bluuebunny/crossref_metadata_2025 huggingface dataset:
Situational analysis of service provision for adolescents with mental and neurological disorders in in two districts of Ghana
Authors: Formentos Adrienne , Ae-Ngibise Kenneth Ayuurebobi , Nyame Solomon , Asante Kwaku Poku
Published: April 2021

Background

Prevalence among adolescents with mental disorders are about 20% worldwide. In 2012, Ghana enacted the Mental Health Act, Act 846 to regulate mental health care, but did not include specific programmatic details of service provision nor any measurable indicators for adolescent mental health. Currently no service programmes focused on adolescents and no aggregated data exists documenting prevalence of mental and neurological disorders among adolescents. In the Brong Ahafo region, mental health providers carry out simultaneous programmes to diagnose, treat, and counsel patients. There is a need to investigate how these service programmes are currently functioning as measured by World Health Organisation guidelines. This study therefore, investigated quality of service provision for adolescents with mental disorders in Kintampo North and South districts of central Ghana.

Methods

Mixed method approach of quantitative and qualitative data collection, organization, and analysis was implored. Quantitative method data collection used case registers to identify mental and neurological disorders among adolescents. Qualitative methods used in-depth interviews of service providers, primary caregivers, and users of healthcare on the services available to treat mental and neurological disorders among adolescents. A combination of quality standards tools was used to assess services.

Results

Epilepsy was the most common treated disorder among adolescents receiving services at the four facilities in the two districts. Providers and stakeholders had limited or no training in adolescent mental health. Validated diagnostic tools were not being used to rule out differential diagnosis; medication procurement was a challenge to consistent treatment. Data collection and analysis was not standardized. Providers, stakeholders, patients, and their primary caregivers reported challenges with funding, transportation logistics, and stigma against people with mental and neurological disorders.

Conclusion

There are few mental health service providers for people living with mental disorders in the two Kintampo districts, with no specific services for adolescents. The Mental Health Act 846 of 2012 is an important milestone in mental health care but there are not specific plans for its implementation. Community sensitization, education in mental health and neurological disorders, and advocacy against stigma are all successful programmes that have the potential to be scaled up.
Impact of intensive training on mental health, the experience of Port Said, Egypt
Authors: Bellizzi Saverio , Khalil Amal , Sawahel Ahmed , Nivoli Alessandra , Lorettu Liliana , Said Dina Sabry , Padrini Susanna
Published: April 2021

Background

Mental disorder is extremely common globally and integration of mental health in primary health services represents a critical gap especially in low- and middle-income Countries like Egypt. The World Health Organization has repeatedly called for effective training and support of primary care providers in the identification and treatment of mental health problems over the last decades.

Methods

This paper aimed to evaluate attitudes and knowledge of health care providers toward mentally ill patients and measure knowledge and retention of training messages over time. A 3-day mental health training workshop for nurses of public health facilities in the Governorate of Port Said was organized. Pre-training and post-training questionnaires (immediately after the workshop and 3 months later) were used. Significance of gain in scores was examined between baseline and following cross sectional rounds.

Results

The 73 participants in the study revealed a statistically significant improvement in knowledge and attitude toward mental health from the baseline (pre-training), from a general mean score for desirable answers of 10.5 (± 1.2) to 21.2 (± 0.6). However, results slightly declined three months after from the workshop (18.5 (± 0.6)).

Conclusions

Intensive short-term training on mental illness could be instrumental in improving knowledge and attitudes in countries like Egypt with extensive needs in terms of quality of comprehensive healthcare at primary and secondary level. However, additional evidence is needed to improve retention of information over time and to translate knowledge into clinical practice.
Clinical outcome of patients with differentiated thyroid cancer and raised antithyroglobulin antibody levels: a retrospective study
Authors: Ora Manish , Nazar Aftab Hasan , Mishra Prabhakar , Barai Sukanta , Arya Amitabh , Pradhan Prasanta Kumar , Gambhir Sanjay
Published: April 2021

Background

Thyroglobulin (Tg) is a specific tumor marker for differentiated thyroid cancer (DTC). However, in the presence of an antithyroglobulin antibody (TgAb), it becomes unreliable. The purpose of the study was to assess the long-term outcome of DTC patients with raised TgAb.

Method

In a retrospective study, we included patients with DTC who had raised TgAb following total thyroidectomy. We excluded patients with persistently raised Tg (≥ 1 ng/ml) or radioiodine avid disease. Serial TgAb levels, excellent response (ER), incomplete response (IR), and anatomical recurrence were evaluated.

