tbuckley/cabot-search huggingface dataset:
Tackling typhoid fever in South Asia: lessons from Vietnam
Authors: Buddha Basnyat, Abhilasha Karkey
Journal: The Lancet Global Health (2019)

Biblical diseases like typhoid fever continue to plague South Asia, a densely populated region of 1·8 billion people. Typhoid fever, also known as enteric fever, comprises both typhoid fever (caused by Salmonella enterica serotype Typhi [S Typhi]) and paratyphoid fever (caused by Salmonella enterica serotype Paratyphi A).1 The mode of transmission is faecal-oral. All health-care workers in South Asia are familiar with this disease. Because there is no reliable rapid diagnostic test available, many health-care workers use the ubiquitous and antiquated Widal test to make a diagnosis.
Poly-TLR agonist polyantigenic vaccine cadi-05 in advanced bladder cancer
Authors: Bakulesh M. Khamar
Journal: Cancer Research (2006)

2904  Cadi-05 is a novel Poly-TLR, poly-antigenic vaccine containing Mycobacterium W. It is a potent Th1 response enhancer as revealed by cytokine profile. In a phase I study of patients with advanced bladder cancer T3a or more and electing not to undergo surgical therapy, it was used along with radiotherapy. Six patients recruited had hematuria as presenting symptom. Five patients had the size of tumor ranging from 2 × 3 cms. to 4 × 6 cms., belonging to T3a as per TNM (Tumor node metastasis) classification they belonged to age group 46-62 years of which four were males. All presented with hematuria. All the patients received External beam radiation therapy. All also received Cadi-05 systemically by way of intradermal injections. Radiation was by parallel opposed pelvic portals to the whole pelvis up to 50 Gy/25 #, followed by 18 Gy to target volume by one anterior and two posterior oblique portals @ 2 Gy /# to five patients with T3a disease. Cadi-05 was given once every month for six months to this group. The sixth patient was having an intravesical lesion of size 8.9x7.6 cm extending to rectus abdominis and belonged to T3b group. He received Cadi-05 at the interval of two weeks and total radiation of 20gy.All were followed with cystoscopy and or CT scan. All became asymptomatic withi six weeks and achieved complete response. with no recurrence of disease. The five with T3a have been followed up for more than two years while the sixth is followed up for 1year and 10 months. Cadi-05 administration seems to provide complete durable response. A phase two study is planned for the same.
Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3
Authors: PaolaSecchiero, FedericaCorallini, AriannaGonelli, RaffaellaDell’Eva, MarcoVitale, SilvanoCapitani, AdrianaAlbini, GiorgioZauli
Journal: Circulation Research (2007)

Nutlin-3, a nongenotoxic activator of the p53 pathway, dose-dependently (range 0.1 to 10 μmol/L) inhibited the formation of capillaries in an in vivo matrigel assay, as well as the formation of capillary-like structures in an in vitro coculture system composed of endothelial cells surrounded by fibroblasts. In contrast to the chemotherapeutic agent doxorubicin, nutlin-3 showed no induction of apoptosis in vitro either in the cocultures or in isolated vascular endothelial cells, even when used at the highest concentration (10 μmol/L). However, treatment with pharmacological inhibitors of the nuclear factor κB and phosphatidylinositol 3-kinase/Akt pathways sensitized endothelial cells to nutlin-3–induced apoptosis. Although nutlin-3 and doxorubicin induced a comparable p53 accumulation in endothelial cells, nutlin-3 was significantly more efficient than doxorubicin in upregulating the p53 target genes CDKN1A/p21, MDM2, and GDF-15, as well as in inhibiting cell cycle progression. However, the predominant in ...
Rate and Prognosis of Brain Ischemia in Patients With Lower-Risk Transient or Persistent Minor Neurologic Events
Authors: Shelagh B. Coutts, Francois Moreau, Negar Asdaghi, Jean-Martin Boulanger, Marie-Christine Camden, Bruce C. V. Campbell, Andrew M. Demchuk, Thalia S. Field, Mayank Goyal, Martin Krause, Jennifer Mandzia, Bijoy K. Menon, Robert Mikulik, Andrew M. Penn, Richard H. Swartz, Michael D. Hill
Journal: JAMA Neurology (2019)

