tbuckley/cabot-search huggingface dataset:
Phase I and pharmacokinetic trial of the antitemolerase agent KML001 (KML) and cisplatin (CDDP) in advanced solid tumors.
Authors: Martin J. Edelman, Josephine Louella Feliciano, Miroslav Styblo, Tao Liu, Rena G. Lapidus, Jesse Saunders, Joga Gobburu
Journal: Journal of Clinical Oncology (2013)

2515 Background: Telomerase is overexpressed in most solid tumors and rarely expressed in adult tissues and is therefore a promising target. We have previously demonstrated that KML001 (sodium metaarsenite) displaces hTERT from the nucleus and is cytotoxic (Clin Cancer Res 14:4593-602, 2008). We have also demonstrated that it is synergistic with cisplatin. Methods: Pts with advanced solid tumors, PS 0-1, normal renal and hepatic function were eligible. Treatment was with CDDP 75 mg/m2 day 1 and KML p.o. daily days 1-14 on a 21 day cycle. It was planned that KML doses would be escalated by 2.5 mg beginning at 15 mg/day. A 3+3 design was employed. Blood specimens for arsenic and platinum pk were obtained at hours 0,1,2,3,4,5,6, 24 and day 15 and 22. Tumor blocks were required to assess for telomerase expression. Results: 18 patients (7M,11F) are evaluable for toxicity. Pts were heavily pretreated (median number of prior regimens =3). 16 had prior platinum therapy. The dose limiting toxicity was QTc interval prolongation seen in three patients in cohort 3 (20 mg) (two during cycle 1, one during cycle 2). A PR was seen in a patient with heavily pretreated SCLC in cohort 1. 1 other pt with SCLC and 2 with NSCLC also experienced reduction in disease burden. 10/18 pts received &gt;3 cycles of therapy. Other common toxicities observed were nausea, vomiting and cytopenias. Significant, but not dose limiting, neutropenia or thrombocytopenia (&gt; grade 3) was observed in cohorts 1 and 2. Myelosuppression was primarily seen in pts with prior radiotherapy. Non-compartmental analysis for inorganic arsenic (iAs) and the mono (MAs) and dimethylarsenic (DMAs) metabolites was performed (Table). Conclusions: 1. The combination of KML-001 and CDDP is feasible and active. 2. We are currently evaluating CDDP 75 mg/m2 and KML 17.5 mg in an expansion cohorts of advanced SCLC and NSCLC. 3. Studies of telomerase expression are in progress. (R21CA130349-01) Clinical trial information: NCT01110226. [Table: see text]
Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation
Authors: Elena Y. Senchenkova, Junaid Ansari, Felix Becker, Shantel A. Vital, Zaki Al-Yafeai, Erica M. Sparkenbaugh, Rafal Pawlinski, Karen Y. Stokes, Jennifer L. Carroll, Ana-Maria Dragoi, Cheng Xue Qin, Rebecca H. Ritchie, Hai Sun, Hugo H. Cuellar-Saenz, Mara R. Rubinstein, Yiping W. Han, A. Wayne Orr, Mauro Perretti, D. Neil Granger, Felicity N.E. Gavins
Journal: Circulation (2019)

Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role.Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1-/-) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro.Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1-/- mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease αIIbβ3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (αIIbβ3) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.
Major rise in non-suicidal self harm in England, study shows
Authors: Susan Mayor
Journal: BMJ (2019)

The prevalence of non-suicidal self harm in England nearly tripled over the past 10 years, but this was not matched by a rise in the use of health or other support services by patients who self harm, the first analysis of repeated cross-sectional surveys in the country has found.

“Non-suicidal self harm is increasingly being reported as a way of coping. We need to help people, especially young people, learn more appropriate and effective ways of dealing with emotional stress,” said lead author Sally McManus, from the National Centre for Social Research in London, UK.

