tbuckley/cabot-search huggingface dataset:
SPEG (Striated Muscle Preferentially Expressed Protein Kinase) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity
Authors: Ann P. Quick, Qiongling Wang, Leonne E. Philippen, Giselle Barreto-Torres, David Y. Chiang, David Beavers, Guoliang Wang, Maha Khalid, Julia O. Reynolds, Hannah M. Campbell, Jordan Showell, Mark D. McCauley, Arjen Scholten, Xander H.T. Wehrens
Journal: Circulation Research (2016)

Rationale: Junctional membrane complexes (JMCs) in myocytes are critical microdomains, in which excitation–contraction coupling occurs. Structural and functional disruption of JMCs underlies contractile dysfunction in failing hearts. However, the role of newly identified JMC protein SPEG (striated muscle preferentially expressed protein kinase) remains unclear. Objective: To determine the role of SPEG in healthy and failing adult hearts. Methods and Results: Proteomic analysis of immunoprecipitated JMC proteins ryanodine receptor type 2 and junctophilin-2 (JPH2) followed by mass spectrometry identified the serine–threonine kinase SPEG as the only novel binding partner for both proteins. Real-time polymerase chain reaction revealed the downregulation of SPEG mRNA levels in failing human hearts. A novel cardiac myocyte-specific Speg conditional knockout (MCM- Speg fl/fl ) model revealed that adult-onset SPEG deficiency results in heart failure (HF). Calcium (Ca 2+ ) and transverse-tubule imaging of ventricular myocytes from MCM- Speg fl/fl mice post HF revealed both increased sarcoplasmic reticulum Ca 2+ spark frequency and disrupted JMC integrity. Additional studies revealed that transverse-tubule disruption precedes the development of HF development in MCM- Speg fl/fl mice. Although total JPH2 levels were unaltered, JPH2 phosphorylation levels were found to be reduced in MCM- Speg fl/fl mice, suggesting that loss of SPEG phosphorylation of JPH2 led to transverse-tubule disruption, a precursor of HF development in SPEG-deficient mice. Conclusions: The novel JMC protein SPEG is downregulated in human failing hearts. Acute loss of SPEG in mouse hearts causes JPH2 dephosphorylation and transverse-tubule loss associated with downstream Ca 2+ mishandling leading to HF. Our study suggests that SPEG could be a novel target for the treatment of HF.
TCT-221 Impact of prasugrel versus clopidogrel in smokers and non-smokers undergoing PCI for ACS: Results from the PROMETHEUS Study
Authors: Jaya Chandrasekhar, Usman Baber, Samantha Sartori, Melissa Aquino, Anthony DeFranco, Joseph B. Muhlestein, Sandra Weiss, Timothy D. Henry, Mark B. Effron, Craig E. Strauss, Stuart Y. Keller, Brian A. Baker, William Weintraub, Jennifer Chao, Kanhaiya L. Poddar, Sunil Rao, Samir Kapadia, Annapoorna Kini, Roxana Mehran
Journal: Journal of the American College of Cardiology (2015)
First-in-human, phase I study assessing imalumab (Bax69), a first-in-class anti-oxidized macrophage migration inhibitory factor (oxMIF) antibody in advanced solid tumors.
