bluuebunny/crossref_metadata_2025 huggingface dataset:
Pig farmers have signs of bronchial inflammation and increased numbers of lymphocytes and neutrophils in BAL fluid
Authors: Pedersen B , Iversen M , Bundgaard Larsen B , Dahl R
Published: November 2022

The purpose of this study was to investigate whether pig farmers had inflammation of the bronchial mucosa and activation of bronchoalveolar lavage (BAL) cells. Pig farmers are exposed to high dust levels and have a prevalence of work-related respiratory symptoms. Bronchoscopy and BAL were performed in 27 young large-scale pig farmers, who had never smoked. Fifty three lifetime nonsmoking healthy students participated as controls. All farmers and controls had normal lung function (forced expiratory volume in one second (FEV1) 109 and 105% predicted respectively. Estimation of macroscopic signs of inflammation in the bronchi (erythema, oedema, secretion and friability) showed that pig farmers had significantly increased signs of inflammation. The median score was 3 (range 0-6) compared to a median score of 0 (range 0-3) in controls. More pig farmers than controls (41 versus 25%) had a positive histamine challenge (provocative dose producing a 20% fall in FEV1 (PC20) < or = 32 mg.mL-1) but the difference was not significant. The cell concentration in BAL fluid was identical in the two groups. Pig farmers had a significantly increased percentage of lymphocytes (median 7, range 1-27 versus median 2, range 0-7) and neutrophils (median 2, range 0-30 versus median 1, range 0-4) compared to controls. Spontaneous migration (19.8 versus 5.5 microns) and chemotaxis (62.6 versus 11.2 microns) was significantly increased in pig farmers compared to controls. After stimulation with zymosan and phorbol myristrate acetate (PMA), the reactive oxygen radical generation of purified alveolar macrophages was also significantly increased in pig farmers. Lifetime nonsmoking pig farmers with normal lung function have macroscopic signs of bronchial inflammation and an increased number of neutrophils in bronchoalveolar lavage. Their alveolar macrophages showed biological signs of activation. The inflammation of pig farmers bronchi may be early signs of bronchitis.
Development of doped ZnO-based biomimicking and tumor-targeted nanotheranostics to improve pancreatic cancer treatment
Authors: Barui Sugata , Percivalle Nicolò Maria , Conte Marzia , Dumontel Bianca , Racca Luisa , Carofiglio Marco , Cauda Valentina
Published: November 2022

Despite different nanomaterials were developed so far against cancer, their potential drawbacks are still scarcely considered. The off-target delivery of a therapeutic compound, as well as the non-specific uptake of these nanomaterials by healthy tissues or organs, and their potential immunogenicity are some of the major issues that still have to be faced prior to a successful clinical translation. This work aims to develop an innovative theranostic, biocompatible, and drug-loaded nanoconstruct based on Gadolinium-doped Zinc Oxide (ZnO-Gd) nanocrystals (NCs), focusing on one of the most lethal diseases, i.e., pancreatic cancer. The use of zinc oxide is motivated by the huge potential of this nanomaterial already demonstrated for in vitro and in vivo applications, while the Gadolinium doping confers magnetic properties useful for diagnostics. Furthermore, an innovative biomimetic shell is here used to coat the NCs: it is composed of a lipid bilayer made from extracellular vesicles (EVs) combined with other synthetic lipids and a peptide targeting the pancreatic tumor microenvironment. To complete the nanoconstruct therapeutic function, Gemcitabine, a first-line drug for pancreatic cancer treatment, was adsorbed on the ZnO-Gd NCs prior to the coating with the above-mentioned lipidic shell. The aim of this work is thus to strongly enhance the therapeutic capability of the final nanoconstruct, providing it with high biocompatibility, colloidal stability in biological media, efficient cargo loading and release properties, as well as active targeting for site-selective drug delivery. Furthermore, the magnetic properties of the ZnO-Gd NCs core can in future allow efficient in situ bioimaging capabilities based on Magnetic Resonance Imaging technique. The obtained nanoconstructs were tested on two different pancreatic cancer cell lines, i.e., BxPC-3 and the metastatic AsPC-1, proving high cell internalization levels, mediated by the targeting peptide exposed on the nanoconstruct. Cellular cytotoxicity assay performed on both cell lines dictated ~ 20% increased cell killing efficacy of Gemcitabine when delivered through the nanoconstruct rather than as a free drug. Taken together, our designed theranostic nanoconstruct can have a significant impact on the standard treatment of pancreatic cancer.
Assessing soil microbes that drive fairy ring patterns in temperate semiarid grasslands
Authors: Li Jiahuan , Guo Lizhu , Wilson Gail W. T. , Cobb Adam B. , Wang Kun , Liu Li , Zhao Huan , Huang Ding
Published: November 2022

Background

Fairy rings occur in diverse global biomes; however, there is a critical knowledge gap regarding drivers of fairy rings in grassland ecosystems. Grassland fairy rings are characterized belowground by an expanding mycelial front and aboveground by vigorous vegetation rings that develop concentrically with each growing season. We evaluated fairy ring dynamics in a field study conducted in semiarid grasslands to elucidate above- and belowground interactions driving distinct vegetation patterns. We followed this initial field investigation with a complementary greenhouse experiment, using soils collected from specific fairy ring zones (inside, ring-edge, outside) to examine plant-soil-microbial interactions under controlled conditions. We selected Leymus chinensis (a dominant grass) as our model plant species to assess the role of diverse fairy ring microbial communities on plant growth and nutrition.