She warned, “The availability of services needs to be improved, especially for young people, so that health, education, and social care professionals can discuss the subject with …
Abstract 5456: Vascular Endothelial Cells Endothelin-1 Deficiency Decreased Vascular Protection in Atherosclerosis Mouse Model
Authors: Dyah Wulan Anggrahini, Noriaki Emoto, Kazuhiko Nakayama, Bambang Widyantoro, Kazuya Miyagawa, Hidemi Nonaka, Vita Yanti Anggraeni, Yaz Y. Kisanuki, Masashi Yanagisawa, Kenichi Hirata
Journal: Circulation (2008)

Endothelium plays important role in protective mechanism of vascular wall. The balance between endothelin-1 (ET-1) and nitric oxide provide endothelial barrier to lipoprotein retain and macrophage recruitment. In contrasts, ET-1 is also a strong vasoconstrictor. In this study, we aim to determine the role of vascular endothelial cells-derived ET-1 in the development of atherosclerosis. For that purpose, we crossbred Vascular Endothelial Cells-specific ET-1 Knockout (VEETKO) mice to ApoEKO mice. ApoE/VEET-DKO exhibited significantly lower ET-1 plasma and mRNA level as compared to ApoEKO mice. No significant differences of blood pressure, plasma cholesterol or lipid profiles were observed in both mice. Surprisingly, after 8 weeks of western diet, we found that the atherosclerotic lesion was exaggerated in the aortic sinus and brachiochepalic artery of ApoE/VEET-DKO mice (n=7) as compared to those of ApoEKO mice (n=7) (ratio/vessel wall, 0.93±0.13vs.0.49±0.09, p&lt;0.05). We further showed the increase in macrophage plaque content and peritoneal macrophage recruitment in DKO mice. To understand the mechanism of vascular protection, we found lower eNOS mRNA level in DKO mice despite only lower tendency of ETB receptor expression. Functionally, the mice lacking ET-1 in endothelial cells showed impaired NO-mediated endothelial function. Decreased vascular protection further led to increase plaque instability in DKO mice. Here we showed that plaque of DKO mice was more lipid enrich as compared to that of ApoEKO (ratio/lesion, 0.56±0.03vs.0.42±0.04, p&lt;0.05). Moreover, lack of ET-1 significantly reduced matrix synthesis following lower SMCs accumulation in the lesion (ratio/vessel wall, 0.28±0.06vs.0.57±0.08, p&lt;0.05), which was mediated by TGFβ. Interestingly, despite similar advance-typed lesion formed, 15% of DKO mice exhibited plaque hemorrhage in brachiochepalic artery. In conclusion, we demonstrated the increase in atherosclerosis and plaque instability in our model. This further suggests that ET-1 produced from vascular endothelial cells is required for protective mechanism in vascular wall in balance with nitric oxide production. Our data imply for the careful monitoring in the use of ET receptor antagonist in clinical setting.
Facile Phototherapeutic Nanoplatform by Integrating a Multifunctional Polymer and MnO<sub>2</sub> for Enhancing Tumor Synergistic Therapy
Authors: Menglong Zhao, Mingjuan Xie, Jungu Guo, Wei Feng, Yunjian Xu, Xiangmei Liu, Shujuan Liu, Qiang Zhao
Journal: Advanced Healthcare Materials (2019)

