bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells
Authors: Kohno Keizo , Koya-Miyata Satomi , Harashima Akira , Tsukuda Takahiko , Katakami Masataka , Ariyasu Toshio , Ushio Shimpei , Iwaki Kanso
Published: January 2021

Background

NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase.

Results

NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity.

Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production.

Conclusion

It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.
Mortality among male cigar and cigarette smokers in the USA
Authors: Rodu Brad , Plurphanswat Nantaporn
Published: January 2021

Background

Cigars and cigarettes are both smoked, but much less is known about the former’s long-term health effects, due to its low prevalence and infrequent collection of cigar information in national surveys.

Purpose

We conducted a follow-up mortality study of cigar-smoking men age 40–79 years in National Health Interview Surveys (NHIS).

Methods

We used pooled NHIS files linked to the National Death Index to obtain follow-up from year of interview to year of death or December 31, 2015. We developed categories of cigarette and cigar smoking that accommodate dual and former use of both products. We used Cox proportional hazards models, adjusted for age, race/ethnicity, marital status, education, income and region to estimate hazard ratios (HRs, 95% confidence intervals, CI) for mortality from all causes, heart diseases, malignant neoplasms, cerebrovascular disease, chronic lower respiratory diseases and two mutually exclusive categories: smoking-related and other diseases.

Results

There were 14,657 deaths from all causes, including 3426 never tobacco users, 3276 exclusive cigarette smokers and 176 exclusive cigar users. The latter had no statistically significant evidence of increased mortality from all causes, heart diseases, malignant neoplasms, cerebrovascular disease, smoking-related diseases or other causes. In contrast, the mortality experience of dual users of cigars and cigarettes and cigar smokers who formerly used cigarettes is similar to exclusive cigarette smokers.

Conclusions

This study provides evidence that male cigar smokers age 40 + years had elevated mortality risks. However, after accounting for cigarette smoking and other confounding variables, we found significantly increased mortality only among dual and former users of cigarettes.
The English and Chinese language versions of the Short Form 12-item Health Survey are equivalent
Authors: Fong Daniel Y. T. , Wong Janet Y. H. , Choi Edmond P. H. , Lam K. F. , Kwok C.
Published: January 2021

Background

The Short Form 12-item Health Survey (SF-12v2) was originally developed in English, but it is also available in Hong Kong (HK) Chinese. While both language versions had their measurement properties well assessed in their respective populations, their measurement invariance in scores has not been examined. Therefore, we aimed to assess their measurement invariance.

Methods

We conducted a cross-sectional study on individuals aged 18 years or older at a university campus. Those who were bilingual in English and Chinese were randomly assigned to self-complete either the standard English or the HK Chinese SF-12v2. Measurement invariance of the two components and eight scales of the SF-12v2 was concluded if the corresponding 90% confidence interval (CI) for the difference between the two language versions entirely fell within the minimal clinically important difference of ± 3 units. Multiple-group confirmatory factor analysis (CFA) was also performed.

Results

A total of 1013 participants completed the SF-12v2 (496 in English and 517 in HK Chinese), with a mean age of 22 years (Range 18–58), and 626 participants (62%) were female. There were no significant differences in demographics. Only the physical and mental components and the mental health (MH) scale had their 90% CIs (0.21 to 1.61, − 1.00 to 0.98, and − 0.86 to 2.84, respectively) completely fall within the ± 3 units. The multiple-group CFA showed partial strict invariance.

Conclusions

The English and HK Chinese versions of the SF-12v2 can be used in studies with their two components and MH scores pooled in the analysis.
Validation of the WHOQOL-Bref: psychometric properties and normative data for the Norwegian general population
Authors: Kalfoss Mary H. , Reidunsdatter Randi J. , Klöckner Christian A. , Nilsen Marianne
Published: January 2021

Background

The World Health Organization’s Quality of Life Questionnaire (WHOQOL-Bref) is a frequently used instrument to assess the quality of life in both healthy and ill populations. Inquiries of the psychometric properties of the WHOQOL-Bref report that the validity and reliability is generally satisfactory. However, some studies fail to support a four-factor dimensionality; others report poor reliability of the social and environmental domain; and there may be some challenges of supporting construct validity across age. This paper evaluates the psychometric properties of the Norwegian WHOQOL-Bref and extends previous research by testing for measurement invariance across age, gender and education level. In addition, we provide updated normative data for the Norwegian population.

Methods

We selected a random sample of the Norwegian population (n = 654) aged 18–75 years. Participants filled out the WHOQOL-Bref, the Utrecht Work Engagement Scale and various sociodemographic variables.

Results

We found an acceptable convergent and discriminate validity and internal consistency of the physical, psychological and environmental domains, but a marginal reliability was found for the social domain. The factor loadings were invariant across gender, education and age. Some items had low factor loadings and explained variance, and the model fit for the age group 60–75 years were less satisfactory.