Results

In our field study, plants on the ring-edge produced greater shoot biomass with higher concentrations of N and P, compared to plants inside the ring or adjacent (outside) controls. Soil microbial community biomarkers indicate shifts in relative microbial biomass as fairy rings expand. Inside the ring, plant roots showed greater damage from pathogenic fungi, compared to outside or ring-edge. Our greenhouse experiment confirmed that inoculation with live ring-edge soil generally promoted plant growth but decreased shoot P concentration. Inoculation with soil collected from inside the ring increased root pathogen infection and reduced shoot biomass.

Conclusion

We propose that soil microbial activity within ring-edges promotes plant growth via mobilization of plant-available P or directed stimulation. However, as the ring expands, L. chinensis at the leading edge may increase pathogen accumulation, resulting in reduced growth at the center of the ring in subsequent growing seasons. Our results provide new insights into the plant-soil-microbial dynamics of fairy rings in grasslands, helping to elucidate these mysterious vegetation patterns.
Characteristics of population structure, antimicrobial resistance, virulence factors, and morphology of methicillin-resistant Macrococcus caseolyticus in global clades
Authors: Zhang Yu , Min Shengyi , Sun Yuxuan , Ye Jiaquan , Zhou Zhemin , Li Heng
Published: November 2022

Macrococcus caseolyticus is an opportunistic pathogen that is frequently isolated from dairy products and veterinary infections. Recent studies have reported the possibility of methicillin resistance that be transferred among staphylococcal species in foods. The present study examined the population structure, antimicrobial resistance, virulence factors, and morphology of methicillin-resistant M. caseolyticus by investigation of 94 genomes derived from both isolates in beef (n = 7) and pork (n = 2) at Shanghai and those deposited in public domain (n = 85). Phylogenetically, M. caseolyticus were divided into four clades, which each consisted of genomes isolated from continent of European countries (82.4%, n = 78), Asian countries (11.3%, n = 10), United States (4.1%, n = 4), Australia (1%, n = 1), and Sudan (1%, n = 1). The M. caseolyticus isolated from present study formed a genetically distinguished clade, which was characterized by novel alleles in the traditional 7-gene MLST scheme. Furthermore, we identified 24 AMR genes that were associated with 10 classes of antimicrobial agents in M. caseolyticus. Most AMR genes were carried by dominant plasmids such as rep7a, rep22 and repUS56. The genomes in the global clades carried significantly less AMR genes (p < 0.05) and more virulence factors (p < 0.001) than present clade. Virulence factors were detected in methicillin resistant M. caseolyticus including genes coding hemolysin, adherence, biofilm formation, exotoxin, and capsule that associated to human health and infection. Finally, as the close relative of the genus Staphylococcus, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were performed for morphological comparison that M. caseolyticus has a larger diameter and thicker cell wall compared with S. aureus ATCC 25,923. Taken together, our study suggested that M. caseolyticus mediating divergent antimicrobial resistance and virulence factors could serve as the vector for methicillin resistance habitats in foodborne microorganisms.
Cholesterol efflux regulator ABCA1 exerts protective role against high shear stress-induced injury of HBMECs via regulating PI3K/Akt/eNOS signaling
Authors: Li Zhe , Li Jia-Nan , Li Qiang , Liu Chun , Zhou Lin-Hua , Zhang Qi , Xu Yi
Published: November 2022

Background

In brain, microvascular endothelial cells are exposed to various forces, including shear stress (SS). However, little is known about the effects of high shear stress (HSS) on human brain microvascular endothelial cells (HBMECs) and the underlying mechanism. The cholesterol efflux regulator ATP-binding cassette subfamily A member 1 (ABCA1) has been demonstrated to exert protective effect on HBMECs. However, whether ABCA1 is involved in the mechanism underneath the effect of HSS on HBMECs remains obscure. In the present study, a series of experiments were performed to better understand the effect of HSS on cellular processes of HBMECs and the possible involvement of ABCA1 and PI3K/Akt/eNOS in the underlying mechanisms.

Results

HBMECs were subjected to physiological SS (PSS) or high SS (HSS). Cell migration was evaluated using Transwell assay. Apoptotic HBMECs were detected by flow cytometry or caspase3/7 activity. IL-1β, IL-6, MCP-1 and TNF-α levels were measured by ELISA. RT-qPCR and western blotting were used for mRNA and protein expression detection, respectively. ROS and NO levels were detected using specific detection kits. Compared to PSS, HBMECs exhibited decreased cell viability and migration and increased cell apoptosis, increased levels of inflammatory cytokines, and improved ROS and NO productions after HSS treatment. Moreover, HSS downregulated ABCA1 but upregulated the cholesterol efflux-related proteins MMP9, AQP4, and CYP46 and activated PI3K/Akt/eNOS pathway. Overexpression of ABCA1 in HBMECS inhibited PI3K/Akt/eNOS pathway and counteracted the deleterious effects of HSS. Contrary effects were observed by ABCA1 silencing. Inhibiting PI3K/Akt/eNOS pathway mimicked ABCA1 effects, suggesting that ABCA1 protects HBMECs from HSS via PI3K/Akt/eNOS signaling.

