tbuckley/cabot-search huggingface dataset:
Divergent Long-Term Detection Rates of Proximal and Distal Advanced Neoplasia in Fecal Immunochemical Test Screening Programs
Authors: Manuel Zorzi, Cesare Hassan, Giulia Capodaglio, Elena Narne, Anna Turrin, Maddalena Baracco, Antonella Dal Cin, Annarita Fiore, Giancarla Martin, Alessandro Repici, Douglas Rex, Massimo Rugge
Journal: Annals of Internal Medicine (2018)

Short-term studies have reported that the fecal immunochemical test (FIT) is less accurate in detecting proximal than distal colorectal neoplasia.To assess the long-term detection rates for advanced adenoma and colorectal cancer (CRC), according to anatomical location.Retrospective study.Population-based, organized screening program in the Veneto region of Italy.Persons aged 50 to 69 years who completed 6 rounds of FIT screening.At each screening round, the detection rates for advanced adenoma and cancer, as well as the proportional interval cancer rate (PICR), were calculated by anatomical location (proximal colon, distal colon, or rectum).Between 2002 and 2014, a total of 123 347 participants had 441 647 FITs. The numbers of advanced adenomas and cancer cases detected, respectively, were 1704 and 200 in the proximal colon, 3703 and 324 in the distal colon, and 1220 and 209 in the rectum. Although the detection rate for proximal colon cancer declined only from the first to the second screening round (0.63 to 0.36 per 1000 screenees), the rate for both distal colon and rectal cancer steadily decreased across 6 rounds (distal colon, 1.65 in the first round to 0.17 in the sixth; rectum, 0.82 in the first round to 0.17 in the sixth). Similar trends were found for advanced adenoma (proximal colon, 5.32 in the first round to 4.22 in the sixth; distal colon, 15.2 in the first round to 5.02 in the sixth). Overall, 150 cases of interval cancer were diagnosed. The PICR was higher in the proximal colon (25.2% [95% CI, 19.9% to 31.5%]) than the distal colon (6.0% [CI, 3.9% to 8.9%]) or rectum (9.9% [CI, 6.9% to 13.7%]).Participants with irregular attendance were censored. Those who had a false-positive result on a previous FIT but negative colonoscopy results were included in subsequent rounds.This FIT-based, multiple-round, long-term screening program had a negligible reduction in detection rates for neoplastic lesions in the proximal versus the distal colon after the first round. This was related to a higher PICR in the proximal colon and suboptimal efficacy in preventing the age-related proximal shifting of CRC.None.
Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer
Authors: Shunsuke Kitajima, Elena Ivanova, Sujuan Guo, Ryohei Yoshida, Marco Campisi, Shriram K. Sundararaman, Shoichiro Tange, Yoichiro Mitsuishi, Tran C. Thai, Sayuri Masuda, Brandon P. Piel, Lynette M. Sholl, Paul T. Kirschmeier, Cloud P. Paweletz, Hideo Watanabe, Mamiko Yajima, David A. Barbie
Journal: Cancer Discovery (2018)

Abstract KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL)–mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS-mutant lung cancers, remains obscure. Here, we report that LKB1 loss results in marked silencing of stimulator of interferon genes (STING) expression and insensitivity to cytoplasmic double-strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape. Significance: Oncogenic KRAS-mutant lung cancers remain treatment-refractory and are resistant to ICB in the setting of LKB1 loss. These results begin to uncover the key underlying mechanism and identify strategies to restore STING expression, with important therapeutic implications because mitochondrial dysfunction is an obligate component of this tumor subtype. See related commentary by Corte and Byers, p. 16. This article is highlighted in the In This Issue feature, p. 1
Abstract 13615: High-Dose Simvastatin Induce Insulin Resistance During Acute Myocardial Infarction by Inhibiting Intracellular Insulin Signaling, Without Attenuating Its Clinical Benefit
Authors: Luiz S Carvalho, Filipe A Moura, Riobaldo M Cintra, Patrícia O Prada, Mario J Saad, Otavio R Coelho, Andrei C Sposito
Journal: Circulation (2015)

