bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge, attitude, and practice of pharmacy and medical students regarding self-medication, a study in Zabol University of Medical Sciences; Sistan and Baluchestan province in south-east of Iran
Authors: Hashemzaei Mahmoud , Afshari Mahdi , Koohkan Zahra , Bazi Ali , Rezaee Ramin , Tabrizian Kaveh
Published: January 2021

Background

Self-medication is defined as using medicinal products to treat the disorders or symptoms diagnosed by oneself. Although informed self-medication is one of the ways to reduce health care costs, inappropriate self-treatment can pose various risks including drug side effects, recurrence of symptoms, drug resistance, etc. The purpose of this study was to investigate the knowledge, attitude, and practice of pharmacy and medical students toward self-medication.

Methods

This study was conducted in Zabol University of Medical Sciences in 2018. Overall, 170 pharmacy and medical students were included. A three-part researcher-made questionnaire was designed to address the students’ knowledge, attitude, and practice. Statistical analysis was performed in SPSS 25 software.

Results

According to the results, 97 (57.1%) students had carried out self-medication within the past 6 months. Overall, the students self-medicated on average 4.2 ± 2.9 times per year. Self-medication was more common in male students (65.4%, P = 0.043). Cold was the most common ailment treated with self-medication (93.2%), and antibiotics (74.4%) were the most commonly used drugs. The primary information sources used by the students were their previous prescriptions (47.4%). Pharmacy students had a higher level of drug information (P < 0.001). There was a statistically significant association between the level of drug information and the tendency for self-medication (P = 0.005). Disease recurrence was the most common negative complication of self-medication.

Conclusion

There is a need to educate pharmacy and medical students regarding self-medication and its side effects. The high prevalence of self-medication and the overuse of antibiotics can pose a significant risk of drug resistance.
Prokaryotic virus host predictor: a Gaussian model for host prediction of prokaryotic viruses in metagenomics
Authors: Lu Congyu , Zhang Zheng , Cai Zena , Zhu Zhaozhong , Qiu Ye , Wu Aiping , Jiang Taijiao , Zheng Heping , Peng Yousong
Published: January 2021

Background

Viruses are ubiquitous biological entities, estimated to be the largest reservoirs of unexplored genetic diversity on Earth. Full functional characterization and annotation of newly discovered viruses requires tools to enable taxonomic assignment, the range of hosts, and biological properties of the virus. Here we focus on prokaryotic viruses, which include phages and archaeal viruses, and for which identifying the viral host is an essential step in characterizing the virus, as the virus relies on the host for survival. Currently, the method for determining the viral host is either to culture the virus, which is low-throughput, time-consuming, and expensive, or to computationally predict the viral hosts, which needs improvements at both accuracy and usability. Here we develop a Gaussian model to predict hosts for prokaryotic viruses with better performances than previous computational methods.

Results

We present here Prokaryotic virus Host Predictor (PHP), a software tool using a Gaussian model, to predict hosts for prokaryotic viruses using the differences of k-mer frequencies between viral and host genomic sequences as features. PHP gave a host prediction accuracy of 34% (genus level) on the VirHostMatcher benchmark dataset and a host prediction accuracy of 35% (genus level) on a new dataset containing 671 viruses and 60,105 prokaryotic genomes. The prediction accuracy exceeded that of two alignment-free methods (VirHostMatcher and WIsH, 28–34%, genus level). PHP also outperformed these two alignment-free methods much (24–38% vs 18–20%, genus level) when predicting hosts for prokaryotic viruses which cannot be predicted by the BLAST-based or the CRISPR-spacer-based methods alone. Requiring a minimal score for making predictions (thresholding) and taking the consensus of the top 30 predictions further improved the host prediction accuracy of PHP.

Conclusions

The Prokaryotic virus Host Predictor software tool provides an intuitive and user-friendly API for the Gaussian model described herein. This work will facilitate the rapid identification of hosts for newly identified prokaryotic viruses in metagenomic studies.
Horizontally acquired antibacterial genes associated with adaptive radiation of ladybird beetles
Authors: Li Hao-Sen , Tang Xue-Fei , Huang Yu-Hao , Xu Ze-Yu , Chen Mei-Lan , Du Xue-Yong , Qiu Bo-Yuan , Chen Pei-Tao , Zhang Wei , Ślipiński Adam , Escalona Hermes E. , Waterhouse Robert M. , Zwick Andreas , Pang Hong
Published: January 2021

Background

Horizontal gene transfer (HGT) has been documented in many herbivorous insects, conferring the ability to digest plant material and promoting their remarkable ecological diversification. Previous reports suggest HGT of antibacterial enzymes may have contributed to the insect immune response and limit bacterial growth. Carnivorous insects also display many evolutionary successful lineages, but in contrast to the plant feeders, the potential role of HGTs has been less well-studied.

Results

Using genomic and transcriptomic data from 38 species of ladybird beetles, we identified a set of bacterial cell wall hydrolase (cwh) genes acquired by this group of beetles. Infection with Bacillus subtilis led to upregulated expression of these ladybird cwh genes, and their recombinantly produced proteins limited bacterial proliferation. Moreover, RNAi-mediated cwh knockdown led to downregulation of other antibacterial genes, indicating a role in antibacterial immune defense. cwh genes are rare in eukaryotes, but have been maintained in all tested Coccinellinae species, suggesting that this putative immune-related HGT event played a role in the evolution of this speciose subfamily of predominant predatory ladybirds.