Results

A total of seventy-six patients were included in the study. Patients with IR had higher baseline TgAb (1071.27 ± 1216.17 vs. 99.61 ± 91.29 IU/ml, p < 0.001) and central compartment lymph node metastases (70.8% vs. 46.4%, p = 0.035) in comparison to those in the ER group. In the first follow-up, 64 (84.2%) patients had a stable or fall in the TgAb (0 to − 98.3%). Sixty-eight patients received high-dose radioiodine therapy (RIT). Out of these, 59 (86.5%) had transient, and 51 (75%) had a long-term fall in TgAb. After a follow-up period of 58.74 ± 26.26 months, 63.2% (48 out of 76) patients had IR. Nine (11.8%) patients had a rising TgAb level (3.7–170.9%) from baseline. Eleven patients underwent 18F-FDG PET/CT, and five of them demonstrated metabolically active recurrent disease. Three patients underwent cervical lymph nodes dissection. None of the patients died during the follow-up period.

Conclusion

High post-operative TgAb levels and central compartment lymph nodal metastases are risk factors for IR. RIT leads to a significant fall in the TgAb in these patients. The low level of raised TgAb is associated with an excellent outcome. Patients with recurrences had very high baseline TgAb > 1000 IU/ml. Raised TgAb was associated with good clinical outcomes and not associated with increased mortality.
Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway
Authors: Liu Xiaofeng , Su Kunqi , Sun Xiaoyan , Jiang Yang , Wang Lijun , Hu Chenyu , Zhang Chunfeng , Lu Min , Du Xiaojuan , Xing Baocai
Published: April 2021

Background

Cancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC.

Methods

Through analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms.

Results

Sec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/β-catenin signaling. Mechanistically, Sec62 bound to β-catenin and inhibited the degradation of β-catenin. Sec62 competitively disrupted the interaction between β-catenin and APC to inhibit the β-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m6A-mediated stabilization of Sec62 mRNA.

Conclusions

Sec62 upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of CRC by binding to β-catenin and enhancing Wnt signalling. Thus, m6A modification-Sec62-β-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.
Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer
Authors: Iyyanki Tejaswi , Zhang Baozhen , Wang Qixuan , Hou Ye , Jin Qiushi , Xu Jie , Yang Hongbo , Liu Tingting , Wang Xiaotao , Song Fan , Luan Yu , Yamashita Hironobu , Chien Ruby , Lyu Huijue , Zhang Lijun , Wang Lu , Warrick Joshua , Raman Jay D. , Meeks Joshua J. , DeGraff David J. , Yue Feng
Published: April 2021

Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown.

Result

We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration.

Conclusion

In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.
Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial
Authors: Roelz Roland , Schubach Fabian , Coenen Volker A. , Jenkner Carolin , Scheiwe Christian , Grauvogel Jürgen , Niesen Wolf-Dirk , Urbach Horst , Taschner Christian , Seufert Jochen , Kätzler Jürgen , Beck Jürgen , Reinacher Peter C.
Published: April 2021

Background

Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer’s solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH.

Methods

This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0–3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints.

Discussion

New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer’s solution.

Trial registration

Deutsches Register Klinischer Studien (German Clinical Trials Register),DRKS00015645. Registered on 8 May 2019
Clinical, microbiological, and immunological effects of systemic probiotics in periodontal treatment: study protocol for a randomized controlled trial
Authors: Retamal-Valdes Belen , Teughels Wim , Oliveira Laryssa Macedo , da Silva Rebeca Nascimento , Fritoli Aretuza , Gomes Patricia , Soares Geisla Mary Silva , Temporão Natalie , Furquim Camila Pinheiro , Duarte Poliana Mendes , Doyle Helio , Faveri Marcelo , Figueiredo Luciene Cristina , Feres Magda
Published: April 2021

Background

The association of scaling and root planing (SRP) with systemic metronidazole (MTZ) plus amoxicillin (AMX) has shown to be an effective treatment protocol, particularly for periodontitis stages III and IV, generalized. More recently, probiotics have also been suggested as a promising adjunctive treatment for periodontal diseases due to their antimicrobial and anti-inflammatory properties. Therefore, the aim of this randomized clinical trial (RCT) is to evaluate the clinical, microbiological, and immunological effects of probiotics as adjuncts to SRP alone or with MTZ+AMX in the treatment of periodontitis.

Methods

Subjects with periodontitis are being randomly assigned to receive (i) SRP alone, or with (ii) two probiotic lozenges/day for 90 days (Prob), (iii) MTZ (400 mg) and AMX (500 mg) thrice a day (TID) for 14 days (MTZ+AMX), or (iv) Prob and MTZ+AMX. Subjects are being monitored for up to 12 months post-treatment. Nine subgingival plaque samples per patient are being collected at baseline and at 3, 6, and 12 months post-therapy and analyzed by checkerboard DNA–DNA hybridization for 40 bacterial species. Peripheral blood and gingival crevicular fluid (GCF) of four randomly selected periodontal sites will be analyzed by means of a multiplex fluorescent bead-based immunoassay for 17 cyto/chemokines.