Authors: Devalingam Mahalingam, Manish R. Patel, Jasgit C. Sachdev, Lowell L. Hart, Neils Halama, Ramesh K. Ramanathan, John Sarantopoulos, Xiaochun Liu, Salim Yazji, Dirk Jaeger, Deyaa Rafaat Adib, Randolf Kerschbaumer, Apostolia Maria Tsimberidou
Journal: Journal of Clinical Oncology (2015)

2518 Background: MIF is a pleiotropic cytokine involved in tumor proliferation, invasiveness, angiogenesis, and the proinflammatory microenvironment. oxMIF is the pathogenic form mainly in tumor and its surrounding stroma. Imalumab (Bax69) is a novel recombinant, fully-human, monoclonal antibody that targets oxMIF, inhibiting tumorigenesis. Preclinical data demonstrated that Imalumab has antitumor activities and acceptable toxicities. Methods: The primary endpoint of this dose-escalation study (3+3 design) was to assess maximum tolerated dose (MTD). The secondary endpoints were to assess antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (PD). Patients (pts) received intravenous (IV) Imalumab [28-d cycles; 2 dose schedules (DS)]: biweekly in all solid tumors (DS1); weekly in metastatic colorectal cancer (mCRC) (DS2). Results: As of Dec 2014, 28 pts were analyzed. DS1 = 19pts in 6 cohorts (1, 3, 10, 25, 37.5, and 50 mg/kg), and DS2 = 9 pts in 2 cohorts (10& 25 mg/kg). AUC and Cmaxincreased with dose. Dose escalation was stopped at 50 mg/kg (DS1) and 25mg/kg (DS2). An MTD was not reached for either DS. One pt reported dose-limiting toxicities: hypersensitivity pneumonitis (DS1; 50 mg/kg). There were no other grade 3 & 4 treatment related adverse events (trAEs). Grade 2 trAEs include: fatigue (n = 2), peripheral edema (n = 1), infusion reaction (n = 1), urticaria (n = 1). About 86% of pts had no trAE > G1. Stable disease (SD) ≥ 4 mo was seen in 7 heavily pre-treated pts, including 1 pt with NSCLC who achieved SD > 13.4 mo. In DS2; Pre- and on-therapy tumor biopsies showed satisfactory tissue penetration of Imalumab with regulation of PI3K-AKT-mTOR downstream signaling, TNF-α signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis in all 5 biopsy evaluable patients. Based on clinical PK & PD study, 10mg/kg weekly was considered a biologically active dose and sufficient to reach ≥ 95% target binding by the end of first cycle. Conclusions: Imalumab was well tolerated and showed single agent antitumor activity in heavily pretreated pts. An MTD was not reached. Recommended phase II dose (RP2D) is 10 mg/kg IV weekly. NCT01765790 Clinical trial information: NCT01765790.
TCT-407 Anatomical And Physiological Changes After Paclitaxel-Coated Balloon For Atherosclerotic De Novo Coronary Lesions: Serial IVUS-VH And FFR study
Authors: Soe Hee Ann, Gillian K. Balbir Singh, Bon-Kwon Koo, Eun-Seok Shin
Journal: Journal of the American College of Cardiology (2015)
Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database
Authors: Jan Franko, Qian Shi, Jeffrey P Meyers, Timothy S Maughan, Richard A Adams, Matthew T Seymour, Leonard Saltz, Cornelis J A Punt, Miriam Koopman, Christophe Tournigand, Niall C Tebbutt, Eduardo Diaz-Rubio, John Souglakos, Alfredo Falcone, Benoist Chibaudel, Volker Heinemann, Joseph Moen, Aimery De Gramont, Daniel J Sargent, Axel Grothey
Journal: The Lancet Oncology (2016)
Impaired hepato-renal function defined by the MELD XI score as prognosticator in acute heart failure
Authors: Jan Biegus, Robert Zymliński, Mateusz Sokolski, Paweł Siwołowski, Piotr Gajewski, Sylwia Nawrocka‐Millward, Elżbieta Poniewierka, Ewa A. Jankowska, Waldemar Banasiak, Piotr Ponikowski
Journal: European Journal of Heart Failure (2016)
Extraosseous uptake on bone scan in a patient with malignant hypercalcemia
Authors: Yueh-An Lu, Kai-Huang Kao, Shen-Yang Lee, Ya-Chung Tian, Hsiang-Hao Hsu
Journal: Kidney International (2016)

A 63-year-old man was admitted to the nephrology ward with low back pain, anorexia, upper abdominal pain, cough, and exertional dyspnea, which he had for several weeks. He was pale and anicteric, and decreased skin turgor and bruises were noted. One year before his admission, he was diagnosed with extramammary Paget’s disease over the left scrotum and inguinal area, and had received surgical excision. Initial laboratory testing revealed pancytopenia with immature cells and erythroblasts. Serum chemistry showed blood urea nitrogen 131 mg/dl, creatinine 5.53 mg/dl, calcium 14.7 mg/dl, phosphate 7.0 mg/dl, albumin 4.31 g/dl, intact parathyroid hormone 6.1 pg/ml, 25-hydroxyvitamin D 20 ng/ml, and 1,25-dihydroxyvitamin