bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunoglobulin G4-Related Disease Accompanied by Primary Myelofibrosis: Case Report
Authors: Liu Ziwei , Zhang Shangzhu , Zhang Wen , Feng Jun , Li Mengtao , Zeng Xiaofeng
Published: May 2021

Immunoglobulin G4-related disease (IgG4-RD) is a heterogeneous autoimmune fibrosing disorder that presents common pathologic features but with unclear etiology. We report a rare case of IgG4-RD accompanied by primary myelofibrosis that eventually transformed into acute myeloid leukemia. A 50-year-old woman suffered from progressive lacrimal and parotid gland enlargement, diaphoresis, and rapid weight loss. Important clinical findings included remarkable leukocytosis, hyperglobulinemia, and splenomegaly. IgG4-RD was confirmed by salivary gland biopsy. Meanwhile, myelofibrosis was diagnosed according to histopathological findings of bone marrow and genetic mutation test of peripheral blood. The patient was on corticosteroid treatment. However, she developed into acute myeloid leukemia (AML) in the 8th month of follow-up. Our case suggested that myeloproliferative neoplasm (MPN) may co-occur with IgG4-RD. Bone morrow aspiration and genetic tests are helpful for throughout evaluation. An active search for hematological malignancies is warranted at diagnosis and during follow-up for patients who present with unexplained leukocytosis, pancytopenia, splenomegaly, or weight loss.
Respiratory Aspergillus Colonization Was Associated With Relapse of Acute Exacerbation in Patients With Chronic Obstructive Pulmonary Disease: Analysis of Data From A Retrospective Cohort Study
Authors: Wu Yi-xing , Zuo Yi-hui , Cheng Qi-jian , Huang Yi , Bao Zhi-yao , Jin Xiao-yan , Gao Xi-wen , Tu Chun-lin , Hu Wei-ping , Hang Jing-qing , Wang Wei-qin , Zhang Feng-ying , Zhang Jing
Published: May 2021

Background: Patients with chronic obstructive pulmonary disease (COPD) are more susceptible to Aspergillus colonization or infection. Several studies have demonstrated that invasive pulmonary Aspergillosis (IPA) and Aspergillus hypersensitivity (AH) have a detrimental effect on COPD. However, it remains to be clarified whether Aspergillus colonization is associated with acute exacerbation of COPD (AECOPD). This study aimed to explore the impact of Aspergillus colonization in the lower respiratory tract on AECOPD.

Method: Patients with Aspergillus colonization were identified from a retrospective cohort of hospitalized AECOPD from 2011 to 2016 in eight centers in Shanghai, China. The demographic information, conditions of the stable stage, clinical characteristics during hospitalization, and 1-year follow-up information after discharge were collected and compared to participants without fungi colonization.

Result: Twenty-six hospitalized AECOPD patients with Aspergillus colonization and 72 controls were included in the final analysis after excluding patients with other fungi isolation and matching. The rates of recurrence of acute exacerbation within 90 days and 180 days after discharge in the patients with Aspergillus colonization were both significantly higher than that in the fungi negative patients (90 days: 19.2 vs. 4.2%, p = 0.029; 180 days: 23.1 vs. 4.2%, p = 0.010), and the all-cause mortality within 1 year was also higher (11.5 vs. 0.0%, p = 0.017). Multivariate logistic regression analysis showed that Aspergillus colonization was an independent risk factor for the recurrence of acute exacerbation within 90 days and 180 days (90 days: OR = 8.661, 95% CI: 1.496-50.159, p = 0.016; 180 days: OR =10.723, 95% CI: 1.936-59.394, p = 0.007).

Conclusion:Aspergillus colonization may predict poor prognosis of AECOPD while leading to an increased risk of recurrent AECOPD in a short period.
ACE2 and SARS-CoV-2 Infection Risk: Insights From Patients With Two Rare Genetic Tubulopathies, Gitelman's and Bartter's Syndromes
Authors: Calò Lorenzo A. , Rigato Matteo , Sgarabotto Luca , Gianesello Lisa , Bertoldi Giovanni , Ravarotto Verdiana , Davis Paul A.
Published: May 2021

COVID-19 is spreading globally with the angiotensin converting enzyme (ACE)-2 serving as the entry point of SARS-CoV-2 virus. This raised concerns how ACE2 and the Renin-Angiotensin (Ang)-System (RAS) are to be dealt with given their roles in hypertension and their involvement in COVID-19's morbidity and mortality. Specifically, increased ACE2 expression in response to treatment with ACE inhibitors (ACEi) and Ang II receptor blockers (ARBs) might theoretically increase COVID-19 risk by increasing SARS-CoV-2 binding sites. However, ACE2 is part of the protective counter-regulatory ACE2-Ang1-7-MasR axis, which opposes the classical ACE-AngII-AT1R regulatory axis. We used Gitelman's and Bartter's syndromes (GS/BS) patients, rare genetic tubulopathies that have endogenously increased levels of ACE2, to explore these issues. Specifically, 128 genetically confirmed GS/BS patients, living in Lombardia, Emilia Romagna and Veneto, the Northern Italy hot spots for COVID-19, were surveyed via telephone survey regarding COVID-19. The survey found no COVID-19 infection and absence of COVID-19 symptoms in any patient. Comparison analysis with the prevalence of COVID-19 in those regions showed statistical significance (p < 0.01). The results of the study strongly suggest that increased ACE2 does not increase risk of COVID-19 and that ACEi and ARBs by blocking excessive AT1R-mediated Ang II activation might favor the increase of ACE2-derived Ang 1-7. GS/BS patients' increased ACE2 and Ang 1-7 levels and their characteristic chronic metabolic alkalosis suggest a mechanism similar to that of chloroquine/hydroxychloroquine effect on ACE2 glycosylation alteration with resulting SARS-COV-2 binding inhibition and blockage/inhibition of viral entry. Studies from our laboratory are ongoing to explore GS/BS ACE2 glycosylation and other potential beneficial effects of BS/GS. Importantly, the absence of frank COVID-19 or of COVID-19 symptoms in the BS/GS patients cohort, given no direct ascertainment of COVID-19 status, suggest that elevated ACE2 levels as found in GS/BS patients at a minimum render COVID-19 infection asymptomatic and thus that COVID-19 symptoms are driven by ACE2 levels.
Endophytic Bacterial Isolates From Halophytes Demonstrate Phytopathogen Biocontrol and Plant Growth Promotion Under High Salinity
Authors: Christakis Christos A. , Daskalogiannis Georgia , Chatzaki Anastasia , Markakis Emmanouil A. , Mermigka Glykeria , Sagia Angeliki , Rizzo Giulio Flavio , Catara Vittoria , Lagkouvardos Ilias , Studholme David J. , Sarris Panagiotis F.
Published: May 2021