Conclusion

Our work demonstrates that, in a manner analogous to HGT-facilitated plant feeding, enhanced immunity through HGT might have played a key role in the prey adaptation and niche expansion that promoted the diversification of carnivorous beetle lineages. We believe that this represents the first example of immune-related HGT in carnivorous insects with an association with a subsequent successful species radiation.
Safety and feasibility of apheresis to harvest and concentrate parasites from subjects with induced blood stage Plasmodium vivax infection
Authors: Odedra Anand , Mudie Kari , Kennedy Glen , Watts Rebecca E. , Rossignol Emilie , Mitchell Hayley , Gower Jeremy , Rebelo Maria , Pava Zuleima , Pawliw Rebecca , Woolley Stephen , Lalloo David G. , Robinson Greg , Lynch Sean , Collins Katharine A. , Amante Fiona , McCarthy James
Published: January 2021

Background

In the absence of a method to culture Plasmodium vivax, the only way to source parasites is ex vivo. This hampers many aspects of P. vivax research. This study aimed to assess the safety of apheresis, a method for selective removal of specific components of blood as a means of extracting and concentrating P. vivax parasites.

Methods

An iterative approach was employed across four non-immune healthy human subjects in single subject cohorts. All four subjects were inoculated with ~ 564 blood stage P. vivax (HMP013-Pv) and subjected to apheresis 10 to 11 days later. Blood samples collected during apheresis (haematocrit layers 0.5% to 11%) were tested for the presence and concentration of P. vivax by microscopy, flow cytometry, 18S rDNA qPCR for total parasites, and pvs25 qRT-PCR for female gametocyte transcripts. Safety was determined by monitoring adverse events. Malaria transmission to mosquitoes was assessed by membrane feeding assays.

Results

There were no serious adverse events and no significant safety concerns. Apheresis concentrated asexual parasites by up to 4.9-fold (range: 0.9–4.9-fold) and gametocytes by up to 1.45-fold (range: 0.38–1.45-fold) compared to pre-apheresis densities. No single haematocrit layer contained > 40% of all the recovered P. vivax asexual parasites. Ex vivo concentration of parasites by Percoll gradient centrifugation of whole blood achieved greater concentration of gametocytes than apheresis. Mosquito transmission was enhanced by up to fivefold in a single apheresis sample compared to pre-apheresis.

Conclusion

The modest level of parasite concentration suggests that the use of apheresis may not be an ideal method for harvesting P. vivax.

Trial Registration Australia New Zealand Clinical Trials Registry (ANZCTR) Trial ID: ACTRN12617001502325 registered on 19th October 2017. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373812.
The importance of modeling the human cerebral vasculature in blunt trauma
Authors: Subramaniam Dhananjay Radhakrishnan , Unnikrishnan Ginu , Sundaramurthy Aravind , Rubio Jose E. , Kote Vivek Bhaskar , Reifman Jaques
Published: January 2021

Background

Multiple studies describing human head finite element (FE) models have established the importance of including the major cerebral vasculature to improve the accuracy of the model predictions. However, a more detailed network of cerebral vasculature, including the major veins and arteries as well as their branch vessels, can further enhance the model-predicted biomechanical responses and help identify correlates to observed blunt-induced brain injury.

Methods

We used an anatomically accurate three-dimensional geometry of a 50th percentile U.S. male head that included the skin, eyes, sinuses, spine, skull, brain, meninges, and a detailed network of cerebral vasculature to develop a high-fidelity model. We performed blunt trauma simulations and determined the intracranial pressure (ICP), the relative displacement (RD), the von Mises stress, and the maximum principal strain. We validated our detailed-vasculature model by comparing the model-predicted ICP and RD values with experimental measurements. To quantify the influence of including a more comprehensive network of brain vessels, we compared the biomechanical responses of our detailed-vasculature model with those of a reduced-vasculature model and a no-vasculature model.

Results

For an inclined frontal impact, the predicted ICP matched well with the experimental results in the fossa, frontal, parietal, and occipital lobes, with peak-pressure differences ranging from 2.4% to 9.4%. For a normal frontal impact, the predicted ICP matched the experimental results in the frontal lobe and lateral ventricle, with peak-pressure discrepancies equivalent to 1.9% and 22.3%, respectively. For an offset parietal impact, the model-predicted RD matched well with the experimental measurements, with peak RD differences of 27% and 24% in the right and left cerebral hemispheres, respectively. Incorporating the detailed cerebral vasculature did not influence the ICP but redistributed the brain-tissue stresses and strains by as much as 30%. In addition, our detailed-vasculature model predicted strain reductions by as much as 28% when compared to current reduced-vasculature FE models that only include the major cerebral vessels.

Conclusions

Our study highlights the importance of including a detailed representation of the cerebral vasculature in FE models to more accurately estimate the biomechanical responses of the human brain to blunt impact.
Placental pathology of the third trimester pregnant women from COVID-19
Authors: Gao Likun , Ren Jiacai , Xu Li , Ke Xiaokang , Xiong Lin , Tian Xiaoli , Fan Cuifang , Yan Honglin , Yuan Jingping
Published: January 2021

Aims

To explore the clinical characteristics and placental pathological changes of pregnant women with 2019 novel coronavirus (CoV) disease (COVID-19) in the third trimester, and to assess the possibility of vertical transmission.

