bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Molecular Diagnosis Of JAK2V617F Negative MPN By Targeted Deep Sequencing Using The Ion Torrent PGM
Authors: Klose Nathan , Tallack Michael R , Magor Graham , Mollee Peter , Perkins Andrew C
Published: November 2019

Myeloproliferative neoplasms (MPN) are a heterogeneous group of blood disorders characterized by excess production of mature blood cells, increased risk of thrombotic complications and slow progression to myelofibrosis or, less often, leukemia. Activation of the JAK-STAT signaling pathway is a common underlying feature of these diseases and JAK kinase inhibitors are efficacious in the more advanced forms of disease. Most cases of polycythemia vera (PV) and approximately 60% of essential thrombocythemia (ET) and primary myelofibrosis (MF) harbor a point mutation in JAK2 (V617F) which leads to constitutive JAK-STAT signaling and factor independent cell growth. The remaining 40% of cases of MF and ET harbor a broad range of mutations in many genes including those involved in cytokine receptor signaling, other components or the JAK-STAT pathway or epigenetic regulators. This poses a challenge for rapid molecular diagnosis. Also, since ET is essentially a diagnosis of exclusion of reactive causes of thrombocytosis, many cases of chronic ‘ET’ may not be clonal hematological neoplasms but reactive conditions.

We have developed a rapid deep sequencing pipeline to detect mutations in 65 genes which have been implicated in MPN through previous reports of human mutations, mouse models of MPN, or other known components of hematopoietic cytokine receptor signaling. We used 10ng of DNA from blood to amplify and sequence all the exons of these 65 genes using Ampliseq and Ion Torrent PGM. Using 318 PGM chips and 8-fold multiplexing we achieved on average 200 fold coverage of the target exome. The bioinformatics of SNP validation and rapid generation of reports will be presented. From a pilot study of 30 cases referred for molecular diagnosis, we have detected the likely causative mutation in approximately 80% of ET and MF where JAK2 is wild type. Many of these mutations are known to be causative in MPN, including those in MPL, ASXL1, SET2, SH2B3 (LNK), EZH2, CBL, DNMT3A and other genes. We have identified a novel inherited mutation in a family with MPN and validated it in BAF3 factor-independency assays. We have identified further novel mutations in JAK3, EED, DNMT3A, APC and two phosphatases involved in silencing activated JAK-STAT pathway components. The biological significance of these is under investigation and progress will be reported. In many cases we find evidence for clonal evolution involving secondary mutations in epigenetic modifying proteins on top of driver mutations in the JAK-STAT pathway.

In short, targeted exome re-sequencing using Ampliseq and Ion Torrent PGM provides a rapid and relatively cheap method for molecular diagnosis and characterization of most cases of MPN.

Disclosures:

Perkins: Novartis Oncology: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.
The EBV Oncogene LMP1 Protects Lymphoma Cells From Cell Death Through The Collagen-Mediated Activation Of Discoidin Domain Receptor 1
Authors: Zumla Cader Fathima , Vockerodt Martina , Bose Shikha , Nagy Eszter , Brundler Marie-Anne , Kearns Pamela R , Murray Paul G
Published: November 2019

The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumour microenvironment which is composed of a variety of cell types, as well as non-cellular components such as collagen. Although HRS cells harbour oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumour microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal centre B cells, the presumed progenitors of HRS cells, up-regulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We show that HRS cells intimately associated with collagen frequently over-express DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. We also show that ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75, Burkitt lymphoma cells, following etoposide treatment. Conversely, inhibition of DDR1, by RNA interference, significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma from apoptosis and suggest an important contribution of the tumour microenvironment in promoting the oncogenic effects of EBV.

Disclosures:

No relevant conflicts of interest to declare.
Significant Improvement In Quality Of Life (QoL) In Patients With Chronic Myeloproliferative Neoplasms and Myelofibrosis Treated With JAK-1 and JAK-2 Inhibitor Ruxolitinib. A Single Institution Experience In Mexico
Authors: Vargas-Viveros Pablo , Monroy Rafael Hurtado , Candelaria-Hernandez Myrna
Published: November 2019

Introduction

Myeloproliferative Neoplasms can shorten the life of patients and affect severely their quality of life as a result of constitutional symptoms mediated by cytokines and from massive splenomegaly characteristic of these diseases. The objective measurement of symptoms in Myelofibrosis is essential for the presence of general constitutional symptoms as fatigue and is considered adverse prognostic value for survival. The systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with JAK-2 inhibitors.

Material and Methods

To assess the impact on quality of life in patients with Myeloproliferative Neoplasms treated with the inhibitor Ruxolitinib, there was applied the questionnaire Myelofibrosis Symptom Assessment Form (Mesa et al. Leukemia Research. 2009: 33; 1199-1203) to 16 patients included in the Compassionate Use of Ruxolitinib Program: 8 men and 8 women were included with a median age of 63 years; 4 patients with primary Myelofibrosis, 3 with Myelofibrosis post Polycitemia vera and 9 with Myelofibrosis post essential Thrombocythemia. The median patient follow-up was 9 months. The patients started with a dose of 20 mg Ruxolitinib orally every 12 hours.