Statistical analyses

The significance of differences in each group (over the course of the study) will be sought using repeated measures ANOVA or Friedman tests and among groups (at each time point) using either ANOVA/ANCOVA or Kruskal-Wallis tests, depending on normality of the data. The chi-square test will be used to compare differences in the frequency of subjects achieving the clinical endpoint for treatment (≤ 4 sites with PD ≥ 5 mm) at 1 year and of self-perceived adverse effects. A stepwise forward logistic regression analysis will be performed in order to investigate the impact of different predictor variables on the percentage of patients achieving the clinical endpoint for treatment. The Number Needed to Treat (NNT) with different treatment protocols will be also calculated. Statistical significance will be set at 5%.

Trial registration

ClinicalTrials.gov NCT03733379. Registered on November 7, 2018.
Rhodosporidium sp. DR37: a novel strain for production of squalene in optimized cultivation conditions
Authors: Shakeri Shahryar , Khoshbasirat Farshad , Maleki Mahmood
Published: April 2021

Background

Rhodosporidium strain, a well-known oleaginous yeast, has been widely used as a platform for lipid and carotenoid production. However, the production of squalene for application in lipid-based biofuels is not reported in this strain. Here, a new strain of Rhodosporidium sp. was isolated and identified, and its potential was investigated for production of squalene under various cultivation conditions.

Results

In the present study, Rhodosporidium sp. DR37 was isolated from mangrove ecosystem and its potential for squalene production was assessed. When Rhodosporidium sp. DR37 was cultivated on modified YEPD medium (20 g/L glucose, 5 g/L peptone, 5 g/L YE, seawater (50% v/v), pH 7, 30 °C), 64 mg/L of squalene was produced. Also, squalene content was obtained as 13.9% of total lipid. Significantly, use of optimized medium (20 g/L sucrose, 5 g/L peptone, seawater (20% v/v), pH 7, 25 °C) allowed highest squalene accumulation (619 mg/L) and content (21.6% of total lipid) in Rhodosporidium sp. DR37. Moreover, kinetic parameters including maximum specific cell growth rate (μmax, h−1), specific lipid accumulation rate (qp, h−1), specific squalene accumulation rate (qsq, h−1) and specific sucrose consumption rate (qs, h−1) were determined in optimized medium as 0.092, 0.226, 0.036 and 0.010, respectively.

Conclusions

This study is the first report to employ marine oleaginous Rhodosporidium sp. DR37 for accumulation of squalene in optimized medium. These findings provide the potential of Rhodosporidium sp. DR37 for production of squalene as well as lipid and carotenoids for biofuel applications in large scale.

Graphic abstract
The complete genome sequence of Listeria monocytogenes strain S2542 and expression of selected genes under high-pressure processing
Authors: Duru Ilhan Cem , Bucur Florentina Ionela , Andreevskaya Margarita , Ylinen Anne , Crauwels Peter , Grigore-Gurgu Leontina , Nikparvar Bahareh , Rode Tone Mari , Laine Pia , Paulin Lars , Løvdal Trond , Riedel Christian U. , Bar Nadav , Borda Daniela , Nicolau Anca Ioana , Auvinen Petri
Published: April 2021

Objectives

The study aims to generate the whole genome sequence ofL. monocytogenesstrain S2542 and to compare it to the genomes of strains RO15 and ScottA. In addition, we aimed to compare gene expression profiles ofL. monocytogenesstrains S2542, ScottA and RO15 after high-pressure processing (HPP) using ddPCR.

Results

The whole genome sequence ofL. monocytogenesS2542 indicates that this strain belongs to serotype 4b, in contrast to the previously reported serotype 1/2a. Strain S2542 appears to be more susceptible to the treatment at 400 MPa compared to RO15 and ScottA strains. In contrast to RO15 and ScottA strains, viable cell counts of strain S2542 were below the limit of detection after HPP (400 MPa/8 min) when stored at 8 °C for 24 and 48 h. The transcriptional response of all three strains to HPP was not significantly different.
Evaluation of extracorporeal cardiopulmonary resuscitation eligibility criteria for out-of-hospital cardiac arrest patients
Authors: Lee Brendan , Clay Adam , Sy Eric
Published: April 2021

Objectives

To evaluate the number of out-of-hospital cardiac arrest (OHCA) patients eligible for extracorporeal cardiopulmonary resuscitation (ECPR) in Saskatchewan and their clinical outcomes, including survival and neurological outcomes at discharge. ECPR eligibility was assessed, using clinical criteria from the University of British Columbia (UBC, Canada), University of Michigan (UM, United States), University of California (UC, United States) and a restrictive ECPR criteria.