Abstract Recent studies indicate that the synergistic phototherapy (SPT) process can simultaneously generate heat for photothermal therapy (PTT) and singlet oxygen ( 1 O 2 ) for photodynamic therapy (PDT) to overcome the recurrence of tumors. However, the hypoxic environment in tumors seriously limits the therapeutic effect of the oxygen‐dependent PDT, leading to the domination of PTT in the SPT process. Therefore, it is urgent to develop a novel SPT platform for overcoming hypoxia in tumors and improving the therapeutic effect of both PTT and PDT. In this work, a novel phototherapeutic platform based on a nanocomposite of aza‐BODIPY/manganese dioxide (MnO 2 ) is developed via simple electrostatic self‐assembly. In this design, MnO 2 nanosheets, which could produce heat and catalyze endogenous hydrogen peroxide (H 2 O 2 ) to generate oxygen, are prepared as a nanocarrier. After being coated with the as‐prepared water‐soluble aza‐BODIPY‐based polymer (PPAIB), the obtained MnO 2 @PPAIB performs as a smart phototherapeutic agent for enhancing the efficiency of both PTT and PDT. More importantly, compared to PPAIB, MnO 2 @PPAIB generates more heat and reactive oxygen species to realize the enhanced therapy effects of PTT and PDT. Hence, this work provides a new method to enhance the therapeutic efficacy of SPT by using a polymer/MnO 2 nanoplatform to improve the oxygen concentration and produce more heat.
Donor human leukocyte antigen-G single nucleotide polymorphisms are associated with post-lung transplant mortality
Authors: Julieta Lazarte, Jin Ma, Tereza Martinu, Liran Levy, William Klement, Matthew White, Jacob Pelling, Zehong Guan, Sassan Azad, Jussi Tikkanen, Vivek Rao, George Tomlinson, Diego Delgado, Shaf Keshavjee, Stephen C. Juvet
Journal: European Respiratory Journal (2019)

Human leukocyte antigen (HLA)-G is a non-classical HLA that inhibits immune responses. Its expression is modified by single nucleotide polymorphisms (SNPs), which are associated with transplant outcomes. Our aim was to investigate the association of donor and recipient HLA-G SNPs with chronic lung allograft dysfunction (CLAD) and mortality after lung transplantation. In this single-centre study, we examined 11 HLA-G SNPs in 345 consecutive recipients and 297 donors of a first bilateral lung transplant. A multivariable Cox proportional hazards model assessed associations of SNPs with death and CLAD. Transbronchial biopsies (TBBx) and bronchoalveolar lavage (BAL) samples were examined using quantitative PCR, ELISA and immunofluorescence. Over a median of 4.75 years, 142 patients (41%) developed CLAD; 170 (49%) died. Multivariable analysis revealed donor SNP +3142 (GG+CG versus CC) was associated with increased mortality (hazard ratio 1.78, 95% CI 1.12–2.84; p=0.015). In contrast, five donor SNPs, -201(CC), -716(TT), -56(CC), G*01:03(AA) and 14 bp INDEL, conferred reduced mortality risk. Specific donor–recipient SNP pairings reduced CLAD risk. Predominantly epithelial HLA-G expression was observed on TBBx without rejection. Soluble HLA-G was present in higher concentrations in the BAL samples of patients who later developed CLAD. Specific donor SNPs were associated with mortality risk after lung transplantation, while certain donor–recipient SNP pairings modulated CLAD risk. TBBx demonstrated predominantly epithelial, and therefore presumably donor-derived, HLA-G expression in keeping with these observations. This study is the first to demonstrate an effect of donor HLA-G SNPs on lung transplantation outcome.
Endocuff-assisted colonoscopy for surveillance of serrated polyposis syndrome: a multicenter randomized controlled trial
Authors: Liseth Rivero-Sánchez, Jorge López Vicente, Luis Hernandez Villalba, Ignasi Puig, Coral Arnau-Collell, Lorena Moreno, Mireia Díaz, Cristina Rodriguez de Miguel, Teresa Ocaña, Leticia Moreira, Miriam Cuatrecasas, Sabela Carballal, Ariadna Sánchez, Oswaldo Ortiz, Josep Llach, Francesc Balaguer, María Pellisé
Journal: Endoscopy (2019)