Conclusions

The original four-factor dimensionality of the WHOQOL-Bref displayed a better fit to the data compared to the one-factor solution and is recommended for use in the Norwegian population. The WHOQOL-Bref is suitable to use across gender, education and age, but for assessment in the oldest age group, the WHOQOL-Old module could be a good supplementary, but further studies are needed.
Regulation of ARHGAP19 in the endometrial epithelium: a possible role in the establishment of uterine receptivity
Authors: Liang Jingjie , Li Kui , Chen Kaiyu , Liang Junyong , Qin Ti , He Jiayi , Shi Shuang , Tan Qiang , Wang Zhengguang
Published: January 2021

Background

The establishment of uterine receptivity is essential for embryo implantation initiation and involves a significant morphological transformation in the endometrial epithelial cells (EECs). The remodeling of junctional complexes and membrane-associated cytoskeleton is crucial for epithelial transformation. However, little is known about how this process is regulated in EECs during the receptive phase. ARHGAP19 is a Rho GTPase-activating protein that participates in various cytoskeletal-related events, including epithelial morphogenesis. Here, we investigated the role of ARHGAP19 in endometrial epithelial transformation during the establishment of uterine receptivity. The upstream regulator of ARHGAP19 was also investigated.

Methods

ARHGAP19 expression was examined in mouse uteri during early pregnancy and in human EEC lines. The role of ARHGAP19 was investigated by manipulating its expression in EECs. The effect of ARHGAP19 on junctional proteins in EECs was examined by western blotting and immunofluorescence. The effect of ARHGAP19 on microvilli was examined by scanning electron microscopy. The upstream microRNA (miRNA) was predicted using online databases and validated by the dual-luciferase assay. The in vivo and in vitro effect of miRNA on endogenous ARHGAP19 was examined by uterine injection of miRNA agomirs and transfection of miRNA mimics or inhibitors.

Results

ARHGAP19 was upregulated in the receptive mouse uteri and human EECs. Overexpression of ARHGAP19 in non-receptive EECs downregulated the expression of junctional proteins and resulted in their redistribution. Meanwhile, upregulating ARHGAP19 reorganized the cytoskeletal structure of EECs, leading to a decline of microvilli and changes in cell configuration. These changes weakened epithelial cell polarity and promoted the transition of non-receptive EECs to a receptive phenotype. Besides, miR-192-5p, a miRNA that plays a key role in maintaining epithelial properties, was validated as an upstream regulator of ARHGAP19.

Conclusion

These results suggested that ARHGAP19 may contribute to the transition of EECs from a non-receptive to a receptive state by regulating the remodeling of junctional proteins and membrane-associated cytoskeleton.
Pre-exposure prophylaxis makes it possible to better live one’s sexuality and guide men who have sex with men towards a responsible approach to their health: a phenomenological qualitative study about primary motivations for PrEP
Authors: Bistoquet Marie , Makinson Alain , Tribout Vincent , Perrollaz Cyril , Bourrel Gérard , Reynes Jacques , Oude Engberink Agnès
Published: January 2021

Background

Pre-exposure prophylaxis (PrEP) for HIV is instrumental in the prevention of HIV for HIV-uninfected persons, by drastically reducing the risk of acquisition in the case of high-risk exposures. Despite its demonstrated efficacy, it remained under-prescribed in France until 2018. The principal aim of this study was to understand the motivations of Men who have Sex with Men (MSM) who started using PrEP in Montpellier, France.

Methods

A phenomenological study was undertaken, using semi-structured interviews with twelve participants attending the University Hospital of Montpellier for PrEP. Interviews were analysed by means of triangulation up to the point of theoretical saturation, using a semio-pragmatic method.

Results

Fear of HIV infection, personalised regular follow-up, and the wish to take care of one’s health were the primary motivational factors. PrEP allows for a better sexual life restoring a sense of freedom despite the risks of STI, deemed manageable by PrEPers. PrEP does not modify long-term risk-taking behaviours but helps them better live their own sexuality and guides them towards a responsible approach to sexuality. Unclear information on PrEP, delivered by their family doctor, public campaigns or the media, leads to misrepresentations or negative social representation, including within the MSM community, which may delay its implementation.

Conclusions

Fear of HIV infection and the benefits of regular medical follow-up to take care of one’s health were motivational factors of importance for the use of PrEP by MSM in this study. PrEP transforms all existential dimensions of their lived experience, improving sexual identity and happiness. There is a need to improve professional awareness of the effectiveness of PrEP and to develop a patient centered approach, to disseminate information more widely to the general public and among MSM to reduce stigmatisation.
Structural disruption of the blood–brain barrier in repetitive primary blast injury
Authors: Uzunalli Gozde , Herr Seth , Dieterly Alexandra M. , Shi Riyi , Lyle L. Tiffany
Published: January 2021

Background

Blast-induced traumatic brain injury (bTBI) is a growing health concern due to the increased use of low-cost improvised explosive devices in modern warfare. Mild blast exposures are common amongst military personnel; however, these women and men typically do not have adequate recovery time from their injuries due to the transient nature of behavioral symptoms. bTBI has been linked to heterogeneous neuropathology, including brain edema, neuronal degeneration and cognitive abnormalities depending on the intensity of blast overpressure and frequency. Recent studies have reported heterogeneity in blood–brain barrier (BBB) permeability following blast injury. There still remains a limited understanding of the pathologic changes in the BBB following primary blast injuries. In this study, our goal was to elucidate the pathologic pattern of BBB damage through structural analysis following single and repetitive blast injury using a clinically relevant rat model of bTBI.

