bluuebunny/crossref_metadata_2025 huggingface dataset:
System-wide identification of novel de-ubiquitination targets for USP10 in gastric cancer metastasis through multi-omics screening
Authors: Zeng Zhi , Li Yina , Zhou Heng , Li Mingyang , Ye Juan , Li Dan , Zhu Yuxi , Zhang Yonggang , Zhang Xu , Deng Yunchao , Li Juan , Gu Lijuan , Wu Jie
Published: June 2024

Objective

Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function.

Methods

In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis.

Results

After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma.

Conclusions

Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.
Causal relationship between prostatic diseases and prostate cancer: a mendelian randomization study
Authors: Huang Jiaguo , Sun Ji , Wang Kai , Zheng Liying , Fan Yi , Qian Biao
Published: June 2024

Background

Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are unclear.

Methods

We assessed the causal relationship between prostatitis or BPH and PCa using a two-sample Mendelian randomization (MR) approach. The data utilized in this study were sourced from genome-wide association study. The association of genetic variants from cohorts of prostatitis or BPH and PCa patients was determined using inverse-variance weighted and MR Egger regression techniques. The direction of chance was determined using independent genetic variants with genome-wide significance (P < 5 × 10–6). The accuracy of the results was confirmed using sensitivity analyses.

Results

MR analysis showed that BPH had a significant causal effect on PCa (Odds Ratio = 1.209, 95% Confidence Interval: 0.098–0.281, P = 5.079 × 10− 5) while prostatitis had no significant causal effect on PCa (P > 0.05). Additionally, the pleiotropic test and leave-one-out analysis showed the two-sample MR analyses were valid and reliable.

Conclusions

This MR study supports that BPH has a positive causal effect on PCa, while genetically predicted prostatitis has no causal effect on PCa. Nonetheless, further studies should explore the underlying biochemical mechanism and potential therapeutic targets for the prevention of these diseases.
LMO family gene polymorphisms and Wilms tumor susceptibility in Chinese children: a five-center case-control study
Authors: Fu Wen , Deng Linqing , Yan Xiaosong , Hua Rui-Xi , Zhang Jiao , Zhou Haixia , Deng Changmi , Li Suhong , Cheng Jiwen , Ruan Jichen , He Jing , Liu Guochang
Published: June 2024

Background

Wilms tumor is the most prevalent embryonal kidney malignancy in children worldwide. Previous genome-wide association study (GWAS) identified that LIM domain only 1 (LMO1) gene polymorphisms affected the susceptibility to develop certain tumor types. Apart from LMO1, the LMO gene family members also include LMO2-4, each of which has oncogenic potential.

Methods

We conducted this five-center case‒control study to assess the correlations between single nucleotide polymorphisms in LMO family genes and Wilms tumor susceptibility. Odds ratios and 95% confidence intervals were calculated to evaluate the strength of the association.

Results

We found LMO1 rs2168101 G > T and rs11603024 C > T as well as LMO2 rs7933499 G > A were significantly associated with Wilms tumor risk. Stratified analysis demonstrated a protective role of rs2168101 GT/TT genotypes against Wilms tumor in the subgroups of age ≤ 18 months, males and clinical stages I/II compared to the rs2168101 GG genotype. Nevertheless, carriers with the rs11603024 TT genotype were more likely to have an increased risk of Wilms tumor than those with rs11603024 CC/CT genotypes in age > 18 months. And the rs11603024 was identified as a protective polymorphism for reducing the risk of Wilms tumor in the sex- and gender- subgroup. Likewise, carriers with the rs7933499 GA/AA genotypes were at significantly elevated risk of Wilms tumor in age ≤ 18 months and clinical stages I/II.

Conclusion

Overall, our study identified the importance of LMO family gene polymorphisms on Wilms tumor susceptibility in Chinese children. Further investigations are needed to validate our conclusions.

Graphical Abstract
Comparing times of self-harm presentations to hospital emergency departments in children, adolescents, young adults and adults: a national registry study 2007–2019
Authors: McEvoy David , Joyce Mary , Mongan David , Clarke Mary , Codd Mary
Published: June 2024

Purpose

The few studies that have explored self-harm presentation times at hospital emergency departments (EDs) – an important factor that can determine if a patient receives a mental health assessment – primarily focus on adult samples. This study examined the times of self-harm presentations to EDs, self-harm methods used, mental health assessments, and admission data across different age-groups.

