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PubMed1995

Emv30null NOD-scid mice. An improved host for adoptive transfer of autoimmune diabetes and growth of human lymphohematopoietic cells.

When used as hosts in passive transfer experiments, a stock of NOD/Lt mice congenic for the severe combined immunodeficiency (scid) mutation have provided great insight to the contributions of various T-cell populations in the pathogenesis of autoimmune insulin-dependent diabetes mellitus (IDDM). Moreover, NOD-scid mice support higher levels of human lymphohematopoietic cell growth than the C.B-17-scid strain in which the mutation originated. However, the ability to perform long-term lymphohematopoietic repopulation studies in the NOD-scid stock has been limited by the fact that most of these mice develop lethal thymic lymphomas beginning at 20 weeks of age. These thymic lymphomas are characterized by activation and subsequent genomic reintegrations of Emv30, an endogenous murine ecotropic retrovirus unique to the NOD genome. To test the role of this endogenous retrovirus in thymomagenesis, we produced a stock of Emv30null NOD-scid mice by congenic replacement of the proximal end of chromosome 11 with genetic material derived from the closely related NOR/Lt strain. Thymic lymphomas still initiate in Emv30null NOD-scid females, but their rate of progression is significantly retarded since the frequency of tumors weighing between 170 and 910 mg at 25 weeks of age was reduced to 20.8% vs. 76.2% in Emv30% segregants. The thymic lymphomas that did develop in Emv30null NOD-scid mice were not characterized by a compensatory increase in mink cell focus-forming proviral integrations, which initiate thymomagenesis in other susceptible mouse strains. Significantly, the ability of standard NOD T-cells to transfer IDDM to the Emv30null NOD-scid stock was not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Refinement of the 6q chromosomal region implicated in transient neonatal diabetes.

Transient neonatal diabetes mellitus (TNDM) is estimated to occur in approximately 1 in 500,000 births and represents 50-60% of cases of neonatal diabetes. The pattern of inheritance of TNDM and its association with chromosome 6 uniparental disomy is consistent with the presence on chromosome 6 of an imprinted gene involved in pancreatic beta-cell development. Systematic screening for chromosome 6 abnormalities in nine families with 13 individuals affected by TNDM revealed paternal isodisomy of chromosome 6 in one child and paternally derived trisomy of the chromosomal region 6q in six children from three unrelated families. To delineate more accurately the region suspected of harboring the gene of interest, precise mapping of the duplicated area was performed in children exhibiting partial 6q trisomy by using microsatellite markers. The smallest region of duplication observed in our patients was flanked by markers D6S308 and D6S1010, which are separated by <1 cM. These findings confirm that TNDM may result from the overexpression of a gene located on chromosome 6q that is exclusively expressed from the paternal allele at least during some periods of life and further refine the localization of this gene.

Aneuploidy↗
PubMed2002

Challenges and strategies for investigating the genetic complexity of common human diseases.

There is substantial interest in the identification of genes underlying susceptibility to complex human diseases because of the potential utility of such genes in disease prediction or therapy. Type 1 diabetes is an example of one such disorder and is presumed to arise from the effect of multiple genes and environmental factors. One identified locus has a major effect on type 1 diabetes susceptibility (IDDM1), whereas other loci have significant, yet small, individual effects (IDDM2, IDDM15). It is unclear whether susceptibility for type 1 diabetes arises because of the effects of loci acting independently or whether there are important interactions between loci. Although genetic tools are continuing to be developed to enable examination of candidate regions, the means to identify and narrow "true" susceptibility regions continues to be limited by the lack of statistical power resulting from inadequately sized collections of families. This report provides an evaluation of the approaches for identification of regions harboring type 1 diabetes genes, methods to identify the gene regions that interact to define the risk for type 1 diabetes, and efforts to fine-map the variants responsible.

Chromosome Mapping↗
PubMed2000

Characterization of a virus obtained from snakeheads Ophicephalus striatus with epizootic ulcerative syndrome (EUS) in the Philippines.

