (FXPOI). Only 20% of female premutation carriers develop early ovulatory dysfunction, the reason for this incomplete penetrance is unknown. This study validated the mathematical model in premutation alleles, after assigning each allele a score representing allelic complexity. Subsequently, allelic scores were used to investigate the impact of allele complexity on age at amenorrhea for 58 premutation cases (116 alleles) previously published.
METHODS
The allelic score was determined using a formula previously described by our group. The impact of each allelic score on age at amenorrhea was analyzed using Pearson's test and a contour plot generated to visualize the effect.
RESULTS
Correlation of allelic score revealed two distinct complexity behaviors in premutation alleles. No significant correlation was observed between the allelic score of premutation alleles and age at amenorrhea. The same lack of significant correlation was observed regarding normal-sized alleles, despite a nearly significant trend.
CONCLUSIONS
Our results suggest that the use of allelic scores combination have the potential to explain female infertility, namely the development of FXPOI, or ovarian dysfunction, despite the lack of correlation with age at amenorrhea. Such a finding is of great clinical significance for early identification of females at risk of ovulatory dysfunction, enhancement of fertility preservation techniques, and increasing the probability for a successful pregnancy in females with premutations. Additional investigation is necessary to validate this hypothesis.
Topics: Humans; Female; Fragile X Mental Retardation Protein; Amenorrhea; Alleles; Primary Ovarian Insufficiency; Adult; Heterozygote; Mutation; Fragile X Syndrome; Age Factors; Young Adult; Adolescent
PubMed: 38907244
DOI: 10.1186/s12958-024-01227-5