tbuckley/cabot-search huggingface dataset:
Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder
Authors: Noah S. Philip, Jennifer Barredo, Emily Aiken, Victoria Larson, Richard N. Jones, M. Tracie Shea, Benjamin D. Greenberg, Mascha van ’t Wout-Frank
Journal: American Journal of Psychiatry (2019)

Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD.Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors.Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen's d=0.39); depression was improved with iTBS compared with the sham treatment (d=-0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=-0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=-0.74 and -0.63, respectively), depression (d=-0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity.iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.
Abstract 1163: HR23A expression modulates drug resistance through regulation of autophagy and stem cell properties in cancer cells
Authors: Show-Mei Chuang, Chung-Yun Yu, Bang-Hung Liu, Sheng-Chih Lin, Shao-Yi Tang
Journal: Cancer Research (2019)

Abstract DNA-damaging agents are commonly used as anticancer therapeutics. Unfortunately, drug resistance arises through a combination of mechanisms, with the sensitivity of cells to apoptosis depending on the balance between apoptotic and survival signals. Our previous studies show that knockdown of HR23A, an accessory protein involved in nucleotide-excision repair (NER) at an early lesion-recognition step, induces autophagy, increases the resistance to cisplatin, oxaliplatin, 5-FU and docetaxel. However, knockdown of HR23A contributed no effect to the sensitivity of tamoxifen or irinotecan. In present study, we found that knockdown of HR23A displayed more sensitivity to the treatment of doxorubicin in A549 cell line. Knockdown of HR23A enhanced cell death via increased ER stress-mediated apoptosis but not autophagy, suggesting a different role of HR23A in response to doxorubicin. Further investigation revealed that HR23A-knockdown cells appear to undergo epithelial-mesenchymal transition and take on certain attributes of cancer stemness. Our experiments show that depletion of HR23A enhances epithelial-mesenchymal transition, EMT regulator protein levels such as Twist1, Slug and Zeb1, cancer cell migration and various cancer stemness properties, including the expression of major pluripotency factors, the capacity for tumor-sphere formation in culture and the expression of cancer stem cell surface markers. The increases of these stemness properties are reversed by ectopic expression of HR23A or further knockdown of Twist1 in HR23A-depleted cells. Furthermore, HR23A directly targets the Twist1 protein and contributes to regulating Twist1 protein stability without changing its gene transcription. Together, our data suggest that knockdown of HR23A induces autophagy, undergoes epithelial-mesenchymal transition and promotes stemness properties, thus leading to the resistance to DNA-damaging agents. Citation Format: Show-Mei Chuang, Chung-Yun Yu, Bang-Hung Liu, Sheng-Chih Lin, Shao-Yi Tang. HR23A expression modulates drug resistance through regulation of autophagy and stem cell properties in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1163.
ToxNav germline genetic testing and PROMinet digital mobile application toxicity monitoring: results of a prospective single centre clinical utility study (PRECISE STUDY)
Authors: L. Lee, T. Starkey, S. Sivakumar, S. Fotheringham, G. Mozolowski, V. Shearwood, C. Palles, P. Camilleri, R. Kerr, D. Kerr
Journal: Annals of Oncology (2019)
Abstract 12831: Effects of Air Pollution and Other Environmental Parameters on All-Cause Mortality in Singapore
Authors: Andrew Fu Wah Ho, Siti Nur Nadiah Bte Mohd Yazid, Huili Zheng, Arul Earnest, Yih Yng Ng, Nan Liu, Sean Shao Wei Lam, Marcus Eng Hock Ong, Jin Ming Koh, Kang Hao Cheong
Journal: Circulation (2018)

Introduction: Ambient air pollution is a risk factor for a diverse range of acute and chronic diseases worldwide, including cardiac arrests and respiratory illnesses. This study aims to investigate...
Should the supply of cannabis be legalised now?
Authors: Molly Meacher, David Nutt, Jonathan Liebling, Robin M Murray, Adam Gridley
Journal: BMJ (2019)

Strict regulation would allow for healthier cannabis consumption than the criminally controlled current supply can offer, say <b>Molly Meacher</b>, <b>David Nutt</b>, and <b>Jonathan Liebling</b>. But <b>Robin Murray</b> and <b>Adam Gridley</b> worry that legalisation could increase cannabis use and associated psychiatric disorders
Reply letter to: “Letter to Editor: Risk factors and complications contributing to mortality in elderly patients with fall-induced femoral fracture: A cross-sectional analysis based on trauma registry data of 2,407 patients”
Authors: Sheng-En Chou, Cheng-Shyuan Rau, Yu-Chin Tsai, Shiun-Yuan Hsu, Hsiao-Yun Hsieh, Ching-Hua Hsieh
Journal: International Journal of Surgery (2019)
Endoscopic ultrasound-guided cholecystoduodenostomy for acute cholecystitis with removal of large (missed) cystic duct stones
Authors: Nader Bakheet, Yervant Ichkhanian, Thomas M. Runge, Kia Vosoughi, Mouen A. Khashab
Journal: Endoscopy (2019)

