A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin ...remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis.
Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas.
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Adolescent idiopathic scoliosis (AIS) is a common structural deformity of the spine affecting adolescent individuals globally. The disorder is polygenic and is accompanied by the association of ...various genetic loci. Genetic studies in Chinese and Japanese populations have shown the association of genetic variants of SOX9 with AIS curve severity. However, no genetic study evaluating the association of SRY-Box Transcription Factor 9 (SOX9) variants with AIS predisposition has been conducted in any Indian population. Thus, we aimed to investigate the association of the genetic variants of the SOX9 along with 0.88 Mb upstream region with AIS susceptibility in the population of Northwest India.
In total, 113 AIS cases and 500 non-AIS controls were recruited from the population of Northwest India in the study and screened for 155 genetic variants across the SOX9 gene and 0.88 Mb upstream region of the gene using Global Screening Array-24 v3.0 chip (Illumina). The statistical significance of the Bonferroni threshold was set at 0.000322.
The results showed the association of 11 newly identified variants; rs9302936, rs7210997, rs77736349, rs12940821, rs9302937, rs77447012, rs8071904, rs74898711, rs9900249, rs2430514, and rs1042667 with the AIS susceptibility in the studied population. Only one variant, rs2430514, was inversely associated with AIS in the population, while the ten variants were associated with the AIS risk. Moreover, 47 variants clustered in the gene desert region of the SOX9 gene were associated at a p-value ≤ 0.05.
The present study is the first to demonstrate the association of SOX9 enhancer locus variants with AIS in any South Asian Indian population. The results are interesting as rs1042667, a 3' untranslated region (UTR) variant in the exon 3 and upstream variants of the SOX9 gene, were associated with AIS susceptibility in the Northwest Indian population. This provides evidence that the variants in the enhancer region of SOX9 might regulate its gene expression, thus leading to AIS pathology and might act as an important gene for AIS susceptibility.
Introduction: Hemodialysis (HD) requires blood exposure to infectious materials through the extracorporeal circulation for a prolonged period, and exposure to risk factors for nosocomial infections ...is always there. Aims and Objectives: To determine the prevalence of hepatitis B and hepatitis C in patients undergoing hemodialysis and evaluate the various modes of transmission involved in the causation of the infection. Materials and Methods: A total of 60 patients with chronic kidney disease, admitted to our hospital for HD, were screened for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies. A questionnaire was designed to evaluate risk factors and data were generated to evaluate the significance of the association. Results: Out of 60 subjects, an anti-HCV antibody was detected in 31.68% of patients and 11.66% of patients were positive for HBsAg. The maximum anti-HBV-positive patients were in >60 years of age group (11.53%), whereas the maximum HCV-positive patients were between 41 and 50 age group (23.07%). Most of the HCV-positive patients (54.54%), as well as HBV-positive patients (23.52%), received hemodialysis 50 to 100 times. The major primary disease-causing end-stage renal disease (ESRD) included chronic nephritis (35%). The duration of dialysis, multiple blood transfusions, drug addiction, and body piercing/tattooing were also observed as significant risk factors. Conclusion: In HD patients, viral hepatitis poses a significant health hazard, particularly in developing countries. HBV vaccination, strict adherence to the universal precautions, segregation of HBV-positive patients can control HBV infection in HD units. However, for HCV, the absence of a specific vaccine and the nosocomial transmission of the virus increase the peril more.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non-small cell lung cancers (NSCLC). We used ...profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209), 2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis.
Mutation in isocitrate dehydrogenase 1 (IDH1) at R132 (IDH1(R132MUT)) is frequent in low-grade diffuse gliomas and, within glioblastoma (GBM), has been proposed as a marker for GBMs that arise by ...transformation from lower-grade gliomas, regardless of clinical history. To determine how GBMs arising with IDH1(R132MUT) differ from other GBMs, we undertook a comprehensive comparison of patients presenting clinically with primary GBM as a function of IDH1(R132) mutation status.
In all, 618 treatment-naive primary GBMs and 235 lower-grade diffuse gliomas were sequenced for IDH1(R132) and analyzed for demographic, radiographic, anatomic, histologic, genomic, epigenetic, and transcriptional characteristics.
Investigation revealed a constellation of features that distinguishes IDH1(R132MUT) GBMs from other GBMs (including frontal location and lesser extent of contrast enhancement and necrosis), relates them to lower-grade IDH1(R132MUT) gliomas, and supports the concept that IDH1(R132MUT) gliomas arise from a neural precursor population that is spatially and temporally restricted in the brain. The observed patterns of DNA sequence, methylation, and copy number alterations support a model of ordered molecular evolution of IDH1(R132MUT) GBM in which the appearance of mutant IDH1 protein is an initial event, followed by production of p53 mutant protein, and finally by copy number alterations of PTEN and EGFR.
Although histologically similar, GBMs arising with and without IDH1(R132MUT) appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events. Optimal clinical management should account for the distinction between these GBM disease subtypes.
