tbuckley/cabot-search huggingface dataset:
Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma
Authors: Scott R. Plotkin, Dan G. Duda, Alona Muzikansky, Jeffrey Allen, Jaishri Blakeley, Tena Rosser, Jian L. Campian, D. Wade Clapp, Michael J. Fisher, James Tonsgard, Nicole Ullrich, Coretta Thomas, Gary Cutter, Bruce Korf, Roger Packer, Matthias A. Karajannis
Journal: Journal of Clinical Oncology (2019)

Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS.Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers.Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma.High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.
Long-Term Survival after Transplantation in Patients with Chronic Myeloid Leukemia from HLA-Compatible Unrelated Donors: May the Stem Cell Source Influence the Outcome?
Authors: Michael Koldehoff, Ahmet H. Elmaagacli, Hellmut Dietmar Ottinger, Ulrich Dührsen, Dietrich W. Beelen
Journal: Blood (2018)
IFITM3-Mediated Regulation of Cell Membrane Dynamics Is Essential for Malignant B-Cell Transformation
Authors: Jae-Woong Lee, Huimin Geng, Derek S Dinson, Gang Xiao, Kadriye Nehir Cosgun, Lai N Chan, Zhengshan Chen, Michael Farzan, Jae U Jung, Arun P Wiita, Markus Muschen
Journal: Blood (2018)
Phase I Study of Yttrium-90 Labeled ANTI-CD25 (aTac) Monoclonal Antibody PLUS BEAM for Autologous Hematopoietic Cell Transplantation (AHCT) in Patients with Mature T-Cell NON-Hodgkin Lymphoma, the "a-TAC-BEAM Regimen"
Authors: Jasmine Zain, Jennifer Simpson, Joycelynne Palmer, Jeffrey Wong, Savita Dandapani, David Colcher, Nicole Karras, Alex F. Herrera, Amandeep Salhotra, Auayporn P. Nademanee, Ryotaro Nakamura, Eileen P. Smith, Ni-Chun Tsai, David Yamauchi, Erasmus Kofi Poku, Van Eric Biglang-awa, John E. Shively
Journal: Blood (2020)
Abstract 793: Macrophage Transcription Factor EB Attenuates Left Ventricular Remodeling Via Lysosomal Lipolysis
Authors: Ali Javaheri, Geetika Bajpai, Antonino Picataggi, Smrithi Mani, Layla Foroughi, Hosannah Evie, Attila Kovacs, Carla Weinheimer, Krzystztof Hyrz, Trent Evans, Qingli Xiao, Andrea Ballabio, Jin-Moo Lee, Scot Matkovich, Babak Razani, Joel Schilling, Kory J Lavine, Abhinav Diwan
Journal: Circulation Research (2019)

Background: Autophagy, lipid metabolism, and inflammation are interrelated cellular processes that implicate lysosomes in human disease. After ischemia reperfusion (IR) injury, inflammasome activation and interleukin 1-beta (IL1-beta) secretion promote heart failure progression. Whether macrophage autophagy and lysosomal biogenesis can attenuate post-IR remodeling and inflammation is unknown. We hypothesized that macrophages exhibit lysosome dysfunction and autophagic impairment after IR injury, and that augmentation of macrophage lysosomal biogenesis via macrophage-specific overexpression of transcription factor EB (Mf-TFEB), a master regulator of autophagy and lysosomal biogenesis, would attenuate myocardial remodeling and inflammation in ischemic cardiomyopathy. Methods and Results: In mice subject to IR injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal and autophagic impairment. To ameliorate post-IR macrophage lysosomal injury, we expressed Mf-TFEB in a closed-chest IR murine model using a tamoxifen-inducible CX3CR1erCre and TFEB overexpression cassette bearing a Cre-excisable STOP codon. Compared to Cre-only controls, Mf-TFEB mice had significantly increased left ventricular (LV) ejection fraction 28-days post-IR (40% relative increase, p=0.002, n=15-17 per group), decreased abundance of pro-inflammatory macrophages, and reduced levels of IL1-beta in myocardial tissue. Surprisingly, neither inflammasome suppression nor TFEB-mediated attenuation of post-IR remodeling required intact macro-autophagy as evidenced by Mf-TFEB-mediated rescue of post-IR LV dysfunction in mice with concomitant inducible ATG5 ablation. RNA sequencing of flow-sorted macrophages from post-IR mice identified lysosomal acid lipase amongst other lipases regulated by TFEB. Mechanistically, pharmacologic inhibition of lysosomal acid lipase specifically abrogated the in vivo effects of TFEB on post-IR remodeling. Conclusions: Our findings suggest that macrophage TFEB regulates lysosomal lipolysis to attenuate inflammasome activity and protect against post-IR LV dysfunction, suggesting an alternative paradigm for how lysosome function may impact acute inflammation in vivo.
Abstract 916: Evidence of Cardiac Myosin Dephosphorylation by Two Distinct Pools of Myosin Light Chain Phosphatases
Authors: Audrey N Chang
Journal: Circulation Research (2019)