Results

The questionnaire was administered to all patients at each visit and the results of the ratings of the patients were presented as median of each answer at baseline, 3, 6 and 12 months of follow-up (table 1). By comparing the differences of each parameter measured between the start and at 3, 6 and 12 months were statistically significant for all variables (P <0.001, CI: 95%). The most significant changes were observed when comparing data at baseline and follow-up to the maximum time, however were obvious from the first quarter of observation on fatigue and symptoms dependent splenomegaly in most general symptoms, which actually disappeared completely after 3 months of treatment and not relapsed during the track and in the perception of the quality of life of patients. The variables with lower proportional change recorded were general activity, mood, walking tolerance and everyday work.

Discussion and conclusions

The treatment of Myeloproliferative Neoplasms with Ruxolitinib represents a major advance in the management of malignant Myeloproliferative and achieved excellent improvement in overall constitutional symptom control, splenomegaly and the general perception of the quality of life of these patients. The objective measurement of symptoms of Myelofibrosis is essential, since the presence of general constitutional symptoms as fatigue is considered adverse prognostic value for survival and systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with inhibitors JAK-2.

Disclosures:

No relevant conflicts of interest to declare.
Irish Hospitals Meet Proposed International Guidelines For Non-Hodgkin Lymphoma Management, But Areas For Improvement Remain
Authors: Crotty Rory , Crowley Maeve P , Cahill Mary R , Healey Bird Brian R
Published: November 2019

Introduction

High-grade non-Hodgkin lymphoma is an aggressive condition that requires equally aggressive management. Due to the possibility of curative treatment if the disease is effectively managed, rapid diagnosis, precise staging, and swift commencement of treatment are crucial. In Ireland there is little reliable data on how closely guidelines in non-Hodgkin lymphoma treatment are followed. In order to obtain better data, we replicated a recent study carried out in the Netherlands by Wennekes and colleagues (J Clin Oncol 2011 April 10;29(11): 1436-1444).

Methods

This study was carried out in two hospitals in Cork, Ireland. Ethical approval was obtained from the Cork Research Ethics Committee. We used the National Cancer Registry of Ireland and records of the Citywide Lymphoma Conference to identify high-grade non-Hodgkin lymphoma patients treated at the participating centers. 125 patient records were identified. This was similar to the sample size used by Wennekes. The quality markers used in the Dutch study were chosen as data points. This set was then slightly modified to account for local guideline differences. Data was obtained through a systematic, retrospective chart review.

Results

When analyzing the data, 90% adherence was set as a target. This was in keeping with previous research. Of our 22 quality markers, 11 reached the target level. Diagnosis and staging markers were generally well adhered to. 93% of non-CNS lymphoma patients received an RCHOP or DA-EPOCH-R regimen, 92.8% of patients were diagnosed with an appropriate biopsy, and 92% received a histological diagnosis before treatment was commenced. Scores regarding treatment were close to the target level. 83.5% of patients began chemotherapy within four weeks of diagnosis, and 74.1% of patients received a histological diagnosis within three weeks of presentation. Lower adherence was noted in areas relating to the communication of results. Use of the Cheson criteria to report radiological response was very limited. 12.8% of PET reports and 5% of CT reports used the Cheson criteria. In addition, the patient’s Ann Arbor staging was rarely included on CT and PET reports – 0% and 2.4% respectively.

Conclusion

This is the first replication of the Dutch study on non-Hodgkin lymphoma management. Irish hospitals are meeting non-Hodgkin lymphoma management guidelines in 11 of 22 areas. Adherence for the remaining areas ranges from 83.5% to 0%. Further studies in different Irish centers will provide important data to increase the external validity of this study.

Disclosures:

No relevant conflicts of interest to declare.
Sequential Treatment With Bendamustine, Rituximab, Chlorambucil and Fludarabine Leads To a Major Survival Improvement Of Patients With Chronic Lymphocytic Leukemia (CLL) In Routine Care
Authors: Weide Rudolf , Feiten Stefan , Friesenhahn Vera , Heymanns Jochen , Kleboth Kristina , Thomalla Jörg , van Roye Christoph , Köppler Hubert
Published: November 2019

Introduction

Progress has been made in diagnosis and treatment of patients with CLL who receive their treatment within prospective clinical trials. Due to necessary inclusion and exclusion criteria only a very limited number of patients are treated in studies. Therefore results from clinical trials can't be transferred into routine care. No clinical practice data are available how patients with CLL are diagnosed and treated in routine care and whether improvements in survival are achieved.

Methods

A retrospective analysis of all patients with CLL who were treated in an oncology group practice in Germany between 1995-2012. Relevant clinical data concerning diagnosis, treatment and survival were transferred from clinical files into a database and analyzed statistically using SPSS and SURVSOFT.