Conclusion

These results advanced our understanding on the mechanisms of HSS on HBMECs and potentiated ABCA1/PI3K/Akt/eNOS pathway as therapeutic target for cerebrovascular diseases.
Real-world data: a brief review of the methods, applications, challenges and opportunities
Authors: Liu Fang , Panagiotakos Demosthenes
Published: November 2022

Background

The increased adoption of the internet, social media, wearable devices, e-health services, and other technology-driven services in medicine and healthcare has led to the rapid generation of various types of digital data, providing a valuable data source beyond the confines of traditional clinical trials, epidemiological studies, and lab-based experiments.

Methods

We provide a brief overview on the type and sources of real-world data and the common models and approaches to utilize and analyze real-world data. We discuss the challenges and opportunities of using real-world data for evidence-based decision making This review does not aim to be comprehensive or cover all aspects of the intriguing topic on RWD (from both the research and practical perspectives) but serves as a primer and provides useful sources for readers who interested in this topic.

Results and Conclusions

Real-world hold great potential for generating real-world evidence for designing and conducting confirmatory trials and answering questions that may not be addressed otherwise. The voluminosity and complexity of real-world data also call for development of more appropriate, sophisticated, and innovative data processing and analysis techniques while maintaining scientific rigor in research findings, and attentions to data ethics to harness the power of real-world data.
Applying the 4Ps of social marketing to retain and engage participants in longitudinal cohort studies: generation 2 Raine study participant perspectives
Authors: Costello Leesa , Dare Julie , Dontje Manon , Lambert Claire , Straker Leon
Published: November 2022

Background

Investigations of participant retention in longitudinal health and medical research, document  strategies that work best but overlook social marketing’s capacity to influence participant retention. After applying the social marketing framework: the idea that determining what longitudinal participants ‘buy’ (product), at what cost (price), in what location (place) and through which communication channels (promotion),  this paper  aims to inform and enhance retention efforts.

Methods

This qualitative study was conducted through in-depth interviews with participants from the Raine Study that began in Western Australia in 1989. The Generation 2 participants, initially enrolled into the Raine Study as babies by their parents (Generation 1), are now young adults invited to attend follow-up studies and tests every few years. Our study defined ‘active’ participants (n = 17) as those who agreed to attend their 27 year follow-up, and ‘inactive’ (n = 12) participants as those who had attended neither of the past two follow-ups (22 and 27 years).

Results

Raine Study participants experienced core, actual and augmented product benefits. Inactive participants focused on the costs (price) associated with participation, and were more likely to suggest tele-health (place) strategies to overcome barriers to follow-up attendance. Both active and inactive participants found professional processes and friendly staff made the Raine Study environment appealing, suggested that social media (promotion) was underutilised, and offered novel ideas to enhance engagement.

Conclusions

Social marketing can support the development of differentiated strategies addressing the unique needs and wants of active and inactive participants. Sophisticated cohort segmentation can reach participants in a more meaningful way, reinforce the study ‘brand’ and guard against attrition.
Survival nomograms for colorectal carcinoma patients with lung metastasis and lung-only metastasis, based on the SEER database and a single-center external validation cohort
Authors: Liu Lin-Lin , Sun Jun-Die , Xiang Zuo-Lin
Published: November 2022

Background

We analysed the survival of colorectal cancer (CRC) patients with lung metastasis and lung-only metastasis and determined the risk factors for lung metastasis in CRC patients.

Methods

Data from colorectal cancer patients with lung metastasis diagnosed from 2010 to 2015 were obtained from the SEER database. Survival was analysed using the Kaplan–Meier method and log-rank test, the Cox proportional hazards regression model, and a competing risk model. The predictive ability of the nomgram was assessed by the concordance index (C-index) and calibration curves. The data from the SEER database for the period 2016–2019 was used as an external validation set. The characteristics of 70 CRC patients treated at Shanghai East Hospital between 2016 and 2019 were retrospectively analysed and data from China was chosen as an external validation set.

Results

The median survival time for colorectal cancer patients with lung metastasis was 12 months, while this value was 24 months in patients with lung-only metastasis. Among all CRC patients with lung metastasis, age, grade, T stage, N stage, presence of liver, brain or bone metastasis, anatomic site and surgery were related to overall survival (OS). In CRC patients with lung-only metastasis, age, T stage, marital status, chemotherapy and surgery were independent prognostic factors affecting OS. Two nomograms predicting OS were established, with great discrimination (C-index between 0.67 and 0.81) and excellent calibration. Factors including age, race, sex, tumour grade, T stage, N stage, presence of liver, brain or bone metastasis, marital status, insurance status and anatomic location were related to the occurrence of lung metastasis in CRC patients.

Conclusion

We developed two reliable clinical prediction models among CRC patients to predict the OS rates in patients with lung metastasis and lung metastasis only.
Whether surgical resection or biopsy makes difference in single lesion primary central nervous system lymphoma: a single center retrospective cohort study
Authors: Cheng Xin , Chen Haoran , Sun Chongran , Zhang Buyi , Zhang Jianmin , Wang Yongjie
Published: November 2022

Background

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease. The role of surgical resection in PCNSL has always been the center of debate. Here we investigated the clinical and follow-up data of single lesion PCNSL operated in our center, focusing on the comparison between surgical resection and biopsy.