Muscle myosins are hexameric proteins comprised of two each of the heavy chain, essential light chain, and regulatory light chain (RLC). In normal beating hearts, cardiac myosin RLC is phosphorylated, and the extents maintained at ~0.45 mol phosphate/mol RLC by the balanced activities of cardiac-specific myosin light chain kinases (cMLCK) and phosphatases (cMLCP). Hearts in failure have decreased cMLCK expression and RLC phosphorylation, indicating maintenance of near half-maximal RLC phosphorylation levels is necessary for normal function. However, how cMLCK and cMLCP activities are regulated is unclear. MLCP has been biochemically defined as a trimeric protein comprised of a regulatory myosin target subunit (MYPT1 in smooth muscles, and MYPT2 in striated muscles), a catalytic subunit PP1cβ, and a small subunit M20. Interrogations into the specificity and regulatory activity of smooth muscle MLCP using conditional MYPT1 knockout animals have provided evidence of MYPT1-independent RLC phosphatase activity, which contradicts long-standing dogma. Extending upon recent studies of PP1cβ knockout in smooth muscles, we knocked out PP1cβ from the cardiac muscle to test the hypothesis that a distinct MYPT-independent pool of PP1cβ activity directly contributes to cRLC dephosphorylation. Two weeks post gene-ablation, PP1cβ protein was reduced by &gt;60%, and cRLC phosphorylation in beating hearts was increased to 0.6 mol phosphate/mol cRLC, without significant changes in MYPT1 or MYPT2 expression. Additionally, we measured MYPT-dependent and MYPT-independent PP1cβ phosphatase activities toward cRLC dephosphorylation in mouse cardiac myofibrils. These studies provide further evidence that cardiac RLC is dephosphorylated by two distinct pools of MLCP activities.
Effect of Sirolimus on Immune Reconstitution Following Myeloablative Allogeneic Stem-Cell Transplantation: A Post-Hoc Analysis of a Randomized Controlled Trial Comparing Sirolimus/Tacrolimus with Tacrolimus/Methotrexate (BMT CTN 0402)
Authors: Mahasweta Gooptu, Haesook T. Kim, Alan Howard, Sung W. Choi, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Corey S. Cutler
Journal: Blood (2018)
Combined Administration of Recombinant TGF-β1 and DMSO Decreases the in Vitro Inflammatory Properties of Neutrophils from Sickle Cell Anemia Individuals
Authors: Lidiane S. Torres, Lediana I. Miguel, Merav E. Shaul, Zvi G. Fridlender, Wilson A. Ferreira, Flavia C. Leonardo, Sara T. Olalla Saad, Fernando F. Costa, Nicola Conran
Journal: Blood (2018)
Modern Trends in Rheumatology.
Journal: Annals of Internal Medicine (1968)

Journal Article Modern trends in rheumatology Get access Modern trends in rheumatology Edited by Alan G. S. Hill. Pp. ix+394, illustrated. London: Butterworths. 1966. 95s. Postgraduate Medical Journal, Volume 43, Issue 501, July 1967, Page 507, https://doi.org/10.1136/pgmj.43.501.507-c Published: 01 July 1967
Non-Genotoxic Conditioning Efficiently Depletes Host Hematopoietic Stem Cells and Facilitates Robust Multi-Lineage Engraftment in a Mouse Model of Fanconi Anemia
Authors: Meera Srikanthan, Kevin G. Haworth, Christina M. Ironside, Jerry Chen, Adam J. Hartigan, Rahul Palchaudhuri, Anthony E. Boitano, Michael P. Cooke, Hans-Peter Kiem
Journal: Blood (2018)
CD7 Expression On Blasts Of Myelodysplastic Syndromes Is Associated With Apoptosis Resistance With Decreased Expression Of The Proapoptotic Protein Bad and An Independent Unfavorable Prognostic Factor Together With The Revised IPSS Score In Patients
Authors: Yasuko Hamada, Hideto Tamura, Mariko Ishibashi, Namiko Okuyama, Asaka Kondo, Keiichi Moriya, Kiyoyuki Ogata, Keiji Kakumoto, Yoshihide Miyazaki, Akira Matsuda, Kaoru Tohyama, Yasunori Ueda, Mineo Kurokawa, Hirohiko Shibayama, Nobuhiko Emi, Kinuko Mitani, Tomoki Naoe, Haruo Sugiyama, Koiti Inokuchi
Journal: Blood (2013)
Safety and Efficacy of Mirabegron: Analysis of a Large Integrated Clinical Trial Database of Patients with Overactive Bladder Receiving Mirabegron, Antimuscarinics, or Placebo
Authors: Christopher R. Chapple, Francisco Cruz, Linda Cardozo, David Staskin, Sender Herschorn, Nurul Choudhury, Matthias Stoelzel, John Heesakkers, Emad Siddiqui
Journal: European Urology (2019)

