tbuckley/cabot-search huggingface dataset:
Abstract 8938: Heightened Renal Sympathetic Nerve Activity in Response to High Salt Intake After Renal Ischemia-Reperfusion Injury: Role Of TRPV1
Authors: Shuang Q Yu, Donna H Wang
Journal: Circulation (2011)

Increased salt sensitivity occurs following ischemia-reperfusion (I/R) injury of the kidney. We test the hypothesis that renal sympathetic nerve activity is increased in response to high salt (HS) intake after I/R of the kidney, which can be prevented by activation of the transient receptor potential vanilloid type 1 (TRPV1) prior to renal I/R. Rats were fed a 0.4 % NaCl diet for 5 wks after I/R, following by a 4 % NaCl diet for 4 more wks in four groups: Sham, I/R, I/R+high dose capsaicin (HDC), and I/R+low dose capsaicin (LDC). TRPV1 was activated or down-regulated by s.c. injection of a low (1 mg/kg) or high (100 mg/kg) dose of capsaicin, respectively, 3 hrs before I/R. Renal TRPV1 protein expression was decreased after I/R and further reduced in I/R+HDC but unchanged in I/R+LDC compared to Sham (Sham: 0.44±0.04 vs I/R: 0.26±0.02 vs I/R+HDC: 0.17±0.01 vs I/R+LDC: 0.38±0.05, p&lt;0.05). Systolic blood pressure and renal excretory function were not different among four groups 5 wks after I/R, but gradually elevated or deteriorated, respectively, when switched to HS for the remaining 4 wks in I/R and I/R+HDC but not I/R+LDC, with greater intensity in I/R+HDC ( p&lt;0.05). At the end of HS treatment, afferent renal nerve activity in response to unilateral intra-pelvis administration of capsaicin was decreased in I/R and further suppressed in I/R+HDC but unchanged in I/R+LDC (Sham: 123±7 vs I/R: 81±9 vs I/R+HDC: 37±6 vs I/R+LDC: 120±13%, p&lt;0.05). Efferent renal nerve activity in response to intrathecal administration of muscimol (3 nmol/kg), a selective activator of GABA-A receptors, was decreased in I/R and further suppressed in I/R+HDC but unchanged in I/R+LDC (Sham: -21±1 vs I/R: -42±3 vs I/R+HDC: -53±2 vs I/R+LDC: -25±4%, p&lt;0.05). Urinary norepinephrine levels were increased in I/R and further elevated in I/R+HDC but unchanged in I/R+LDC (Sham: 785±98 vs I/R: 1311±98 vs I/R+HDC: 1731±140 vs I/R+LDC: 1018±85 ng/day, p&lt;0.05). These data show that renal sympathetic drive is increased in response to HS intake after I/R, which can be prevented by TRPV1 activation prior to renal I/R, indicating that TRPV1 may prevent increased salt sensitivity after I/R via suppression of heightened renal sympathetic nerve activity.
Modified Glasgow Prognostic Score associated with survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors
Authors: Jacqueline T Brown, Yuan Liu, Julie M Shabto, Dylan Martini, Deepak Ravindranathan, Emilie Elise Hitron, Greta Anne Russler, Sarah Caulfield, Lauren Yantorni, Shreyas Subhash Joshi, Haydn Kissick, Kenneth Ogan, Bassel Nazha, Bradley C Carthon, Omer Kucuk, Wayne B Harris, Viraj A Master, Mehmet Asim Bilen
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI. Methods We retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP&gt;10 mg/L and/or albumin&lt;3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis. Results 156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, p&lt;0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p&lt;0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno’s c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533). Conclusion The mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.
Effects of Patient-Initiated Visits on Patient Satisfaction and Clinical Outcomes in a Type 1 Diabetes Outpatient Clinic: A 2-Year Randomized Controlled Study
Authors: Nina Drøjdahl Ryg, Jeppe Gram, Maryam Haghighi, Claus Bogh Juhl
Journal: Diabetes Care (2021)

