Germline pathogenic variants in TP53 are associated with Li‐Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, ...including early‐onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer‐related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53‐specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53‐specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.
Here, we detail the work of the ClinGen TP53 Variant Curation Expert Panel focused on adapting the ACMG/AMP variant curation guidelines to germline variants in TP53. The use of these guidelines and sharing of clinical data led to a reduction in the number of variants of uncertain significance. Moreover, the use of these guidelines is recommended as the standard strategy for TP53 variant classification.
Engineered carbon nanotubes are currently used in many consumer and industrial products such as paints, sunscreens, cosmetics, toiletries, electronic processes and industrial lubricants. Carbon ...nanotubes are among the more widely used nanoparticles and come in two major commercial forms, single-walled carbon nanotubes (SWCNT) and the more rigid, multi-walled carbon nanotubes (MWCNT). The low density and small size of these particles makes respiratory exposures likely. Many of the potential health hazards have not been investigated, including their potential for carcinogenicity. We, therefore, utilized a two stage initiation/promotion protocol to determine whether inhaled MWCNT act as a complete carcinogen and/or promote the growth of cells with existing DNA damage. Six week old, male, B6C3F1 mice received a single intraperitoneal (ip) injection of either the initiator methylcholanthrene(MCA, 10 μg/g BW, i.p.), or vehicle (corn oil). One week after i.p. injections, mice were exposed by inhalation to MWCNT (5 mg/m³, 5 hours/day, 5 days/week) or filtered air (controls) for a total of 15 days. At 17 months post-exposure, mice were euthanized and examined for lung tumor formation.
Twenty-three percent of the filtered air controls, 26.5% of the MWCNT-exposed, and 51.9% of the MCA-exposed mice, had lung bronchiolo-alveolar adenomas and lung adenocarcinomas. The average number of tumors per mouse was 0.25, 0.81 and 0.38 respectively. By contrast, 90.5% of the mice which received MCA followed by MWCNT had bronchiolo-alveolar adenomas and adenocarcinomas with an average of 2.9 tumors per mouse 17 months after exposure. Indeed, 62% of the mice exposed to MCA followed by MWCNT had bronchiolo-alveolar adenocarcinomas compared to 13% of the mice that received filtered air, 22% of the MCA-exposed, or 14% of the MWCNT-exposed. Mice with early morbidity resulting in euthanasia had the highest rate of metastatic disease. Three mice exposed to both MCA and MWCNT that were euthanized early had lung adenocarcinoma with evidence of metastasis (5.5%). Five mice (9%) exposed to MCA and MWCNT and 1 (1.6%) exposed to MCA developed serosal tumors morphologically consistent with sarcomatous mesotheliomas, whereas mice administered MWCNT or air alone did not develop similar neoplasms.
These data demonstrate that some MWCNT exposures promote the growth and neoplastic progression of initiated lung cells in B6C3F1 mice. In this study, the mouse MWCNT lung burden of 31.2 μg/mouse approximates feasible human occupational exposures. Therefore, the results of this study indicate that caution should be used to limit human exposures to MWCNT.
Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of ...knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.
Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests ...overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (
P<.01). Six genes (
DAO, GRM3, GRM4, GRIN2B, IL2RB, and
TUBA8) met this criterion for bipolar I disorder; only
DAO has been previously associated with bipolar disorder. Six genes (
RGS4, SCA1, GRM4, DPYSL2, NOS1, and
GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one,
GRID1, shows a novel association with schizophrenia. In addition, six genes (
DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and
NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways.
During aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We found that the ability of MuSCs to regenerate is ...regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia inhibited MuSC proliferation in vitro and severely impaired injury-induced muscle regeneration in vivo. In aged muscle, a cell intrinsic defect in MuSC ciliation was associated with the decrease in regenerative capacity. Exogenous activation of Hedgehog signaling, known to be localized in the primary cilium, promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG1.3) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aged MuSCs and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.
Previously, we reported a rat S1 protein that is antigenically related to statin, a nonproliferating cell-specific marker; however, it shares high homology with the known human elongation factor-1 ...alpha (EF-1 alpha). To differentiate S1 from rat EF-1 alpha and to study their respective regulation for expression, a rat EF-1 alpha cDNA clone was isolated and characterized. The nucleotide and deduced amino acid sequences of this partial rat EF-1 alpha cDNA are compared with that of human and mouse as well as with rat S1. Both their messages were detected in rat brain by EF-1 alpha- or S1-specific probes. However, the mRNA encoding EF-1 alpha is more abundant than that encoding S1. S1 and EF-1 alpha expression were investigated in the parotid and submandibular glands of untreated rats and those treated with isoproterenol, a proliferation-inducing catecholamine. Quantitative solution hybridization demonstrated a dramatic reduction (approximately 68 ) in the S1 mRNA following isoproterenol injection in proliferation-responsive parotid glands and a mild reduction (approximately 20 ) of S1 steady-state messages in the proliferation-refractile submandibular glands. A slight increase or no changes of EF-1 alpha levels in both parotid and submandibular glands following isoproterenol treatment are also observed. Therefore, the EF-1 alpha and S1 genes are different genes, both expressed and regulated in vivo, but in differential quantitative and qualitative patterns.