Background: Hyperglycemia during the acute phase of myocardial infarction (MI) is a strong marker of mortality, but statin use in this set can potentially induce dysglycemia. We aimed to identify whether statins also induce hyperglycemia during MI and the related mechanisms as well as to evaluate its clinical relevance. Methods: We prospectively studied 550 patients with ST-elevation MI treated without (WS) or with simvastatin (S) at 20, 40 or 80 mg/day. Of these, 27 non-diabetics were randomized to S10 or S80mg/day and performed euglycemic hyperinsulinemic clamp (EHC) associated with abdominal adipose tissue biopsy after 40 minutes of insulin infusion in the second (D2) and sixth (D6) days after MI. Measurements of plasma glucose, insulin, C-peptide on admission (D1) and fifth (D5) day were performed in all patients. Results: Between D2 and D6, insulin sensitivity index (ISi) measured by EHC increased (20±60%) in the S10 group and reduced (-6±28%) in S80 (p=0.025). Analysis of the biopsies by Western-blot showed a reduction in phosphorylation/activation of Akt and IRS-1 in patients treated with S80 compared to those treated with S10. Among the 550 patients, ISi was estimated by HOMA2S (plasma glucose and insulin) and varied in 40±145% (WS), 22±117% (S20), 16±61 % (S40) and -2%±88% (S80) between D1 and D5 (p=0.001). Insulin secretion at D1 estimated by HOMA2B (glucose and C-peptide) (p=0.001) and the dose of S (p=0.009) were the only independent markers of a fall in HOMA2S between D1 and D5. Among patients not treated with statins or taking 20mg/day (WS + S20), plasma glucose ≥140mg/dl at admission (stress hyperglycemia) increased by 2.25x (95% confidence interval [CI] 1.30-3.85, p=0.004) the risk of death or MI after mean 634±501 days; but not in those treated with S40 or S80 (p=0.727). Stress hyperglycemia also increased the incidence of death in 30 days after MI in the WS + S20 group (HR 3.15, 95%CI 1.41-7.01; p=0.003), but not in the S40 + S80 group (p=0.858) Conclusion: The use of high-dose simvastatin in MI reduces IS through the inhibition of intracellular insulin signaling pathways. IS impairment is dependent on the dose of statin and the reserve of insulin secretion. However, high-dose statins attenuate the short- and long-term clinical impact of hyperglycemia in MI.
AB1430-HPR Effectiveness of functional rigid taping on pain, function and kinesiophobia in patients with low back pain
Authors: F.M Kavak, B. Kavak, E. Tonga
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> A small number of studies in the literature suggest that rigid bands applied with different techniques in different regions are effective treatment techniques. On the other hand, there is no study of how rigid bands are effective in the treatment of acute and subacute lumbar pain. <h3>Objectives</h3> Purpose of this study is to determine the efficiency of functional tape application to patients with acute or subacute low back pain. <h3>Methods</h3> 40 patients with acute-subacute low back pain were divided into two groups: control and experimental group. To control group, McKenzie exercises, Transcutaneous Electrical Nerve Stimulation (TENS), Hot Pack (HP) and pulsed ultrasound treatments were applied. To experimental group, functional taping were applied in addition of these treatments. Range of Motion (ROM), Visual Analogue Scale (VAS), Tampa Scale of Kinesiophobia (TSK) and The Oswestry Disability Index (ODI) were evaluated pre- and post-treatment and datas were analysed with statistical methods. In analysis; p value was accepted p&lt;0,05 for t test and Mann Whitney U test process. <h3>Results</h3> In the measurements that compared the improvement of both groups, based on pre- and post-treatment evaluations; improvement in the experimental group was significantly higher in all of these parameters of ROM, VAS, TSK and ODI than in the control group (p&lt;0,05). <h3>Conclusions</h3> The use of functional rigid taping in patients with acute and subacute low back pain provided a statistically significant improvement in all measured values of patients and provide better results than the control group. However, there is a need for comparative new studies in order to measure the effectiveness of rigid taping in a more accurate way. <h3>References</h3> [1] Faqih A, et al. Effect of rigid taping on pain angait parameters in knee osteoarthritis", International Journal of Cur Research Review, 2015, 7(1), January; 24–27. [2] Polakowski EG. <i>Systematıc review of musculoskeletal taping methods</i>. University Of Pittsburgh, School of Health and Rehabilitation Sciences Bachelors of Philosophy; 2015 <h3>Acknowledgements</h3> We want to thanks to Dr Murat Dalkılıç for his support. <h3>Disclosure of Interest</h3> None declared
The challenges of treating a high grade glioma in a pregnant patient
Authors: Dr Priyanka Patel, Dr Ronald Beaney, Dr Angela Swampillai, Prof Keyoumars Ashkan, Mr Ranj Bhangoo, Ms Laura Mullens, Ms Victoria Hurwitz, Dr Lucy Brazil
Journal: Neuro-Oncology (2018)

