tbuckley/cabot-search huggingface dataset:
Patterns of care and treatment outcomes in older patients with biliary tract cancer.
Authors: Anne M. Horgan, Mairead G McNamara, Priya Aneja, Lisa W Le, Elizabeth McKeever, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2014)

315 Background: Although cancers of the biliary tree (BTC) are more common in older age-groups, treatment approaches and outcomes are understudied in this population. Methods: Data from 913 patients diagnosed with BTC from January 1987 to July 2013 and treated at Princess Margaret Cancer Center, Toronto were analyzed. The impact of age, patient and disease characteristics on survival outcomes were assessed. Results: Five hundred and ninety four patients ≤70 years and 319 patients &gt;70 years were identified. Older patients were less likely to receive active therapy - 154 (26%) patients ≤70 yrs received best supportive care alone compared to 130 (41%) of those &gt;70 yrs; p&lt;0.0001. The characteristics of those receiving active therapy (surgery +/- chemotherapy) are shown (table). For patients receiving active treatment, ECOG PS (p=0.002) and disease stage (p&lt;0.0001) independently predicted overall survival. Adjusting for these variables, median survival did not differ between older and younger patients, median survival 20.1 (95% CI [17.8, 23.3]) and 20.5 (95% CI [18.7, 23]) months respectively; HR 1.064 (95% CI [0.86, 1.32]). Conclusions: In this large retrospective analysis, older patients with BTC are less likely to undergo surgery or chemotherapy. Active therapy results in similar survival benefits, irrespective of age. [Table: see text]
The Flower of Paradise: The Institutionalized Use of the Drug Qat in North Yemen.
Journal: Annals of Internal Medicine (1987)

I. Introduction.- II. History and Social Structure of North Yemen.- III. A Short History of Qat and Its Use.- IV. A Social Institution.- V. The Qat Experience.- VI. The Agriculture and Economics of Qat.- VII. The Botany, Chemistry and Pharmacology of Qat.- VIII. Qat and the Question of Addiction.- IX. Qat and Health.- X. Conclusion.- Name Index.
COVID-19 and nicotine as a mediator of ACE-2
Authors: Janice M. Leung, Chen Xi Yang, Don D. Sin
Journal: European Respiratory Journal (2020)

We recently reported that current smokers and those with COPD had higher airway epithelial cell expression of the angiotensin-converting enzyme II (ACE-2) viral entry receptor [1]. We thus read with great interest the work of P. Russo and co-workers, which proposes a mechanism for this finding, namely that this upregulation is mediated by nicotine exposure specifically through the α7 subtype of nicotine acetylcholine receptors (α7-nAChR). While exposure to increasing concentrations of nicotine caused epithelial cells to increase ACE-2 levels, subsequent gene silencing of α7-nAChR appeared to significantly dampen this response. A secondary transcriptome sequencing analysis of our cohort (consisting of 42 subjects who underwent bronchoscopy for epithelial cell brushings [1]) reveals evidence in support of this hypothesis. α7-nAChR may upregulate ACE-2 <https://bit.ly/2xS0cfT>
The black sheep of class IIa: HDAC7 SIKens the heart
Authors: Joshua G. Travers, Tianjing Hu, Timothy A. McKinsey
Journal: Journal of Clinical Investigation (2020)

Class IIa histone deacetylases (HDACs) repress cardiomyocyte hypertrophy through association with the prohypertrophic transcription factor (TF) myocyte enhancer factor-2 (MEF2). The four class IIa HDACs - HDAC4, -5, -7, and -9 - are subject to signal-dependent phosphorylation by members of the Ca2+/calmodulin-dependent protein kinase (CaMK) group. In response to stress, HDAC4, HDAC5, and HDAC9 undergo phosphorylation-induced nuclear export in cardiomyocytes, freeing MEF2 to stimulate progrowth genes; it was generally assumed that HDAC7 is also antihypertrophic. However, in this issue of the JCI, Hsu and colleagues demonstrate that, in sharp contrast to the other class IIa HDACs, HDAC7 is constitutively localized to the cardiomyocyte cytoplasm, where it promotes cardiac hypertrophy. Phosphorylation of HDAC7 by the CaMK group member salt-inducible kinase 1 (SIK1) stabilized the deacetylase, leading to increased expression of c-Myc, which in turn stimulated a pathological gene program. These unexpected findings highlight the SIK1/HDAC7 signaling axis as a promising target for the treatment of cardiac hypertrophy and heart failure.
Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice
Authors: Karsten Boldt, Dorus A. Mans, Jungyeon Won, Jeroen van Reeuwijk, Andreas Vogt, Norbert Kinkl, Stef J.F. Letteboer, Wanda L. Hicks, Ron E. Hurd, Jürgen K. Naggert, Yves Texier, Anneke I. den Hollander, Robert K. Koenekoop, Jean Bennett, Frans P.M. Cremers, Christian J. Gloeckner, Patsy M. Nishina, Ronald Roepman, Marius Ueffing
Journal: Journal of Clinical Investigation (2011)