Methods

A validated, open-ended shock tube model was used to deliver single or repetitive primary blast waves. The pathology of the BBB was assessed using immunofluorescence and immunohistochemistry assays. All data were analyzed using the one-way ANOVA test.

Results

We have demonstrated that exposure to repetitive blast injury affects the desmin-positive and CD13-positive subpopulations of pericytes in the BBB. Changes in astrocytes and microglia were also detected.

Conclusion

This study provides analysis of the BBB components after repetitive blast injury. These results will be critical as preventative and therapeutic strategies are established for veterans recovering from blast-induced traumatic brain injury.
Factors associated with involuntary admissions: a register-based cross-sectional multicenter study
Authors: Maina G. , Rosso G. , Carezana C. , Mehanović E. , Risso F. , Villari V. , Gariglio L. , Cardano M.
Published: January 2021

Background

Despite the EU recommendations on mental health, involuntary admission has been under researched in Italy for a long time and the overall picture of involuntary admission still appears fragmentary. The aims of this study are to evaluate involuntary admission rates in the Piedmont Region (Italy) and to investigate clinical and service-related variables associated with involuntary admission.

Methods

This is a cross-sectional retrospective multicenter study involving all psychiatric inpatients units of the general hospitals of Piedmont Region. Data on hospitalizations during 2016 were collected by consulting hospital discharge registers. The analyses were performed on two samples: 6018 patients (data analysis was run on first hospitalization during the study period for those with multiple admissions) and 7881 inpatient episodes. The association between involuntary admission and socio-demographic and clinical characteristics was examined through t-test for continuous variables, and Pearson’s Chi-square test for categorical variables. Multilevel modeling was applied in logistic regression models with two levels: for the first model center and participants and for the second model center and inpatient episodes.

Results

Of 6018 inpatients, 10.1% were admitted involuntarily at first hospitalization, while the overall compulsory treatment rate was slightly lower (9.1%) in the inpatient episodes sample (n = 7881). The involuntary admission rates ranged from 0.8 to 21% among study centers. Involuntary admissions were primarily associated with younger age, diagnosis of schizophrenia or substance use disorders, longer duration of hospital stay, mechanical restraint episodes, and fewer subsequent hospitalizations during the study period.

Conclusions

The rate of involuntary admission in the Piedmont Region was lower than the mean rate across countries worldwide. There were noteworthy differences in rates of involuntary admission among psychiatric units, although no relationship was found with characteristics of the psychiatric wards or of the areas where hospitals are located.
How effective are social norms interventions in changing the clinical behaviours of healthcare workers? A systematic review and meta-analysis
Authors: Tang Mei Yee , Rhodes Sarah , Powell Rachael , McGowan Laura , Howarth Elizabeth , Brown Benjamin , Cotterill Sarah
Published: January 2021

Background

Healthcare workers perform clinical behaviours which impact on patient diagnoses, care, treatment and recovery. Some methods of supporting healthcare workers in changing their behaviour make use of social norms by exposing healthcare workers to the beliefs, values, attitudes or behaviours of a reference group or person. This review aimed to evaluate evidence on (i) the effect of social norms interventions on healthcare worker clinical behaviour change and (ii) the contexts, modes of delivery and behaviour change techniques (BCTs) associated with effectiveness.

Methods

Systematic review and meta-analysis of randomised controlled trials. Searches were undertaken in seven databases. The primary outcome was compliance with a desired healthcare worker clinical behaviour and the secondary outcome was patient health outcomes. Outcomes were converted into standardised mean differences (SMDs). We performed meta-analyses and presented forest plots, stratified by five social norms BCTs (social comparison,credible source,social reward,social incentiveandinformation about others’ approval). Sources of variation in social norms BCTs, context and mode of delivery were explored using forest plots, meta-regression and network meta-analysis.

Results

Combined data from 116 trials suggested that social norms interventions were associated with an improvement in healthcare worker clinical behaviour outcomes of 0.08 SMDs (95%CI 0.07 to 0.10) (n= 100 comparisons), and an improvement in patient health outcomes of 0.17 SMDs (95%CI 0.14 to 0.20) (n= 14), on average. Heterogeneity was high, with an overallI2of 85.4% (healthcare worker clinical behaviour) and 91.5% (patient health outcomes).Credible sourcewas more effective on average, compared to control conditions (SMD 0.30, 95%CI 0.13 to 0.47,n= 7).Social comparisonalso appeared effective, both on its own (SMD 0.05, 95%CI 0.03 to 0.08,n= 33) and with other BCTs, and seemed particularly effective when combined withprompts/cues(0.33, 95%CI 0.22 to 0.44,n= 5).

