Rapid analysis of SARS-CoV-2 genomic data plays a crucial role in surveillance and adoption of measures in controlling spread of Covid-19. Fast, inclusive and adaptive methods are required for the ...heterogenous SARS-CoV-2 sequence data generated at an unprecedented rate.
We present an updated version of the SARS-CoV-2 analysis module of our automated computational pipeline, Infectious Pathogen Detector (IPD) 2.0, to perform genomic analysis to understand the variability and dynamics of the virus. It adopts the recent clade nomenclature and demonstrates the clade prediction accuracy of 92.8%. IPD 2.0 also contains a SARS-CoV-2 updater module, allowing automatic upgrading of the variant database using genome sequences from GISAID. As a proof of principle, analyzing 208,911 SARS-CoV-2 genome sequences, we generate an extensive database of 2.58 million sample-wise variants. A comparative account of lineage-specific mutations in the newer SARS-CoV-2 strains emerging in the UK, South Africa and Brazil and data reported from India identify overlapping and lineages specific acquired mutations suggesting a repetitive convergent and adaptive evolution.
A novel and dynamic feature of the SARS-CoV-2 module of IPD 2.0 makes it a contemporary tool to analyze the diverse and growing genomic strains of the virus and serve as a vital tool to help facilitate rapid genomic surveillance in a population to identify variants involved in breakthrough infections. IPD 2.0 is freely available from http://www.actrec.gov.in/pi-webpages/AmitDutt/IPD/IPD.html and the web-application is available at http://ipd.actrec.gov.in/ipdweb/ .
This study focuses on investigating and using machine learning (ML) methods to identify faults in renewable microgrids. It highlights the difficulties and intricacies associated with these dynamic ...energy systems. The examination of real-world data obtained from solar and wind power production, battery storage status, fault signals, and machine learning model performance highlights the complex nature of fault detection techniques in renewable microgrids. An analysis of data on renewable energy production demonstrates oscillations in the outputs of solar and wind power, highlighting differences of about 5-10% across certain time periods, thereby illustrating the intermittent characteristics of renewable energy sources. Simultaneously, the energy stored in batteries inside the microgrid shows a progressive decrease of about 3-5% in stored energy levels across time intervals, indicating possible consequences for the stability of the system. The fault detection signals display erratic patterns, which emphasize the intricacies involved in finding and categorizing issues inside the system. The assessment of machine learning models, which includes both supervised and unsupervised learning methods, reveals many performance measures. Supervised models provide greater accuracy rates, often ranging from 85% to 90%. However, they are prone to occasional misclassifications. In contrast, unsupervised models provide a moderate level of accuracy, often ranging from 75% to 80%. They exhibit flexibility in detecting faults, but their precision is limited. The study highlights the need of using a combination of supervised and unsupervised machine learning models to improve the accuracy of fault detection in renewable microgrids. These results provide valuable understanding of the intricacies and difficulties of fault detection procedures, which may lead to further progress in improving the dependability and durability of renewable microgrid systems.
Abstract
The analysis of the SARS-CoV-2 genome datasets has significantly advanced our understanding of the biology and genomic adaptability of the virus. However, the plurality of advanced ...sequencing datasets—such as short and long reads—presents a formidable computational challenge to uniformly perform quantitative, variant or phylogenetic analysis, thus limiting its application in public health laboratories engaged in studying epidemic outbreaks. We present a computational tool, Infectious Pathogen Detector (IPD), to perform integrated analysis of diverse genomic datasets, with a customized analytical module for the SARS-CoV-2 virus. The IPD pipeline quantitates individual occurrences of 1060 pathogens and performs mutation and phylogenetic analysis from heterogeneous sequencing datasets. Using IPD, we demonstrate a varying burden (5.055–999655.7 fragments per million) of SARS-CoV-2 transcripts across 1500 short- and long-read sequencing SARS-CoV-2 datasets and identify 4634 SARS-CoV-2 variants (~3.05 variants per sample), including 449 novel variants, across the genome with distinct hotspot mutations in the ORF1ab and S genes along with their phylogenetic relationships establishing the utility of IPD in tracing the genome isolates from the genomic data (as accessed on 11 June 2020). The IPD predicts the occurrence and dynamics of variability among infectious pathogens—with a potential for direct utility in the COVID-19 pandemic and beyond to help automate the sequencing-based pathogen analysis and in responding to public health threats, efficaciously. A graphical user interface (GUI)-enabled desktop application is freely available for download for the academic users at http://www.actrec.gov.in/pi-webpages/AmitDutt/IPD/IPD.html and for web-based processing at http://ipd.actrec.gov.in/ipdweb/ to generate an automated report without any prior computational know-how.