The mutations that cause Leber congenital amaurosis (LCA) lead to photoreceptor cell death at an early age, causing childhood blindness. To unravel the molecular basis of LCA, we analyzed how mutations in LCA5 affect the connectivity of the encoded protein lebercilin at the interactome level. In photoreceptors, lebercilin is uniquely localized at the cilium that bridges the inner and outer segments. Using a generally applicable affinity proteomics approach, we showed that lebercilin specifically interacted with the intraflagellar transport (IFT) machinery in HEK293T cells. This interaction disappeared when 2 human LCA-associated lebercilin mutations were introduced, implicating a specific disruption of IFT-dependent protein transport, an evolutionarily conserved basic mechanism found in all cilia. Lca5 inactivation in mice led to partial displacement of opsins and light-induced translocation of arrestin from photoreceptor outer segments. This was consistent with a defect in IFT at the connecting cilium, leading to failure of proper outer segment formation and subsequent photoreceptor degeneration. These data suggest that lebercilin functions as an integral element of selective protein transport through photoreceptor cilia and provide a molecular demonstration that disrupted IFT can lead to LCA.
Response to: ‘Questions on ‘Sequencing of the MHC region defines<i>HLA-DQA</i>1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population’ by Guo<i>et al</i>’ by Regueiro and Gonzalez
Authors: Jianping Guo, Tao Zhang, Xiaowei Li, Hongzhi Cao, Zhanguo Li
Journal: Annals of the Rheumatic Diseases (2020)

We appreciate Dr Gonzalez’s interest and comments on our recent publication ‘Sequencing of the major histocompatibility complex (MHC) region defines human leukocyte antigen (HLA)-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population’.1 2 Dr Gonzalez’s comments provide us with an opportunity to clarify and discuss the frequencies of amino-acids at position DQα1:160 and the protective association of DRβ1:37N in rheumatoid arthritis (RA), and to improve our study.

One of the concerns Dr Gonzalez expressed is the frequencies of three amino-acids (Asp (D), Ala (A) and Ser (S)) at DQα1:160 do not sum up to 1.0, that is, 0.20, 0.22 and ≈0.02 in controls; 0.36, 0.37 and ≈0.01 in RA patients. The explanation is that the ‘minor frequencies’ was set as default …
William Frankland: the “grandfather of allergy”
Authors: John Illman
Journal: BMJ (2020)

Photo credit: Imperial College London

William Frankland (“Bill”), the British clinical allergist who transformed global understanding of allergies, has died aged 108. He developed the pollen count in order to help people with hay fever, worked with Alexander Fleming, treated the Iraqi president Saddam Hussein, and survived three and a half years as a Japanese prisoner of war. Working for the NHS for 70 years, he published several papers as a centenarian, the last in 2019. A little more than a year ago, he was still jetting off to international conferences and communicating with patients.

Frankland combined a unique scientific talent with humanity and compassion. I knew him when he was on the General Practitioner editorial advisory board while I was editor. He was easy going, modest, and humorous, with an incisive intellect and a passion for communicating with both professional and lay audiences.

His landmark discovery in 1954, in a trial published in the Lancet , showed how pre-season injections of the protein component of pollen greatly reduced symptoms of hay fever and asthma in the hay fever season.