Halophytic endophytes potentially contribute to the host’s adaptation to adverse environments, improving its tolerance against various biotic and abiotic stresses. Here, we identified the culturable endophytic bacteria of three crop wild relative (CWR) halophytes: Cakile maritima, Matthiola tricuspidata, and Crithmum maritimum. In the present study, the potential of these isolates to improve crop adaptations to various stresses was investigated, using both in vitro and in-planta approaches. Endophytic isolates were identified by their 16S rRNA gene sequence and evaluated for their ability to: grow in vitro in high levels of NaCl; inhibit the growth of the economically important phytopathogens Verticillium dahliae, Ralstonia solanacearum, and Clavibacter michiganensis and the human pathogen Aspergillus fumigatus; provide salt tolerance in-planta; and provide growth promoting effect in-planta. Genomes of selected isolates were sequenced. In total, 115 endophytic isolates were identified. At least 16 isolates demonstrated growth under increased salinity, plant growth promotion and phytopathogen antagonistic activity. Three showed in-planta suppression of Verticillium growth. Furthermore, representatives of three novel species were identified: two Pseudomonas species and one Arthrobacter. This study provides proof-of-concept that the endophytes from CWR halophytes can be used as “bio-inoculants,” for the enhancement of growth and stress tolerance in crops, including the high-salinity stress.
Resisting the Heat: Bacterial Disaggregases Rescue Cells From Devastating Protein Aggregation
Authors: Katikaridis Panagiotis , Bohl Valentin , Mogk Axel
Published: May 2021

Bacteria as unicellular organisms are most directly exposed to changes in environmental growth conditions like temperature increase. Severe heat stress causes massive protein misfolding and aggregation resulting in loss of essential proteins. To ensure survival and rapid growth resume during recovery periods bacteria are equipped with cellular disaggregases, which solubilize and reactivate aggregated proteins. These disaggregases are members of the Hsp100/AAA+ protein family, utilizing the energy derived from ATP hydrolysis to extract misfolded proteins from aggregates via a threading activity. Here, we describe the two best characterized bacterial Hsp100/AAA+ disaggregases, ClpB and ClpG, and compare their mechanisms and regulatory modes. The widespread ClpB disaggregase requires cooperation with an Hsp70 partner chaperone, which targets ClpB to protein aggregates. Furthermore, Hsp70 activates ClpB by shifting positions of regulatory ClpB M-domains from a repressed to a derepressed state. ClpB activity remains tightly controlled during the disaggregation process and high ClpB activity states are likely restricted to initial substrate engagement. The recently identified ClpG (ClpK) disaggregase functions autonomously and its activity is primarily controlled by substrate interaction. ClpG provides enhanced heat resistance to selected bacteria including pathogens by acting as a more powerful disaggregase. This disaggregase expansion reflects an adaption of bacteria to extreme temperatures experienced during thermal based sterilization procedures applied in food industry and medicine. Genes encoding for ClpG are transmissible by horizontal transfer, allowing for rapid spreading of extreme bacterial heat resistance and posing a threat to modern food production.
Fort CnoX: Protecting Bacterial Proteins From Misfolding and Oxidative Damage
Authors: Dupuy Emile , Collet Jean-François
Published: May 2021

How proteins fold and are protected from stress-induced aggregation is a long-standing mystery and a crucial question in biology. Here, we present the current knowledge on the chaperedoxin CnoX, a novel type of protein folding factor that combines holdase chaperone activity with a redox protective function. Focusing on Escherichia coli CnoX, we explain the essential role played by this protein under HOCl (bleach) stress, discussing how it protects its substrates from both aggregation and irreversible oxidation, which could otherwise interfere with refolding. Finally, we highlight the unique ability of CnoX, apparently conserved during evolution, to cooperate with the GroEL/ES folding machinery.
The Added Value of Cerebral Imaging in Patients With Pyogenic Spinal Infection
Authors: Behmanesh Bedjan , Gessler Florian , Kessel Johanna , Keil Fee , Seifert Volker , Bruder Markus , Setzer Matthias
Published: May 2021

Background: The incidence of pyogenic spinal infection has increased in recent years. In addition to treatment of the spinal infection, early diagnosis and therapy of coexisting infections, especially of secondary brain infection, are important. The aim of this study is to elucidate the added value of routine cerebral imaging in the management of these patients.