This is the first report of the isolation and characterization of a fish virus from the Philippines. The virus was isolated using snakehead spleen cells (SHS) from severely lesioned epizootic ulcerative syndrome (EUS)-affected snakehead Ophicephalus striatus from Laguna de Bay, in January 1991. The virus induced cytopathic effects (CPE) in SHS cells yielding a titer of 3.02 x 10(6) TCID50 ml(-1) at 25 degrees C within 2 to 3 d. Other susceptible cell lines included bluegill fry (BF-2), catfish spleen (CFS) and channel catfish ovary (CCO) cells. Replication in chinook salmon embryo cells (CHSE-214) was minimal while Epithelioma papulosum cyprini cells (EPC) and rainbow trout gonad cells (RTG-2) were refractory. Temperatures of 15 to 25 degrees C were optimum for virus replication but the virus did not replicate at 37 degrees C. The virus can be stored at -10 and 8 degrees C for 30 and 10 d, respectively, without significant loss of infectivity. Viral replication was logarithmic with a 2 h lag phase; viral assembly in the host cells occurred in 4 h and release of virus occurred 8 h after viral infection. A 1-log difference in TCID50 titer between the cell-free virus and the total virus was noted. Freezing and thawing the virus caused a half-log drop in titer. Viral exposure to chloroform or heating to 56 degrees C for 30 min inactivated the virus. Exposure to pH 3 medium for 30 min resulted in a more than 100-fold loss of viral infectivity. The 5-iododeoxyuridine (IUdR) did not affect virus replication, indicating a RNA genome. Neutralization tests using the Philippine virus, the ulcerative disease rhabdovirus (UDRV) and the infectious hematopoietic necrosis virus (IHNV) polyvalent antisera showed slight cross-reaction between the Philippine virus antiserum and UDRV but established no serological relationship with SHRV and IHN virus. Transmission electron microscopy (TEM) of SHS cells infected with the virus showed virus particles with typical bullet morphology and an estimated size of 65 x 175 nm. The Philippine virus was therefore a rhabdovirus, but the present study did not establish its role in the epizootiology of EUS.

Animals↗
PubMed2026

Clinical implementation of next-generation sequencing in tertiary health system: the Rijeka retrospective study.

OBJECTIVE: This study aimed to assess the diagnostic yield, clinical indications, and utility of next-generation sequencing (NGS) testing since its implementation through collaboration between the University of Rijeka Faculty of Medicine and the Clinical Hospital Centre Rijeka. MATERIALS AND METHODS: This retrospective study included patients referred between 2018 and 2023 from the Clinical Hospital Centre Rijeka to the University of Rijeka Faculty of Medicine for genetic testing, primarily using exome sequencing. RESULTS: Between April 2018 and December 2023, 412 patients were referred for exome sequencing, of whom 353 (85.7%) underwent diagnostic genetic testing. A notable increase in tests ordered was observed over time. Patients were most frequently referred from Pediatrics (55.0%), Neurology (29.5%), Cardiology (7.4%), Ophthalmology (3.4%), and others (4.7%). A diagnosis was confirmed in 103/353 patients, corresponding to an overall diagnostic yield of 29.2%, and an adjusted diagnostic yield of 27.2% after collapsing related individuals into single family units. In these confirmed cases, 83 distinct disorders involving 71 unique genes were identified, with most patients showing heterozygous variants and several recurrent disorders and genes. Variants of uncertain significance were reported in 35/353 (9.9%) patients. CONCLUSION: The 27.2% diagnostic yield demonstrates effective integration of NGS into tertiary clinical practice. The recent introduction of medical genetics specialization is expected to further improve referral quality, variant interpretation, and overall diagnostic outcomes.

exome sequencing↗
PubMed2026

Deciphering the genomic landscape of novel Acinetobacter non-baumannii lineages causing neonatal septicemia: carbapenem resistance and virulence.

BACKGROUND: Acinetobacter non-baumannii (Anb) species are reported worldwide to cause infections in both adults and neonates, although less frequently than Acinetobacter baumannii. However, limited information is available on their genomic diversity, resistance mechanisms, and virulence potential. This study investigates novel Anb isolates causing neonatal septicemia in India to characterize their resistance and pathogenic traits. METHODS: Anb isolates from neonatal blood cultures (2007-2025) were identified by VITEK2 Compact system, MALDI-TOF MS, and Whole-genome sequencing (WGS). Antimicrobial susceptibility was tested by VITEK2. Genomic analysis included MLST, resistome, virulome, plasmid typing, integrons, and core-genome phylogeny analysis. In vitro and in vivo studies assessed pathogenic potential of Anb species. RESULTS: Anb infections were low (11%) among the neonates during the study period. WGS revealed 11 novel Sequence Types (STs) which include A. indicus, A. variabilis, A. schindleri, and A. bereziniae. Six out of these eleven Anbs harbored carbapenemases such as bla NDM-1 and/or bla OXA-58-like genes (bla OXA-58, bla OXA-420). bla NDM-1 was acquired via Tn125 transposon. ISAba125 was located upstream of bla NDM-1, and a conserved structure extending to IS91 family transposase was detected in bla NDM-1-harboring genomes. bla OXA-58-like genes were found to be associated with ISAba3. Most carbapenemases were likely located on chromosome. Class 1 integrons carrying multiple antimicrobial resistance genes (ARGs) and diverse plasmid replicase families were detected in Anbs. Core genome phylogeny showed that the study Anbs were not closely related to the global Anbs. In vitro virulence-associated assays (biofilm formation, surface motility, adherence/invasion, apoptosis) and in vivo lethality in murine infection model showed reduced pathogenicity, reinforcing earlier observations that Anb species are generally less virulent than A. baumannii. Several virulence factors (VFs) were detected; however, no clear correlation was observed between virulence genes, in vitro pathogenicity, and in vivo lethality. CONCLUSION: These results indicate the multifactorial nature of Anb pathogenicity and the current limitations of knowledge of its VFs. However, the presence of numerous VFs suggests a capacity to cause disease, particularly in vulnerable host populations such as neonates. Furthermore, the presence of multiple ARGs indicates a strong potential for persistence and dissemination in hospital environments with high antibiotic pressure. Overall, these findings underscore the importance of continued AMR surveillance, genome characterization and further investigations into Anb pathogenicity.