Methods and results

The placenta tissues were evaluated by using immunohistochemistry for inflammatory cells and Hofbauer cells, and using severe acute respiratory syndrome (SARS) CoV-2 RNA Fluorescence In-Situ Hybridization (FISH) and SARS-CoV-2 spike protein immunofluorescence (IF) double staining. All eight placentas from the third trimester pregnancy women were studied. All patients were cured, no clinical or serological evidence pointed to vertical transmission of SARS-CoV-2. Features of maternal vascular malperfusion (MVM) such as increased syncytial knots were present in all 8 cases (8/8), and increased focal perivillous fibrin depositions were presented in 7 cases (7/8). No significate chronic histiocytic intervillositis was noted in the placenta. The number of macrophages and inflammatory cells such as T cells, B cells and plasma cells in the placental villous was not significantly increased in all cases. Moreover, all of eight cases demonstrated negative results by FISH using a SARS-CoV-2 virus RNA probe and by IF using a monoclonal antibody against SARS-CoV-2 spike protein.

Conclusions

We found no evidence of vertical transmission and adverse maternal-fetal outcomes in the placentas of third trimester COVID-19 pregnancy women, which provided further information for the clinical management of those women in the third trimester. However, further studies are still needed for patients with infections in different stage of gestation, especially in first and second trimester.
Deep learning-based automatic delineation of the hippocampus by MRI: geometric and dosimetric evaluation
Authors: Pan Kaicheng , Zhao Lei , Gu Song , Tang Yi , Wang Jiahao , Yu Wen , Zhu Lucheng , Feng Qi , Su Ruipeng , Xu Zhiyong , Li Xiadong , Ding Zhongxiang , Fu Xiaolong , Ma Shenglin , Yan Jun , Kang Shigong , Zhou Tao , Xia Bing
Published: January 2021

Background

Whole brain radiotherapy (WBRT) can impair patients’ cognitive function. Hippocampal avoidance during WBRT can potentially prevent this side effect. However, manually delineating the target area is time-consuming and difficult. Here, we proposed a credible approach of automatic hippocampal delineation based on convolutional neural networks.

Methods

Referring to the hippocampus contouring atlas proposed by RTOG 0933, we manually delineated (MD) the hippocampus on the MRI data sets (3-dimensional T1-weighted with slice thickness of 1 mm, n = 175), which were used to construct a three-dimensional convolutional neural network aiming for the hippocampus automatic delineation (AD). The performance of this AD tool was tested on three cohorts: (a) 3D T1 MRI with 1-mm slice thickness (n = 30); (b) non-3D T1-weighted MRI with 3-mm slice thickness (n = 19); (c) non-3D T1-weighted MRI with 1-mm slice thickness (n = 11). All MRIs confirmed with normal hippocampus has not been violated by any disease. Virtual radiation plans were created for AD and MD hippocampi in cohort c to evaluate the clinical feasibility of the artificial intelligence approach. Statistical analyses were performed using SPSS version 23. P < 0.05 was considered significant.

Results

The Dice similarity coefficient (DSC) and Average Hausdorff Distance (AVD) between the AD and MD hippocampi are 0.86 ± 0.028 and 0.18 ± 0.050 cm in cohort a, 0.76 ± 0.035 and 0.31 ± 0.064 cm in cohort b, 0.80 ± 0.015 and 0.24 ± 0.021 cm in cohort c, respectively. The DSC and AVD in cohort a were better than those in cohorts b and c (P < 0.01). There is no significant difference between the radiotherapy plans generated using the AD and MD hippocampi.

Conclusion

The AD of the hippocampus based on a deep learning algorithm showed satisfying results, which could have a positive impact on improving delineation accuracy and reducing work load.
Impact of four-dimensional cone-beam computed tomography on target localization for gastric mucosa-associated lymphoid tissue lymphoma radiotherapy: reducing planning target volume
Authors: Shimohigashi Yoshinobu , Toya Ryo , Saito Tetsuo , Kono Yumiko , Doi Yasuhiro , Fukugawa Yoshiyuki , Watakabe Takahiro , Matsumoto Tadashi , Kai Yudai , Maruyama Masato , Oya Natsuo
Published: January 2021

Background

Radiotherapy of gastric mucosa-associated lymphoid tissue (MALT) lymphoma should be delivered to the entire stomach with planning target volume (PTV) that accounts for variations in stomach volume, respiratory movement, and patient set-up error. In this study, we evaluated whether the use of four-dimensional cone-beam computed tomography (4D-CBCT) reduces the PTV.

Methods

Eight patients underwent radiotherapy with 15 fractions of gastric MALT lymphoma using 4D-CBCT. PTV structures of 5–30 mm margins (5 mm intervals) from the clinical target volume (CTV) delineated based on the 4D-CT images (CTV-4D) were generated. For the target localization, we performed matching based on skin marking (skin matching), bone anatomy (bone matching), and stomach anatomy (4D soft-tissue matching) based on registration between planning CT and 4D-CBCT images from 10 phases. For each patient, we calculated the covering ratio (CR) of the stomach with variable PTV structures, based on the 4D-CBCT images, with a total of 150 phases [CR (%) = (number of covering phases/150 phases) × 100], for three target localization methods. We compared the CR values of the different target localization methods and defined the PTV with an average CR of ≥ 95% for all patients.