Conclusions

Social norms interventions appeared to be an effective method of changing the clinical behaviour of healthcare workers and have a positive effect on patient health outcomes in a variety of health service contexts. Although the overall result is modest and variable, there is the potential for social norms interventions to be applied at large scale.

Trial registration

PROSPEROCRD42016045718.
Comparison of 5 × 5 Gy and 10 × 3 Gy for metastatic spinal cord compression using data from three prospective trials
Authors: Rades Dirk , Cacicedo Jon , Conde-Moreno Antonio J. , Segedin Barbara , Lomidze Darejan , Ciervide Raquel , Hollaender Niels H. , Schild Steven E.
Published: January 2021

Background

In a palliative situation like metastatic spinal cord compression (MSCC), overall treatment time of radiotherapy should be as short as possible. This study compared 5 × 5 Gy in 1 week to 10 × 3 Gy in 2 weeks in a prospective cohort.

Methods

Forty patients receiving 5 × 5 Gy in a phase II trial were matched 1:2 to 213 patients receiving 10 × 3 Gy in two previous prospective studies for tumor type, ambulatory status, time developing motor deficits, interval between tumor diagnosis and MSCC and visceral metastases. These factors were consistent in all three patients (triple) used for each 1:2 matching. Groups were compared for local progression-free survival (LPFS), motor function, ambulatory status, and overall survival (OS).

Results

After matching, 32 triples remained for analyses (N = 96 in total). Six-month LPFS-rates were 94% after 5 × 5 Gy and 87% after 10 × 3 Gy (p = 0.36), 6-month OS-rates 43% and 35% (p = 0.74). Improvement of motor function was achieved in 59% and 34% of patients (p = 0.028); overall response rates (improvement or no further progression of motor deficits) were 94% and 89% (p = 0.71). Post-treatment ambulatory rates were 81% after 5 × 5 Gy and 85% after 10 × 3 Gy (p = 0.61). Of non-ambulatory patients, 50% (6/12) and 46% (11/24) regained the ability to walk (p = 1.00).

Conclusions

5 × 5 Gy in 1 week appeared similarly effective as 10 × 3 Gy in 2 weeks. These results may not be applicable to long-term survivors and should be confirmed in a randomized trial directly comparing 5 × 5 Gy and 10 × 3 Gy.

Trial registrationclinicaltrials.gov NCT03070431. Registered 27 February 2017.
Effect of under triage on early mortality after major pediatric trauma: a registry-based propensity score matching analysis
Authors:   For the TRENAU Group, Ageron François-Xavier , Porteaud Jordan , Evain Jean-Noël , Millet Anne , Greze Jules , Vallot Cécile , Levrat Albrice , Mortamet Guillaume , Bouzat Pierre
Published: January 2021

Background

Little is known about the effect of under triage on early mortality in trauma in a pediatric population. Our objective is to describe the effect of under triage on 24-h mortality after major pediatric trauma in a regional trauma system.

Methods

This cohort study was conducted from January 2009 to December 2017. Data were obtained from the registry of the Northern French Alps Trauma System. The network guidelines triage pediatric trauma patients according to an algorithm shared with adult patients. Under triage was defined by the number of pediatric trauma patients that required specialized trauma care transported to a non-level I pediatric trauma center on the total number of injured patients with critical resource use. The effect of under triage on 24-h mortality was assessed with inverse probability treatment weighting (IPTW) and a propensity score (Ps) matching analysis.

Results

A total of 1143 pediatric patients were included (mean [SD], age 10 [5] years), mainly after a blunt trauma (1130 [99%]). Of the children, 402 (35%) had an ISS higher than 15 and 547 (48%) required specialized trauma care. Nineteen (1.7%) patients died within 24 h. Under triage rate was 33% based on the need of specialized trauma care. Under triage of children requiring specialized trauma care increased the risk of death in IPTW (risk difference 6.0 [95% CI 1.3–10.7]) and Ps matching analyses (risk difference 3.1 [95% CI 0.8–5.4]).

Conclusions

In a regional inclusive trauma system, under triage increased the risk of early death after pediatric major trauma.
How decisive is the number of distal arterial anastomoses in coronary bypass surgery?
Authors: Jegaden Olivier J. L. , Farhat Fadi , Jegaden Margaux P. O. , Hassan Amar O. , Lapeze Joel , Eker Armand
Published: January 2021

Background

The benefit of arterial revascularization in coronary surgery remains controversial. The incremental value of additional grafts to the left internal thoracic artery (ITA) has been mainly assessed according to the number of arterial grafts, possibly limiting the detection of its actual impact. We analyzed the influence of the number of distal arterial anastomoses (DAA) performed on late mortality in patients having received from one to three arterial grafts.