Methods

All consecutive cases of single lesion PCNSL between October 2004 and December 2019 were retrospectively collected from the database of the Second Affiliated Hospital of Zhejiang University, School of Medicine. Patients were divided into resection group and biopsy group. Clinical information including age, gender, Karnofsky performance status, imaging features and postoperative treatment was collected from the medical records. All the patients were followed for survival analysis.

Results

A total of 105 patients with PCNSL were finally involved in our analysis. Neither PFS nor OS were significantly different between the resection group and biopsy group. The univariate analysis revealed that age < 60 and therapeutic treatment were significant predictors of longer PFS and OS. In the multivariate analysis, age (HR = 3.09, 95% CI 1.31–7.28, p = 0.01) and therapeutic treatment (HR = 0.25, 95% CI 0.07– 0.83, p = 0.02) were independent prognostic markers with OS. Multivariable Cox regression analyses also revealed that only age (HR = 2.29 (95% CI, 1.11–4.71, p = 0.03) was independent prognostic marker for PFS.

Conclusions

In single lesion PCNSL, there was no significant difference between the resection group and biopsy group for both PFS and OS. Younger age and postoperative treatment have been proved to be indicators of better prognosis.
Non-booking for antenatal care and risks for vertical HIV transmission among women in Chitungwiza, Zimbabwe: a cross-sectional study
Authors: Mandima Patricia , Schaay Nikki , Ngara Bernard , Lembani Martina
Published: November 2022

Background

The success of prevention of mother to child transmission of HIV (PMTCT) programs dependents on pregnant women accessing antenatal care (ANC) services. Failure to access ANC throughout the course of pregnancy presents a missed opportunity to fully utilize PMTCT services and a high risk for vertical HIV transmission. Whilst not booking for ANC was about 6% in Zimbabwe, according to the 2015 Zimbabwe Demographic and Health Survey, it is important to determine the local burden of pregnant women both un-booked for ANC and living with HIV. in Chitungwiza city, to inform local response. This study aimed at determining the proportion of women un-booked for antenatal care and among them, the proportion of women who were with HIV and to identify risk factors associated with not-booking for ANC in Chitungwiza city in Zimbabwe.

Methods

A cross-sectional study was conducted involving a review of clinic records for 4400 women who received postnatal care at all 4 maternity clinics in Chitungwiza city between 01 January 2017 and 31 December 2017. Bivariate and multiple logistic regression analysis with Chi squared test were used to determine risk factors associated with booking status while adjusting for other study variables. All statistics tests’ decisions were concluded at 5% level of significance. All data analysis was performed using STATA (version 13) statistical package.

Results

A total of 4400 women were attended to and of these, 19% were un-booked for ANC, while a total of 3% of the women were both un-booked and living with HIV. The women with HIV were 0.24 times less likely to book for ANC than HIV negative women, adjusted OR = 0.76 (95% CI: 0.61–0.98). Women aged 20–34 years were 1.3 times more likely to book than the teenagers, adjusted OR = 1.3 (95% CI: 1.04–1.62).

Conclusion

The proportion of women not booked for ANC of 19% was unexpectedly high. With 3% of pregnant women in Chitungwiza having both HIV and no access to ANC, the risk for vertical HIV transmission remains. More need to be done to improve ANC access, targeting teenage mothers and those living with HIV who are more less likely to access ANC.
Combined atezolizumab and nab-paclitaxel in the treatment of triple negative breast cancer: a meta-analysis on their efficacy and safety
Authors: Sharmni Vishnu K. , Win Thin Thin , Aye Saint Nway , Basavaraj Arun Kumar
Published: November 2022

Background

Triple negative breast cancer (TNBC) is clinically aggressive breast cancer with a poor prognosis. Approximately 20% of TNBC has been found to express programmed death ligand 1 (PD-L1), making it a potential therapeutic target. As a PD-L1 inhibitor, atezolizumab is a recently approved immunotherapeutic drug for TNBC, this meta-analysis (MA) was aimed to review the randomized controlled trial studies (RCTs) of combined atezolizumab and nab-paclitaxel in the treatment of TNBC and synthesize the evidence-based results on its effectiveness and safety.

Method

We searched PubMed, Embase, EBSCOhost and ClinicalTrials.gov for the eligible RCTs which compared the efficacy and safety of combined atezolizumab and nab-paclitaxel with nab-paclitaxel alone. The outcomes analyzed included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse effects (AEs).

Results

A total of six RCTs were included in this MA. For efficacy, although OS was not significantly prolonged with combined atezolizumab and nab-paclitaxel (HR 0.90, 95% CI [0.79, 1.01], p=0.08), this combination therapy significantly improved PFS (HR 0.72, 95% CI [0.59, 0.87], p=0.0006) and ORR (RR 1.25, 95% CI [0.79, 1.01] p<0.00001). For safety, any AEs, haematological, gastrointestinal, and liver AEs showed no statistically significant differences between the atezolizumab and nab-paclitaxel combination group and nab-paclitaxel alone group. However, serious AEs, high grade, dermatological, pulmonary, endocrine, and neurological AEs were significantly lower with nab-paclitaxel alone compared to atezolizumab and nab-paclitaxel combined (p-value range from <0.00001 to 0,02).