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung carcinomas in smokers being the predominant form of the disease. Although previous studies have ...identified important common somatic mutations in lung cancers, they have primarily focused on a limited set of genes and have thus provided a constrained view of the mutational spectrum. Recent cancer sequencing efforts have used next-generation sequencing technologies to provide a genome-wide view of mutations in leukaemia, breast cancer and cancer cell lines. Here we present the complete sequences of a primary lung tumour (60x coverage) and adjacent normal tissue (46x). Comparing the two genomes, we identify a wide variety of somatic variations, including >50,000 high-confidence single nucleotide variants. We validated 530 somatic single nucleotide variants in this tumour, including one in the KRAS proto-oncogene and 391 others in coding regions, as well as 43 large-scale structural variations. These constitute a large set of new somatic mutations and yield an estimated 17.7 per megabase genome-wide somatic mutation rate. Notably, we observe a distinct pattern of selection against mutations within expressed genes compared to non-expressed genes and in promoter regions up to 5 kilobases upstream of all protein-coding genes. Furthermore, we observe a higher rate of amino acid-changing mutations in kinase genes. We present a comprehensive view of somatic alterations in a single lung tumour, and provide the first evidence, to our knowledge, of distinct selective pressures present within the tumour environment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells ...(CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard.
Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs. We report similar performance for the various platforms tested in capturing CTCs, and find that capture efficiency is dependent on the level of EpCAM expression. We demonstrate that captured CTCs are amenable to biomarker analyses such as HER2 status, qRT-PCR for breast cancer subtype markers, KRAS mutation detection, and EGFR staining by immunofluorescence (IF). We quantify cell surface expression of EGFR in metastatic lung cancer patient samples. In addition, we determined HER2 status by IF and FISH in CTCs from metastatic breast cancer patients. In the majority of patients (89%) we found concordance with HER2 status from patient tumor tissue, though in a subset of patients (11%), HER2 status in CTCs differed from that observed in the primary tumor. Surprisingly, we found CTC counts to be higher in ER+ patients in comparison to HER2+ and triple negative patients, which could be explained by low EpCAM expression and a more mesenchymal phenotype of tumors belonging to the basal-like molecular subtype of breast cancer.
Our data suggests that molecular characterization from captured CTCs is possible and can potentially provide real-time information on biomarker status. In this regard, CTCs hold significant promise as a source of tumor material to facilitate clinical biomarker evaluation. However, limitations exist from a purely EpCAM based capture system and addition of antibodies to mesenchymal markers could further improve CTC capture efficiency to enable routine biomarker analysis from CTCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Achromobacter xylosoxidans is an emerging nosocomial pathogen which is commonly found in the environment. In hospital settings, especially in ICU, it can be a cause of nosocomial infection. It is ...commonly found in the humidifiers in ICU settings and it is also commonly associated with the immunocompromised state of patient having comorbidities. The objective of the study was to study the prevalence of Achromobacter xylosoxidans and its antimicrobial sensitivity pattern. The Retrospective analysis was done of the culture reports positive for Achromobacter xylosoxidans by VITEK 2 method and its Antimicrobial sensitivity pattern was analysed from the period of September 2021 to February 2023.The maximum (54.54%) infection was seen in the age group >50 years. The maximum number (66.2%) of Achromobacter xylosoxidans were isolated from Suction tip, followed by blood (8%) and Tracheal Tip (5%). Surgical ICU contributed to the maximum number of infections i.e. 40.2%, followed by Respiratory ICU (22.1%). Maximum sensitivity was seen for Cotrimoxazole and Meropenem (around 80%), followed by Cefoperazone-Sulbactam (74%), Imipenem, Levofloxacin, Ceftazidime (around 65%). The sensitivity was minimal for Ceftriaxone (0%), Aztreonam (1.3%), and Gentamicin (5.2%). The most common risk factors/ comorbidities associated with Achromobacter infections was recent ICU admission (87.01%). The antibiotic sensitivity trends to all the antibiotics used, declined from 2021 to 2022. The antibiotic of choice to our conclusion is Cotrimoxazole, followed by Piperacillin-Tazobactam. Colistin should be kept as a reserve drug for the last resort treatment. The bacteria should not be ignored as it can lead to various opportunistic infections in immunocompromised patients, causing hindrance in the treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The swine (H1N1) virus responsible for worldwide pandemics since 2009 is now causing seasonal epidemics. Since then alarming spikes of swine flu cases have been reported from Uttarakhand every year. ...There are limited studies conducted in this Himalayan belt to evaluate the clinical and epidemiological profile of the patients admitted in tertiary care hospitals.
This study aims to summarize the clinical and epidemiological attributes of swine flu and to approximate the burden of Influenza A H1N1 (Swine Flu) cases in this Himalayan belt.
Clinical and epidemiological characteristics of influenza A H1N1 cases from October 2018 to April 2019 were retrospectively and descriptively analyzed using data from the Medical Records Section and the isolation ward at Shri Guru Ram Rai Institute of Medical and Health Sciences; Shri Mahant Indiresh hospital.
A total of 1126 (51.6%) patients were tested of which 30% (338) patients were found to be H1N1 positive. Maximum cases and positivity were detected in the months of January (26.4%), February (50.3%), and March (14.8%), and the patients in the age groups of 41-50 (21.9%) and 51-60 years (19.3%) accounted for majority of the cases. The most common symptoms were fever (85.8%), cough (82.2%), sore throat (82%), and breathlessness (71.3%). A case fatality ratio of 10.9% was observed. A significant statistical association (
value < 0.00001) was reported between co-morbid conditions and death.
According to the results of this study, close caution should be exercised in case of patients infected with H1N1 particularly those with co-morbidities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. ...Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a DNA damage response. By recruiting MRE11 and BRCC3 to stabilize TRF2 at the ends of telomeres, PARP1 blocked chromosomal fusion. Exposure of ALT-dependent tumor cells to a subset of PARPi induced a conformational change in PARP1 that limited binding to MRE11 and BRCC3 and delayed release of the TRF2-mediated block on lethal telomeric fusion. These results therefore provide a basis for PARPi treatment of ALT-dependent tumors, as well as establish chromosome fusion as a biomarker of their activity.
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