Abstract Background and study aims Serrated polyposis syndrome (SPS) is a condition with high risk for colorectal cancer. The Endocuff device has been shown to increase adenoma detection in the general and screening population. We aimed to ascertain whether Endocuff-assisted colonoscopy increases detection of serrated lesions in comparison with standard colonoscopy during the surveillance of patients with SPS. Methods In a multicenter randomized controlled study, patients who met SPS criteria I and/or III under surveillance (previous resection of all serrated lesions ≥ 4 mm) were consecutively randomly allocated 1:1 to Endocuff-assisted colonoscopy or standard colonoscopy, performed by expert endoscopists. The main outcome was the mean number of serrated lesions detected per patient. Results 122 patients (standard colonoscopy n = 60; Endocuff-assisted colonoscopy n = 62; 59 % men; mean age 60.6 (standard deviation [SD] 7.5) were included at 4 centers. Baseline variables (demographic data, SPS phenotype, colorectal cancer [CRC] history, cumulative polyps, and follow-up), cecal intubation rate, and withdrawal time were similar between groups. There was no statistically significant difference between Endocuff-assisted colonoscopy and standard colonoscopy for the mean number of serrated lesions detected per patient: 5.8 (95 % confidence interval [95 %CI] 4.4 – 7.2) and 5.0 (3.9 – 6.1), respectively (P = 0.36). There were also no differences between Endocuff-assisted and standard colonoscopy for detection of sessile serrated lesions (mean number per patient 2.5 [1.3 – 3.6] vs. 2.0 [1.1 – 3.0], P = 0.54) and adenomas (0.9 [0.5 – 1.3] vs. 0.5 [0.3 – 0.7], P = 0.12). Conclusion Use of Endocuff-assisted colonoscopy did not significantly increase the number of serrated lesion detected per patient during surveillance of SPS.
Evaluation of the Incidence of New-Onset Atrial Fibrillation After Aortic Valve Replacement
Authors: Rajat Kalra, Nirav Patel, Rajkumar Doshi, Garima Arora, Pankaj Arora
Journal: JAMA Internal Medicine (2019)

Data on the burden of new-onset atrial fibrillation after transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (AVR) is limited mostly to small series or post hoc analyses of clinical trials.To evaluate the incidence of new-onset atrial fibrillation and assess the incidence of in-hospital mortality associated with new-onset atrial fibrillation after TAVI and AVR.In this population-based observational study using the National Inpatient Sample and a validation cohort from the New York state inpatient database, the National Inpatient Sample was queried from January 1, 2012, to September 30, 2015, and the New York state inpatient database was queried from January 1, 2012, to December 31, 2014. Hospitalizations of adults undergoing TAVI or isolated AVR were examined. The incidence of in-hospital mortality across groups with new-onset atrial fibrillation was assessed in the National Inpatient Sample cohort using multivariable logistic regression modeling. Statistical analysis was conducted from August 20, 2018, to March 19, 2019.The primary outcome was the occurrence of new-onset atrial fibrillation, which was identified by excluding hospitalizations in which atrial fibrillation was present on admission. The secondary outcome was in-hospital mortality in TAVI and AVR hospitalizations with and without new-onset atrial fibrillation.A total of 48 715 TAVI hospitalizations (47.4% women and 52.6% men; mean [SD] age, 81.3 [8.1] years; 82.3% white) and 122 765 AVR hospitalizations (39.0% women and 61.0% men; mean [SD] age, 67.8 [12.0] years; 78.0% white) were identified. New-onset atrial fibrillation occurred in 50.4% of TAVI hospitalizations and 50.1% of AVR hospitalizations. In the multivariable-adjusted model, TAVI and AVR hospitalizations with new-onset atrial fibrillation had higher odds of in-hospital mortality compared with hospitalizations without new-onset atrial fibrillation (TAVI: odds ratio, 1.57; 95% CI, 1.21-2.04; and AVR: odds ratio, 1.36; 95% CI, 1.08-1.70). The results were then confirmed with the New York state inpatient database, which contains a present on arrival indicator. The incidence of new-onset atrial fibrillation was 14.1% (244 of 1736 hospitalizations) after TAVI and 30.6% (1573 of 5141 hospitalizations) after AVR in the New York state inpatient database.In this large nationwide study, a substantial burden of new-onset atrial fibrillation was observed after TAVI and AVR. The incidence of new-onset atrial fibrillation was higher after AVR than after TAVI in a patient-level state inpatient database.
Abstract 15397: Kcnk3 Channel Inactivation Leads to Pulmonary Vascular Alterations in Rat
Authors: Mélanie Lambert, Aurélie Hautefort, Boris Manoury, David Montani, Marc Humbert, Frédéric Perros, Fabrice Antigny
Journal: Circulation (2017)