A 64-year-old woman was diagnosed with severe acute calculous cholecystitis. She was not a candidate for surgery because of associated co-morbidities, including idiopathic pulmonary fibrosis and severe aortic stenosis. Magnetic resonance imaging (MRI) showed a distended gallbladder with multiple stones inside but no choledocholithiasis was seen. The decision was made to perform endoscopic ultrasound (EUS)-guided cholecystoduodenostomy to drain the gallbladder.
Abstract 15314: Left Ventricular Dysfunction in Children and Adolescents With Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Paweena Chungsomprasong, Robert Hamilton, Wietske Luining, Shi-Joon Yoo, Meena Fatah, Cedric Manlhiot, Brian W Mccrindle, Lars Grosse-Wortmann
Journal: Circulation (2015)

Background: Involvement of the left ventricle (LV) is increasingly recognized in adults with arrhythmogenic right ventricular cardiomyopathy (ARVC) but it is unclear whether LV function is compromised in children with this condition. The aim of this study was examine myocardial contractility in pediatric patients with suspected ARVC. Methods: For this retrospective study, patients with a work-up for ARVC were classified into ‘no’, ‘possible’, ‘borderline’ or ‘definite’ ARVC according to the revised Task Force Criteria (rTFC). Ventricular size and function as well as LV myocardial strain and torsion were measured by cardiac magnetic resonance (CMR). Results: A total of 142 patients were enrolled, of whom 58 (41%) had no, 32 (23%) possible, 29 (20%) borderline and 23 (16%) definite ARVC. The groups were similar in age at CMR. With higher rTFC score, z scores (Z) of right ventricular (RV) ejection fraction (EF) were lower (p&lt;0.001) while z-RV end diastolic volume (EDV) and z-LV EDV were larger (p=0.002 and 0.013, respectively). LV EF did not differ between rTFC categories. Global circumferential strain (GCS) of the LV was lower in patients in higher rTFC categories (p=0.018). Z-LVEDV correlated with z-RVEDV (r2 = 0.69, p&lt;0.001) and z- LVEF correlated with z-RVEF (r2 = 0.55, p &lt;0.001). Z-LVEF and z-RVEF correlated with LV GCS (r2 = 0.48, p&lt;0.001 and r2 = 0.46, p&lt;0.001, respectively) and torsion (r2 = 0.21, p=0.032 for both). Forty-two patients had a follow-up CMR, after a median interval of 2.6 years (0.4- 8.4). The rate of deterioration of LV or RV EF or EDV did not differ between rTFC categories. A more rapid increase of z-RVEDV was associated with a faster decline in z-RVEF (r2 = -0.383, p=0.004) and z-LVEF (r2 = -0.45, p=0.001). A decline of z-LVEF over time correlated with that of z-RVEF (r2 = 0.60, p&lt;0.001) and z-LVEDV increase correlated with z-RVEDV increase (r2 = 0.84, p&lt;0.001). Conclusion: LV myocardial dysfunction is present in young patients with suspected or confirmed ARVC. Quantification of myocardial mechanics with CMR may be a useful tool to detect early LV involvement in ARVC. Progressive LV dysfunction and enlargement appear to parallel those of the RV.
The effects and preventability of 2627 patient safety incidents related to health information technology failures: a retrospective analysis of 10 years of incident reporting in England and Wales
Authors: Guy Martin, Saira Ghafur, Isabella Cingolani, Joshua Symons, Dominic King, Sonal Arora, Ara Darzi
Journal: The Lancet Digital Health (2019)