Mirabegron, a β3-adrenoreceptor agonist, is an alternative drug to antimuscarinics for overactive bladder (OAB) symptoms.To summarise safety and efficacy reporting of mirabegron treatment for OAB symptoms.Pooled data analysed from 10 phase 2-4, double-blind, 12-wk mirabegron monotherapy studies in adults with OAB who had received one or more doses of study drug.Mirabegron: 25 and 50mg; antimuscarinics: solifenacin (2.5, 5, and 10mg) and tolterodine extended release (4mg).Baseline OAB-related characteristics, intrinsic and extrinsic factors, and analyses by age (<65 vs ≥65yr and <75 vs ≥75yr) and sex were assessed. Solifenacin 2.5 and 10mg groups were not included in the efficacy analyses (small patient numbers). Safety was evaluated using the proportion of treatment-emergent adverse events. Efficacy variables were derived from bladder diaries (baseline and week 12).Baseline hypertension and diabetes were more frequent across treatment groups in the older versus younger age groups and in men versus women. Within sexes, frequencies were similar between treatment groups. Some differences were observed in baseline characteristics, including type of incontinence and medical history between sexes. No previously unreported safety concerns were identified. Improvements in efficacy (mean number of incontinence episodes/24h, micturitions/24h, urgency episodes/24h, volume voided/micturition, and nocturia episodes) versus placebo were observed in all treatment groups. Significant treatment-by-subgroup interactions included change from baseline in the mean number of incontinence episodes/24h by age (<65 vs ≥65yr), nocturia by age (<65 vs ≥65yr and <75 vs ≥75yr), and urgency episodes by previous OAB medication.Data from this integrated database of 10 mirabegron studies reaffirm the safety and efficacy profiles of mirabegron, solifenacin, and tolterodine in adults of different age groups and sexes.Overactive bladder is a complex of symptoms including a compelling desire to pass urine that leads to increased frequency, which may lead to a degree of incontinence if you do not reach the toilet in time and may wake you from sleep. We pooled data from 10 different studies of mirabegron in patients with overactive bladder symptoms, and looked at the effect in the total number of patients who received the treatment, as well as in different age groups and between men and women. No new safety concerns were identified, and mirabegron improved the symptoms of overactive bladder.
Programmed Death-1 and Programmed Death-Ligand 1 Expression Patterns in Pediatric Lymphoma
Authors: Akihiro Tamura, Makiko Yoshida, Nobuyuki Yamamoto, Nanako Nino, Naoko Nakatani, Takayuki Ichikawa, Sayaka Nakamura, Atsuro Saito, Aiko Kozaki, Kenji Kishimoto, Toshiaki Ishida, Daiichiro Hasegawa, Yoshiyuki Kosaka
Journal: Blood (2018)
Abstract 909: Determining the Role of the Co-chaperone BAG3 at the Cardiac Myofilament
Authors: Thomas G Martin, Valerie Myers, Monte Willis, Arthur Feldman, Jonathan A Kirk
Journal: Circulation Research (2019)