Background: Pulmonary arterial hypertension (PAH) is a severe and lethal cardio-pulmonary disease characterized by a progressive occlusion of the distal pulmonary arteries. Mutations in the KCNK3 g...
Rapid and Sustained Long‐Term Efficacy and Safety of Canakinumab in Patients With Cryopyrin‐Associated Periodic Syndrome Ages Five Years and Younger
Authors: Paul A. Brogan, Michael Hofer, Jasmin B. Kuemmerle‐Deschner, Isabelle Koné‐Paut, Joachim Roesler, Tilmann Kallinich, Gerd Horneff, Inmaculada Calvo Penadés, Belén Sevilla‐Perez, Laurence Goffin, Bernard R. Lauwerys, Helen J. Lachmann, Yosef Uziel, Xiaoling Wei, Ronald M. Laxer
Journal: Arthritis & Rheumatology (2019)

Objective To assess long‐term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin‐associated periodic syndrome ( CAPS ). Methods CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal‐onset multisystem inflammatory disease ( NOMID ) received a starting dose of 4 mg/kg in this open‐label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C‐reactive protein ( CRP ) and amyloid A ( SAA ). Adverse events ( AE s) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. Results Of the 17 patients enrolled, 12 (71%) had Muckle‐Wells syndrome, 4 (24%) had NOMID , and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as “absent” at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AE s suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE ( SAE ). None of the AE s or SAE s required interruption of canakinumab therapy. Conclusion Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non‐live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long‐term use of canakinumab for CAPS in children ≤5 years of age.
Noncoding RNAs in cancer therapy resistance and targeted drug development
Authors: Wen-Tao Wang, Cai Han, Yu-Meng Sun, Tian-Qi Chen, Yue-Qin Chen
Journal: Journal of Hematology & Oncology (2019)

Noncoding RNAs (ncRNAs) represent a large segment of the human transcriptome and have been shown to play important roles in cellular physiology and disease pathogenesis. Increasing evidence on the functional roles of ncRNAs in cancer progression emphasizes the potential of ncRNAs for cancer treatment. Here, we summarize the roles of ncRNAs in disease relapse and resistance to current standard chemotherapy and radiotherapy; the current research progress on ncRNAs for clinical and/or potential translational applications, including the identification of ncRNAs as therapeutic targets; therapeutic approaches for ncRNA targeting; and ncRNA delivery strategies in potential clinical translation. Several ongoing clinical trials of novel RNA-based therapeutics were also emphasized. Finally, we discussed the perspectives and obstacles to different target combinations, delivery strategies, and system designs for ncRNA application. The next approved nucleic acid drug to treat cancer patients may realistically be on the horizon.
Traveling down the Long Road to Type 1 Diabetes Mellitus Prevention
Authors: Clifford J. Rosen, Julie R. Ingelfinger
Journal: New England Journal of Medicine (2019)

Type 1 diabetes mellitus, a chronic autoimmune disease that usually begins in childhood, affects more than 1.25 million Americans,1 and its worldwide prevalence is increasing. Although insulin was discovered almost a century ago and the technologies for administering and monitoring insulin treatment have improved quality of life and reduced complications from the condition, the disease remains incurable. Accordingly, investigative efforts have centered on prevention, aiming to either delay or prevent disease onset. However, that requires the elucidation of the relevant pathophysiological mechanisms that lead to the pancreatic beta-cell destruction thought to be the root cause of type 1 diabetes. Early . . .