tbuckley/cabot-search huggingface dataset:
Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer
Authors: Hongbo Wang, Zaiming Lu, Xiangxuan Zhao
Journal: Journal of Hematology & Oncology (2019)

Abstract Hepatocellular carcinoma (HCC, also called primary liver cancer) is one of the most fatal cancers in the world. Due to the insidiousness of the onset of HCC and the lack of effective treatment methods, the prognosis of HCC is extremely poor, and the 5-year average survival rate is less than 10%. Exosomes are nano-sized microvesicle and contain various components such as nucleic acids, proteins, and lipids. Exosomes are important carriers for signal transmission or transportation of material from cell to cell or between cells and tissues. In recent years, exosomes have been considered as potential therapeutic targets of HCC. A large number of reports indicate that exosomes play a key role in the establishment of an HCC microenvironment, as well as the development, progression, invasion, metastasis, and even the diagnosis, treatment, and prognosis of HCC. However, the exact molecular mechanisms and roles of exosomes in these processes remain unclear. We believe that elucidation of the regulatory mechanism of HCC-related exosomes and its signaling pathway and analysis of its clinical applications in the diagnosis and treatment of HCC can provide useful clues for future treatment regimens for HCC. This article discusses and summarizes the research progress of HCC-related exosomes and their potential clinical applications.
Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation
Authors: Janet Chou, Anas M. Alazami, Faris Jaber, Rodrigo Hoyos-Bachiloglu, Jennifer Jones, Sabrina Weeks, Mohammed F. Alosaimi, Wayne Bainter, Brittney Cangemi, Yousef R. Badran, Reem Mohammed, Fayhan Alroqi, Abduarahman Almutairi, Noufa Al-Onazi, Sulaiman AlAjaji, Bander Al-Saud, Rand Arnaout, Megan Elkins, Sridevi Devana, Juliet Imperial, Betty Li, Linnea Drexhage, Anas M. Abdel Rahman, Minnie Jacob, Hadi Haddad, Rima Hanna-Wakim, Ghassan Dbaibo, Michel J. Massaad, Majed Dasouki, Raymond Mikhael, Zeina Baz, Raif S. Geha, Hamoud Al-Mousa
Journal: Journal of Allergy and Clinical Immunology (2019)
Periodontal therapeutics: Current host‐modulation agents and future directions
Authors: Lorne M. Golub, Hsi‐Ming Lee
Journal: Periodontology 2000 (2019)

Abstract With the recognition in the 1960s and 1970s of the periodontopathic importance of the microbial biofilm and its specific anaerobic microorganisms, periodontitis was treated as an infectious disease (more recently, as a dysbiosis). Subsequently, in the 1980s, host‐response mechanisms were identified as the mediators of the destruction of the collagen‐rich periodontal tissues (gingiva, periodontal ligament, alveolar bone), and the periodontopathogens were now regarded as the "trigger" of the inflammatory/collagenolytic response that characterizes actively destructive periodontitis. Also at this time a new pharmacologic strategy emerged, entitled "host‐modulation therapy", based on 2 major findings: (1) that the ability of tetracycline antibiotics to inhibit periodontal breakdown was due (in large part) to their previously unrecognized ability to inhibit the host‐derived matrix metalloproteinases (notably, the collagenases, gelatinases, macrophage metalloelastase), and by mechanisms unrelated to the antimicrobial properties of these medications; and (2) that nonsteroidal anti‐inflammatory drugs, such as flurbiprofen, again by nonantimicrobial mechanisms, could reduce the severity of periodontitis (however, the adverse effects of long‐term therapy precluded their development as safe and effective host‐modulatory agents). Additional mechanistic studies resulted in the development of novel nonantimicrobial formulations (Periostat® [now generic] and Oracea®) and compositions of tetracyclines (notably chemically modified tetracycline‐3) as host‐modulator drugs for periodontitis, arthritis, cardiovascular and pulmonary diseases, cancer, and, more recently, for local and systemic bone loss in postmenopausal women. Identification of the cation‐binding active site in the tetraphenolic chemically modified tetracycline molecules drove the development of a new category of matrix metalloproteinase‐inhibitor compounds, with a similar active site, the biphenolic chemically modified curcumins. A lead compound, chemically modified curcumin 2.24, has demonstrated safety and efficacy in vitro, in cell culture, and in vivo in mouse, rat, rabbit, and dog models of disease. In conclusion, novel host‐modulation compounds have shown significant promise as adjuncts to traditional local therapy in the clinical management of periodontal disease; appear to reduce systemic complications of this all‐too‐common "inflammatory/collagenolytic" disease; and Oracea® is now commonly prescribed for inflammatory dermatologic diseases.
Abstract A09: CD4 T cells mediated protumorigenic pathway in pancreatic cancer
Authors: Prasenjit Dey, Jun Li, Jianhua Zhang, Huamin Wang, Wen-Ting Liao, Vincent P Bernard, Giannicola Genovese, Anirban Maitra, Anders Strom, Ronald A. DePinho
Journal: Cancer Research (2019)

