tbuckley/cabot-search huggingface dataset:
The Mystery of Rap1 Suppression of Oncogenic Ras
Authors: Ruth Nussinov, Hyunbum Jang, Mingzhen Zhang, Chung-Jung Tsai, Anna A. Sablina
Journal: Trends in cancer (2020)

Rap1, a small GTPase very similar to Ras, suppresses oncogenic Ras phenotype; albeit not completely. The initial hypothesis was that Ras and Rap1 compete for a common target, but none has been found.One reported function of Rap1 is to modulate the activity of Raf kinases, thus MAPK signaling. Based on published observations, we propose that Rap1 suppresses MAPK signaling via Raf-1 but not via BRAF. We suggest that Rap1 high-affinity binding to Raf-1's cysteine-rich domain (CRD) disfavors Rap1 interaction with Raf-1's Ras-binding domain (RBD). BRAF's CRD has lower affinity to Rap1; its RBD can bind to Rap1.The presence of active Rap1 in oncogenic Ras nanoclusters reduces (dilutes) the number of the oncogenic Ras molecules in the cluster, thus suppressing Ras activation of Raf-1 but not of BRAF.We suggest that Rap1 suppression of Ras is likely to be Ras and Rap1 isoform specific. Decades ago, Rap1, a small GTPase very similar to Ras, was observed to suppress oncogenic Ras phenotype, reverting its transformation. The proposed reason, persisting since, has been competition between Ras and Rap1 for a common target. Yet, none was found. There was also Rap1's puzzling suppression of Raf-1 versus activation of BRAF. Reemerging interest in Rap1 envisages capturing its Ras suppression action by inhibitors. Here, we review the literature and resolve the enigma. In vivo oncogenic Ras exists in isoform-distinct nanoclusters. The presence of Rap1 within the nanoclusters reduces the number of the clustered oncogenic Ras molecules, thus suppressing Raf-1 activation and mitogen-activated protein kinase (MAPK) signaling. Nanoclustering suggests that Rap1 suppression is Ras isoform dependent. Altogether, a potent Rap1-like inhibitor appears unlikely. Decades ago, Rap1, a small GTPase very similar to Ras, was observed to suppress oncogenic Ras phenotype, reverting its transformation. The proposed reason, persisting since, has been competition between Ras and Rap1 for a common target. Yet, none was found. There was also Rap1's puzzling suppression of Raf-1 versus activation of BRAF. Reemerging interest in Rap1 envisages capturing its Ras suppression action by inhibitors. Here, we review the literature and resolve the enigma. In vivo oncogenic Ras exists in isoform-distinct nanoclusters. The presence of Rap1 within the nanoclusters reduces the number of the clustered oncogenic Ras molecules, thus suppressing Raf-1 activation and mitogen-activated protein kinase (MAPK) signaling. Nanoclustering suggests that Rap1 suppression is Ras isoform dependent. Altogether, a potent Rap1-like inhibitor appears unlikely.
Abstract P448: Neighborhood Built Environment is Associated With Odds of Chronic Disease Death Among Participants in the Bogalusa Heart Study
Authors: Christopher E Anderson, Lydia A Bazzano, Stephanie Broyles, Maeve E Wallace, Queendaleen Chukwurah, Jeanette Gustat
Journal: Circulation (2020)

Relationships of the built environment (BE) with physical activity (PA) and health outcomes have been reported, though data is limited in rural settings. This study was conducted to assess relationships between BE around the residence and death from chronic disease in rural residents. We hypothesized that BE more conducive to PA would be associated with lower odds of chronic disease death. Participants in the Bogalusa Heart Study, a long-running cohort study in rural Louisiana, with a valid address of residence and either deceased of a chronic disease (cases) or observed (controls) since 1998 were included (N=2,052). Cases were identified in the National Death Index (N=111). BE features on the street segment of residence were assessed with the Rural Active Living Assessment tool and Google Street View. Scores for walkability, overall and in domains (including path features, aesthetics, land use), were calculated for street segments and in buffers of 0.25, 0.50, 1.00 and 1.50 miles. Associations of BE scores with chronic disease death were assessed with generalized estimating equations logistic regression models that accommodated clustering in street segments and census tracts, and were adjusted for age, sex, race, census tract population density and percent living in poverty. Cases were of similar age (45 at death vs 44 at last visit), more likely to be male (59 vs 43%) and less likely to be white (52 vs 66%) than controls. Significant associations were observed between scores for path features, aesthetics and land use and odds of chronic disease death in buffers of 0.25, 0.50, 1.00 and 1.50 miles. In 0.25 mile buffers, 1-point higher scores for path features, aesthetics and land use were associated with 1.12 (95% CI 1.02, 1.23), 0.66 (95% CI 0.53, 0.82) and 0.49 (95% CI 0.32,0.76) times the odds of chronic disease death, respectively. Significant associations highlight the importance of land use development conducive to PA (i.e. higher density and better condition residential settlement) and improved community aesthetics (i.e. greenspace presence and maintenance) to improved health in rural populations. More research is needed to identify a mechanism for the unexpected association between path features (i.e. presence of a path) and increased odds of chronic disease death. Rural BE improvements face barriers (lower population density), and these reported associations may guide feasible approaches to improved rural health.
Abstract P513: Alcohol Type and Ideal Cardiovascular Health in The Multi-Ethnic Study of Atherosclerosis
Authors: Oluseye Ogunmoroti, Olatokunbo Osibogun, Robyn L McClelland, Mariana Lazo, Lena Mathews, Victor Okunrintemi, Ebenezer Oni, Gregory L Burke, Erin D Michos
Journal: Circulation (2020)