Methods: This was a retrospective single-center study. Cerebral imaging consisting of cerebral magnetic resonance imaging (cMRI) was performed to detect brain infection in patients with a primary pyogenic spinal infection.

Results: We analyzed a cohort of 61 patients undergoing cerebral imaging after diagnosis of primary pyogenic spinal infection. The mean age in this cohort was 68.7 years and the gender distribution consisted of 44 males and 17 females. Spinal epidural abscess was proven in 32 (52.4%) patients. Overall positive blood culture was obtained in 29 (47.5%) patients, infective endocarditis was detected in 23 (37.7%) patients and septic condition at admission was present in 12 (19.7%) Patients. Coexisting brain infection was detected in 2 (3.3%) patients. Both patients revealed clinical signs of severe sepsis, reduced level of consciousness (GCS score 3), were intubated, and died due to multi-organ failure.

Conclusions: Brain infection in patients with spinal infection is very rare. Of 61 patients with pyogenic spinal infection, two patients had signs of cerebral infection shown by imaging, both of whom were in a coma (GCS 3), and sepsis.
Associations Between White Matter Hyperintensity Burden, Cerebral Blood Flow and Transit Time in Small Vessel Disease: An Updated Meta-Analysis
Authors: Stewart Catriona R. , Stringer Michael S. , Shi Yulu , Thrippleton Michael J. , Wardlaw Joanna M.
Published: May 2021

Cerebral small vessel disease (SVD) is a major contributor to stroke and dementia, characterized by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 systematic review, identifying 30 new studies, 27 cross-sectional (n = 2,956) and 3 longitudinal (n = 440). Cross-sectionally, 10/27 new studies (n = 1,019) included sufficient data for meta-analysis, which we meta-analyzed with 24 previously reported studies (n = 1,161), total 34 (n = 2,180). Our meta-analysis showed that patients with lower CBF had worse WMH burden (mean global CBF: standardized mean difference (SMD): −0.45, 95% confidence interval (CI): −0.64, −0.27). Longitudinally, associations between baseline CBF and WMH progression varied: the largest study (5 years, n = 252) found no associations, while another small study (4.5 years, n = 52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found that CBF was lower in WMH than in normal-appearing white matter in an additional meta-analysis (5 cross-sectional studies; n = 295; SMD: −1.51, 95% CI: −1.94, −1.07). These findings highlight that relationships between resting CBF and WMH are complex. Further longitudinal studies analyzing regional CBF and subsequent WMH change are required to determine the role of CBF in SVD progression.
Comatose With Basilar Artery Occlusion: Still Odds of Favorable Outcome With Recanalization Therapy
Authors: Ritvonen Juhani , Sairanen Tiina , Silvennoinen Heli , Virtanen Pekka , Salonen Oili , Lindsberg Perttu J. , Strbian Daniel
Published: May 2021

Background: Around 30–60% of patients with basilar artery occlusion (BAO) present with coma, which is often considered as a hallmark of poor prognosis.

Aim: To examine factors that will help predict outcomes in patients with BAO comatose on admission.

Methods: A total of 312 patients with angiography-proven BAO were analyzed. Comas were assessed as Glasgow Coma Scale (GCS) of ≤8 or impaired level of consciousness ascertained in the medical records. Outcomes were evaluated with the modified Rankin Scale (mRS) over a phone call at 3 months. In our study, 53 patients were excluded due to inadequate data on the level of consciousness.

Results: In total, 103/259 (39.8%) of BAO patients were comatose on admission. Factors associated with acute coma were higher age, coronary artery disease, convulsions, extent of early ischemia by posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) < 8, absence of patent posterior collateral vasculature, and occlusion over multiple segments of BA. A total of 21/103 (20.4%) of comatose patients had a favorable outcome (mRS 0–3), and 12/103 (11.7%) had a good outcome (mRS 0–2). Factors associated with a favorable outcome in comatose BAO patients were younger age (p = 0.010), less extensive baseline ischemia (p = 0.027), recanalization (p = 0.013), and avoiding symptomatic intracranial hemorrhage (sICH) (p = 0.038). Factors associated with the poorest outcome or death (mRS 5–6) were older age (p = 0.001), diabetes (p = 0.022), atrial fibrillation (p = 0.016), lower median GCS [4 (IQR 3.6) vs. 6 (5–8); p = 0.006], pc-ASPECTS < 8 (p = 0.003), unsuccessful recanalization (p = 0.006), and sICH (p = 0.010). Futile recanalization (mRS 4–6) was significantly more common in comatose patients (49.4 vs. 18.5%, p < 0.001).