Abstract A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. This Kras*-driven heterotypic signaling circuit in the early and advance tumor microenvironment enables cooperative protumorigenic interactions in early steps of the neoplastic transformation process as well as in promoting growth of established tumors, providing novel therapeutic targets in the Kras* pathway for this intractable disease. Here, we explored the role of Kras* in protumorigenic signaling interactions between cancer cells and host cells in tumor microenvironment. Early-stage malignant lesions and advanced tumors show close proximity of Kras* expressing cancer cells and abundant invading TH2 (CD4+ Gata-3+) cells, which can produce IL-4 and IL-13. Single-cell analysis of low- and high-grade IPMN and PDAC patient samples revealed CD4+ T-cell infiltration and higher percentage of the CD4+ T cells are Gata3+ TH2 subtypes compared to T-bet+ TH1 cells. Similarly, imaging mass spectrometry analysis showed presence of CD4+ T cells in close proximity to cancer cells. Mechanistic studies identified Jak1-Stat6 as the primary signaling pathway downstream of IL-4/IL-13 activated IL-4 receptor complexes in cancer cells. Integrated transcriptomic and chromatin immunoprecipitation sequencing (ChIP-seq) profiling identified cMyc, specifically its upstream enhancer element, as a direct target of activated Stat6. Metabolomic analysis demonstrated that IL-4/13STAT6cMyc upregulation drives increased glycolysis along with upregulated expression of key glycolysis enzymes, forging a link between Kras*-driven glycolysis via paracrine activation of cMyc. Citation Format: Prasenjit Dey, Jun Li, Jianhua Zhang, Huamin Wang, Wen-Ting Liao, Vincent P Bernard, Giannicola Genovese, Anirban Maitra, Anders Strom, Ronald A. DePinho. CD4 T cells mediated protumorigenic pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A09.
Abstract 15421: Rapid Cardioversion of Recent-Onset Atrial Fibrillation in the Emergency Department With Vernakalant: Insights From the Multinational Spectrum Registry
Authors: Beate Ritz, Alfonso Martin, José L Merino, Johan-Emil Bager, Hans Domanovits, Todd Juhlin, Samuel Levy, W.Douglas Weaver, Juha Hartikainen, Jose Carbajosa
Journal: Circulation (2019)

Introduction: Vernakalant is a relatively atrial-selective antiarrhythmic agent for conversion of recent-onset atrial fibrillation (AF). SPECTRUM was a post-authorisation safety study of vernakalan...
SX-007, a small molecule TGF-β receptor I kinase inhibitor, prolongs animal survival in the syngeneic SMA560 glioma model
Authors: Thomas-Toan Tran, Jing Ying Ma, Irene Kerr, Lisa Janssen, Ann Kapoun, Andrew Lam, Glenn McEnroe, Barry Hart, Jonathan Axon, Alison Murphy, Andrew A. Protter, Linda S. Higgins, Darren H. Wong
Journal: Cancer Research (2005)

