bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitive to Infection but Strong in Defense—Female Sex and the Power of Oestradiol in the COVID-19 Pandemic
Authors: Newson Louise , Manyonda Isaac , Lewis Rebecca , Preissner Robert , Preissner Saskia , Seeland Ute
Published: May 2021

The incidence of SARS-CoV2 infections is around 15% higher in premenopausal women compared to age matched men, yet the fatality rate from COVID-19 is significantly higher in men than women for all age strata. Sex differences have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), with SARS-CoV 2 virus infection sex differences appear more dramatic. The regulation and expression of the angiotensin converting enzyme 2 (ACE2) is the key for this special coronavirus SARS-CoV-2 to enter the cell. 17β-oestradiol increases expression level and activity of angiotensin converting enzyme-2 (ACE2) and the alternative signaling pathway of Ang II via the angiotensin II receptor type II (AT2R) and the Mas receptor is more dominant in female sex than in male sex. Maybe a hint to explain the higher infection risk in women. The same hormonal milieu plays a major role in protecting women where morbidity and mortality are concerned, since the dominant female hormone, oestradiol, has immune-modulatory properties that are likely to be protective against virus infections. It is also known that the X chromosome contains the largest number of immune-related genes, potentially conferring an advantage to women in efficient immune responsiveness. Lifestyle factors are also likely to be contributory. Premenopausal women could possibly face higher exposure to infection (hence higher infection rates) because economic conditions are often less favorable for them with less opportunity for home office work because of jobs requiring mandatory attendance. Due to the additional task of childcare, it is likely that contact times with other people will be longer. Women generally make healthier lifestyle choices, thus reducing the disease burden that confers high risk of mortality in COVID-19 infected men. This narrative review aims to present key concepts and knowledge gaps on the effects of oestrogen associated with SARS-CoV2 infection and COVID-19 disease.
A Specifically Designed Injector for Controlled Lube Oil Addition in View of Investigation of Pre-Ignition Phenomena in Dual–Fuel/Gas Engines
Authors: Süess Pascal , Schneider Bruno , Wüthrich Dario , Wüthrich Silas , Herrmann Kai
Published: May 2021

Internal combustion engines will continue to play a role during a transitional phase, especially in heavy-duty or marine applications. In this context, lean-burn gas/dual-fuel combustion is an attractive concept to reduce CO2, combined with considerably lower particulate and NOX pollution, and with efficiencies comparable to diesel combustion. However, ignition processes still pose considerable challenges, with pre-ignition in particular being a major issue. The underlying mechanisms are probably based on self-ignition of lube oil in hot zones. In order to investigate fundamentals of such phenomena in optically accessible test rigs, a novel injector was specifically developed to induce pre-ignitions artificially. The so-called “PieZo-Droplet-Injector” (PZDI) enables dosing of minor amounts of lubricating oil or even the injection of single droplets with diameters in the range of 100–200 µm. The working principle relies on a needle actuated with a piezo stack, which pushes a certain amount of lube oil in a bore so that (even single) droplets can be ejected through an adjustable nozzle. To confirm the PZDI functionality and to investigate droplet characteristics based on adjustable operating parameters, tests were performed under ambient conditions as well as in a constant volume combustion chamber under reasonable pressure and temperature conditions. Overall, the PZDI showed an excellent behavior in terms of capabilities to inject small amounts or even single droplets of lube oil. At last, this specially developed injector allows selective lube oil addition in an optically accessible engine test facility for upcoming examination of pre-ignition phenomena under real operating conditions.
Teaching and Learning Core Values in General Practice/Family Medicine: A Narrative Review
Authors: Michels Nele R. M. , Maagaard Roar , Švab Igor , Scherpbier Nynke
Published: May 2021

General Practice/Family Medicine (GP/FM) is a key discipline within primary health care and so by extension for the whole health care system. An essential condition for effective GP/FM care is a work force that is highly qualified. As society is changing rapidly, a revision of the GP/FM definition is ongoing, in addition to a recent movement of identifying related core values. In this paper, we want to give an overview on how these new paths and perspectives are currently reflected in GP/FM teaching and training. We selected four core values that fit in with possible future visions: person-centered care, continuity of care, cooperation in care, and community-oriented care. By a narrative review, we observed that GP/FM education toward core values is often built around overarching topics. Teaching and learning take place in specific contexts, most of all through placements within communities, primary care settings, or hospital wards. Mixed teaching- and training methods are used combining knowledge, skills, and attitude. Furthermore, collaboration with other health professionals and peers is stressed, in addition to the importance of role models, a holistic focus and the involvement of patients. Since these core values are important within GP/FM and rather few studies on the educational aspects and learning tools were found we advocate encouraging each other more to share good practices, certainly the innovative ones specifically related to GP/FM.
Effects of Normoxia, Hyperoxia, and Mild Hypoxia on Macro-Hemodynamics and the Skeletal Muscle Microcirculation in Anesthetised Rats
Authors: Damiani Elisa , Casarotta Erika , Orlando Fiorenza , Carsetti Andrea , Scorcella Claudia , Domizi Roberta , Adrario Erica , Ciucani Silvia , Provinciali Mauro , Donati Abele
Published: May 2021

Objectives: Excessive oxygen (O2) administration may have a negative impact on tissue perfusion by inducing vasoconstriction and oxidative stress. We aimed to evaluate the effects of different inhaled oxygen fractions (FiO2) on macro-hemodynamics and microvascular perfusion in a rat model.