Results

The average CR for all patients increased from 17.9 to 100%, 19.6 to 99.8%, and 33.8 to 100%, in the skin, bone, and 4D soft-tissue matchings, respectively, as the PTV structures increased from 5 to 30 mm. The CR obtained by 4D soft-tissue matching was superior to that obtained by skin (P = 0.013) and bone matching (P = 0.008) for a PTV structure of 15 mm margin. The PTV required an additional margin of 20 mm (average CR: 95.2%), 25 mm (average CR: 99.1%), and 15 mm (average CR: 98.0%) to CTV-4D for the skin, bone, and 4D soft-tissue matchings, respectively.

Conclusions

This study demonstrates that the use of 4D-CBCT reduces the PTV when applying 4D soft-tissue matching, compared to skin and bone matchings. Additionally, bone matching does not reduce the PTV as compared with traditional skin matching.
Clinical outcome and pathologic correlation of stereotactic body radiation therapy as a bridge to transplantation for advanced hepatocellular carcinoma: a case series
Authors: Wang Ying-Fu , Dai Yang-Hong , Lin Chun-Shu , Chang Hao-Chih , Shen Po-Chien , Yang Jen-Fu , Hsiang Chih-Weim , Lo Cheng-Hsiang , Huang Wen-Yen
Published: January 2021

Background

Stereotactic body radiotherapy (SBRT) is an emerging modality for hepatocellular carcinoma (HCC). However, there is scant information about its safety and effectiveness in the neoadjuvant setting prior to liver transplantation (LT). We present the clinical outcome and pathologic assessment of SBRT followed by LT for patients with advanced HCC.

Methods

This retrospective study included HCC patients treated with neoadjuvant SBRT prior to LT between 2009 and 2018. Radiographic response and adverse effects, including radiation-induced liver disease (RILD), were evaluated. Pathologic response was assessed by the percentage of tumor necrosis relative to the total tumor volume. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan–Meier method.

Results

Fourteen patients underwent SBRT for a total of 25 HCC lesions, followed by LT. The median tumor size was 4.45 cm in diameter, and the median prescribed dose was 45 Gy in 5 fractions. SBRT provided significant AFP reduction, 100% infield control, and a 62.5% response rate. The maximum detected toxicity included grade 3 thrombocytopenia and two grade 3–4 hyperbilirubinemia. One patient developed non-classic RILD. Patients were bridged to LT with a median time of 8.4 months after SBRT, and 23.1% of them achieved a complete pathologic response. The median OS and RFS were 37.8 and 18.3 months from the time of LT, respectively.

Conclusions

SBRT provides favorable tumor control and acceptable adverse effects for patients awaiting LT. Further prospective studies to test SBRT as a bridging therapy for LT are feasible.
Treatment of femoral neck fractures: sliding hip screw or cannulated screws? A meta-analysis
Authors: Xia Yutong , Zhang Wendong , Zhang Zhen , Wang Jingcheng , Yan Lianqi
Published: January 2021

Purpose

Femoral neck fractures are still unsolved problems nowadays; sliding hip screw (SHS) and cannulated compression screw (CCS) are the most commonly used devices. We evaluated the clinical outcomes and complications in the treatment of femoral neck fractures between SHS and CCS in this meta-analysis to find which is better.

Methods

We searched PubMed, Embase, Cochrane library up to 24 August 2020 and retrieved any studies comparing sliding hip screw and cannulated compression screw in treatment of femoral neck fractures; the main outcomes and complications were extracted from the studies which were included.

Results

Nine studies involving 1662 patients (828 patients in the SHS group and 834 patients in the CCS group) were included in this study. SHS had higher rate of avascular necrosis (RR = 1.30, 95% CI 1.08–1.56, p = 0.005), and CCS had higher rate of implant removal (RR = 0.63, 95% CI 0.43–0.93, p = 0.02). No significant statistical difference in non-union, implant failure, infection, replacement, mortality, orthopedic complications, non-orthopedic complications, and total revision between SHS and CCS group.

Conclusion

Both devices have their pros and cons; SHS had a higher rate of avascular necrosis, and CCS had a higher rate of implant removal rate. No significant statistical difference in non-union, implant failure, infection, replacement, mortality, orthopedic complications, non-orthopedic complications, and total revision between SHS and CCS group.
Genipin and insulin combined treatment improves implant osseointegration in type 2 diabetic rats
Authors: Zhang Jiajia , Wang Ya-nan , Jia Tingting , Huang Haiyun , Zhang Dongjiao , Xu Xin
Published: January 2021

Background

Type 2 diabetes mellitus (T2DM) has a harmful effect on the stability and osseointegration of dental implants. T2DM induces mitochondrial damage by inhibiting AMPK signaling, resulting in oxidative stress and poor osteogenesis in the peri-implant bone area. Genipin is a major component of gardenia fruits with strong antioxidant, anti-inflammation, and antidiabetic actions, and it also can activate mitochondrial quality control via the AMPK pathway. The purpose of this study was to investigate the effects of genipin and insulin treatment on implant osseointegration in T2DM rats and explore the underlying mechanisms.