Methods

Retrospective review of 3685 primary isolated coronary artery bypass grafting (CABG) performed from 1989 to 2014 was conducted with a 13-year mean follow-up. One arterial graft (SITA) was used in 969 patients, two arterial grafts, ITA or gastroepiploic artery (GEA), in 1883 patients (BITA: 1644; SITA+GEA: 239), and three arterial grafts in 833 patients (BITA+GEA). Totally, 795 patients (22%) received one DAA, 1142 patients (31%) two, 1337 patients (36%) three, and 411 patients (11%) four or more. A sub-group analysis was done in the 2104 patients with 3-vessel disease who received at least 2 arterial grafts.

Results

In this series the early mortality was 1.6% and it was not influenced by the surgical technique. Late mortality was significantly influenced by age, gender, heart failure, LV ejection fraction, diabetes status, complete revascularization, number of arterial grafts, number of DAA, both ITA, sequential ITA graft, GEA graft. In multivariable analysis with Cox regression model, the number of DAA was the only technical significant independent prognosis factor of late survival (p < 0.0001), predominant over both ITA, complete revascularization and number of arterial grafts. The impact of the number of DAA on survival was found discriminant from 1 to 3; after 3 there was no more additional effect. In 3-vessel disease patients who received at least 2 arterial grafts, the number of DAA remained a significant independent prognosis factor of late survival (p < 0.0001).

Conclusions

The number of distal arterial anastomoses is an independent predictor of long-term survival, predominant over the number of arterial grafts and the completeness of the revascularization; higher the number, better the late survival. It is a strong support of the extensive use of arterial grafting in CABG.
Perioperative outcomes of coronary artery bypass graft surgery in Johannesburg, South Africa
Authors: Reiche Samantha , Mpanya Dineo , Vanderdonck Katharina , Mogaladi Shungu , Motshabi-Chakane Palesa , Tsabedze Nqoba
Published: January 2021

Background

The perioperative complications in patients with coronary artery disease undergoing coronary artery bypass graft (CABG) surgery have been reported predominantly from developed countries, with a paucity of data from sub-Saharan Africa. We aim to report on the clinical characteristics and perioperative complications in patients with obstructive coronary artery disease, managed with CABG surgery at a tertiary academic hospital in Johannesburg, South Africa.

Methods

We retrospectively reviewed data from adult patients who underwent CABG surgery during a 17-year period (January 2000 – December 2017). Data was collected from the cardiothoracic surgery department’s pre- and postoperative reports, the cardiology department’s medical records, and anaesthesiology’s intra-operative reports. We collected demographic, biochemical, clinical, surgical, echocardiographic, and angiographic data. Outcomes data collected included perioperative complications and mortality.

Results

We analysed 1218 consecutive patient records. The study cohort consisted of 951 (78.1%) males, and the mean age was 60.1 ± 10.1 years. During the study period, 137 (11.2%) patients demised with cardiac and sepsis-related causes of death accounting for 49.6 and 37.2%, respectively. Other perioperative complications included excessive bleeding in 222 (18.2%), prolonged ventilation (exceeding 48 h) in 139 (11.4%), and sternal sepsis in 125 (10.3%). On univariate logistic regression analysis, advanced age, a lower left ventricular ejection fraction, smoking, increased cardiopulmonary bypass (CPB) time, and a higher European System for Cardiac Operative Risk Evaluation (EuroSCORE) II were all significantly associated with mortality. The EuroSCORE II [OR: 0.15 95%CI: 0.09–0.22; p = 0.000], and prolonged CPB time [OR: 0.01 CI: 0.00–0.02; p = 0.000] were independent predictors of in-hospital all-cause mortality.

Conclusions

In our study, the crude perioperative mortality rate was 11.2%. Our mortality rate was significantly higher than the mortality rates reported in other developed and developing countries. To better understand the factors driving this high mortality rate, a prospective outcomes registry has been initiated, and this promises to inform on our contemporary mortality and morbidity outcomes.
Preoperative virtual simulation for synchronous multiple primary lung cancers using three-dimensional computed tomography lung reconstruction: a case report
Authors: Wu Weichun , Wu Yimin , Shen Gang , Zhang Guofei
Published: January 2021

Background

As the positions and sizes of nodules in synchronous multiple primary lung cancer (SMPLC) patients differ, the development of surgical strategies to maximize long-term survival and preserved postoperative pulmonary function in SMPLC patients for whom surgical resection is an alternative strategy presents challenges.

Case presentation

We provide a case managed through video-assisted thoracoscopic surgery (VATS) resection using three-dimensional computed tomography lung reconstruction (3D-CTLR) to reconstruct lobes containing pulmonary nodules to preoperatively simulate and intraoperatively guide the extent and method of resection.

Conclusion

The successful attempt demonstrates a technically simplified, feasible alternative to preoperative plans utilizing less invasive VATS to manage SMPLC.
Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up
Authors: Starosta Rodrigo Tzovenos , Boyer Suzanne , Tahata Shawn , Raymond Kimiyo , Lee Hee Eun , Wolfe Lynne A. , Lam Christina , Edmondson Andrew C. , Schwartz Ida Vanessa Doederlein , Morava Eva
Published: January 2021

Background

The congenital disorders of glycosylation (CDG) are a heterogeneous group of rare metabolic diseases with multi-system involvement. The liver phenotype of CDG varies not only according to the specific disorder, but also from patient to patient. In this study, we sought to identify common patterns of liver injury among patients with a broad spectrum of CDG, and to provide recommendations for follow-up in clinical practice.

