bluuebunny/crossref_metadata_2025 huggingface dataset:
Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: A retrospective study
Authors: Kondo Masahiro , Hotta Yuji , Yamauchi Karen , Sanagawa Akimasa , Komatsu Hirokazu , Iida Shinsuke , Kimura Kazunori
Published: October 2020

Background: Novel agents such as proteasome inhibitors have been developed for several years to treat multiple myeloma. Although multiple myeloma is a low-risk disease for developing tumor lysis syndrome (TLS), treatment with these novel therapies might increase TLS risk. Previous studies, mostly case reports or case series, have reported bortezomib-induced TLS in patients with multiple myeloma. This study aimed to investigate risk factors associated with TLS development in multiple myeloma patients.Methods: We retrospectively investigated incidences of laboratory and clinical TLS (LTLS and CTLS, respectively) in patients who received primary therapy for treatment-naive, symptomatic multiple myeloma between May 2007 and January 2018. We used multivariate logistic regression analyses to evaluate the associations between TLS and several parameters previously reported to be associated with increased risk.Results: This study included 210 patients with multiple myeloma, of which ten (4.8%) had LTLS and seven (3.3%) had CTLS. The characteristics of the administered anticancer or prophylactic antihyperuricemic agents were similar between patients with and without TLS. Multivariate analyses revealed that TLS was most strongly associated with bortezomib-containing therapy (odds ratio = 3.40, P = 0.069), followed by male sex (odds ratio = 2.29, P = 0.153). In a subgroup analysis focused on men, treatment with bortezomib-containing therapy was significantly associated with increased risk of TLS (odds ratio = 8.51, P = 0.046).Conclusion: In the present study, we investigated the risk factors associated with TLS development in 210 multiple myeloma patients, which, to the best of our knowledge, is the largest number of patients reported to date. Furthermore, this study is the first to evaluate TLS risk factors in MM by adjusting for the effects of potential confounding factors in patients’ backgrounds. Consequently, we found that bortezomib-containing therapy increases the risk of TLS in male patients with multiple myeloma. TLS risk should be evaluated further in low-risk diseases such as multiple myeloma, since a significant number of novel therapies can achieve high antitumor responses.
Low Engagement in HIV Services and Progress through the Treatment Cascade among Key Populations Living with HIV in Mozambique: Alarming Gaps in Knowledge of Status
Authors: Boothe Makini , Sathane Isabel , Baltazar Cynthia Semá , Chicuecue Noela , Horth Roberta , Fazito Erika , Raymond Henry Fisher
Published: October 2020

Background: Mozambique has a generalized HIV epidemic of 13.5% among the general population. Early modeling exercises in Mozambique estimate that key populations (KPs), defined as men who have sex with men (MSM), female sex workers (FSW), and people who inject drugs (PWID), along with their partners account for about one third of all new infections. There is limited data describing the engagement of KP living with HIV in testing, care and treatment services. Methods: We conducted a secondary data analysis of HIV-positive participants in the first Bio-behavioral Surveillance (BBS) surveys in Mozambique conducted 2011-2014 in order to assess service uptake and progress though the HIV treatment cascade among MSM, FSW, and PWID. Unweighted pooled estimates were calculated for each key population group. Results: Among HIV-positive MSM, 63.2% of participants had ever received an HIV test, 8.8% were aware of their status, 6.1% reported having been linked to care, while 3.5% initiated ART and were currently on treatment. Of the HIV-infected FSW participants, 76.5% reported a previous HIV test and 22.4% were previously aware of their status. Linkage to care was reported by 20.1%, while 12.7% reported having initiated ART and 11.8% reported being on treatment at the time of the survey. Among HIV-infected PWID participants, 79.9% had previously received an HIV test, 63.2% were aware of their HIV status, and 49.0% reported being linked to care for their HIV infection. ART initiation was reported by 42.7% of participants, while 29.4% were on ART at the time of the survey. Conclusion: Among the three high risk populations in Mozambique, losses occurred throughout critical areas of service uptake with the most alarming breakpoint occurring at knowledge of HIV status. Special attention should be given to increasing HIV testing and linkage to ART treatment. Future surveys will provide the opportunity to monitor improvements across the cascade in line with global targets and should include viral load testing to guarantee a more complete picture of the treatment cascade.
Genome-Wide Identification and Analysis of Class III Peroxidases in Betula pendula
Authors: Cai Kewei , Chen Song , Liu Yi , Zhao Xiyang , Chen Su
Published: October 2020

