Up regulation of caveolin-1 during H2O2 induced oxidative stress

Caveolae ("little caves") are 50 -100 nm invaginations seen on the plasma membrane of most cells. Caveolin-1, the marker protein of caveolae in most tissues, is the structural and functional unit of caveolae. Previous studies have demonstrated the tumor suppressor capability of caveolin-1. Our lab has already shown that expression of caveolin-1 induces premature senescence in cells, possibly including those with malignant potential. We proposed that this might explain the tumor suppressor function of caveolin-1. We have further shown that oxidative stress induces premature senescence through up regulation of caveolin-1. To further elucidate the molecular mechanisms underlying this process, we used H2O2 as a model to generate stress induced premature senescence (SIPS) and examined the response of caveolin-1 promoter under these conditions. Constructs with serially truncated segments of the mouse caveolin-1 gene promoter linked to a luciferase reporter gene were made and luciferase assays were carried out. These experiments demonstrated that the critical regions lay in two segments: -222/-372 and -91/-150 of the promoter region. A consensus Sp1 binding sequence was identified within each deleted segment. Gel shift analysis of protein binding from nuclear extracts to these caveolin promoter DNA sequences confirmed that transcription factors were binding to the Sp1 consensus elements as part of the transcriptional response to H2O2 induced senescence. Further deletion mutagenesis of the individual Sp1 consensus sites confirmed the identity of the transcription factor to be Sp1. These findings suggest that Sp1 mediates oxidant induced up regulation of caveolin-1 expression. In subsequent experiments, we examined the effect of inhibitors of p38 Mitogen activated protein kinase pathway on the levels of caveolin-1 expression during SIPS by western blot and luciferase assay. We found that this pathway plays a direct role in the up regulation of caveolin-1 during SIPS, possibly through modification of Sp1 to increase its activity.Public Health Importance: Cancer is a leading public health concern. Cav-1 has been shown to be a tumor suppressor gene involved in a large number of human tumors. Induction of premature senescence in cells with malignant potential is thought to be a vital tumor suppressor function. Our study aims to define the tumor suppressor capacity of Cav-1 by elucidating the pathway by which it induces premature senescence

Survival According to Primary Tumor Location, Stage, and Treatment Patterns in Locoregional Gastroenteropancreatic High-grade Neuroendocrine Carcinomas

Background: Although the gastrointestinal tract (including the pancreas, gastroenteropancreatic (GEP) is the most common site for extrapulmonary neuroendocrine carcinoma (NEC), the current treatment patterns of locoregional GEP NEC and in particular, the role of surgical resection is unclear. Methods: Data from the National Cancer Database between 2004 and 2016 were used for this study. Results: Of 2314 GEP NEC cases (stages I–III), 52.5% were stage III. Colon was the most common site (30%); 30.9% of all cases were small cell morphology. Age, morphology, stage, and primary site were associated with significant differences in treatment patterns. Management of NEC mimicked that of adenocarcinomas arising at the respective sites: colon NEC most likely to be treated with surgery and chemotherapy; anal and esophageal NEC was primarily likely to receive chemotherapy and radiation, and rectal NEC mostly likely to receive trimodality therapy. However, 25%-40% of patients did not undergo surgical resection even at sites typically managed with curative resection, and there was a trend toward lesser resection over time. The prognostic impact of surgical resection was significant across all stages and correlated with variations in survival across primary sites. Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I–II patients (HR 0.63) and showed a strong trend in stage III (HR 0.77) patients. Conclusions: Treatment patterns in GEP NEC vary considerably according to stage and primary tumor site. Surgery significantly improved survival in stages I–II patients and showed a strong trend in stage III patients regardless of primary tumor location and other perioperative therapies.publishedVersio

FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer

Desenvolupament clínic; Fruquintinib; Càncer colorrectal metastàtic refractariDesarrollo clinico; Fruquintinib; Cáncer colorrectal metastásico refractarioClinical development; Fruquintinib; Refractory metastatic colorectal cancerFruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan

NRG GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US)

Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera™, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs. serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs. more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate vs. delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June, 2022. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169

Peningkatan Prestasi Belajar CAD Mahasiswa Teknik Otomotif Non-Reguler FT UNY melalui Pembuatan “Pohon Kata” Perintah dalam Program AutoCAD

Penelitian ini bertujuan meningkatkan prestasi belajar mata kuliah Computer Aided Design (CAD) mahasiswa prodi Teknik Otomotif Non-Reguler yang dinyatakan dalam bentuk rerata nilai akhir semester yang berasal dari komponen nilai tugas harian, nilai ujian tengah semester dan nilai ujian akhir semester. Penelitian quasi-eksperimen ini terdiri dari tahapan penelitian diawali dengan penyusunan materi pembelajaran sejumlah pokok bahasan tertentu dalam satu job sheet (lembar kerja), dilanjutkan dengan pembuatan bantuan “Pohon Kata” perintah dalam Auto CAD kepada kelas eksperimen yang ditentukan secara random dari dua kelas peserta kuliah Auto CAD pada Semester Genap 2008/2009. Kedua kelas diamati prestasinya, baik kecepatan penyelesaiannya maupun kualitas kebenaran gambarnya. Prestasi belajar kedua kelas juga diukur melalui pemberian ujian tengah semester dan ujian akhir semester. Setelah data prestasi kedua kelas terkumpul dilanjutkan dengan analisis statistik melalui uji beda (t-test) setelah sebelumnya dilakukan uji persyaratan analisis yang ternyata dapat dipenuhi. Hasil penelitian ini disimpulkan bahwa: prestasi belajar CAD mahasiswa pada kelas yang diberi perlakuan strategi pembelajaran menggunakan “Pohon Kata” perintah dalam Program Auto CAD lebih baik dibanding prestasi belajar CAD mahasiswa pada kelas yang tidak diberi perlakuan (75,41>70,89), dengan demikian pembelajaran CAD menggunakan media “Pohon Kata” perintah dalam Program Auto CAD dapat meningkatkan prestasi belajar mahasiswa Teknik Otomotif Program Non-Reguler

A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613

Background: HER2 (ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibodybased (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio \u3e 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (\u3e5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 - 7.6) months in TP group and 3.7 (95%CI: 1.6 - 6.7) months in CETIRI group (p = 0.35). Grade≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of31%.Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy

Response time analysis of COTS-Based multicores considering the contention on the shared memory bus

The current industry trend is towards using Commercially available Off-The-Shelf (COTS) based multicores for developing real time embedded systems, as opposed to the usage of custom-made hardware. In typical implementation of such COTS-based multicores, multiple cores access the main memory via a shared bus. This often leads to contention on this shared channel, which results in an increase of the response time of the tasks. Analyzing this increased response time, considering the contention on the shared bus, is challenging on COTS-based systems mainly because bus arbitration protocols are often undocumented and the exact instants at which the shared bus is accessed by tasks are not explicitly controlled by the operating system scheduler; they are instead a result of cache misses. This paper makes three contributions towards analyzing tasks scheduled on COTS-based multicores. Firstly, we describe a method to model the memory access patterns of a task. Secondly, we apply this model to analyze the worst case response time for a set of tasks. Although the required parameters to obtain the request profile can be obtained by static analysis, we provide an alternative method to experimentally obtain them by using performance monitoring counters (PMCs). We also compare our work against an existing approach and show that our approach outperforms it by providing tighter upper-bound on the number of bus requests generated by a task