Conclusions: One in five BAO patients with acute coma had a favorable outcome. Older patients with cardiovascular comorbidities and already existing ischemic lesions before reperfusion therapies tended to have a poor prognosis, especially if no recanalization is achieved and sICH occurred.
Musical Hallucinations in Chronic Pain: The Anterior Cingulate Cortex Regulates Internally Generated Percepts
Authors: Schmitgen Ashlyn , Saal Jeremy , Sankaran Narayan , Desai Maansi , Joseph Isabella , Starr Philip , Chang Edward F. , Shirvalkar Prasad
Published: May 2021

The anterior cingulate cortex (ACC) has been extensively implicated in the functional brain network underlying chronic pain. Electrical stimulation of the ACC has been proposed as a therapy for refractory chronic pain, although, mechanisms of therapeutic action are still unclear. As stimulation of the ACC has been reported to produce many different behavioral and perceptual responses, this region likely plays a varied role in sensory and emotional integration as well as modulating internally generated perceptual states. In this case series, we report the emergence of subjective musical hallucinations (MH) after electrical stimulation of the ACC in two patients with refractory chronic pain. In an N-of-1 analysis from one patient, we identified neural activity (local field potentials) that distinguish MH from both the non-MH condition and during a task involving music listening. Music hallucinations were associated with reduced alpha band activity and increased gamma band activity in the ACC. Listening to similar music was associated with different changes in ACC alpha and gamma power, extending prior results that internally generated perceptual phenomena are supported by circuits in the ACC. We discuss these findings in the context of phantom perceptual phenomena and posit a framework whereby chronic pain may be interpreted as a persistent internally generated percept.
Deep Learning-Based Prediction Model for Breast Cancer Recurrence Using Adjuvant Breast Cancer Cohort in Tertiary Cancer Center Registry
Authors: Kim Ji-Yeon , Lee Yong Seok , Yu Jonghan , Park Youngmin , Lee Se Kyung , Lee Minyoung , Lee Jeong Eon , Kim Seok Won , Nam Seok Jin , Park Yeon Hee , Ahn Jin Seok , Kang Mira , Im Young-Hyuck
Published: May 2021

Several prognosis prediction models have been developed for breast cancer (BC) patients with curative surgery, but there is still an unmet need to precisely determine BC prognosis for individual BC patients in real time. This is a retrospectively collected data analysis from adjuvant BC registry at Samsung Medical Center between January 2000 and December 2016. The initial data set contained 325 clinical data elements: baseline characteristics with demographics, clinical and pathologic information, and follow-up clinical information including laboratory and imaging data during surveillance. Weibull Time To Event Recurrent Neural Network (WTTE-RNN) by Martinsson was implemented for machine learning. We searched for the optimal window size as time-stamped inputs. To develop the prediction model, data from 13,117 patients were split into training (60%), validation (20%), and test (20%) sets. The median follow-up duration was 4.7 years and the median number of visits was 8.4. We identified 32 features related to BC recurrence and considered them in further analyses. Performance at a point of statistics was calculated using Harrell's C-index and area under the curve (AUC) at each 2-, 5-, and 7-year points. After 200 training epochs with a batch size of 100, the C-index reached 0.92 for the training data set and 0.89 for the validation and test data sets. The AUC values were 0.90 at 2-year point, 0.91 at 5-year point, and 0.91 at 7-year point. The deep learning-based final model outperformed three other machine learning-based models. In terms of pathologic characteristics, the median absolute error (MAE) and weighted mean absolute error (wMAE) showed great results of as little as 3.5%. This BC prognosis model to determine the probability of BC recurrence in real time was developed using information from the time of BC diagnosis and the follow-up period in RNN machine learning model.
RNA-Sequencing Reveals Heat Shock 70-kDa Protein 6 (HSPA6) as a Novel Thymoquinone-Upregulated Gene That Inhibits Growth, Migration, and Invasion of Triple-Negative Breast Cancer Cells
Authors: Shen Shiyi , Wei Chunli , Fu Junjiang
Published: May 2021

Objective

Breast cancer has become the first highest incidence which surpasses lung cancer as the most commonly diagnosed cancer, and the second highest mortality among women worldwide. Thymoquinone (TQ) is a key component from black seed oil and has anti-cancer properties in a variety of tumors, including triple-negative breast cancer (TNBC).

Methods

RNA-sequencing (RNA-seq) was conducted with and without TQ treatment in TNBC cell line BT-549. Gene Ontology (GO) function classification annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for these genes were conducted. Western blot and semi-quantitative RT-PCR were used to verify the regulated gene. Functional assays by overexpression or knocking down were performed for HSPA6 and its mediator TQ for inhibiting growth, migration and invasion of TNBC cells. The regulatory mechanisms and prognosis for HSPA6 for breast cancer survival were conducted through bioinformatics and online databases.

Results

As a result, a total of 141 downregulated and 28 upregulated genes were identified and 18 differentially expressed genes, which might be related to carcinomas, were obtained. Interestingly, GO and KEGG pathway showed their roles on anti-cancer and anti-virus. Further analysis found that the HSPA6 gene was the high significantly upregulated gene, and showed to inhibit TNBC cell growth, migration and invasion. High expression of HSPA6 was positively correlated with long overall survival (OS) in patients with breast cancer, indicating the tumor-suppressive roles for HSPA6. But DNA methylation of HSPA6 may not be the regulatory mechanism for HSPA6 mRNA upregulation in breast cancer tissues, although the mRNA levels of HSPA6 were increased in these cancer tissues compared with normal tissues. Moreover, TQ enhanced the inhibitory effect of migration and invasion when HSPA6 was overexpressed; while HSPA6 was knocked down, TQ attenuated the effects of HSPA6-promoted migration and invasion, demonstrating a partially dependent manner through HSPA6 by TQ treatment.

Conclusion

We have successfully identified a novel TQ-targeted gene HSPA6, which shows the inhibitory effects on growth, migration and invasion in TNBC cells. Therefore, identification of HSPA6 not only reveals a new TQ regulatory mechanism, but also provides a novel candidate gene for clinical management and treatment of breast cancer, particularly for TNBC.
Thoracoscopy for Esophageal Diverticula After Esophageal Atresia With Tracheo-Esophageal Fistula
Authors: Yong Zhao , Dingding Wang , Kaiyun Hua , Yichao Gu , Yanan Zhang , Junmin Liao , Shen Yang , Shuangshuang Li , Peize Wang , Jinshi Huang
Published: May 2021

Background: Esophageal diverticulum (ED) is an extremely rare complication of congenital esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) surgery. We aimed to investigate feasible methods for the treatment of this rare complication.

