tbuckley/cabot-search huggingface dataset:
A potential role for the Rictor-mTOR complex in regulating myogenic differentiation
Authors: Lili Shu, Peter J. Houghton
Journal: Cancer Research (2006)

4247  The target of rapamycin (TOR), a highly conserved Ser/Thr kinase, plays a central role in the control of eukaryotic cell growth. TOR exists in two functionally and structurally distinct complexes, TOR complex 1 with Raptor (TORC1) and TOR complex 2 with Rictor (TORC2). TORC1 controls cell growth via a rapamycin-sensitive signaling branch regulating translation, transcription, nutrient uptake, ribosome biogenesis, and autophagy. TORC2 controls the organization of the actin cytoskeleton through a rapamycin-insensitive signaling. Rapamycin, a very specific inhibitor of mTOR signaling inhibits myogenic differentiation in C2C12 myoblasts. However, exactly why mTOR signaling is essential in myogenic differentiation remains obscure. We have analyzed complexes of mTOR in membranous , cytosolic, and nuclear fractions of C2C12 myoblasts in the presence or absence of rapamycin under conditions of proliferation (growth medium,GM) or conditions that force differentiation (differentiation medium, DM). Immunofluorescence staining and immunoprecipitation/western blot analysis were used to determine the subcellular localization of proteins. Both Rictor and mTOR were detected in all three fractions. Rapamycin decreased the total mTOR and reduced phosphorylation of mTOR(pSer2481) in the membrane fraction. Rictor and mTOR complexes were co-immunoprecipitated from the membrane and cytosol fractions, but only trace amounts of binding Rictor could be detected in the nuclear fraction. Rapamycin decreased the interaction of Rictor-mTOR in all fractions, and the phosphorylation of cytosolic Akt(pSer473) was dramatically decreased. Immunofluorescence staining showed that mTOR and mTOR(pSer2448) were detected in both cytoplasm and nucleus, however, mTOR(pSer2481) was predominantly nuclear. Although Rictor was detected mainly in membranes and in cytoplasm, rapamycin induced nuclear localization of Rictor especially in DM. These results suggest that Rictor-mTOR complex may be necessary for C2C12 myoblasts differentiation and this complex is also (indirectly) rapamycin sensitive. As the Rictor-mTOR complex might be the Akt(pSer473) kinase, we propose that when C2C12 cells are cultured in DM in the presence of rapamycin, the Rictor-mTOR complex is disrupted and dissociated Rictor proteins translocate to the nucleus, and therefore Akt signaling is inhibited. This research is supported by CA77776 and CA23099 and by ALSAC.
Clinicopathologic features and impact of metastasectomy in patients with BRAF-mutant metastatic colorectal cancer.
Authors: Jianwei Zhang, Cailu Shen, Jianxia Li, Zehua Wu, Huabin Hu, Yue Cai, Xiaoyu Xie, Jiayu Ling, Yanhong Deng
Journal: Journal of Clinical Oncology (2021)

e15547 Background: BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC), while the non-V600E mutation mCRC patients showed better prognosis than that of V600E mutation. The clinicopathologic features between V600E and non-V600E mutation has not yet been fully evaluated. And the impact of metastasectomy for patients with BRAF-mutant mCRC was not well-known. Methods: A retrospective study was conducted to evaluate the clinical and pathological characteristics of patients with BRAF-mutant mCRC. Next generation sequencing (22-gene panel) was performed in some of the patients. Survival was also analyzed in the cohort of BRAF V600E and non-V600E mutation with or without metastasectomy. Results: Between December 2014 and August 2020, 116 patients with BRAF-mutant mCRC were enrolled, including 94 patients with BRAF V600E mutation and 22 patients with non-V600E mutation. Significant difference was observed in the prevalence of peritoneal metastasis (69.1% vs. 27.3%, P = 0.001) and lung metastasis (11.7% vs. 36.4%, P = 0.009) between BRAF V600E mutation and non-V600E mutations. In genomic profile, SMAD4 mutation (30.7% vs. 13.7%) showed higher prevalence in patients with BRAF V600E mutation than that of non-V600E mutations, while RAS mutation (18.2% vs. 6.4%) and FBXW7 mutation (13.7% vs 3.1%) had higher incidence in BRAF non-V600E mutations than that of V600E mutation. Patients with BRAF V600E mutation showed a poorer overall survival than those with non-V600E mutations (13.9 vs. 26.8 months, P = 0.038). Totally, 46 patients received metastasectomy after systemic treatment. The median survival for BRAF V600E patients with or without metastasectomy was not reach (42.3+ months) vs. 8.3 months, respectively ( P &lt; 0.001), and for non-V600E patients with or without metastasectomy was not reach (64.2+ months) vs. 23.3 months, respectively (P &lt; 0.001). In multivariate analysis, ECOG performance status (0-1 vs. 2) ( P = 0.001), Staging (IVa-b vs. IVc) ( P = 0.01) and metastasectomy ( P = 0.001) were independent prognostic factors of overall survival. Conclusions: BRAF V600E mutation defines a subgroup of mCRC with worse prognosis. Metastasectomy might improve the survival benefit in carefully selected BRAF-mutant mCRC patients after systemic treatment.