6033  Many cancers overexpress transforming growth factor beta (TGF-β), a protein that plays a major role in tumor progression by regulating cell proliferation, angiogenesis, metastasis and immunosupression. Glioblastoma multiformae (GBM) is one such cancer. TGF-β secretion may play a role in the highly invasive nature of the disease and appears to be responsible for the suppressed immune system in GBM patients. The therapeutic potential of SX-007, an orally bioavailable small molecule TGF-β RI kinase inhibitor (IC50=33 nM), was investigated in the SMA560 model, a syngeneic murine model of glioma. SMA560 cells were implanted into the right striatum of male VM/Dk mice. Dosing began three days after implanting tumor cells and continued until the end of the study. The efficacy of SX-007 was assessed at 5, 20 and 40 mg/kg po qd in the SMA560 model. Maximal efficacy was observed at 20 mg/kg (median survival=24 days). Increasing dosing from 20 mg/kg once to twice daily did not result in improved survival benefit. From each study, approximately 20% of animals from the groups dosed with 20 mg/kg SX-007 remained alive at the end of the study (Day 35). These long-term survivors appear to be disease-free. In a separate study, the animals were sacrificed at Day 15 and brain tissue removed to verify that SX-007 reached the site of action. The levels of phosphorylated Smad 2/3 and transcription of TGF-β related genes (most notable, PAI-1) were reduced in tumors from compound-treated animals confirming an inhibition of TGF-β signaling. In addition, there was increased CD3+ T-cell infiltration into the tumor and a concomitant increase in caspase-3 staining in the brain tissue of compound-treated animals as measured by immunohistochemistry demonstrating a functional consequence of inhibiting TGF-β signaling. SX-007 can modulate TGF-β signaling pathway in vivo and treatment with SX-007 is associated with an improvement in animal survival. Survival benefit is due, at least in part, to a reversal of the immune suppressed state allowing for rejection of the tumor. Thus SX-007 may be useful in the treatment of glioblastoma.
The Elusive Nature of Delay Discounting as a Transdiagnostic Process in Psychiatric Disorders—The Devil Is in the Detail
Authors: Joseph A. King, Stefan Ehrlich
Journal: JAMA Psychiatry (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Rescue ERCP after delayed migration of a lumen-apposing metal stent following endoscopic ultrasound-guided choledochoduodenostomy
Authors: Claudio Zulli, Jean-Loup Dumont, Fabrizio Cereatti, Vincenzo Ceci, Thierry Tuszynski, Maurizio Fazi, Gianfranco Donatelli
Journal: Endoscopy (2019)

Endoscopic retrograde cholangiopancreatography (ERCP) can be challenging in patients with altered anatomy or luminal narrowing. Endoscopic ultrasound-guided biliary drainage (EUS-BD) by placement of a lumen-apposing metal stent (LAMS; Hot-Axios; Boston Scientific, Marlborough, Massachusetts, USA) has emerged as an effective technique to allow biliary access after failed ERCP in a high-volume center [1].
The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest
Authors: Alexandre Pichard, Sara Marcatili, Jihad Karam, Julie Constanzo, Riad Ladjohounlou, Alan Courteau, Marta Jarlier, Nathalie Bonnefoy, Sebastian Patzke, Vilde Stenberg, Peter Coopman, Guillaume Cartron, Isabelle Navarro-Teulon, Ada Repetto-Llamazares, Helen Heyerdahl, Jostein Dahle, Manuel Bardiès, Jean-Pierre Pouget
Journal: Leukemia (2019)

Abstract Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 ( 177 Lu)-lilotomab (Betalutin ® ) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177 Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt’s lymphoma) cell xenografts, 177 Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177 Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177 Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177 Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177 Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.
Academic publishers urge Trump not to demand open access for federally funded research
Authors: Owen Dyer
Journal: BMJ (2019)

More than 125 journal publishers and scientific and medical societies have signed a letter to Donald Trump asking him to reverse a policy they believe is being prepared that would require any journal publishing research that received US federal funding to make the article freely available without a subscription, immediately on publication.1

Currently, under the terms of a 2013 agreement, journal publishers may charge readers for federally funded research articles for 12 months from publication, after which the paywall must come down.