Glioblastoma diagnosis carries a poor prognosis. A combination of surgical resection and chemo-radiotherapy is the current standard of care with median survival rates of 15 months. A 33 year old lady, pregnant at 26 + 3 weeks gestation presented with a left parietal tumour. Complete resection confirmed a grade IV glioblastoma. Foetal health remained stable and termination was not considered. The patient attended for discussion on adjuvant treatments and was informed of the time critical nature of radiotherapy; temozolomide was not advised during pregnancy. With the patient understanding the increased risks to the foetus, the radiotherapy process for delivering 60Gy/30 fractions was initiated. Standard radiotherapy plans were created using both VMAT and 3D-CRT technique. At the planning CT fiducials were placed at the xiphersternum to represent the maximum superior foetal extent and measurements taken. Using a phantom and TLDs, an estimated dose to the foetus was 30mGy from a VMAT plan and 20mGy from 3-field 3DCRT, assuming a 0.5mm equivalent lead apron. The effects to the foetus were calculated using the Health Protection Agency document RCE-9. Radiotherapy increased the incidence of childhood cancer from 1/500 to 1/250. Additional risk of inheritable effects was (1/6700) and deterministic effects was below the threshold. The increased dose of 10mGy from 3DCRT to VMAT plan meant the additional risk of childhood cancer increased from 1/625 to 1/400. Although considered safe, the patient decided against radiotherapy until after delivery at 32 weeks. We will also present a case of a patient diagnosed with a frontal anaplastic astrocytoma at 19 weeks gestation. The patient consented to go ahead with radiotherapy with similar foetal radiation doses. Considering the health of the foetus and mother brings a unique challenge when planning the management of high grade gliomas.
Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
Authors: Daniela N. Petrusca, Denise Toscani, Feng Ming Wang, Cheolkyu Park, Colin D. Crean, Judith L. Anderson, Silvia Marino, Khalid S. Mohammad, Dan Zhou, Rebecca Silbermann, Quanhong Sun, Noriyoshi Kurihara, Deborah L. Galson, Nicola Giuliani, G. David Roodman
Journal: Journal of Hematology & Oncology (2018)

In spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug-resistant clones. We previously showed that MM cells upregulate the transcriptional repressor, growth factor independence 1 (Gfi1), in bone marrow stromal cells (BMSCs) that induces prolonged inhibition of osteoblast differentiation. However, the role of Gfi1 in MM cells is unknown.Human primary CD138+ and BMSC were purified from normal donors and MM patients' bone marrow aspirates. Gfi1 knockdown and overexpressing cells were generated by lentiviral-mediated shRNA. Proliferation/apoptosis studies were done by flow cytometry, and protein levels were determined by Western blot and/or immunohistochemistry. An experimental MM mouse model was generated to investigate the effects of MM cells overexpressing Gfi1 on tumor burden and osteolysis in vivo.We found that Gfi1 expression is increased in patient's MM cells and MM cell lines and was further increased by co-culture with BMSC, IL-6, and sphingosine-1-phosphate. Modulation of Gfi1 in MM cells had major effects on their survival and growth. Knockdown of Gfi1 induced apoptosis in p53-wt, p53-mutant, and p53-deficient MM cells, while Gfi1 overexpression enhanced MM cell growth and protected MM cells from bortezomib-induced cell death. Gfi1 enhanced cell survival of p53-wt MM cells by binding to p53, thereby blocking binding to the promoters of the pro-apoptotic BAX and NOXA genes. Further, Gfi1-p53 binding could be blocked by HDAC inhibitors. Importantly, inoculation of MM cells overexpressing Gfi1 in mice induced increased bone destruction, increased osteoclast number and size, and enhanced tumor growth.These results support that Gfi1 plays a key role in MM tumor growth, survival, and bone destruction and contributes to bortezomib resistance, suggesting that Gfi1 may be a novel therapeutic target for MM.
Increased Mortality Among Patients With vs Without Cirrhosis and Autoimmune Hepatitis
Authors: Floris F. van den Brand, Koen S. van der Veen, Ynto S. de Boer, Nicole M. van Gerven, Birgit I. Lissenberg-Witte, Ulrich Beuers, Karel J. van Erpecum, Henk R. van Buuren, Jannie W. den Ouden, Johannus T. Brouwer, Jan M. Vrolijk, Robert C. Verdonk, Bart van Hoek, Ger H. Koek, Joost P.H. Drenth, Marleen M.J. Guichelaar, Chris J.J. Mulder, Elisabeth Bloemena, Carin M.J. van Nieuwkerk, Gerd Bouma, T.C.M.A. Schreuder, E.J. van der Wouden, J.J.M. van Meyel, L.C. Baak, P.H.G.M. Stadhouders, M. Klemt-Kropp, M.A.M.T. Verhagen, A. Bhalla, J.Ph. Kuijvenhoven
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract MP055: T- Wave Axis Deviation, Coronary Artery Disease, Atrial Fibrillation, Heart Failure, Stroke and Cardiovascular Mortality: The MOLI-SANI Study
Authors: Augusto Di Castelnuovo, Marialaura Bonaccio, Simona Costanzo, Livia Rago, Amalia De Curtis, Deodato Assanelli, Fabio Badilini, Martino Vaglio, Mariarosaria Persichillo, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello
Journal: Circulation (2017)