Methods: Isoflurane-anesthetised spontaneously breathing male Wistar rats were equipped with arterial (carotid artery) and venous (jugular vein) catheters and tracheotomy, and randomized into three groups: normoxia (FiO2 21%, n = 6), hyperoxia (FiO2 100%, n = 6) and mild hypoxia (FiO2 15%, n = 6). Euvolemia was maintained by infusing Lactate Ringer solution at 10 ml/kg/h. At hourly intervals for 4 h we collected measurements of: mean arterial pressure (MAP); stroke volume index (SVI), heart rate (HR), respiratory rate (by means of echocardiography); arterial and venous blood gases; microvascular density, and flow quality (by means of sidestream dark field videomicroscopy on the hindlimb skeletal muscle).

Results: MAP and systemic vascular resistance index increased with hyperoxia and decreased with mild hypoxia (p < 0.001 in both cases, two-way analysis of variance). Hyperoxia induced a reduction in SVI, while this was increased in mild hypoxia (p = 0.002). The HR increased under hyperoxia (p < 0.05 vs. normoxia at 3 h). Cardiax index, as well as systemic O2 delivery, did not significantly vary in the three groups (p = 0.546 and p = 0.691, respectively). At 4 h, microvascular vessel surface (i.e., the percentage of tissue surface occupied by vessels) decreased by 29 ± 4% in the hyperoxia group and increased by 19 ± 7 % in mild hypoxia group (p < 0.001). Total vessel density and perfused vessel density showed similar tendencies (p = 0.003 and p = 0.005, respectively). Parameters of flow quality (microvascular flow index, percentage of perfused vessels, and flow heterogeneity index) remained stable and similar in the three groups.

Conclusions: Hyperoxia induces vasoconstriction and reduction in skeletal muscle microvascular density, while mild hypoxia has an opposite effect.
Seasonal Variation in Viral Infection Rates and Cell Sizes of Infected Prokaryotes in a Large and Deep Freshwater Lake (Lake Biwa, Japan)
Authors: Shen Shang , Shimizu Yoshihisa
Published: May 2021

As viruses regulate prokaryotic abundance and the carbon cycle by infecting and lysing their prokaryotic hosts, the volume of infected prokaryotes is an important parameter for understanding the impact of viruses on aquatic environments. However, literature regarding the seasonal and spatial variations in the cell volume of infected prokaryotes is limited, despite the volume of the prokaryotic community varying dynamically with season and water column depth. Here, we conducted a field survey for two annual cycles in a large and deep freshwater lake (Lake Biwa, Japan), where large prokaryotes inhabit the deeper layer during the stratified period. We used transmission electron microscopy to reveal the seasonal and spatial variation in the frequency of viral infection and cell volume of infected prokaryotes. We found that the viral infection rate in the surface layer increased when estimated contact rates increased during the middle of the stratified period, whereas the infection rate in the deeper layer increased despite low estimated contact rates during the end of the stratified period. In addition, in the deeper layer, the fraction of large prokaryotes in the total and infected prokaryotic communities increased progressively while the number of intracellular viral particles increased. We suggest different ways in which the viral abundance is maintained in the two water layers. In the surface layer, it is speculated that viral abundance is supported by the high viral infection rate because of the high activity of prokaryotes, whereas in the deeper layer, it might be supported by the larger number of intracellular viral particles released from large prokaryotes. Moreover, large prokaryotes could contribute as important sources of organic substrates via viral lysis in the deeper layer, where labile dissolved organic matter is depleted.
The Composition of Root-Associated Bacteria and Fungi of Astragalus mongholicus and Their Relationship With the Bioactive Ingredients
Authors: Li Yanmei , Liu Yang , Zhang Hui , Yang Yan , Wei Gehong , Li Zhefei
Published: May 2021

Astragalus membranaceus (Fisch.) Bge. var. mongholicus, which is used in traditional Chinese medicine, contains several bioactive ingredients. The root-associated microbial communities play a crucial role in the production of secondary metabolites in plants. However, the correlation of root-associated bacteria and fungi with the bioactive ingredients production in A. mongholicus has not been elucidated. This study aimed to examine the changes in soil properties, root bioactive ingredients, and microbial communities in different cultivation years. The root-associated bacterial and fungal composition was analyzed using high-throughput sequencing. The correlation between root-associated bacteria and fungi, soil properties, and six major bioactive ingredients were examined using multivariate correlation analysis. Results showed that soil properties and bioactive ingredients were distinct across different cultivation years. The composition of the rhizosphere microbiome was different from that of the root endosphere microbiome. The bacterial community structure was affected by the cultivation year and exhibited a time-decay pattern. Soil properties affected the fungal community composition. It was found that 18 root-associated bacterial operational taxonomic units (OTUs) and four fungal OTUs were positively and negatively correlated with bioactive ingredient content, respectively. The abundance of Stenotrophomonas in the rhizosphere was positively correlated with astragaloside content. Phyllobacterium and Inquilinus in the endosphere were positively correlated with the calycosin content. In summary, this study provided a new opportunity and theoretical reference for improving the production and quality of in A. mongholicus, which thus increase the pharmacological value of A. mongholicus.
Different Cultivation Environments Affect the Yield, Bacterial Community and Metabolites of Cordyceps cicadae
Authors: Zeng Zhaoying , Mou Dan , Luo Li , Zhong Wenlin , Duan Lin , Zou Xiao
Published: May 2021