Conclusion

Atezolizumab combined with nab-paclitaxel was associated with improved outcomes in the treatment of TNBC; however, this combination resulted in more toxicity compared to nab-paclitaxel alone. While nab-paclitaxel alone produced chemotherapy-related AEs, the combination of atezolizumab with nab-paclitaxel produced AEs, especially immune-related AEs such as haematological, pulmonary, endocrine, and neurological AEs.

Trial registration

This research work of systematic review has been registered on PROSPERO (Registration number: CRD42022297952).
Childhood immunization and age-appropriate vaccinations in Indonesia
Authors: Chu Hoi , Rammohan Anu
Published: November 2022

Background

Childhood immunization is a cost-effective way to protect individuals against communicable diseases. However, although there is a large literature on childhood immunization in Indonesia, there is a paucity of research on the age-appropriateness on measles and DTwP-3 vaccination, and the inequities in immunization coverage across Indonesia.

Methods

In this paper, using seven waves of data from the nationally representative Indonesia Demographic and Health Surveys (DHS) covering the period 1991- 2017, we empirically analyse the socio-economic and demographic factors influencing the uptake of four routine vaccines (BCG, Polio-3, DTwP-3, and Measles). Specifically, using multivariate regression analysis, we identify the socio-economic and demographic factors influencing childhood immunization coverage. We further analyse the socio-economic and demographic correlates of the age-appropriateness of the measles and DTwP-3 vaccination coverage.

Results

Our findings show that parental education and use of healthcare services are strong predictors of full immunization and age-appropriate vaccinations. This study also finds evidence of spatial heterogeneity in both full immunization rates and age-appropriate vaccinations for measles and DTwP-3 vaccines.

Conclusions

Our analysis finds that despite an improvement in the timing of vaccinations over the last two decades, a significant proportion of children continue to receive their measles and DTwP vaccinations age inappropriately. In particular, we find that maternal education and maternal engagement with healthcare services are critical in improving age appropriateness of vaccinations. From a policy perspective, these results call for concerted efforts by policy makers to address regional gaps in access to health services and immunization coverage, as well as to improve the age-appropriateness of vaccination.
Quality and accuracy of gastric cancer related videos in social media videos platforms
Authors: Hu Ren-hao , Zhang Hai-bin , Yuan Biao , Zhang Ke-hui , Xu Jia-yi , Cui Xi-mao , Du Tao , Song Chun , Zhang Shun , Jiang Xiao-hua
Published: November 2022

Background

Gastric cancer is a major public health problem worldwide. Social media has affected public’s daily lives in ways no one ever thought possible. Both TikoTok and its Chinese version Douyin are the most popular short video posting platform. This study aimed to evaluate the quality, accuracy, and completeness of videos for gastric cancer on TikTok and Douyin.

Methods

The terms “gastric cancer” was searched on TikTok in both English and Japanese, and on Douyin in Chinese. The first 100 videos in three languages (website’s default setting) were checked. QUality Evaluation Scoring Tool (QUEST) and DISCERN as the instrument for assessing the quality of the information in each video. Content was analysed under six categories (aetiology, anatomy, symptoms, preventions, treatments, and prognosis). The educational value and completeness were evaluated with a checklist developed by the researchers.

Results

A total of 78 videos in English, 63 in Japanese, and 99 in Chinese were analyzed. The types of sources were as follows: 6.4% in English, 4.8% in Japanese, and 57.6% in Chinese for health professionals; 93.6% in English, 95.2% in Japanese, and 3.0% in Chinese for private users; none in English and Japanese, but 39.4% in Chinese for other sources. In all, 20.5% in English, 17.5% in Japanese, and 93.9% in Chinese of videos had useful information about gastric cancer. Among the useful videos, the videos published in Chinese had the highest QUEST(p < 0.05) and DISCERN scores(p < 0.05), followed by those published in Japanese. Among the educational videos, prognosis in English (37.5%), symptoms in Japanese (54.5%), and prevention in Chinese (47.3%) were the most frequently covered topic.

Conclusions

TikTok in English and Japanese might not fully meet the gastric cancer information needs of public, but Douyin in Chinese was the opposite.
HMG20A was identified as a key enhancer driver associated with DNA damage repair in oral squamous cell carcinomas
Authors: Na Li , Meijie Zhang , Wenjing Zhai , Bing Zhou , Yanhao Duan , Shanshan Liu , Yongle Qiu
Published: November 2022

Background

Oral squamous cell carcinoma (OSCC) is the main type of oral cancer. Disturbing DNA repair is an invaluable way to improve the effectiveness of tumor treatment. Here, we aimed to explore the key enhancer drivers associated with DNA damage repair in OSCC cells.

Methods

Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA) and Kaplan-Meier analysis were applied to explore the relationship among DNA repair-related genes expression and clinical phenotypes based on The Cancer Genome Atlas (TCGA) database. HOMER software and Integrative Genomics Viewer were applied to identify and visualize enhancers using GSE120634. Toolkit for Cistrome Data Browser was applied to predict transcription factors. Human Protein Atlas Database was used to analyze the protein levels of transcription factors in OSCC and control tissues. Seventy-two OSCC patients were included in this study. qRT-PCR was used to detect transcription factor expression in OSCC and adjacent control tissues collected in this study. qRT-PCR and ChIP-qPCR were used to verify the binding of transcription factors to enhancers, and regulation of target genes transcription. Transcription factor knockdown and control cells were treated with cisplatin. CCK8 was used to detect cell viability and proliferation. Western blotting was implemented to detect the levels of DNA repair-related proteins. Transwell assay was used to detect cell invasion.

