tbuckley/cabot-search huggingface dataset:
Pathways potentiated by oncogenic Ras to modulate apoptosis induced by anticancer agent FR901228
Authors: Ping Song, Jingxiong Wei, Hwa-Chain Robert Wang
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4121 

Growing evidence has shown that ras oncogene-induced cellular transformation results in increased susceptibility of cells to specific anticancer agents. Identifying targets for anticancer agents to selectively induce apoptosis of ras -transformed cells and to bypass normal counterpart cells is pivotal to increase the effectiveness of chemotherapy for cancer patients with aberrant Ras activation. Using a tetracycline-inducible expression system to induce ectopically expressed H-Ras and cellular transformation, we have investigated the roles of Ras-induced signaling pathways in a novel anticancer depsipeptide FR901228-induced apoptosis. FR901228 possesses activity to inhibit histone deacetylase and exhibits selectivity to induce apoptosis of ras -transformed cells. We have found that the PI3-K pathway plays an anti-apoptotic role whereas the SAPK/p38 pathway plays a pro-apoptotic role in FR901228-induced apoptosis in both Ras-transformed and non-transformed counterpart cells. Interestingly, the ERK pathway plays an anti-apoptotic role in non-transformed cells; however, it plays a pro-apoptotic role in Ras-transformed cells in response to FR901228 treatment. We have also verified that procaspase-3 protein content is highly elevated in fully ras -transformed cells. The protein synthesis of procaspase-3 is increased with unchanged protein stability in ras -transformed cells. Blockage of the ERK pathway results in profound reduction of transcript and protein content of procaspase-3, indicating that the ERK pathway is involved in procaspase-3 gene expression. Suppression of caspase-3 activity by specific inhibitors results in reduced cell death induced by FR901228. The elevated procaspase-3 protein content appears to play an important role in facilitating the proteolytic production of active caspase-3 during selective induction of apoptosis of ras -transformed cells by FR901228 whereas FR901228 induces growth arrest of non-transformed counterpart cells. The ERK pathway may contribute to the pro-apoptotic role of oncogenic H-Ras to FR901228 treatment via the procaspase-3 to caspase-3 pathway. Accordingly, focusing on the elevated procaspase-3 as a molecular target to produce active caspase-3 in ras -related cancer cells may lead to increased effectiveness of chemotherapy by facilitating apoptosis of ras -transformed cells.
Natural compounds modulate the crosstalk between apoptosis- and autophagy-regulated signaling pathways: Controlling the uncontrolled expansion of tumor cells
Authors: Cornelia Braicu, Oana Zanoaga, Alina-Andreea Zimta, Adrian Bogdan Tigu, Kaitlyn L. Kilpatrick, Anupam Bishayee, Seyed Mohammad Nabavi, Ioana Berindan-Neagoe
Journal: Seminars in Cancer Biology (2020)
A novel therapeutic human monoclonal antibody for the treatment of ovarian cancer
Authors: Steven Kanner, Zili An, Nandini Ganguly, Kendall Morrison, Karen Morrison, Pia Challita-Eid, Arthur Raitano, Daulet Satpaev, Xiao-Chi Jia, Jean Gudas, Aya Jakobovits
Journal: Cancer Research (2008)