Background: Light to moderate alcohol consumption is associated with lower incidence of cardiovascular disease (CVD) and favorable cardiovascular health (CVH). However, the association between alcohol type and ideal CVH is yet to be established. This study examined the relationship between alcohol type and ideal CVH as measured by the American Heart Association Life’s Simple 7 (LS7) metrics. Methods: We analyzed data from 6,389 men and women aged 45-84 years from a multi-ethnic cohort free of CVD at baseline. Alcohol type (wine, beer and liquor), assessed from a food frequency questionnaire, was categorized as never, &gt;0 but &lt;1 drink/day, 1-2 drinks/day and &gt;2 drinks/day. Each LS7 metric (smoking, physical activity, body mass index, diet, blood pressure, total cholesterol and blood glucose) was scored 0-2 points, with 2 indicating “ideal”, 1 “intermediate” and 0 “poor”. The maximum CVH score attainable ranged from 0-14 points (inadequate score, 0-8; average, 9-10; optimal, 11-14). We used multinomial logistic regression to examine the association between alcohol type and CVH adjusted for age, sex, race/ethnicity, education, income, health insurance and study site. Results: The mean (SD) age of study participants was 62 (10) years and 53% were women. Participants who consumed 1-2 drinks/day of wine had higher odds of having optimal CVH scores compared to those who never drank wine [prevalence odds ratio (POR) 1.50 (1.02-2.20), Table ]. In comparison to participants who never drank beer, those who consumed 1-2 and &gt;2 drinks/day of beer had lower odds of having optimal scores [POR 0.49 (0.27-0.86) &amp; 0.27 (0.12-0.58), respectively]. Additionally, those who consumed 1-2 and &gt;2 drinks/day of liquor had lower odds of having optimal scores compared to those who never drank liquor [POR 0.52 (0.30-0.89) &amp; 0.28 (0.14-0.55), respectively]. Conclusion: In this cross sectional analysis, moderate consumption of wine was associated with favorable CVH. However, consumption of beer or liquor was associated with poorer CVH.
Self‐Propelled PLGA Micromotor with Chemotactic Response to Inflammation
Authors: Jiamian Wang, B. Jelle Toebes, Adelina S. Plachokova, Qian Liu, Dongmei Deng, John A. Jansen, Fang Yang, Daniela A. Wilson
Journal: Advanced Healthcare Materials (2020)

Abstract Local drug delivery systems have recently been developed for multiple diseases that have the requirements of site‐specific actions, prolonged delivery periods, and decreased drug dosage to reduce undesirable side effects. The challenge for such systems is to achieve directional and precise delivery in inaccessible narrow lesions, such as periodontal pockets or root canals in deeper portions of the dentinal tubules. The primary strategy to tackle this challenge is fabricating a smart tracking delivery system. Here, drug‐loaded biodegradable micromotors showing self‐propelled directional movement along a hydrogen peroxide concentration gradient produced by phorbol esters‐stimulated macrophages are reported. The drug‐loaded poly(lactic‐co‐glycolic acid) micromotors with asymmetric coverage of enzyme (patch‐like enzyme distribution) are prepared by electrospraying and postfunctionalized with catalase via 1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide coupling. Doxycycline, a common drug for the treatment of periodontal disease, is selected as a model drug, and the release study by high‐performance liquid chromatography is shown that both the postfunctionalization step and the presence of hydrogen peroxide have no negative influence on drug release profiles. The movement behavior in the presence of hydrogen peroxide is confirmed by nanoparticle tracking analysis. An in vitro model is designed and confirmed the response efficiency and directional control of the micromotors toward phorbol esters‐stimulated macrophages.
The Number of Discarded Kidneys Is Likely Much Larger Than Reported
Authors: Ryan A. Denu, Norman Fost
Journal: JAMA Internal Medicine (2020)