Background: Class III peroxidases (POD) proteins are widely present in the plant kingdom that are involved in a broad range of physiological processes including stress responses and lignin polymerization throughout the plant life cycle. However, little is known about the POD genes in Betula pendula, although it has been characterized in Arabidopsis, rice, poplar, maize and Chinese pear. The POD genes remain to be determined in Betula pendula.Results: A total of 90 nonredundant POD genes were identified in Betula pendula. (designated BpPODs). These POD genes were divided into twelve groups based on their phylogenetic relationships. The BpPODs are unevenly distributed on the 14 chromosomes. In addition, some BpPODs were located sequentially in tandem on chromosomes, inferred that tandem duplication contributes to the expansion of the POD gene family in Betula pendula. Analysis of the distribution of conserved domains of BpPOD proteins showed that all these proteins contain highly conserved motifs. We also investigated their expression patterns in different tissues, the results show that some BpPODs might play significant roles in root, xylem, leaf and flower. Furthermore, under low temperature conditions, some BpPODs showed different expression patterns at different times. Conclusions: Comprehensive study of the POD genes suggests that their functional diversity during Betula pendula growth and development. Our findings provide a basis for further functional analysis on POD gene family in Betula pendula.
Reactive Attachment Disorder Symptoms and Prosocial Behavior in Middle Childhood: The Role of Secure Base Script Knowledge
Authors: Cuyvers Bien , Vervoort Eleonore , Bosmans Guy
Published: October 2020

Background: Children with attachment disorder show prosocial behavior problems. Children with a reactive attachment disorder show inhibited and emotionally withdrawn behavior. Consequently, these children typically display prosocial behavior problems. However, the underlying mechanism between reactive attachment disorder and prosocial behavior problems is still unclear and findings in literature are mixed. Methods : The current study investigated the role of children’s attachment representations in this association. Attachment representations reflect knowledge about a cognitive script regarding the attachment figure as a source for support (Secure Base Script). We tested whether secure base script knowledge 1) mediates or 2) moderates the link between reactive attachment disorder and prosocial behavior problems in 83 children (6-11 years; 83.1% boys) recruited from special education schools for children with behavioral problems. Children completed a pictorial Secure Base Script Test. Their reactive attachment disorder symptoms were assessed during an interview with the primary caregivers. Primary caregivers and teachers filled out a prosocial behavior questionnaire about the child. Results : Results did not support the mediation hypothesis, but evidence for the moderation hypothesis was found. Secure base script knowledge attenuated the negative association between attachment disorder symptoms and prosocial behavior. Conclusions : These findings contribute to the discussion about the link between attachment representations and attachment disorders.
Mesenchymal stem cells desensitize castration-resistant prostate cancer to docetaxel chemotherapy via inducing TGF-β1-mediated cell autophagy
Authors: Yu Yang , Zhang Wen-tao , Yang Fu-han , Guo Ya-dong , Ye Lin , Yao Xu-dong
Published: October 2020

Background: Mesenchymal stem cells (MSCs) have been proved to accelerate prostate cancer (PCa) castration resistance progression. The purpose of this study is to investigate the contribution of MSCs to the development of docetaxel resistance in castration-resistant prostate cancer (CRPC) cells and its potential mechanisms. Methods: The effect of MSCs on CRPC cells resistance to docetaxel was determined using in-vivo and in-vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses. Results: MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel. Conclusions: These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.
Genomic analysis of worldwide sheep breeds reveals PDGFD as a major target of fat-tail selection in sheep
Authors: Dong Kunzhe , Yang Min , Han Jiangang , Ma Qing , Han Jilong , Song Ziyi , Luosang Cuicheng , Gorkhali Neena Amatya , Yang Bohui , He Xiaohong , Ma Yuehui , Jiang Lin
Published: October 2020

Background: Fat tail is a unique trait in sheep acquired during domestication. Several genomic analyses have been conducted in sheep breeds from limited geographic origins to identify the genetic factors underlying this trait. Nevertheless, these studies obtained different candidates. The results of these regional studies were easily biased by the breed structures. Results: To minimize the bias and distinguish the true candidates, we used an extended data set of 968 sheep representing 18 fat-tailed breeds and 14 thin-tailed breeds from around the world, and integrated two statistical tests to detect selection signatures, including Genetic Fixation Index (FST) and difference of derived allele frequency (ΔDAF). The results showed that platelet derived growth factor D (PDGFD) exhibited the highest genetic differentiation between fat- and thin-tailed sheep breeds. Analysis of sequence variation identified that a 6.8-kb region within the first intron of PDGFD is likely the target of positive selection and contains regulatory mutation(s) in fat-tailed sheep. Histological and gene expression analyses demonstrated that PDGFD expression is associated with maturation and hemostasis of adipocytes. Further retrospective analysis of public transcriptomic datasets revealed that PDGFD expression is down-regulated during adipogenesis in both human and mouse, and is higher in fat tissues of obese individuals than that in lean individuals. Conclusions: These results reveal that PDGFD is the predominant factor for the fat tail phenotype in sheep by contributing to adiopogenesis and maintaining the hemostasis of mature adipocytes. This study provides insights into the selection of fat-tailed sheep and has important application to animal breeding, as well as obesity-related human diseases.
Ergogenic effect of pre-exercise chicken broth ingestion on a high-intensity cycling time-trial
Authors: barbaresi silvia , Blancquaert Laura , Nikolovski Zoran , de Jager Sarah , Wilson Mathew , Everaert Inge , De Baere Siegrid , Croubels Siska , De Smet Stefaan , Cable Tim , Derave Wim
Published: October 2020