Background Novel interventions are needed to reach young people and adult men with HIV services given the low HIV testing rates in these population sub-groups. We assessed the feasibility and ...acceptability of a peer-led oral HIV self-testing (HIVST) intervention in Kasensero, a hyperendemic fishing community (HIV prevalence: 37-41%) in Rakai, Uganda. Methods This study was conducted among young people (15-24 years) and adult men (25+ years) between May and August 2019. The study entailed distribution of HIVST kits by trained "peer-leaders," who were selected from existing social networks and trained in HIVST distribution processes. Peer-leaders received up to 10 kits to distribute to eligible social network members (i.e. aged 15-24 years if young people or 25+ years if adult man, not tested in the past 3 months, and HIV-negative or of unknown HIV status at enrolment). The intervention was evaluated against the feasibility benchmark of 70% of peer-leaders distributing up to 70% of the kits that they received; and the acceptability benchmark of >80% of the respondents self-testing for HIV. Results Of 298 enrolled into the study at baseline, 56.4% (n = 168) were young people (15-24 years) and 43.6% (n = 130) were adult males (25+ years). Peer-leaders received 298 kits and distributed 296 (99.3%) kits to their social network members. Of the 282 interviewed at follow-up, 98.2% (n = 277) reported that they used the HIVST kits. HIV prevalence was 7.4% (n = 21). Of the 57.1% (n = 12) first-time HIV-positives, 100% sought confirmatory HIV testing and nine of the ten (90%) respondents who were confirmed as HIV-positive were linked to HIV care within 1 week of HIV diagnosis. Conclusion Our findings show that a social network-based, peer-led HIVST intervention in a hyperendemic fishing community is highly feasible and acceptable, and achieves high linkage to HIV care among newly diagnosed HIV-positive individuals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose To compare rates and severity of complications between infants undergoing cataract surgery with and without intraocular lens (IOL) implantation. Design Prospective randomized clinical trial. ...Methods A total of 114 infants were enrolled in the Infant Aphakia Treatment Study, a randomized, multi-center (12) clinical trial comparing the treatment of unilateral aphakia in patients under 7 months of age with a primary IOL implant or contact lens. The rate, character, and severity of intraoperative complications, adverse events, and additional intraocular surgeries during the first 5 postoperative years in the 2 groups were examined. Results There were more patients with intraoperative complications (28% vs 11%, P = .031), adverse events (81% vs 56%, P = .008), and more additional intraocular surgeries (72% vs 16%, P < .0001) in the IOL group than in the contact lens group. However, the number of patients with adverse events in the contact lens group increased (15 to 24) in postoperative years 2–5 compared to the first postoperative year, while it decreased (44 to 14) in years 2–5 compared to the first postoperative year in the IOL group. If only one half of the patients in the contact lens (aphakic) group eventually undergo secondary IOL implantation, the number of additional intraocular surgeries in the 2 groups will be approximately equal. Conclusion The increased rate of complications, adverse events, and additional intraocular surgeries associated with IOL implantation in infants <7 months of age militates toward leaving babies aphakic if it is considered likely that the family will be successful with contact lens correction.
Abstract
The molecular gas in galaxies traces both the fuel for star formation and the processes that can enhance or suppress star formation. Observations of the molecular gas state can thus point to ...when and why galaxies stop forming stars. In this study, we present Atacama Large Millimeter/submillimeter Array observations of the molecular gas in galaxies evolving through the post-starburst phase. These galaxies have low current star formation rates (SFRs), regardless of the SFR tracer used, with recent starbursts ending within the last 600 Myr. We present CO (3–2) observations for three post-starburst galaxies, and dense gas HCN/HCO
+
/HNC (1–0) observations for six (four new) post-starburst galaxies. The post-starbursts have low excitation traced by the CO spectral-line energy distribution up to CO (3–2), more similar to early-type than starburst galaxies. The low excitation indicates that lower density rather than high temperatures may suppress star formation during the post-starburst phase. One galaxy displays a blueshifted outflow traced by CO (3–2). MaNGA observations show that the ionized gas velocity is disturbed relative to the stellar velocity field, with a blueshifted component aligned with the molecular gas outflow, suggestive of a multiphase outflow. Low ratios of HCO
+
/CO, indicating low fractions of dense molecular gas relative to the total molecular gas, are seen throughout post-starburst phase, except for the youngest post-starburst galaxy considered here. These observations indicate that the impact of any feedback or quenching processes may be limited to low excitation and weak outflows in the cold molecular gas during the post-starburst phase.
An NCI-sponsored, randomized clinical trial tested whether patients with relapsed ovarian cancer might benefit from surgical debulking of tumors followed by chemotherapy, as compared with ...chemotherapy alone. No significant outcome differences were noted between the patients who underwent surgery and those treated with chemotherapy alone.
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