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Demonstration of the efficacy of compound CFAK-C4 targeting FAK-VEGFR3 protein-protein interaction in gastric cancer.
Authors: Elena V. Kurenova, Sartaj Singh Sanghera, Jianqun Liao, Michael Yemma, William G. Cance
Journal: Journal of Clinical Oncology (2013)

e22143 Background: While the emerging data strongly suggest that FAK is an excellent target for developmental therapeutics of cancer, kinase inhibitors of FAK have shown crossreactivity with other protein kinases and toxicity in preclinical and clinical studies. It is known that FAK acts pleiotropically, as a kinase and as a scaffolding protein, and our goal is to explore targeting the scaffolding function of FAK to inhibit protein-protein interactions important for tumor progression. Previously, we have shown that FAK physically interacts with VEGFR3 and we identified small molecule inhibitor CFAK-C4 that targets this site of interaction. Both of these kinases are overexpressed in gastric cancers and were found to be independent poor prognostic factors. The prognosis of patients with gastric cancer remains unfavorable and molecular based treatments are necessary for a potential breakthrough in the therapy of this disease. We hypothesize that FAK-VEGFR3 interaction provides essential survival signals for gastric tumor growth and that simultaneous inhibition of these signals will inhibit tumor progression. Methods: Effects of CFAK-C4 on gastric cancer cell lines AGS and NCI-N87 were examined by MTT assay (viability), colony formation assay and Western blotting (phosphorylation, apoptosis). Subcutaneous mouse model was used to demonstrate effect of CFAK-C4 in vivo. Results: CFAK-C4 specifically blocked phosphorylation of VEGFR3 and FAK, directly inhibited cell viability (p&lt;0.05), increased cell detachment and inhibited colony formation in a dose-dependent manner (range 1-100µM). CFAK-C4 (50mg/kg, IP) effectively caused tumor regression in vivo, when administered alone and its effects were synergistic (p&lt;0.05) with chemotherapy. In vivo effects of C4 were confirmed by a decrease in tumor FAK and VEGFR3 phosphorylation, and disruption of their complexes. Conclusions: In this study we have shown that CFAK-C4 inhibits FAK-VEGFR3 signaling in gastric cancer cells and affects tumor growth. This result demonstrates that targeting the scaffolding function of FAK is a unique approach of highly-specific molecular-targeted therapy and can be used to develop oral-based cancer therapeutics.
Stimuli‐Responsive Delivery of Growth Factors for Tissue Engineering
Authors: Moyuan Qu, Xing Jiang, Xingwu Zhou, Canran Wang, Qingzhi Wu, Li Ren, Jixiang Zhu, Songsong Zhu, Peyton Tebon, Wujin Sun, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2020)

Growth factors (GFs) play a crucial role in directing stem cell behavior and transmitting information between different cell populations for tissue regeneration. However, their utility as therapeutics is limited by their short half-life within the physiological microenvironment and significant side effects caused by off-target effects or improper dosage. "Smart" materials that can not only sustain therapeutic delivery over a treatment period but also facilitate on-demand release upon activation are attracting significant interest in the field of GF delivery for tissue engineering. Three properties are essential in engineering these "smart" materials: 1) the cargo vehicle protects the encapsulated therapeutic; 2) release is targeted to the site of injury; 3) cargo release can be modulated by disease-specific stimuli. The aim of this review is to summarize the current research on stimuli-responsive materials as intelligent vehicles for controlled GF delivery; Five main subfields of tissue engineering are discussed: skin, bone and cartilage, muscle, blood vessel, and nerve. Challenges in achieving such "smart" materials and perspectives on future applications of stimuli-responsive GF delivery for tissue regeneration are also discussed.
Evidence for a ‘window of opportunity’ in hidradenitis suppurativa treated with adalimumab: a retrospective, real‐life multicentre cohort study*
Authors: A.V. Marzano, G. Genovese, G. Casazza, C. Moltrasio, P. Dapavo, G. Micali, R. Sirna, P. Gisondi, A. Patrizi, V. Dini, D. Bianchini, L. Bianchi, L. Fania, F. Prignano, A. Offidani, L. Atzori, V. Bettoli, S.P. Cannavò, M. Venturini, M. R. Bongiorno, A. Costanzo, G. Fabbrocini, K. Peris
Journal: British Journal of Dermatology (2020)