Methods

Patients were enrolled in the Frontiers in Congenital Disorders of Glycosylation natural history study. We analyzed clinical history, molecular genetics, serum markers of liver injury, liver ultrasonography and transient elastography, liver histopathology (when available), and clinical scores of 39 patients with 16 different CDG types (PMM2-CDG, n = 19), with a median age of 7 years (range: 10 months to 65 years). For patients with disorders which are treatable by specific interventions, we have added a description of liver parameters on treatment.

Results

Our principal findings are (1) there is a clear pattern in the evolution of the hepatocellular injury markers alanine aminotransferase and aspartate aminotransferase according to age, especially in PMM2-CDG patients but also in other CDG-I, and that the cholangiocellular injury marker gamma-glutamyltransferase is not elevated in most patients, pointing to an exclusive hepatocellular origin of injury; (2) there is a dissociation between liver ultrasound and transient elastography regarding signs of liver fibrosis; (3) histopathological findings in liver tissue of PMM2-CDG patients include cytoplasmic glycogen deposits; and (4) most CDG types show more than one type of liver injury.

Conclusions

Based on these findings, we recommend that all CDG patients have regular systematic, comprehensive screening for liver disease, including physical examination (for hepatomegaly and signs of liver failure), laboratory tests (serum alanine aminotransferase and aspartate aminotransferase), liver ultrasound (for steatosis and liver tumors), and liver elastography (for fibrosis).
A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels
Authors: Gambeta Eder , Gandini Maria A. , Souza Ivana A. , Ferron Laurent , Zamponi Gerald W.
Published: January 2021

A novel missense mutation in the CACNA1A gene that encodes the pore forming α1 subunit of the CaV2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed CaV2.1 channels. Whole-cell patch clamp recordings of wild type and mutant CaV2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H CaV2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in CaV2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.
Hepatic NOD2 promotes hepatocarcinogenesis via a RIP2-mediated proinflammatory response and a novel nuclear autophagy-mediated DNA damage mechanism
Authors: Zhou Yi , Hu Liang , Tang Wenqing , Li Dongping , Ma Lijie , Liu Hongchun , Zhang Shuncai , Zhang Xiaojie , Dong Ling , Shen Xizhong , Chen She , Xue Ruyi , Zhang Si
Published: January 2021

Background

Key hepatic molecules linking gut dysbiosis and hepatocarcinogenesis remain largely unknown. Gut-derived gut microbiota contains pathogen-associated molecular patterns (PAMPs) that may circulate into the liver and, consequently, be recognized by hepatic pattern recognition receptors (PRRs). NOD2, a general intracellular PRR, recognizes muramyl dipeptide (MDP), present in both gram (+) and gram (−) bacteria. Here, we investigated the role of NOD2 as a molecular sensor translating gut dysbiosis signaling into hepatocarcinogenesis.

Methods

NOD2 expression was measured in clinical hepatocellular carcinoma (HCC) samples using qPCR (80 pairs), western blotting (30 pairs) and immunostaining (141 pairs). The role of NOD2 in hepatocarcinogenesis was examined in the hepatocyte-specific Nod2-knockout (Nod2△hep), Rip2-knockout (Rip2△hep), Lamin A/C-knockout (Lamn△hep) and Rip2/Lamin A/C double-knockout (Rip2/Lamn△hep) mice models of diethylnitrosamine (DEN)/CCl4-induced HCC.

Results

NOD2 was upregulated and activated in HCC samples, and high NOD2 expression correlated with poor prognosis in HCC patients. Hepatic NOD2 deletion in vivo decreased DEN/CCl4-induced HCC by reducing the inflammatory response, DNA damage and genomic instability. NOD2 activation increased liver inflammation via RIP2-dependent activation of the MAPK, NF-κB and STAT3 pathways. Notably, a novel RIP2-independent mechanism was discovered, whereby NOD2 activation induces the nuclear autophagy pathway. We showed that NOD2 undergoes nuclear transport and directly binds to a component of nuclear laminae, lamin A/C, to promote its protein degradation, leading to impaired DNA damage repair and increased genomic instability.

Conclusions

We reveal a novel bridge, bacterial sensor NOD2, linking gut-derived microbial metabolites to hepatocarcinogenesis via induction of the inflammatory response and nuclear autophagy. Thus, we propose hepatic NOD2 as a promising therapeutic target against HCC.
Exosomal ANGPTL1 attenuates colorectal cancer liver metastasis by regulating Kupffer cell secretion pattern and impeding MMP9 induced vascular leakiness
Authors: Jiang Kai , Chen Haiyan , Fang Yimin , Chen Liubo , Zhong Chenhan , Bu Tongtong , Dai Siqi , Pan Xiang , Fu Dongliang , Qian Yucheng , Wei Jingsun , Ding Kefeng
Published: January 2021

Background

Angiopoietin-like protein 1 (ANGPTL1) has been proved to suppress tumor metastasis in several cancers. However, its extracellular effects on the pre-metastatic niches (PMNs) are still unclear. ANGPTL1 has been identified in exosomes, while its function remains unknown. This study was designed to explore the role of exosomal ANGPTL1 on liver metastasis in colorectal cancer (CRC).

