Quantitative Assessment of Hab Watershed Using Geoinformatics

Morphometric assessment of the watersheds is considered highly critical to appraise its hydrological characteristics, such as, general geology, structure, geomorphology and climate conditions. In this study, morphometric analysis of Hab Watershed has been carried out through Geospatial Technology (RS & GIS) in a systematic manner to examine its Geo-hydrological characteristics. The drainage network of Hab is typically dendritic and semi-dendritic indicating its heterogeneous lithology. Recent study reveals increase in stream order, substantially decreases the stream total length. drainage density of the Hab Watershed indicates the characteristics of its typical soil. Drainage texture value for Hab watershed is 0.18. Low drainage density value reveals that the region has a permeable and porous subsurface material with low relief. The shape of the basin has been observed as quite elongated. The findings of this study reveal that GIS based morphometric analysis is highly effective tool for geo-hydrological study of watersheds

Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

Objective: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. Design: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. Results: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06). Conclusions: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications

Pengembangan Media Audiovisual BEKU dengan Model Pembelajaran Auditory Intelectually Repetition pada Teks Berita

Penelitian ini bertujuan untuk mengembangkan media pembelajaran BEKU pada materi teks berita kelas VIII dengan berbasis model pembelajaran auditory intellectually repetition dan mengetahui kelayakan media pembelajaran tersebut dan respons peserta didik terhadap media pembelajaran. Dalam prosesnya, penelitian ini menggunakan metode pengembangan atau Research and Development (RnD). Dalam mengumpulkan data, peneliti menggunakan teknik wawancara dan angket sebagai teknik pengumpulan data. Subjek dalam penelitian ini adalah ahli materi, ahli media, dan peserta didik kelas VIII SMP Negeri 14 Tangerang Selatan. Hasil penelitian yaitu: 1) validasi ahli materi dengan persentase 91% dengan kategori sangat layak dan validasi ahli media dengan persentase 100% dengan kategori sangat layak 2) respons peserta didik secara keseluruhan memperoleh persentase 92,5% dengan kriteria sangat layak. Dapat disimpulkan bahwa media pembelajaran BEKU pada teks berita rakyat kelas VIII dengan berbasis model pembelajaran auditory intellectually repetition sangat layak digunakan dalam pembelajaran.Kata Kunci: Media Pembelajaran BEKU, Teks Berita, Auditory IntelectuallyRepetition

Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma

DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies

MicroRNA 31-3p expression and benefit from anti-EGFR inhibitors in metastatic colorectal cancer patients enrolled in the prospective phase II PROSPECT-C trial

PURPOSE: Anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies (mABs) are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumour location (sidedness) are predictive markers of patients' response to anti-EGFR mABs. Recently, low microRNA-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here we aimed to validate the predictive power of microRNA-31-3p in a prospective cohort of chemo-refractory mCRC patients treated with single agent anti-EGFR mABs. EXPERIMENTAL DESIGN: microRNA-31-3p was tested by in-situ hybridization in ninety-one pre-treatment core biopsies from metastatic deposits of forty-five mCRC patients. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in microRNA-31-3p expression over treatment. MicroRNA-31-3p expression, sidedness, and RAS status in pre-treatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination. RESULTS: Patients with low microRNA-31-3p expression in pre-treatment biopsies showed better overall response rate, as well as better progression free and overall survival, compared to those with high microRNA-31-3p expression. The prognostic effect of microRNA-31-3p was independent from age, gender and sidedness. No significant changes in the expression of microRNA-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mABs. MicroRNA-31-3p scores were similar when pre-treatment biopsies were compared with treatment-na\uefve archival tissues (often primary CRC).Conclusions: Our study validates the role of microRNA-31-3p as potential predictive biomarker of selection for anti-EGF mABs

Ultra-sensitive mutation detection and genome-wide DNA copy number reconstruction by error corrected circulating tumour DNA sequencing

Abstract Minimally invasive circulating free DNA (cfDNA) analysis can portray cancer genome landscapes but highly sensitive and specific genetic approaches are necessary to accurately detect mutations with often low variant frequencies. We developed a targeted cfDNA sequencing technology using novel off-the-shelf molecular barcodes for error correction, in combination with custom solution hybrid capture enrichment. Modelling based on cfDNA yields from 58 patients shows that our assay, which requires 25ng of cfDNA input, should be applicable to >95% of patients with metastatic colorectal cancer. Sequencing of a 163.3 kb target region including 32 genes detected 100% of single nucleotide variants with 0.15% variant frequency in cfDNA spike-in experiments. Molecular barcode error correction reduced false positive mutation calls by 98.6%. In a series of 28 patients with metastatic colorectal cancers, 80 out of 91 (88%) mutations previously detected by tumour tissue sequencing were called in the cfDNA. Call rates were similar for single nucleotide variants and small insertions/deletions. Mutations only called in cfDNA but not detectable in matched tumour tissue included, among others, a subclonal resistance driver mutation to anti-EGFR antibodies in the KRAS gene, multiple activating PIK3CA mutations in each of two patients (indicative of parallel evolution), and TP53 mutations originating from clonal haematopoiesis. Furthermore, we demonstrate that cfDNA off-target read analysis allows the reconstruction of genome wide copy number aberration profiles from 71% of these 28 cases. This error-corrected ultra-deep cfDNA sequencing assay with a target region that can be readily customized enables broad insights into cancer genomes and evolution

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.M.G., A.Woolston, L.J.B., and B.G. were supported by CRUK, a charitable donation from Tim Morgan, Cancer Genetics UK and the Constance Travis Trust. G.S. was funded by an Institute of Cancer PhD Studentship, R.G.E. by a Spanish Society of Medical Oncology (FSEOM) grant for Translational Research in Reference Centers. The study was also supported by the ICR/RMH NIHR Biomedical Research Center for Cancer, by the CRUK Immunotherapy Accelerator (ICR/RMH, UCL) and by a Wellcome Trust Strategic Grant (105104/Z/14/Z)