Physician concern about delaying lung cancer treatment while awaiting biomarker testing: Results of a survey of U.S. oncologists.
Authors: Kathryn Finch Mileham, Upal Kunal Basu Roy, Suanna Steeby Bruinooge, Janet Freeman-Daily, Edward B. Garon, Liz Garrett-Mayer, Shadia Ibrahim Jalal, Bruce E. Johnson, Amy Moore, Raymond U. Osarogiagbon, Lauren Rosenthal, Caroline Schenkel, Robert A. Smith, Shamsuddin Virani, Mary Weber Redman, Gerard A. Silvestri
Journal: Journal of Clinical Oncology (2021)

9067 Background: With rapid advancements in biomarker testing informing lung cancer treatment decisions, clinicians are challenged to maintain knowledge of who, what and when to test and how to treat based on test results. An ASCO taskforce including representatives from the American Cancer Society National Lung Cancer Roundtable and patient advocates conducted a study to assess biomarker testing and treatment practices for patients with advanced non-small cell lung cancer (aNSCLC) among U.S. oncologists. Methods: A survey was sent to 2374 ASCO members – lung cancer specialists and general oncologists. Eligibility required treating ≥1 lung cancer patient/month. Proportions were estimated across groups and compared using chi-square tests. Results: 170 responses were analyzed. 59% of respondents work at an academic center (i.e., have a fellowship program), while 41% work at a community (non-academic hospital/health system/private practice). Nearly all (98%) believe biomarker results should be received within 1 or 2 weeks of ordering, yet 37% wait an average of 3 or 4 weeks for results. Of respondents who usually wait 3 or 4 weeks, 37% initiate a non-targeted systemic treatment while waiting. Respondents from community practices were more likely to initiate non-targeted systemic treatment if results were not available after 2 weeks (59% compared to 40% of academic respondents; p = 0.013). ). When asked about reasons for not testing, respondents &lt;5 years since training were more likely to report that delaying treatment while waiting for results was always/often a concern compared to those &gt;6 years from training (41% vs 19%). Respondents reported high testing rates in both non-squamous and squamous aNSCLC. Roughly equal representation of generalists/specialists and academic/community respondents helps mitigate potential concerns about external validity. Conclusions: Respondents indicated that treatment decisions are impacted by delays in biomarker test results. Clinicians should be informed about when it is safe and appropriate to defer treatment while biomarker testing is pending. Respondents suggest that diagnostic biomarker testing companies should strive to expedite results.[Table: see text]
Social Determinants of Health and Geographic Variation in Medicare per Beneficiary Spending
Authors: Yongkang Zhang, Jing Li, Jiani Yu, Robert Tyler Braun, Lawrence P. Casalino
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Despite substantial geographic variation in Medicare per beneficiary spending in the US, little is known about the extent to which social determinants of health (SDoH) are associated with this variation. <h3>Objective</h3> To determine the associations between SDoH and county-level price-adjusted Medicare per beneficiary spending. <h3>Design, Setting, and Participants</h3> This cross-sectional study used county-level data on 2017 Medicare fee-for-service (FFS) spending, patient demographic characteristics (eg, age and gender) and clinical risk score, supply of health care resources (eg, number of hospital beds), and SDoH measures (eg, median income and unemployment rate) from multiple sources. Multivariable regressions were used to estimate the association of the variation in spending across quintiles with SDoH. <h3>Main Outcomes and Measures</h3> 2017 county-level price-adjusted Medicare Parts A and B spending per beneficiary. SDoH measures included socioeconomic position, race/ethnicity, social relationships, and residential and community context. <h3>Results</h3> Among 3038 counties with 33 495 776 Medicare FFS beneficiaries (18 352 336 [54.8%] women; mean [SD] age, 72 [1.5] years), mean Medicare price-adjusted per beneficiary spending for counties in the highest spending quintile was $3785 (95% CI, $3706-$3862) higher, or 49% higher, than spending for bottom-quintile counties (mean [SD] spending per beneficiary, $11 464 [735] vs $7679 [522];<i>P</i> &lt; .001). The total contribution (including through both direct and indirect pathways) of SDoH was 37.7% ($1428 of $3785) of this variation, compared with 59.8% ($2265 of $3785) by patient clinical risk, 14.5% ($549 of $3785) by supply of health care resources, and 19.8% ($751 of $3785) by patient demographic characteristics. When all factors were included within the same model, the direct contribution of SDoH was associated with 5.8% of the variation, compared with 4.6% by supply, 4.7% by patient demographic characteristics, and 62.0% by patient clinical risk. <h3>Conclusions and Relevance</h3> These findings suggest social determinants of health are associated with considerable proportions of geographic variation in Medicare spending. Policies addressing SDoH for disadvantaged patients in certain regions have the potential to contain health care spending and improve the value of health care; patient SDoH may need to be accounted for in publicly reported physician performance, and in value-based purchasing incentive programs for health care professionals.