Results

DNA repair was positively associated with the OSCC metastatic phenotype. Patients in the cluster with high expression of DNA repair-related genes had a worse prognosis and a higher proportion of advanced stage, low-differentiation, alcohol consumption and smoking compared to the cluster with low DNA repair-related gene expression. Seventeen metastasis-specific enhancer-controlled upregulated DNA repair-related genes, with the top two upregulated genes being ADRM1 26 S proteasome ubiquitin receptor (ADRM1) and solute carrier family 12 member 7 (SLC12A7) were screened. High mobility group 20 A (HMG20A) was the key prognostic enhancer driver regulating metastasis-specific DNA repair-related genes, with higher expression in OSCC tissues than normal control tissues, and higher expression in metastatic OSCC tissues than non-metastatic OSCC tissues. HMG20A bound to the metastasis-specific enhancers of ADRM1 and SLC12A7, thereby promoting ADRM1 and SLC12A7 expression. Knockdown of HMG20A enhanced cisplatin sensitivity of cells, and inhibited OSCC cells from repairing DNA damage caused by cisplatin, as well as proliferation and invasion of OSCC cells.

Conclusion

HMG20A was identified as the key prognostic enhancer driver regulating DNA repair in OSCC cells, providing a new therapeutic target for OSCC.
The end of life experiences of people living with socio-economic deprivation in the developed world: an integrative review
Authors: Bowers Sarah P , Chin Ming , O’Riordan Maire , Carduff Emma
Published: November 2022

Background

Those experiencing socioeconomic deprivation have poorer quality of health throughout their life course which can result in poorer quality of death – with decreased access to palliative care services, greater use of acute care, and reduced access to preferred place of care compared with patients from less deprived populations.

Aim

To summarise the current global evidence from developed countries on end-of-life experience for those living with socio-economic deprivation.

Design

Integrative review in accordance with PRISMA.A thorough search of major databases from 2010–2020, using clear definitions of end-of-life care and well-established proxy indicators of socio-economic deprivation. Empirical research describing experience of adult patients in the last year of life care were included.

Results

Forty studies were included from a total of 3508 after screening and selection. These were deemed to be of high quality; from a wide range of countries with varying healthcare systems; and encompassed all palliative care settings for patients with malignant and non-malignant diagnoses. Three global themes were identified: 1) multi-dimensional symptom burden, 2) preferences and planning and 3) health and social care interactions at the end of life.

Conclusions

Current models of healthcare services are not meeting the needs of those experiencing socioeconomic deprivation at the end-of-life. Further work is needed to understand the disparity in care, particularly around ensuring patients voices are heard and can influence service development and delivery.
Numeric and morphological studies of the African lion (Panthera leo leo) pectoral limb
Authors: Onwuama Kenechukwu Tobechukwu , Kigir Esther Solomon , Jaji Alhaji Zubair , Salami Suleiman Olawoye
Published: November 2022

Background

The Importance of the appendicular skeleton in the conformation, shape and physiology of wild animals especially carnivores for adaptation and survival cannot be overemphasized, as limited and obsolete information on the bones of the forelimb necessitated this study. Matured adult African lions (Male and female) that weighed 173 kg and 112 kg were obtained at different times after post mortem examinations of their carcasses. Bone preparation was achieved via cold water maceration after proper skin and muscle removal to a barest minimum.

Results

The acromion process of the scapula consisted of a ventral hamate and caudal suprahamate processes. The Clavicle was absent in this species. The musculospiral groove of the humerus was more or less absent while its supracondyloid foramen and crest were positioned above the medial condyle and lateral condyle respectively. The radio-ulna presented a twisted appearance with the radius slightly curved thereby creating an extensive interosseous space that spanned its entire length. The seven (7) carpal bones were uniquely arranged in two rows while the 5 metacarpals anchored 5 digits with 3 phalanges except the first with 2 phalanges each. Two sesamoid bones were located on the ventral surface of each Metacarpophalangeal joint. None was seen on its dorsal surface. The 3rd phalanx had a unique appearance with a crescent plate projecting from the ventral cavity. The average total number of bones constituting the pectoral limb was 80.

Conclusion

Numerical information and detailed anatomical features of the pectoral limb bones of the African lion (Panthera leo leo) have added some valuable literature to science. This further serves as a baseline data for future scientific exposition on this species.
Distribution and concordance of PD-L1 expression by routine 22C3 assays in East-Asian patients with non-small cell lung cancer
Authors: Fu Fangqiu , Deng Chaoqiang , Sun Wenrui , Zheng Qiang , Jin Yan , Li Yuan , Zhang Yang , Chen Haiquan
Published: November 2022

Background

Currently, programmed death ligand-1 (PD-L1) expression has been widely applied in clinical trials and real-world clinical practice as a major biomarker for the efficacy of immune-checkpoint inhibitors. The purpose of this study is to reveal the distribution and concordance of PD-L1 expression in a large-scale consecutive cohort from East-Asian patients with non-small cell lung cancer (NSCLC).

Methods

PD-L1 testing was conducted using 22C3 assays, and cases were categorized into the high, low, and no expression of PD-L1 based on the tumor proportion score (TPS). Target-capture next-generation sequencing was used to identify molecular events.