3977  AGS-8 is a novel cell surface protein expressed in over 70% of ovarian cancer patients, predominantly in advanced stages of serous adenocarcinoma. Amongst normal tissues, AGS-8 is restricted predominantly to testis and the red pulp of spleen. Functional validation studies demonstrated AGS-8 to be an oncogene involved in tumor cell proliferation, survival, migration and cell-cell interaction. Recombinant expression of AGS-8 in murine 3T3 cells led to aggressive tumor growth in mice, and its expression in tumor cells such as OVCAR-5 enhanced their intrinsic in vivo growth. AGS-8 induced tube formation in vitro and significant angiogenesis in vivo.  The XenoMouse® technology was employed to generate AGS-8M4, a fully human IgG1κ monoclonal antibody (MAb) with a Kd = 5 x 10-9 M for cell surface AGS-8. The MAb exhibits potent inhibitory activity in all functional assays, including inhibition of tube formation in vitro, and migration and invasion of cells expressing recombinant AGS-8. Significant anti-tumor efficacy of AGS-8M4 in vivo was observed in both endogenous and recombinant models expressing AGS-8, including growth inhibition of well-established tumors. Efficacy of AGS-8M4 was maintained completely after MAb de-glycosylation, indicating an intrinsic anti-tumor activity of the MAb without significant contribution by immune effector functions. Studies evaluating the mechanism of action of AGS-8M4 and efficacy with small molecule drug combinations are underway. These data validate AGS-8 as an attractive target for ovarian cancer, and establish AGS-8M4 as a potential therapeutic MAb for this cancer indication.
EFFECTIVENESS OF RIFAMPIN, RIFABUTIN, AND RIFAPENTINE FOR PREVENTIVE THERAPY OF TUBERCULOSIS IN MICE (VOL 148, PG 1541, 1993)
Authors: B H Ji, C Truffotpernot, C Lacroix, M C Raviglione, R J Obrien, P Olliaro, G Roscigno, J Grosset
Journal: American Journal of Respiratory and Critical Care Medicine (1994)
Cytoreductive Nephrectomy in Metastatic Patients with Signs or Symptoms: Implications for Renal Cell Carcinoma Guidelines
Authors: Alessandro Larcher, Giuseppe Fallara, Giuseppe Rosiello, Chiara Re, Gianfranco Baiamonte, Stefano Agnesi, Daniele Cignoli, Gianmarco Colandrea, Giuseppe Basile, Alberto Briganti, Andrea Salonia, Roberto Bertini, Francesco Montorsi, Umberto Capitanio
Journal: European Urology (2020)
Endoscopic transgastric cholecystectomy: a novel approach for minimally invasive cholecystectomy
Authors: Xin-Yang Liu, Quan-Lin Li, Xiao-Yue Xu, Jia-Xin Xu, Ming-Yan Cai, Ping Wang, Ping-Hong Zhou
Journal: Endoscopy (2020)

Natural-orifice transluminal endoscopic surgery (NOTES) has been developed as a step towards less invasive procedures. Transvaginal, transgastric, and transcolonic cholecystectomy have been described, but mostly carried out with the assistance of laparoscopic guidance, or with another device for extraction, such as a second endoscope or transabdominal instrument [1] [2] [3]. We report a novel technique called endoscopic transgastric cholecystectomy (ETGC) that is carried out with a single scope and without laparoscopic guidance or other transabdominal instruments.
Association of Normal Systolic Blood Pressure Level With Cardiovascular Disease in the Absence of Risk Factors
Authors: Seamus P. Whelton, John W. McEvoy, Leslee Shaw, Bruce M. Psaty, Joao A. C. Lima, Matthew Budoff, Khurram Nasir, Moyses Szklo, Roger S. Blumenthal, Michael J. Blaha
Journal: JAMA Cardiology (2020)

