tbuckley/cabot-search huggingface dataset:
Monitoring glycaemic control in patients with diabetes mellitus
Authors: Ravinder Sodi, Kim McKay, Srilatha Dampetla, Joseph M Pappachan
Journal: BMJ (2018)

### What you need to know

A 73 year old man with obesity and type 2 diabetes mellitus was referred to the diabetes clinic for advice. He had chronic kidney disease stage 3 and chronic anaemia from angiodysplasia of the small intestine. He was on insulin glargine 35 units every night and soluble human insulin 30 units three times daily before main meals. He was referred because of the discrepancy between his high fasting plasma glucose concentrations (16-21 mmol/L) and lower than expected haemoglobin A1c (HbA1c) concentration (49 mmol/mol) (expected with this fasting plasma glucose concentration ~108-140 mmol/mol or 12-15%). Table 1 gives glucose and HbA1c reference intervals. Other selected blood tests were: haemoglobin 106 g/L (reference interval: 125-180), ferritin 315 µg/L (reference interval: 24-250), creatinine 107 µmol/L (reference interval: 59-104), and albumin 32 g/L (reference interval: 35-50).

View this table:

Table 1 
Reference interval for fasting glucose and HbA1c



### Monitoring diabetes mellitus

The diagnosis of diabetes mellitus is well described1234; however, the monitoring of diabetes with HbA1c (which is common practice) has introduced some uncertainty. Glycaemic control is integral to effective treatment of diabetes.12 HbA1c concentration is used as the biomarker for long term glycaemic control as it correlates well with average blood glucose levels over a period of 90-120 days …
The Dynamic Origins of Type 1 Diabetes
Authors: R. David Leslie, Struan F.A. Grant
Journal: Diabetes Care (2018)

Over a century ago, there was diabetes and only diabetes. Subsequently, diabetes came to be much more discretely defined (1) by age at onset (childhood or adult onset), clinical phenotype (lean or obese), treatment (insulin dependent or not insulin dependent), and, more recently, immune genotype (type 1 or type 2 diabetes). Although these categories broadly describe groups, they are often insufficient to categorize specific individuals, such as children having non–insulin-dependent diabetes and adults having type 1 diabetes (T1D) even when not requiring insulin. Indeed, ketoacidosis at presentation can be a feature of either T1D or type 2 diabetes. That heterogeneity extends to the origins and character of both major types of diabetes. In this issue of Diabetes Care , Redondo et al. (2) leverage the TrialNet study of subjects with a single diabetes-associated autoantibody at screening in order to explore factors determining progression to multiple autoantibodies and, subsequently, the pathogenesis of T1D.

T1D is initiated by presumed nongenetic event(s) operating in children with potent genetic susceptibility. But there is substantial heterogeneity even within the origins of this disease. Those nongenetic events evoke different autoantibodies such that T1D patients with insulin autoantibodies (IAA) have different features from those with GAD autoantibodies (GADA) (3,4). The former, in contrast with the latter, are younger both at seroconversion and at development of clinical diabetes, the two groups having different genetic risk and those with IAA having greater insulin secretory loss (3,4) (Fig. 1). These observations hint at distinct disease-associated networks leading to T1D, perhaps induced by distinct nongenetic events. Such disease-associated pathways could operate in unison, especially in children with T1D, who often have multiple autoantibodies.



Figure 1 
The incidence of insulin-treated T1D in the first 35 years of life. Cases with multiple autoantibodies have different features (as illustrated) than those with …
Extracellular Electron Transfer Transcends Microbe-Mineral Interactions
Authors: Scott H. Saunders, Dianne K. Newman
Journal: Cell Host & Microbe (2018)

Extracellular electron transfer (EET) allows microbes to drive their metabolism through interactions with minerals or electrodes. In recent work, Light et al. (2018) discover a specialized EET pathway in Listeria monocytogenes with homologs in pathogens and gut commensals, suggesting that EET plays important roles in diverse environments.
Acute and repeat-dose toxicity study of the(6-maleimidocaproyl)hydrazone derivative of doxorubicin in mice, rats, and dogs
Authors: Felix Kratz, Hans-Martin Kauffmann, Gerrit Ehling, Clemens Unger
Journal: Cancer Research (2005)