Results

We performed a retrospective cohort study of 200 OHCA patients (August 1, 2017-May 31, 2019) in Regina, Saskatchewan. Sixty-one (30%) were female, the median age was 64 years (interquartile range [IQR], 52–78), the median CPR duration was 30 min (IQR 12–47), and 20% survived to discharge. Two (1%) patients received ECPR but did not meet any ECPR criteria. Nineteen (10%), thirty (15%), twenty-two (11%), and seven (4%) patients were ECPR-eligible, using the UBC, UM, UC, and restrictive criteria. However, none of these patients had received ECPR. Only two (11%), two (7%), two (9%), and one (14%) of these patient(s) survived to discharge, respectively. Neurological outcomes were unfavourable among all ECPR-eligible patients. Future study at our centre will be necessary on how to implement ECPR program to further improve these outcomes.
Methylation of SERPINA1 gene promoter may predict chronic obstructive pulmonary disease in patients affected by acute coronary syndrome
Authors: Rotondo John Charles , Aquila Giorgio , Oton-Gonzalez Lucia , Selvatici Rita , Rizzo Paola , De Mattei Monica , Pavasini Rita , Tognon Mauro , Campo Gianluca Calogero , Martini Fernanda
Published: April 2021

Background

Diagnostic biomarkers for detecting chronic obstructive pulmonary disease (COPD) in acute coronary syndrome (ACS) patients are not available. SERPINA1, coding for the most potent circulating anti-inflammatory protein in the lung, has been found to be differentially methylated in blood cells from COPD patients. This study aimed to investigate the methylation profile of SERPINA1 in blood cells from ACS patients, with (COPD+) or without COPD (COPD−).

Methods

Blood samples were from 115 ACS patients, including 30 COPD+ and 85 COPD− according to lung function phenotype, obtained with spirometry. DNA treated with sodium bisulfite was PCR-amplified at SERPINA1 promoter region. Methylation analysis was carried out by sequencing the PCR products. Lymphocytes count in ACS patients was recorded at hospital admission and discharge.

Results

SERPINA1 was hypermethylated in 24/30 (80%) COPD+ and 48/85 (56.5%) COPD− (p < 0.05). Interestingly, at hospital discharge, lymphocytes count was higher in COPD− patients carrying SERPINA1 hypermethylated (1.98 × 103 ± 0.6 cell/µl) than in COPD− carrying SERPINA1 hypomethylated (1.7 × 103 ± 0.48 cell/µl) (p < 0.05).

Conclusions

SERPINA1 is hypermethylated in blood cells from COPD+ patients. COPD− carrying SERPINA1 hypermethylated and high lymphocytes count may be at risk of COPD development. Therefore, SERPINA1 hypermethylation may represent a potential biomarker for predicting COPD development in ACS patients.
A randomized, controlled clinical trial of autologous stromal vascular fraction cells transplantation to promote mechanical stretch-induced skin regeneration
Authors: Tan Poh-Ching , Chao Pei-Chuan , Cheng Chen , Chen Chu-Hsin , Huang Ru-Lin , Zhou Shuang-Bai , Xie Yun , Li Qing-Feng
Published: April 2021

Background

The regeneration response of the skin to mechanical stretching in vivo has been explored in reconstructive surgery to repair large-scale deformities. The ability of the skin to regenerate limits the reconstructive outcome. Here, we propose an approach in which autologous stromal vascular fraction (SVF) cells and mechanical stretching are combined to overcome this limitation and promote skin regeneration.

Methods

This randomized, blinded, placebo-controlled clinical trial screened 22 participants undergoing tissue expansion with exhausted regeneration. Twenty eligible participants received intradermal injections of the SVF or placebo treatments. Follow-ups were conducted at 4, 8, and 12 weeks to assess efficacy and at 2 years to assess safety. The primary endpoint was the expanded skin thickness at 12 weeks. The secondary endpoints included skin thickness at 4 and 8 weeks, the expansion index (EI), and the skin texture score at 12 weeks.

Results

The skin thickness of the SVF group was significantly higher than that of the control group at both 8 weeks (mean difference 0.78 [95% CI − 1.43 to − 0.11]; p = 0.018) and 12 weeks (0.65 [95% CI − 1.30 to − 0.01]; p = 0.046). In the SVF group, the increase in skin thickness was significant at 4 weeks (0.49 [95% CI − 0.80 to − 0.06]; p = 0.010) to 8 weeks (0.45 [95% CI − 0.92 to 0.02]; p = 0.026) and maintained after 12 weeks, whereas that in the control group was reduced after 8 weeks (0.42 [95% CI − 0.07 to 0.91]; p = 0.037). The SVF group showed greater EI increases than the control group (0.50 [95% CI − 0.00 to 0.99]; p = 0.047). The skin texture scores in the SVF group were greater than those in the control group at 12 weeks. Histologically, SVF-treated expanded skin showed more proliferating cells and blood vessels, and the extracellular matrix volume increased. No severe adverse events occurred.