Methods: We retrospectively reviewed all patients with EA/TEF at Beijing Children's Hospital from January 2015 to September 2019. The clinicopathological features of patients with ED after EA/TEF surgery were recorded. Follow-up was routinely performed after surgery until December 2020.

Results: Among 198 patients with EA/TEF, ED only occurred in four patients (2.02%; one male, three female). The four patients had varying complications after the initial operation, including anastomotic leakage (3/4), esophageal stenosis (3/4), and recurrence of TEF (1/4). The main clinical symptoms of ED included recurrent pneumonia (4/4), coughing (4/4), and dysphagia (3/4). All ED cases occurred near the esophageal anastomosis. Patients' age at the time of diverticulum repair was 6.6–16.8 months. All patients underwent thoracoscopic esophageal diverticulectomy (operation time: 1.5–3.5 h). Anastomotic leakage occurred in one patient and spontaneously healed after 2 weeks. The other three patients had no peri-operative complications. All patients were routinely followed up after surgery for 14–36 months. During the follow-up period, all patients could eat orally, had good growth and weight gain, and showed no ED recurrence or anastomotic leakage on esophagogram.

Conclusions: ED is a rare complication after EA/TEF surgery and is a clear indication for diverticulectomy. During the midterm follow-up, thoracoscopic esophageal diverticulectomy was safe and effective for ED after EA/TEF surgery.
Chinese Herbal Medicine for Chemotherapy-Induced Leukopenia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials
Authors: Wang Qing , Ye Hui , Wang Qiu-qin , Li Wei-tong , Yu Bei-bei , Bai Ya-mei , Xu Gui-hua
Published: May 2021

Aim: We conducted a systematic review of high-quality randomized controlled trials (RCTs) to assess the efficacy and safety of Chinese herbal medicine (CHM) for the treatment of chemotherapy-induced leukopenia (CIL).

Methods: Eight electronic databases were searched from the date of inception to November 4, 2020 for high-quality RCTs that met the requirements of at least four key domains of the Cochrane risk of bias (RoB) tool. RevMan 5.3 was applied for the meta-analysis.

Results: Fourteen RCTs involving 1,053 patients were included. The pooled results showed that CHM + chemotherapy exerted greater beneficial effects on white blood cell (WBC), neutrophil (NEU), hemoglobin (Hb), and platelet (PLT) counts in addition to the Karnofsky performance scale (KPS) score, but showed no significant difference on granulocyte colony-stimulating factor (G-CSF) dosage compared with chemotherapy alone. Placebo (PBO) + chemotherapy and CHM + chemotherapy groups showed no significant differences in terms of reduction of the incidence of neutropenia. CHM + chemotherapy was superior to Western medicine (WM) + chemotherapy in improving the WBC count, KPS, infection amount, G-CSF use rate, and incidence of leukopenia. In addition, no severe adverse events were observed in the 14 RCTs.

Conclusion: CHM in combination with chemotherapy could effectively improve the clinical symptoms of CIL when compared with chemotherapy alone or Western medicine + chemotherapy, except when comparing with PBO + chemotherapy. While CHMs were generally safe for clinical use and exerted no severe side effects in the 14 RCTs, high-quality RCTs with larger sample sizes are essential to reduce study heterogeneity.
Current Bioequivalence Study Designs in South Korea: A Comprehensive Analysis of Bioequivalence Study Reports Between 2013 and 2019
Authors: Huh Ki Young , Kim Eunwoo , Lee Soyoung , Yoo Hyounggyoon , Yoon Seonghae , Yu Kyung-Sang , Chung Jae-Yong
Published: May 2021

Demonstration of bioequivalence (BE) is mandatory while developing generic drugs. The scientific concept of BE applies equally to different regulatory agencies. However, the application of the concept may differ for each agency, which can affect the design of BE studies. To evaluate the study practices in terms of the BE concept in South Korea, we retrospectively analyzed BE study reports available from Ministry of Food and Drug Safety between 2013 and 2019. Statistical estimation of the pharmacokinetic parameters, including peak concentration and area under the concentration–time curve to the last measurable concentration, as well as study design, number of subjects in a study, study duration, fasting status, and formulation of specific drugs were obtained. The drugs were classified per World Health Organization Anatomical Therapeutic Chemical Classification and Biopharmaceutics Classification System. Post-hoc intrasubject coefficient of variation and corresponding sample sizes were calculated from the 90% confidence intervals of pharmacokinetic parameters. A total of 143 generic drugs in 588 BE studies were analyzed. The largest number of studies were performed in the area of Cardiovascular system (172 studies), followed by Nervous system (143 studies) and Alimentary tract and metabolism (92 studies). Overall, BE studies in South Korea were conducted in accordance with the global guideline despite the differences in details. BE studies were focused on the several therapeutic areas and conducted in a similar manner. The number of subjects was generally larger than that estimated with 90% power.
In silico Prediction of Skin Sensitization: Quo vadis?
Authors: Ta Giang Huong , Weng Ching-Feng , Leong Max K.
Published: May 2021