4192  (6-maleimidocaproyl)hydrazone of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models compared to doxorubicin and is currently being evaluated in a phase I study. In order to establish the toxicity profile of this prodrug, acute and repeat-dose toxicity studies were performed with DOXO-EMCH in CD1-mice, Sprague Dawley rats and Beagle dogs, under GLP regulations. The LD50 of DOXO-EMCH was above 60 mg/kg doxorubicin equivalents in both male and female mice (LD50 of doxorubicin in CD-1 mice is ∼ 12 mg/kg). In Sprague Dawley rats the LD50 was ∼23 mg/kg and ∼46 mg/kg doxorubicin equivalents for males and females, respectively (LD50 of doxorubicin in Sprague-Dawley rats is ∼10.5 mg/kg). The major clinical sign that was noted following intravenous administration of DOXO-EMCH in mice and rats was a dose-dependent peripheral neuropathy that, in general, developed as a delayed toxicity 1-3 weeks after application. The observed neurotoxicity has been well documented for Sprague Dawley rats treated with doxorubicin at a dose of 5 and 10 mg/kg. In Beagle dogs, the maximum tolerated dose (MTD) was not reached for DOXO-EMCH at 4.5 mg/kg doxorubicin equivalents (LD50 of doxorubicin is ∼2.5 mg/kg body weight in beagle dogs). A 4-cycle intravenous study with DOXO-EMCH at dose levels of 2.5, 5.0 or 7.5 mg/kg doxorubicin equivalents in rats revealed approximately three-fold less side effects on the hemolymphoreticular system when compared to 2.5 mg/kg doxorubicin, whereas effects on the testes/oligospermia seem to be comparable between both drugs. A No Observable Adverse Effect Level (NOAEL) for DOXO-EMCH of 4 x 2.5 mg/kg doxorubicin equivalents was established in this study, which is equivalent to the MTD of doxorubicin in rats. In a 2-cycle study over a period of six weeks in Beagle dogs (intravenous administration of DOXO-EMCH at dose levels of 1.5, 3.0 or 4.5 mg/kg doxorubicin equivalents) dose-related systemic histamine-like reactions within the first 3 hours after injection were noted in all treated groups. Only transient and temporary effects on hematology, urinary function as well as on histopathology in mid- and/or high-dose animals were observed. The low dose of 2 x 1.5 mg/kg was considered to be the NOAEL in this study, which is equivalent to twice the MTD of doxorubicin in Beagle dogs. In summary, the toxicity studies with DOXO-EMCH in mice, rats or dogs did not identify any other special toxicity when compared to the toxicity data for doxorubicin. Preclinical tolerance for DOXO-EMCH was considerably higher in mice, rats and dogs compared to doxorubicin.
<i>EGFR</i> and <i>MET</i> Amplifications Determine Response to HER2 Inhibition in <i>ERBB2</i>-Amplified Esophagogastric Cancer
Authors: Francisco Sanchez-Vega, Jaclyn F. Hechtman, Pau Castel, Geoffrey Y. Ku, Yaelle Tuvy, Helen Won, Christopher J. Fong, Nancy Bouvier, Gouri J. Nanjangud, Joanne Soong, Efsevia Vakiani, Mark Schattner, David P. Kelsen, Robert A. Lefkowitz, Karen Brown, Mario E. Lacouture, Marinela Capanu, Marissa Mattar, Besnik Qeriqi, Fabiola Cecchi, Yuan Tian, Todd Hembrough, Rebecca J. Nagy, Richard B. Lanman, Steven M. Larson, Neeta Pandit-Taskar, Heiko Schöder, Christine A. Iacobuzio-Donahue, David H. Ilson, Wolfgang A. Weber, Michael F. Berger, Elisa de Stanchina, Barry S. Taylor, Jason S. Lewis, David B. Solit, Jorge A. Carrasquillo, Maurizio Scaltriti, Nikolaus Schultz, Yelena Y. Janjigian
Journal: Cancer Discovery (2018)