Methods

Streptozotocin-induced diabetic rats received implant surgery in their femurs and were then assigned to five groups that were subjected to different treatments for three months: control group, T2DM group, insulin-treated T2DM group (10 IU/kg), genipin-treated T2DM group (50 mg/kg), and the genipin and insulin combination-treated T2DM group. Then, we regularly assessed the weight and glucose levels of the animals. Rats were euthanized at 3 months after the implantation procedure, and the femora were harvested for microscopic computerized tomography analysis, biomechanical tests, and different histomorphometric assessment.

Results

The results indicated that the highest blood glucose and oxidative stress levels were measured for the T2DM group, resulting in the poorest osseointegration. The combination-treated T2DM group mitigated hyperglycemia and normalized, reactivated AMPK signaling, and alleviated oxidative stress as well as reversed the negative effect of osseointegration. There were beneficial changes observed in the T2DM-genipin and T2DM-insulin groups, but these were less in comparison to the combination treatment group.

Conclusion

Our study suggests that treatment with genipin in combination with insulin could be an effective method for promoting implant osseointegration in T2DM rats, which may be related to AMPK signaling.
Structural alteration of lung parenchyma in patients with NF1: a phenotyping study using multidetector computed tomography (MDCT)
Authors: Avanesov Maxim , Well Lennart , Laqmani Azien , Derlin Thorsten , Riccardi Vincent M. , Adam Gerhard , Mautner Victor-Felix , Salamon Johannes
Published: January 2021

Background

Diffuse interstitial lung disease have been described in Neurofibromatosis type 1 (NF1), but its diversity and prevalence remain unknown. The aim of this study was to assess the prevalence and characteristics of (NF1)-associated lung manifestations in a large single-center study using multidetector computed tomography (MDCT) and to evaluate the smoking history, patients’ age, genetics, and the presence of malignant peripheral nerve sheath tumors (MPNST) as potential influencing factors for lung pathologies.

Methods

In this retrospective study, 71 patients with NF1 were evaluated for the presence of distinctive lung manifestations like reticulations, consolidations, type of emphysema, pulmonary nodules and cysts. All patients underwent F-18-FDG PET/CT scans, which were reviewed by two experienced radiologists in consensus. Patients’ subgroups were formed based on their smoking history (current smokers/previous smokers/never smokers), age (< 12 years, 12–18 years, > 18 years), and presence of MPNST (MPNST/no MPNST). In 57 patients (80%), genetic analysis of sequences coding for the neurofibromin on chromosome 17 was performed, which was correlated with different lung pathologies.

Results

Among all NF1 patients (33 ± 14 years, 56% females), 17 patients (24%) were current smokers and 62 patients (87%) were > 18 years old. Pulmonary cysts, nodules, and paraseptal emphysema were the most common pulmonary findings (35%, 32%, 30%). The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking. Cysts were observed only in adults, whereas no significant correlation between age and all other pulmonary findings was found (p > 0.05). Presence of MPNST was accompanied by higher rates of intrapulmonary nodules and pulmonary metastasis. Neither the presence nor absence of any of the specific gene mutations was associated with any particular lung pathology (p > 0.05).

Conclusions

All pulmonary findings in NF1 patients occurred independently from specific mutation subtypes, suggesting that many NF1 mutations can cause various pulmonary pathologies. The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking, indicating the value of smoking secession or the advice not to start smoking in NF1 patients as preventive strategy for clinicians. For screening of pulmonary manifestations in NF1 patients, an MDCT besides medical history and physical examination is mandatory in clinical routine.
Neuroendocrine liver metastasis from the small intestine: Is surgery beneficial for survival?
Authors: Selberherr Andreas , Freermann Simon , Koperek Oskar , Niederle Martin B. , Riss Philipp , Scheuba Christian , Niederle Bruno
Published: January 2021

Background

Neuroendocrine neoplasia of the small intestine (siNEN) are frequently diagnosed with liver metastases. The impact of the presence of liver metastases on overall survival and the necessity of surgery for liver metastasis is discussed controversially. The aim of this study is to evaluate and compare the overall long-term survival of patients with siNENs with and without liver metastasis at initial diagnosis and the possible benefit of surgical treatment as compared to active surveillance of metastases. 123 consecutive patients with siNENs were treated between 1965 and 2016. All clinical and histological records were reevaluated including analysis of the proliferation rates in all specimens. The 1-, 5-, 10- and 20-year overall survival was estimated by Kaplan–Meier analysis for patients with and without liver metastasis and according to the type of treatment (surgical vs. surveillance) of liver metastases if present.

Results

The 1-, 5-, 10- and 20-year overall survival rate was 89.0%, 68.4%, 52.8% and 31.0% in patients without and 89.5%, 69.5%, 33.2% and 3.6% in those with liver metastases. No statistically significant differences were observed comparing the two groups. Within the group of patients with liver metastases, the type of treatment (surgical vs. surveillance) was in favor of patients undergoing surgery. Multivariate analysis showed that the presence of liver metastases upon diagnosis was an individual risk factor associated with worse survival.