Bcl-2-associated athanogene 3 (BAG3) is an adaptor protein often associated with protein quality control. In the heart, decreased BAG3 expression is linked to dilated cardiomyopathy. Mutations to BAG3 can result in myofibrillar disarray, indicating a possible role at the sarcomere. One previous study found BAG3 has a role in maintaining sarcomere structure, however this was in neonatal myocytes. Whether BAG3 has any role in the myofilament of the adult myocyte is unknown. To determine if BAG3 is present in the cardiac sarcomere and identify the myofilament-BAG3 interactome, we used co-immunoprecipitation of the myofilament fraction from mouse LV and mass spectrometry. This revealed a robust interaction of BAG3 with the myofilament. Furthermore, BAG3 interacted with a heat shock protein (HSPB8) known to assist in the removal of protein aggregates, which are abundant after MI. To determine the mechanistic role of BAG3, we overexpressed the protein in mice hearts using adeno-associated virus 9. At baseline, overexpression caused a slight decrease in skinned myocyte calcium sensitivity compared to WT. This effect may be due to BAG3’s interaction with β-adrenergic receptors, which can cause PKA phosphorylation of thin filament proteins known to reduce calcium sensitivity. Preliminary data support this. We then exposed these mice to left anterior descending coronary artery ligation to induce MI. Compared to shams, MI decreased maximum calcium activated force (F max ) in the WT mice, but BAG3 overexpression restored F max to near sham levels. We also studied the functional impact of a known disease-causing mutation discovered in humans, P209L. Transgenic overexpression of P209L BAG3 had no effect on F max , calcium sensitivity, or cooperativity, suggesting the mutation may not interfere with domains in BAG3 required for its myofilament role. This work is the first to show a functional role for BAG3 in the adult myofilament. However, our findings reveal a complex interaction in which the effect of altered BAG3 expression varies with context. The P209L mutation findings suggest that not all BAG3 mutations have shared phenotypes, a conclusion supported by recent clinical work. Further research is necessary to understand BAG3’s myofilament role in health and disease.
Abstract 513: Exosomes Derived From Podoplanin Positive Cells Induce Fibrosis and Inflammation in Healthy Mouse Heart
Authors: Maria Cimini, Venkata N Garikipati, Chunlin Wang, May Truongcao, Grace Huang, Vandana Mallaredy, Cindy Benedict, Raj Kishore
Journal: Circulation Research (2019)

Superseding fibrosis is the leading cause of the adverse remodeling after myocardial infarction (MI); inflammation and paracrine signals enhance the fibrosis and ventricular dysfunction and inhibit the favorable repair. It has been reported that cells expressing Podoplanin (PDPN), a platelet aggregation- inducing type I transmembrane glycoprotein, appear around 2 days after MI as a signal of activation. We hypothesized that exosomes derived from these cells may actively affect the biology of fibrosis and inflammation. PDPN+ cells were isolated from hearts of mice 2 days after MI, expanded in a selective media and treated with TNFα, Angiotensin II or the combination of both. Exosomes derived from activated PDPN+ cells were isolated from the conditioned media and used in vitro for the treatment of mouse cardiac endothelial cells (mCECs), mouse embryonal fibroblast (MEF) and monocytes and in vivo for the treatment of healthy mouse hearts. Data from q-PCR showed that stimulated PDPN+ cells derived exosomes reprogramed mCECs to the endothelial lymphatic phenotype enhancing the expression of the major lymphatic lineage markers and upregulated the expression of fibrotic markers suggesting an endothelial-mesenchymal transition. Furthermore, stimulated PDPN+ cells derived exosomes drove the fibroblast to myo-fibroblast phenotype and activated monocytes toward pro-inflammatory lineage with an increased expression of TNFα and IL- 1β. In vivo, stimulated PDPN+ cells derived exosomes were initially injected in to the left ventricle of healthy mouse hearts followed with additional boosters delivered by retro-orbital vein injection. Treated mice developed an extended epicardial fibrosis with a subsequent impairment in the contractility and increase in the end diastolic and systolic volumes. In conclusion stimulated PDPN+ cells derived exosomes may impair the biology of mCECs, fibroblast and monocytes leading to adverse remodeling after MI.
Six years of experience in citoreductive surgery and the application of HIPEC-oxaliplatin.
Authors: Srdjan Nikolic, Milan Zegarac, Igor Djurisic, Aleksandar Martinovic, Milan Kocic, Zorica Tomasevic
Journal: Journal of Clinical Oncology (2013)