Acinetobacter non-baumannii↗
PubMed2026

Real-World Treatment Patterns and Clinical Outcomes After First-Line Therapy in Patients with KRAS G12C-Mutant Advanced Non-Small-Cell Lung Cancer in the United States.

BACKGROUND: Approximately 13% of NSCLC cases have KRAS G12C mutations. As therapeutic strategies targeting KRAS G12C-mutant NSCLC evolve, it is important to understand clinical presentation and current outcomes for these patients. METHODS: This retrospective study used data from two US nationwide databases, an electronic health records (EHR) database and a clinico-genomic database (CGDB) of EHR data linked to data from comprehensive genomic profiling tests. Eligible patients had advanced NSCLC, initiated first-line therapy from August 2018 to December 2022, and had KRAS test results. Clinicopathologic characteristics, treatments, real-world progression-free survival (rwPFS), and overall survival (OS) were analyzed. RESULTS: There were 1227 patients with KRAS G12C-mutant NSCLC in the EHR database and 447 in the CGDB. First-line regimen was platinum-based chemotherapy plus pembrolizumab for 46% and pembrolizumab monotherapy for 20%. Less than 40% of patients received second-line therapy. Median (95% CI) OS for KRAS G12C-mutant NSCLC patients in the EHR was 17.0 (15.2-18.9) months. Variables significantly associated with shorter OS included PD-L1 <1%, brain metastases, STK11 co-mutation, and poor performance status. Patients treated with platinum-based chemotherapy plus pembrolizumab had median rwPFS of 5.3 (4.5-7.3) months and OS of 12.8 (11.1-17.3) months in the CGDB; median OS was 15.6 (12.5-18.6) months in the EHR. Patients with PD-L1 &#x2265; 50% treated with pembrolizumab monotherapy had median rwPFS of 4.6 (3.0-15.6) months and OS of 20.4 (10.3-38.5) months in the CGDB; median OS was 22.1 (18.7-30.7) in the EHR. CONCLUSIONS: These data provide a real-world benchmark of outcomes for patients with KRAS G12C-mutant NSCLC receiving the current standard of care and indicate an unmet need for more effective first-line therapies.

KRAS G12C↗
PubMed2006

Role of detection of microsatellite instability in Chinese with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer.

AIM: To detect microsatellite instability (MSI) in patients with hereditary nonpolyposis colorectal cancer or ordinary hereditary colorectal cancer and to provide criteria for screening the kindreds with hereditary nonpolyposis colorectal cancer at molecular level. METHODS: MSI was detected in the specimens from 20 cases with HNPCC, 20 cases with ordinary hereditary colorectal cancer and 20 cases with sporadic colorectal cancer by means of polymerase chain reaction-single strand conformation polymorphism. RESULTS: The positive rate of MSI was 85% (17/20) in HNPCC group, 40% (8/20) in ordinary hereditary colorectal cancer group and 10% (2/20) in the sporadic colorectal cancer group respectively. The differences were significant. The mean ages of the three groups were 43.6, 52.2, and 61.8 years respectively, which increased gradually. The incidence of right hemicolon cancer was 64.7%, 37.5%, and 0% respectively, which decreased gradually and had significant difference. The expression ratio of BAT26 and BAT25 was 94.1% respectively, which was highest in the 5 gene sites studied. The incidence of poorly differentiated adenocarcinoma was 70.6% in HNPCC group among high frequency microsatellite instability (MSI-H), which was higher than the other two groups, which had 50% and 50% respectively. CONCLUSION: The incidence of MSI-H is higher in HNPCC group. The detection of MSI is simple and economical and has high correlation with the clinicopathologic feature of HNPCC and can be used as a screening method to detect the germ line mutation of the mismatch repair gene.

Adult↗
PubMed2026

Development of a Real-Time Reverse Transcription Polymerase Chain Reaction Assay for Una Virus.