Results

580 CLL patients with a median age of 67 (35-92) were identified. At initial diagnosis 446 patients (76.9 %) were in Binet stage A, 69 (11.9%) Binet stage B and 31 (5.3%) Binet stage C. Due to external diagnosis of 34 patients (5.9%) the stage at initial diagnosis couldn't be retrieved. 323 patients (55.7 %) never received any treatment. 257 patients (44.3%) needed therapy with a median of 2 therapy lines (1-11). Regimens most frequently applied were: Bendamustine-containig (66.9%), Rituximab-containing (62.3%), Chlorambucil-containing (61.5%), Bendamustine+Rituximab-combinations (48.2%) and Fludarabine-containing (40.9%). 21.0% of patients were treated within a clinical trial. 5 and 10 year absolute overall survival was 83.6% and 60.9%. Relative survival after 5 and 10 years was 96.1% and 82.3%. Median overall survival according to Binet stage was 16 years for Binet A, 9 years for Binet B and 8 years for Binet C. Median relative survival was 20.8 years for Binet A, 14.0 years for Binet B and 8.6 years for Binet C. Patients who needed therapy had a median overall survival of 11 years (0-41) compared to 18 years (0-23+) of patients who never needed any therapy.

Conclusions

55.7% of CLL-patients never needed any therapy. Patients who needed therapy had a much lower life expectancy compared to patients who never needed therapy. Treatment consisted mainly of Bendamustine, Rituximab, Chlorambucil, Bendamustine+Rituximab-combinations and Fludarabine leading to a marked prolongation of survival compared to historical controls and registry data.

Disclosures:

No relevant conflicts of interest to declare.
The effect of folate analogues and vitamin B12 on provision of thymine nucleotides for DNA synthesis in megaloblastic anemia
Authors: Taheri MR , Wickremasinghe RG , Jackson BF , Hoffbrand AV
Published: November 2019

The role of vitamin B12 in the folate dependent biosynthesis of thymidine nucleotides is controversial. In an attempt to clarify this, three methods have been used to assess the relative efficacy of vitamin B12 (hydroxocobalamin) and various folate analogues in titrated concentrations at correcting ‘de novo’ thymidylate synthesis by megaloblastic human marrow cells: (1) The deoxyuridine (dU) suppression test which analyses the reduction in (3H)-thymidine labeling of DNA by unlabeled dU. Marrow cells were also labeled with (6–3H)-dU with assessment of (2) its incorporation into DNA and (3) the accumulation of (6–3H)-deoxyuridine monophosphate (3H-dUMP). The three methods gave similar results. In both, N6-formyl tetrahydrofolate (formyl-FH4) was the most effective agent at correcting thymidylate synthesis in megaloblastic anemia due to vitamin B12 or folate deficiency. Vitamin B12 corrected the lesion in vitamin B12 deficiency but not in folate deficiency. Tetrahydrofolate (FH4) and folic acid were effective in deficiency of vitamin B12 or folate, although in both deficiencies they were less effective than formyl-FH4. Methyl-FH4 was effective in folate deficiency but not in vitamin B12 deficiency. These results confirm the failure of methyl-FH4 utilisation in vitamin B12 deficiency. They suggest that if vitamin B12 is needed in the formylation of FH4, this is a minor role in provision of the correct coenzyme for thymidylate synthesis compared with its major role of provision of FH4 from methyl- FH4.
Eosinophilic cytoplasmic inclusions in fetal leukocytes: are Auer bodies a recapitulation of fetal morphology?
Authors: Newburger PE , Novak TJ , McCaffrey RP
Published: November 2019

Among the most striking morphological features of acute nonlymphoblastic leukemias (ANLL) is the occurrence of eosinophilic cytoplasmic inclusions known as Auer rods on Auer bodies. We examined immature myeloid cells from the peripheral blood of 9 human fetuses of 16–19 wk gestation for the presence of such structures. Five of these 9 samples contained cytoplasmic inclusions, which were identical to the Auer rods typically seen in blast cells from patients with ANLL. The incidence of positive cells was low (1–5 cells/10,000 cells surveyed). The inclusions were azurophilic with Wright-Giemsa staining and were cytochemically positive with peroxidase, acid phosphatase, and Sudan black staining. We observed no inclusions in identically prepared control myeloid cells from the bone marrow of 5 patients with acute lymphoblastic leukemia in remission and 3 patients with chronic myelogenous leukemia in stable phase. Nor were they present in peripheral blood myeloid cells of 10 normal adults. Myeloid precursors in long-term bone marrow culture from 2 normal adult donors did not develop the inclusions during 24 hr of incubation with prostaglandin F2 (the abortifacient). These observations suggest that Auer rod formation is an occasional but normal phenomenon in fetal hematopoiesis.
Correction to: Environmental factors and wood qualities of African blackwood, Dalbergia melanoxylon, in Tanzanian Miombo natural forest
Authors: Nakai Kazushi , Ishizuka Moriyoshi , Ohta Seiichi , Timothy Jonas , Jasper Makala , Lyatura Njabha M. , Shau Victor , Yoshimura Tsuyoshi
Published: November 2019