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer. SIGNIFICANCE: Analysis of patients with ERBB2-amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR/ERBB2 coamplification and MET amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones.See related commentary by Klempner and Catenacci, p. 166.This article is highlighted in the In This Issue feature, p. 151.
OP0039 High disease activity and disability at one year in two clusters of patients with rheumatoid arthritis defining themselves as in an acceptable state at treatment initiation
Authors: J. Gwinnutt, K. Hyrich, M. Lunt, A. Barton, S. Verstappen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> A significant proportion of patients with rheumatoid arthritis (RA) define themselves as in a ‘patient acceptable symptom state’ (PASS) at methotrexate (MTX) initiation. Within this heterogeneous group, there are likely to be clinical phenotypes associated with poor outcome. <h3>Objectives</h3> To identify distinct phenotypes of symptoms within patients in PASS at baseline and to compare disability and disease activity scores of these patients over one year. <h3>Methods</h3> The Rheumatoid Arthritis Medication Study (RAMS) is a one year prospective cohort of patients with RA starting MTX. At baseline, patients reported demographics, completed the Health Assessment Questionnaire (HAQ), pain/fatigue visual analogue scales (VAS) and the Hospital Anxiety and Depression Scale (HADS). A research nurse conducted a 28 swollen and tender joint count and the Disease Activity Score (DAS28) was calculated. DAS28 and HAQ were assessed again at 12 months. Patients also answered the dichotomous question ‘Is your current condition satisfactory, when you take your general functioning and your current pain into consideration?’ Only those answering yes at baseline were included in the analysis. Phenotypes were identified using K-medians cluster analysis based on baseline swollen/tender joint count, HAQ, VAS-pain, VAS-fatigue and HADS-depression. The ‘elbow method’ was used to select the number of clusters. Quantile regression was used to compare the 12 month HAQ and DAS28 scores between clusters, controlling for age and gender. <h3>Results</h3> Five clusters were identified within the 300 patients in PASS at baseline (mean (sd) age=61.4 (12.1) years, 186 (62%) women) (table 1). Compared to Cluster 1, patients in higher clusters had worse HAQ (median difference (95% CI) vs Cluster 1: Cluster 2=0.36 (0.11, 0.61); Cluster 3=0.19 (-0.11, 0.49); Cluster 4=0.74 (0.47, 1.00); Cluster 5=0.89 (0.54, 1.24)) and worse DAS28 at 12 months (median difference (95% CI) vs Cluster 1: Cluster 2=0.43 (-0.06, 0.91); Cluster 3=0.40 (-0.19, 0.99); Cluster 4=0.89 (0.36, 1.41); Cluster 5=1.28 (0.59, 1.96). <h3>Conclusions</h3> Despite all patients reporting they were satisfied with their condition at baseline, five distinct clinical phenotypes were identified. These clusters can identify ‘reticent’ patients who are likely to have poor outcomes in the future. <h3>Disclosure of Interest</h3> None declared
SAT0286 Retention rate and safety data of biosimilar ct-p13 in ankylosing spondylitis patients: data from the korean college of rheumatology biologics registry
Authors: H.-A. Kim, E.-Y. Lee, S.-K. Lee, Y.-B. Park, K. Shin
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> CT-P13 is a biosimilar prescribed in a number of countries for indications approved for the reference infliximab (RINF), including ankylosing spondylitis (AS), rheumatoid arthritis, and inflammatory bowel diseases. Clinical data of CT-P13 have been analysed in previous clinical trials, demonstrating equivalence of efficacy and pharmacokinetic profile to RINF. However, there are few studies showing long-term data of its drug survival or safety. <h3>Objectives</h3> To investigate the drug retention rate and safety data of biosimilar CT-P13 in Korean AS patients. <h3>Methods</h3> Subjects were AS patients enrolled in the Korean College of Rheumatology biologics registry (KOBIO). Data from patients who received RINF and CT-P13 were included in the analysis<sup>Dec 2012</sup> ~ .<sup>Dec 2017</sup> Discontinuation was defined as switching or stopping the biologic agent. Kaplan-Meier curve and Cox proportional hazard model were used for further analysis. Reason for RINF or CT-P13 discontinuation was also assessed. <h3>Results</h3> Data from 399 AS patients (CT-P13; 256, RINF; 143) were analysed. The mean age of patients was 39.0 in the CT-P13 group, and 73% were males. The mean disease duration was 4.1 years. Eighty percent of patients were first-time biologic users. Discontinuation of CT-P13 occurred in 30.9% (switching in 17.6%) of patients during follow-up. The drug retention rate of first-line users of CT-P13 was marginally higher compared with second or more (≥2)-line users of CT-P13, first-line users of RINF, and ≥2 line users of CT-P13 in Korean AS patients (p=0.0518). The reason of discontinuation was inefficacy (42.7%), adverse events (20.2%), clinical improvement (7.9%), and others (18.0%) in the CT-P13 group. The incidence of adverse events of CT-P13, including infusion reaction (n=10), mycobacterial infection (n=2), and skin eruption (n=1) was comparable to that of RINF. <h3>Conclusions</h3> Our study demonstrates that the drug retention rate of CT-P13, especially in first-line users was relatively higher than that of RINF,[H1] and CT-P13 showed a reasonable long-term safety profile in Korean AS patients. <h3>Disclosure of Interest</h3> None declared
Disparity between burden and budget for mental health
Authors: Shekhar Saxena
Journal: The Lancet Public Health (2018)