OBJECTIVE We investigated the effects of replacing regular outpatient follow-up through prescheduled visits with patient-initiated visits on patient satisfaction and clinical variables of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS A 24-month randomized controlled trial in which adults with T1D were allocated to either patient-initiated unlimited access to outpatient visits or usual care through regular prescheduled visits. The primary outcome was seven patient-reported experience measures of patient satisfaction focused on benefit of consultation and accessibility of the outpatient clinic. Secondary outcomes included clinical variables of diabetes and use of staff resources. RESULTS We enrolled 357 outpatients (intervention, n = 178; control, n = 179). After 24 months, participants in the intervention group experienced more benefit from consultations compared with baseline within groups (P &amp;lt; 0.05) and fewer unnecessary visits compared with control subjects (P &amp;lt; 0.05). Patient needs covered and satisfaction with the outpatient clinic were high and unchanged in both groups, and accessibility was increased (three questions, all P &amp;lt; 0.05). A calculated 7-item patient satisfaction sum score favored the intervention group over control subjects (P &amp;lt; 0.001). There were no significant changes in glycated hemoglobin (HbA1c), LDL, blood pressure, and complication status. The mean number of outpatient visits over 24 months (± SD) was lower in the intervention group compared with control subjects (4.4 ± 2.8 vs. 6.3 ± 2.7; P &amp;lt; 0.001), while the number of telephone contacts was higher (3.1 ±3.4 vs. 2.5 ± 3.2; P &amp;lt; 0.001). CONCLUSIONS Patient satisfaction remained high or improved with patient-initiated on-demand use of the diabetes outpatient clinic, with no decline in the quality of diabetes care, and a reduction in the use of staff resources.
US opioids: Johnson and Johnson and drug distributors offer $26bn to end thousands of lawsuits
Authors: Owen Dyer
Journal: BMJ (2021)

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Response to Comment on Albogami et al. Glucagon-Like Peptide-1 Receptor Agonists and Chronic Lower Respiratory Disease Exacerbations Among Patients With Type 2 Diabetes. Diabetes Care 2021;44:1344–1352
Authors: Yasser Albogami, Kenneth Cusi, Michael J Daniels, Yu-Jung J. Wei, Almut G. Winterstein
Journal: Diabetes Care (2021)

We welcome Drs. Foer and Cahill sharing their recent findings (1,2) on the association of glucagon-like peptide 1 receptor agonists with fewer respiratory disease exacerbations and providing their perspective on our study (3).

One of the main challenges researchers encounter when conducting comparative effectiveness studies of glucose-lowering agents is selecting the most appropriate comparator (4 …
Emerging Technologies for In Vitro Inhalation Toxicology
Authors: Ajay Vikram Singh, Anthony Romeo, Kassandra Scott, Sandra Wagener, Lars Leibrock, Peter Laux, Andreas Luch, Pranali Kerkar, Shidin Balakrishnan, Sarada Prasad Dakua, Byung‐Wook Park
Journal: Advanced Healthcare Materials (2021)

Abstract Respiratory toxicology remains a major research area in the 21st century since current scenario of airborne viral infection transmission and pollutant inhalation is expected to raise the annual morbidity beyond 2 million. Clinical and epidemiological research connecting human exposure to air contaminants to understand adverse pulmonary health outcomes is, therefore, an immediate subject of human health assessment. Important observations in defining systemic effects of environmental contaminants on inhalation metabolic dysfunction, liver health, and gastrointestinal tract have been well explored with in vivo models. In this review, a framework is provided, a paradigm is established about inhalation toxicity testing in vitro, and a brief overview of breathing Lungs‐on‐Chip (LoC) as design concepts is given. The optimized bioengineering approaches and microfluidics with their fundamental pros, and cons are presented. There are different strategies that researchers apply to inhalation toxicity studies to assess a variety of inhalable substances and relevant LoC approaches. A case study from published literature and frame arguments about reproducibility as well as in vitro/in vivo correlations are discussed. Finally, the opportunities and challenges in soft robotics, systems inhalation toxicology approach integrating bioengineering, machine learning, and artificial intelligence to address a multitude model for future toxicology are discussed.
O16-2 Prognostic impacts of change in skeletal muscle mass during neoadjuvant chemotherapy in patients with esophageal cancer
Authors: Tsuyoshi Harada, Noriatsu Tatematsu, Junnya Ueno, You Koishihara, Nobuko Konishi, Takuya Fukushima, Tetsuya Tsuji, Shuichi Mitsunaga, Daisuke Kotani, Takashi Kojima, Hisashi Fujiwara, Takeo Fujita
Journal: Annals of Oncology (2021)
Protecting women and girls from tobacco and alcohol promotion
Authors: Emma Feeny, Katie Dain, Cherian Varghese, George A Atiim, Dag Rekve, Hebe N Gouda
Journal: BMJ (2021)