Methods

Using data from the National Self-Harm Registry Ireland over a 13-year timeframe (2007–2019), this study compared times, days, seasons, methods of self-harm, and admission data for children (8–12 years), adolescents (13–17 years), young adults (18–25 years) and adults (> 25 years).

Results

The majority of the 152,474 self-harm presentations (78.6%) for all ages occurred out-of-hours (outside the standard working hours or in-hours times of 09:00–17:00, Monday-Friday). The four hours before midnight had the highest proportions of self-harm presentations for adolescents (27.9%) and adults (23.1%), whereas the four hours after midnight had the highest proportion of self-harm presentations for young adults (22.9%). The 16:00-midnight timeframe had highest proportion of self-harm presentations in children (52.3%). Higher proportions of patients received a mental health assessment in-hours compared to out-of-hours among young adults (78.2% vs. 73.3%) and adults (76.1% vs. 72.0%). Self-harm presentations were lowest during summer months in children and adolescents.

Discussion

Hospitals should ensure that adequate resources are available for individuals presenting with self-harm, especially in the case of overcrowded EDs, and protocols need to be designed for those presenting with self-harm due to intoxication. In line with national policy, protocols for patients presenting during out-of-hours should be designed that can incorporate services from allied health multidisciplinary teams, social work, addiction services and counselling organisations. Given the lower rates of self-harm during school holidays for children and adolescents, the school environment must be considered in the context of mental health and self-harm public health prevention interventions.
Prevalence of insufficient physical activity among adult residents of Tehran: a cross-sectional report from Tehran Cohort Study (TeCS)
Authors: Mossavarali Shervin , Vaezi Ali , Heidari Amirhossein , Shafiee Akbar , Jalali Arash , Alaeddini Farshid , Saadat Soheil , Masoudkabir Farzad , Hosseini Kaveh , Vasheghani-Farahani Ali , Sadeghian Saeed , Boroumand Mohamamdali , Karimi Abbasali
Published: June 2024

Background

Insufficient physical activity (PA) is a major risk factor for non-communicable diseases (NCDs) and one of the leading causes of premature mortality worldwide. This study examined the prevalence and independent determinants of insufficient PA among adults resident of Tehran utilizing Tehran Cohort Study Data (TeCS).

Method

We used the recruitment phase data from the TeCS with complete data on PA. PA was assessed through a Likert-scaled question and categorized into three groups. Utilizing data from the 2016 national census, the age- and sex-weighted prevalence of insufficient PA in Tehran was determined. The adjusted logistic regression model is used to neutralize influencing factors and determine the factors associated with insufficient PA.

Result

The weighted prevalence of insufficient PA was 16.9% among the 8213 adult citizens of Tehran, with a greater prevalence among females (19.0% vs. 14.8% among males). Additionally, older age groups, unemployed, housewives, and illiterate educated participants displayed a much higher prevalence of insufficient PA (p < 0.001). Moreover, Tehran’s central and southern districts had higher rates of insufficient PA. Concerning the adjusted regression model, older age (Odds ratio [OR]: 4.26, 95% confidence interval [95% CI]: 3.24–5.60, p < 0.001), a lower education level (p < 0.001), unemployment (OR: 1.80, 95% CI: 1.28–2.55, p = 0.001), being a housewife (OR: 1.44, 95% CI: 1.15–1.80, p = 0.002), higher body mass index (BMI) (OR for BMI > 30: 1.85, 95% CI: 1.56–2.18, p < 0.001), opium consumption (OR: 1.92, 95% CI: 1.46–2.52, p < 0.001), diabetes mellitus (OR: 1.25, 95% CI: 1.06–1.48, p = 0.008), hypertension (OR: 1.29, 95% CI: 1.11–1.50, p = 0.001), and coronary artery diseases (OR: 1.30, 95% CI: 1.05–1.61, p = 0.018), were significantly associated with insufficient PA.

Conclusions

The identified associated factors serve as a valuable guide for policymakers in developing tailored intervention strategies to address the needs of high-risk populations, particularly among older adults and females.
Salvage Latarjet may provide worse outcomes in terms of recurrent instability and returning to sports compared to primary Latarjet: a systematic review of comparative studies
Authors: Zhang Chunsen , Yang Songyun , Pang Long , Li Tao , Li Yinghao , Wang Haoyuan , Huang Yizhou , Tang Xin
Published: June 2024

Background

The Latarjet procedure (LP) is performed as a primary stabilization procedure (primary LP) and a salvage procedure when an earlier shoulder stabilization procedure has failed (salvage LP). However, whether primary LP or salvage LP provides better outcomes for anterior shoulder instability remains unknown.