<h3>Importance</h3> The risk of atherosclerotic cardiovascular disease (ASCVD) at currently defined normal systolic blood pressure (SBP) levels in persons without ASCVD risk factors based on current definitions is not well defined. <h3>Objective</h3> To examine the association of SBP levels with coronary artery calcium and ASCVD in persons without hypertension or other traditional ASCVD risk factors based on current definitions. <h3>Design, Setting, and Participants</h3> A cohort of 1457 participants free of ASCVD from the Multi-Ethnic Study of Atherosclerosis who were without dyslipidemia (low-density lipoprotein cholesterol level ≥160 mg/dL or high-density lipoprotein cholesterol level &lt;40 mg/dL), diabetes (fasting glucose level ≥126 mg/dL), treatment for hyperlipidemia or diabetes, or current tobacco use, and had an SBP level between 90 and 129 mm Hg. Participants receiving hypertension medication were excluded. Coronary artery calcium was classified as absent or present and adjusted hazard ratios (aHRs) were calculated for incident ASCVD. The study was conducted from March 27, 2018, to February 12, 2020. <h3>Exposures</h3> Systolic blood pressure. <h3>Main Outcomes and Measures</h3> Presence or absence of coronary artery calcium and incident ASCVD events. <h3>Results</h3> Of the 1457 participants, 894 were women (61.4%); mean (SD) age was 58.1 (9.8) years and mean (SD) follow-up was 14.5 (3.9) years. There was an increase in traditional ASCVD risk factors, coronary artery calcium, and incident ASCVD events with increasing SBP levels. The aHR for ASCVD was 1.53 (95% CI, 1.17-1.99) for every 10-mm Hg increase in SBP levels. Compared with persons with SBP levels 90 to 99 mm Hg, the aHR for ASCVD risk was 3.00 (95% CI, 1.01-8.88) for SBP levels 100 to 109 mm Hg, 3.10 (95% CI, 1.03-9.28) for SBP levels 110 to 119 mm Hg, and 4.58 (95% CI, 1.47-14.27) for SBP levels 120 to 129 mm Hg. <h3>Conclusions and Relevance</h3> Beginning at an SBP level as low as 90 mm Hg, there appears to be a stepwise increase in the presence of coronary artery calcium and the risk of incident ASCVD with increasing SBP levels. These results highlight the importance of primordial prevention for SBP level increase and other traditional ASCVD risk factors, which generally seem to have similar trajectories of graded increase in risk within values traditionally considered to be normal.
SAT0303 SINGLE-CELL DECONVOLUTION OF SKIN FIBROBLAST HETEROGENEITY IN PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: Q. Yan, R. Li, L. Lu
Journal: Annals of the Rheumatic Diseases (2020)

Background: Fibroblast heterogeneity and homeostasis has long been recognized in patients with systemic sclerosis (SSc). However, there is no common consensus on fibroblast subtypes, lineages, biological properties, signaling, and plasticity, which severely hampers our understanding of SSc pathogenesis. Objectives: This study is aimed to comprehensively classify skin fibroblast populations from SSc patients. Methods: We applied single-cell RNA sequencing on skin fibroblasts from two SSc patients and two health control (HC) with matched age and sex. Cell clustering were mainly determined by UMAP with batch effect correction. Differently expressed genes in each cell cluster was analyzed by Gene Set Enrichment Analysis (GSEA). Results: With an unbiased approach, single-cell transcriptome analyses showed classified and defined eight fibroblast types in SSc skin and six in normal skin. The cell types seldom overlapped between the patients and HC. Extracellular interaction and collagen production were remarkably stronger in SSc fibroblasts. A subgroup of dramatic cell proliferation and activation was defined only in SSc fibroblast. Two subtypes responding inflammatory stimuli were only found in SSc patients. Furthermore, delineation of their differentiation trajectory was achieved by a machine learning method. Conclusion: This collection of single-cell transcriptomes and the distinct classification of fibroblast subsets provide a new resource for understanding the fibroblast landscape and the roles of fibroblasts in SSc. References: N/A Disclosure of Interests: None declared
COVID-19 Monitoring and Response Among U.S. Air Force Basic Military Trainees — Texas, March–April 2020
Authors: Joseph E. Marcus, Dianne N. Frankel, Mary T. Pawlak, Theresa M. Casey, Rebecca S. Blackwell, Francis V. Tran, Mathew J. Dolan, Heather C. Yun
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial morbidity and mortality since it was first described in December 2019 (1). Based on epidemiologic data showing spread in congregate settings (2-4), national, state, and local governments instituted significant restrictions on large gatherings to prevent transmission of disease in early March 2020. This and other nonpharmaceutical interventions (NPIs) have shown initial success in slowing the pandemic across the country (5). This report examines the first 7 weeks (March 1-April 18) of implementation of NPIs in Basic Military Training (BMT) at a U.S. Air Force base. In a population of 10,579 trainees, COVID-19 incidence was limited to five cases (47 per 100,000 persons), three of which were in persons who were contacts of the first patient. Transmission of symptomatic COVID-19 was successfully limited using strategies of quarantine, social distancing, early screening of trainees, rapid isolation of persons with suspected cases, and monitored reentry into training for trainees with positive test results after resolution of symptoms.
Type 1 Diabetes and COVID-19: Preliminary Findings From a Multicenter Surveillance Study in the U.S.
Authors: Osagie A. Ebekozien, Nudrat Noor, Mary Pat Gallagher, G. Todd Alonso
Journal: Diabetes Care (2020)