Cordyceps cicadae is an entomogenous fungus with important uses in traditional Chinese medicine. However, its wild resources have not met consumers’ demand due to excessive harvesting practices. Artificial cultivation is therefore an important alternative, but research on cultivating C. cicadae in natural habitats has not been reported. In this study, we aimed to explore the viability of cultivating C. cicadae in a natural habitat, in the soil of Pinus massoniana forest. We assessed and compared the yield, metabolite contents and bacterial community composition of C. cicadae grown in the Antheraea pernyi pupae at different growth stages, and under different cultivation conditions, in the soil of a natural habitat and in sterile glass bottles. Our results showed that cultivating C. cicadae in a natural habitat is feasible, with up to 95% of pupae producing C. cicadae fruiting bodies. The content of nitrogen compounds (amino acids) in C. cicadae cultivated in a natural habitat was significantly higher than in glass bottles, while the yield and carbon compound (mannitol and polysaccharide) and nucleoside (cordycepin and adenosine) contents were lower. Different bacterial genera were enriched in C. cicadae at different growth stages and cultivation environments, and these bacterial genera were closely related to metabolites contents during growth. This study demonstrated the viability of a novel cultivation method of C. cicadae, which could be used as an alternative to wild stocks of this fungus. These findings provided new insights into the growth mechanism of C. cicadae and its interaction with soil microorganisms.
Mini Review: Bacterial Membrane Composition and Its Modulation in Response to Stress
Authors: Willdigg Jessica R. , Helmann John D.
Published: May 2021

Antibiotics and other agents that perturb the synthesis or integrity of the bacterial cell envelope trigger compensatory stress responses. Focusing onBacillus subtilisas a model system, this mini-review summarizes current views of membrane structure and insights into how cell envelope stress responses remodel and protect the membrane. Altering the composition and properties of the membrane and its associated proteome can protect cells against detergents, antimicrobial peptides, and pore-forming compounds while also, indirectly, contributing to resistance against compounds that affect cell wall synthesis. Many of these regulatory responses are broadly conserved, even where the details of regulation may differ, and can be important in the emergence of antibiotic resistance in clinical settings.
Recent Advances in Protein Homology Detection Propelled by Inter-Residue Interaction Map Threading
Authors: Bhattacharya Sutanu , Roche Rahmatullah , Shuvo Md Hossain , Bhattacharya Debswapna
Published: May 2021

Sequence-based protein homology detection has emerged as one of the most sensitive and accurate approaches to protein structure prediction. Despite the success, homology detection remains very challenging for weakly homologous proteins with divergent evolutionary profile. Very recently, deep neural network architectures have shown promising progress in mining the coevolutionary signal encoded in multiple sequence alignments, leading to reasonably accurate estimation of inter-residue interaction maps, which serve as a rich source of additional information for improved homology detection. Here, we summarize the latest developments in protein homology detection driven by inter-residue interaction map threading. We highlight the emerging trends in distant-homology protein threading through the alignment of predicted interaction maps at various granularities ranging from binary contact maps to finer-grained distance and orientation maps as well as their combination. We also discuss some of the current limitations and possible future avenues to further enhance the sensitivity of protein homology detection.
Risk Score for Predicting Dysphagia in Patients After Neurosurgery: A Prospective Observational Trial
Authors: Zeng Li , Song Yu , Dong Yan , Wu Qian , Zhang Lu , Yu Lei , Gao Liang , Shi Yan
Published: May 2021

Background: Acquired dysphagia is common in patients with tracheal intubation and neurological disease, leading to increased mortality. This study aimed to ascertain the risk factors and develop a prediction model for acquired dysphagia in patients after neurosurgery.

Methods: A multicenter prospective observational study was performed on 293 patients who underwent neurosurgery. A standardized swallowing assessment was performed bedside within 24 h of extubation, and logistic regression analysis with a best subset selection strategy was performed to select predictors. A nomogram model was then established and verified.

Results: The incidence of acquired dysphagia in our study was 23.2% (68/293). Among the variables, days of neurointensive care unit (NICU) stay [odds ratio (OR), 1.433; 95% confidence interval (CI), 1.141–1.882; P = 0.005], tracheal intubation duration (OR, 1.021; CI, 1.001–1.062; P = 0.175), use of a nasogastric feeding tube (OR, 9.131; CI, 1.364–62.289; P = 0.021), and Acute Physiology and Chronic Health Evaluation (APACHE)-II C score (OR, 1.709; CI, 1.421–2.148; P < 0.001) were selected as risk predictors for dysphagia and included in the nomogram model. The area under the receiver operating characteristic curve was 0.980 (CI, 0.965–0.996) in the training set and 0.971 (0.937–1) in the validation set, with Brier scores of 0.045 and 0.056, respectively.

Conclusion: Patients who stay longer in the NICU, have a longer duration of tracheal intubation, require a nasogastric feeding tube, and have higher APACHE-II C scores after neurosurgery are likely to develop dysphagia. This developed model is a convenient and efficient tool for predicting the development of dysphagia.
Benchmarking the Extent and Speed of Reperfusion: First Pass TICI 2c-3 Is a Preferred Endovascular Reperfusion Endpoint
Authors: Yoo Albert J. , Soomro Jazba , Andersson Tommy , Saver Jeffrey L. , Ribo Marc , Bozorgchami Hormozd , Dabus Guilherme , Liebeskind David S. , Jadhav Ashutosh , Mattle Heinrich , Zaidat Osama O.
Published: May 2021

Background and Purpose: End-of-procedure substantial reperfusion [modified Treatment in Cerebral Ischemia (mTICI) 2b-3], the leading endpoint for thrombectomy studies, has several limitations including a ceiling effect, with recent achieved rates of ~90%. We aimed to identify a more optimal definition of angiographic success along two dimensions: (1) the extent of tissue reperfusion, and (2) the speed of revascularization.