Background: chicken meat extract is a popular functional food in Asia. It is rich in the bioactive compounds carnosine and anserine, two histidine-containing dipeptides (HCD). Studies suggest that acute pre-exercise ingestion of chicken extracts has important applications towards exercise performance and fatigue control, but the evidence is equivocal. This study aimed to evaluate the ergogenic potential of the pre-exercise ingestion of a homemade chicken broth (CB) vs a placebo soup on a short-lasting, high-intensity cycling exercise. Methods: fourteen men participated in this double-blind, placebo-controlled, crossover intervention study. Subjects ingested either CB, thereby receiving 46.4 mg/kg body weight of HCD, or a placebo soup (similar in taste without HCD) 40 min before an 8 min cycling time trial (TT) was performed. Venous blood samples were collected at arrival (fasted), before exercise and at 5 min recovery. Plasma HCD were measured with UPLC-MS/MS and glutathione (in red blood cells) was measured through HPLC. Capillary blood samples were collected at different timepoints before and after exercise. Results: a significant improvement (p=0.033; 5.2%) of the 8 min TT mean power was observed after CB supplementation compared to placebo. Post-exercise plasma carnosine (p<0.05) and anserine (p<0.001) was significantly increased after CB supplementation and not following placebo. No significant effect of CB supplementation was observed either on blood glutathione levels, nor on capillary blood analysis. Conclusions: oral CB supplementation improved the 8 min TT performance albeit it did not affect the acid-base balance or oxidative status parameters. Further research should unravel the potential role and mechanisms of HCD, present in CB, in this ergogenic approach.
Striatal Dopamine Transporter Spect Quantification: Head-To-Head Comparison Between Two Three-Dimensional Automatic Tools
Authors: Morbelli Silvia , Arnaldi Dario , Cella Eugenia , Raffa Stefano , Donegani Isabella , Capitanio Selene , Massa Federico , Miceli Alberto , Filippi Laura , Chincarini Andrea , Nobili Flavio
Published: October 2020

Purpose. Our aim was the head-to-head comparison between two automatic tools for semi-quantification of striatal dopamine transporter (DAT) specific-to-non displaceable (SBR) ratio brain SPECT values in a naturalistic cohort of patients.
Procedures. We analyzed consecutive scans from one-hundred and fifty-one outpatients submitted to brain DAT SPECT for a suspected parkinsonism. Images were post-processed using a commercial (Datquant®) and a free (BasGanV2) software. Reading by expert was the gold-standard. A subset of patients with pathological or borderline scan was evaluated with the clinical Unified Parkinson’s disease rating scale, motor part (MDS-UPDRS-III).
Results. SBR, putamen-to-caudate (P/C) ratio, and both P and C asymmetries were highly correlated between the two software with Pearson’s ‘r’ correlation coefficients ranging from .706 to .887. Correlation coefficients with the MDS-UPDRS III score were higher with caudate than with putamen SBR values with both software, and in general higher with BasGanV2 than with Datquant® . Datquant® correspondence with expert reading was 84.1% (94.0% by additionally considering the P/C ratio as a further index). BasGanV2 correspondence with expert reading was 80.8% (86.1% by additionally considering the P/C ratio).
Conclusions. Both Datquant® and BasGanV2 work reasonably well and similarly one another in semi-quantification of DAT SPECT. Both tools have their own strength and pitfalls that must be known in detail by users in order to obtain the best help in visual reading and reporting of DAT SPECT.
Leptin down-regulates KCC2 activity and controls chloride homeostasis in the neonatal rat hippocampus.
Authors: Dumon Camille , Belaidouni Yasmine , Diabira Diabe , Appleyard Suzanne , Wayman Gary , Gaiarsa Jean-Luc
Published: October 2020

The canonical physiological role of leptin is to regulate hunger and satiety acting on specific hypothalamic nuclei. Beyond this key metabolic function; leptin also regulates many aspects of development and functioning of neuronal hippocampal networks throughout life. Here we show that leptin controls chloride homeostasis in the developing rat hippocampus in vitro. The effect of leptin relies on the down-regulation of the potassium/chloride extruder KCC2 activity and is present during a restricted period of postnatal development. This study confirms and extends the role of leptin in the ontogenesis of functional GABAergic inhibition and helps understanding how abnormal levels of leptin may contribute to neurological disorders.
Atypical presentations of pulmonary sarcoidosis: Three cases report and literature review
Authors: Zhang Qian , Huang Hui , Wang Na , Feng Ruie , Xu Zuojun
Published: October 2020