A preoperative-progesterone intervention increases disease-free survival in patients with breast cancer, with an unknown underlying mechanism. We elucidated the role of non-coding RNAs in response to ...progesterone in human breast cancer.
Whole transcriptome sequencing dataset of 30 breast primary tumors (10 tumors exposed to hydroxyprogesterone and 20 tumors as control) were re-analyzed to identify differentially expressed non-coding RNAs followed by real-time PCR analyses to validate the expression of candidates. Functional analyses were performed by genetic knockdown, biochemical, and cell-based assays.
We identified a significant downregulation in the expression of a long non-coding RNA, Down syndrome cell adhesion molecule antisense DSCAM-AS1, in response to progesterone treatment in breast cancer. The progesterone-induced expression of DSCAM-AS1 could be effectively blocked by the knockdown of progesterone receptor (PR) or treatment of cells with mifepristone (PR-antagonist). We further show that knockdown of DSCAM-AS1 mimics the effect of progesterone in impeding cell migration and invasion in PR-positive breast cancer cells, while its overexpression shows an opposite effect. Additionally, DSCAM-AS1 sponges the activity of miR-130a that regulates the expression of ESR1 by binding to its 3'-UTR to mediate the effect of progesterone in breast cancer cells. Consistent with our findings, TCGA analysis suggests that high levels of miR-130a correlate with a tendency toward better overall survival in patients with breast cancer.
This study presents a mechanism involving the DSCAM-AS1/miR-130a/ESR1 genomic axis through which progesterone impedes breast cancer cell invasion and migration. The findings highlight the utility of progesterone treatment in impeding metastasis and improving survival outcomes in patients with breast cancer.
Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for ...lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.
Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes-WHSC1L1, LETM2, and FGFR1-is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.
These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer.
We designed this study to evaluate efficacy of modified gemcitabine and oxaliplatin (mGEMOX) over best supportive care (BSC) or fluorouracil (FU) and folinic acid (FA) in unresectable gall bladder ...cancer (GBC).
Patients with unresectable GBC were enrolled for single center randomized study. Arm A, BSC; arm B, FU 425 mg/m(2) and FA 20 mg/m(2) intravenous (IV) bolus weekly for 30 weeks (FUFA); arm C, gemcitabine 900 mg/m(2) and oxaliplatin 80 mg/m(2) IV infusion on days 1 and 8 every 3 weeks for maximum of six cycles. Eighty-one patients were randomly assigned, arms A (n = 27), B (n = 28), and C (n = 26).
Complete response plus partial response in the three groups was 0 (0%), four (14.3%), and eight (30.8%) respectively (P < .001). Two patients in the mGEMOX arm and one patient in the FUFA arm underwent curative resection after chemotherapy. One patient in the mGEMOX arm had complete pathologic response. Median overall survival (OS) was 4.5, 4.6, and 9.5 months for the BSC, FUFA, and mGEMOX arms (P = .039), respectively. Progression-free survival (PFS) was 2.8, 3.5, and 8.5 months for the three groups (P < .001). There was no difference in grade 3/4 toxicities in the chemotherapy arms except transaminitis, which was more prevalent in mGEMOX arm (P = .04). Two patients in the FUFA arm and 10 patients in the mGEMOX arm had grade 3 or 4 myelosuppression. Two patients in the mGEMOX group had neutropenic fever that resolved with antibiotics.
This randomized controlled trial confirmed the efficacy of chemotherapy (mGEMOX) compared with BSC and FUFA in improving OS and PFS in unresectable GBC.