In the original publication of the article [1], the scientific name of Mlondondo was misspelled as “Xeoderis stuhlmannii” instead of “Xeroderris stuhlmannii” in Table 1. The corrected table 1 is given in this correction article.
Correlation between kidney transplantation and colorectal cancer in hemodialysis patients: A nationwide, retrospective, population-based cohort study
Authors: Wang Han-En , Liao Yu-Chan , Hu Je-Ming , Wu Wen-Chih , Chou Wan-Yun , Chen Yong-Chen , Chou Yu-Ching , Hung Chi-Feng , Tian Yu-Feng , You San-Lin , Sun Chien-An
Published: November 2019

Background

Kidney transplantation (KT) correlates with an increased risk of developing several malignancies; however, the risk of colorectal cancer (CRC) after KT remains debatable and has been marginally explored. Hence, in this nationwide, retrospective, population-based cohort study, we aimed to examine the correlation between KT and CRC in a large-scale population-based Chinese cohort.

Methods

We identified a total of 3739 regular hemodialysis patients undergoing KT (exposed cohort) and 42,324 hemodialysis patients not undergoing KT (non-exposed cohort) between 2000 and 2008 from Taiwan’s National Health Insurance Research Database (NHIRD). Both cohorts were followed up from January 1, 2000, to the date of CRC diagnosis, death, or the end of 2013. Using Kaplan–Meier method, we measured the cumulative incidence of CRC in each cohort. Furthermore, Cox proportional hazards models were used to compute hazards ratios (HRs) and 95% confidence intervals (CIs) to estimate the correlation between KT and CRC in hemodialysis patients.

Results

The Kaplan–Meier analysis revealed that the cumulative incidence of CRC was significantly higher in the exposed cohort than in the non-exposed cohort (log-rank test, P < 0.001). After adjusting for potential confounders, the exposed cohort exhibited a significantly increased risk of CRC compared with the non-exposed cohort (adjusted HR, 1.34; 95% CI, 1.11–1.62).

Conclusions

Hemodialysis patients undergoing KT have a significantly higher risk of CRC than those not undergoing KT. Cancer should continue to be a primary focus of prevention during KT.
Noninvasive multimodal imaging in diagnosing polypoidal choroidal vasculopathy
Authors: Yang Jingyuan , Yuan Mingzhen , Wang Erqian , Xia Song , Chen Youxin
Published: November 2019

Purpose

To investigate the diagnostic accuracy of noninvasive multimodal imaging methods in diagnosing polypoidal choroidal vasculopathy (PCV) and distinguishing PCV from typical neovascular age-related macular degeneration (nvAMD).

Methods

Retrospective study. Imaging features of noninvasive multimodal imaging methods, including fundus photography (FP), B-scan optical coherence tomography (OCT), en face OCT, OCT angiography, and autofluorescence, of 103 eyes with PCV or typical nvAMD were reviewed. Diagnostic strategy was established based on imaging features and was validated in other 105 eyes with PCV or typical nvAMD.

Results

Features of subretinal orange nodule on FP, thumb-like PED on OCT, notched PED on OCT, bubble sign on OCT, and Bruch’s membrane depression under serosanguinous PED on OCT were more common. When the diagnostic strategy of using at least 2 of 5 features was performed, there is 0.88 sensitivity and 0.92 specificity for diagnosing PCV. The results of the validation test further confirmed the diagnostic strategy with 0.94 sensitivity and 0.93 specificity.

Conclusions

Noninvasive multimodal imaging, especially FP and B-scan OCT, provide high sensitivity and specificity for diagnosing PCV and distinguishing PCV from typical nvAMD, when at least 2 of 5 suggestive imaging features are present.
The prevalence and clinical characteristics of pertussis-associated pneumonia among infants in Botswana
Authors: Abu-Raya Bahaa , Goldfarb David M. , Smieja Marek , Luinstra Kathy , Richard-Greenblatt Melissa , Steenhoff Andrew P. , Feemster Kristen A. , Arscott-Mills Tonya , Cunningham Coleen K. , Shah Samir S. , Patel Mohamed Zaakir , Kelly Matthew S. , Sadarangani Manish
Published: November 2019

Background

There are scant data on the prevalence and clinical course of pertussis disease among infants with pneumonia in low- and middle-income countries. While pertussis vaccination coverage is high (≥90%) among infants in Botswana, human immunodeficiency virus (HIV) infection affects nearly one-third of pregnancies.

We aimed to evaluate the prevalence and clinical course of pertussis disease in a cohort of HIV-unexposed uninfected (HUU), HIV-exposed uninfected (HEU), and HIV-infected infants with pneumonia in Botswana.

Methods

We recruited children 1–23 months of age with clinical pneumonia at a tertiary care hospital in Gaborone, Botswana between April 2012 and June 2016. We obtained nasopharyngeal swab specimens at enrollment and tested these samples using a previously validated in-house real-time PCR assay that detects a unique sequence of the porin gene of Bordetella pertussis.