Background: Deviation of frontal plane T-wave axis (TDev) is a reliable measure of ventricular repolarisation abnormality. Objectives: We investigated the associations and possible mediators between TDev and the risk of coronary artery disease (CHD), atrial fibrillation (AF), heart failure (HF), stroke and cardiovascular mortality. Methods: A large sample of 21,287 Moli-sani participants (54.0±10 years, 46% women), randomly recruited from the general adult population of Southern Italy and free of clinically and ECG recognized vascular disease (including HF), were followed for a median of 4.3 years. TDev was measured from a standard 12-lead resting electrocardiogram. ECG abnormalities were identified by the MINNESOTA codes. Results: After adjusting for a large panel of covariates (see the Table), subjects with abnormal TDev showed a significant increase in the risk of CHD, AF, HF and CVD mortality, but not with stroke (Table). Associations with CHD and HF (but not AF or CVD mortality) were slightly reduced but remained significant after further adjustment for other ECG abnormalities (Table). Subjects with abnormal TDev showed higher levels of subclinical inflammation (measured by C-reactive protein, WBC, platelet counts and ratio of granulocytes to lymphocytes), hs-troponin I and hs-NT-proBNP (p&lt;0.001 for all). However, while additional adjustment for inflammation markers did not change the association of TDev with any clinical outcome, further adjustment for troponin I or NT-proBNP or both determined a reduction ranging from 7.9 to 23.7% for the association of TDev with HF and from 20.7 to 33.8% for the association of TDev with CHD. Conclusions: Deviation of TDev is associated with an increased risk of HF or CHD, independently from a large panel of covariates and other ECG abnormalities. The association was partially explained by the increase in hs-troponin I and hs-NT-proBNP levels.
Abstract 18012: Catheter-Based Label-Free Optical Coherence Tomography (OCT)-Fluorescence Lifetime Imaging (FLIM) for the Assessment of High-Risk Coronary Plaques
Authors: Sun Won Kim, Hyeong Soo Nam, Woo Jae Kang, Joon Woo Song, Min Woo Lee, Tae-Shik Kim, Wang-Yuhl Oh, Hongki Yoo, Jin Won Kim
Journal: Circulation (2017)

Background: Plaque destabilization is associated with lipid-rich core containing abundant macrophages, however, there is a lack of high-resolution imaging enabling such level of plaque characteriza...
Abstract A37: Tobacco smoke increases lung adenocarcinoma risk by downregulating TGF-beta and AhR-regulated focal adhesion proteins involved in injury resolution
Authors: Theresa Ryan Stueve, Chenchen Yang, Crystal N. Marconett, Chunli Yan, Beiyun Zhou, Zea Borok, Ite A. Laird-Offringa
Journal: Clinical Cancer Research (2018)