Concerned that there was no guidance for patients about the duration of the pollen season, Frankland mounted a “pollen trap” on the roof of St Mary’s Hospital, London, to identify different types of pollen. The automatic volumetric spore trap could sample eight litres of air per minute. Beginning in the early 1960s, Frankland or a colleague reported the daily count at 10 30 am to the Times and the Daily Telegraph . Pollen counts now feature in weather …
Covid-19: UK advisory panel members are revealed after experts set up new group
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The UK government has disclosed some of the members of its Scientific Advisory Group for Emergencies (SAGE) after being criticised for a lack of transparency over its handling of the covid-19 pandemic and concerns over who was attending meetings.

A list of the SAGE membership has been published,1 with two names withheld because of a lack of consent over being named. Fifty members have been listed, including some that were already known, such as Neil Ferguson from Imperial College London, whose modelling study led to the government tightening restrictions.2

Responding to the publication, the chair of the parliamentary Science and Technology Committee, Greg Clark, said, “This was something my committee called for in order to provide public reassurance that government decisions …
Efficacy of BCG vaccine
Authors: E. Bellin
Journal: JAMA (1994)

To the Editor.  —In their meta-analysis of the published literature on BCG vaccine, Dr Colditz and colleagues 1 attempt to summarize BCG's protective effect by building a statistical model with variables for geographic latitude and validity scores. Geographic latitude is a variable without biological cogency (though some stretches have been attempted), yet it is retained in the model because it conveniently explains 41% of the variability. I suspect that its primary function is to attenuate the impact of the largest, most recent, and most damaging prospective study on the thesis that BCG vaccine is effective—the Madras study. 2 We should note that the Madras study is larger than the next three studies in size combined 1(Table 1) and found no protective effect. The Madras study was felt necessary at the time to finally prove the utility of BCG vaccine, yet its results are ignored without a call for additional study.
Covid-19: Concern about social care’s ability to cope with pandemics was raised two years ago
Authors: Michael Day
Journal: BMJ (2020)

Mounting criticism of UK ministers’ failure to prevent the spread of covid-19 through care homes has been fanned by the leak of a government report from two years ago warning that the country was ill prepared for the next pandemic.

Based on the findings of a government simulation of a flu pandemic, codenamed Exercise Cygnus, the 57 page Public Health England document, passed to the Guardian , concluded that the UK would be unable to cope with the “extreme demands” of a flu-like pandemic.

In particular it raised concerns about the social care system’s ability to provide the level of support people needed, raising questions over whether ministers ever implemented any of the document’s 26 recommendations, including boosting the capacity of care homes and staff numbers. It also warned of the challenge facing homes asked …
Abstract P047: Association of 1,5-anhydroglucitol with Subclinical Cardiovascular Disease
Authors: Menglu Liang, John William (Bill) McEvoy, Yuan Chen, A. Richey Sharrett, Elizabeth Selvin
Journal: Circulation (2016)

Introduction: Serum 1,5-anhydroglucitol (1,5-AG) concentrations decrease in the setting of acute hyperglycemia, making 1,5-AG a useful biomarker of glucose peaks. In recent studies, 1,5-AG has been associated with clinical cardiovascular disease events. However, the association between 1,5-AG and subclinical vascular disease is unknown. Hypothesis: 1,5-AG will be associated with subclinical myocardial damage (assessed by cardiac troponin T measured using a novel highly sensitive assay (hs-cTnT)) and subclinical atherosclerosis (assessed by ultrasound-detected carotid intima-media thickness (cIMT)), particularly in persons with diabetes. Methods: We measured 1,5-AG in 10,753 participants in the ARIC Study at visit 2 (1990[[Unable to Display Character: &amp;#8211;]]1992) and conducted a cross-sectional analysis to characterize the associations of 1,5-AG with elevated hs-cTnT (≥ 14 ng/L) or thick cIMT (top quartile, ≥0.79 mm) using logistic regression models. We also evaluated the prospective association between baseline 1,5-AG and incident elevated hs-cTnT at 6-years using Poisson regression models. Results: Among diabetics, those with 1,5-AG &lt;6 ug/mL were 5 times more likely to have prevalent elevated hs-TnT at baseline compared to non-diabetics with 1,5-AG &gt;10 ug/mL (adjusted OR 4.67, 95%CI, 3.27[[Unable to Display Character: &amp;#8211;]]6.68) and almost 2 times more likely to be in the top quartile of the cIMT (adjusted OR 1.75, 95%CI 1.39-2.19). 1,5-AG &lt;6 ug/mL in persons with diabetes was also significantly associated with 6-year incident elevated hs-TnT: RR 2.26 (95%CI, 1.50[[Unable to Display Character: &amp;#8211;]]3.39). The associations of 1,5-AG with elevated hs-TnT and thick cIMT were non-linear and mostly driven by persons with diabetes (Figure). Conclusions: 1,5-AG was associated with prevalent and incident subclinical cardiovascular disease in persons with diabetes in the community. Our results suggest that glucose peaks may be relevant for the development of subclinical cardiac damage and atherosclerosis in persons with diabetes.
Abstract 9561: Undernourishment and Atherosclerosis: A Study of Carotid Plaque and Aortic Calcification With Outcomes
Authors: Shih-Chieh Chien, Chun-Ho Yun, Chung-lieh Hung, Hung-I Yeh
Journal: Circulation (2019)