Background: Sarcoidosis is a systematic disease with unknown etiology and lung involved predominantly and also known as a “great mimicker” in lung disease for its characteristics of various appearances in radiology images.Case presentation: In this article, we present three sarcoidosis patients with atypical manifestation in their imaging performance, including cavitation sign, reversed-halo sign and distributed small nodules with ground glass opacities in both lungs resembled the manifestation of chronic hypersensitive pneumonia. They were diagnosed with sarcoidosis after the confirmation by pathological evidence and received relevant corticosteroid treatment. We also made a literature review from “pubmed” databases to analysis the atypical sarcoidosis performances in past five years. Conclusions: The atypical manifestation on HRCT of sarcoidosis patients presented in different types which could be ignored by clinicians. Pathology biopsy and clinical characteristics are valuable clues for precise diagnose of sarcoidosis. Thus, clinicians should be on high alert of differential diagnosis and reasonable treatment.
Parthenolide inhibits the growth of non-small cell lung cancer by targeting epidermal growth factor receptor
Authors: Li Xiaoling , Huang Riming , Li Mingyue , Zhu Zheng , Chen Zhiyan , Cui Liao , Luo Hui , Luo Lianxiang
Published: October 2020

Background: EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of EGFR mutated NSCLC. Parthenolide, a natural product of parthenolide, which belongs to the sesquiterpene lactone family and has a variety of biological and therapeutic activities, including anti-cancer effects. However, its effect on non-small cell lung cancer is little known. Methods: The CCK‑8 assay and colony formation assays were used to assess cell viability. Flow cytometry was used to measure the cell apoptosis. In silico molecular docking was used to evaluate the binding of parthenolide to EGFR. Network pharmacology analysis was was used to evaluate the key gene of parthenolide target NSCLC. Western blotting was used to evaluate the key proteins involved apoptosis and EGFR signalling. The effect of parthenolide treatment in vivo was determined by using a xenograft mouse model.Results: In this study, parthenolide could induce apoptosis and growth inhibition in the EGFR mutated lung cancer cells. Parthenolide also reduces the phosphorylation of EGFR as well as its downstream signaling pathways MAPK/ERK and PI3K/Akt. Molecular docking analysis of EGFR binding site with parthenolide show that the anti-cancer effect of parthenolide against NSCLC is mediated by a strong binding to EGFR. Network pharmacology analysis show parthenolide suppresses NSCLC via inhibition of EGFR expression. In addition, parthenolide inhibits the growth of H1975 xenografts in nude mice, which is associated with the inhibition of the EGFR signaling pathway. Conclusions: Taken together, these results demonstrate effective inhibition of parthenolide in NSCLC cell growth by targeting EGFR through downregulation of ERK and AKT expression, which could be promisingly used for patients carrying the EGFR mutation.
Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer and Choroidal Metastases: Long-Term Outcome and Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Authors: Bouchez Clémentine , Pluvy Johan , Soussi Ghassen , Nguenang Marina , Brosseau Solenn , Tourne Morgan , Collin Mégane , Théou-Anton Nathalie , Guyard Alice , Ammar Jamila , Khalil Antoine , Zalcman Gérard , Gounant Valérie
Published: October 2020

Background: Choroidal metastases are the most common eye metastatic site. The prevalence of choroidal metastases in NSCLC patients has been reported to vary from 0.2% to 7% in historical series. Although previously reported, little is known about choroidal metastasis in Epidermal Growth Factor Receptor (EGFR)-mutant Non-small cell lung cancer (NSCLC). This study sought to describe the prevalence of choroidal metastases among patients with EGFR-mutated NSCLC and their characteristics, and to estimate their impact on prognosis.Methods: We conducted a single-center retrospective study including all consecutive metastatic EGFR-mutant NSCLC patients, from Sept. 2015 to Oct. 2018. The EGFR-mutant NSCLC patients were identified via the Department of Genetics’ files. Patients who exhibited choroidal metastases were compared to patients without choroidal metastases. Kaplan-Meier analysis and log-rank test were conducted to assess median overall survival (OS) from diagnosis for the two groups. The study was approved by the IRB as CEPRO number #2020-010.Results: Prevalence of choroidal metastases in EGFR-mutated NSCLCs was 8.4% (7/83). Five were women, and four current or former smokers. Molecular analysis showed three tumors with exon 19 deletion, three with L858R mutation, and one with complex exon 21 mutation. The choroidal metastases were symptomatic in six/seven patients. Visual disturbances decreased in all but one symptomatic cases upon EGFR TKI, and the choroidal response was maintained over time.Median follow-up was 42.2 mo (95%CI [37.2 - 47.1]). Median OS in the choroidal metastasis group was 23.4 mo (95%CI [0.1 - 51.4]) versus 27.9 mo (95%CI [16.9 - 38.9]) in the non-choroidal metastasis group (p=0.32). In the choroidal metastasis group, 2-year and 5-year OS were 47.6% and 0%, respectively, versus 55.8% and 26.3% in the non-choroidal metastasis subset.Conclusions: Choroidal metastases in NSCLC EGFR-mutant patients are rare but should be systematically suspected in case of visual disturbance. TKIs are efficient for treating visual symptoms. Whether choroidal metastases confer a worse prognosis remains unclear owing to the third-generation EGFR TKI osimertinib first-line registration.
Pancreatic Cancer Stem Cells May Define Tumor Stroma Characteristics and Recurrence Patterns in Pancreatic Ductal Adenocarcinoma
Authors: Askan Gokce , Sahin Ibrahim Halil , Chou Joanne F. , Yavas Aslihan , Capanu Marinela , Iacobuzio-Donahue Christine A. , Basturk Olca , O'Reilly Eileen M
Published: October 2020