Conclusion

The presence of liver metastasis at initial diagnosis does not have a statistically significant influence on survival. Surgery for hepatic metastasis seems to show a benefit for overall survival and may be indicated especially in patients symptomatic due to high tumor burden and serotonin hypersecretion to reduce hormone activity.
Schizophrenia risk ZNF804A interacts with its associated proteins to modulate dendritic morphology and synaptic development
Authors: Dong Fengping , Mao Joseph , Chen Miranda , Yoon Joy , Mao Yingwei
Published: January 2021

Schizophrenia (SZ) is a devastating brain disease that affects about 1% of world population. Among the top genetic associations,zinc finger protein 804A(ZNF804A) gene encodes a zinc finger protein, associated with SZ and biolar disorder (BD). Copy number variants (CNVs) ofZNF804Ahave been observed in patients with autism spectrum disorders (ASDs), anxiety disorder, and BD, suggesting thatZNF804Ais a dosage sensitive gene for brain development. However, its molecular functions have not been fully determined. Our previous interactomic study revealed that ZNF804A interacts with multiple proteins to control protein translation and neural development. ZNF804A is localized in the cytoplasm and neurites in the human cortex and is expressed in various types of neurons, including pyramidal, dopaminergic, GABAergic, and Purkinje neurons in mouse brain. To further examine the effect of gene dosage ofZNF804Aon neurite morphology, both knockdown and overexpression ofZNF804Ain primary neuronal cells significantly attenuate dendritic complex and spine formation. To determine the factors mediating these phenotypes, interestingly, three binding proteins of ZNF804A, galectin 1 (LGALS1), fasciculation and elongation protein zeta 1 (FEZ1) and ribosomal protein SA (RPSA), show different effects on reversing the deficits. LGALS1 and FEZ1 stimulate neurite outgrowth at basal level but RPSA shows no effect. Intriguingly, LGALS1 but not FEZ1, reverses the neurite outgrowth deficits induced by ZNF804A knockdown. However, FEZ1 and RPSA but not LGALS1, can ameliorate ZNF804A overexpression-mediated dendritic abnormalities. Thus, our results uncover a critical post-mitotic role of ZNF804A in neurite and synaptic development relevant to neurodevelopmental pathologies.
A receptor-antibody hybrid hampering MET-driven metastatic spread
Authors: Modica Chiara , Basilico Cristina , Chiriaco Cristina , Borrelli Nicla , Comoglio Paolo M. , Vigna Elisa
Published: January 2021

Background

The receptor encoded by the MET oncogene and its ligand Hepatocyte Growth Factor (HGF) are at the core of the invasive-metastatic behavior. In a number of instances genetic alterations result in ligand-independent onset of malignancy (METaddiction). More frequently, ligand stimulation of wild-type MET contributes to progression toward metastasis (METexpedience). Thus, while MET inhibitors alone are effective in the first case, combination therapy with ligand inhibitors is required in the second condition.

Methods

In this paper, we generated hybrid molecules gathering HGF and MET inhibitory properties. This has been achieved by ‘head-to-tail’ or ‘tail-to-head’ fusion of a single chain Fab derived from the DN30 MET antibody with a recombinant ‘ad-hoc’ engineered MET extracellular domain (decoyMET), encompassing the HGF binding site but lacking the DN30 epitope.

Results

The hybrid molecules correctly bind MET and HGF, inhibit HGF-induced MET downstream signaling, and quench HGF-driven biological responses, such as growth, motility and invasion, in cancer cells of different origin. Two metastatic models were generated in mice knocked-in by the human HGF gene: (i) orthotopic transplantation of pancreatic cancer cells; (ii) subcutaneous injection of primary cells derived from a cancer of unknown primary. Treatment with hybrid molecules strongly affects time of onset, number, and size of metastatic lesions.

Conclusion

These results provide a strategy to treat metastatic dissemination driven by the HGF/MET axis.
High-resolution analysis of cell-state transitions in yeast suggests widespread transcriptional tuning by alternative starts
Authors: Chia Minghao , Li Cai , Marques Sueli , Pelechano Vicente , Luscombe Nicholas M. , van Werven Folkert J.
Published: January 2021

Background

The start and end sites of messenger RNAs (TSSs and TESs) are highly regulated, often in a cell-type-specific manner. Yet the contribution of transcript diversity in regulating gene expression remains largely elusive. We perform an integrative analysis of multiple highly synchronized cell-fate transitions and quantitative genomic techniques in Saccharomyces cerevisiae to identify regulatory functions associated with transcribing alternative isoforms.

Results

Cell-fate transitions feature widespread elevated expression of alternative TSS and, to a lesser degree, TES usage. These dynamically regulated alternative TSSs are located mostly upstream of canonical TSSs, but also within gene bodies possibly encoding for protein isoforms. Increased upstream alternative TSS usage is linked to various effects on canonical TSS levels, which range from co-activation to repression. We identified two key features linked to these outcomes: an interplay between alternative and canonical promoter strengths, and distance between alternative and canonical TSSs. These two regulatory properties give a plausible explanation of how locally transcribed alternative TSSs control gene transcription. Additionally, we find that specific chromatin modifiers Set2, Set3, and FACT play an important role in mediating gene repression via alternative TSSs, further supporting that the act of upstream transcription drives the local changes in gene transcription.