Introduction: Undernourishment in the context of low serum albumin (SA) was tightly associated with atherosclerotic diseases. However, its clinical correlate with thoracic calcification burden (TAC...
Public/private partnerships, at what price?
Authors: Maarten Boers
Journal: Annals of the Rheumatic Diseases (2020)

Public/private partnerships, at what price?From a scientific viewpoint, Huizenga and colleagues are completely right to endorse 'disruption' by public-private partnerships as a way to 'accelerate innovation and enable translation of the rapidly expanding cellular and molecular understanding of disease pathogenesis into the development of new therapeutic agents'. 1 However, one of their examples (monoclonal antibodies leading to the development of anti-tumour necrosis factor (TNF) treatment) highlights an aspect they did not discuss: publicly funded science leading to drugs marketed at prices society cannot afford.In my opinion, the current model of drug development is broke and also needs to be disrupted.I say this in full awareness of the many great advances for example the field of rheumatology has enjoyed.A recent study by SOMO, an independent organisation that researches multinationals, suggests that pharmaceutical companies have switched from innovation to financial instruments in order to sustain themselves and increase their profitability. 2Also, drug development is mostly targeted at areas of high potential profit, including diseases where orphan status can be obtained, rather than areas of high societal need.From the company's and shareholder's viewpoint, this is entirely legitimate.But from the societal viewpoint, it is highly suboptimal.We need to fundamentally rethink how we want to progress science and drug development, so that new treatments can become available at affordable prices.As an aside, this includes a rethink on the outrageously complex, slow and expensive process of drug approval.For now, scientists and society should become less naive and wary of partnerships in which they offer knowledge 'for free', with nothing in return except the opportunity to buy back the results of their knowledge at premium prices.
Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis
Authors: Karin Hartmann, Jason Gotlib, Cem Akin, Olivier Hermine, Farrukh T. Awan, Elizabeth Hexner, Michael J. Mauro, Hans D. Menssen, Suman Redhu, Stefanie Knoll, Karl Sotlar, Tracy I. George, Hans-Peter Horny, Peter Valent, Andreas Reiter, Hanneke C. Kluin-Nelemans
Journal: Journal of Allergy and Clinical Immunology (2020)

Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level. We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM. In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated by using a specific physician-reported questionnaire. Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms. QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
Phase I/II study of docetaxel, ifosfamide, and doxorubicin in advanced, recurrent, or metastatic soft tissue sarcoma (STS)
Authors: R. Suppiah, G. T. Budd, L. Wood, P. Elson
Journal: Journal of Clinical Oncology (2005)