The use of health information technology (IT) is rapidly increasing to support improvements in the delivery of care. Although health IT is delivering huge benefits, new technology can also introduce unique risks. Despite these risks, evidence on the preventability and effects of health IT failures on patients is scarce. In our study we therefore sought to evaluate the preventability and effects of health IT failures by examining patient safety incidents in England and Wales. We designed our study as a retrospective analysis of 10 years of incident reporting in England and Wales. We used text mining with the words "computer", "system", "workstation", and "network" to explore free-text incident descriptors to identify incidents related to health IT failures following a previously described approach. We then applied an n-gram model of searching to identify contiguous sequences of words and provide spatial context. We examined incident details, recorded harm, and preventability. Standard descriptive statistics were applied. Degree of harm was identified according to standardised definitions and preventability was assessed by two independent reviewers. We identified 2627 incidents related to health IT failures. 2557 (97%) of 2627 incidents were assessed for harm (70 incidents were excluded). 2106 (82%) of 2557 health IT failures caused no harm to patients, 331 (13%) caused low harm, 102 (4%) caused moderate harm, 14 (1%) caused severe harm, and four (<1%) contributed to the death of a patient. 1964 (75%) of 2627 incidents were deemed to be preventable. Health IT is fundamental to the delivery of high-quality care, yet there is a poor understanding of the effects of IT failures on patient safety and whether they can be prevented. Failures are complex and involve interlinked aspects of technology, people, and the environment. Health IT failures are undoubtedly a potential source of substantial harm, but they are likely to be under-reported. Worryingly, three-quarters of IT failures are potentially preventable. There is a need to see health IT as a fundamental tenet of patient safety, develop better methods for capturing the effects of IT failures on patients, and adopt simple measures to reduce their probability and mitigate their risk. The National Institutes of Health Research Imperial Patient Safety Translational Research Centre at Imperial College London.
Abstract 1108: Intestine-specific homeobox recruits p300/CBP-associated factor and bromodomain-containing protein 4 to promote epithelial-mesenchymal transition
Authors: Li-Ting Wang, Shyh-Shin Chiou, Shih-Hsien Hsu
Journal: Cancer Research (2019)

Abstract The epithelial-mesenchymal transition is an important process in the cancer progression, but its occurrence and the regulatory mechanism are not fully understood. Intestine specific homeobox acted both as a proto-oncogene and upstream regulator of EMT markers, by which modulates tumorigenic initiation and progression in lung cancer cells. ISX acetylated by PCAF recruits bromodomain-containing protein 4, to initiate chromatin remodeling, and up-regulated EMT downstream regulators in tumors cells. Ectopic expression of ISX was shown to enhance TWIST1, Snail1 expression by recruiting BRD4 to enhance Pol II dependent transcription, lead in to remodeling of the tumor microenvironment. In NSCLC carcinoma, increased ISX expression was noted correlating with distinct clinical metastatic features and poor prognosis. These results suggest that theISX-BRD4 axis mediates EMT signaling and exerts significant regulatory effects on tumor initiation and metastasis. Citation Format: Li-Ting Wang, Shyh-Shin Chiou, Shih-Hsien Hsu. Intestine-specific homeobox recruits p300/CBP-associated factor and bromodomain-containing protein 4 to promote epithelial-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1108.
Abstract 3560: MicroRNA-665 promotes metastasis of breast cancer by targeting nuclear receptor subfamily 4 group A member 3
Authors: Xinge Zhao
Journal: Cancer Research (2019)

Abstract Background: It is the result of metastasis to the lymph nodes or other organs that leads breast cancer (BC) patients to death. Then the early detection of metastasis in BC is helpful to regulate progression of BC and then predict prognosis of BC patients. Since the abnormal level of miRNAs are bound up with BC and metastasis, of which may act as biomarkers to predict prognosis of BC, we find that expression level of miR-665 is ectopic up-regulated in BC patients and it may serve as an estimable biomarker of prognosis of BC patients. Methods: The expressions of miRNA were detected by our current microarray system and verified by quantitative real-time reverse transcription-PCR (qRT-PCR). In Student’s t-test and Kaplan-Meier analysis, the levels of miR-665 were positively correlated with poor survival in BC patients. Multivariate survival analysis identified either miR-665 expression or TNM stage as an independent prognostic factor of BC. Diverse roles of miR-665 played in various cellular functions were examined by loss-of-function and gain-of-function effects in vitro and in vivo. Dual-luciferase reporter gene experiment was then used to confirm the direct complementation between miR-665 and NR4A3, accompanied by activating the epithelial-mesenchymal transition (EMT). Furthermore, siRNAs targeting NR4A3 were used to rescue cell migration and invasion in miR-665 knockdown cells. Results: Expression of miR-665 was upregulated which predicted poor prognosis in BC patients. Since miR-665 may regulate key processes of tumorigenesis, targeting of NR4A3 was proved to promote cell migration and invasion by activating the EMT. Accordingly, either silencing of miR-665 or over-expressing of NR4A3 rescued the migration and invasion phenotype in vitro. Conclusions: Our study suggests that miR-665 plays an important part in progression of BC and promotes cell migration as well as invasion by down-regulation of NR4A3. The data collectively indicate that miR-665 is an onco-miRNA and may represents a potential predictor for diagnosis and prognosis of BC. Citation Format: Xinge Zhao. MicroRNA-665 promotes metastasis of breast cancer by targeting nuclear receptor subfamily 4 group A member 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3560.
Abstract 2291: Single cell capture and molecular analysis of live CTCs using integrated microwells and single cell aspirator
Authors: Charlotte N. Stahlfeld, Jake J. Tokar, David Quigley, David Niles, Jamie M. Sperger, Felix Feng, Joshua M. Lang
Journal: Cancer Research (2019)