During the past decade, the incidence of EGFR mutation has been shown to vary across different ethnicities. It occurs at the rate of 10-15% in North Americans and Europeans, 19% in African-Americans, ...20-30% in various East Asian series including Chinese, Koreans, and Japanese. Frequency of EGFR mutations in India however remains sparsely explored.
We report 23% incidence of Epidermal growth factor receptor (EGFR) mutations in 907 Non small cell lung cancer (NSCLC) patients of Indian ethnicity, in contrast to 10-15% known in Caucasians and 27-62% among East Asians. In this study, EGFR mutations were found to be more common in never-smokers 29.4% as compared to smokers 15.3%. Consistent with other populations, mutation rates among adenocarcinoma-males were predominantly lower than females with 32% incidence. However unlike Caucasians, EGFR mutation rate among adenocarcinoma-never-smoker females were comparable to males suggesting lack of gender bias among never smokers likely to benefit from EGFR targeted therapy.
This study has an overall implication for establishing relevance for routine EGFR mutation diagnostics for NSCLC patients in clinics and emphasizes effectiveness for adoption of EGFR inhibitors as the first line treatment among Indian population. The intermediate frequency of EGFR mutation among Indian population compared to Caucasians and East Asians is reminiscent of an ancestral admixture of genetic influence from Middle Easterners, Central Asians, and Europeans on modern- Indian population that may confer differential susceptibility to somatic mutations in EGFR.
The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number ...alterations, immunohistochemical, and phospho‐proteome array profiling indicates ERBB2 alterations in 40% early‐stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co‐occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2‐specific, EGFR‐specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor‐associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho‐ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo‐adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti‐EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti‐EGFR treatment in colorectal cancer.
What's new?
This study presents the first genomic landscape of early‐stage gallbladder cancer among an understudied ethnic population. Besides suggesting anti‐EGFR therapy as a therapeutic option based on ERBB2 alteration, the evidence suggests that presence of KRAS (G12V) but not KRAS (G13D) mutation may impede treatment response. The findings could potentially lead to early adoption of a clinical algorithm to treat gallbladder cancer patients under neo‐adjuvant or adjuvant settings similar to the one commonly used for anti‐EGFR treatment in colorectal cancer. Furthermore, the findings rationalize inclusion of gallbladder patients under genomically matched basket clinical trials such as the NCI‐Molecular Analysis for Therapy Choice.
Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development. Here we show that a peak of ...genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations, is necessary for normal esophageal squamous development, promotes differentiation and proliferation of basal tracheal cells and cooperates in induction of pluripotent stem cells. SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC.
•Human lung cancer cells injected through mouse-tail vein colonize mouse lungs within 24 h and form lung tumors in about 30 days.•Pretreatment of mice with weekly or daily dosing of erlotinib reduces ...but does not abolish tail vein injected lung cancer cells to form lung tumors.•Pretreatment of mice with weekly or daily dosing of osimertinib abolish lung cancer cells injected through a tail vein to form lung tumors.•The low-dose once-a-week adjuvant osimertinib could have lower toxicity, higher affordability, and potentially affect acquired resistance.
The recently conducted ADAURA trial concludes daily dosing of adjuvant osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), improves disease-free survival with stage IB/II/IIIA EGFR -mutated non-small cell lung cancer patients in comparison to placebo. We have developed a preclinical orthotopic mouse model, using luciferase tagged lung adenocarcinoma cells harboring EGFR TKI sensitive exon 19 deletion to model and extend trial implications comparing a weekly vs daily dosing outcome of osimertinib to a first-generation TKI- erlotinib. We find that 100% of mice in both the groups receiving osimertinib daily or weekly before injection of cells show a complete absence of homing of cells in mice's lungs from day three until day 18 post-injection of cells. On the other hand, 25% and 75% of mice receiving erlotinib daily and weekly before injecting cells show homing of cells to the lungs. The tumors observed in the lungs, when dissected at day 30, confirmed the colonization of the injected cells homing to the organ. Thus, our study establishes the efficacy of pretreatment with osimertinib in reducing tumor cells' homing to mouse lungs in an in vivo mouse model.
Display omitted
PDF