Skin direct contact with chemical or physical substances is predisposed to allergic contact dermatitis (ACD), producing various allergic reactions, namely rash, blister, or itchy, in the contacted skin area. ACD can be triggered by various extremely complicated adverse outcome pathways (AOPs) remains to be causal for biosafety warrant. As such, commercial products such as ointments or cosmetics can fulfill the topically safe requirements in animal and non-animal models including allergy. Europe, nevertheless, has banned animal tests for the safety evaluations of cosmetic ingredients since 2013, followed by other countries. A variety of non-animal in vitro tests addressing different key events of the AOP, the direct peptide reactivity assay (DPRA), KeratinoSens™, LuSens and human cell line activation test h-CLAT and U-SENS™ have been developed and were adopted in OECD test guideline to identify the skin sensitizers. Other methods, such as the SENS-IS are not yet fully validated and regulatorily accepted. A broad spectrum of in silico models, alternatively, to predict skin sensitization have emerged based on various animal and non-animal data using assorted modeling schemes. In this article, we extensively summarize a number of skin sensitization predictive models that can be used in the biopharmaceutics and cosmeceuticals industries as well as their future perspectives, and the underlined challenges are also discussed.
Strategy, Progress, and Challenges of Drug Repurposing for Efficient Antiviral Discovery
Authors: Li Xinlei , Peng Tao
Published: May 2021

Emerging or re-emerging viruses are still major threats to public health. Prophylactic vaccines represent the most effective way to prevent virus infection; however, antivirals are more promising for those viruses against which vaccines are not effective enough or contemporarily unavailable. Because of the slow pace of novel antiviral discovery, the high disuse rates, and the substantial cost, repurposing of the well-characterized therapeutics, either approved or under investigation, is becoming an attractive strategy to identify the new directions to treat virus infections. In this review, we described recent progress in identifying broad-spectrum antivirals through drug repurposing. We defined the two major categories of the repurposed antivirals, direct-acting repurposed antivirals (DARA) and host-targeting repurposed antivirals (HTRA). Under each category, we summarized repurposed antivirals with potential broad-spectrum activity against a variety of viruses and discussed the possible mechanisms of action. Finally, we proposed the potential investigative directions of drug repurposing.
Gegen Qinlian Decoction Ameliorates Hyperuricemia-Induced Renal Tubular Injury via Blocking the Inflammatory Signaling Pathway
Authors: Wang Xiao-Jun , Qi Yi-Ding , Guan Hao-Chen , Lin Hua-Gang , He Pei-Qing , Guan Kang-Wei , Fu Lei , Ye Mao-Qing , Xiao Jing , Wu Tao
Published: May 2021

Background: Gegen Qinlian decoction (GGQLD) is a typical traditional Chinese medicine (TCM) prescription documented in Shang Han Lun. Clinically, GGQLD has been utilized to manage the inflammatory symptoms of metabolic diseases and to protect against renal damage in China. In the present study, a hypothesis was proposed that the multi-target solution of GGQLD produced anti-inflammatory effects on ameliorating hyperuricemia (HUA).

Methods: A total of 30 primary HUA patients receiving GGQLD treatment (two doses daily) for 4 weeks were selected. Then, differences in uric acid (UA) levels and expression of peripheral blood mononuclear cells (PBMCs) and urinary exosomes before and after treatment were analyzed. The therapeutic indexes for the active ingredients in GGQLD against HUA were confirmed through pharmacological subnetwork analysis. Besides, the HUA rat model was established through oral gavage of potassium oxonate and treated with oral GGQLD. In addition, proximal tubular epithelial cells (PTECs) were stimulated by UA and intervened with GGQLD for 48 h. Subsequently, RNA-seq, flow cytometry, and confocal immunofluorescence microscopy were further conducted to characterize the differences in UA-mediated inflammation and apoptosis of human renal tubular epithelial cells pre- and post-administration of GGQLD. In the meanwhile, quantitative real-time PCR (qPCR) was carried out to determine gene expression, whereas a western blotting (WB) assay was conducted to measure protein expression.

Results: Our network analysis revealed that GGQLD treated HUA via the anti-inflammatory and antiapoptotic pathways. Additionally, NLPR3 expression significantly decreased in PBMCs and urinary exosomes of HUA patients after GGQLD treatment. In vivo, GGQLD treatment alleviated HUA-induced renal inflammation, which was associated with decreased expression of NLRP3 inflammasomes and apoptosis-related mRNAs. Moreover, GGQLD promoted renal UA excretion by inhibiting the activation of GSDMD-dependent pyroptosis induced by NLRP3 inflammasomes and by reducing apoptosis via the mitochondrial apoptosis signaling pathway in vitro.

Conclusion: This study indicates that GGQLD efficiently reduces inflammatory responses while promoting UA excretion in HUA. Our findings also provide compelling evidence supporting the idea that GGQLD protects against the UA-mediated renal tubular epithelial cell inflammation through the mitochondrial apoptosis signaling pathways. Taken together, these findings have demonstrated a novel therapeutic method for the treatment of HUA.
Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction
Authors: Lee Hewang , Jose Pedro A
Published: May 2021

Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity (increased waist circumference), hyperglycemia, dyslipidemia (high triglyceride blood levels, low high-density lipoprotein blood levels), and increased blood pressure. Oxidative stress, caused by the imbalance between pro-oxidant and endogenous antioxidant systems, is the primary pathological basis of MetS. The major sources of reactive oxygen species (ROS) associated with MetS are nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases and mitochondria. In this review, we summarize the current knowledge regarding the generation of ROS from NADPH oxidases and mitochondria, discuss the NADPH oxidase- and mitochondria-derived ROS signaling and pathophysiological effects, and the interplay between these two major sources of ROS, which leads to chronic inflammation, adipocyte proliferation, insulin resistance, and other metabolic abnormalities. The mechanisms linking MetS and chronic kidney disease are not well known. The role of NADPH oxidases and mitochondria in renal injury in the setting of MetS, particularly the influence of the pyruvate dehydrogenase complex in oxidative stress, inflammation, and subsequent renal injury, is highlighted. Understanding the molecular mechanism(s) underlying MetS may lead to novel therapeutic approaches by targeting the pyruvate dehydrogenase complex in MetS and prevent its sequelae of chronic cardiovascular and renal diseases.
Atrophy Resistant vs. Atrophy Susceptible Skeletal Muscles: “aRaS” as a Novel Experimental Paradigm to Study the Mechanisms of Human Disuse Atrophy
Authors: Bass Joseph J. , Hardy Edward J. O. , Inns Thomas B. , Wilkinson Daniel J. , Piasecki Mathew , Morris Robert H. , Spicer Abi , Sale Craig , Smith Ken , Atherton Philip J. , Phillips Bethan E.
Published: May 2021

Objective

Disuse atrophy (DA) describes inactivity-induced skeletal muscle loss, through incompletely defined mechanisms. An intriguing observation is that individual muscles exhibit differing degrees of atrophy, despite exhibiting similar anatomical function/locations. We aimed to develop an innovative experimental paradigm to investigate Atrophy Resistant tibialis anterior (TA) and Atrophy Susceptible medial gastrocnemius (MG) muscles (aRaS) with a future view of uncovering central mechanisms.

Method

Seven healthy young men (22 ± 1 year) underwent 15 days unilateral leg immobilisation (ULI). Participants had a single leg immobilised using a knee brace and air-boot to fix the leg (75° knee flexion) and ankle in place. Dual-energy X-ray absorptiometry (DXA), MRI and ultrasound scans of the lower leg were taken before and after the immobilisation period to determine changes in muscle mass. Techniques were developed for conchotome and microneedle TA/MG muscle biopsies following immobilisation (both limbs), and preliminary fibre typing analyses was conducted.

Results

TA/MG muscles displayed comparable fibre type distribution of predominantly type I fibres (TA 67 ± 7%, MG 63 ± 5%). Following 15 days immobilisation, MG muscle volume (–2.8 ± 1.4%, p < 0.05) and muscle thickness decreased (−12.9 ± 1.6%, p < 0.01), with a positive correlation between changes in muscle volume and thickness (R2 = 0.31, p = 0.038). Importantly, both TA muscle volume and thickness remained unchanged.

Conclusion

The use of this unique “aRaS” paradigm provides an effective and convenient means by which to study the mechanistic basis of divergent DA susceptibility in humans, which may facilitate new mechanistic insights, and by extension, mitigation of skeletal muscle atrophy during human DA.
Genome-Wide Transcriptional Responses of Marine Nematode Litoditis marina to Hyposaline and Hypersaline Stresses
Authors: Xie Yusu , Zhang Pengchi , Zhang Liusuo
Published: May 2021

Maintenance of osmotic homeostasis is essential for all organisms, especially for marine animals in the ocean with 3% salinity or higher. However, the underlying molecular mechanisms that how marine animals adapt to high salinity environment compared to their terrestrial relatives, remain elusive. Here, we investigated marine animal’s genome-wide transcriptional responses to salinity stresses using an emerging marine nematode model Litoditis marina. We found that the transthyretin-like family genes were significantly increased in both hyposaline and hypersaline conditions, while multiple neurotransmitter receptor and ion transporter genes were down-regulated in both conditions, suggesting the existence of conserved strategies for response to stressful salinity environments in L. marina. Unsaturated fatty acids biosynthesis related genes, neuronal related tubulins and intraflagellar transport genes were specifically up-regulated in hyposaline treated worms. By contrast, cuticle related collagen genes were enriched and up-regulated for hypersaline response. Given a wide range of salinity tolerance of the marine nematodes, this study and further genetic analysis of key gene(s) of osmoregulation in L. marina will likely provide important insights into biological evolution and environmental adaptation mechanisms in nematodes and other invertebrate animals in general.
Autonomous Robots for Space: Trajectory Learning and Adaptation Using Imitation
Authors: Ashith Shyam R. B. , Hao Zhou , Montanaro Umberto , Dixit Shilp , Rathinam Arunkumar , Gao Yang , Neumann Gerhard , Fallah Saber
Published: May 2021

This paper adds on to the on-going efforts to provide more autonomy to space robots and introduces the concept of programming by demonstration or imitation learning for trajectory planning of manipulators on free-floating spacecraft. A redundant 7-DoF robotic arm is mounted on small spacecraft dedicated for debris removal, on-orbit servicing and assembly, autonomous and rendezvous docking. The motion of robot (or manipulator) arm induces reaction forces on the spacecraft and hence its attitude changes prompting the Attitude Determination and Control System (ADCS) to take large corrective action. The method introduced here is capable of finding the trajectory that minimizes the attitudinal changes thereby reducing the load on ADCS. One of the critical elements in spacecraft trajectory planning and control is the power consumption. The approach introduced in this work carry out trajectory learning offline by collecting data from demonstrations and encoding it as a probabilistic distribution of trajectories. The learned trajectory distribution can be used for planning in previously unseen situations by conditioning the probabilistic distribution. Hence almost no power is required for computations after deployment. Sampling from a conditioned distribution provides several possible trajectories from the same start to goal state. To determine the trajectory that minimizes attitudinal changes, a cost term is defined and the trajectory which minimizes this cost is considered the optimal one.
The Distribution of Open Clusters in the Galaxy
Authors: Monteiro Hektor , Barros Douglas A. , Dias Wilton S. , Lépine Jacques R. D.
Published: May 2021