Methods

Exosomes were isolated by ultracentrifugation. The ANGPTL1 level was detected in exosomes derived from human CRC tissues. The effects of exosomal ANGPTL1 on CRC liver metastasis were explored by the intrasplenic injection mouse model. The liver PMN was examined by vascular permeability assays. Exosomal ANGPTL1 localization was validated by exosome labeling. The regulatory mechanisms of exosomal ANGPTL1 on Kupffer cells were determined by RNA sequencing. qRT-PCR, Western Blot, and ELISA analysis were conducted to examine gene expressions at mRNA and protein levels.

Results

ANGPTL1 protein level was significantly downregulated in the exosomes derived from CRC tumors compared with paired normal tissues. Besides, exosomal ANGPTL1 attenuated liver metastasis and impeded vascular leakiness in the liver PMN. Moreover, exosomal ANGPTL1 was mainly taken up by KCs and regulated the KCs secretion pattern, enormously decreasing the MMP9 expression, which finally prevented the liver vascular leakiness. In mechanism, exosomal ANGPTL1 downregulated MMP9 level in KCs by inhibiting the JAK2-STAT3 signaling pathway.

Conclusions

Taken together, exosomal ANGPTL1 attenuated CRC liver metastasis and impeded vascular leakiness in the liver PMN by reprogramming the Kupffer cell and decreasing the MMP9 expression. This study suggests a suppression role of exosomal ANGPTL1 on CRC liver metastasis and expands the approach of ANGPTL1 functioning.
PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells
Authors: Liotti Federica , Kumar Narender , Prevete Nella , Marotta Maria , Sorriento Daniela , Ieranò Caterina , Ronchi Andrea , Marino Federica Zito , Moretti Sonia , Colella Renato , Puxeddu Efiso , Paladino Simona , Kano Yoshihito , Ohh Michael , Scala Stefania , Melillo Rosa Marina
Published: January 2021

Background

The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC).

Methods

PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice.

Results

Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation.

Conclusions

PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.
The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat
Authors: Hwang Jung Wook , Lee Min Ji , Chung Tae Nyoung , Lee Han A. Reum , Lee Jung Ho , Choi Seo Yoon , Park Ye Jin , Kim Chul Hee , Jin Isom , Kim Seong Hoon , Kwak Hyo-Bum , Heo Jun-Won , Na Kwangmin , Choi Sangchun , Choi Yong-Soo , Kim Kyuseok
Published: January 2021

Background

Sepsis has a high mortality rate, but no specific drug has been proven effective, prompting the development of new drugs. Immunologically, sepsis can involve hyperinflammation, immune paralysis, or both, which might pose challenges during drug development. Recently, mitochondrial transplantation has emerged as a treatment modality for various diseases involving mitochondrial dysfunction, but it has never been tested for sepsis.

Methods

We isolated mitochondria from L6 muscle cells and umbilical cord mesenchymal stem cells and tested the quality of the isolated mitochondria. We conducted both in vivo and in vitro sepsis studies. We investigated the effects of intravenous mitochondrial transplantation on cecal slurry model in rats in terms of survival rate, bacterial clearance rate, and the immune response. Furthermore, we observed the effects of mitochondrial transplantation on the immune reaction regarding both hyperinflammation and immune paralysis. To do this, we studied early- and late-phase cytokine production in spleens from cecal slurry model in rats. We also used a lipopolysaccharide (LPS)-stimulated human PBMC monocyte model to confirm the immunological effects of mitochondrial transplantation. Apoptosis and the intrinsic apoptotic pathway were investigated in septic spleens.

Results

Mitochondrial transplantation improved survival and bacterial clearance. It also mitigated mitochondrial dysfunction and apoptosis in septic spleens and attenuated both hyperinflammation and immune paralysis in the spleens of cecal slurry model in rats. This effect was confirmed with an LPS-stimulated human PBMC study.

Conclusions

In rat polymicrobial cecal slurry model, the outcome is improved by mitochondrial transplantation, which might have an immunomodulatory effect.
High B3GALT5 expression confers poor clinical outcome and contributes to tumor progression and metastasis in breast cancer
Authors: Liao Yu-Mei , Wang Ya-Hui , Hung Jung-Tung , Lin Yu-Ju , Huang Yen-Lin , Liao Guo-Shiou , Hsu Ya-Ling , Wu Jen-Chien , Yu Alice L.
Published: January 2021

Background

Existence of breast cancer stem cells (BCSCs) is implicated in disease relapse, metastasis, and resistance of treatment. β1,3-Galactosyltransferase 5 (B3GALT5) has been shown to be a pro-survival marker for BCSCs. However, little is known about the prognostic significance of B3GALT5 in breast cancer.