Maintenance therapy with 5-fluoruracil/leucovorin (5FU/LV) plus panitumumab (pmab) or 5FU/LV alone in RAS wildtype (WT) metastatic colorectal cancer (mCRC) - the PANAMA trial (AIO KRK 0212).
Authors: Dominik Paul Modest, Meinolf Karthaus, Stefan Frühauf, Ullrich Graeven, Lothar Müller, Alexander Koenig, Ludwig Fischer Von Weikersthal, Karel Caca, Albrecht Kretzschmar, Eray Goekkurt, Siegfried Haas, Annika Kurreck, Arndt Stahler, Volker Heinemann, Swantje Held, Armin Jarosch, David Horst, Stefan Kasper, Sebastian Stintzing, Tanja Trarbach
Journal: Journal of Clinical Oncology (2021)

3503 Background: Planned discontinuation or stop-and-go use of oxaliplatin are established strategies in the systemic therapy of mCRC. Consequently, and irrespective of antibody use, 5FU/LV represents the standard backbone of most maintenance strategies. Unlike VEGF-targeted substances, there is limited evidence that EGFR-antibodies add efficacy to 5FU/LV maintenance in RAS wildtype ( RAS WT) mCRC patients. Methods: Following induction therapy with six cycles of 5FU/LV, oxaliplatin (FOLFOX) and pmab, the trial randomized maintenance therapy with 5FU/LV plus pmab vs. 5FU/LV alone in a 1:1 fashion in patients (pts) with RAS WT mCRC. The primary endpoint was PFS (progression-free survival: time from randomization until progression or death). With 218 events needed for PFS, the trial was designed to demonstrate superiority of the 5FU/LV+ pmab arm vs. 5FU/LV alone with a hazard ratio (HR) of 0.75, power of 80% and a significance level of 10%. Secondary endpoints included overall survival (OS), objective response to induction- and maintenance therapy as well as quality of life. The trial is registered with ClinicalTrials.gov, NCT01991873. Results: The full analysis set consists of 248 pts (125 pts 5FU/LV + pmab and 123 pts 5FU/LV) who were randomized and received maintenance therapy. Median age was 66 vs. 65 years, male patients were 69.6% vs. 63.4%, ECOG 0 was 56.8% vs. 60.2% in the respective trial arms (5FU/LV+ pmab vs. 5FU/LV). At data cut-off, with 218 events, PFS of maintenance therapy was improved with 5FU/LV+ pmab vs. 5FU/LV alone (8.8 (80% CI 7.6-10.2) months vs. 5.7 (80% CI 5.6-6.0) months, HR 0.72 (80%CI 0.60-0.85), p = 0.014). OS (event rate 54.4%) numerically favoured the 5FU/LV+ pmab arm (28.7 (95% CI 25.4-39.1) months) as compared to 5FU/LV alone (25.7 (95% CI 22.2-28.2) months), HR 0.84 (95% CI 0.60-1.18). Conclusion: In RAS WT mCRC, maintenance therapy with 5FU/LV+ pmab appears to be superior to 5FU/LV alone and should be regarded as standard of care maintenance regimen following induction therapy with FOLFOX plus pmab. Clinical trial information: NCT01991873.
The impact of the COVID-19 pandemic on stage at diagnosis of breast and colorectal cancers.