The study by Daniel Vigo and colleagues1 provides new secondary analysis to strengthen the case for increased investments in mental health in the Americas. These data are very timely coming soon after the publication of the Lancet Commission for Global Mental Health and Sustainable Development,2 which recommended reframing mental health and making larger investments nationally and internationally.
MRI bone marrow oedema precedes lumbar bone stress injury diagnosis in junior elite cricket fast bowlers
Authors: Alex Kountouris, Kevin Sims, David Beakley, Anna E Saw, John Orchard, Andrew Rotstein, Jill L Cook
Journal: British Journal of Sports Medicine (2018)

Lumbar bone stress injury ('bone stress injury') is common in junior fast bowlers. The repetitive loading of cricket fast bowling may cause bone marrow oedema (BMO), detectable on MRI, before the bowler suffers from symptomatic bone stress injury. We investigated the temporal relationship between BMO, bone stress injury, along with bowling workload correlates, in elite junior fast bowlers throughout a cricket season.65 junior fast bowlers were prospectively monitored for one 8-month cricket season. For research purposes, participants had up to six MRI scans at set times in the season; findings were withheld from them and their clinicians. Standard practices for bowling workload monitoring and injury diagnosis were followed.15 (23%) participants developed bone stress injury during the study. All 15 of these participants had BMO detected on at least one of the preceding MRI scans, including the scan immediately prior to diagnosis. The risk of BMO progressing to bone stress injury during the season was greatest for participants with BMO present 2 weeks prior to the national championship tournament (period of high load) (RR=18.9, OR=44.8). Both bone stress injury and BMO were associated with bowling a higher percentage of days in training and having a shorter bowling break during the season. The number of balls bowled and acute-to-chronic workload were not associated with imaging abnormalities or injury.The presence of BMO on MRI in asymptomatic junior cricket fast bowlers confers a very high risk for bone stress injury. The risk may be managed by MRI screening and monitoring bowling frequency.
A Diagnostic Algorithm That Combines Quantitative 18F-FDG PET Parameters and Contrast-Enhanced CT Improves Posttherapeutic Locoregional Restaging and Prognostication of Survival in Patients With Esophageal Cancer
Authors: Dietmar Tamandl, Barbara Fueger, Alexander Haug, Rainer Schmid, Judith Stift, Sebastian F. Schoppmann, Aysegül Ilhan-Mutlu, Ahmed Ba-Ssalamah
Journal: Clinical Nuclear Medicine (2018)