Results

B. pertussis was identified in 1/248 (0.4%) HUU, 3/110 (2.7%) HEU, and 0/33 (0.0%) HIV-infected children. All pertussis-associated pneumonia cases occurred in infants 1–5 months of age (prevalence, 1.0% [1/103] in HUU and 4.8% [3/62] in HEU infants). No HEU infants with pertussis-associated pneumonia were taking cotrimoxazole prophylaxis at the time of hospital presentation. One HUU infant with pertussis-associated pneumonia required intensive care unit admission for mechanical ventilation, but there were no deaths.

Conclusions

The prevalence of pertussis was low among infants and young children with pneumonia in Botswana. Although vaccination against pertussis in pregnancy is designed to prevent classical pertussis disease, reduction of pertussis-associated pneumonia might be an important additional benefit.
Seasonal variations in the occurrence of acute appendicitis and their relationship with the presence of fecaliths in children
Authors: Hsu Yao-Jen , Fu Yu-Wei , Chin Taiwai
Published: November 2019

Background

Acute appendicitis (AA) is the most common surgical condition in children. Although a higher incidence of AA in summer has been reported, the reason for this observation remains unclear. The purpose of this study was to compare the clinical findings of AA patients who underwent appendectomies during the summer months with those who underwent the procedure during the non-summer months.

Methods

The clinical data of 171 patients who underwent appendectomy from January 2013 to December 2016 were reviewed. The patients were divided into a summer group (from May to October) and a non-summer group (from November to April) based on the month when appendectomy was performed. All patients were under 18 years of age at the time of surgery. The medical records including laboratory data, computed tomography scans, pathology reports and operative notes were reviewed.

Results

The number of patients with AA was higher in the summer group than in the non-summer group (101 vs. 70 patients). No significant differences in the laboratory results between the two groups of patients were observed. The percentage of AA patients who presented with a fecalith was significantly lower in the summer group (33.6%) than in the non-summer group (55.7%). No significant differences in the incidence of appendiceal perforations and abscesses, as well as postoperative complications were observed between the two groups.

Conclusions

The percentage of AA patients with fecaliths in summer was lower than that in the non-summer months. The increase in the number of AA patients in summer may be due to the increased occurrence of lymphoid hyperplasia, which may be correlated with the yearly outbreak of enterovirus infection during this period.
The long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy combined with radical cystectomy versus radical cystectomy alone for bladder cancer: a propensity-score matching study
Authors: Wahafu Wasilijiang , Liu Sai , Xu Wenbin , Wang Mengtong , He Qingbao , Song Liming , Wang Mingshuai , Yang Feiya , Hua Lin , Niu Yinong , Xing Nianzeng
Published: November 2019

Background

Bladder cancer is a complex disease associated with high morbidity and mortality. Management of bladder cancer before radical cystectomy continues to be controversial. We compared the long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy (IAC) versus no IAC (NIAC) before radical cystectomy (RC) for bladder cancer.

Methods

We performed a retrospective review of patients who underwent either one-shot IAC or NIAC before RC between October 2006 and November 2015. A propensity-score matching (1:3) was performed based on key characters. The Kaplan-Meier method was utilized to estimate survival probabilities, and the log-rank test was used to compare survival outcomes between different groups. A multivariable Cox proportional hazard model was used to estimate survival outcomes.

Results

Twenty-six patients were treated using IAC before RC, and 123 NIAC patients also underwent RC. After matching, there was no significant difference between groups in baseline characteristics, perioperative variables, complication outcomes or tumor characteristics. Compared with clinical tumor stages, pathological tumor stages demonstrated a significant decrease (P = 0.002) in the IAC group. There was no significant difference in overall survival (OS, p = 0.354) or cancer-specific survival (CSS, p = 0.439) between the groups. Among all patients, BMI significantly affected OS (p = 0.004), and positive lymph nodes (PLN) significantly affected both OS (p<0.001) and CSS (p = 0.010).

Conclusions

One-shot neoadjuvant IAC before RC shows safety and tolerability and provides a significant advantage in pathological downstaging but not in OS or CSS. Further study of neoadjuvant combination therapeutic strategies with RC is needed.
Risk of early mortality and cardiovascular disease in type 1 diabetes: a comparison with type 2 diabetes, a nationwide study
Authors: Lee You-Bin , Han Kyungdo , Kim Bongsung , Lee Seung-Eun , Jun Ji Eun , Ahn Jiyeon , Kim Gyuri , Jin Sang-Man , Kim Jae Hyeon
Published: November 2019

Background

Both type 1 and type 2 diabetes are well-established risk factors for cardiovascular disease and early mortality. However, few studies have directly compared the hazards of cardiovascular outcomes and premature death among people with type 1 diabetes to those among people with type 2 diabetes and subjects without diabetes. Furthermore, information about the hazard of cardiovascular disease and early mortality among Asians with type 1 diabetes is sparse, although the clinical and epidemiological characteristics of Asians with type 1 diabetes are unlike those of Europeans. We estimated the hazard of myocardial infarction (MI), hospitalization for heart failure (HF), atrial fibrillation (AF), and mortality during follow-up in Korean adults with type 1 diabetes compared with those without diabetes and those with type 2 diabetes.