The revenue from those 12 months is essential to pay the costs of publication, the letter’s signatories argue. But, they write, “we have learned that …
Tracheomalacia and bronchomalacia in children: response to the ERS statement
Authors: Colin Wallis, Kostas Priftis, Anne Chang, Fabio Midulla, Jayesh Bhatt
Journal: European Respiratory Journal (2019)

<b>A working definition for tracheobronchomalacia in children is provided in the task force document published by the ERS in 2019. This may require review in due course as further research into the dynamic aspects of malacia and clinical correlation emerges.</b>http://bit.ly/2rNuq08
Bend it like Beckham or fix them like Florence—proportional representation of healthcare in New Year honours: an observational study
Authors: John A Emelifeonwu, James E Hazelwood, Oscar Nolan, Emma Sharland, Anna O’Donald, Alison Peet, Ricky Frazer
Journal: BMJ (2019)

Abstract Objectives To compare the proportional representation of healthcare workers in receipt of New Year honours (NYHs) with workers in other industries and to determine whether the NYH system has gender or geographical biases. Design Observational study of the UK honours system with a comparative analysis of proportional representation of the UK workforce and subgroup analyses of gender and geographical representations. Participants Recipients of NYHs from 2009 to 2018. Main outcome measures Absolute risk of receiving an NYH based on industry, gender, or region of the UK. Relative risk of receiving an NYH for services to healthcare compared with other industries. Results 10 989 NYHs were bestowed from 2009 to 2018, 47% of which were awarded to women. 832 awards (7.6%) were for services to healthcare. People working in sport and in the arts and media were more likely to receive NYHs than those working in healthcare (relative risks of 22.01 (95% confidence interval 19.91 to 24.34) and 5.84 (5.31 to 6.44), respectively). There was no significant difference between the rate of receiving honours for healthcare and for science and technology (P=0.22). 34% (3741) of awards were issued to people living in London and in the southeast of England, and only 496 of 1447 (34%) higher order awards (knighthoods, damehoods, companions of honour, and commanders of the order of the British empire) were received by women. Conclusions In relation to the size of its workforce, a career in healthcare is not as “honourable” as careers in certain other industries. Geographical and gender biases might exist in the honours system.
Dolutegravir-Based or Low-Dose Efavirenz–Based Regimen for the Treatment of HIV-1
Authors: Charles Kouanfack, Mireille Mpoudi-Etame, Pierrette Omgba Bassega, Sabrina Eymard-Duvernay, Sandrine Leroy, Sylvie Boyer, Martine Peeters, Alexandra Calmy, Eric Delaporte
Journal: New England Journal of Medicine (2019)

An efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz–based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings.
Abstract I14: Polymerase theta synthetic lethal interaction in homologous recombination-deficient pancreatic ductal adenocarcinoma
Authors: Annie Wang, Andrea Zamperone, Mohammad Sohail, Lidong Wang, Fiyinfolu Balogun, Jiufeng Li, Ende Zhao, Daniel Diolaiti, Agnel Sfeir, Diane M. Simeone
Journal: Cancer Research (2019)