The Centers for Disease Control and Prevention states that individuals with diabetes are at higher risk for severe illness with coronavirus disease 2019 (COVID-19) and poorer health outcomes (1). Research suggests the underlying reason for an increased risk of COVID-19 complications in individuals with diabetes may be poor glycemic control or hyperglycemia (2). Information on clinical outcomes for patients with type 1 diabetes who have confirmed cases of COVID-19 is limited. To our knowledge, this is the first U.S.-based multicenter study that addresses these questions in a population with type 1 diabetes.

This study aimed to examine patient characteristics and adverse outcomes among patients with type 1 diabetes with confirmed COVID-19. As a secondary objective, we investigated patient attributes and clinical outcomes in people with COVID-19–like symptoms for whom testing was unavailable or results were pending.

The T1D Exchange Quality Improvement Collaborative (T1DX-QI) (3) is conducting this study in collaboration with an additional 49 endocrinology clinics (a total of 64 U.S. sites). The study was approved as exempt by a central review …
FRI0182 RISK FACTORS ASSOCIATED WITH RENAL INVOLVEMENT IN PRIMARY SJÖGREN’S SYNDROME: DATA FROM THE SPANISH SJÖGRENSER COHORT
Authors: J. Narváez, C. Sánchez-Piedra, M. Fernandez Castro, V. Martinez Taboada, A. Olive, J. Rosas, A. García-Vadillo, E. Judez, E. Ruiz Lucea, L. Romani, J. L. Andreu
Journal: Annals of the Rheumatic Diseases (2020)

Objectives: To investigate the prevalence, risk factors, and effects of primary renal disease on morbidity and mortality in patients with primary Sjögren’s syndrome (pSS). Methods: All patients in the SJÖGRENSER (registry of adult SSp patients of the Spanish Society of Rheumatology, cross-sectional phase) cohort were retrospectively investigated for the presence of clinically significant renal involvement directly related to pSS activity. Results: Of the 437 patients investigated, 39 (9%) presented overt renal involvement during follow-up. Severe renal disease necessitating kidney biopsy was relatively rare (23%). Renal involvement may complicate pSS at any time during the disease course and is associated with severe disease (indicated by higher scores of involvement, activity, and damage), systemic multiorgan involvement, and a higher frequency of lymphoma. Multivariate analysis showed that older age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.07), higher European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index scores (OR 1.1, CI 1.03–1.18), serum anti-La/SSB positivity (OR 6.44, CI 1.36–30.37), and non-vasculitic cutaneous involvement (OR 8.64, 1.33–55.90) were independently associated with this complication. Chronic renal failure developed in 23 of 39 patients (59%); only 1 of them progressed to end-stage renal disease necessitating renal replacement therapy. Patients with renal disease showed higher Sjögren’s syndrome disease damage index scores (SSDDI), higher rates of hospitalization due to disease activity and higher rates of clinically relevant comorbidities. Conclusion: Renal involvement is an uncommon complication in pSS that was observed in 9% of patients. Although categorized as a non-negligible comorbidity, this condition shows a favorable prognosis. Disclosure of Interests: None declared
Changes in Aged Fibroblast Lipid Metabolism Induce Age-Dependent Melanoma Cell Resistance to Targeted Therapy via the Fatty Acid Transporter FATP2
Authors: Gretchen M. Alicea, Vito W. Rebecca, Aaron R. Goldman, Mitchell E. Fane, Stephen M. Douglass, Reeti Behera, Marie R. Webster, Curtis H. Kugel, Brett L. Ecker, M. Cecilia Caino, Andrew V. Kossenkov, Hsin-Yao Tang, Dennie T. Frederick, Keith T. Flaherty, Xiaowei Xu, Qin Liu, Dmitry I. Gabrilovich, Meenhard Herlyn, Ian A. Blair, Zachary T. Schug, David W. Speicher, Ashani T. Weeraratna
Journal: Cancer Discovery (2020)

Older patients with melanoma (&amp;gt;50 years old) have poorer prognoses and response rates to targeted therapy compared with young patients (&amp;lt;50 years old), which can be driven, in part, by the aged microenvironment. Here, we show that aged dermal fibroblasts increase the secretion of neutral lipids, especially ceramides. When melanoma cells are exposed to the aged fibroblast lipid secretome, or cocultured with aged fibroblasts, they increase the uptake of lipids via the fatty acid transporter FATP2, which is upregulated in melanoma cells in the aged microenvironment and known to play roles in lipid synthesis and accumulation. We show that blocking FATP2 in melanoma cells in an aged microenvironment inhibits their accumulation of lipids and disrupts their mitochondrial metabolism. Inhibiting FATP2 overcomes age-related resistance to BRAF/MEK inhibition in animal models, ablates tumor relapse, and significantly extends survival time in older animals. Significance: These data show that melanoma cells take up lipids from aged fibroblasts, via FATP2, and use them to resist targeted therapy. The response to targeted therapy is altered in aged individuals because of the influences of the aged microenvironment, and these data suggest FATP2 as a target to overcome resistance. See related commentary by Montal and White, p. 1255.. This article is highlighted in the In This Issue feature, p. 1241
Clonally Related Viable Nontuberculous Mycobacteria in Gastric Juice and Sputum in People with Cystic Fibrosis
Authors: Chris Ward, Hafez Al Momani, Audrey Perry, John D. Perry, Amaran Krishnan, Rhys Jones, Mike Griffin, Jeff Pearson, Stephen Bourke
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
AB1134 ULTRASOUND FINDINGS IN HAND JOINTS INVOLVEMENT: A COMPARATIVE STUDY BETWEEN PSORIATIC AND RHEUMATOID ARTHRITIS
Authors: A. R. Ahmed, S. Tharwat, A. M. Abd el-Khalek, E. E. Eltoraby
Journal: Annals of the Rheumatic Diseases (2020)

Background: Psoriasis is a common skin disease that is associated with multiple conditions. The most prevalent coexisting condition is psoriatic arthritis (PsA) which develops in up to 30% of patients with psoriasis and characterized by diverse clinical features often resulting in delayed diagnosis and treatment. [1] Objectives: The aim of this study was to investigate the potential of ultrasound (US) in the differential diagnosis between rheumatoid arthritis (RA) and PsA at the level of small joints of the hand and wrist. Methods: Fifteen patients with PsA of the hands and wrists and 20 age and sex-matched RA patients were examined with musculoskeletal US. Radiocarpal, midcarpal, distal radioulnar, metacarpophalangeal (MCP), proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints and flexor and extensor tendons (in wrist and hand) were examined bilaterally. Synovitis, erosions and tenosynovitis were scored according to semiquantitative method.[2] Results: Among 510 and 680 joints examined in PsA and RA respectively, certain US features such as synovitis and erosions at the DIP were exclusively detected in PsA (p&lt;0.001). Synovitis was frequently present at the radioulnar joints in RA in comparison to PsA patients (52.5% vs 26.7% respectively, p=0.029). Joint effusion was frequently detected at radiocarpal and midcarpal joints in RA in comparison to PsA (p=0.047, 0.039 respectively). Effusion at the 3 rd PIP joints was more significantly present in PSA than RA (p=0.037),while erosions were significantly detected at radiocarpal joints in RA in comparison to PsA patients (45%vs 20%respectively,p=0.029).Tenosynovitis was significantly detected at the extensor tendons in RA and at the flexor tendons in PsA patients (p=0.021, 0.022 respectively). Conclusion: There are significant differences in the US findings of the hand and wrist that can help to distinguish between RA and PsA References: [1]Ritchlin, C.T., R.A. Colbert, and D.D. Gladman, Psoriatic arthritis. New England Journal of Medicine, 2017. 376 (10): p. 957-970. [2]Szkudlarek, M., et al., Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis. Arthritis &amp; Rheumatism: Official Journal of the American College of Rheumatology, 2003. 48 (4): p. 955-962. Figure 1 Sixty year old male patient with RA for 5 years,presented with pain and swelling at the wrist.Gray scale ultrasound sagittal view shows sever synovial proliferation at the radiocarpal joint Acknowledgments: Not applicable Disclosure of Interests: None declared
AB0687 THE PROBABILITY OF SPONDYLОARTHRITIS IN PATIENTS WITH UVEITIS
Authors: A. Godzenko, I. Razumova, I. Guseva
Journal: Annals of the Rheumatic Diseases (2020)