Conclusions

Transplantation of SVF cells can expedite the potency of mechanical stretch-induced skin regeneration and provide clinical reconstruction with plentiful tissue.

Trial registration

This trial was registered with the Chinese Clinical Trial Registry, ChiCTR2000039317 (registered 23 October 2020—retrospectively registered).
Classical scrapie in small ruminants is caused by at least four different prion strains
Authors: Marín-Moreno Alba , Aguilar-Calvo Patricia , Espinosa Juan Carlos , Zamora-Ceballos María , Pitarch José Luis , González Lorenzo , Fernández-Borges Natalia , Orge Leonor , Andréoletti Olivier , Nonno Romolo , Torres Juan María
Published: April 2021

The diversity of goat scrapie strains in Europe has recently been studied using bioassays in a wide collection of rodent models, resulting in the classification of classical scrapie into four different categories. However, the sole use of the first passage does not lead to isolate adaptation and identification of the strains involved and might therefore lead to misclassification of some scrapie isolates. Therefore, this work reports the complete transmission study of a wide collection of goat transmissible spongiform encephalopathy (TSE) isolates by intracranial inoculation in two transgenic mouse lines overexpressing either small ruminant (TgGoat-ARQ) or bovine (TgBov) PrPC. To compare scrapie strains in sheep and goats, sheep scrapie isolates from different European countries were also included in the study. Once the species barrier phenomenon was overcome, an accurate classification of the isolates was attained. Thus, the use of just two rodent models allowed us to fully differentiate at least four different classical scrapie strains in small ruminants and to identify isolates containing mixtures of strains. This work reinforces the idea that classical scrapie in small ruminants is a prion disease caused by multiple different prion strains and not by a single strain, as is the case for epidemic classical bovine spongiform encephalopathy (BSE-C). In addition, the clear dissimilarity between the different scrapie strains and BSE-C does not support the idea that classical scrapie is the origin of epidemic BSE-C.
RRM2 silencing suppresses malignant phenotype and enhances radiosensitivity via activating cGAS/STING signaling pathway in lung adenocarcinoma
Authors: Jiang Xueping , Li Yangyi , Zhang Nannan , Gao Yanping , Han Linzhi , Li Shuying , Li Jiali , Liu Xingyu , Gong Yan , Xie Conghua
Published: April 2021

Background

As one of the most common malignancy, lung adenocarcinoma (LUAD) is characterized by low 5-year survival rate. This research aimed to investigate the effects of ribonucleotide reductase regulatory subunit M2 (RRM2) on malignant biological behaviors and activation of cGAS/STING pathway. We also explored the synergistic sensitization mechanisms of RRM2 and radiotherapy.

Methods

Bioinformatic tools were used to evaluate the clinical significance of RRM2 in LUAD patients. The roles of RRM2 in malignant phenotype and DNA damage in LUAD cells were investigated with cell proliferation, colony formation, immunofluorescence, modified Boyden chamber and comet assays. The mouse models were used to evaluate the biological significance of RRM2 in vivo. Cytotoxic T cell infiltration was evaluated via flow cytometric analysis and immunohistochemistry staining in C57BL/6 mice. We also explored the synergistic effects of RRM2 silencing and radiation on LUAD cells with apoptosis assay and immunoblotting in vitro.

Results

Bioinformatic analysis revealed that RRM2 had diagnostic values for LUAD patients. Higher levels of RRM2 predicted worse prognosis. RRM2 silencing inhibited LUAD cell proliferation, invasion and migration. RRM2 knockdown induced S phase arrest and DNA damage. RRM2 silencing induced cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, and the downstream targets were regulated in a STING-dependent manner. Knockdown of RRM2 suppressed tumor growth in the xenograft tumor models. RRM2 deficiency increased CD8 + T cells in the tumor tissues and spleens. Furthermore, RRM2 silencing had synergistic effects with radiation on inhibiting cell proliferation and promoting apoptosis. Meanwhile, this combination promoted the activation of cGAS/STING signaling pathway synergistically, and simultaneously increased expression of IFNβ, CCL5 and CXCL10.

Conclusion

Our results demonstrated that RRM2 silencing had anti-tumor values and activated the cGAS/STING signaling pathway. RRM2 silencing increased CD8 + T cells infiltration. RRM2 silencing cooperated with radiation to inhibit LUAD cell proliferation, promote apoptosis and enhance the activation of cGAS/STING signaling pathway. RRM2 could be a promising target for tumor regression through cancer immunotherapy in LUAD.
Outcome of acute kidney injury: how to make a difference?
Authors: Jamme Matthieu , Legrand Matthieu , Geri Guillaume
Published: April 2021

Background

Acute kidney injury (AKI) is one of the most frequent organ failure encountered among intensive care unit patients. In addition to the well-known immediate complications (hydroelectrolytic disorders, hypervolemia, drug overdose), the occurrence of long-term complications and/or chronic comorbidities related to AKI has long been underestimated. The aim of this manuscript is to briefly review the short- and long-term consequences of AKI and discuss strategies likely to improve outcome of AKI.