Gender transformative measures could curb the industries' expansion into low and middle income countries, contain the burden of chronic disease, and promote gender equity, argue <b>Emma Feeny and colleagues</b>
The European Medicines Agency Review of Luspatercept for the Treatment of Adult Patients With Transfusion-dependent Anemia Caused by Low-risk Myelodysplastic Syndromes With Ring Sideroblasts or Beta-thalassemia
Authors: Julio Delgado, Caroline Voltz, Milena Stain, Ewa Balkowiec-Iskra, Brigitte Mueller, Johanna Wernsperger, Iwona Malinowska, Christian Gisselbrecht, Harald Enzmann, Francesco Pignatti
Journal: HemaSphere (2021)

Luspatercept is a recombinant fusion protein that selectively binds to ligands belonging to the transforming growth factor-beta superfamily, resulting in erythroid maturation and differentiation. On June 25, 2020, a marketing authorization valid through the European Union (EU) was issued for luspatercept for the treatment of adult patients with transfusion-dependent anemia caused by very low-, low-, and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, or those with transfusion-dependent beta thalassemia (BT). Luspatercept was evaluated in 2 separate phase 3, double-blind, placebo-controlled multicentre trials. The primary endpoints of these trials were the percentage of patients achieving transfusion independence over ≥8 weeks or longer for patients with MDS, and the percentage of patients achieving a ≥33% reduction in transfusion burden from baseline to week 13–24 for patients with BT. In the MDS trial, the percentage of responders was 37.91% versus 13.16%, P &lt; 0.0001, for patients receiving luspatercept versus placebo, respectively. In the BT trial, the percentage of responders was 21.4% versus 4.5% ( P &lt; 0.0001) for luspatercept versus placebo, respectively. Treatment with luspatercept led to similar incidences of adverse events (AEs), but higher incidences of grade ≥3 AEs and serious AEs compared to placebo. The most frequently reported treatment-emergent AEs (≥15%) in the pooled luspatercept group were headache; back pain, bone pain, and arthralgia; diarrhea; fatigue; pyrexia; and cough. The aim of this article is to summarize the scientific review of the application, which led to the regulatory approval in the EU.
Targeting LAG3/GAL-3 to overcome immunosuppression and enhance anti-tumor immune responses in multiple myeloma
Authors: Jooeun Bae, Fabrizio Accardi, Teru Hideshima, Yu-Tzu Tai, Rao Prabhala, Aaron Shambley, Kenneth Wen, Sean Rowell, Paul G. Richardson, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Leukemia (2021)

Abstract Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate decreased CD4 + Th cells, increased Treg and G-type MDSC, and upregulation of immune checkpoints on effector/regulatory and CD138 + cells in MM patients, compared MGUS/SMM patients or healthy individuals. Among the checkpoints profiled, LAG3 was most highly expressed on proliferating CD4 + Th and CD8 + Tc cells in MM patients BMMC and PBMC. Treatment with antibody targeting LAG3 significantly enhanced T cells proliferation and activities against MM. XBP1/CD138/CS1-specific CTL generated in vitro displayed anti-MM activity, which was further enhanced following anti-LAG3 treatment, within the antigen-specific memory T cells. Treg and G-type MDSC weakly express LAG3 and were minimally impacted by anti-LAG3. CD138 + MM cells express GAL-3, a ligand for LAG3, and anti-GAL-3 treatment increased MM-specific responses, as observed for anti-LAG3. Finally, we demonstrate checkpoint inhibitor treatment evokes non-targeted checkpoints as a cause of resistance and propose combination therapeutic strategies to overcome this resistance. These studies identify and validate blockade of LAG3/GAL-3, alone or in combination with immune strategies including XBP1/CD138/CS1 multipeptide vaccination, to enhance anti-tumor responses and improve patient outcome in MM.
P25-6 Dynamic alteration of peripheral immune cells in patients with NSCLC received anti-PD-1 therapy and clinical efficacy
Authors: Naruo Yoshimura, Toshinori Kaifu, Kazuya Takeda, Yuri Atobe, Takanobu Sasaki, Takafumi Sugawara, Toshiharu Tabata, Takashi Ohrui, Akira Nakamura
Journal: Annals of Oncology (2021)
Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype
Authors: Jacqueline M. Bliley, Mathilde C. S. C. Vermeer, Rebecca M. Duffy, Ivan Batalov, Duco Kramer, Joshua W. Tashman, Daniel J. Shiwarski, Andrew Lee, Alexander S. Teplenin, Linda Volkers, Brian Coffin, Martijn F. Hoes, Anna Kalmykov, Rachelle N. Palchesko, Yan Sun, Jan D. H. Jongbloed, Nils Bomer, Rudolf A. de Boer, Albert J. H. Suurmeijer, Daniel A. Pijnappels, Maria C. Bolling, Peter van der Meer, Adam W. Feinberg
Journal: Science Translational Medicine (2021)