In this work we explore the new catalog of galactic open clusters that became available recently, containing 1,750 clusters that have been re-analyzed using the Gaia DR2 catalog to determine the stellar memberships. We used the young open clusters as tracers of spiral arms and determined the spiral pattern rotation speed of the Galaxy and the corotation radius, the strongest Galactic resonance. The sample of open clusters used here is increased by dozens of objects with respect to our previous works. In addition, the distances and ages values are better determined, using improvements to isochrone fitting and including an updated extinction polynomial for the Gaia DR2 photometric band-passes, and the Galactic abundance gradient as a prior for metallicity. In addition to the better age determinations, the catalog contains better positions in the Galactic plane and better proper motions. This allow us to discuss not only the present space distribution of the clusters, but also the space distribution of the clusters's birthplaces, obtained by integration of the orbits for a time equal to their age. The value of the rotation velocity of the arms (28.5 ± 1.0 km s−1 kpc−1) implies that the corotation radius (Rc) is close to the solar Galactic orbit (Rc/R0 = 1.01±0.08), which is supported by other observational evidence discussed in this text. A simulation is presented, illustrating the motion of the clusters in the reference frame of corotation. We also present general statistics of the catalog of clusters, like spatial distribution, distribution relative to height from the Galactic plane, and distribution of ages and metallicity. An important feature of the space distribution, the corotation gap in the gas distribution and its consequences for the young clusters, is discussed.
Examining the Relationship of Clinical and Laboratory Parameters With Infectiousness to Phlebotomus perniciosus and Its Potential Infectivity in Dogs With Overt Clinical Leishmaniasis
Authors: Gizzarelli Manuela , Bosco Antonio , Foglia Manzillo Valentina , Bongiorno Gioia , Bianchi Riccardo , Giaquinto Daniela , Ben Fayala Nour El Houda , Varloud Marie , Crippa Alessia , Gradoni Luigi , Cringoli Giuseppe , Maurelli Maria Paola , Rinaldi Laura , Oliva Gaetano
Published: May 2021

Infected dogs are considered the main domestic animal reservoirs for Leishmania infantum parasite. Infectiousness to competent phlebotomine vectors has been associated with many factors, the main being the severity of the disease exhibited by infected dogs. This study examines the relationship between different clinical parameters and the infectiousness to colonized Phlebotomus perniciosus sand flies having a blood meal on dogs. Data obtained in the present study come from an untreated group of Leishmania sick dogs submitted to xenodiagnosis for the evaluation of a spot on insecticide solution. Seventeen dogs were diagnosed as affected by leishmaniasis through clinical examination, immunofluorescence antibody test (IFAT) serology, and loop-mediated isothermal amplification (LAMP). The disease severity (clinical score) was staged by using a numeric value derived from eight clinical and parasitological parameters. Xenodiagnosis was performed on caged dogs exposed for 1.5 h to sand-fly bites. The following parameters related to sand flies were examined: blood feeding (% of blood engorged females), promastigote detection (% of promastigote-positive sand flies), promastigote burden, and the promastigote stage maturation (potential transmissibility rate). Statistical relationship between the clinical score and entomological parameters was investigated, as well as the possible correlation between each clinical and laboratory parameters and sand fly infection/infectivity. The severity of clinical score may influence the blood feeding by, and the probability of promastigote detection in, sand flies; skin lesions seem to be the main factor that influences the rate of blood feeding. Promastigote burden is related to IFAT titer, skin lesions, and clinical score. All entomological parameters are strongly related among them. This study confirms that both P. perniciosus infection and infectivity are influenced by a dog's clinical condition.
GPs’ use and understanding of the benefits and harms of treatments for long-term conditions: a qualitative interview study
Authors: Treadwell Julian , Crocker Joanna , Rushforth Alexander , Mahtani Kamal , Greenhalgh Trish
Published: May 2021

Background

To support shared decision making and improve the management of polypharmacy, it is recommended that GPs take into account quantitative information on the benefits and harms of treatments (QIRx). Quantitative evidence shows GPs’ knowledge of this is low.

Aim

To explore GPs’ attitudes to and understanding of QIRx for long-term conditions.

Design and setting

Qualitative interview study in UK general practice.

Method

Semi-structured interviews were carried out with 15 GPs. Audiorecordings were transcribed verbatim and a framework approach was used for analysis.

Results

Participants described knowing or using QIRx for only a few treatments. There was awareness of this knowledge deficit coupled with low confidence in statistical terminology. Some GPs perceived an absence of this information as an important barrier to optimal care, while others were content to follow guidelines. In the absence of this knowledge, other strategies were described to individualise treatment decisions. The idea of increasing the use of QIRx appealed to most participants, with imagined benefits for patients and themselves. However, potential barriers were described: a need for accessible information that can be understood and integrated into real-world practice, system factors, and communication challenges.

Conclusion

GPs were aware of their knowledge deficit with regard to an understanding of QIRx. Most participants were positive about the idea of increasing their use of QIRx in practice but described important challenges, which need to be considered when designing solutions.