Background: Herein, we investigate the relationship between pancreatic stem cell markers (PCSC markers), CD44, and epithelial-specific antigen (ESA), tumor stroma, and the impact on recurrence outcomes in pancreatic ductal adenocarcinoma (PDAC) patients.Methods: PDAC patients who underwent surgical resection between 01/2012 -06/2014 were identified. CD44 and ESA expression was assessed by immunohistochemistry. Stroma was classified as loose, moderate, and dense based on fibroblast content. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared between subgroups by log-rank test. The association between PCSC markers and stroma type was assessed by Fisher`s exact test. Results: N= 93 PDAC patients were identified. The number of PDAC patients with dense, moderate density, and loose stroma was 11 (12%), 51 (54%), and 31 (33%) respectively. PDAC with CD44+/ESA- had highest rate of loose stroma (63%) followed by PDAC CD44+/ESA+ (50%), PDAC CD44-/ESA+ (35%), CD44-/ESA- (9%) (p=0.0033). No local recurrence was observed in patients with dense stroma and 9 had distant recurrence. The highest rate of cumulative local recurrence observed in patients with loose stroma. No statistically significant difference in RFS and OS were observed among subgroups (P=0.089). Conclusions: These data indicate PCSCs may have an important role in stroma differentiation in PDAC. Although not reaching statistical significance, we observed more local recurrences in patients with loose stroma, and no local recurrence was seen in patients with dense stroma suggesting tumor stroma may influence the recurrence pattern in PDAC patients.
Empowering Traditional Birth Attendants as Agents of Maternal and Neonatal Immunization Uptake in Nigeria: a repeated measures design.
Authors: IWU Chinedu Anthony , Uwakwe Kenechi , Oluoha Uchechukwu Raphael , Duru chukwuma , NWAIGBO ERNEST
Published: October 2020

Background: Adequate immunization coverage in rural communities remain a challenge in Nigeria. Traditional birth attendants (TBAs) form an integral part of the social, cultural and religious fabric in most rural communities in Nigeria. Despite their limitations in handling the complications of childbirth, TBAs are widely accepted and patronized, especially in rural areas. The objectives of the project were to empower TBAs and assess the use of a culturally adapted audio-visual workshop intervention to change their knowledge, attitude and willingness to promote immunization uptake.Methods: A repeated-measures design that used a convenience sampling technique to select 90 TBAs from the three geopolitical zones of Imo State, Nigeria. The TBAs were engaged through a culturally adapted audio-visual workshop. Data were collected before and immediately after intervention using a pretested questionnaire. Chi square test was done to determine any significant association with the zone of practice and paired sample t-test analysis to determine any significant pre and post intervention change. Level of significance was set at p ≤ ·05. Results: More than half of the TBAs had at most, a secondary level of education (54·4 %). The average length of time they practiced as TBAs was 16 years with an average of ten birth deliveries per month. After the intervention, all the respondents (100%) reported a willingness to always promote immunization uptake and also, there was a statistically significant increase in Knowledge (p<·000). Similarly, the level of knowledge in the post intervention period appeared to be significantly associated with the zone of practice (p= ·027). Conclusion: The workshop intervention empowered the TBAs irrespective of their zones of residence by successfully improving their knowledge, though at varying levels; and consequently, their willingness to always promote immunization uptake.
Altered striatal dopamine levels in Parkinson’s disease VPS35 D620N mutant transgenic aged mice
Authors: Vanan Sarivin , Zeng Xiaoxia , Chia Sook Yoong , Varnäs Katarina , Jiang Mei , Zhang Ke , Saw Wuan Ting , Padmanabhan Parasuraman , Yu Wei-Ping , Zhou Zhi-Dong , Halldin Christer , Gulyás Balázs , Tan Eng-King , Zeng Li
Published: October 2020

Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.
Hepatocellular carcinoma: Intratumoral EpCAM-positive cancer stem cell heterogeneity identifies high-risk tumor subtype
Authors: Krause Jenny , von Felden Johann , Casar Christian , Fründt Thorben W. , Galaski Johanna , Schmidt Constantin , Jung Caroline , Ittrich Harald , Weidemann Sören Alexander , Krech Till , Heumann Asmus , Li Jun , Fischer Lutz , Sauter Guido , Lohse Ansgar W. , Wege Henning , Schulze Kornelius
Published: October 2020