The anti-tumour necrosis factor (TNF)-α adalimumab is the only licenced biologic for moderate-to-severe hidradenitis suppurativa (HS). No predictors of response have been identified so far.To identify clinical parameters predicting response to adalimumab and confirm its efficacy/safety.The data of 389 patients with HS treated with adalimumab in 21 Italian centres were reviewed. Sex, age at onset/diagnosis/baseline, body mass index, smoking, phenotype, previous treatments, concomitant antibiotics and 'therapeutic delay', defined as the time from HS onset to adalimumab initiation, were assessed. Response to adalimumab and its impact on quality of life (QoL) were evaluated using the Hidradenitis Suppurativa Clinical Response (HiSCR) and the Dermatology Life Quality Index (DLQI) or the Visual Analogue Scale for pain (VAS pain), respectively. Logistic regression analysis was performed.The therapeutic delay correlated to lack of response to adalimumab at week 16 [odds ratio (OR) 1·92 for therapeutic delay > 10 years; 95% confidence interval (CI) 1·28-2·89; P = 0·0016). HiSCR was achieved in 43·7% and 53·9% patients at week 16 and 52, respectively. Significant reductions in both DLQI and VAS pain were found between week 16 vs. baseline (P < 0·0001 for both) and week 52 vs. baseline (P < 0·0001 for both). Previous immunosuppressants inversely correlated to HiSCR at week 52 (OR = 1·74, 95% CI 1·04-2·91, P = 0·0342).Inverse correlation between therapeutic delay and clinical response was found, supporting early adalimumab use and providing evidence for a 'window of opportunity' in HS treatment. Adalimumab efficacy and safety were confirmed, along with patients' QoL improvement. Immunosuppressants could negatively influence the response to adalimumab inducing a switch to non-TNF-α-driven pathways.
The effectiveness of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in relation to renal function
Authors: T. ten Doesschate, E. van Haren, R.A. Wijma, B.C.P. Koch, M.J.M. Bonten, C.H. van Werkhoven
Journal: Clinical Microbiology and Infection (2020)

ObjectivesWe evaluated the effect of renal function on clinical failure rates of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in primary care.MethodsData were retrospectively obtained from 78 Dutch general practitioner (GP) practices between 2013 and 2019. Eligible episodes in patients (>11 years) were those requiring 5 days of nitrofurantoin (NF5), single-dose fosfomycin–trometamol (FT1), 3 days of trimethoprim (TMP3) for uncomplicated cystitis, or 7 days of nitrofurantoin (NF7) or trimethoprim (TMP7) for complicated cystitis. Clinical failure was defined as second antibiotic prescription for cystitis or pyelonephritis within 28 days post-prescription. Mixed effects regression analysis was used, with patient and GP practice as random effects and demography, comorbidity, and cystitis history as fixed effects.ResultsAdjusted odds ratios (aORs) for clinical failure per 10mL/min decrease in estimated glomerular filtration rate (eGFR) were 1.05 (95% CI: 1.01–1.09) for NF5 (n = 24,591), 0.96 (95% CI: 0.92–1.01) for FT1 (n = 5359), 0.98 (95% CI: 0.89–1.08) for TMP3 (n = 1064), 1.05 (95% CI: 1.02–1.09) for NF7 (n = 10,628) and 1.02 (95% CI: 0.93–1.14) for TMP7 (n = 831). In uncomplicated cystitis and eGFR ≥60 mL/min, clinical failures occurred in 14.6% (1895/12 980) of NF5-treated, 20.7% (266/1283) of FT1-treated (aOR versus NF5 1.37, 95% CI 1.18–1.59) and 20.8% (66/318) of TMP3-treated patients (aOR 1.42, 95% CI 1.07–1.87 versus NF5). In uncomplicated cystitis and eGFR <60 mL/min, FT1 resulted in 16.0% (39/244) and NF5 in 23.3% clinical failures (110/472), aOR: 0.61, 95% CI: 0.39–0.95).ConclusionsIn eGFR ≥60 mL/min treatment with fosfomycin or trimethoprim for uncomplicated cystitis was associated with more clinical failure than treatment with nitrofurantoin, while in eGFR <60 mL/min nitrofurantoin was associated with more clinical failure than fosfomycin–trometamol. Renal function, if known, should be considered in the clinical decision-making for cystitis treatment.
Abstract P279: Prevalence and Independent Metabolic Factors of Non-alcoholic Fatty Liver Disease in Acute Stroke Patients Aged 40-79 Years
Authors: Takahisa Mori, Kazuhiro Yoshioka
Journal: Circulation (2020)