Methods: Core-lab adjudicated TICI scores for the first three passes of EmboTrap and the final all-procedures result were analyzed in the ARISE II multicenter study. The clinical impact of extent of reperfusion and speed of reperfusion (first-pass vs. later-pass) were evaluated. Clinical outcomes included 90-day functional independence [modified Rankin Scale (mRS) 0–2], 90-day freedom-from-disability (mRS 0–1), and dramatic early improvement [24-h National Institutes of Health Stroke Scale (NIHSS) improvement ≥ 8 points].

Results: Among 161 ARISE II subjects with ICA or MCA M1 occlusions, reperfusion results at procedure end showed substantial reperfusion in 149 (92.5%), excellent reperfusion in 121 (75.2%), and complete reperfusion in 79 (49.1%). Reperfusion rates on first pass were substantial in 81 (50.3%), excellent reperfusion in 62 (38.5%), and complete reperfusion in 44 (27.3%). First-pass excellent reperfusion (first-pass TICI 2c-3) had the greatest nominal predictive value for 90-day mRS 0–2 (sensitivity 58.5%, specificity 68.6%). There was a progressive worsening of outcomes with each additional pass required to achieve TICI 2c-3.

Conclusions: First-pass excellent reperfusion (TICI 2c-3), reflecting rapid achievement of extensive reperfusion, is the technical revascularization endpoint that best predicted functional independence in this international multicenter trial and is an attractive candidate for a lead angiographic endpoint for future trials.

Clinical Trial Registration:http://www.clinicaltrials.gov, identifier NCT02488915.
Lactobacillus acidophilus ATCC 4356 Alleviates Renal Ischemia–Reperfusion Injury Through Antioxidant Stress and Anti-inflammatory Responses and Improves Intestinal Microbial Distribution
Authors: Zhang Peng , Han Xiuwu , Zhang Xin , Zhu Xuhui
Published: May 2021

Background: Ischemia–reperfusion injury (IRI) is one of the main causes of acute kidney injury. Our previous results have shown that anti-oxidative stress decreased in the renal IRI model. This study aimed to investigate the effect of Lactobacillus acidophilus ATCC 4356 on oxidative stress, inflammation, and intestinal flora in renal IRI.

Methods: The model of renal IRI was established by cross-clamping the renal pedicle with non-traumatic vascular forceps. H&E staining was applied to observe the damage of kidney tissue in each group. The concentrations of serum blood urea nitrogen (BUN), creatinine (Cre), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) were detected by biochemical kit. ELISA measured the concentrations of interleukin (IL)-1β, IL-8, IL-4, and IL-10. qRT-PCR was performed to detect molecular expressions of ATCC 4356, oxidative stress-related factors [nuclear factor-related factor 2 (Nrf2), heme oxygenase 1 (HO-1)], inflammatory factors [tumor necrosis factor (TNF)-α, IL-1β, IL-8, interferon (IFN)-γ, IL-4, IL-10], and apoptosis-related factors [caspase 3, Bax, Bcl2, high-mobility group box protein 1 (HMGB1)]. Except for ATCC 4356, the protein expression of the above indicators was detected by Western blot. The apoptosis level of renal tissue cells was detected by TdT-mediated dUTP nick end labeling (TUNEL). 16S rDNA gene sequencing was used to detect the changes of microbial species in the contents of the duodenum and screen out the differentially expressed flora.

Results: Both the glomeruli and renal tubules of ischemia/reperfusion (I/R) mice were severely damaged. H&E result displayed that L. acidophilus ATCC 4356 attenuated the infiltration of inflammatory cells caused by I/R. ATCC 4356 reduced the high expression of BUN and Cre in I/R mice with a dose effect. It also reduced the high expression of MDA, TNF-α, IL-1β, IL-8, IFN-γ, caspase 3, Bax, and HMGB1 in I/R mice, while it increased the low expression of SOD, GSH, Nrf2, HO-1, IL-4, IL-10, and Bcl2 in I/R mice. ATCC 4356 inhibited the high level of apoptosis in the kidney tissue of I/R mice. In IRI mice, the top 3 different gut microbiota were Helicobacter, cultivated_bacterium, and k__Bacteria_ASV_3 compared with sham mice. Oral L. acidophilus ATCC 4356 reversed this change.

Conclusion:L. acidophilus ATCC 4356 attenuated renal IRI through anti-oxidative stress and anti-inflammatory response and improved the intestinal microbial distribution.
Treatment-Related Serious Adverse Events of Immune Checkpoint Inhibitors in Clinical Trials: A Systematic Review
Authors: Ouyang Tao , Cao Yanyan , Kan Xuefeng , Chen Lei , Ren Yanqiao , Sun Tao , Yan Liangliang , Xiong Bin , Liang Bin , Zheng Chuansheng
Published: May 2021

Background

Immune Checkpoint Inhibitors (ICI) have been progressively used in cancer treatment and produced unique toxicity profiles. This systematic review aims to comprehend the patterns and occurrence of treatment-related adverse events (trAEs) based on ICI.

Methods

PICOS/PRISMA methods were used to identify published English-language on PubMed, Web of Science, and Scopus from 2015 to 2020. Published clinical trials on ICI monotherapy, combined ICIs, and ICI plus other treatment with tabulated data on grade≥3 trAEs were included. Odds ratio (OR), χ2 tests were used to analyze for effect size and associations.