Background: The translational interest in the intratumoral heterogeneity of hepatocellular carcinoma (HCC) has been increasing. The dismal prognosis of this pathology is linked to the features of the HCC harbouring cancer stem cells (CSC), represented by EpCAM-expression. However, the extent of the impact of intratumoral distribution of CSC-features, both on the recurrence after curative resection and on clinical outcome, remains unknown. To address this, we investigated the spatial heterogeneity of CSC-features with the aim of identifying the unique HCC patient subgroups amenable to adjuvant treatment.Methods: We designed a tissue microarray (TMA) from patients who had received liver resection between 2011 and 2017. Tumor specimens were sampled at multiple locations (n=3-8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: (i) negative (E-/-); (ii) heterogeneous (E-/+); and (iii) homogeneous (E+/+). The groups were further analysed with regard to time-to-recurrence (TTR) and recurrence-free-survival (RFS).Results: We included 314 tumor spots from 69 patients (76.8% male, median age 66 years, liver cirrhosis/fibrosis 75.8). The risk factors were alcohol abuse (26.2%), NASH (13.1%), HBV (15.5%), HCV (17.9%) and others (27.4%), representative of a typical Western cohort. E+/+ patients experienced significantly shorter TTR and RFS compared to E+/- (and E-/-) patients (TTR 5 vs. 19 months, p=0.022; RFS 5 vs. 14 vs. 21 months, p=0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (>400 ng/ml, p=0.031).Conclusions: Spatial heterogeneity of EpCAM-expression was markedly present in the cohort. Of note, only homogeneous EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. We identified a unique HCC subtype associated with a high risk of tumor recurrence.
Common Causes and Characteristics of Adverse Drug Reactions in Older Adults: A Retrospective Study
Authors: Woo Seong-Dae , Yoon Jiwon , Doo Go-Eun , Park Youjin , Lee Youngsoo , Lee So-Hee , Lee Young-Hee , Ye Young-Min
Published: October 2020

Background: Aging populations are often accompanied by comorbidity and polypharmacy, leading to increases in adverse drug reactions (ADRs). We sought to evaluate the causes and characteristics of ADRs in older Korean adults (≥65 years) in comparison to younger individuals (<65 years).Methods: Of 37,523 cases reported at a Korean pharmacovigilance center from 2011 to 2018, we reviewed 18,842 ADRs of certain or probable causality on the basis of WHO-UMC criteria. We estimated the number of ADRs per 1,000 patients exposed to the major culprit drugs, and incidence rate ratios were obtained to assess high- and low-risk medications in older adults.Results: In total, 4,152 (22.0%) ADRs were reported for 3,437 older adults (mean age, 74.6 years and 57.3% female). Tramadol (rate ratio, 1.32; 95% confidence interval [CI], 1.21-1.44; P<0.001) and fentanyl (1.49, 1.16-1.92, P=0.002) posed higher risks of ADRs in the older adults, whereas nonsteroidal anti-inflammatory drugs (NSAIDs) (0.35, 0.30-0.40, P<0.001) and iodinated contrast media (ICM) (0.82, 0.76-0.89, P<0.001) posed lower risks. Ratios of serious ADRs to NSAIDs (odds ratio, 2.16; 95% CI, 1.48-3.15; P<0.001) and ICM (2.09, 1.36-3.21, P=0.001) were higher in the older adults than in the younger patients. Analgesics primarily elicited cutaneous ADRs in the younger patients and gastrointestinal reactions in the older adults. ICM more commonly led to anaphylaxis in the older adults than the younger patients (3.0% vs. 1.6%, P=0.019). Conclusion: For early detection of ADRs in older adults, better understanding of differences in the causes and characteristics thereof in comparison to the general population is needed.
Quantitative Proteomic Analyses Reveal That Energy Metabolism and Protein Biosynthesis Reinitiation are Responsible for the Initiation of Bolting Induced by High Temperature in Lettuce (Lactuca sativa L.)
Authors: Hao Jing-hong , Su He-Nan , Zhang Li-li , Liu Chao-jie , Han Ying-yan , Qin Xiao-xiao , Fan Shuang-xi
Published: October 2020

Background

Lettuce (Lactuca sativa L.), one of the most economically important leaf vegetables, exhibits early bolting under high-temperature conditions. Early bolting leads to loss of commodity value and edibility, leading to considerable loss and waste of resources. However, the initiation and molecular mechanism underlying early bolting induced by high temperature remains largely elusive.
Results

To better understand this phenomenon, the bolting initiation period of lettuce was defined, and a comparative proteomic analysis was conducted in the initiation period of bolting induced by a high temperature (33 °C) and a control temperature (20 °C) using iTRAQ-based proteomics, phenotypic measurement, and biological verification by RT-qPCR. Morphological and microscopic observation showed that the initiation of bolting occurred 8 days after high-temperature treatment. Fructose rapidly accumulated after high-temperature treatment. During bolting initiation, of the 3305 identified proteins, a total of 93 proteins exhibited differential abundances, 38 of which were up-regulated, and 55 were down-regulated. Approximately 38% of the proteins were involved in metabolic pathways and were mainly clustered in energy metabolism and protein synthesis. Furthermore, some proteins involved in sugar synthesis were differentially expressed, which were also associated with energy production.
Conclusions