Abstract Background: The most prevalent type of lung cancer—lung adenocarcinoma—arises from the most distal reaches of the lung in the alveolar epithelium. The alveolar epithelium consists of two cell types: (i) thin type I alveolar epithelial cells (AT1) that facilitate gas exchange and constitute more than 90% of the alveolar surface, and (ii) cuboidal surfactant-producing type II (AT2) cells. Following injury, dynamic interactions between extracellular matrix components, integrins, focal adhesion proteins, and cytoskeletal components allow AT2 progenitor cells to migrate, spread, and transdifferentiate into AT1 cells to restore the denuded epithelial barrier. Methods: Utilizing primary human AT2 cells isolated from lung transplant remnants, our lab has established and extensively profiled an in vitro model of epithelial restitution, wherein AT2 cells differentiate over a period of six days into terminally differentiated AT1-like cells. Because cigarette smoking is the most recognized risk factor for lung adenocarcinoma (LUAD), and because the alveolar space is the primary target of tobacco smoke, we also compared the RNA-seq profiles of AT2&amp;gt;AT1 differentiation to those of A549 LUAD cells exposed to cigarette smoke condensate (CSC). Results: We find that CSC downregulates many factors that are upregulated in the AT2&amp;gt;AT1 restitution model, particularly integrins, extracellular matrix components, and novel focal adhesion proteins that are also downregulated in LUAD relative to adjacent normal tissue. We describe regulation of four such novel focal adhesion proteins, specifically by TGF-β and aryl hydrocarbon receptor (AhR)-mediated mechanisms. Conclusions: Our findings shed light on early mechanisms in the carcinogenic process, and support the notion that alveolar cells engaged in repeated cycles of injury and repair are critical actors in LUAD risk trajectories. Note: This abstract was not presented at the conference. Citation Format: Theresa Ryan Stueve, Chenchen Yang, Crystal N. Marconett, Chunli Yan, Beiyun Zhou, Zea Borok, Ite A. Laird-Offringa. Tobacco smoke increases lung adenocarcinoma risk by downregulating TGF-beta and AhR-regulated focal adhesion proteins involved in injury resolution [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A37.
The New American Joint Committee on Cancer TNM Staging System for Pancreatic Cancer—Balancing Usefulness With Prognostication
Authors: Colin M. Court, O. Joe Hines
Journal: JAMA Surgery (2018)

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Author Correction: Parent-of-origin-specific signatures of de novo mutations
Authors: Jakob M Goldmann, Wendy S W Wong, Michele Pinelli, Terry Farrah, Dale Bodian, Anna B Stittrich, Gustavo Glusman, Lisenka E L M Vissers, Alexander Hoischen, Jared C Roach, Joseph G Vockley, Joris A Veltman, Benjamin D Solomon, Christian Gilissen, John E Niederhuber
Journal: Nature Genetics (2018)
Diagnosing male infertility
Authors: James Wall, Channa N Jayasena
Journal: BMJ (2018)

### What you need to know

Around 1 in 7 couples in the UK1 seek treatment for infertility when they are unable to conceive, despite regular unprotected intercourse. Male infertility describes any factor in men that may prevent a couple from becoming pregnant. In nearly half of infertility cases, the male partner has suboptimal sperm parameters.23 Some cases of idiopathic infertility may have underlying male aetiology. Both partners need to be assessed for infertility, so the couple should ideally be seen together. In this practice pointer, we discuss a practical approach for non-specialists to diagnose male factor infertility in primary care.

In about a third of patients, no cause is identified.2 The infographic outlines common causes such as hormonal, testicular, or obstructive factors. In a prospective cohort study of 1737 men with infertility, undescended testes (10.7%), genetic abnormalities (7.8%), and obstruction (5.9%) were the most common causes.4 Sixty percent of participants in that study were overweight or obese, which may cause sperm DNA damage and suppress reproductive hormone secretion.5 Genitourinary infection, urological surgery during childhood, and illicit drugs are common and under-recognised causes of male infertility. Varicoceles increase scrotal temperature and reduce testicular perfusion.6 A meta-analysis of observational studies noted that varicoceles were associated with reduced sperm quality.7 Forty percent of men with primary infertility …