Main body

We reviewed the literature, focusing on the consequences of AKI in all its aspects and the management of AKI. We addressed the importance of clinical management for improving outcomes AKI. Finally, we have also proposed candidate future strategies and management perspectives.

Conclusion

AKI must be considered as a systemic disease. Due to its short- and long-term impact, measures to prevent AKI and limit the consequences of AKI are expected to improve global outcomes of patients suffering from critical illnesses.
Arsenic trioxide synergistically promotes the antileukaemic activity of venetoclax by downregulating Mcl-1 in acute myeloid leukaemia cells
Authors: Cho Hyunsoo , Jang Ji Eun , Eom Ju-In , Jeung Hoi-Kyung , Chung Haerim , Kim Jin Seok , Cheong June-Won , Min Yoo Hong
Published: April 2021

Background

The evasion of apoptosis through dysregulated Bcl-2 family members is a hallmark of leukaemia stem cells (LSCs) in acute myeloid leukaemia (AML). Therefore, targeting Bcl-2 with venetoclax has been suggested as an attractive strategy for inducing apoptosis in AML LSCs. However, the selective inhibition of Bcl-2 in AML often leads to upregulation of Mcl-1, another dominant anti-apoptotic Bcl-2 family protein conferring venetoclax resistance.

Methods

We assessed the combined effect of venetoclax and arsenic trioxide (ATO) on leukaemic cell viability, apoptosis, combination index, and cell cycle in the human LSC-like KG1 and KG1a cells. The synergistic effect of venetoclax and ATO on apoptosis was also examined in primary CD34+and CD34+CD38−LSCs from the bone marrow (BM) of AML patients, and compared with those from healthy donors.

Results

Venetoclax efficiently impaired cell viability and dose-dependently promoted apoptosis when combined with ATO; their synergism was aptly represented by the combination index. The combination of venetoclax and ATO impaired cell cycle progression by restricting cells within the sub-G1 phase and facilitating caspase-dependent apoptotic cell death associated with the loss of mitochondrial membrane potential, while sparing healthy BM haematopoietic stem cells. Mechanistically, ATO mitigated venetoclax-induced upregulation of Mcl-1 by the inhibition of AKT and ERK, along with activation of GSK-3β. This led to the Mcl-1 destabilisation, triggering Noxa and Bim to facilitate apoptosis and the consequent activation of the apoptosis executioner protein Bak. Moreover, the combination promoted phosphorylation of ATM, Chk2, p38, and H2AX, indicating an active DNA damage response.

Conclusions

Our findings demonstrate the synergistic, preferential antileukaemic effects of venetoclax and ATO on LSCs, providing a rationale for preclinical and clinical trials by combining these agents already being used in clinical practice to treat acute leukaemia.
Epidemiology of dengue virus infections in Nepal, 2006–2019
Authors: Rijal Komal Raj , Adhikari Bipin , Ghimire Bindu , Dhungel Binod , Pyakurel Uttam Raj , Shah Prakash , Bastola Anup , Lekhak Binod , Banjara Megha Raj , Pandey Basu Dev , Parker Daniel M. , Ghimire Prakash
Published: April 2021

Background

Dengue is one of the newest emerging diseases in Nepal with increasing burden and geographic spread over the years. The main objective of this study was to explore the epidemiological patterns of dengue since its first outbreak (2006) to 2019 in Nepal.

Methods

This study is a retrospective analysis that covers the last 14 years (2006–2019) of reported dengue cases from Epidemiology Diseases Control Division (EDCD), Ministry of Health and Population, Government of Nepal.Reported cases were plotted over time and maps of reported case incidence were generated (from 2016 through 2019). An ecological analysis of environmental predictors of case incidence was conducted using negative binomial regression.

Results

While endemic dengue has been reported in Nepal since 2006, the case load has increased over time and in 2019 a total of 17 992 dengue cases were reported from 68 districts (from all seven provinces). Compared to the case incidence in 2016, incidence was approximately five times higher in 2018 [incidence rate ratio (IRR): 4.8; 95% confidence interval (CI) 1.5–15.3] and over 140 times higher in 2019 (IRR: 141.6; 95%CI45.8–438.4). A one standard deviation increase in elevation was associated with a 90% decrease in reported case incidence (IRR: 0.10; 95%CI0.01–0.20). However, the association between elevation and reported cases varied across the years. In 2018 there was a cluster of cases reported from high elevation Kaski District of Gandaki Province. Our results suggest that dengue infections are increasing in magnitude and expanding out of the lowland areas to higher elevations over time.