Early treatment of patients with transient ischemic attack (TIA) reduces the risk of stroke. However, many patients present with symptoms that have an uncertain diagnosis. Patients with motor, speech, or prolonged symptoms are at the highest risk for recurrent stroke and the most likely to undergo comprehensive investigations. Lower-risk patients are much more likely to be cursorily investigated.To establish the frequency of acute infarct defined by diffusion restriction detected on diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) scan (DWI positive).The Diagnosis of Uncertain-Origin Benign Transient Neurological Symptoms (DOUBT) study was a prospective, observational, international, multicenter cohort study of 1028 patients with low-risk transient or minor symptoms referred to neurology within 8 days of symptom onset. Patients were enrolled between June 1, 2010, and October 31, 2016. Included patients were 40 years or older and had experienced nonmotor or nonspeech minor focal neurologic events of any duration or motor or speech symptoms of short duration (≤5 minutes), with no previous stroke.Patients underwent a detailed neurologic assessment prior to undergoing a brain MRI within 8 days of symptom onset.The primary outcome was restricted diffusion on a brain MRI scan (acute stroke).A total of 1028 patients (522 women and 506 men; mean [SD] age, 63.0 [11.6] years) were enrolled. A total of 139 patients (13.5%) had an acute stroke as defined by diffusion restriction detected on MRI scans (DWI positive). The final diagnosis was revised in 308 patients (30.0%) after undergoing brain MRI. There were 7 (0.7%) recurrent strokes at 1 year. A DWI-positive brain MRI scan was associated with an increased risk of recurrent stroke (relative risk, 6.4; 95% CI, 2.4-16.8) at 1 year. Absence of a DWI-positive lesion on a brain MRI scan had a 99.8% negative predictive value for recurrent stroke. Factors associated with MRI evidence of stroke in multivariable modeling were older age (odds ratio [OR], 1.02; 95% CI, 1.00-1.04), male sex (OR, 2.03; 95% CI, 1.39-2.96), motor or speech symptoms (OR, 2.12; 95% CI, 1.37-3.29), ongoing symptoms at assessment (OR, 1.97; 95% CI, 1.29-3.02), no prior identical symptomatic event (OR, 1.87; 95% CI, 1.12-3.11), and abnormal results of initial neurologic examination (OR, 1.71; 95% CI, 1.11-2.65).This study suggested that patients with transient ischemic attack and symptoms traditionally considered low risk carry a substantive risk of acute stroke as defined by diffusion restriction (DWI positive) on a brain MRI scan. Early MRI is required to make a definitive diagnosis.
Impact of Cumulative Inflammation, Cardiac Risk Factors, and Medication Exposure on Coronary Atherosclerosis Progression in Rheumatoid Arthritis
Authors: George A. Karpouzas, Sarah R. Ormseth, Elizabeth Hernandez, Matthew J. Budoff
Journal: Arthritis & Rheumatology (2019)

Objective To explore incidence and progression of coronary atherosclerosis and identify determinants in patients with rheumatoid arthritis ( RA ). We specifically evaluated the impact of inflammation, cardiac risk factors, duration of medication exposure, and their interactions on coronary plaque progression. Methods One hundred one participants with baseline coronary computed tomography angiography findings underwent follow‐up assessment a mean ± SD of 83 ± 3.6 months after baseline. Plaque burden was reported as the segment involvement score (describing the number of coronary segments with plaque) and the segment stenosis score (characterizing the cumulative plaque stenosis over all evaluable segments). Plaque composition was classified as noncalcified, mixed, or calcified. Coronary artery calcium ( CAC ) was quantified using the Agatston method. Results Total plaque increased in 48% of patients, and progression was predicted by older age, higher cumulative inflammation, and total prednisone dose ( P &lt; 0.05). CAC progressors were older, more obese, hypertensive, and had higher cumulative inflammation compared to nonprogressors ( P &lt; 0.05). Longer exposure to biologics was associated with lower likelihood of noncalcified plaque progression, lesion remodeling, and constrained CAC change in patients without baseline calcification, independent of inflammation, prednisone dose, or statin exposure (all P &lt; 0.05). Longer statin treatment further restricted noncalcified plaque progression and attenuated the effect of inflammation on increased plaque and CAC ( P &lt; 0.05). Stringent systolic blood pressure ( BP ) control further weakened the effect of inflammation on total plaque progression. Conclusion Inflammation was a consistent and independent predictor of coronary atherosclerosis progression in RA . It should therefore be specifically targeted toward mitigating cardiovascular risk. Biologic disease‐modifying antirheumatic drugs, statins, and BP control may further constrain plaque progression directly or indirectly.
Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial
Authors: Anna Maria Di Giacomo, Alessia Covre, Francesca Finotello, Dietmar Rieder, Riccardo Danielli, Luca Sigalotti, Diana Giannarelli, Florent Petitprez, Laetitia Lacroix, Monica Valente, Ornella Cutaia, Carolina Fazio, Giovanni Amato, Andrea Lazzeri, Santa Monterisi, Clelia Miracco, Sandra Coral, Andrea Anichini, Christoph Bock, Amelie Nemc, Aram Oganesian, James Lowder, Mohammad Azab, Wolf H. Fridman, Catherine Sautès-Fridman, Zlatko Trajanoski, Michele Maio
Journal: Clinical Cancer Research (2019)