Abstract Resistance to targeted therapies can be caused by acquired genomic alterations in genes that code for the targeted protein. Circulating tumor cells (CTCs) provide an accessible source of tumor cells from diverse metastatic lesions from which to evaluate the frequency of genomic alterations that can be matched to distinct phenotypes, including therapeutic resistance. Successful analysis of the diversity of molecular mechanisms of therapeutic resistance requires isolation of live tumor cells for nucleic acid extraction. We have developed a semi-automated single cell aspirating platform to enrich and isolate live, rare cell populations for downstream molecular analysis. Using immortalized cell lines, we were able to enrich a target population of cells from a mixed population resulting a high purity sample (71.7-83.8%) to interrogate. Target cells were captured for nucleic acid extraction for downstream gene expression to validate enrichment. We demonstrate the ability to achieve high quality whole genome and transcriptome endpoints from low cell numbers in cell lines: the lower threshold for cellular input required to attain whole genome amplification (WGA) products reliable for downstream sequencing applications is now being validated. We also isolated CTCs from patient blood samples and showed phenotypic heterogeneity of EpCAM expression among individual CTCs. EpCAMhigh and EpCAMlow CTCs were detected, with a broad range of fluorescent intensities (141.2-5804.56 MFI). Using the phenotypic characterization of EpCAM expression, individual live CTCs were identified and captured for evaluation of their genomic heterogeneity. We have identified molecular heterogeneity in these cells that may reflect heterogeneity driving treatment resistance in CRPC. Early identification of treatment resistant clones may help develop intervention strategies that prolong the efficacy of molecular targeted therapies. Citation Format: Charlotte N. Stahlfeld, Jake J. Tokar, David Quigley, David Niles, Jamie M. Sperger, Felix Feng, Joshua M. Lang. Single cell capture and molecular analysis of live CTCs using integrated microwells and single cell aspirator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2291.
Task Shifting in Surgery—What US Health Care Can Learn From Ghana
Authors: Sherry M. Wren, Adam L. Kushner
Journal: JAMA Surgery (2019)

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Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with relapsed/refractory chronic myelomonocytic leukemia (CMML).
Authors: Mrinal Mahesh Patnaik, Haris Ali, Vikas Gupta, Gary J. Schiller, Sangmin Lee, Abdulraheem Yacoub, Moshe Talpaz, Halyna Wysowskyj, Shay Shemesh, Janice Chen, Christopher Brooks, Enrique Poradosu, Nicole Rupprecht, Animesh Dev Pardanani, Ayalew Tefferi, Eunice S. Wang, Minakshi Taparia, Srdan Verstovsek, Joseph Khoury, Naveen Pemmaraju
Journal: Journal of Clinical Oncology (2019)

7059 Background: Patients with chronic myelomonocytic leukemia (CMML) have historically poor outcomes, with ~6-7 mos median OS in relapsed/refractory (r/r) setting. Splenomegaly is a poor prognostic factor and potential target in CMML. CD123 is detected on blasts, monocytes, and neoplastic microenvironmental plasmacytoid dendritic cell (pDC) infiltrates part of the CMML malignant clone (Solary, et al). Tagraxofusp, a novel CD123 targeted therapy, demonstrated high levels of activity in BPDCN, an aggressive hematologic malignancy derived from CD123-expressing pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel approach in CMML. Methods: Multicenter, 2-stage Ph1/2 enrolling patients (pts) with r/r CMML. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed on days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing), pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 20 pts (12 CMML-1; 8 CMML-2) enrolled. 18 pts 2nd-line (2 pts in 1L), HMAs most common prior therapy. Median age 69 (43-80); 81% male. 11 (52%) had baseline splenomegaly (spleen palpable below left costal margin by physical exam) of 2-27 cm. Most common TRAEs: hypoalbuminaemia (35%), thrombocytopenia (35%), nausea (30%), vomiting (30%), and fatigue (20%). Most common ≥Gr3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome in 3 pts (15%; all Gr1&amp;2). 100% (10/10) of pts with splenomegaly had spleen response: 80% (8/10) had reductions ≥50% and 67% (4/6) with spleen size ≥5 cm had reductions ≥50%. 3 pts achieved bone marrow complete responses, including 1 pt bridged to SCT in remission. Conclusions: Tagraxofusp demonstrated single agent activity in CMML as 80% of pts showed ≥50% reduction in splenomegaly by palpation. Splenomegaly in CMML, as in myelofibrosis, is a major cause of morbidity and associated with poor prognosis and impaired QoL. Targeting splenomegaly in myeloid neoplasms with proliferative features may be an important therapeutic goal. Given CD123 expression on CMML blasts, monocytes, and malignant pDCs, tagraxofusp may offer a targeted approach, especially in pts with splenomegaly. Updated safety and efficacy data to be presented. Registrational trial planned. Clinical trial information: NCT02268253.