This is the first report on the metabolic changes involved in bolting initiation in lettuce. Our study suggested that energy metabolism and ribosomal proteins are pivotal components during bolting initiation. This study could provide a potential regulatory mechanism for the initiation of early bolting by high temperature, which could have applications in the manipulation of lettuce for breeding.
Digital Insecticide-treated nets (ITNs) mass distribution campaign in the particular context of covid-19 pandemic in Benin: lessons learned and challenges.
Authors: AIKPON ROCK , Affoukou Cyriaque , Hounkpatin Benjamin , Eclou Dieu-Donné , Cyaka Yves , Egwu Elijah , Agbessi Narcisse , Tokponon Filémon , Salifou Sahidou , Salami Lamidhi , Hounto Aurore Ogouyemi
Published: October 2020

Background: In 2020, Benin has implemented a digital Insecticide-treated nets (ITNs) mass distribution campaign in the particular context of covid-19 pandemic and then, offered important lessons to share. This paper aims to describe the implementation process as well as the lessons learned and challenges from this campaign. Methods: A descriptive design was used for reporting the planning and implementation process of ITNs campaign. Moreover, the changes and adaptations related to covid-19 pandemic are well described. Results: A total of 3,175,773 households were registered corresponding to a total of 14,423,998 persons (13.55% more from projection). Moreover, 94.16 % (13,581,637 people) of enumerated population were protected. A total of 7,652,166 ITNs were distributed countrywide.Conclusions: High political commitment, engagement and support add to the financial and technical supports from partners were the essential factors that make 2020 ITNs mass campaign success in Benin despite the particular context of COVID-19 pandemic. It is essential to maintain the prevention activities for malaria and this could substantially reduce the overall impact of the COVID-19 pandemic in the populations at malaria risk.
Childhood stunting and associated factors among irrigation and non-irrigation user Northwest, Ethiopia: a comparative cross-sectional study
Authors: Sema Balew , Azage Muluken , Tirfie Mulat
Published: October 2020

Background: Stunting is a critical public health problem of developing countries like Ethiopia. Different interventions like irrigation activity have been carried out by the government of Ethiopia to improve the nutritional status of the community. However, there is scanty of data on childhood stunting and its associated factors between irrigation user and non-irrigation user. Objective: To assess the magnitude of childhood stunting and its associated factors between irrigation and non-irrigation user in North Mecha District, Northwest Ethiopia. Methods: A community-based comparative cross-sectional study design was employed from October to November 2019. A systematic sampling was used to draw mothers with children age 6-59 months (582 irrigated and 582 non- irrigated household users). Data were collected using questionnaire and anthropometric measurement tools. Multivariable logistic regression was used to identify the predictors of stunting. Adjusted odds ratios with 95% CI were used to determine the degree of association between independent and outcome variable. A-p-value <0.05 was used as cutoff point to declare statistically significant variables with the outcome variable. Results: The prevalence of childhood stunting (6-59 months) among irrigation users [32.8% at 95%CI (29-37)] was slightly higher than non-usurers [40.2% at 95%CI (36-44)]. However, the difference did not show significant variation. The odds of childhood stunting were higher among a child from a mother had no antenatal visit, a child whose age was between 12 and 47 months, a child from a mother who did not use water and soap always for washing hands, and a child who had fever. Conclusion: The prevalence of childhood stunting was high and did not show significant variation between irrigation and non-irrigation users. A child from mother had no antenatal visit, whose age was between 12 and 47 months, a mother who did not use water and soap always for washing hands, and who had fever were factors associated with higher child stunting. Thus, the identified modifiable factors should be strengthened to reduce stunting.
An innovative pharmacology curriculum for medical students: promoting higher order cognition, learner-centered coaching, and constructive feedback through a social pedagogy framework
Authors: McHugh Douglas , Yanik Andrew J , Mancini Michael R
Published: October 2020

Background

Ongoing developments in medical education recognize the move to curricula that support self-regulated learning processes, skills of thinking, and the ability to adapt and navigate uncertain situations as much as the knowledge base of learners. Difficulties encountered in pursuing this reform, especially for pharmacology, include the tendency of beginner learners not to ask higher-order questions and the potential incongruency between creating authentic spaces for self-directed learning and providing external expert guidance. We tested the feasibility of developing, implementing, and sustaining an innovative model of social pedagogy as a strategy to address these challenges.

Methods

Constructivism, communities of practice, and networked learning theory were selected as lenses for development of the model. 365 first-year medical students participated between 2014-2018; they were introduced to pharmacodynamics and pharmacokinetics via 15 online modules that each included: learning objectives, a clinical vignette, teaching video, cumulative concept map, and small group wiki assignment. Five-person communities organized around the 15 wiki assignments were a key component where learners answered asynchronous, case-based questions that touched iteratively on Bloom’s cognitive taxonomy levels. The social pedagogy model’s wiki assignments were explored using abductive qualitative data analysis.

Results

Qualitative analysis revealed that learners acquired and applied a conceptual framework for approaching pharmacology as a discipline, and demonstrated adaptive mastery by evaluating and interacting competently with unfamiliar drug information. Learners and faculty acquired habits of self-directed assessment seeking and learner-centered coaching, respectively; specifically, the model taught learners to look outward to peers, faculty, and external sources of information for credible and constructive feedback, and that this feedback could be trusted as a basis to direct performance improvement.