Methods

We used Korean National Health Insurance Service datasets of preventive health check-ups from 2009 to 2016 in this retrospective longitudinal study. The hazard ratios of MI, HF, AF, and mortality during follow-up were analyzed using the Cox regression analyses according to the presence and type of diabetes in ≥ 20-year-old individuals without baseline cardiovascular disease (N = 20,423,051). The presence and type of diabetes was determined based on the presence of type 1 or type 2 diabetes at baseline.

Results

During more than 93,300,000 person-years of follow-up, there were 116,649 MIs, 135,532 AF cases, 125,997 hospitalizations for HF, and 344,516 deaths. The fully-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident MI, hospitalized HF, AF, and all-cause death within the mean follow-up of 4.6 years were higher in the type 1 diabetes group than the type 2 diabetes [HR (95% CI) 1.679 (1.490–1.893) for MI; 2.105 (1.901–2.330) for HF; 1.608 (1.411–1.833) for AF; 1.884 (1.762–2.013) for death] and non-diabetes groups [HR (95% CI) 2.411 (2.138–2.718) for MI; 3.024 (2.730–3.350) for HF; 1.748 (1.534–1.993) for AF; 2.874 (2.689–3.073) for death].

Conclusions

In Korea, the presence of diabetes was associated with a higher hazard of cardiovascular disease and all-cause death. Specifically, people with type 1 diabetes had a higher hazard of cardiovascular disease and all-cause mortality compared to people with type 2 diabetes.
Microvascular complications burden (nephropathy, retinopathy and peripheral polyneuropathy) affects risk of major vascular events and all-cause mortality in type 1 diabetes: a 10-year follow-up study
Authors: Garofolo Monia , Gualdani Elisa , Giannarelli Rosa , Aragona Michele , Campi Fabrizio , Lucchesi Daniela , Daniele Giuseppe , Miccoli Roberto , Francesconi Paolo , Del Prato Stefano , Penno Giuseppe
Published: November 2019

Background

Microvascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes.

Methods

We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis.

Results

Out of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59–7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65–15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42–94.57], p < 0.0001). After adjustments, HRs were: 1 MC 2.05 (95% CI 0.88–4.76), 2 MC 1.98 (95% CI 0.75–5.21), 3 MC 7.02 (95% CI 2.44–20.20, p = 0.002). Forty-nine subjects (6.7%) had at least one cardiovascular event, and cumulative incidence went from no-MC 2.2% (Ref) to 1 MC 5.0%; (HR 2.27 [95% CI 0.96–5.38]), 2 MC 26.8% (HR 12.88 [95% CI 5.82–28.50]) and 3 MC 40.9% (HR 29.34 [95% CI 11.59–74.25], p < 0.0001). Upon adjustments, HRs were: 1 MC 1.59 (95% CI 0.65–3.88), 2 MC 4.33 (95% CI 1.75–10.74), 3 MC 9.31 (95% CI 3.18–27.25, p < 0.0001). Thirty-five individuals (4.8%) had at least one coronary event, which cumulative incidence increased with MC burden (p < 0.0001).

Conclusions

In type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.
Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial
Authors: Chihara Atsuko , Tanaka Atsushi , Morimoto Takeshi , Sakuma Mio , Shimabukuro Michio , Nomiyama Takashi , Arasaki Osamu , Ueda Shinichiro , Node Koichi
Published: November 2019

Background

Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain.

Aim and methods

We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353).

Results

There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06).

Conclusion

These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy.

Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.
MicroRNA-140-5p inhibits salivary adenoid cystic carcinoma progression and metastasis via targeting survivin
Authors: Qiao Zhu , Zou Yue , Zhao Hu
Published: November 2019

Background

Salivary adenoid cystic carcinoma (SACC) is one of the most frequent carcinomas derived from the salivary gland. Growing evidence implied the involvement of microRNAs (miRNAs) in SACC progression and metastasis. This study aimed to determine the regulatory role of miR-140-5p in SACC progression and metastasis and to explore the underlying mechanisms.

Materials and methods

MiR-140-5p and survivin mRNA expression levels were determined by quantitative real-time PCR; protein levels were evaluated by western blot assay; cell proliferation, growth, invasion, apoptosis and caspase-3 activity were evaluated by respective in vitro functional assays; xenograft nude mice model was used to assess the in vivo tumor growth; a luciferase reporter assay determined the interaction between miR-140-5p and survivin.