Results

This review included 145 clinical trials involving 21786 patients. Grade 3-5 trAEs were more common with ICI when they were plused with other treatments compared with ICI monotherapy(54.3% versus 17.7%, 46.1%, p<0.05). Grade 3-5 trAEs were also more common with CTLA-4 mAbs compared with anti-PD-1 and anti-PD-L1 (34.2% versus 15.1%, 13.6%, p<0.05). Hyperthyroidism (OR 3.8, 95%CI 1.7–8.6), nausea (OR 3.7, 95%CI 2.5–5.3), diarrhea (OR 2.7, 95%CI 2.2–3.2), colitis (OR 3.4, 95%CI 2.7–4.3), ALT increase (OR 4.9, 95%CI 3.9–6.1), AST increase (OR 3.8, 95%CI 3.0–4.9), pruritus (OR 2.4, 95%CI 1.5–3.9), rash (OR 2.8, 95%CI 2.1–3.8), fatigue (OR 2.8, 95%CI 2.2–3.7), decreased appetite (OR 2.4, 95%CI 1.5–3.8), and hypophysitis (OR 2.0, 95%CI 1.2–3.3) were more frequent with combined ICIs. Diarrhea (OR 8.1, 95%CI 6.4–10.3), colitis (OR 12.2, 95%CI 8.7–17.1), ALT increase (OR 5.1, 95%CI 3.5–7.4), AST increase (OR 4.2, 95%CI 2.8–6.3), pruritus (OR 4.1, 95%CI 2.0–8.4), rash (OR 4.4, 95%CI 2.9–6.8), hypophysitis (OR 12.1, 95%CI 6.3–23.4) were more common with CTLA-4 mAbs; whereas pneumonitis (OR 4.7, 95% CI 2.1–10.3) were more frequent with PD-1 mAbs.

Conclusions

Different immune checkpoint inhibitors are associated with different treatment-related adverse events profiles. A comprehensive data in this systematic review will provide comprehensive information for clinicians.
Using Population-Based Cancer Registration Data and Period Analysis to Accurately Assess and Predict 5-Year Relative Survival for Lung Cancer Patients in Eastern China
Authors: Li Runhua , Zhang Min , Cheng Yongran , Jiang Xiyi , Tang Huijuan , Wang Liangyou , Chen Tianhui , Chen Bicheng
Published: May 2021

Background

The assessment of long-term survival of lung cancer patients based on data from population-based caner registries, using period analysis, was scarce in China. We aimed to accurately assess the long-term survival of lung cancer patients, and to predict the long-term survival in the future, using cancer registry data from Taizhou City, eastern China.

Methods

Four cancer registries with high-quality data were selected. Patients diagnosed with lung cancer during 2004–2018 were included. The long-term survival was evaluated using period analysis, with further stratification by sex, age at diagnosis and region. Additionally, projected 5-year relative survival (RS) of lung cancer patients for 2019-2023 was evaluated, using model-based period analysis.

Results

The 5-year RS of lung cancer patients diagnosed during 2014–2018 was 40.2% (31.5% for men and 56.2% for women). A moderate age gradient was observed for the period estimate, with the estimate decreasing from 50.5 to 26.5% in the age group of 15–44 years and ≥75 years, respectively. The 5-year RS of urban area was higher than that of rural area (52.3% vs. 38.9%). The overall projected 5-year RS of lung cancer patients was 52.7% for 2019–2023, with estimate of 43.0 and 73.2% for men and women, respectively. A moderate age gradient was also observed for the projected estimate. Moreover, estimate reached nearly 50% for rural and urban areas.

Conclusion

Period analysis tended to provide the up-to-date and precise survival estimates for lung cancer patients, which is worth further application, and provides important evidence for prevention and intervention of lung cancer.
Risk Factors and Survival of Patients With Liver Metastases at Initial Metastatic Breast Cancer Diagnosis in Han Population
Authors: Lin Shaoyan , Mo Hongnan , Li Yiqun , Guan Xiuwen , Chen Yimeng , Wang Zijing , Yuan Peng , Wang Jiayu , Luo Yang , Fan Ying , Cai Ruigang , Li Qiao , Chen Shanshan , Zhang Pin , Li Qing , Ma Fei , Xu Binghe
Published: May 2021

The risk factors for morbidity and mortality in patients with breast cancer liver metastases (BCLM) upon initial metastatic breast cancer (MBC) diagnosis have not been adequately identified in Han population. Data of 3,161 female patients who were initially diagnosed with MBC from December 1991 to September 2019 and treated in the China National Cancer Center were extracted and a total of 2,263 MBC patients were included in our study, among which 550 patients had liver metastases. Multivariable logistic regression was performed to identify risk factors for the presence of liver metastases at initial MBC diagnosis. Univariable and multivariable Cox proportional hazards regression analyses were conducted to determine prognostic factors for the survival of BCLM patients. Patients with hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive (35.0% of the entire population) subtype had the highest incidence of liver metastases. De novo stage IV breast cancer, HR−/HER2+ and HR+/HER2+ subtypes were associated with higher odds of liver metastases and patients with lung metastases had lower risk of liver metastases at initial MBC diagnosis. The median overall survival of BCLM patients was 31.4 months and BCLM patients with HR+/HER2− subtype had the longest survival of 38.2 months. Older age, worse performance status, later stage of initial breast cancer, triple-negative subtype and lung metastases were significantly associated with a poorer prognosis in BCLM patients. Our study offers insights into the incidence and prognosis of BCLM patients at initial MBC diagnosis in Han population.
Complete Remission of Advanced Adrenocortical Cancer Following Mitotane Monotherapy: A Case Report and Literature Review of Predictive Markers
Authors: Tőke Judit , Jakab Zsuzsanna , Stark Júlia , Huszty Gergely , Reismann Péter , Tóth Miklós
Published: May 2021