Authors: Jade Zhou, Shelly Kane, Celia Ramsey, Melody Ann Akhondzadeh, Ananya Banerjee, Rebecca Arielle Shatsky, Kathryn A. Gold
Journal: Journal of Clinical Oncology (2021)

6501 Background: Effective cancer screening leads to a substantial increase in the detection of earlier stages of cancer, while decreasing the incidence of later stage cancer diagnoses. Timely screening programs are critical in reducing cancer-related mortality in both breast and colorectal cancer by detecting tumors at an early, curable stage. The COVID-19 pandemic resulted in the postponement or cancellation of many screening procedures, due to both patient fears of exposures within the healthcare system as well as the cancellation of some elective procedures. We sought to identify how the COVID-19 pandemic has impacted the incidence of early and late stage breast and colorectal cancer diagnoses at our institution. Methods: We examined staging for all patients presenting to UCSD at first presentation for a new diagnosis of malignancy or second opinion in 2019 and 2020. Treating clinicians determined the stage at presentation for all patients using an AJCC staging module (8 th edition) in the electronic medical record (Epic). We compared stage distribution at presentation in 2019 vs 2020, both for cancers overall and for colorectal and breast cancer, because these cancers are frequently detected by screening. Results: Total numbers of new patient visits for malignancy were similar in 2019 and 2020 (1894 vs 1915 pts), and stage distribution for all cancer patients was similar (stage I 32% in 2019 vs 29% in 2020; stage IV 26% in both 2019 and 2020). For patients with breast cancer, we saw a lower number of patients presenting with stage I disease (64% in 2019 vs 51% in 2020) and a higher number presenting with stage IV (2% vs 6%). Similar findings were seen in colorectal cancer (stage I: 22% vs 16%; stage IV: 6% vs 18%). Conclusions: Since the COVID-19 pandemic, there has been an increase in incidence of late stage presentation of colorectal and breast cancer, corresponding with a decrease in early stage presentation of these cancers at our institution. Cancer screening is integral to cancer prevention and control, specifically in colorectal and breast cancers which are often detected by screening, and the disruption of screening services has had a significant impact on our patients. We plan to continue following these numbers closely, and will present data from the first half of 2021 as it becomes available.
Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer
Authors: Libin Zhang, Yanhui Chen, Han Wang, Zheyuan Xu, Yang Wang, Sixing Li, Jun Liu, Yun Chen, Hongli Luo, Lijia Wu, Ying Yang, Henghui Zhang, Hao Peng
Journal: Journal for ImmunoTherapy of Cancer (2021)

Programmed cell death ligand 1 (PD-L1) expressed on tumor and immune cells are both associated with the response to programmed cell death 1 (PD-1) pathway blockade therapy. Here, we examine the role of CD8+PD-L1+ tumor-infiltrating lymphocyte (Tils) in the tumor microenvironment of non-small cell lung cancer (NSCLC).Tumor tissue samples of a total of 378 patients from two NSCLC cohorts were collected retrospectively. Tumor genetic variations were measured by targeted next-generation sequencing of 543 oncogenes. Tils were assessed by multiplex immunohistochemistry assay. Correlations among Tils, tumor genetic variations, and clinicopathological characteristics were analyzed.The levels of CD8+PD-L1+ Tils varied in NSCLC tumor tissues. Tumor samples with high CD8+PD-L1+ Tils had higher levels of CD8+ Tils, CD68+ macrophages, PD-L1+ tumor cells, PD-1+ Tils, and CD163+ M2-type macrophages, and also had a higher tumor mutation burden, all of which collectively constituted a typically hot but immunosuppressive tumor microenvironment. Therefore, in a non-immunotherapy cohort, we observed that the higher the CD8+PD-L1+ Tils level in the tumor tissue, the worse the prognosis (progression-free survival; cohort A, stage I-II tumor; p=0.005). Contrarily, in an immunotherapy cohort, where the immune suppression was blocked by anti-PD-1 treatment, the higher the CD8+PD-L1+ Tils level, the better the response to the anti-PD-1 treatment (complete response/partial response vs stable disease/progressive disease; cohort B; p=0.0337).CD8+PD-L1+ Tils may be an indicator of the hot but immunosuppressive tumor microenvironment which is related to a high tumor mutation burden. PD-1 pathway blockade therapy can help to mitigate this immunosuppression and obtain better curative effects.