The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab.Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics.Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples (n = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly (P < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly (P < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis (n = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8+, PD-1+ T cells and in CD20+ B cells in posttreatment tumor cores.Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.
Abstract 14380: The Effect of Canakinumab on the Rates of Non-ST-Segment Elevation and ST-Segment Elevation Myocardial Infarctions
Authors: Joshua Lang, Robert J Glynn, Tom Thuren, Peter Libby, Paul M Ridker, Brendan Everett
Journal: Circulation (2018)

Background: Patients with prior myocardial infarction (MI) are at risk for recurrent acute coronary syndrome, including ST-segment elevation MI (STEMI) and non-ST-segment myocardial infarction (NST...
A phase II pilot trial with RP101 in advanced pancreatic carcinoma
Authors: R. Fahrig, D. Quietzsch, V. Heinemann, A. Liebert, M. Haenel
Journal: Journal of Clinical Oncology (2006)

14000 Background: (E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU, RP101), which supports apoptosis and prevents the acquisition of chemoresistance, was tested in cultured human pancreatic tumor cells. RP101 down-regulated uridine phosphorylase, a marker of poor prognosis, and APEX1, which is involved in DNA repair, and repressed Stat-3 and its target VEGF. Furthermore, RP101 activated antitumor immunity. These results encouraged us to investigate the effect of RP101 in combination with gemcitabine (GEM) and cisplatin (CIS) in patients with advanced pancreatic cancer. Methods: A phase II pilot trial was designed to compare the GEM/CIS/RP101 combination to historical GEM/CIS combination. The primary endpoint was survival. 13 pts with histological documented pancreatic carcinoma received GEM 1.000 mg/m 2 plus CIS 50 mg/m 2 on days 1 and 15 of a 28-day schedule. RP101 treatment was on the same day and for four days after chemotherapy (500 mg/day). Results: All patients showed at least a stable disease, and 33% of them a PR. As a historical control, 22 pts were selected by random generator from 98 patients enrolled in a previous Phase III study performed in the same centers, 15 with stage IV and 7 with stage III disease, resulting in a similar proportion of stage III to IV patients as in the RP101 co-treatment group (nine stage IV and four stage III). In the RP101-co-treatment group the median survival was significantly longer than that of the historical control group (447 days vs. 186 days, p=0.007). Time to progression (TTP) was also prolonged (280 days vs. 104 days, p=0.004). Ten of the 13 pts lived longer than one year, 4 nearly two years after first treatment. Conclusions: The combined use of GEM/CIS/RP101 prolonged progression-free and overall survival in locally advanced and metastatic pancreatic cancer when compared to all published studies with all combinations of drugs. A repeat study with GEM/RP101 shows similar promising results indicating that the combination of RP101 with GEM should be explored in larger studies in patients with advance pancreatic cancer. [Table: see text]
Use and Discontinuation of Insulin Treatment Among Adults Aged 75 to 79 Years With Type 2 Diabetes
Authors: Jonathan Z. Weiner, Anjali Gopalan, Pranita Mishra, Kasia J. Lipska, Elbert S. Huang, Neda Laiteerapong, Andrew J. Karter, Richard W. Grant
Journal: JAMA Internal Medicine (2019)