Conclusions

There is a high risk of dengue outbreak in the lowland Terai region, with increasing spread towards the mid-mountains and beyond as seen over the last 14 years. Urgent measures are required to increase the availability of diagnostics and resources to mitigate future dengue epidemics.
Brain insulin signaling and cerebrovascular disease in human postmortem brain
Authors: Arvanitakis Zoe , Capuano Ana W. , Wang Hoau-Yan , Schneider Julie A. , Kapasi Alifiya , Bennett David A. , Ahima Rexford S. , Arnold Steven E.
Published: April 2021

Insulin is an important hormone for brain function, and alterations in insulin metabolism may be associated with neuropathology. We examined associations of molecular markers of brain insulin signaling with cerebrovascular disease. Participants were enrolled in the Religious Orders Study (ROS), an ongoing epidemiologic community-based, clinical-pathologic study of aging from across the United States. Using cross-sectional analyses, we studied a subset of ROS: 150 persons with or without diabetes, matched 1:1 by sex on age-at-death and education. We used ELISA, immunohistochemistry, and ex vivo stimulation with insulin, to document insulin signaling in postmortem midfrontal gyrus cortex tissue. Postmortem neuropathologic data identified cerebrovascular disease including brain infarcts, classified by number (as none for the reference; one; and more than one), size (gross and microscopic infarcts), and brain region/location (cortical and subcortical). Cerebral vessel pathologies were assessed, including severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy. In separate regression analyses, greater AKT1 phosphorylation at T308 following ex vivo stimulation with insulin (OR = 1.916; estimate = 0.650; p = 0.007) and greater pS616IRS1 immunolabeling in neuronal cytoplasm (OR = 1.610; estimate = 0.476; p = 0.013), were each associated with a higher number of brain infarcts. Secondary analyses showed consistent results for gross infarcts and microinfarcts separately, but no other association including by infarct location (cortical or subcortical). AKT S473 phosphorylation following insulin stimulation was associated with less amyloid angiopathy severity, but not with other vessel pathology including atherosclerosis and arteriolosclerosis. In summary, insulin resistance in the human brain, even among persons without diabetes, is associated with cerebrovascular disease and especially infarcts. The underlying pathophysiologic mechanisms need further elucidation. Because brain infarcts are known to be associated with lower cognitive function and dementia, these data are relevant to better understanding the link between brain metabolism and brain function.
A reconstruction error-based framework for label noise detection
Authors: Salekshahrezaee Zahra , Leevy Joffrey L. , Khoshgoftaar Taghi M.
Published: April 2021

Label noise is an important data quality issue that negatively impacts machine learning algorithms. For example, label noise has been shown to increase the number of instances required to train effective predictive models. It has also been shown to increase model complexity and decrease model interpretability. In addition, label noise can cause the classification results of a learner to be poor. In this paper, we detect label noise with three unsupervised learners, namely$$\textit{principal component analysis} \hbox { (PCA)}$$principal componentanalysis(PCA),$$\textit{independent component analysis} \hbox { (ICA)}$$independent componentanalysis(ICA), and autoencoders. We evaluate these three learners on a credit card fraud dataset using multiple noise levels, and then compare results to the traditional Tomek links noise filter. Our binary classification approach, which considers label noise instances as anomalies, uniquely uses reconstruction errors for noisy data in order to identify and filter label noise. For detecting noisy instances, we discovered that the autoencoder algorithm was the top performer (highest recall score of 0.90), while Tomek links performed the worst (highest recall score of 0.62).
Web-based authentic inquiry experiences in large introductory classes consistently associated with significant learning gains for all students
Authors: Wu X. Ben , Sandoval Carolyn , Knight Stephanie , Jaime Xavier , Macik Maria , Schielack Jane F.
Published: April 2021

Background

Continuous calls for reform in science education emphasize the need to provide science experiences in lower-division courses to improve the retention of STEM majors and to develop science literacy and STEM skills for all students. Open or authentic inquiry and undergraduate research are effective science experiences leading to multiple gains in student learning and development. Most inquiry-based learning activities, however, are implemented in laboratory classes and the majority of them are guided inquiries. Although course-based undergraduate research experiences have significantly expanded the reach of the traditional apprentice approach, it is still challenging to provide research experiences to nonmajors and in large introductory courses. We examined student learning through a web-based authentic inquiry project implemented in a high-enrollment introductory ecology course for over a decade.

Results

Results from 10 years of student self-assessment of learning showed that the authentic inquiry experiences were consistently associated with significant gains in self-perception of interest and understanding and skills of the scientific process for all students—both majors and nonmajors, both lower- and upper-division students, both women and men, and both URM and non-URM students. Student performance in evaluating the quality of an inquiry report, before and after the inquiry project, also showed significant learning gains for all students. The authentic inquiry experiences proved highly effective for lower-division students, nonmajors, and women and URM students, whose learning gains were similar to or greater than those of their counterparts. The authentic inquiry experiences were particularly helpful to students who were less prepared with regard to the ability to evaluate a scientific report and narrowed the performance gap.