Conclusions

The integrative analysis of multiple cell-fate transitions suggests the presence of a regulatory control system of alternative TSSs that is important for dynamic tuning of gene expression. Our work provides a framework for understanding how TSS heterogeneity governs eukaryotic gene expression, particularly during cell-fate changes.
SPIN reveals genome-wide landscape of nuclear compartmentalization
Authors: Wang Yuchuan , Zhang Yang , Zhang Ruochi , van Schaik Tom , Zhang Liguo , Sasaki Takayo , Peric-Hupkes Daniel , Chen Yu , Gilbert David M. , van Steensel Bas , Belmont Andrew S. , Ma Jian
Published: January 2021

We report SPIN, an integrative computational method to reveal genome-wide intranuclear chromosome positioning and nuclear compartmentalization relative to multiple nuclear structures, which are pivotal for modulating genome function. As a proof-of-principle, we use SPIN to integrate nuclear compartment mapping (TSA-seq and DamID) and chromatin interaction data (Hi-C) from K562 cells to identify 10 spatial compartmentalization states genome-wide relative to nuclear speckles, lamina, and putative associations with nucleoli. These SPIN states show novel patterns of genome spatial organization and their relation to other 3D genome features and genome function (transcription and replication timing). SPIN provides critical insights into nuclear spatial and functional compartmentalization.
Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals
Authors: Martín Guiomar , Márquez Yamile , Mantica Federica , Duque Paula , Irimia Manuel
Published: January 2021

Background

Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing.

Results

We generate a massive resource for Arabidopsis thaliana, PastDB, comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets reveals that A. thaliana shows high levels of AS, similar to fruitflies, and that, compared to animals, disproportionately uses AS for stress responses. We identify core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that is tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, are overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion.

Conclusions

Non-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.
The reality of informed consent: empirical studies on patient comprehension—systematic review
Authors: Pietrzykowski Tomasz , Smilowska Katarzyna
Published: January 2021

Background

Informed consent is a basic concept of contemporary, autonomy-based medical practice and facilitates a shared decision-making model for relations between physicians and patients. Thus, the extent to which patients can comprehend the consent they grant is essential to the ethical viability of medicine as it is pursued today. However, research on patients’ comprehension of an informed consent’s basic components shows that their level of understanding is limited.

Methods

Systemic searches of the PubMed and Web of Science databases were performed to identify the literature on informed consent, specifically patients’ comprehension of specific informed consent components.

Results

In total, 14 relevant articles were retrieved. In most studies, few clinical trial participants correctly responded to items that examined their awareness of what they consented to. Participants demonstrated the highest level of understanding (over 50%) regarding voluntary participation, blinding (excluding knowledge about investigators’ blinding), and freedom to withdraw at any time. Only a small minority of patients demonstrated comprehension of placebo concepts, randomisation, safety issues, risks, and side effects.

Conclusions

We found that participants’ comprehension of fundamental informed consent components was low, which is worrisome because this lack of understanding undermines an ethical pillar of contemporary clinical trial practice and questions the viability of patients’ full and genuine involvement in a shared medical decision-making process.
Controlling of two destructive zooplanktonic predators in Chlorella mass culture with surfactants
Authors: Wen Xiaobin , Zhang Aoqi , Zhu Xiaoyan , Liang Lin , Huo Yan , Wang Kaixuan , Yu Youzhi , Geng Yahong , Ding Yi , Li Yeguang
Published: January 2021

Background

Predatory flagellates and ciliates are two common bio-contaminants which frequently cause biomass losses in Chlorella mass culture. Efficient and targeted ways are required to control these contaminations in Chlorella mass cultivation aiming for biofuel production especially.

Results

Five surfactants were tested for its ability to control bio-contaminations in Chlorella culture. All five surfactants were able to eliminate the contaminants at a proper concentration. Particularly the minimal effective concentrations of sodium dodecyl benzene sulfonate (SDBS) to completely eliminate Poterioochromonas sp. and Hemiurosomoida sp. were 8 and 10 mg L−1, respectively, yet the photosynthesis and viability of Chlorella was not significantly affected. These results were further validated in Chlorella mass cultures in 5, 20, and 200 m2 raceway ponds.

Conclusions

A chemical method using 10 mg L−1 SDBS as pesticide to control predatory flagellate or ciliate contamination in Chlorella mass culture was proposed. The method helps for a sustained microalgae biomass production and utilization, especially for biofuel production.
Efficacy of plasma exchange for antineutrophil cytoplasmic antibody-associated systemic vasculitis: a systematic review and meta-analysis
Authors: Yamada Yosuke , Harada Makoto , Hara Yuuta , Iwabuchi Ryohei , Hashimoto Koji , Yamamoto Shuhei , Kamijo Yuji
Published: January 2021

Objective

To assess through systematic review and meta-analysis whether plasma exchange (PE) is associated with prognosis in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients.

Methods

A systematic search of PubMed, MEDLINE, Embase, and CENTRAL databases from inception to 17 June 2020 was conducted. Ongoing or unpublished trials were also searched in ClinicalTrials.gov and the World Health Organization trials portal. Randomised controlled trials (RCTs) comparing PE vs. non-PE in AAV patients (microscopic polyangiitis [MPA], granulomatosis with polyangiitis [GPA], or eosinophilic granulomatosis with polyangiitis [EGPA]) were included. The combined risk ratio (RR) was calculated by the random-effects model using the Mantel-Haenszel method. Heterogeneity was measured using the I2 statistic. Primary outcomes were mortality, clinical remission (CR), and adverse events (AEs).