Methods

Two independent reviewers performed the literature search based on the PRISMA guidelines. A comprehensive search of PubMed, Embase, web of science and Cochrane Library was performed from their inception date to December 4, 2023. Inclusion criteria mainly included the comparison of postoperative outcomes between primary and salvage LP, English language, and full text availability. Two reviewers independently examined the literature, collected data, and evaluated the methodological robustness of the included studies. The Methodological Index for Nonrandomized Studies was used to evaluate the quality of nonrandomized studies. Recurrent instability, complications, reoperations, return to sports, patient-reported outcomes, and range of motion were assessed. Statistical evaluations were conducted using Manager V.5.4.1 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results

Twelve studies were included in the systematic review, with 940 shoulders undergoing primary LP and 631 shoulders undergoing salvage LP. Statistically significant differences in favor of primary LP were found in 2 of the 11 and 2 of 4 included studies in terms of recurrent instability and returning to the same sports (RTS) at preinjury level, respectively. In terms of the visual analog scale, subjective shoulder value and the Western Ontario Shoulder Instability Index, 2 of the 4, 1 of the 3 and 1 of the 3 included studies reported statistically significant differences in favor of primary LP. Differences were not noticed regarding complications, reoperations, the time to RTS, the Rowe score, the Athletic Shoulder Outcome Scoring System, and forward flexion.

Conclusion

Current evidence suggests that compared with primary LP, salvage LP may provide inferior postoperative outcomes in terms of recurrent instability and the rate of RTS at preinjury level. Primary and salvage LP may yield comparable efficacy in terms of complications, reoperations, the rate of RTS, the time to RTS, pain, shoulder function, and range of motion.

Prospero id

CRD42023492027.
Trends in inpatient orthopedic surgery during the COVID-19 pandemic in Japan: a nationwide data study
Authors: Nishizawa Mitsuhiro , Nagata Kosei , Adejuyigbe Babapelumi , Shinozaki Tomohiro , Yamada Koji
Published: June 2024

Background

Coronavirus disease 2019 (COVID-19) has resulted in substantial morbidity and mortality globally. The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) covers 99.9% of health insurance claim receipts by general practitioners. The purpose of this study is to investigate the nationwide number of inpatient orthopedic surgeries in Japan during the effect of state of emergency (SoE) due to COVID-19.

Method

The NDB has been publicly available since 2014. We retrospectively reviewed the NDB from April 2019 to March 2022. We gathered the monthly number of all inpatient orthopedic surgeries. We also classified orthopedic surgeries into the following 11 categories by using K-codes, Japanese original surgery classification: fracture, arthroplasty, spine, arthroscopy, hardware removal, hand, infection/amputation, ligament/tendon, tumor, joint, and others. By using the average number from April to December 2019 as the reference period, we investigated the increase or decrease orthopedic surgeries during the pandemic period.

Results

The NDB showed that the average number of total inpatient orthopedic surgeries during the reference period was 115,343 per month. In May 2020, monthly inpatient orthopedic surgeries decreased by 29.6% to 81,169 surgeries, accounting for 70.3% of the reference period. The second SoE in 2021 saw no change, while the third and fourth SoEs showed slight decreases compared to the reference period. Hardware removal and tumor surgeries in May 2020 decreased to 45.3% and 45.5%, respectively, while fracture surgeries had relatively small decreases.

Conclusion

According to NDB, approximately 1.3 million orthopedic inpatient surgeries were performed or claimed in a year in Japan. In May 2020, the first SoE period of the COVID-19 pandemic, the number of inpatient orthopedic surgeries in Japan decreased by 30%. Meanwhile, the decrease was relatively small during the SoE periods in 2021.
Color change of tooth-colored restorative materials bonded to silver diamine fluoride-treated dentine: a systematic review
Authors: Sabbagh Sedigheh , Movahhed Taraneh , Bagheri Hossein , Sadeghi Masoumeh , Shahid Saroash , Mohammadi Homeira
Published: June 2024

Background

The desirable properties of silver diamine fluoride (SDF) make it an effective agent for managing dental caries and tooth hypersensitivity. There are several clinical instances that SDF application might precede the placement of direct tooth-colored restorations. On the other hand, SDF stains demineralized/carious dental tissues black, which might affect the esthetic outcomes of such restorations. Color is a key parameter of esthetics in dentistry. Therefore, this study aims to systematically review dental literature on color/color change of tooth-colored restorations placed following the application of SDF on dentine.