Conclusions

These findings suggest that authentic inquiry experiences can serve as an effective approach for engaging students in high-enrollment, introductory science courses. They can facilitate development of science literacy and STEM skills of all students, skills that are critical to students’ personal and professional success and to informed engagement in civic life.
Weak faults at megathrust plate boundary respond to tidal stress
Authors: Tonegawa Takashi , Kimura Toshinori , Shiraishi Kazuya , Yabe Suguru , Fukao Yoshio , Araki Eiichiro , Kinoshita Masataka , Sanada Yoshinori , Miura Seiichi , Nakamura Yasuyuki , Kodaira Shuichi
Published: April 2021

Lateral spatial variations of weak portions at the plate boundary in subduction zones have been estimated primarily by the distribution of slow earthquakes mainly occurring around seismogenic zones. However, the detailed depth profile of weak faults remains elusive. Here, we deployed six ocean bottom seismometers in the Nankai subduction zone, Japan, to observe reflections originated from drilling vesselChikyuship noise (hydroacousticPwave) that was persistently radiated from a fixed position at the sea surface, and retrievedP-to-s(Ps) reflections from multiple dipping faults near the plate boundary. ThePsamplitudes were stacked and compared according to the degrees of tidal stresses, and high amplitudes were observed at high tide (compression). A migration technique shows that the locations where velocity contrasts fluctuate were estimated at both the megasplay fault and another fault between the megasplay fault and the top of the oceanic crust. This indicates that the physical properties of these faults are altered by tidal stress. The physical-property changes are attributed to fluid connections and isolations within the faults due to tidal stress fluctuations, inducing the variation of seismic anisotropy. Such a variation was confirmed by a three-dimensional numerical simulation for wave propagation with anisotropic medium. Our observation suggests that multiple weak faults are present around the plate boundary, and the obtained changes of fault physical properties may have implications for in-depth understanding of tidal triggering of earthquakes.
A serious-gamification blueprint towards a normalized attention
Authors: Alqithami Saad
Published: April 2021

Attention is an important commodity in the human skills set. It can be trained to overcome deficits in the short term which might be based on multiple cognitive complications to entail inability to keep focus and mined wondering. On the long term, however, it might be a symptom of chronic diseases that acquire attention to include the spectra of many mental health disorders, e.g., attention deficit hyperactivity disorder (ADHD). This paper, therefore, introduces a generic reference model that guides in the design of proper treatment method for patients in short of attention to engage in a game-based environment in order to enhance the behavior of their current state of attention which may hopefully lead to a better focus. When considering the volatility of traditional cognitive behavioral therapies (CBTs), the model reflects and analyzes evolving serious games design directed for the treatment of ADHD. It serves as an instrument that spawn over a specific treatment design since it introduces essential components that depicts essential units of traditional CBT when they are modularly combined. The components will be introduced and the processes of the reference model will be elaborated as a roadmap for the formation and the operation of augmented reality treatment games.
Successful treatment of adult cecorectal intussusception caused by cecum cancer with mobile cecum: a case report
Authors: Shimoyama Hayato , Ueno Kimihiko , Samizo Masahiro
Published: April 2021

Background

Intussusception occurs when a segment of the bowel (the intussusceptum) telescopes into an adjacent segment (the intussuscipiens). Adult intussusception occurs rarely and often requires surgical resection for its treatment. We describe the case of an adult patient with extremely rare cecorectal intussusception treated using a novel combined transabdominal and trans-anal approach, which has not yet been reported in the literature.

Case presentation

A 71-year-old woman was transferred to our hospital for the treatment of upper abdominal pain. Physical examination, laboratory tests, and imaging inspections showed strangulated bowel obstruction induced by intussusception associated with the intra-rectal mass. We performed an emergency operation and treated the intussusception using a combined transabdominal and trans-anal approach. The intraoperative findings revealed bloody ascites and a potentially malignant tumor that had moved toward the anal side from peritoneal reflection. The tumor served as the lead point in the cecum with mobile cecum. After reducing the intussusception using the combined procedure, we removed the ileocecal portion. The intraoperative and histopathological findings suggested that cecum cancer with mobile cecum had caused the cecorectal intussusception. The patient had an uneventful postoperative course, except for postoperative pulmonary pneumonia.

Conclusion

To the best of our knowledge, this is the first reported case of adult cecorectal intussusception due to cecum cancer with mobile cecum successfully treated using the combined transabdominal and trans-anal approach. This combined procedure may be useful in treating the intussusception where the lead point is distal from the peritoneal reflection.