Una virus (UNAV) is an understudied alphavirus with the capacity to infect humans. Although it was discovered decades ago in South America, little is still known about this virus because accurate diagnostic tests are still needed. The first UNAV-specific real-time reverse transcription polymerase chain reaction (rRT-PCR) test is described in the present study. This assay targets the nonstructural protein 1 coding region and was designed from an alignment using all available UNAV sequences. The linear range of the UNAV rRT-PCR extended from 6.2 to 0.2 log10 copies/&#xb5;L, with a lower limit of 95% detection of 2.0 copies/&#xb5;L. The assay offered sensitive UNAV detection in contrived whole-blood samples. In addition, no amplification was observed in the assay when tested with genomic RNA from multiple closely related arboviruses. The UNAV rRT-PCR exhibits high sensitivity and specificity, which is critical for research into this virus in regions where multiple related alphaviruses co-circulate.

Journal Article↗
PubMed2026

Systematic common and rare variant association testing in 392,030 whole genomes in All of Us.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

Journal Article↗
PubMed1999

Symmetric replication of an unstable isodicentric Xq chromosome derived from isolocal maternal sister chromatid recombination.

An amniocyte culture was found to be mosaic for 45,X/46,X, idic(X)(p11.2)/ 47,X, idic(X)(p11.2),idic(X)(p11.2) cell lines, reflecting mitotic nondisjunction of the idic(X)(p11.2) chromosome. Upon learning of abnormal karyotype and ultrasound findings, the parents decided to discontinue the pregnancy. Subsequent cultures of fetal skin, kidney, and lung were mosaic 45,X/46,X,idic(X)(p11.2) reflecting mitotic loss of the unstable idic(X)(p11.2) chromosome. C-banding and in situ hybridization of X chromosome-specific alpha-satellite probe to metaphase fetal cells confirmed two centromeres on the idic(X)(p11.2) chromosome with both centromeres appearing to be active in two-thirds of cells. This result was confirmed by centromere protein-E (CENP-E) antibody staining which delineated 80% of scored cells with two active centromeres and 20% with 1 active centromere. Bromodeoxyuridine (BrdU) incorporation and acridine orange staining characterized the DNA replication pattern of the idic(X)(p11.2) chromosome as late and symmetrically replicating. Polymerase chain reaction analysis of highly polymorphic loci determined that the normal X chromosome carried paternal alleles and the idic(X)(p11.2) chromosome carried maternal alleles from only one grandparental chromosome. Overall, the results suggest that recombination occurred between two maternal sister chromatids both in the same chromosome band Xp11.2 (isolocal) prior to maternal meiosis II anaphase to generate an unstable maternal idic(X)(p11.2) chromosome. Additional factors that could contribute to i(Xq) and idic(X) formation and instability are discussed along with a mechanism to explain the high frequency of intrauterine loss in 45,X pregnancies.

Adult↗
PubMed1999

[Leishmaniasis and human immunodeficiency virus: an emerging co-infection?].

Although not considered as indicative of AIDS, leishmaniasis presents a number of epidemiologic and clinical features that promote opportunistic infection in HIV patients. Accurate assessment of the incidence of this type of co-infection is difficult due to underestimation in endemic areas such as Africa and Asia. In these areas the WHO estimates that 2 to 9 p. 100 of HIV patients will develop leishmaniasis/HIV co-infection which could become a major concern. The characteristics of this co-infection have been documented. It is observed in adults between 20 and 40 years of age with a strong male sex bias. The visceral form is most frequent. Manifestations are similar to those observed in immunocompetent subjects but with the possibility of asymptomatic and low-grade forms (10 p. 100) and unusual locations suggesting multiorgan spreading in absence of host immune response. In addition to the time-tested standard procedures for diagnosis of parasitic disease, new serologic tests and genomic amplification are now available. Pentavalent antimonials have long been considered as the treatment of choice but they are not always effective and can have untoward effects. Amphotericine B especially in the liposomal form is a good alternative. The particularly high incidence of recurrence suggests that follow-up may be indicated but the modalities of prophylaxis have yet to be defined.

AIDS-Related Opportunistic Infections↗
PubMed2000

Risk of hepatitis and retroviral infections among blood donors and introduction of nucleic acid testing (NAT).

Blood donors represent a carefully selected population of individuals. In particular, they have reduced prevalence and incidence rates for hepatitis and retroviral markers when compared to the general population. Serological testing of all donations further decreases the risk of collecting an infectious blood unit to negligible levels. Nevertheless, a significant fraction of this residual risk will be eliminated by the introduction of nucleic acid testing for viral genomic material in donor samples. This testing, which has already reached the initial phases of implementation, will be performed on pooled samples, at least in the first instance.

Blood Donors↗