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.
Studies of xenobiotic-induced gut microbiota dysbiosis: from correlation to mechanisms
Authors: Liang Chi, Pengcheng Tu, Hongyu Ru, Kun Lu
Journal: Gut Microbes (2021)

Environmental chemicals can alter gut microbial community composition, known as dysbiosis. However, the gut microbiota is a highly dynamic system and its functions are still largely underexplored. Likewise, it is unclear whether xenobiotic exposure affects host health through impairing host-microbiota interactions. Answers to this question not only can lead to a more precise understanding of the toxic effects of xenobiotics but also can provide new targets for the development of new therapeutic strategies. Here, we aim to identify the major challenges in the field of microbiota-exposure research and highlight the need to exam the health effects of xenobiotic-induced gut microbiota dysbiosis in host bodies. Although the changes of gut microbiota frequently co-occur with the xenobiotic exposure, the causal relationship of xenobiotic-induced microbiota dysbiosis and diseases is rarely established. The high dynamics of the gut microbiota and the complex interactions among exposure, microbiota, and host, are the major challenges to decipher the specific health effects of microbiota dysbiosis. The next stage of study needs to combine various technologies to precisely assess the xenobiotic-induced gut microbiota perturbation and the subsequent health effects in host bodies. The exposure, gut microbiota dysbiosis, and disease outcomes have to be causally linked. Many microbiota-host interactions are established by previous studies, including signaling metabolites and response pathways in the host, which may use as start points for future research to examine the mechanistic interactions of exposure, gut microbiota, and host health. In conclusion, to precisely understand the toxicity of xenobiotics and develop microbiota-based therapies, the causal and mechanistic links of exposure and microbiota dysbiosis have to be established in the next stage study.
Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort
Authors: AnnaLynn M. Williams, Kevin R. Krull, Carrie R. Howell, Pia Banerjee, Tara M. Brinkman, Sue C. Kaste, Robyn E. Partin, Deokumar Srivastava, Yutaka Yasui, Gregory T. Armstrong, Leslie L. Robison, Melissa M. Hudson, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2021)

Eight percent of young-adult childhood cancer survivors meet criteria for frailty, an aging phenotype associated with poor health. In the elderly general population, frailty is associated with neurocognitive decline; this association has not been examined in adult survivors of childhood cancer.Childhood cancer survivors 18-45 years old (≥ 10 years from diagnosis) were clinically evaluated for prefrailty or frailty (respectively defined as ≥ 2 or ≥ 3 of: muscle wasting, muscle weakness, low energy expenditure, slow walking speed, and exhaustion [Fried criteria]) and completed neuropsychologic assessments at enrollment (January 2008-June 2013) and 5 years later. Weighted linear regression using inverse of sampling probability estimates as weights compared differences in neurocognitive decline in prefrail and frail survivors versus nonfrail survivors, adjusting for diagnosis age, sex, race, CNS-directed therapy (cranial radiation, intrathecal chemotherapy, and neurosurgery), and baseline neurocognitive performance.Survivors were on average 30 years old and 22 years from diagnosis; 18% were prefrail and 6% frail at enrollment. Frail survivors declined an average of 0.54 standard deviation (95% CI, -0.93 to -0.15) in short-term verbal recall, whereas nonfrail survivors did not decline (β = .22; difference of βs = -.76; 95% CI, -1.19 to -0.33). Frail survivors declined more than nonfrail survivors on visual-motor processing speed (β = -.40; 95% CI, -0.67 to -0.12), cognitive flexibility (β = -.62; 95% CI, -1.02 to -0.22), and verbal fluency (β = -.23; 95% CI, -0.41 to -0.05). Prefrail and frail survivors experienced greater declines in focused attention (prefrail β = -.35; 95% CI, -0.53 to -0.17; frail β = -.48; 95% CI, -0.83 to -0.12) compared with nonfrail survivors.Over approximately 5 years, prefrail and frail young-adult survivors had greater declines in cognitive domains associated with aging and dementia compared with nonfrail survivors. Interventions that have global impact, designed to target the mechanistic underpinnings of frailty, may also mitigate or prevent neurocognitive decline.