Methods

Comprehensive search of PubMed, Embase, Scopus and ISI Web of Science databases (until August 2023) as well as reference lists of retrieved studies was performed. In vitro studies reported color or color change of tooth-colored restorative materials applied on SDF-treated dentine were included. Methodological quality assessment was performed using RoBDEMAT tool. Pooled weighted mean difference (WMD) and 95% confidence interval (95% CI) was calculated.

Results

Eleven studies/reports with a total of 394 tooth-colored restorations placed following a) no SDF (control) or b) SDF with/without potassium iodide (KI)/glutathione dentine pre-treatments were included. Color change was quantified using ∆E formulas in most reports. The pooled findings for the comparison of resin-based composite (RBC) restorations with and without prior 38% SDF + KI application revealed no statistically significant differences in ∆E values at short- and long-term evaluations (~ 14 days: WMD: -0.56, 95% CI: -2.09 to 0.96; I2: 89.6%, and ~ 60 days: WMD: 0.11; 95% CI: -1.51 to 1.72; I2: 76.9%). No studies provided sufficient information for all the items in the risk of bias tool (moderate to low quality).

Conclusions

The limited evidence suggested comparable color changes of RBC restorations with and without 38% SDF + KI pre-treatment up to 60 days. The included studies lacked uniformity in methodology and reported outcomes. Further studies are imperative to draw more definite conclusions.

Protocol registration

The protocol of this systematic review was registered in PROSPERO database under number CRD42023485083.
Investigation of adhesion status of Candida species to the surface of resin materials produced at different angles with additive manufacturing
Authors: Turanoglu Omer F. , Talay Cevlik Esra , Vural Caner
Published: June 2024

Background

The aim of this study was to evaluate the adhesion of Candida glabrata, Candida albicans, Candida krusei, Candida parapsilosis and Candida tropicalis yeasts to disk-shaped resin materials produced from resin which used in the production of surgical guide with 0, 45 and 90-degrees printing orientations by Liquid Crystal Display additive manufacturing technology.

Methods

Disk-shaped specimens were printed with surgical guide resin using the Liquid Crystal Display production technique in 3 printing orientations (0, 45 and 90-degrees). Surface roughness and contact angle values were evaluated. Real-Time PCR analysis was performed to evaluate Candida adhesion (C. glabrata, C. albicans, C. krusei, C. parapsilosis and C. tropicalis) Field emission scanning electron microscope (FESEM) images of the materials were obtained.

Results

Specimens oriented at 45-degrees demonstrated higher surface roughness (P < .05) and lower contact angle values than other groups. No significant difference was found in the adhesion of C. glabrata, C. albicans, and C. parapsilosis among specimens printed at 0, 45, and 90-degrees orientations (P > .05). A higher proportion of C. krusei and C. tropicalis was found in the specimens printed at orientation degrees of 45 = 90 < 0 with statistical significance. Analyzing the adhesion of all Candida species reveals no statistical disparity among the printing orientations.

Conclusions

The surface roughness, contact angle, and adhesion of certain Candida species are affected by printing orientations. Hence, careful consideration of the printing orientation is crucial for fabricating products with desirable properties. In 45-degree production, roughness increases due to the layered production forming steps, whereas in 0-degree production, certain Candida species exhibit high adhesion due to the formation of porous structures. Consequently, considering these factors, it is advisable to opt for production at 90-degrees, while also considering other anticipated characteristics.
Ameloblastic fibrosarcoma of the maxilla arising in an old woman, a rare case report and literature review
Authors: Liu Shiyue , Li Hong , Dong Youhong , Zhang Dongdong
Published: June 2024

Background

Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic tumor, commonly occurring in young adults and typically affecting the mandibular region. We report an exceptionally rare and highly atypical case of AFS in an elderly female patient originating from the maxillary bone.