9060 Background: Based on early reports of efficacy of docetaxel (T) in STS, we undertook a single institution phase I/II trial to determine the response rate (RR), dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of the addition of T to doxorubicin (A) and ifosfamide (I) in advanced STS. Methods: Patients with PS 0–2, adequate end organ function, and advanced, recurrent, or metastatic STS without prior chemotherapy were enrolled in a dose escalation trial with mesna and G-CSF. Dose levels are shown in the table below. MTD was defined as the dose producing DLTs in 2 or greater of the 3–6 patients treated. Results: 21 patients were accrued. Median age: 55 (28–78) years. Histology: leiomyosarcoma 10, spindle cell sarcoma 3, synovial sarcoma 2, angiosarcoma 1, fibrous histiocytoma 1, epitheliod hemangio-endothelioma 1, and 3 not specified. Toxicities: Dose level I: 1 grade 3 leukopenia; 1 grade 4 neutropenia. Level II: 7 grade 3 hematologic; 2 grade 4 hematologic. Level III: 5 grade 3 hematologic; 14 grade 4 hematologic. Level IV: 2 grade 3 hematologic; 6 grade 4 hematologic. MTD was level III (A 60 mg/m2, I 6.0 g/m2, and T 60 mg/m2). DLT was myelosuppression. All grade 4 toxicities were hematologic. Other grade 3 toxicities included: fatigue in 1, hypocalcemia 1, hypokalemia 2, hyperglycemia 1. Patients received a median of 2 cycles (range 2–9). Eight patients (38%) achieved partial response (PR). PR occurred after six cycles in 5 patients. 17 of 21 patients died. Median overall survival: 17 months (95% CI, 9.1–33.6 months). Survival of the living patients: 33.5, 63, 65.3, and 70.3 months. Conclusions: The recommended Phase II dose of this combination is level III: A 60 mg/m2, I 6.0 g/m2, T 60 mg/m2, with mesna and G-CSF. The RR is similar to that of AI in other trials, however the survival is better than anticipated. T may have some activity in combination with other agents in STS. No significant financial relationships to disclose.
HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
Authors: Chiranjeevi Bodda, Line S. Reinert, Stefanie Fruhwürth, Timmy Richardo, Chenglong Sun, Bao-cun Zhang, Maria Kalamvoki, Anja Pohlmann, Trine H. Mogensen, Petra Bergström, Lotta Agholme, Peter O’Hare, Beate Sodeik, Mads Gyrd-Hansen, Henrik Zetterberg, Søren R. Paludan
Journal: The Journal of Experimental Medicine (2020)

Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain.
Abstract 12769: Improving Performance of Technetium-99m Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis
Authors: Daniel R Davies, John Wells W Askew, Joanne Benson, Panithaya Chareonthaitawee, Geoffrey Johnson, Robert Glynn, Eli Muchtar, Angela Dispenzieri, Morie A Gertz, Martha Grogan, Margaret M Redfield, Omar F AbouEzzeddine
Journal: Circulation (2019)

Introduction: Technetium-99m pyrophosphate (99mTc PYP) scintigraphy is considered reliable for the non-invasive diagnosis of transthyretin cardiac amyloidosis (TTR-CA). Conventional planar uptake r...
Age-Related EBV-Associated B-Cell Lymphoproliferative Disorders: Comparison with EBV-Positive Classical Hodgkin Lymphoma in Elderly Patients
Authors: Naoko Asano, Kazuhito Yamamoto, Jun-Ichi Tamaru, Takashi Oyama, Fumihiro Ishida, Koichi Ohshima, Tadashi Yoshino, Naoya Nakamura, Shigeo Mori, Osamu Yoshie, Yoshie Shimoyama, Yasuo Morishima, Tomohiro Kinoshita, Shigeo Nakamura
Journal: Blood (2008)
Study of the Quantitative, Functional, Cytogenetic and Immunoregulatory Properties of Bone Marrow Mesenchymal Stem Cells in Patients with B-Cell Chronic Lymphocytic Leukemia
Authors: Charalampos Pontikoglou, Maria-Christina Kastrinaki, Mirjam Klaus, Christina H. Kalpadakis, Pavlos Katonis, Kalliopi Alpantaki, Gerasimos Pangalis, Helen Papadaki
Journal: Blood (2012)
Keith Raymond Ross
Authors: Deepak Kalra, Janet Anderson
Journal: BMJ (2020)

Keith Raymond Ross was consultant general paediatrician and neonatologist in Wolverhampton from 1975 to 2003. Soon after qualifying he worked in New York, and then at Boston Children’s Hospital. He returned to Southampton and moved to Aberdeen before being appointed consultant paediatrician at a relatively young age in Wolverhampton. When appointed he was the third consultant paediatrician ever in Wolverhampton, a department that has since evolved …