Introduction: Non-alcoholic fatty liver disease (NAFLD) is reported to be a predictor of cardiovascular disease (CD). NAFLD is probably associated with stroke in middle and old-aged patients. Hypothesis: In acute stroke patients aged 40-79 years, prevalence of NAFLD on admission is high and its metabolic factors are body mass index (BMI), triglycerides (TG), some fatty acids, blood sugar or HbA1c and aspartate aminotransferase / alanine aminotransferase ratio (AST/ALT ratio) as well as reported in ischemic heart disease. Methods: We included acute stroke patients aged 40-79 years who 1) were admitted from August 2016 to July 2019 within 24 hours of onset, 2) underwent abdominal ultrasonography and 3) took blood examination of serum fatty acids on admission. We evaluated prevalence and associated metabolic factors of non-alcoholic fatty liver disease. Results: Among 1672 acute stroke patients, 676 patients met our inclusive criteria. Their median age was 70 years, 267 patients (39.5%) had NAFLD. In NAFLD and non-NAFLD patients, median age was 68 and 71 years (p&lt;0.0001), BMI was 24.8 and 21.6 kg/m 2 (p&lt;0.0001), Alb was 4.2 and 4.0 g/dl (p&lt;0.0001), HbA1c was 6.0 and 5.8 % (p&lt;0.0001), T-CHO was 206 and 198 mg/dl (p&lt;0.05), TG was 135 and 93 mg/dl (p&lt;0.0001), palmitic acid (PA) was 727 and 627.4 μg/ml (p&lt;0.0001), oleic acid (OA) was 672.6 and 563.1 μg/ml (p&lt;0.0001), linoleic acid (LiA) was 772.3 and 730.2 μg/ml (p&lt;0.05), dihomo-gamma-linolenic acid (DGLA) was 34.1 and 26.5 μg/ml (p&lt;0.0001) and AST/ALT ratio was 1.09 and 1.36 (p&lt;0.0001), respectively. Conclusions: In acute stroke patients aged 40-79 years, prevalence of NAFLD on admission was high and metabolic factors of NAFLD were younger Age, higher BMI, higher serum concentrations of Alb, T-CHO, TG and fatty acids, higher HbA1c and lower AST/ALT ratio.
Abstract MP07: Automated, Personalized Feedback and Behavioral Nudges to Improve Workplace Food Choices and Prevent Weight Gain: Choosewell 365 Randomized Controlled Trial
Authors: Anne N Thorndike, Jessica L McCurley, Emily D Gelsomin, Eric B Rimm, Yuchiao Chang, Bianca Porneala, Emma Anderson, Charles Johnson, Douglas E Levy
Journal: Circulation (2020)

Importance: Workplace health promotion programs often have limited reach and effectiveness because they are time-intensive and not integrated with the work environment. Objective: Conduct a randomized controlled trial testing an automated intervention combined with workplace cafeteria traffic-light labels to prevent weight gain and increase healthy food choices. Methods: 602 hospital employees who regularly used 6 on-site cafeterias and paid with their ID were randomized in 2016-18. Cafeteria labels identified healthy (green), less healthy (yellow), and unhealthy (red) items. Participants completed visits, surveys, and dietary recalls at baseline and 12 months (end of intervention). The intervention group received personalized emails (2/week) and letters (1/month) that were automatically generated by a software platform that integrated cafeteria sales, health, and survey data. Emails included a log of weekly purchases (item, traffic light label, and calories) and health tips. Letters included social norm comparisons and small incentives for healthy purchases. The control group received standard lifestyle advice in monthly letters. A Healthy Purchasing Score was calculated by weighting purchased items by traffic light labels (red=0; yellow=0.5; green=1) using 12 mo of purchases during both baseline (pre-intervention) and intervention. Differences in differences in health outcomes, purchases, and dietary quality were compared, with missing values imputed. Results: Participants were 43.6 years (mean), 79% female, and 81% white. The intervention group increased healthy purchases compared to control, but changes in BMI and health outcomes were not different (see Table). Conclusion: An automated intervention linked to the workplace food environment increased healthy food choices but did not prevent weight gain. To improve health, this scalable healthy eating intervention could be augmented with additional technology to improve other health behaviors, such as physical activity, both at work and home.