Case presentation

A 66-year-old woman was admitted with a two-week history of a lump in her left upper molar. CT scans suggested a cyst in the maxillary bone. An incisional biopsy revealed a spindle cell neoplasm. MRI showed abnormalities in the left maxilla, indicating a possible tumorous lesion. The patient underwent a subtotal maxillectomy, wide tumor excision, intraoral epithelial flap transplantation, and dental extraction. Histology identified atypical tumor cells with visible mitotic figures. Immunohistochemistry showed negative for PCK and CD34 expression, but positive for Vimentin and SMA expression. The Ki-67 proliferation index ranged from 30 to 50%. These findings suggested a potentially malignant soft tissue tumor in the left maxilla, leaning towards a diagnosis of AFS. The patient received postoperative radiotherapy. There was no recurrence during the six-month follow-up.

Conclusion

Based on repeated pathological evidence, we report a rare case of an elderly female with AFS originating from the maxillary bone. Surgery and postoperative radiotherapy resulted in a favorable outcome.
Facial soft-tissue shape changes after fixed edgewise treatment with premolar extraction in individual artificial-intelligence-classified facial profile patterns
Authors: Tanikawa Chihiro , Tan Tzee Jen , Takada Kenji
Published: June 2024

Objective

To examine the patterns of pretreatment facial soft tissue shape in orthodontic cases with premolar extraction using artificial intelligence (AI) and to investigate the corresponding changes.

Methods

One hundred and fifty-two patients who underwent orthodontic treatment with premolar extraction were enrolled. Lateral cephalograms were obtained before and after the treatment. For each record, the outlines of the nose-lip-chin profile and corresponding 21 cephalometric variables were extracted. The AI method classified pretreatment records into three subject groups based on the feature variables extracted from the outline. Dentoskeletal and soft tissue facial form changes observed after treatment were compared statistically (P < 0.05) between the groups using ANOVA. Multivariate regression models were used for each group.

Results

Group 1 (n = 59) was characterized by Class II high-angle retrognathic mandible with an incompetent lip, group 2 (n = 55) by Class I malocclusion with retruded and thin lips, and group 3 (n = 38) by Class I malocclusion with an everted superior lip before treatment. The ratios of anteroposterior soft tissue to hard tissue movements in Group 1 were 56% (r = 0.64) and 83% (r = 0.75) for the superior and inferior lips, respectively, whereas those in Group 2 were 49% (r = 0.78) and 91% (r = 0.80), and 40% (r = 0.54) and 79% (r = 0.70), respectively, in Group 3.

Conclusions

The modes of facial form changes differed depending on the pre-treatment profile patterns classified by the AI. This indicates that the determination of the pre-treatment profile pattern can help in the selection of soft tissue to hard tissue movement ratios, which helps estimate the post-treatment facial profile with a moderate to high correlation.
Direct and indirect estimation of adolescent sexual intercourse and contraceptive use in Rajasthan India: an application of the best friend methodology
Authors: Bell Suzanne O. , Ahmad Danish , Khanna Anoop , Thomas Haley L. , Moreau Caroline
Published: June 2024

Background

Existing estimates of adolescent sexual and reproductive health (ASRH) behaviors may be a gross undercount given the sensitivity of this behavior in Indian culture. The objective of this study was to estimate ASRH behaviors in Rajasthan, India using direct questions and the best friend approach that seeks to reduce social desirability bias.

Methods

We used population-based data of adolescents aged 15–19 in Rajasthan collected between September and December 2022. Data include whether the respondent and her closest female friend ever had a partner, ever had sex, ever used contraception, and were currently using contraception. We estimated respondent and best friend ASRH outcomes separately, overall and among unmarried adolescents for whom we anticipate social desirability bias is greatest.

Results

The best friend approach performed well, with method assumptions largely met even before adjustments. Respondent and best friend estimates were similar among all adolescents except for current contraceptive use, which was higher for friends (though not significantly so). However, we observed large differences in ASRH behaviors between unmarried respondents and friends, with a significantly higher percentage of friends who ever had a partner (4.3% respondents, 11.6% friends), and a slightly higher percentage who ever had sex (2.4%, 3.8%) and who were currently using contraception (17.0%, 19.7% among those in need of contraception).