Establishment of the Safe and Efficient CRISPR/Cas9-RNP Based Gene-Correction Platform of ELANE Mutations in iPSCs of Severe Congenital Neutropenia (CN) Patients with No Response to G-CSF and High Risk to Develop Leukemia
Authors: Masoud Nasri, Benjamin Dannenmann, Perihan Mir, Tessa Skroblyn, Anna Solovjeva, Maksim Klimiankou, Cornelia Zeidler, Lothar Kanz, Karl Welte, Julia Skokowa
Journal: Blood (2017)
糖尿病マウスにおける長期血糖コントロールのための異物反応を軽減する回収可能な移植としてのミリメートル厚ゼニスレット含有繊維【JST・京大機械翻訳】
Authors: Watanabe Takaichi, Okitsu Teru, Ozawa Fumisato, Nagata Shogo, Matsunari Hitomi, Nagashima Hiroshi, Nagaya Masaki, Teramae Hiroki, Takeuchi Shoji
Journal: Biomaterials (2020)
Long term outcomes following critical care hospital admission: A prospective cohort study of UK biobank participants
Authors: Joanne McPeake, Theodore J Iwashyna, Philip Henderson, Alastair H Leyland, Daniel Mackay, Tara Quasim, Matthew Walters, Michael Harhay, Martin Shaw
Journal: The Lancet Regional Health - Europe (2021)

: This study aimed to understand the impact of a critical care admission on long-term outcomes, compared to other hospitalised patients without a critical care encounter. A secondary aim was to examine the interrelationship between emotional, physical, and social problems during recovery.
Distress in a pandemic: The association of the coronavirus disease-2019 (COVID-19) pandemic with distress and quality of life in hematopoietic stem cell transplantation (HSCT).
Authors: Hermioni L. Amonoo, Carlisle E. W. Topping, Madison A. Clay, Thomas William LeBlanc, Joseph A. Greer, Stephanie Lee, Jennifer Temel, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2021)

7032 Background: The global COVID-19 pandemic has drastically disrupted cancer care, potentially exacerbating patients’ distress levels. Patients with hematologic malignancies undergoing HSCT may be especially vulnerable to this pandemic stress given their well-documented heightened psychological distress and impaired quality of life (QOL). However, the association of the COVID-19 pandemic with distress and QOL is not well understood. Methods: We conducted a cross-sectional analysis of data from 205 patients with hematologic malignancies undergoing HSCT who were enrolled in a multi-site, randomized supportive care trial. We compared baseline pre-HSCT distress (depression, anxiety, and posttraumatic stress disorder [PTSD] symptoms) and QOL between participants enrolled pre-COVID-19 (i.e., 03/2019-01/2020) and during the COVID-19 pandemic (i.e., 03/2020-01/2021). We used the Hospital Anxiety &amp; Depression Scale, PTSD Checklist, and Functional Assessment of Cancer Therapy-Bone Marrow Transplant to assess symptoms of depression, anxiety, and PTSD, as well as QOL respectively. We used regression models adjusting for age, gender, race, relationship status, and cancer diagnosis to examine the relationship between the period of enrollment and patient-reported distress and QOL. Results: Prior to COVID-19, 124 participants enrolled, and 81 participants enrolled during the COVID-19 pandemic. The two cohorts had similar baseline demographic and disease risk factors. Most participants were non-Hispanic (n = 185; 90.2%), White (n = 138; 86.3%), and female (n = 131; 64.5%) with a mean (SD) age of 54.9 (11.7) years. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT depression (B = 0.004; 95% CI, -0.02 to 0.03; p = 0.73), anxiety (B = 0.008; 95% CI, -0.01 to 0.03; p = 0.44), PTSD (B = 0.004; 95% CI, -0.004 to 0.01; p = 0.35) symptoms or QOL (B = -0.003; 95% CI, -0.02 to 0.01; p = 0.68). Conclusions: Contrary to the widespread notion that the COVID-19 pandemic has worsened distress in patients with cancer, we found no differences in pre-HSCT distress or QOL in patients with hematologic malignancies undergoing HSCT prior to or during the COVID-19 pandemic. Our findings highlight the need to comprehensively explore the multifactorial causes (e.g., illness experience, treatment burden) of distress and QOL deficits in HSCT recipients irrespective of the COVID-19 pandemic.
Distinguishing septic shock from non-septic shock in postsurgical patients using gene expression
Authors: Pedro Martínez-Paz, Marta Aragón-Camino, Esther Gómez-Sánchez, Mario Lorenzo-López, Estefanía Gómez-Pesquera, Alejandra Fadrique-Fuentes, Pilar Liu, Álvaro Tamayo-Velasco, Christian Ortega-Loubon, Marta Martín-Fernández, Hugo Gonzalo-Benito, Emilio García-Morán, María Heredia-Rodríguez, Eduardo Tamayo
Journal: Journal of Infection (2021)