Mitotane has been used for the treatment of adrenocortical cancer (ACC) for over 50 years. Despite its widespread use both in monotherapy and in combination with chemotherapeutics, our knowledge of its mechanism of action and therapeutic efficacy is scarce. The number of patients with advanced ACC who have achieved complete remission documented by detailed clinical data is below ten. We report a case of a 64-year-old woman with a non-functional ACC. Histological examination showed vascular invasion, Ki67 of 10% and a mitotic count of 3/10 high-power field. Immunohistochemistry revealed p53 positivity. Pathological TNM grade was reported as T2N0M0, ENSAT stage 2. Nine months after the initial diagnosis, re-staging CT revealed multiple peritoneal nodules, lymph node and kidney metastases confirmed by histologic examination. Mitotane monotherapy was started with a maintenance dose between 2.0 and 2.5 grams/day. Partial remission was established at six months. Subsequently, for another 12 months, each of the three-monthly CT scans confirmed complete remission. Nineteen months after the initiation of mitotane, an unexpected sudden death occurred. A detailed autopsy work-up, performed in the full awareness of oncological history, confirmed complete remission. The authors review the molecular biomarkers and clinical features reported as predictors of response to mitotane monotherapy.
The Clinical and Imaging Characteristics Associated With Neurological Sequelae of Pediatric Patients With Acute Necrotizing Encephalopathy
Authors: Zhu Hong-Min , Zhang Si-Min , Yao Cong , Luo Meng-Qing , Ma Hui-Jing , Lei Tao , Yuan Chun-Hui , Wu Ge-Fei , Hu Jia-Sheng , Cai Chun-Quan , Liu Zhi-Sheng
Published: May 2021

Background: Acute necrotizing encephalopathy of childhood (ANE) is a rare but rapidly progressing encephalopathy. Importantly, the exact pathogenesis and evidence-based treatment is scarce. Thus, we aimed to identify the clinical, imaging, and therapeutic characteristics that associated with prognosis of pediatric ANE patients.

Methods: A retrospective study was conducted on pediatric patients with ANE who were admitted to Wuhan Children's Hospital between January 2014 and September 2019. All cases met the diagnostic criteria for ANE proposed by Mizuguchi in 1997. The clinical information and follow-up data were collected. The prognostic factors were analyzed by trend chi-square test and Goodman–Kruskal gamma test.

Results: A total of 41 ANE patients ranging in age from 8.9 to 142 months were included in this study. Seven cases (17%) died, and the other 34 survivors had different degrees of neurological sequelae. Factors tested to be significantly correlated with the severity of neurological sequelae were the intervals from prodromal infection to acute encephalopathy (G = −0.553), conscious disturbance (r = 0.58), endotracheal intubation (r = 0.423), elevation of alanine aminotransferase (r = 0.345), aspartate aminotransferase (r = 0.393), and cerebrospinal fluid protein (r = 0.490). In addition, dynamic magnetic resonance imaging (MRI) evaluation on follow-up revealed that the total numbers of brain lesion location (χ2 = 6.29, P < 0.05), hemorrhage (r = 0.580), cavitation (r = 0.410), and atrophy (r = 0.602) status were significantly correlated with the severity of neurological sequelae, while early steroid therapy (r = −0.127 and 0.212, respectively) and intravenous immunoglobulin (IVIG) (r = 0.111 and −0.023, respectively) within 24 h or within 72 h after onset showed no association.

Conclusions: Intervals from prodromal infection to acute encephalopathy (≤1 day), total numbers of brain lesion location (≥3), the recovery duration of hemorrhage and atrophy (>3 months), and the presence of cavitation predict severe neurological sequelae in pediatric patients with ANE. Early treatments, including steroid therapy and IVIG, had no correlation with better outcomes. Further studies are needed to establish a consensus guideline for the management of ANE.
Histamine can be Formed and Degraded in the Human and Mouse Heart
Authors: Neumann Joachim , Grobe Juliane M. , Weisgut Jacqueline , Schwelberger Hubert G. , Fogel Wieslawa Agnieszka , Marušáková Margaréta , Wache Hartmut , Bähre Heike , Buchwalow Igor B. , Dhein Stefan , Hofmann Britt , Kirchhefer Uwe , Gergs Ulrich
Published: May 2021

Histamine is metabolized by several enzymesin vitroandin vivo. The relevance of this metabolism in the mammalian heartin vivois unclear. However, histamine can exert positive inotropic effects (PIE) and positive chronotropic effects (PCE) in humans via H2-histamine receptors. In transgenic mice (H2-TG) that overexpress the human H2receptor in cardiomyocytes but not in wild-type littermate mice (WT), histamine induced PIE and PCE in isolated left or right atrial preparations. These H2-TG were used to investigate the putative relevance of histamine degrading enzymes in the mammalian heart. Histidine, the precursor of histamine, increased force of contraction (FOC) in human atrial preparations. Moreover, histamine increased the phosphorylation state of phospholamban in human atrium. Here, we could detect histidine decarboxylase (HDC) and histamine itself in cardiomyocytes of mouse hearts. Moreover, our data indicate that histamine is subject to degradation in the mammalian heart. Inhibition of the histamine metabolizing enzymes diamine oxidase (DAO) and monoamine oxidase (MAO) shifted the concentration response curves for the PIE in H2-TG atria to the left. Moreover, activity of histamine metabolizing enzymes was present in mouse cardiac samples as well as in human atrial samples. Thus, drugs used for other indication (e.g. antidepressants) can alter histamine levels in the heart. Our results deepen our understanding of the physiological role of histamine in the mouse and human heart. Our findings might be clinically relevant because we show enzyme targets for drugs to modify the beating rate and force of the human heart.
Derivation of a Human In Vivo Benchmark Dose for Perfluorooctanoic Acid From ToxCast In Vitro Concentration–Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation
Authors: Loizou George , McNally Kevin , Dorne Jean-Lou C. M. , Hogg Alex
Published: May 2021