Conclusions

We observed potential benefits of using the best friend methodology in estimating premarital sexual activity, but further work is needed to refine social network-based measures of sensitive adolescent behaviors in larger study samples to better understand ASRH needs.
Addressing label noise for electronic health records: insights from computer vision for tabular data
Authors: Yang Jenny , Triendl Hagen , Soltan Andrew A. S. , Prakash Mangal , Clifton David A.
Published: June 2024

The analysis of extensive electronic health records (EHR) datasets often calls for automated solutions, with machine learning (ML) techniques, including deep learning (DL), taking a lead role. One common task involves categorizing EHR data into predefined groups. However, the vulnerability of EHRs to noise and errors stemming from data collection processes, as well as potential human labeling errors, poses a significant risk. This risk is particularly prominent during the training of DL models, where the possibility of overfitting to noisy labels can have serious repercussions in healthcare. Despite the well-documented existence of label noise in EHR data, few studies have tackled this challenge within the EHR domain. Our work addresses this gap by adapting computer vision (CV) algorithms to mitigate the impact of label noise in DL models trained on EHR data. Notably, it remains uncertain whether CV methods, when applied to the EHR domain, will prove effective, given the substantial divergence between the two domains. We present empirical evidence demonstrating that these methods, whether used individually or in combination, can substantially enhance model performance when applied to EHR data, especially in the presence of noisy/incorrect labels. We validate our methods and underscore their practical utility in real-world EHR data, specifically in the context of COVID-19 diagnosis. Our study highlights the effectiveness of CV methods in the EHR domain, making a valuable contribution to the advancement of healthcare analytics and research.
Diversity of Rickettsia species in collected ticks from Southeast Iran
Authors: Qorbani Ali , Khalili Mohammad , Nourollahifard Saeidreza , Mostafavi Ehsan , Farrokhnia Mehrdad , Esmaeili Saber
Published: June 2024

Rickettsia occurs worldwide and rickettsiosis is recognized as an emerging infection in several parts of the world. Ticks are reservoir hosts for pathogenic Rickettsia species in humans and domestic animals. Most pathogenic Rickettsia species belong to the spotted Fever Group (SFG). This study aimed to identify and diagnose tick fauna and investigate the prevalence of Rickettsia spp. in ticks collected from domestic animals and dogs in the rural regions of Kerman Province, Southeast Iran. In this study, tick species (fauna) were identified and 2100 ticks (350 pooled samples) from two genera and species including Rhipicephalus linnaei (1128) and Hyalomma deteritum (972) were tested to detect Rickettsia genus using Real-time PCR. The presence of the Rickettsia genus was observed in 24.9% (95%CI 20.28–29.52) of the pooled samples. Sequencing and phylogenetic analyses revealed the presence of Rickettsia aeschlimannii (48.98%), Rickettsia conorii israelensis (28.57%), Rickettsia sibirica (20.41%), and Rickettsia helvetica (2.04%) in the positive samples. The results showed a significant association between county variables and the following variables: tick spp. (p < 0.001), Rickettsia genus infection in ticks (p < 0.001) and Rickettsia spp. (p < 0.001). In addition, there was a significant association between tick species and host animals (dogs and domestic animals) (p < 0.001), Rickettsia spp infection in ticks (p < 0.001), and Rickettsia spp. (p < 0.001). This study indicates a high prevalence of Rickettsia spp. (SFG) in ticks of domestic animals and dogs in rural areas of Kerman Province. The health system should be informed of the possibility of rickettsiosis and the circulating species of Rickettsia in these areas.
Breast cancer patient-derived organoids for the investigation of patient-specific tumour evolution
Authors: Mazzucchelli Serena , Signati Lorena , Messa Letizia , Franceschini Alma , Bonizzi Arianna , Castagnoli Lorenzo , Gasparini Patrizia , Consolandi Clarissa , Mangano Eleonora , Pelucchi Paride , Cifola Ingrid , Camboni Tania , Severgnini Marco , Villani Laura , Tagliaferri Barbara , Carelli Stephana , Pupa Serenella M. , Cereda Cristina , Corsi Fabio
Published: June 2024

Background

A reliable preclinical model of patient-derived organoids (PDOs) was developed in a case study of a 69-year-old woman diagnosed with breast cancer (BC) to investigate the tumour evolution before and after neoadjuvant chemotherapy and surgery. The results were achieved due to the development of PDOs from tissues collected before (O-PRE) and after (O-POST) treatment.

Methods

PDO cultures were characterized by histology, immunohistochemistry (IHC), transmission electron microscopy (TEM), scanning electron microscopy (SEM), confocal microscopy, flow cytometry, real-time PCR, bulk RNA-seq, single-cell RNA sequencing (scRNA-seq) and drug screening.