D 12.9 pg/ml. Monoclonal gammopathy was not seen on serum and urine electrophoresis. Serum free light chain assay results were normal. Computed tomography showed tumor recurrence in the perineum with multiple lymph node (inguinal, pelvic, and iliac) enlargements and osteolytic lesions of bone. Tc-99m methylene diphosphonate bone scintigraphy (Figure 1) revealed multiple focal areas of increased uptake involving the thoracolumbar spine, rib cage, and left acetabulum. There was also increased uptake over both lung fields and gastric area, suggestive of metastatic calcification. Bone marrow biopsy from the patient’s right iliac crest revealed metastatic poorly differentiated carcinoma, which was positive for human epidermal growth factor receptor 2. After treatment of hypercalcemia with saline solution hydration and loop diuretics, the patient received human epidermal growth factor receptor 2–targeted therapy with weekly 120 mg trastuzumab i.v. injection. Twelve weeks later, the patient’s serum creatinine level decreased to 1.08 mg/dl and calcium was 9.9 mg/dl. Repeated bone scintigraphy (Figure 2) revealed completely resolved metastatic calcification in the stomach and lungs, and also less evidence of other osseous uptakes at the thoracolumbar spine and rib cage.Figure 2Bone scintigraphy after treatment reveals completely resolved nonosseous metastatic calcification in stomach and lung, and also less intense osseous uptakes at the thoracolumbar spine (arrows) and rib cage (arrowheads).View Large Image Figure ViewerDownload (PPT) Nonosseous accumulation of the bone marker Tc-99m methylene diphosphonate may occur in hypercalcemic syndromes. Lung involvement may be symptomatic and sometimes severe. Abnormalities typically improve with resolution of hypercalcemia.
Phase II randomized study of dose-dense docetaxel (Doc) and cisplatin (Cis) every two weeks with pegfilgrastim (Pfil) and darbepoetin alfa (Darb) with and without the chemoprotector BNP7787 in patients with advanced non-small cell lung cancer (NSCLC): CAL
Authors: M. R. Green, A. A. Miller, X. F. Wang, L. Gu, E. E. Vokes
Journal: Journal of Clinical Oncology (2007)

7617 Background: We sought to explore the toxicity, feasibility, and response rate of dose-dense Doc and Cis with growth factor support without [A] and with [B] a novel chemoprotector in patients with NSCLC. Methods: Patients with measurable disease, stage IIIB (effusion) or IV, performance status (PS) 0–1, no prior chemotherapy, and adequate organ function were eligible. Treatment with Doc 75 mg/m 2 ? Cis 75 mg/m 2 both IV over 1 hr day 1 with Darb 200 mcg SC day 1 and Pfil 6 mg SC day 2 randomized to without/with BNP before Cis was repeated every other week (1 cycle = 2 weeks) for up to 6 cycles. Response was determined after 3 and 6 cycles. Because of anticipated neurotoxicity (NT), the primary statistical endpoint was to differentiate between grade =2 NT rates of 30% in [A] and 10% in [B]: 90% power, two-tailed p&lt;0.10, 76 patients per arm. Feasibility was prospectively defined as febrile neutropenia in &lt;10% of patients and =1 treatment delay per cycles 1–3 and 4–6 in &lt;20% of patients. Objective response rates of &gt;35% were required to merit further investigation. Results: Between 8/04 and 3/06, 160 patients were enrolled but 5 never started therapy and 4 were ineligible: male/female, 99/52; white/black/other, 126/23/2; median age 62 (range, 30–88); PS 0/1, 69/82; stage IIIB/IV 14/137; [A]/[B], 76/75 well balanced. Sensory/motor/either NT grade =2 occurred in 28/14/32% on [A] and 19/19/29% on [B]. The incidence of febrile neutropenia was 1%. Treatment was delayed in cycles 1–3/cycles 4–6 in 3/3 patients in [A] and 1/5 patients in [B]. Completion rates for 3/6 cycles were 87/51% in [A] and 84/52% in [B]. By intent to treat, complete/partial response rates were 4/46% in [A] and 3/47% in [B]. Median estimated overall/progression-free survival times are10/6 months in [A] and 11/6 months in [B]. Overall, grade 3+4 neutropenia and thrombocytopenia occurred in =10% and anemia in 12% of patients. Non-hematologic toxicity was mild. Six deaths were thought to be treatment related. Conclusions: This dose-dense treatment regimen is feasible, tolerable, and worthy of further investigation in NSCLC. BNP did not result in significant protection from NT. No significant financial relationships to disclose.
Hip fractures as a complication of cancer care in perimenopausal women with breast cancer.
Authors: B. J. Edwards, W. J. Gradishar, D. W. Raisch, A. Bunta, A. T. Samaras, D. P. West, J. M. Mckoy, S. Singhal, C. L. Bennett
Journal: Journal of Clinical Oncology (2010)

e11086 Background: Aromatase inhibitors have been recently implicated in hip fractures. We report the occurrence of hip fractures in middle aged women with early stage breast cancer, and perform a systematic review of bone health care in breast cancer patients. Methods: Cases of hip fractures presented to the Bone Health and Osteoporosis Center at Northwestern University between January 2005 and December 2008. Functional status at 12 months was assessed with the National Health Interview survey. Systematic review including case reports, literature review of MEDLINE, EMBASE, and FDA Adverse event reporting system (AERS) from January 1998 through December 2008. Search terms included breast cancer, bone loss, osteopenia, osteoporosis, malignancy, cancer treatment, menopause, adriamycin, cytoxan, tamoxifen, and aromatase inhibitors (exemestane, anastrazole, letrozole). Results: Six women sustained hip fractures, patients' were Caucasian with a mean age of 53.5 ± 3.5 years, five women had densitometry consistent with osteopenia (T-score <-1.0 and > -2.5), and one osteoporosis (T- score < -2.5). Vitamin D deficiency and low calcium absorption were identified in two cases, while an additional case had vitamin D insufficiency with high urinary calcium loss. Four cases were estrogen receptor positive. Although women reported their pre-fracture function as independent in all functional activities, 12 months after the hip fracture women reported moderate functional impairment with greatest difficulty in performing heavy housekeeping, climbing stairs and shopping. The FDA AERS included 54 cases of hip, femur, and tibia fractures in middle aged women (40-64 years) in women with breast cancer. Conclusions: Chemotherapy induced early menopause and aromatase inhibitor use contribute to accelerated bone loss, which can result in hip fractures in premenopausal cancer survivors. Premenopausal cancer survivors may sustain hip fractures at younger ages and at higher bone densities, and result in considerable functional decline. Greater awareness of this adverse drug effect is needed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, Novartis, Roche Procter and Gamble
Psychoeducational Intervention to Reduce Fear of Cancer Recurrence in People at High Risk of Developing Another Primary Melanoma: Results of a Randomized Controlled Trial
Authors: Mbathio Dieng, Phyllis N. Butow, Daniel S.J. Costa, Rachael L. Morton, Scott W. Menzies, Shab Mireskandari, Stephanie Tesson, Graham J. Mann, Anne E. Cust, Nadine A. Kasparian
Journal: Journal of Clinical Oncology (2016)

Purpose People with a history of melanoma commonly report a fear of cancer recurrence (FCR), yet psychologic support is not routinely offered as part of ongoing melanoma care. This randomized controlled trial examined the efficacy of a psychoeducational intervention to reduce FCR and improve psychologic adjustment in this patient group compared with usual care. Methods The intervention comprised a newly developed psychoeducational resource and three telephone-based psychotherapeutic sessions over a 1-month period timed in accordance with dermatologic appointments. Participants were randomly assigned to intervention (n = 80) or usual care (n = 84). Assessments were completed at baseline, 1 month, and 6 months after dermatologic appointments. Linear mixed models were used to examine differences between treatment and control groups for patient-reported outcomes, including FCR, anxiety, stress, depression, melanoma-related knowledge, health behaviors, satisfaction with melanoma care, unmet needs, and health-related quality of life. Results At 6 months, the intervention group reported lower FCR severity, trigger, and distress scores than the control group in the baseline-adjusted models; the between-group mean difference was -1.9 for FCR severity (95% CI, -3.1 to -0.7; P = .002), -2.0 for FCR triggers (95% CI, -3.3 to -0.7; P = .003), and -0.7 for FCR distress (95% CI, -1.3 to -0.1; P = .03). The decrease in FCR severity (but not triggers or distress) remained statistically significant after adjustment for other covariates ( P = .04). At 6 months, the intervention group also reported lower stress (-1.6; 95% CI, -3.1 to -0.2; P = .03) and improved melanoma-related knowledge (1.7; 95% CI, 0.8 to 2.6; P < .001) compared with the control group. No differences were found between groups for other secondary outcomes. Conclusion This newly developed evidence-based psychoeducational intervention was effective in reducing FCR and stress and increasing melanoma-related knowledge in people at high risk for another melanoma.
ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 Appropriate Use Criteria for Cardiac Computed Tomography
Authors: Allen J. Taylor, Manuel Cerqueira, John McB. Hodgson, Daniel Mark, James Min, Patrick O'Gara, Geoffrey D. Rubin
Journal: Circulation (2010)

The American College of Cardiology Foundation, along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac computed tomography (CCT) is frequently considered. The present document is an update to the original CCT/cardiac magnetic resonance appropriateness criteria published in 2006, written to reflect changes in test utilization, to incorporate new clinical data, and to clarify CCT use where omissions or lack of clarity existed in the original criteria. The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Ninety-three clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of CCT angiography for diagnosis and risk assessment in patients with low or intermediate risk or pretest probability for coronary artery disease was viewed favorably, whereas testing in high-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Use of noncontrast computed tomography for calcium scoring was rated as appropriate within intermediate- and selected low-risk patients. Appropriate applications of CCT are also within the category of cardiac structural and functional evaluation. It is anticipated that these results will have an impact on physician decision making, performance, and reimbursement policy, and that they will help guide future research.
Novel Genetic Causes of Pituitary Adenomas
Authors: Francisca Caimari, Márta Korbonits
Journal: Clinical Cancer Research (2016)

Abstract Recently, a number of novel genetic alterations have been identified that predispose individuals to pituitary adenomas. Clinically relevant pituitary adenomas are relatively common, present in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior lobe of the pituitary gland, and cause disease due to hormonal alterations and local space-occupying effects. The pathomechanism of pituitary adenomas includes alterations in cell-cycle regulation and growth factor signaling, which are mostly due to epigenetic changes; somatic and especially germline mutations occur more rarely. A significant proportion of growth hormone- and adrenocorticotrophin-secreting adenomas have activating somatic mutations in the GNAS and USP8 genes, respectively. Rarely, germline mutations predispose to pituitary tumorigenesis, often in a familial setting. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and McCune-Albright syndrome. Pituitary tumors have also been described in association with neurofibromatosis type 1, DICER1 syndrome, and SDHx mutations. Pituitary adenomas with no other associated tumors have been described as familial isolated pituitary adenomas. Patients with AIP or GPR101 mutations often present with pituitary gigantism either in a familial or simplex setting. GNAS and GPR101 mutations that arise in early embryonic age can lead to somatic mosaicism involving the pituitary gland and resulting in growth hormone excess. Senescence has been suggested as the key mechanism protecting pituitary adenomas turning malignant in the overwhelming majority of cases. Here we briefly summarize the genetic background of pituitary adenomas, with an emphasis on the recent developments in this field. Clin Cancer Res; 22(20); 5030–42. ©2016 AACR. See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”
Efficacy of repeat hepatectomy for recurrence following curative hepatectomy for colorectal liver metastases: A Retrospective Cohort Study of 128 patients
Authors: Masakazu Hashimoto, Tsuyoshi Kobayashi, Kohei Ishiyama, Kentaro Ide, Masahiro Ohira, Hiroyuki Tahara, Shintaro Kuroda, Michinori Hamaoka, Hiroshi Iwako, Masashi Okimoto, Hideki Ohdan
Journal: International Journal of Surgery (2016)
Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies
Authors: Toshi A Furukawa, Andrea Cipriani, Lauren Z Atkinson, Stefan Leucht, Yusuke Ogawa, Nozomi Takeshima, Yu Hayasaka, Anna Chaimani, Georgia Salanti
Journal: The Lancet Psychiatry (2016)
TCT-439 The beneficial effect of percutaneous coronary intervention over optimal medical therapy in elderly patients with angina pectoris; a prospective randomized trial
Authors: Hoyoun Won, Ae-Young Her, Byeong-Keuk Kim, Yong Hoon Kim, Dong-Ho Shin, Jung-Sun Kim, Young-Guk Ko, Donghoon Choi, Hyuck Moon Kwon, Yangsoo Jang, Myeong-Ki Hong
Journal: Journal of the American College of Cardiology (2015)
An Animal Model to Study Bisphosphonates Associated Osteonecrosis of the Jaw
Authors: Gabriele Pozzato, Silvia Chiandussi, Serena Zacchigna, Franca Dore, Silvia Moimas, Fabrizio Zanconati, Fabio Cavalli, Arturo Mecchia, Michela Faraon, Mauro Giacca, Roberto Di Lenarda, Mauro Giacca, Matteo Biasotto
Journal: Blood (2008)