Conclusions

This social pedagogy model is agnostic with regard to pharmacology and type of health professional learner; therefore, we anticipate its benefits to be transferable to other disciplines.
Hypofractionated proton beam radiotherapy in patients with unresectable liver tumors: multi-institutional prospective results from the Proton Collaborative Group
Authors: Parzen Jacob S , Hartsell William , Chang John , Apisarnthanarax Smith , Molitoris Jason , Durci Michael , Tsai Henry , Urbanic James , Ashman Jonathan , Vargas Carlos , Stevens Craig , Kabolizadeh Peyman
Published: October 2020

Background: Recent advances in radiotherapy techniques have allowed ablative doses to be safely delivered to inoperable liver tumors. In this setting, proton beam radiotherapy (PBT) provides the means to escalate radiation dose to the target volume while sparing the uninvolved liver. This study evaluated the safety and efficacy of hypofractionated PBT for liver tumors, predominantly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).Methods: We evaluated the prospective registry of the Proton Collaborative Group for patients undergoing definitive PBT for liver tumors. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled.Results: To date, 63 patients have been treated at 9 institutions between 2013-2019. Thirty (48%) had HCC and 25 (40%) had ICC. The median dose and biological equivalent dose (BED) delivered was 58.05 GyE (range, 32.5-75) and 80.5 GyE (range, 53.6-100), respectively. The median mean liver BED was 13.9 GyE. Three (4.8%) patients experienced at least one grade ³3 toxicity. With median follow-up of 5.1 months (range, 0.1-40.8), the local control (LC) rate at 1 year was 91.2% for HCC and 90.9% for ICC. The 1-year LC was significantly higher (95.7%) for patients receiving BED greater than 75.2 GyE than for patients receiving BED of 75.2 GyE or lower (84.6%, p = 0.029). The overall survival rate at 1 year was 65.6% for HCC and 81.8% for ICC. Conclusions: Hypofractionated PBT results in excellent LC, sparing of the uninvolved liver, and low toxicity, even in the setting of dose-escalation. Higher dose correlates with improved LC, highlighting the importance of PBT especially in patients with recurrent or bulky disease.
Ceiling Effect of Clomiphene Citrate on the Testosterone to Estradiol Ratio in Eugonadal Infertile Men
Authors: Liao Yian , Chang Hong-Chiang , WANG SHUO-MENG , CHANG YI-KAI
Published: October 2020

Background:
The testosterone to estradiol ratio (T/E2 ratio) reportedly exerts a stronger effect on semen quality and sexual desire than does testosterone alone. Clomiphene citrate is a selective estrogen receptor modulator that has long been used as an empirical treatment option in the management of idiopathic oligozoospermia. Clomiphene may change the hypothalamus–pituitary–gonad axis and result in the alteration of the T/E2 ratio. No reliable data are available regarding the change in the T/E2 ratio after clomiphene use in eugonadism.
Methods:
This study included 24 male patients who were diagnosed with idiopathic infertility with eugonadism. They all received clomiphene citrate (25 mg/day) as empirical treatment. Blood tests for serum testosterone, estradiol, prolactin, luteinizing hormone, and follicle stimulating hormone were performed before and after 4 weeks of clomiphene use. Paired t-tests were used to evaluate the significance of the hormone level change.
Results:
Overall, the patients’ T/E2 ratio did not increase significantly after clomiphene use. In the subgroup analysis, the T/E2 ratio of patients with a baseline ratio of < 0.2 increased significantly after clomiphene use.
Conclusions:
Clomiphene citrate may significantly increase the T/E2 ratio in eugonadal men under the premise of its ceiling effect (T/E2 ratio < 0.20), providing practitioners with guidance on the use of clomiphene in this demographic.
Waste Polystyrene Degradation in the World Oceans: Newly identified sources of Contamination
Authors: Saido Katsuhiko , Kodera Yoichi , Kimukai Hideki , Sato Hideto , Okabe Akifumi , Koizumi Koshiro , Takatama Kohei , Kwon Bum Gun , Chung Seon-Yong , Nishimura Masahiko , Mentese Sibel
Published: October 2020

Since 1970, lumps of plastic breakage into micro/nano pieces has been clearly shown a serious and large source of ocean pollution. To clarify in detail the course of this impact, thermoplastics were decomposed at natural conditions kinetically. And field surveys conducted on four thousand sand and water samples including these at deep-sea sites from around the world during the period, 2000 to 2015. All samples were found to contain styrene oligomers (SOs), that had been generated from drifting polystyrene (PS) degradation. Lumps of plastic not only break up into micro/nano-fragments but also degrade into their basic structure units of plastic. From 1950 to 2015, 4.2 billion metric tons (MT) of SOs were shown to be generated from drifting PS. The monomers are newly and highly significant source of pollution of marine ecosystem directly and global warming of planet and should be given the utmost serious attention.