A computational workflow which integrates physiologically based kinetic (PBK) modeling, global sensitivity analysis (GSA), approximate Bayesian computation (ABC), and Markov Chain Monte Carlo (MCMC) simulation was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow accounts for parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for perfluorooctanoic acid (PFOA) and high throughput screening (HTS) in vitro concentration–response data, determined in a human liver cell line, from the ToxCast/Tox21 database. In vivo benchmark doses (BMDs) for PFOA intake (ng/kg BW/day) and drinking water exposure concentrations (µg/L) were calculated from the in vivo dose responses and compared to intake values derived by the European Food Safety Authority (EFSA). The intake benchmark dose lower confidence limit (BMDL5) of 0.82 was similar to 0.86 ng/kg BW/day for altered serum cholesterol levels derived by EFSA, whereas the intake BMDL5 of 6.88 was six-fold higher than the value of 1.14 ng/kg BW/day for altered antibody titer also derived by the EFSA. Application of a chemical-specific adjustment factor (CSAF) of 1.4, allowing for inter-individual variability in kinetics, based on biological half-life, gave an intake BMDL5 of 0.59 for serum cholesterol and 4.91 (ng/kg BW/day), for decreased antibody titer, which were 0.69 and 4.31 the EFSA-derived values, respectively. The corresponding BMDL5 for drinking water concentrations, for estrogen receptor binding activation associated with breast cancer, pregnane X receptor binding associated with altered serum cholesterol levels, thyroid hormone receptor α binding leading to thyroid disease, and decreased antibody titer (pro-inflammation from cytokines) were 0.883, 0.139, 0.086, and 0.295 ng/ml, respectively, with application of no uncertainty factors. These concentrations are 5.7-, 36-, 58.5-, and 16.9-fold lower than the median measured drinking water level for the general US population which is approximately, 5 ng/ml.
Reduction of Matrix Metallopeptidase 13 and Promotion of Chondrogenesis by Zeel T in Primary Human Osteoarthritic Chondrocytes
Authors: Sanchez Christelle , Hemmer Kathrin , Krömmelbein Natascha , Seilheimer Bernd , Dubuc Jean-Emile , Antoine Christophe , Henrotin Yves
Published: May 2021

Objectives: Zeel T (Ze14) is a multicomponent medicinal product. Initial preclinical data suggested a preventive effect on cartilage degradation. Clinical observational studies demonstrated that Ze14 reduced symptoms of osteoarthritis (OA), including stiffness and pain. This study aimed to explore these effects further to better understand the mode of action of Ze14 on human OA chondrocytes in vitro.

Methods: Primary chondrocytes were obtained from the knees of 19 OA patients and cultured either as monolayers or in alginate beads. The cultures were treated with 20% or 10% (v/v) Ze14 or placebo. For RNA-seq, reads were generated with Illumina NextSeq5000 sequencer and aligned to the human reference genome (UCSC hg19). Differential expression analysis between Ze14 and placebo was performed in R using the DESeq2 package. Protein quantification by ELISA was performed on selected genes from the culture medium and/or the cellular fractions of primary human OA chondrocyte cultures.

Results: In monolayer cultures, Ze14 20% (v/v) significantly modified the expression of 13 genes in OA chondrocytes by at least 10% with an adjusted p-value < 0.05: EGR1, FOS, NR4A1, DUSP1, ZFP36, ZFP36L1, NFKBIZ, and CCN1 were upregulated and ATF7IP, TXNIP, DEPP1, CLEC3A, and MMP13 were downregulated after 24 h Ze14 treatment. Ze14 significantly increased (mean 2.3-fold after 24 h, p = 0.0444 and 72 h, p = 0.0239) the CCN1 protein production in human OA chondrocytes. After 72 h, Ze14 significantly increased type II collagen pro-peptide production by mean 27% (p = 0.0147). For both time points CCN1 production by OA chondrocytes was correlated with aggrecan (r = 0.66, p = 0.0004) and type II collagen pro-peptide (r = 0.64, p = 0.0008) production. In alginate beads cultures, pro-MMP-13 was decreased by Ze14 from day 7–14 (from −16 to −25%, p < 0.05) and from day 17–21 (−22%, p = 0.0331) in comparison to controls.

Conclusion: Ze14 significantly modified the expression of DUSP1, DEPP1, ZFP36/ZFP36L1, and CLEC3A, which may reduce MMP13 expression and activation. Protein analysis confirmed that Ze14 significantly reduced the production of pro-MMP-13. As MMP-13 is involved in type II collagen degradation, Ze14 may limit cartilage degradation. Ze14 also promoted extracellular matrix formation arguably through CCN1 production, a growth factor well correlated with type II collagen and aggrecan production.
Maternal Nicotine Exposure Alters Hippocampal Microglia Polarization and Promotes Anti-inflammatory Signaling in Juvenile Offspring in Mice
Authors: Zhou Li , Tao Xinrong , Pang Gang , Mu Min , Sun Qixian , Liu Fei , Hu Yuting , Tao Huihui , Li Bing , Xu Keyi
Published: May 2021