Results

MiR-140-5p overexpression suppressed SACC cell proliferation and invasion, induced cell apoptosis and inhibited in vivo tumor growth of SACC cells. The loss-of-function studies showed that miR-140-5p knockdown enhanced SACC cell proliferation and invasion, inhibited cell apoptosis and led to an accelerated in vivo tumor growth. The bioinformatics prediction and luciferase reporter assay revealed that miR-140-5p directly targeted survivin 3′ untranslated region, and survivin was inversely regulated by miR-140-5p. Knockdown of survivin exerted tumor-suppressive effects on SACC cells, while enforced expression of survivin counteracted the tumor-suppressive actions of miR-140-5p overexpression in SACC cells. Mechanistically, miR-140-5p modulated the protein expression levels of apoptosis- and epithelial-mesenchymal transition-related mediators as well as matrix metallopeptidase-2/-9 via targeting survivin. More importantly, the down-regulation of miR-140-5p and the up-regulation of survivin were detected in the SACC clinical tissues, and miR-140-5 expression was inversely correlated with survivin mRNA expression level in SACC tissues.

Conclusion

Our data indicated that miR-140-5p suppressed SACC cell proliferation and invasion, induced cell apoptosis via regulating survivin expression. The present study provide evidence that that miR-140-5p could be a promising target for treating SACC, which requires further investigations.
Gender difference in the association of dietary patterns and metabolic parameters with obesity in young and middle-aged adults with dyslipidemia and abnormal fasting plasma glucose in Taiwan
Authors: Lin Li-Yin , Hsu Chien-Yeh , Lee Hsiu-An , Tinkov Alexey A. , Skalny Anatoly V. , Wang Wan-Hsiang , Chao Jane C.-J.
Published: November 2019

Background

The increasing prevalence of obesity has become a pandemic problem, and dietary patterns are one of the important factors causing obesity. Although the correlation between dietary patterns and obesity has been well explored, the gender difference on the association between dietary patterns and obesity remains unclear. The objective of this study examined whether gender difference existed in the relationship of dietary patterns with metabolic parameters and specific indices of adiposity among young and middle-aged adults with dyslipidemia and abnormal fasting plasma glucose (FPG) in Taiwan.

Methods

A total of 14,087 subjects aged between 20 and 50 years with dyslipidemia and abnormal FPG were recruited in Taiwan between 2001 and 2010 for a cross-sectional study. Dyslipidemia was defined primarily according to the National Cholesterol Education Program Adult Treatment Panel III guidelines with minor modification. Abnormal FPG level was defined by the American Diabetes Association. Principal component analysis was conducted to identify dietary patterns. Multivariate logistic regression analysis was performed to evaluate the association of dietary patterns and metabolic parameters with different indices of adiposity including general obesity, central obesity, and high body fat, stratified by gender.

Results

Two dietary patterns derived from principal component analysis were the prudent dietary pattern and the western dietary pattern. Both men and women in the highest quartile of the western dietary pattern had a significantly increased odds ratio of general obesity, central obesity, and high body fat. However, only male subjects in the higher quartiles of the prudent dietary pattern had a significantly decreased odds ratio of all indices of obesity. Both men and women with higher high-density lipoprotein cholesterol and total cholesterol levels had a significantly reduced odds ratio of general and central obesity, while those with higher triglycerides and FPG levels had a significantly increased odds ratio of general and central obesity. Higher low-density lipoprotein cholesterol level was significantly associated with an elevated odds ratio of high body fat, while higher total cholesterol level was significantly correlated with a reduced odds ratio of high body fat only in women.

Conclusions

Gender difference exists in the association of dietary patterns and metabolic parameters with obesity and body fat in young and middle-aged adults with dyslipidemia and abnormal FPG in Taiwan.
Chemerin-induced macrophages pyroptosis in fetal brain tissue leads to cognitive disorder in offspring of diabetic dams
Authors: Liang Zhaoxia , Han Luyang , Sun Dianjianyi , Chen Yanmin , Wu Qi , Zhang Lixia , Zhou Menglin , Chen Danqing
Published: November 2019

Background

Chemerin is highly expressed in the serum, placenta tissue, and umbilical cord blood of diabetic mother; however, the impact of chemerin on cognitive disorders of offspring from mothers with diabetes in pregnancy remains unclear.

Methods

A diabetic phenotype in pregnant mice dams was induced by streptozocin (STZ) injection or intraperitoneal injection of chemerin. Behavioral changes in offspring of diabetic dams and nondiabetic controls were assessed, and changes in chemerin, two receptors of chemerin [chemerin receptor 23 (ChemR23) and chemokine (C-C motif) receptor-like 2 (CCRL2)], macrophages, and neurons in the brain tissue were studied to reveal the underlying mechanism of the behavioral changes.

Results

Chemerin treatment mimicked the STZ-induced symptom of maternal diabetes in mice along with the altered behavior of offspring in the open field test (OFT) assay. In the exploring process for potential mechanism, the brain tissues of offspring from chemerin-treated dams were observed with an increase level of macrophage infiltration and a decrease number of neuron cells. Moreover, an increased level of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like (Asc) protein as well as pyroptosis [characterized by increased active caspase-1 content and secretion of cytokines such as interleukin (IL) 1 beta (IL-1β) and IL-18] more activated in macrophages is also observed in the brain of these diabetic dam’s offspring, in the presence of ChemR23. In vitro, it was found that pyroptosis activation was increased in macrophages separated from the abdominal cavity of normal mice, after chemerin treatment. However, depletion of CCRL2 decreased the level of chemerin in the brain tissues of diabetic dams’ offspring; depletion of ChemR23 decreased macrophage pyroptosis, and depletion of either receptor reversed chemerin-mediated neurodevelopmental deficits and cognitive impairment of offspring of diabetic pregnant dams.

Conclusions

Chemerin induced diabetic pregnant disease and CCRL2 were required to enrich chemerin in the brain of offspring. Aggregation of chemerin could lead to macrophage recruitment, activation of pyroptosis, the release of inflammatory cytokines, a decrease in the number of neurons, and cognitive impairment in offspring in a ChemR23-dependent manner. Targeting CCRL2 and/or ChemR23 could be useful for treating neuropsychological deficits in offspring of dams with diabetes in pregnancy.
Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients
Authors: Traub Jan W. , Pellkofer Hannah L. , Grondey Katja , Seeger Ira , Rowold Christoph , Brück Wolfgang , Husseini Leila , Häusser-Kinzel Silke , Weber Martin S.
Published: November 2019

Background

In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells.

Methods

Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production.

Results

While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation.

Conclusion

Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal.

Trial registration

Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).
The long-term outcomes of a cohort of adolescents and adults from Greece with autism spectrum disorder
Authors: Sevaslidou Isaia , Chatzidimitriou Christina , Abatzoglou Grigoris
Published: November 2019

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Although it is a lifelong condition, treatments and services can improve a person’s symptoms and ability to function. Research on the outcomes in adolescence and adult life and on the associated factors is limited. The objective of the present study is to examine the outcomes as well as the contributing factors in adolescents and adults diagnosed with ASD in Greece.

Method

Participants included 69 parents of individuals diagnosed with ASD in their childhood. Interviews were conducted with the parents, and archived medical and psychological records were collected. Participants had been diagnosed in the Child and Adolescent Unit of the 3d Psychiatric Clinic of the AHEPA Hospital in Thessaloniki, Greece between 1990 and 2007.

Results

The overall outcome was poor in most of cases (22.6% “very poor” and 24.5% “poor”); however, a substantial number had “good” (18.9%) or “very good” (22.6%) outcomes. Severity of initial diagnosis (χ2 = 65.956, DF = 8, p < 0.001), presence of comorbid disorders in childhood (χ2 = 14,085, DF = 4, p < 0.007), current comorbidity (χ2 = 15.834, DF = 4, p = 0.003), and certain developmental milestones [early acquisition of language skills (χ2 = 16.991, DF = 8, p = 0.030)] were positively correlated with adult outcomes.

Conclusions

Overall outcomes in the Greek sample were consistent with international studies. It seems that important contributing factors are comorbidity and especially overall lower cognitive function (intellectual disability), but further research is needed as well as enhanced adult-oriented research and intervention programs.
Teen Mental Health First Aid for years 7–9: a description of the program and an initial evaluation
Authors: Hart Laura M. , Bond Kathy S. , Morgan Amy J. , Rossetto Alyssia , Cottrill Fairlie A. , Kelly Claire M. , Jorm Anthony F.
Published: November 2019

Background

A teen Mental Health First Aid training course for high school students in years 10–12 (tMHFA 10–12) has previously been evaluated in uncontrolled and randomized controlled trials and found to improve Mental Health First Aid intentions, mental health literacy and to reduce stigma. This 3 × 75-min course has more recently been adapted for younger students in years 7–9 (tMHFA 7–9). The present study reports an initial uncontrolled trial of this new training course which aimed to assess feasibility and acceptability of the course and test effects on knowledge, attitudes and behaviour.

Methods

An uncontrolled trial was carried out in five schools with measures taken at pre-test, post-test and 3-month follow-up. The outcomes measured were: quality of first aid intentions to help peers, confidence in helping, stigmatising attitudes, recognition of anxiety disorder, number of adults thought to be helpful, help-seeking intentions, quality of support provided to a peer, quality of support received, and psychological distress. Questions were also asked about satisfaction with the course.

Results

There were 475 students (mean age 13.86 years) who provided data at baseline, with 76% of these providing data at post-test and 75% at follow-up. Sustained changes at follow-up were found for: number of adults thought to be helpful, some components of stigma, recognition of anxiety disorder, and quality of support provided to a peer. However, there was an unexpected decline in willingness to tell others about a mental health problem. Most students found the information presented to be new, easy to understand, and useful.

Conclusions

The tMHFA 7–9 training course produced some positive changes that were sustained over 3 months. However, the changes were not as strong as previously found for older high school students, suggesting the need for further refinement of the course.