The aim of this study was to determine whether the combination of contrast-enhanced CT (CE-CT) and quantitative F-FDG PET parameters improves locoregional restaging in esophageal cancer (EC) after neoadjuvant therapy.Eighty-eight consecutive patients with locally advanced esophageal cancer, who underwent restaging after neoadjuvant chemotherapy or chemoradiotherapy before esophagectomy, were included in this retrospective study. The diagnostic accuracy of CE-CT, visual F-FDG PET/CT (vPET/CT), and quantitative PET parameters was assessed for T and N staging. Histopathology was used as the reference standard. The prognostic value for recurrence-free survival, cancer-specific survival, and overall survival was assessed using Cox regression analysis.Sensitivity, positive predictive value, and accuracy were 78.8%, 70.2%, and 59.0% (CE-CT), and 81.1%, 81.1%, and 68.2% (vPET/CT) for T staging as well as 59.5%, 75.9%, and 50.0% (CE-CT), and 70.2%, 93.7%, and 67.0% (vPET/CT) for N staging, respectively. Tumor length and metabolic tumor volume (MTV) exhibited an incremental increase with advancing T stages (P = 0.002 and 0.038). Contrast-enhanced CT had the highest sensitivity to differentiate advanced T stages (T3/4 vs 0-2; area under the receiver operating curve [AUC], 0.86; P < 0.001), whereas MTV at a threshold of 5.8 mL had the highest sensitivity to detect complete response (T0 vs 1-4; AUC, 0.77; P = 0.002). Contrast-enhanced CT and MTV combined had an even superior accuracy to predict complete response (AUC, 0.82; P < 0.001). The imaging American Joint Committee on Cancer stage provided a better prognostication of recurrence-free survival, cancer-specific survival, and overall survival than either T stage, N stage derived from CE-CT or vPET/CT, or quantitative PET parameters alone.Combined CE-CT and MTV had the highest diagnostic accuracy to identify the posttherapeutic T stage, allowing for robust prediction of recurrence and survival.
Amla, an Ayuervedic herb induces apoptosis in pancreatic cancer cells by activating extracellular signal-regulated kinase
Authors: Yan Shi, Sanjay Batra, Sanjay Srivastava
Journal: Cancer Research (2008)

5471  Amla (Indian gooseberry) a member of genus Emblica officinalis is an important dietary source of vitamin C and phenolic compounds such as tannin and rutin. For decades, it has been used as Ayurvedic medicine for the treatment of inflammation and gastrointestinal related disorders. Here we report for the first time the anti-cancer effects of the aqueous extract of Amla on capan-2 human pancreatic cancer cells and further evaluated the molecular mechanisms of Amla-induced apoptosis. Our results demonstrate that treatment of capan-2 cells with the aqueous extract of Amla for 24h resulted in the significantly reduced survival of cells with an IC50 of about 60µg/ml. Amla also induced apoptosis in a concentration and time-dependent manner as exhibited by caspase-3 and PARP cleavage. Further, Amla treatment resulted in the activation of ERK at Thr-202/Tyr-204 and U0126, an ERK inhibitor offered significant protection against Amla-induced apoptosis in capan-2 cells. In order to determine the role of growth factor receptors in Amla mediated activation of ERK, cells were treated with suramin (growth factor receptor inhibitor) prior to Amla treatment. Suramin pretreatment not only markedly reduced the level of ERK phosphorylation in Amla treated cells but also completely protected the cells from Amla induced apoptosis as assessed by cell death assay and PARP cleavage. Taken together, our results suggest that Amla has a potential to be used as novel therapeutic agent for the treatment of pancreatic cancer. [Supported in part by RO1 grant CA 106953 (to S.K.S) awarded by the National Cancer Institute].
Correction: Epidermal γδ T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult
Authors: Rebecca Gentek, Clément Ghigo, Guillaume Hoeffel, Audrey Jorquera, Rasha Msallam, Stephan Wienert, Frederick Klauschen, Florent Ginhoux, Marc Bajénoff
Journal: The Journal of Experimental Medicine (2018)
Development of Therapeutics for Children—A Tricky Balancing Act
Authors: Michael Cohen-Wolkowiez, Daniel K. Benjamin
Journal: JAMA Pediatrics (2018)

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