e14676 Background: In this abstract we present six years of experience in citoreductive surgery and intraperitoneal chemotherapy (HIPEC) as treatment for patients with peritoneal carcinosis of colorectal carcinoma. Methods: In six years time 61 patient has been operated. Age distribution was from 27 to 76 and median age was 55. Male/female distribution was 18.13%/81.87%. All patients have been treated with intraperitoneal Oxaliplatin with dose of 410mg/m2 in 2 liters of perfusions. In 93.44% cases R0 resection was done and R1 in 3.28%. There was no patient with R2 resection. In 13.1% cases there was Grade I postoperative complication Adjuvant chemotherapy has been applied to 67.21% of operated patients and most had FOLFOX protocol. By the end of this research we still follow up 55,74 % of patients as 44.26% had lethal outcome. Results: Median (95% CI )overall survival(OS) was 51 month(22+ months) . Disease free survival (DFS) was 23 months (16+ months ) . One, two and six years OS was 78.6% ,58.7% and 50.5% One , two and six years DFS was 68.3%, 46.7% and 38.1%. The research has shown that factors such as patient age, sex, preoperative symptoms, synchronous and metachronous carcinosis had no statistically relevant influence on OS. There was statistic relevance in DFS for patients who developed peritoneal carcinosis within 12 months after primary tumor resection(p=0.03) Carcinosis node size has no statistical relevance on OS(p=0.24) and DFS(p=0.64). Involving of left subdiaphragmal region significantly reduces OS(p=0.0022) , but has no statistically relevant influence on DFS(p=0.49). Involving of left iliacal region was on boundary of statistical relevance on OS(p=0.05). Involving of right subdiaphragmal regions statistically significantly reduces OS(p=0.04) , and has no influence on DFS. Involving of small intestine has statistical relevance on OS(p=0.01) As the most important prognosis factor we highlight the peritoneal cancer index (PCI). Patients with PCI less then 13 have statistically better OS (p&lt;0.01) and also statistically better DFS (p&lt;0.05). Conclusions: Our results show that citoreductive surgery followed up by HIPEC with Oxaliplatin should always be considered for patients with colorectal cancer carcinosis.
Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial
Authors: Daniel I Sessler, Lijian Pei, Yuguang Huang, Edith Fleischmann, Peter Marhofer, Andrea Kurz, Douglas B Mayers, Tanja A Meyer-Treschan, Martin Grady, Ern Yu Tan, Sabry Ayad, Edward J Mascha, Donal J Buggy, Gang Tan, Zhiyong Zhang, Helen Keane, Maurice Stokes, Oliver Zotti, Michael Gnant, Silvia Perez-Protto, Jiang Wu, Ivan Parra-Sanchez, Dongsheng Yang, Manal Hassan, John BL Tey
Journal: The Lancet (2019)
Abstract 438: GRAF1 is a Novel Mediator of Parkin-dependent Mitophagy
Authors: Qiang Zhu, Matthew Combs, Xue Bai, Christopher Mack, Joan M Taylor
Journal: Circulation Research (2019)

Selective autophagic removal of damaged mitochondria by Parkin-mediated mitophagy is essential for metabolic homeostasis of long-lived cells and defects in this clearance pathway leads to the accumulation of toxic intermediates and accelerates the pathogenesis of numerous cardiometabolic diseases. This process is facilitated by the recruitment of the autophagosomal protein, LC3, by LC3-binding receptors that accumulate on damaged mitochondria. However, little is known about the precise LC3-receptors that mediate Parkin-dependent mitophagy in cardiomyocytes. Having previously identified a cardioprotective role for GRAF1, our current data indicate that GRAF1 plays critical role in promoting Parkin-dependent mitochondrial clearance. GRAF1 is expressed at high levels in the heart from E17 onwards and is poised to co-regulate actin- and lipid-dynamics by virtue of its multi-domain structure that includes a lipid binding/bending BAR domain, a phospholipid binding PH domain, a Rho-GAP domain, and a protein-interaction SH3 domain. Importantly, GRAF1 depletion in primary cardiomyocytes led to impaired mitochondrial OXPHOX-mediated ATP generation, mitochondrial membrane depolarization, increased mitochondrial-associated ROS, and increased ischemia/reperfusion-dependent myocyte death. These outcomes were accompanied by reduced LC3 mediated autophagic flux and accumulation of damaged mitochondria (and Parkin) in GRAF1 deficient cardiomyocytes and hearts. Mechanistically, we showed that GRAF1 facilitates Parkin-dependent mitophagy by serving as a novel LC3 receptor. GRAF1 is recruited to damaged mitochondria, is phosphorylated in a PINK1/Parkin-dependent fashion, and physically interacts with Parkin and LC3. While multiple LC3 receptors are recruited to depolarized mitochondria and act in a redundant function to promote mitochondrial engulfment, our studies reveal a unique and indispensable role for GRAF1 in this process. Our studies reveal that GRAF1 is distinctive because it facilitates mitochondrial clearance by further facilitating recruitment of Parkin and additional down-stream receptors to damaged mitochondria in a feed-forward fashion.