Results

A total of 4550 patients and 4622 tests of PD-L1 expression were enrolled. There were 3017 (66.3%) patients with no PD-L1 expression (TPS < 1%), 1013 (22.3%) with low PD-L1 expression (TPS 1–49%), 520 (11.4%) with high PD-L1 expression (TPS ≥ 50%). Higher proportions of positive PD-L1 expression (TPS ≥ 1%) were observed in smokers, males, squamous cell carcinoma, and high-grade lung adenocarcinoma. Further analyses revealed fair agreement in primary and metastatic lesions (kappa = 0.533), poor agreement in multi-focal primary tumors (kappa = 0.045), and good agreement in biopsy and resection samples (kappa = 0.662) / two biopsy samples (kappa = 0.711). Mutational analyses revealed association between high PD-L1 expression (TPS ≥ 50%) and EGFR wild-type, KRAS mutation, ALK rearrangement, and TP53 mutation.

Conclusion

The study reveals the unique distribution pattern of PD-L1 expression in a large-scale East-Asian cohort with NSCLC, the concordance of multiple PD-L1 tests, and the association between PD-L1 expression and molecular events. The results shed a light on the optimization of PD-L1 testing in clinical practice.
High levels of soluble RAGE are associated with a greater risk of mortality in COVID-19 patients treated with dexamethasone
Authors: Butcher Lee , Zaldua Jun-Cezar , Carnicero Jose A. , Hawkins Karl , Whitley Janet , Mothukuri Rangaswamy , Evans Phillip A. , Morris Keith , Pillai Suresh , Erusalimsky Jorge D.
Published: November 2022

Blood levels of the soluble receptor for advanced glycation end-products (sRAGE) are acutely elevated during the host inflammatory response to infection and predict mortality in COVID-19. However, the prognostic performance of this biomarker in the context of treatments to reduce inflammation is unclear. In this study we investigated the association between sRAGE and mortality in dexamethasone-treated COVID-19 patients. We studied 89 SARS-CoV-2 positive subjects and 22 controls attending the emergency department of a University Teaching Hospital during the second wave of COVID-19 and measured sRAGE at admission. In positive individuals sRAGE increased with disease severity and correlated with the National Early Warning Score 2 (Pearson’s r = 0.56, p < 0.001). Fourteen out of 72 patients treated with dexamethasone died during 28 days of follow-up. Survival rates were significantly lower in patients with high sRAGE (> 3532 pg/mL) than in those with low sRAGE (p = 0.01). Higher sRAGE levels were associated with an increased risk of death after adjustment for relevant covariates. In contrast, IL-6 did not predict mortality in these patients. These results demonstrate that sRAGE remains an independent predictor of mortality among COVID-19 patients treated with dexamethasone. Determination of sRAGE could be useful for the clinical management of this patient population.
Synergistic effect of chronic kidney disease, neuropathy, and retinopathy on all-cause mortality in type 1 and type 2 diabetes: a 21-year longitudinal study
Authors: Sacchetta Luca , Chiriacò Martina , Nesti Lorenzo , Leonetti Simone , Forotti Giovanna , Natali Andrea , Solini Anna , Tricò Domenico
Published: November 2022

Background

The prognostic value of common and frequently associated diabetic microvascular complications (MVC), namely chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), peripheral neuropathy (DPN), and retinopathy (DR), is well established. However, the impact of their different combinations on long-term mortality has not been adequately assessed.

Methods

We retrospectively analyzed 21-year longitudinal data from 303 patients with long-standing type 1 (T1D) or type 2 diabetes (T2D), who were thoroughly characterized at baseline for the presence of MVC using 99mTc-DTPA dynamic renal scintigraphy, overnight urine collection, cardiovascular autonomic tests, monofilament testing, and dilated fundus oculi examination.

Results

After a 5,244 person-years follow-up, a total of 133 (43.9%) deaths occurred. The presence of CKD and CAN, regardless of other MVC, increased the adjusted all-cause mortality risk by 117% (HR 2.17 [1.45–3.26]) and 54% (HR 1.54 [1.01–2.36]), respectively. Concomitant CKD&CAN at baseline were associated with the highest mortality risk (HR 5.08 [2.52–10.26]), followed by CKD&DR (HR 2.95 [1.63–5.32]), and CAN&DR (HR 2.07 [1.11–3.85]). Compared with patients free from MVC, the mortality risk was only numerically higher in those with any isolated MVC (HR 1.52 [0.87–2.67]), while increased by 203% (HR 3.03 [1.62–5.68]) and 692% (HR 7.92 [2.93–21.37]) in patients with two and three concomitant MVC, respectively.

Conclusions

Our study demonstrates the long-term, synergistic, negative effects of single and concomitant diabetic MVC on all-cause mortality, which should encourage comprehensive screenings for MCV in both T1D and T2D to improve risk stratification and treatment.
Network meta-analysis on the effects of finerenone versus SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease
Authors: Zhang Yaofu , Jiang Li , Wang Junheng , Wang Tongxin , Chien Chieh , Huang Weijun , Fu Xiaozhe , Xiao Yonghua , Fu Qiang , Wang Shidong , Zhao Jinxi
Published: November 2022

Objective

To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis.