Methods

Paired tissues (tumor part and adjacent non-tumor part) from a cohort of 202 women with breast cancer were used to determine the expression levels of B3GALT5 mRNA by qRT-PCR. Kaplan–Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of relapse-free survival (RFS) and overall survival (OS). Both breast cancer cells and cancer stem cells (BCSCs) were used to see the in vitro effects of knockdown or overexpression of B3GALT5 on cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). A patient-derived xenograft (PDX) model was used to see the in vivo effects of knockdown of B3GALT5 in BCSCs on tumor growth and metastasis.

Results

Higher expression of B3GALT5 in 202 breast cancer tissues, especially in adjacent non-tumor tissue, correlated with poor clinical outcomes including shorter OS and RFS in all patients, especially those with early stage breast cancer. In vitro studies showed B3GALT5 could enhance cell migration, invasion, mammosphere formation, and EMT. Of note, B3GALT5 upregulated the expression of β-catenin and EMT activator zinc finger E-box binding homeobox 1 (ZEB1) pathway in BCSCs. In vivo studies showed B3GALT5 expression in BCSCs is critical for not only tumor growth but also lymph node and lung metastasis in PDX mice.

Conclusion

Our results demonstrated the value of B3GALT5 as a prognostic marker of breast cancer, especially among the early stage patients, and its crucial roles in regulating EMT, cell migration, and stemness thereby promoting breast cancer progression.
HiDeF: identifying persistent structures in multiscale ‘omics data
Authors: Zheng Fan , Zhang She , Churas Christopher , Pratt Dexter , Bahar Ivet , Ideker Trey
Published: January 2021

In any ‘omics study, the scale of analysis can dramatically affect the outcome. For instance, when clustering single-cell transcriptomes, is the analysis tuned to discover broad or specific cell types? Likewise, protein communities revealed from protein networks can vary widely in sizes depending on the method. Here, we use the concept of persistent homology, drawn from mathematical topology, to identify robust structures in data at all scales simultaneously. Application to mouse single-cell transcriptomes significantly expands the catalog of identified cell types, while analysis of SARS-COV-2 protein interactions suggests hijacking of WNT. The method, HiDeF, is available via Python and Cytoscape.
Quantitative profiling of N6-methyladenosine at single-base resolution in stem-differentiating xylem of Populus trichocarpa using Nanopore direct RNA sequencing
Authors: Gao Yubang , Liu Xuqing , Wu Bizhi , Wang Huihui , Xi Feihu , Kohnen Markus V. , Reddy Anireddy S. N. , Gu Lianfeng
Published: January 2021

There are no comprehensive methods to identifyN6-methyladenosine (m6A) at single-base resolution for every single transcript, which is necessary for the estimation of m6A abundance. We develop a new pipeline called Nanom6A for the identification and quantification of m6A modification at single-base resolution using Nanopore direct RNA sequencing based on an XGBoost model. We validate our method using methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and m6A-sensitive RNA-endoribonuclease–facilitated sequencing (m6A-REF-seq), confirming high accuracy. Using this method, we provide a transcriptome-wide quantification of m6A modification in stem-differentiating xylem and reveal that different alternative polyadenylation (APA) usage shows a different ratio of m6A.
Efficacy of acupuncture for sciatica: study protocol for a randomized controlled pilot trial
Authors: Yu Fang-Ting , Ni Guang-Xia , Cai Guo-Wei , Wan Wen-Jun , Zhou Xiao-Qing , Meng Xiu-Li , Li Jin-Ling , Tu Jian-Feng , Wang Li-Qiong , Yang Jing-Wen , Fu Hai-Yang , Zhang Xin-Chang , Li Jing , Wang Yan-Fu , Zhang Beng , Zhang Xiao-Hui , Zhang Hao-Lin , Shi Guang-Xia , Liu Cun-Zhi
Published: January 2021

Background

Acupuncture is widely used for pain diseases while evidence of its efficacy for sciatica is insufficient. We aim to explore the feasibility and efficacy of acupuncture with different acupoint selecting strategies for sciatica induced by lumbar disc herniation.

Methods

This is a multicenter, three-arm, patient-assessor-blinded randomized controlled pilot trial. Ninety patients will be assigned randomly into 3 groups including disease-affected meridians (DAM) group, non-affected meridians (NAM) group, and sham acupuncture (SA) group in a 1:1:1 ratio. The trial involves a 4-week treatment along with follow-up for 22 weeks. The primary outcome is the change of leg pain intensity measured by the visual analogue scale (VAS) from baseline to week 4 after randomization. Secondary outcomes include functional status, back pain intensity, and quality of life. Adverse events will also be recorded.

Discussion

The results will inspire the optimal acupuncture strategy for sciatica and help establish a better design as well as power calculation for a full-scale study.

Trial registration

ChiCTR2000030680(Chinese Clinical Trial Registry,http://www.chictr.org.cn, registered on 9 March 2020).