Abstract Recent genomic characterization of PDA reveals that between 20-25 % of PDA harbor recurrent mutations in genes, including BRCA1/2, PALB2, and ATM, which are critical for homologous recombination (HR), an important form of DNA repair. In many patients, these may be germline mutations. This subgroup of PDAs, termed HR-deficient PDA, has emerged as a defined biological entity associated with increased chemoresistance and a more aggressive disease course. The defects in HR observed in these tumors impart cells with a specific vulnerability to PARP inhibitors and platinum-containing therapy. Still, as observed in the case of many other targeted therapies, only a fraction of HR-defective patient tumors respond to PARP inhibition. More so, many patients that initially respond eventually often develop resistance and progress. Therefore, novel therapies which can be effective against HR-defective PDA, alone or in combination with PARP inhibitors or other combinatorial regimens, are urgently needed. We have recently determined that inactivation of the HR pathway is associated with overexpression of polymerase theta (PolO–, also known as POLQ) in PDA. POLQ is a key enzyme that regulates an alternative pathway of DNA repair, known as the alternative non-homologous end-joining (Alt-NHEJ) pathway. In the setting of defective HR, Alt-NHEJ becomes a critical pathway responsible for the repair of DNA breaks and POLQ inhibition in HR-defective tumor cells demonstrates a synthetic lethality phenotype, not observed in cells with intact HR. Furthermore, POLQ knockdown significantly upregulated the cGAS-STING pathway in HR-deficient PDAs linking the DNA damage response to the immune response. Overall, targeting POLQ may represent a novel and in a valuable therapeutic strategy in HR-defective pancreatic cancer, as POLQ inhibitors are currently in development for clinical use. Citation Format: Annie Wang, Andrea Zamperone, Mohammad Sohail, Lidong Wang, Fiyinfolu Balogun, Jiufeng Li, Ende Zhao, Daniel Diolaiti, Agnel Sfeir, Diane M. Simeone. Polymerase theta synthetic lethal interaction in homologous recombination-deficient pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I14.
Identifying the ‘incredible’! Part 2: Spot the difference - a rigorous risk of bias assessment can alter the main findings of a systematic review
Authors: Fionn Büttner, Marinus Winters, Eamonn Delahunt, Roy Elbers, Carolina B Lura, Karim M Khan, Adam Weir, Clare L Ardern
Journal: British Journal of Sports Medicine (2019)

Systematic reviews are a valuable tool to inform healthcare decision-making.1 2 While a single randomised controlled trial (RCT) is insufficient to definitively guide healthcare decisions, a systematic review synthesising multiple RCTs can overcome this limitation. The results of rigorous systematic reviews possess wide-ranging applicability to numerous stakeholders within the evidence-based medicine ‘ecosystem’. Clinicians consult systematic reviews to inform their clinical decisions.3 Researchers rely on systematic reviews to identify knowledge gaps in existing literature.4 Health policymakers use systematic review evidence to inform practice guidelines and legislation.5 6 Journal editors often prioritise systematic reviews for their impact on readership attention and journal metrics.7 Finally, patients are empowered by systematic reviews that assess the beneficial and harmful patient-important outcomes of available management strategies.8 Evidently, systematic review authors have an important responsibility to ensure their findings provide the most accurate results possible.

The biomedical literature expands by 22 systematic reviews daily,9 with no evidence that production is waning. More systematic reviews are desirable if they identify and inform important research questions that improve patient care.10 However, production of this magnitude is problematic when systematic reviews offer ‘extensive redundancy, little value, misleading claims and/or vested interests’.11 As we outlined in part 1, bias is a systematic deviation from the truth in the results of a research study due to limitations in study design, conduct, or analysis.2 Deviations may either overestimate or underestimate a study’s true findings depending of the type and magnitude of bias. As the results of a systematic review are only as valid as the studies it includes, pooling biased results from different studies can compromise the credibility of systematic review findings when no assessment, or a poor assessment, of risk of bias is performed.3 12

Inadequate study design, conduct, or analysis …
Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis
Authors: Maren H Harms, Rozanne C de Veer, Willem J Lammers, Christophe Corpechot, Douglas Thorburn, Harry L A Janssen, Keith D Lindor, Palak J Trivedi, Gideon M Hirschfield, Albert Pares, Annarosa Floreani, Marlyn J Mayo, Pietro Invernizzi, Pier Maria Battezzati, Frederik Nevens, Cyriel Y Ponsioen, Andrew L Mason, Kris V Kowdley, Bettina E Hansen, Henk R van Buuren, Adriaan J van der Meer
Journal: Gut (2019)

The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC.