bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and Regulation of Effector CD8+ T Cell Subsets in B-Cell NHL
Authors: Wu Hongyan , Yang Zhi-Zhang , Kim Hyo Jin , Jalali Shahrzad , Price-Troska Tammy , Ansell Stephen M.
Published: October 2019

Effector CD8+ T cells play a crucial role in anti-tumor immunity. Two major subsets of effector CD8+ T cells have been identified based on expression of KLRG1 and CD127: KLRG1+CD127- short-lived effector cells (SLECs) and KLRG1-CD127+ memory precursor effector cells (MPECs). In B-cell non-Hodgkin lymphoma (NHL), the frequency and function of SLECs and MPECs are unknown. Furthermore, the underlying mechanism by which these two CD8+ subsets were regulated and differentiate in B-cell NHL remains poorly understood. The goal of the present study is therefore to phenotypically and functionally characterize SLECs and MPECs in B-cell NHL. Using patient biopsy specimens, we observed that the median percentage of SLECs was greater than MPECs and was 39.9% (range: 22.7%~ 54.7%) and 18% (range: 7.66%~31.6%), respectively. In controls, the median percentage of SLECs was lower than that of MPECs and was 13.71% (range: 5.26%~29.2%) and 51.63% (range: 22.5%~70.1%) in PBMC and 12.14% (range: 4.01%~26%) and 51.62% (range: 29.2%~70.3%) in tonsil, respectively. Using mass cytometry (CyTOF), we observed that SLECs have higher expression levels of TIGIT and PD-1 and lower expression of CCR7, CD26 and CD27 when compared to MPECs. SLECs were functionally superior to MPECs as the numbers of cytokine (IFN-γ and TNF-α) - and granule (granzyme B and perforin)-producing cells were higher in SLECs than MPECs. However, SLECs had a lower proliferative capacity and a higher apoptosis rate when compared to MPECs. We observed that a reciprocal differentiation pathway exists between SLECs and MPECs. Activation and cytokine stimulation (IL-2 and IL-15) promoted the development of SLECs and decreased the number of MPECs. This effect was reversed when cells were treated with neutralizing antibodies to block IL-2 or IL-15 signaling. We also found that these two subsets had a distinct transcription factor profile as SLECs had higher expression of Eomes and T-bet, and lower expression of Tcf-1than MPECs. IL-2 and IL-15 enhanced the expression of T-bet and decreased the expression of Tcf-1. Taken together, our results show that SLECs are more prevalent than MPECs in B-cell NHL when compared to normal control tissue. These two effector cell subsets have distinct phenotypical and function profiles and their development is controlled by cytokines that may be dysregulated in lymphoma. Despite the fact that SLECs produce more granzyme B and IFN-γ, they are less proliferative and more susceptible to apoptosis. This may compromise an effective anti-tumor immune response in B-cell NHL.

Disclosures

Ansell: Celldex: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding.
Study of Treatment-Free Remission Evaluation in Real-World Chronic Myeloid Leukemia; Cost-Effectiveness Analysis
Authors: Nam Bora , Kim Soktae , Lee Jae Hoon , Yoo Kwai Han , Ahn Jeong-Yeal , Kim Hawk
Published: October 2019

Chronic myeloid leukemia (CML) needs taking life-long tyrosine kinase inhibitor (TKI) which arises serious toxicities such as peripheral occlusive disease and pulmonary hypertension as well as low-grade toxicities. Treatment-free remission (TFR) can make almost half CML patients achieving deep molecular response (DMR) free from TKIs. We investigated total costs of each TKI considering TFR in Korea.

Total numbers of annual newly-diagnosed CML patients were adopted from national cancer registration database. TFR was defined as achieving MR4.5 and lasting for 3 years. The proportion of MR4.5 was adopted from phase III studies of imatinib (IM), nilotinib (NIL) and dasatinib (DAS). TKI management followed life-long Markov model (Fig 1). Willingness to pay (WTP)was calculated for beneficial effects of patients who have achieved TFR and taking no TKIs as 2 times of gross domestic product per capita. Cost of progression was calculated based on the study by Jabbour et al. Patients older than 79y was not included in this study because TFR benefit is not considered in this age group. Duration of treatment and TFR was calculated separately according to age groups. We assumed that taking KTI lasted life-long until median life expectancy in Korea (80.87 years).

Newly diagnosed annual CML patients were 443; 9 in age 0-14, 96 in age 15-34, 125 in age 35-49, 124 in age 50-64 and 89 in age 65-79. The theoretical number of patients who have sustainable TFR was 73 in IM, 93 in DAS and 119 in NIL. TFR as person-year in IM, DAS and NIL were 1940, 2521 and 3247, respectively. TFR (person-year) was very different according to age groups because of different incidence rates; 99.9 in age 0-14, 788.7 in age 15-34, 666.1 in age 35-49, 353.8 in age 50-64 and 33.7 in age 65-79 when IM was applied. TFR (person-year) were 128.2 in age 0-14, 1014.5 in age 15-34, 861.6 in age 35-49, 464.1 in age 50-64 and 52.8 in age 65-79 when DAS was applied. TFR (person-year) were 164.9 in age 0-14, 1305.6 in age 15-34, 1109.4 in age 35-49, 598.3 in age 50-64 and 69.0 in age 65-79 when NIL was applied. WTP according to TFR was 121.3 in IM, 157.5 in DAS and 202.8 billion KW in NIL. Costs by progression were 32.8 in IM, 26.8 in DAS and 22.3 billion KW in NIL. Life-long maintenance costs for patients who did not achieved sustainable TFR without progression were 128.7 in IM, 294.2 in DAS and 327.1 billion KW in NIL. Net costs considering TFR and progression were 40.2 in IM, 163.5 in DAS and 146.6 billion KW in NIL.

Nilotinib was superior to other TKIs in terms of TFR benefit and progression cost according to our life-time Markov model. However, the net cost was lowest in IM. This analysis is limited by our assumption that MR4.5 is achieved by first 5 year and there is no further additional achievement of MR4.5 because of limitation of MR4.5 rates in each TKI trial.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Myd88/CD40 Costimulation to Enhance the Antitumor Activity of CD123-ENG T-Cells for the Immunotherapy of AML
Authors: Doherty Erin , Vaidya Abishek , Wu Xiya , Bonifant Challice L. , Mata Melinda , Leen Ann M. , Gottschalk Stephen , Velasquez Mireya P.
Published: October 2019

Background: Acute myeloid leukemia (AML) represents a treatment challenge due to its poor prognosis and high associated morbidity and mortality rates. Thus, new therapies are needed. CD123-ENG T-cells are cells genetically modified to secrete bispecific antibodies that recognize CD3 (T-cells) and CD123 (AML). Preclinical studies show that these cells recruit bystander T-cells to kill CD123+ blasts in vitro and in vivo. However, CD123-ENGs are unable to maintain sequential killing capability of CD123+ targets. To overcome this limitation, we have devised an approach that provides inducible Myd88/CD40 costimulation activated by a chemical inducer of dimerization (CID). This strategy should increase the persistence, expansion and anti-AML activity of CD123-ENG T-cells.

Methods: We generated a retroviral vector encoding a CD20 safety switch, CD123-ENG, and the inducible costimulatory molecule MyD88.CD40 (iMC) linked by 2A sequences (CD20.2A.CD123-ENG.2A.iMC). We used a vector specific for CD19 (CD20.2A.CD19-ENG.2A.iMC) and non-transduced (NT) cells as controls for non-specific effects of the iMC construct. We genetically modified T-cells using a retroviral transduction protocol and evaluated their effector function +/- CID. We assessed the effector function of transduced T-cells using standard immunological assays and a flow cytometry based sequential killing assay.

Results: We successfully generated CD20.CD123-ENG.iMC T-cells, which maintained a transduction efficiency above 50% throughout our study period. We performed coculture and cytotoxicity assays using NT, CD20.CD123-ENG, CD20.CD19-ENG.iMC and CD20.CD123-ENG.iMC T-cells +/-CID as effectors and MOLM13 (CD123+), Kg1a (CD123+) and K562 (CD123-) as targets. Cocultures were performed +/- CID. CD20.CD123-ENG.iMC T-cells maintained CD123 antigen specificity, as evidenced by cytotoxicity and cytokine assays. CD20.CD123-ENG.iMC T-cells + CID secreted increased IL-2 and IFN-γ in the presence of CD123+ targets (KG1a and MOLM13) when compared to baseline and to CD20.CD123-ENG T-cells. In addition, CD20.CD123-ENG.iMC T-cells + CID displayed enhanced sequential killing capabilities at a 1:1 ratio, compared to CD20.CD123-ENG T-cells.

Conclusion: CD20.CD123-ENG.iMC T-cells recognize and kill CD123+ AML blasts in an antigen dependent manner. In addition, control ENG.iMC T-cells have no antitumor activity, indicating that activation of Myd88/CD40 does not induce nonspecific AML blast killing. CD20.CD123-ENG.iMC T-cells have improved effector function in the presence of CID as judged by increased cytokine production and their ability to sequentially kill CD123+ target cells in vitro. Based on our promising in vitro experiments, we have initiated in vivo studies in AML xenograft models, which are currently in progress.

Disclosures

Leen: Marker: Equity Ownership.
The Fate of Patients with Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Otahal Pavel , Janikova Andrea , Belada David , Prochazka Vit , Mocikova Heidi , Pirnos Jan , Ďuraš Juraj , Kopečková Kateřina , Campr Vit , Pytlik Robert , Blahovcova Petra , Trneny Marek
Published: October 2019

Background:

The outcome of DLBCL patients is improving, it however seems to be very poor for those who are refractory to the therapy. We have decided to analyze this group of patients.

Methodology:

As part of an observational clinical study NiHiL (GovTrial No NCT03199066) we identified the patients treated in the first line by R-CHOP like immunochemotherapy who met at least one criterium: 1. refractory (stable disease - SD or progression) on 1st line therapy (1st l- R), 2. refractory (SD or progression) on salvage (platinum based regimen) (Salv-R), 3. refractory to or relapse/progression within 12 months after ASCT (ASCT-R/R). There were 210 patients diagnosed in the period 2001-2017 who fulfilled the criteria. Progression-free survival (PSF) and overall survival (OS) were estimated from the time of determination of a refractory disease.

Results:

The cohort consisted of 163 patients primarily resistant to the first-line therapy, 31 patients were resistant to the salvage therapy and 16 patients progressed within 12 months after ASCT . At the time of the diagnosis, the median age was 65 years (22-91) (the same as at the refractory disease), 54% were males, 74% had advanced clinical stage (III+IV), 68% had IPI >3, 77% had above-normal LDH, and 45% had a tumor mass >10cm.

The OS from the time of determination of refractory disease was 0.53 years, median PFS was 0.29 years. Patients under 65 years had median survival 0.8 years compared to 0.4 years in the group of patients above 65 years of age. The median PFS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.3, 0.26 and 0.35 years resp. and 5y survival 22%, 0% and 6% resp. The median OS for 1st l-R, Salv-R and ASCT-R/R resp. was 0.55, 0.39 and 0.65 y resp. and 5y survival was 28%, 0% and 13% resp.

Our results demonstrate that resistant DLBCL has an extremely poor prognosis, clearly new effective therapeutic strategies such as CAR-based therapies or others are required.

This work was supported by a research program Progres Q28-9.

Disclosures

Belada: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Target of Erythropoietin, Fam210b, Regulates Erythroid Heme Synthesis By Control of Mitochondrial Iron Import and Regulation of Fech Activity
Authors: Yien Yvette Y , Shi Jiahai , Chen Caiyong , Cheung Jesmine , Grillo Anthony , Shrestha Rishna , Li Liangtao , Zhang Xuedi , Kafina Martin Daniel , Kingsley Paul D. , King Matthew , Ablain Julien , Zon Leonard I. , Palis James , Burke Martin , Bauer Daniel E. , Orkin Stuart H. , Koehler Carla , Phillips John D. , Kaplan Jerry , Ward Diane , Lodish Harvey
Published: October 2019

Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well understood. To better understand these regulatory mechanisms, we profiled gene expression in EPO-treated fetal liver cells to identify novel iron regulatory genes (Figure A). We determined that FAM210B, a mitochondrial inner membrane protein, was essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation (Figure B). Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation (Figure C). These defects were corrected with a lipid-soluble small molecule iron transporter in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter, but is required for optimal mitochondrial iron import during erythroid differentiation (Figure D). FAM210B is also required for optimal FECH activity in differentiating erythroid cells. As FAM210B interacts with the terminal enzymes of the heme synthesis pathway, we propose that FAM210B functions as an adaptor protein to facilitate the formation of an oligomeric mitochondrial iron transport complex, which is required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis (Figure E). Collectively, our data reveal a novel mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.

Figure. Figure.

Disclosures

Palis: Rubies Therapeutics: Consultancy.
Lung clearance index in detection of post-transplant bronchiolitis obliterans syndrome
Authors: Driskel Madeleine , Horsley Alex , Fretwell Laurice , Clayton Nigel , Al-Aloul Mohamed
Published: October 2019

Background

Long-term outcomes after lung transplantation are often limited by the development of obliterative bronchiolitis (OB), which is clinically defined using spirometry as bronchiolitis obliterans syndrome (BOS). Lung clearance index (LCI), derived from multiple breath washout (MBW) testing, is a global measure of ventilation heterogeneity that has previously been shown to be a more sensitive measure of obstructive small airway diseases than spirometry. We aimed to assess the feasibility of LCI in adult lung transplant patients and to compare LCI to BOS grade.

Methods

51 stable adult double-lung transplant recipients performed sulfur hexafluoride MBW in triplicate on a single occasion, using a closed-circuit Innocor device. BOS grades were derived from serial spirometry according to International Society for Heart and Lung Transplantation criteria and, where available, high-resolution computed tomography (HRCT) evidence of OB was recorded.

Results

LCI was successfully performed in 98% of patients. The within-visit coefficient of variation for repeat LCI measurements was 3.1%. Mean LCI increased significantly with BOS grades: no BOS (n=15), LCI 7.6; BOS-0p (n=16), LCI 8.3; BOS-1 (n=11), LCI 9.3; BOS-2–3 (n=9), LCI 13.2 (p<0.001). 27 patients had HRCT within 12 months. LCI in those with HRCT evidence of OB was higher than those without OB (11.1versus8.2, p=0.006). 47% patients displayed abnormal LCI (>7) despite a normal forced expiratory volume in 1 s (FEV1) (>80% of baseline).

Conclusions

LCI measurement in lung transplant recipients is feasible and reproducible. LCI increased with increasing BOS grade. A significant proportion of this cohort had abnormal LCI with preserved FEV1, suggesting early subclinical small airway dysfunction, and supporting a role for MBW in the early identification of BOS.
Small RNA and degradome deep sequencing reveal respective roles of cold-related microRNAs across Chinese wild grapevine and cultivated grapevine
Authors: Wang Pengfei , Yang Yang , Shi Hongmei , Wang Yongmei , Ren Fengshan
Published: October 2019

Background

Chinese wild grapevine (Vitis amurensis) has remarkable cold stress tolerance, exceeding that of the common cultivated grapevine (Vitis vinifera L.).

Result

Here, we surveyed the expression dynamics of microRNAs (miRNAs) across Chinese wild grapevine (cv. Beibinghong) and cultivated grapevine (cv. Cabernet Sauvignon) under cold stress using high-throughput sequencing. We identified 186 known miRNAs in cultivated grape and 427 known miRNAs in Beibinghong. Of the identified miRNAs, 59 are conserved miRNAs orthologous in Cabernet Sauvignon and Beibinghong. In addition, 105 and 129 novel miRNAs were identified in Cabernet Sauvignon and Beibinghong, respectively. The expression of some miRNAs was related to cold stress both in Cabernet Sauvignon and Beibinghong. Many cold-related miRNAs in Cabernet Sauvignon and Beibinghong were predicted to target stress response-related genes such as MYB, WRKY, bHLH transcription factor genes, and heat shock protein genes. However, the expression tendency under cold treatment of many of these miRNAs was different between Cabernet Sauvignon and Beibinghong. Different modes of expression of cultivated and Chinese wild grape miRNAs were indicated in key pathways under cold stress by degradome, target prediction, GO, and KEGG analyses.

Conclusion

Our study indicated three likely reasons that led to the different cold stress tolerance levels of Cabernet Sauvignon and Beibinghong. Specifically, there may be (1) differential expression of orthologous miRNAs between cultivated grapevine and Chinese wild grape; (2) species-specific miRNAs or target genes; or (3) different regulatory models of miRNAs in cultivated and Chinese wild grape in some key pathways.
Ataxia as the main manifestation of tumor-like primary angiitis of the central nervous system: a case report and literature review
Authors: Huang Yu-Jing , Zhang Li , Mao Ying , Nan Guang-Xian
Published: October 2019

Background

Primary angiitis of the central nervous system (PACNS) is a rare disease, and tumor-like primary angiitis of the central nervous system is even rarer. Histopathology is the gold standard for tumor-mimicking PACNS. However, pathological diagnosis is relatively limited due to fewer biopsy opportunities.

Case presentation

A 68-year-old male presented with ataxia, and was diagnosed with tumor-like primary angiitis of the central nervous system. The patient underwent Intravenous drip glucocorticoid therapy (10 mg of dexamethasone, daily). After 10 days, the symptoms of the patient were completely relieved. Radiology revealed that the low density lesion in the right cerebellar hemisphere obviously narrowed. Cyclophosphamide therapy was not initiated.

Conclusion

It is crucial for clinicians to be aware of changes in radiology that indicate PACNS, since the diagnosis of tumor-like PACNS remains quite challenging. Glucocorticoid therapy is an effective therapy in this condition, and the prognosis can be favorable.
A risk factor for early wheezing in infants: rapid weight gain
Authors: Yin Lijuan , Song Ye , Liu Yongfang , Ye Zehui
Published: October 2019

Background

The aim of this study was to investigate the correlation between rapid weight gain and early wheezing.

Methods

This study screened 701 infants with lower respiratory tract infection who were no more than 4 months from Jan 1st to Dec 31st in 2018. According to weight-for-age Z-value (WAZ), these infants were divided into the considerably slow weight gain group (group I), the normal weight gain group (group II) and the excessively rapid weight gain group (group III), respectively. The clinical characteristics, weight growth speeds and serum lipid levels were analyzed, and multivariable Logistic model was conducted to select significant variables.

Results

Our results showed that male (OR = 1.841, 95%CI: 1.233–2.751), family wheezing (OR = 5.118, 95%CI: 2.118–12.365), age (OR = 1.273, 95%CI: 1.155–1.403), eczema (OR = 2.769, 95%CI: 1.793–4.275), respiratory syncytial virus (RSV) infection (OR = 1.790, 95%CI: 1.230–2.604), birth weight (OR = 1.746, 95%CI: 1.110–2.746) and total cholesterol (TC) (OR = 1.027, 95%CI: 1.019–1.036) and ΔWAZ (OR = 1.182, 95%CI: 1.022–1.368) were associated with early wheezing. Results indicated that serum TC (P = 0.018) and ΔWAZ (P = 0.023) were positive correlation with wheezing days.

Conclusion

Besides male, family wheezing, age, eczema, RSV infection, birth weight and TC, the rapid weight growth as a risk factor should be concerned in the early wheezing infants.
Immunosuppressive effect of hispidulin in allergic contact dermatitis
Authors: Thitilertdecha Premrutai , Pluangnooch Panwadee , Timalsena Sunita , Soontrapa Kitipong
Published: October 2019

Background

Long-term use of most immunosuppressants to treat allergic contact dermatitis (ACD) generates unavoidable severe side effects, warranting discovery or development of new immunosuppressants with good efficacy and low toxicity is urgently needed to treat this condition. Hispidulin, a flavonoid compound that can be delivered topically due to its favorable skin penetrability properties, has recently been reported to possess anti-inflammatory and immunosuppressive properties. However, no studies have investigated the effect of hispidulin on Th1 cell activities in an ACD setting.

Methods

A contact hypersensitivity (CHS) mouse model was designed to simulate human ACD. The immunosuppressive effect of hispidulin was investigated via ear thickness, histologic changes (i.e., edema and spongiosis), and interferon-gamma (IFN-γ) gene expression in 1-fluoro-2,4-dinitrobenzene (DNFB)-sensitized mice. Cytotoxicity, total number of CD4+ T cells, and percentage of IFN-γ-producing CD4+ T cells were also investigated in vitro using isolated CD4+ T cells from murine spleens.

Results

Topically applied hispidulin effectively inhibited ear swelling (as measured by reduction in ear thickness), and reduced spongiosis, IFN-γ gene expression, and the number of infiltrated immune cells. The inhibitory effect of hispidulin was observed within 6 h after the challenge, and the observed effects were similar to those effectuated after dexamethasone administration. Hispidulin at a concentration up to 50 μM also suppressed IFN-γ-producing CD4+ T cells in a dose-dependent manner without inducing cell death, and without a change in total frequencies of CD4+ T cells among different concentration groups.

Conclusion

The results of this study, therefore, suggest hispidulin as a novel compound for the treatment of ACD via the suppression of IFN-γ production in Th1 cells.
Evaluating treatment modalities in chronic pain treatment by the multi-criteria decision making procedure
Authors: Sir Ender , Batur Sir Gül Didem
Published: October 2019

Background

Chronic pain is one of the most common complaints of cancer patients. There are many pharmacological and non-pharmacological treatment modalities used for the treatment of pain. Nonetheless, non-pharmacological interventions are preferred because of potential side effects in cases resistant to medical therapy that require a dose increase or potent drug use. In most real-life situations, the decision on which technique to choose is based on the clinical but subjective decisions of the practitioners. This study aimed to find out the best non-pharmacological treatment option for patients with chronic cancer pain by following a rational and reasonable approach.

Methods

Since the evaluation of treatment options requires to make a comparison between a number of alternatives in the light of certain criteria, we utilize the order relation analysis (G1-method) which is a method for determining the weights based on the improved Analytic Hierarchy Process (AHP). The method uses the relative importances on prioritizing the four criteria and eight sub-criteria defined by the experts of three pain physicians, one oncologist, and one oncologic surgeon. Four alternatives are then compared according to the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) using the verbal subjective judgments of the practitioners.

Results

Obtained results indicate that the general medical condition of the patient and the stage of the cancer are the essential factors in the selection of the treatment method. It is followed by the extent of the pain and the level of evidence, respectively. According to the evaluations performed, spinal port and splanchnic nerve radiofrequency thermocoagulation treatments are the first and second priority methods for pain treatment, respectively, compared to lumbar epidural catheter and celiac plexus block.

Conclusions

The results of this study emphasize the need to integrate critical criteria into the decision-making process objectively. This is the first study in which multi-criteria decision-making tools are used in the evaluation and selection of pain management methods in cancer patients.
A novel endothelial damage inhibitor for the treatment of vascular conduits in coronary artery bypass grafting: protocol and rationale for the European, multicentre, prospective, observational DuraGraft registry
Authors: Caliskan Etem , Sandner Sigrid , Misfeld Martin , Aramendi Jose , Salzberg Sacha P. , Choi Yeong-Hoon , Satishchandran Vilas , Iyer Geeta , Perrault Louis P. , Böning Andreas , Emmert Maximilian Y.
Published: October 2019

Background

Vein graft disease (VGD) impairs graft patency rates and long-term outcomes after coronary artery bypass grafting (CABG). DuraGraft is a novel endothelial-damage inhibitor developed to efficiently protect the structural and functional integrity of the vascular endothelium. The DuraGraft registry will evaluate the long-term clinical outcomes of DuraGraft in patients undergoing CABG procedures.

Methods

This ongoing multicentre, prospective observational registry will enrol 3000 patients undergoing an isolated CABG procedure or a combined procedure (ie, CABG plus valve surgery or other surgery) with at least one saphenous vein grafts or one free arterial graft (ie, radial artery or mammary artery). If a patient is enrolled, all free grafts (SVG and arterial will be treated with DuraGraft. Data on baseline, clinical, and angiographic characteristics as well as procedural and clinical events will be collected.

The primary outcome measure is the occurrence of a major adverse cardiac event (MACE; defined as death, non-fatal myocardial-infarction, or need for repeat-revascularisation). Secondary outcome measures are the occurrence of major adverse cardiac and cerebrovascular events (MACCE; defined as death, non-fatal myocardial-infarction, repeat-revascularisation, or stroke), patient-reported quality of life, and health-economic data. Patient assessments will be performed during hospitalisation, at 1-month, 1-year, and annually thereafter to 5 years post-CABG. Events will be adjudicated by an independent clinical events committee. This European, multi-institutional registry will provide detailed insights into clinical outcome associated with DuraGraft.

Discussion

This European, multi-institutional registry will provide detailed insights into clinical outcome associated with the use of DuraGraft. Beyond that, and given the comprehensive data sets comprising of patient, procedural, and graft parameters that are being collected, the registry will enable for multiple subgroup analyses targeting focus groups or specific clinical questions. These may include analysis of subpopulations such as patients with diabetes or multimorbid high-risk patients (patient level), evaluation of relevance of harvesting technique including endoscopic versus open conduit harvesting (procedural level), or particular graft-specific aspects (conduit level).

Trial registration

ClinicalTrials.gov NCT02922088. Registered October 3, 2016.

Ethics and dissemination

The regional ethics committees have approved the registry. Results will be submitted for publication.
Prostatic-specific antigen (PSA) levels in patients with polycystic ovary syndrome (PCOS): a meta-analysis
Authors: Wu Zeng-Hong , Tang Yun , Niu Xun , Pu Fei-Fei , Xiao Xi-Yue , Kong Wen
Published: October 2019

Purpose

The polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder, clinically characterized by oligo-ovulation/chronic anovulation, menstrual irregularities, hyperandrogenism (such as hirsutism, acne), hyperinsulinemia, and obesity. Prostatic-specific antigen (PSA) has been identified as a potential new marker in PCOS women. Although the precise role of PSA in PCOS patients still remains undetermined, PSA might serve as a useful clinical marker and might even represent a new diagnostic criterion of hyperandrogenemia in females of PCOS.

Methods

A meta-analysis was performed in the study to identify the association between the polycystic ovary syndrome and prostatic-specific antigen. To identify eligible original articles, we searched a range of computerized databases, including Medline via PubMed, EMBASE, CNKI and Web of Science with a systematic searching strategy. The characteristics of each study and standard mean differences (SMD) with corresponding confidence intervals (CIs) were calculated and subgroup analysis was performed to analyze heterogeneity.

Results

A total of 532 patients from seven articles were included in the meta-analysis. We identified a significant relationship between polycystic ovary syndrome and prostatic-specific antigen, with a pooled SMD of 0.81 (95% CI: 0.58 to 1.04; P < 0.01). The pooled data were calculated with the random-effects model as a moderate significant heterogeneity was found among the studies.

Conclusions

The meta-analysis suggested that there was a significant association between the polycystic ovary syndrome and prostatic-specific antigen and we should not ignore the role of PSA in the PCOS patients in clinical.
DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure
Authors: Westerman Kenneth , Sebastiani Paola , Jacques Paul , Liu Simin , DeMeo Dawn , Ordovás José M.
Published: October 2019

Background

Epigenome-wide association studies using DNA methylation have the potential to uncover novel biomarkers and mechanisms of cardiovascular disease (CVD) risk. However, the direction of causation for these associations is not always clear, and investigations to-date have often failed to replicate at the level of individual loci.

Methods

Here, we undertook module- and region-based DNA methylation analyses of incident CVD in the Women’s Health Initiative (WHI) and Framingham Heart Study Offspring Cohort (FHS) in order to find more robust epigenetic biomarkers for cardiovascular risk. We applied weighted gene correlation network analysis (WGCNA) and the Comb-p algorithm to find methylation modules and regions associated with incident CVD in the WHI dataset.

Results

We discovered two modules whose activation correlated with CVD risk and replicated across cohorts. One of these modules was enriched for development-related processes and overlaps strongly with epigenetic aging sites. For the other, we showed preliminary evidence for monocyte-specific effects and statistical links to cumulative exposure to traditional cardiovascular risk factors. Additionally, we found three regions (associated with the genes SLC9A1, SLC1A5, and TNRC6C) whose methylation associates with CVD risk.

Conclusions

In sum, we present several epigenetic associations with incident CVD which reveal disease mechanisms related to development and monocyte biology. Furthermore, we show that epigenetic modules may act as a molecular readout of cumulative cardiovascular risk factor exposure, with implications for the improvement of clinical risk prediction.
Electronic self-administered screening for substance use in adult primary care patients: feasibility and acceptability of the tobacco, alcohol, prescription medication, and other substance use (myTAPS) screening tool
Authors: Adam Angéline , Schwartz Robert P. , Wu Li-Tzy , Subramaniam Geetha , Laska Eugene , Sharma Gaurav , Mili Saima , McNeely Jennifer
Published: October 2019

Background

The TAPS Tool is a substance use screening and brief assessment instrument that was developed for use in primary care medical settings. It is one of the first screening instruments to provide rapid assessment of all commonly used substance classes, including illicit and prescription opioids, and is one of the only available screeners designed and validated in an electronic self-administered format (myTAPS). This secondary analysis of data from the TAPS Tool validation study describes the feasibility and acceptability of the myTAPS among primary care patients.

Methods

Adult patients (N = 2000) from five primary care clinics completed the TAPS Tool on a tablet computer (myTAPS), and in an interviewer-administered format. Requests for assistance and time required were tracked, and participants completed a survey on ease of use, utilization of audio guidance, and format preference. Logistic regression was used to examine outcomes in defined subpopulations, including groups that may have greater difficulty completing an electronic screener, and those that may prefer an electronic self-administered approach.

Results

Almost all participants (98.3%) reported that the myTAPS was easy to use. The median time to complete myTAPS screening was 4.0 min (mean 4.48, standard deviation 2.57). More time was required by participants who were older, Hispanic, Black, or reported non-medical prescription drug use, while less time was required by women. Assistance was requested by 25% of participants, and was more frequently requested by those who with lower education (OR = 2.08, 95% CI 1.62–2.67) or age > 65 years (OR = 2.79, 95% CI 1.98–3.93). Audio guidance was utilized by 18.3%, and was more frequently utilized by participants with lower education (OR = 2.01, 95% CI 1.54–2.63), age > 65 years (OR = 1.79, 95% CI 1.22–2.61), or Black race (OR = 1.30, 95% 1.01–1.68). The myTAPS format was preferred by women (OR = 1.29, 95% CI 1.00–1.66) and individuals with drug use (OR = 1.43, 95% CI 1.09–1.88), while participants with lower education preferred the interviewer-administered format (OR = 2.75, 95% CI 2.00–3.78).

Conclusions

Overall, myTAPS screening was feasible and well accepted by adult primary care patients. Clinics adopting electronic screening should be prepared to offer assistance to some patients, particularly those who are older or less educated, and should have the capacity to use an interviewer-administered approach when required.
Fabrication of anisotropic wetting surface with asymmetric structures using geometrical similarity and capillary force
Authors: Lee Ye-Eun , Lee Dong-Ki , Cho Young Hak
Published: October 2019

In the present study, we proposed a fabrication process of anisotropic wetting surfaces with asymmetric grooved parallelogram structures employing basic MEMS processes and micro transfer molding process. A Si substrate and a PDMS mold from Si master were easily self-aligned due to geometrical similarity (all Si wafer have same crystal planes) so that parallelogram microchannels could be formed between the Si substrate and PDMS mold. The parallelogram channels were filled with SU-8 via capillary force, and then the SU-8 parallelogram structures were transferred to an adhesive polymer film. Finally, we obtained an anisotropic wetting surface with SU-8 parallelogram structures, which showed the characteristics of anisotropic wetting and asymmetric flow. The liquid droplets could easily wet in the longitudinal direction of the structures, and the asymmetric flow characteristics of the droplets in the direction perpendicular to the longitudinal direction of the structures could be observed.
Numerical 3D simulation of wire deposition process to predict distortion of parts
Authors: Smetannikov Oleg Yu , Maksimov Petr V. , Trushnikov Dmitriy N. , Permyakov Gleb L. , Belenkiy Vladimir Ya , Farberov Alexander S.
Published: October 2019

In the work, on the basis of the analysis of publications, existing approaches to the numerical modeling of additive processes of product formation are shown. The work itself is devoted to the study of the influence of parameters of the process of surfacing wire materials on the formation of residual deformations in parts. A mathematical formulation of the non-stationary thermomechanical problem is presented, and algorithms for solving the problem using the technology of birth and death of finite elements in the ANSYS package are described. Verification of the model created by the finite element was carried out on the basis of data from the experiment on surfacing a multilayer sample. The effect on the level of residual warping of the following process parameters was studied: the exposure time before the next layer was deposited; the motion path of the burner; ambient temperature. It is shown that the change in ambient temperature is the most effective way to reduce the residual distortions of the form.
Evaluating survival and quality of life with ambulatory chemotherapy in metastatic colorectal cancer.
Authors: Sirilerttrakul Suwannee , Wannakansophon Nopakan , Tangteerakoon Patamaporn , Vongterapak Suluck , Jirajarus Manmana , Ckumdee Sineenuch , Sirachainan Ekaphop , Chansriwong Phichai
Published: October 2019

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Background: Colorectal cancer is an important health problems in Thailand. Chemotherapy treatment that was once delivered only in hospital environments is now administered at patient's home that helping patients to live normal lives during receiving chemotherapy. The chemotherapy regimens are based on a 48 hours 5-fluorouracil infusion combined that need patients to be hospitalized, consequence to decrease QOL and increase cost of treatment. Methods: An observational cohort which enrolled 156 patients at the Ramathibodi hospital from Dec 2015 to Nov 2016. Ambulatory chemotherapy (AC) administered by the central venous access device (CVAD). The regimen as FOLFOX or FOLFIRI, 5-FU were in the elastomeric infusion pump and administered at the patients’ home. The questionnaire of FACT-G and FACT-C scale, cost of treatment were collected at time of enrolment, 2 months and end of treatment. DFS and OS were analyzed in patients who treated with first regimen of metastasis chemotherapy. Nurse coordinator followed up them by phone. Aims: Compares the DFS, OS, QOL score, and cost difference in AC patients compared with inpatient treatment. Results: 156 patients are enrolled that 111 patients treated with AC and 45 patients treated with inpatient. Questionnaire response rate was 86%. Intention to treat analysis revealed significantly improved in social wellbeing and FACT-G (p < 0.001) in AC group. No difference in DFS between AC and inpatient group (12.6 vs 11.9 months, HR 0.82, p = 0.33). Overall survival trended to longer survival in AC arm (2.43 vs 1.83 years, HR 0.78, P = 0.28). The AC reduced cost about 338 US dollars per cycle of chemotherapy. Conclusions: Ambulatory chemotherapy helps colorectal cancer patients to live normal lives by administer treatment at patients' home and results to significantly improve in quality of life . No difference in DFS and OS benefit, but trends in gaining more benefits in ambulatory treatment. Moreover, ambulatory chemotherapy reduced cost of chemotherapy treatment.
A novel function for cyclin D1 as a transcriptional role in oncogenesis and tumor development by ChIP-Seq and RNA-Seq.
Authors: Xiong Yudi , Zhou YunFeng
Published: October 2019

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Background: Cancer is a major public health problem and remains one of the leading causes of death worldwide. Aberrations in cell cycle control is defined as one of the hallmarks of cancer.While cyclin D1 is an essential protein to cell cycle which promote G1 phase into S phase, and frequently overexpressed in many human cancers.Although the participation in cell cycle and tumorigenesis has not been well characterized, new functions have been identified in transgenic mice models, including the transcription of genome, the development of chromosome instability and DNA repair. However, it remains unclear that the function of cyclin D1 independ of involving cell cycle. In this research, our aim is to find the function of cyclin D1 in transcription in human cancers. Methods: We chose the human cervical cancer cell line, C33A as our main research object. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq), to find out the genes differentially expressed in C33A, cyclin D1 knockin C33A and cyclin D1 knockdown C33A. Results: We detected 5590 genes involved in binding with cyclin D1 by ChIP seq, screened 2811 genes upregulation, 2727 genes downregulation in cyclin D1 knockin cells, 2244 genes upregulation, 1738 genes downregulation in cyclin D1 knockdown cells by RNA-seq. Through analysis of the results of ChIP-seq and RNA-seq, we finally identified 422 genes differentially expressed at the RNA level.These genes are highly enriched in Gene Ontology categories and involve in diverse cellular functions via KEGG classification, including translation, replication and repair, signal transduction, cell growth and death. Conclusions: These findings suggested that cyclin D1 can serve both to activate and downregulate gene expression as a transcriptional role directly binding with genome DNA, which means that cyclin D1 may be a key protein during oncogenesis and tumor development.
Microvascular invasion guiding selection of candidates for combination treatment with sorafenib and TACE for intermediate recurrent hepatocellular carcinoma.
Authors: Peng Zhenwei , Chen Shuling , Xiao Han , Wang Yuanqi , Kuang Ming
Published: October 2019

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Background: To investigate the role of sorafenib combined with transarterial chemoembolization (TACE) for the treatment of intermediate recurrent hepatocellular carcinoma (rHCC) after initial hepatectomy and whether the status of microvascular invasion (MVI) could help screen out the appropriate candidates for the combination treatment. Methods: The study was approved by the ethics committee of two tertiary medical centers in China. From Jan 2010 to Dec 2016, 260 consecutive patients with intermediate rHCC after initial hepatectomy who underwent combination treatment or TACE were enrolled. Overall survival (OS) and progression-free survival (PFS) were compared between these two treatments according to MVI status. Results: The 1-, 3-, 5-year OS (77.1% vs. 62.0%, 49.3% vs. 35.2%, 38.9% vs. 20.5%, P = 0.011) and PFS (74.2% vs. 56.5%, 37.5% vs. 18.7%, 37.5% vs. 18.7%, P = 0.003) rates were significantly higher in the combination group than those in the TACE group for intermediate rHCC. For MVI-positive patients, the median OS (17.2 months vs. 12.1 months, P = 0.024) and PFS (17.0 months vs. 11.0 months, P = 0.022) after combination treatment (n = 55) were significantly longer than those after TACE alone (n = 72). For MVI-negative patients, the median OS (42.7 months vs. 32.6 months, P = 0.247) and PFS (24.6 months vs. 17.2 months, P = 0.113) were comparable between combination therapy (n = 73) and TACE alone (n = 60). Multivariate analysis revealed that tumor number, MVI status and treatment allocation were significant predictors of OS and PFS, while the tumor size was another prognostic factor for PFS. Conclusions: Patients with intermediate rHCC can benefit from sorafenib plus TACE treatment, while MVI-positive patients were good candidates for combination treatment.
Impact of CanAssist-Breast in clinical treatment decisions in early stage HR+ breast cancer patients: Asian Scenario.
Authors: Gopalakrishnan Viswanathan , Sankaran Satish , SE Mallikarjuna , Prakash Chandra , Bakre Manjiri Manohar
Published: October 2019

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Background: The utility of multigene prognostic tests in aiding treatment decisions for early stage hormone positive breast cancer patients is well recognized. CanAssist-Breast (CAB) is an immunohistochemistry (IHC) based prognostic test that uses a proprietary algorithm to combine IHC grading of 5 biomarkers and three clinical paramaters (tumor size, node status and Grade) to stratify patients into high or low risk of distant recurrence. CAB has thus far been validated on a retrospective cohort of > 1000 predominantly Asian patients. Distant Metastasis Free Survival (DMFS) of more than 95% was observed with significant separation (P < 0.001) between low-risk and high-risk groups. In this study we demonstrate the usefulness of CanAssist-Breast (CAB) in guiding physicians assess risk of cancer recurrence and to make informed treatment decisions for patients. Methods: A total of 353 Asian patients tested by > 100 physicians were included in this study. Clinical parameters were compiled from hospital data. Treatment decisions were confirmed for > 150 of these patients assess the level of adherence. Risk prediction using the modified Adjuvant! Online protocol was used to compare with performance of CAB. Luminal subtying was performed as per the St. Gallen’s criteria. Results: Majority of patients tested had node negative, T2 and Grade 2 disease. Age and luminal subtypes did not affect the performance of CAB. On comparison with Adjuvant! Online (AOL), CAB categorized twice the number of patients into low-risk. Impact of CAB testing on treatment decisions showed that 96% of low-risk patients were not given chemotherapy and 84% of high-risk patients were given chemotherapy. Overall, we observed that 92% patients were either given or not given chemotherapy based on whether they were stratified as high-risk or low-risk for distant recurrence respectively. Conclusions: CAB stratifies higher percentage of patients into low risk group as compared to AOL. We observed wide acceptance of CAB as a prognostic test for assisting treatment decsions in clinical settings. CAB helped avoid chemotherapy in 70% of patients tested thus providing a cost effective alternative to other prognostic tests currently available.