Background: Uveitis is a heterogeneous group of inflammatory eye diseases, some of which may be associated with spondyloarthritis (SpA). The probability of SpA depends on the clinical features of uveitis. Objectives: To evaluate the probability of SpA depending on the clinical features of uveitis. Methods: 208 patients with uveitis referred from ophthalmologists were assessed at the Institute of Rheumathology. 139 of 208 pts had an acute recurrent course of uveitis, 69-chronic course; 149 of 208 had isolated anterior uveitis, 59 – panuveitis involving the posterior and/or intermediate part of the eye; 160 had unilateral uveitis, 48 – bilateral; 106 had HLA- В27, 102 - without HLA-В27. In addition to HLA- В27, a survey was performed to identify clinical and imaging signs of SpA, including radiography and MRI of sacroiliac joints. In 60 cases (28.8%), various SpA were identified (20 –ankylosing spondylitis, 2- reactive arthritis, 38 – non-radiographic SpA). In 148 pts SpA was not confirmed (4 of them had Behcet ’ s disease, 2-sarcoidosis, 4-toxoplasmosis, 29 - viral uveitis, 1 - Fux syndrome, 2 – Vogt-Koyanagi- Harada syndrome, 2 - multiple sclerosis, 104 – unspecified uveitis). Sensitivity (Se) and specificity (Sp), relative risk (RR), 95% confidence interval (CI), and likelihood ratio (LR) were calculated for each clinical parameter of uveitis with the following assessment of the probability of SpA. Results: Pretest probability of SpA in the group was 28.8%, that corresponds to pretest odds of 0.4. Among 139 pts with acute recurrent uveitis SpA was identified in 45 (32.3%), among 69 with chronic uveitis – in 15 (21.7%), RR-1.49, 95% CI [0.896, 2.475], LR-1.17. Among 149 pts with isolated anterior uveitis SpA was in 55(36.9%), among 59 with panuveitis – in 5(8.5%), RR=4.36, 95% CI [1.8, 10.3], LR-1.43. In a subgroup of 160 pts with unilateral uveitis SpA diagnosed in 51 (31.9%), in a subgroup of 48 with bilateral uveitis – in 9 (18.7%), RR = 1.7, 95% CI [0.9, 3.1], LR-1.14. Among 160 HLA-B27-positive pts SpA detected in 56 (52%), among 102 HLA-B27- negative – in 4 (3.9%), RR=13.4, 95% CI [5.1, 35.8], LR-2.7. Taking into account the pretest odds and likelihood ratio of all parameters, posttest odds was 2.7, that corresponds to posttest probability of 67%. Conclusion: A combination of such signs of uveitis as isolated localization in the anterior part of the eye, acute recurrent course, unilateral inflammation, HLA-B27, increases the probability of SpA more than 2 times References: [1]Sykes M, Hamilton L, Jones C. et al. Prevalence of axial spondyloarthritis in patients with acute anterior uveitis: a cross-sectional study utilising MRIRMD Open. 2018 Feb 24;4(1):e000553. doi: 10.1136/rmdopen-2017-000553. eCollection 2018. [2]Bubová K., Gregová M., Zegzulková K. et al. Active sacroiliitis on magnetic resonance imaging in patients with anterior uveitis. Ann Rheum Dis. 2019; 78(2): A470. https://doi 10.1136/annrheumadis-2019-eular7439 . Disclosure of Interests: None declared