<h3>Importance</h3> Among older individuals with type 2 diabetes, those with poor health have greater risk and derive less benefit from tight glycemic control with insulin. <h3>Objective</h3> To examine whether insulin treatment is used less frequently and discontinued more often among older individuals with poor health compared with those in good health. <h3>Design, Setting, and Participants</h3> This longitudinal cohort study included 21 531 individuals with type 2 diabetes followed for up to 4 years starting at age 75 years. Electronic health record data from the Kaiser Permanente Northern California Diabetes Registry was collected to characterize insulin treatment and glycemic control over time. Data were collected from January 1, 2009, through December 31, 2017, and analyzed from February 2, 2018, through June 30, 2019. <h3>Exposures</h3> Health status was defined as good (&lt;2 comorbid conditions or 2 comorbidities but physically active), intermediate (&gt;2 comorbidities or 2 comorbidities and no self-reported weekly exercise), or poor (having end-stage pulmonary, cardiac, or renal disease; diagnosis of dementia; or metastatic cancer). <h3>Main Outcomes and Measures</h3> Insulin use prevalence at age 75 years and discontinuation among insulin users over the next 4 years (or 6 months prior to death if &lt;4 years). <h3>Results</h3> Of 21 531 patients, 10 396 (48.3%) were women, and the mean (SD) age was 75 (0) years. Nearly one-fifth of 75-year-olds (4076 [18.9%]) used insulin. Prevalence and adjusted risk ratios (aRRs) of insulin use at age 75 years were higher in individuals with poor health (29.4%; aRR, 2.03; 95% CI, 1.87-2.20;<i>P</i> &lt; .01) and intermediate health (27.5%; aRR, 1.85; 95% CI, 1.74-1.97;<i>P</i> &lt; .01) relative to good health (10.5% [reference]). One-third (1335 of 4076 [32.7%]) of insulin users at age 75 years discontinued insulin within 4 years of cohort entry (and at least 6 months prior to death). Likelihood of continued insulin use was higher among individuals in poor health (aRR, 1.47; 95% CI, 1.27-1.67;<i>P</i> &lt; .01) and intermediate health (aRR, 1.16; 95% CI, 1.05-1.30;<i>P</i> &lt; .01) compared with good health (reference). These same prevalence and discontinuation patterns were present in the subset with tight glycemic control (hemoglobin A<sub>1c</sub>&lt;7.0%). <h3>Conclusions and Relevance</h3> In older individuals with type 2 diabetes, insulin use was most prevalent among those in poor health, whereas subsequent insulin discontinuation after age 75 years was most likely in healthier patients. Changes are needed in current practice to better align with guidelines that recommend reducing treatment intensity as health status declines.
Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses
Authors: Maria Cristina Ballesteros-Briones, Eva Martisova, Erkuden Casales, Noelia Silva-Pilipich, Maria Buñuales, Javier Galindo, Uxua Mancheño, Marta Gorraiz, Juan J. Lasarte, Grazyna Kochan, David Escors, Alfonso R. Sanchez-Paulete, Ignacio Melero, Jesus Prieto, Ruben Hernandez-Alcoceba, Sandra Hervas-Stubbs, Cristian Smerdou
Journal: Molecular Therapy (2019)

Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFV-aPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and safe approach for cancer treatment.
Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath
Authors: R. de Vries, M. Muller, V. van der Noort, W.S.M.E. Theelen, R.D. Schouten, K. Hummelink, S.H. Muller, M. Wolf-Lansdorf, J.W.F. Dagelet, K. Monkhorst, A.H. Maitland-van der Zee, P. Baas, P.J. Sterk, M.M. van den Heuvel
Journal: Annals of Oncology (2019)

Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients.
Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53
Authors: Elise Chapiro, Elodie Pramil, M'boyba Diop, Damien Roos-Weil, Clémentine Dillard, Clémentine Gabillaud, Karim Maloum, Catherine Settegrana, Lucile Baseggio, Jean-François Lesesve, Mélanie Yon, Ludovic Jondreville, Claude Lesty, Frederic B Davi, Magali Le Garff-Tavernier, Nathalie M Droin, Philippe DESSEN, Caroline Algrin, Veronique Leblond, Jean Gabarre, Simon Bouzy, virginie eclache, Baptiste Gaillard, Evelyne Callet-Bauchu, Marc Muller, Christine LEFEBVRE, Nathalie NADAL, Antoine Ittel, Stephanie Struski, Marie-Agnès Collonge-Rame, BENOIT QUILICHINI, Sandra Fert-Ferrer, Nathalie Auger, Isabelle Radford-Weiss, Lena Wagner, Sebastian Scheinost, Thorsten Zenz, Santos A. Susin, Olivier A Bernard, Florence Nguyen-Khac
Journal: Blood (2019)
Penalty system for free prescription claims must be “more humane,” say MPs
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The current system of penalty charge notices, which is supposed to discourage people from claiming free prescriptions they are not entitled to, is “heavy handed” and needs to be “substantially overhauled,” MPs have said.1

After reviewing the system the House of Commons Public Account Committee found that it “penalises those who fail to navigate the overly complex exemption criteria and neglects clear evidence of abuse by repeat offenders.”

It also said that the Department of Health and Social Care for England and NHS England have been “shockingly complacent about the fundamental problems with the PCN [penalty charge notice] …
Abstract 12133: Diastology - More Science, Less Artc Impact of 2016 ASE/EACVI Guidelines for Evaluation of Diastolic Function
Authors: Prabhakaran P Gopalakrishnan, Thelma Lasko, Nagapradeep Nagajothi, Robert Biederman
Journal: Circulation (2018)

Background: The 2016 guidelines aimed to simplify diastolic function (DF) assessment by using an algorithmic approach. We report its impact on diastology reporting in a real world setting.Methods: We retrospectively analyzed reports of all transthoracic echos performed in our high volume echo lab, 3