Methods

Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the two drugs and finerenone indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI).

Results

18 RCTs involving 51,496 patients were included. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal outcome and hospitalization for heart failure (HHF) (RR [95% CI]; 0.88 [0.80–0.97], 0.86 [0.79–0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95% CI]; 0.84 [0.78–0.90]), renal outcome (RR [95% CI]; 0.67 [0.60–0.74], HHF (RR [95% CI]; 0.60 [0.53–0.68]), all-cause death (ACD) (RR [95% CI]; 0.89 [0.81–0.91]) and cardiovascular death (CVD) (RR [95% CI]; 0.86 [0.77–0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95% CI]; 0.86 [0.78–0.94]). SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95% CI]; 1.29 [1.13–1.47], 1.31 [1.07–1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95% CI]; 1.36 [1.16–1.59], 1.49 [1.18–1.89], respectively) in renal outcome and HHF.

Conclusions

In patients with T2DM and CKD, SGLT2i, GLP-1 RA and finerenone were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significant effect in reducing cardiovascular events compared with exendin-4 analogues.
Specific triacylglycerol, diacylglycerol, and lyso-phosphatidylcholine species for the prediction of type 2 diabetes: a ~ 16-year prospective study in Chinese
Authors: Zhong Junda , Cheung Chloe Y. Y. , Su Xiuli , Lee Chi-Ho , Ru Yi , Fong Carol H. Y. , Liu Yan , Cheung Cynthia K. Y. , Lam Karen S. L. , Cai Zongwei , Xu Aimin
Published: November 2022

Background

Bioactive lipids play an important role in insulin secretion and sensitivity, contributing to the pathophysiology of type 2 diabetes (T2D). This study aimed to identify novel lipid species associated with incident T2D in a nested case–control study within a long-term prospective Chinese community-based cohort with a median follow-up of ~ 16 years.

Methods

Plasma samples from 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) were first analyzed using untargeted lipidomics. Potential predictive lipid species selected by the Boruta analysis were then verified by targeted lipidomics. The associations between these lipid species and incident T2D were assessed. Effects of novel lipid species on insulin secretion in mouse islets were investigated.

Results

Boruta analysis identified 16 potential lipid species. After adjustment for body mass index (BMI), triacylglycerol/high-density lipoprotein (TG/HDL) ratio and the presence of prediabetes, triacylglycerol (TG) 12:0_18:2_22:6, TG 16:0_11:1_18:2, TG 49:0, TG 51:1 and diacylglycerol (DG) 18:2_22:6 were independently associated with increased T2D risk, whereas lyso-phosphatidylcholine (LPC) O-16:0, LPC P-16:0, LPC O-18:0 and LPC 18:1 were independently associated with decreased T2D risk. Addition of the identified lipid species to the clinical prediction model, comprised of BMI, TG/HDL ratio and the presence of prediabetes, achieved a 3.8% improvement in the area under the receiver operating characteristics curve (AUROC) (p = 0.0026). Further functional study revealed that, LPC O-16:0 and LPC O-18:0 significantly potentiated glucose induced insulin secretion (GSIS) in a dose-dependent manner, whereas neither DG 18:2_22:6 nor TG 12:0_18:2_22:6 had any effect on GSIS.

Conclusions

Addition of the lipid species substantially improved the prediction of T2D beyond the model based on clinical risk factors. Decreased levels of LPC O-16:0 and LPC O-18:0 may contribute to the development of T2D via reduced insulin secretion.
Origin of the 3-methylglutaryl moiety in caprazamycin biosynthesis
Authors: Bär Daniel , Konetschny Benjamin , Kulik Andreas , Xu Houchao , Paccagnella Davide , Beller Patrick , Ziemert Nadine , Dickschat Jeroen S. , Gust Bertolt
Published: November 2022

Background

Caprazamycins are liponucleoside antibiotics showing bioactivity against Gram-positive bacteria including clinically relevant Mycobacterium tuberculosis by targeting the bacterial MraY-translocase. Their chemical structure contains a unique 3-methylglutaryl moiety which they only share with the closely related liposidomycins. Although the biosynthesis of caprazamycin is understood to some extent, the origin of 3-methylglutaryl-CoA for caprazamycin biosynthesis remains elusive.

Results

In this work, we demonstrate two pathways of the heterologous producer Streptomyces coelicolor M1154 capable of supplying 3-methylglutaryl-CoA: One is encoded by the caprazamycin gene cluster itself including the 3-hydroxy-3-methylglutaryl-CoA synthase Cpz5. The second pathway is part of primary metabolism of the host cell and encodes for the leucine/isovalerate utilization pathway (Liu-pathway). We could identify the liu cluster in S. coelicolor M1154 and gene deletions showed that the intermediate 3-methylglutaconyl-CoA is used for 3-methylglutaryl-CoA biosynthesis. This is the first report of this intermediate being hijacked for secondary metabolite biosynthesis. Furthermore, Cpz20 and Cpz25 from the caprazamycin gene cluster were found to be part of a common route after both individual pathways are merged together.

Conclusions

The unique 3-methylglutaryl moiety in caprazamycin originates both from the caprazamycin gene cluster and the leucine/isovalerate utilization pathway of the heterologous host. Our study enhanced the knowledge on the caprazamycin biosynthesis and points out the importance of primary metabolism of the host cell for biosynthesis of natural products.