Results

Four RCTs comparing PE vs. no PE (N = 827) and 1 RCT comparing PE vs. pulse steroid treatment (N = 137) were included. All participants were MPA or GPA patients (no EGPA patients). PE was not associated with main primary outcomes compared with no PE (mortality RR 0.93 [95% confidence interval {CI} 0.70–1.24], I2 = 0%; CR RR 1.02 [95% CI 0.91–1.15], I2 = 0%; and AE RR 1.10 [95% CI 0.73–1.68], I2 = 37%) or pulse steroid (mortality RR 0.99 [95% CI 0.71–1.37]; CR [the Birmingham Vasculitis Activity score] mean difference − 0.53 [95% CI − 1.40–0.34]; and AE RR 1.05 [95% CI 0.74–1.48]). Focusing on the early treatment phases, PE was associated with a reduction in end-stage renal disease incidence compared with both no PE (PE 1/43 vs. no PE 10/41; RR 0.14 [0.03–0.77] at 3 months) and pulse steroid (PE 11/70 vs. pulse steroid 23/67; RR 0.46 [0.24–0.86] at 3 months).

Conclusion

We carried out a systematic review and meta-analysis targeting all AAV patients, including MPA, GPA, and EGPA. In AAV patients, performing PE was not associated with the risk of mortality, CR, and AE. No RCT exists evaluating the efficacy of PE for EGPA; hence, this is required in the future. The results may affect the development of guidelines for AAV and may indicate the direction of future clinical research on AAV.

Trial registration

UMIN R000045239, PROSPERO CRD42020182566.
72-h diurnal RNA-seq analysis of fully expanded third leaves from maize, sorghum, and foxtail millet at 3-h resolution
Authors: Lai Xianjun , Bendix Claire , Zhang Yang , Schnable James C. , Harmon Frank G.
Published: January 2021

Objectives

The purpose of this data set is to capture the complete diurnal (i.e., daily) transcriptome of fully expanded third leaves from the C4 panacoid grasses sorghum (Sorghum bicolor), maize (Zea mays), and foxtail millet (Setaria italica) with RNA-seq transcriptome profiling. These data are the cornerstone of a larger project that examined the conservation and divergence of gene expression networks within these crop plants. This data set focuses on temporal changes in gene expression to identify the network architecture responsible for daily regulation of plant growth and metabolic activities. The power of this data set is fine temporal resolution combined with continuous sampling over multiple days.

Data description

The data set is 72 individual RNA-seq samples representing 24 time course samples each for sorghum, maize, and foxtail millet plants cultivated in a growth chamber under equal intervals of light and darkness. The 24 samples are separated by 3-h intervals so that the data set is a fine scale 72-h analysis of gene expression in the leaves of each plant type. FASTQ files from Illumina sequencing are available at the National Center for Biotechnology Information Sequence Read Archive.
iTRAQ-based proteomic analysis reveals the molecule mechanism of reducing higher alcohols in Chinese rice wine by nitrogen compensation
Authors: Huang Guidong , Ren Hong , Wang Ali , Wan Xinran , Wu Ziying , Zhong Xianfeng
Published: January 2021

Purpose

Higher alcohol is a by-product of the fermentation of wine, and its content is one of the most important parameters that affect and are used to appraise the final quality of Chinese rice wine. Ammonium compensation is an efficient and convenient method to reduce the content of higher alcohols, but the molecule mechanism is poorly understood. Therefore, an iTRAQ-based proteomic analysis was designed to reveal the proteomic changes of Saccharomyces cerevisiae to elucidate the molecular mechanism of ammonium compensation in reducing the content of higher alcohols.

Methods

The iTRAQ proteomic analysis method was used to analyze a blank group and an experimental group with an exogenous addition of 200 mg/L (NH4)2HPO4 during inoculation. The extracted intracellular proteins were processed by liquid chromatography-mass spectrometry and identified using bioinformatics tools. Real-time quantitative polymerase chain reaction was used to verify the gene expression of differentially expressed proteins.

Results

About 4062 proteins, including 123 upregulated and 88 downregulated proteins, were identified by iTRAQ-based proteomic analysis. GO and KEGG analysis uncovered that significant proteins were concentrated during carbohydrate metabolism, such as carbon metabolism, glyoxylate, and dicarboxylate metabolism, pyruvate metabolism, and the nitrogen metabolism, such as amino acid synthesis and catabolism pathway. In accordance with the trend of differential protein regulation in the central carbon metabolism pathway and the analysis of carbon metabolic flux, a possible regulatory model was proposed and verified, in which ammonium compensation facilitated glucose consumption, regulated metabolic flow direction into tricarboxylic acid, and further led to a decrease in higher alcohols. The results of RT-qPCR confirmed the authenticity of the proteomic analysis results at the level of gene.

Conclusion

Ammonium assimilation promoted by ammonium compensation regulated the intracellular carbon metabolism of S. cerevisiae and affected the distribution of metabolic flux. The carbon flow that should have gone to the synthesis pathway of higher alcohols was reversed to the TCA cycle, thereby decreasing the content of higher alcohols. These findings may contribute to an improved understanding of the molecular mechanism for the decrease in higher alcohol content through ammonium compensation.