Accumulating evidence reveal that maternal smoking or perinatal nicotine replacement therapy impairs hippocampal neurogenesis, neural development, and cognitive behaviors in the offspring. Microglia is a source of non-neural regulation of neuronal development and postnatal neurogenesis. In this study, we explored the impact of nicotine on the microglia during the development of hippocampus. Developmental nicotine exposure in a mouse model was conducted by supplementing nicotine in the drinking water to mother mice during gestation and lactation period. We found that juvenile offspring with maternal nicotine exposure presented physical and neurobehavioral development delay and an increase in anxiety-like behavior in the open field test on postnatal day (PND) 20. To further detect possible developmental neurotoxic effects of nicotine in offspring and underlying mechanism, whole genome microarray analysis of the expression profile of the hippocampus was performed on postnatal day 20. Significant alterations in the expression of genes related to inflammatory, neurotransmitter, and synapsis were observed in the hippocampus after maternal nicotine exposure, as compared to the vehicle control. Concurrently, an increase in microglial markers and the presence of M2 polarity state in the hippocampus of the nicotine offspring were observed by histological analysis and confocal z-stacking scanning. The M2 microglial polarization state was further confirmed with in vitro primary microglia culture by cytokine array, and double-positive expression of BDNF/Iba1 in microglia by immunohistochemical staining in the juvenile offspring hippocampus was visualized. We also found that nicotine offspring showed an increase of neurite length in the molecular layer and CA1 by Tuj1 staining, as well as an increase in the expression of synapse associated protein, PSD95, but the expression of NeuroD1 in CA1 and CA3 reduced. In summary, maternal nicotine exposure dysregulates immune-related genes expression by skewing the polarity of M2 microglia in the hippocampus, which may cause abnormal cognitive and behavioral performance in the offspring.
Alteration in the Lipid Profile and the Desaturases Activity in Patients With Severe Pneumonia by SARS-CoV-2
Authors: Pérez-Torres Israel , Guarner-Lans Verónica , Soria-Castro Elizabeth , Manzano-Pech Linaloe , Palacios-Chavarría Adrián , Valdez-Vázquez Rafael Ricardo , Domínguez-Cherit Jose Guillermo , Herrera-Bello Hector , Castillejos-Suastegui Humberto , Moreno-Castañeda Lidia , Alanís-Estrada Gabriela , Hernández Fabián , González-Marcos Omar , Márquez-Velasco Ricardo , Soto María Elena
Published: May 2021

The kidnapping of the lipid metabolism of the host’s cells by severe acute respiratory syndrome (SARS-CoV-2) allows the virus to transform the cells into optimal machines for its assembly and replication. Here we evaluated changes in the fatty acid (FA) profile and the participation of the activity of the desaturases, in plasma of patients with severe pneumonia by SARS-CoV-2. We found that SARS-CoV-2 alters the FA metabolism in the cells of the host. Changes are characterized by variations in the desaturases that lead to a decrease in total fatty acid (TFA), phospholipids (PL) and non-esterified fatty acids (NEFAs). These alterations include a decrease in palmitic and stearic acids (p ≤ 0.009) which could be used for the formation of the viral membranes and for the reparation of the host’s own membrane. There is also an increase in oleic acid (OA; p = 0.001) which could modulate the inflammatory process, the cytokine release, apoptosis, necrosis, oxidative stress (OS). An increase in linoleic acid (LA) in TFA (p = 0.03) and a decreased in PL (p = 0.001) was also present. They result from damage of the internal mitochondrial membrane. The arachidonic acid (AA) percentage was elevated (p = 0.02) in the TFA and this can be participated in the inflammatory process. EPA was decreased (p = 0.001) and this may decrease of pro-resolving mediators with increase in the inflammatory process. The total of NEFAs (p = 0.03), PL (p = 0.001), cholesterol, HDL and LDL were decreased, and triglycerides were increased in plasma of the COVID-19 patients. Therefore, SARS-CoV-2 alters the FA metabolism, the changes are characterized by alterations in the desaturases that lead to variations in the TFA, PL, and NEFAs profiles. These changes may favor the replication of the virus but, at the same time, they are part of the defense system provided by the host cell metabolism in its eagerness to repair damage caused by the virus to cell membranes.
Sex Differences in the Physiological Network of Healthy Young Subjects
Authors: Barajas-Martínez Antonio , Ibarra-Coronado Elizabeth , Fossion Ruben , Toledo-Roy Juan Claudio , Martínez-Garcés Vania , López-Rivera Juan Antonio , Tello-Santoyo Geraldine , Lavin Rusland D. , Gómez José Luis , Stephens Christopher R. , Aguilar-Salinas Carlos A. , Estañol Bruno , Torres Nimbe , Tovar Armando R. , Resendis-Antonio Osbaldo , Hiriart Marcia , Frank Alejandro , Rivera Ana Leonor
Published: May 2021

Within human physiology, systemic interactions couple physiological variables to maintain homeostasis. These interactions change according to health status and are modified by factors such as age and sex. For several physiological processes, sex-based distinctions in normal physiology are present and defined in isolation. However, new methodologies are indispensable to analyze system-wide properties and interactions with the objective of exploring differences between sexes. Here we propose a new method to construct complex inferential networks from a normalization using the clinical criteria for health of physiological variables, and the correlations between anthropometric and blood tests biomarkers of 198 healthy young participants (117 women, 81 men, from 18 to 27 years old). Physiological networks of men have less correlations, displayed higher modularity, higher small-world index, but were more vulnerable to directed attacks, whereas networks of women were more resilient. The networks of both men and women displayed sex-specific connections that are consistent with the literature. Additionally, we carried out a time-series study on heart rate variability (HRV) using Physionet’s Fantasia database. Autocorrelation of HRV, variance, and Poincare’s plots, as a measure of variability, are statistically significant higher in young men and statistically significant different from young women. These differences are attenuated in older men and women, that have similar HRV distributions. The network approach revealed differences in the association of variables related to glucose homeostasis, nitrogen balance, kidney function, and fat depots. The clusters of physiological variables and their roles within the network remained similar regardless of sex. Both methodologies show a higher number of associations between variables in the physiological system of women, implying redundant mechanisms of control and simultaneously showing that these systems display less variability in time than those of men, constituting a more resilient system.