Results

Both PDO cultures recapitulated the histological and molecular profiles of the original tissues, and they showed typical mammary gland organization, confirming their reliability as a personalized in vitro model. Compared with O-PRE, O-POST had a greater proliferation rate with a significant increase in the Ki67 proliferation index. Moreover O-POST exhibited a more stem-like and aggressive phenotype, with increases in the CD24low/CD44low and EPCAMlow/CD49fhigh cell populations characterized by increased tumour initiation potential and multipotency and metastatic potential in invasive lobular carcinoma. Analysis of ErbB receptor expression indicated a decrease in HER-2 expression coupled with an increase in EGFR expression in O-POST. In this context, deregulation of the PI3K/Akt signalling pathway was assessed by transcriptomic analysis, confirming the altered transcriptional profile. Finally, transcriptomic single-cell analysis identified 11 cell type clusters, highlighting the selection of the luminal component and the decrease in the number of Epithelial–mesenchymal transition cell types in O-POST.

Conclusion

Neoadjuvant treatment contributed to the enrichment of cell populations with luminal phenotypes that were more resistant to chemotherapy in O-POST. PDOs represent an excellent 3D cell model for assessing disease evolution.
Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway
Authors: Lv Linlin , Li Shujing , Kang Jie , Li Yulin , Zhao Nannan , Ye Dongman , Qin Fengying , Sun Jing , Yu Tao , Wu Huijian
Published: June 2024

Triple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.
WZ-3146 acts as a novel small molecule inhibitor of KIF4A to inhibit glioma progression by inducing apoptosis
Authors: Yan Tao , Jiang Qing , Ni Guangpu , Ma Haofeng , Meng Yun , Kang Guiqiong , Xu Meifang , Peng Fei , Li Huadong , Chen Xin , Wang Mingguang
Published: June 2024

Background

Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed.

Methods

The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot.

Results

In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects.

Conclusion

In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.
Associations between urine glyphosate levels and metabolic health risks: insights from a large cross-sectional population-based study
Authors: Otaru Sarah , Jones Laura E. , Carpenter David O.
Published: June 2024

Background

The prevalence of metabolic syndrome (MetS) in American adults increased from 37.6% in the 2011–12 period to 41.8% in 2017–2018. Environmental exposure, particularly to common compounds such as glyphosate, has drawn increasing attention as a potential risk factor.

Methods

We employed three cycles of data (2013–2018) from the National Health and Nutrition Examination Survey (NHANES) in a cross-sectional study to examine potential associations between urine glyphosate measurements and MetS incidence. We first created a MetS score using exploratory factor analysis (EFA) of the International Diabetes Federation (IDF) criteria for MetS, with data drawn from the 2013–2018 NHANES cycles, and validated this score independently on an additional associated metric, the albumin-to-creatinine (ACR) ratio. The score was validated via a machine learning approach in predicting the ACR score via binary classification and then used in multivariable regression to test the association between quartile-categorized glyphosate exposure and the MetS score.

Results

In adjusted multivariable regressions, regressions between quartile-categorized glyphosate exposure and MetS score showed a significant inverted U-shaped or saturating dose‒response profile, often with the largest effect for exposures in quartile 3. Exploration of potential effect modification by sex, race, and age category revealed significant differences by race and age, with older people (aged > 65 years) and non-Hispanic African American participants showing larger effect sizes for all exposure quartiles.

Conclusions

We found that urinary glyphosate concentration is significantly associated with a statistical score designed to predict MetS status and that dose–response coefficient is nonlinear, with advanced age and non-Hispanic African American, Mexican American and other Hispanic participants exhibiting greater effect sizes.
Sphingolipid changes in mouse brain and plasma after mild traumatic brain injury at the acute phases
Authors: Mondal Koushik , Del Mar Nobel A. , Gary Ashlyn A. , Grambergs Richard C. , Yousuf Mohd , Tahia Faiza , Stephenson Benjamin , Stephenson Daniel J. , Chalfant Charles E. , Reiner Anton , Mandal Nawajes
Published: June 2024

Background

Traumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI.

Methods

Wildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann–Whitney test) and by Tukey’s correction for multiple comparisons.

Results

In post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days.

Conclusions

Alterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.
Using qualitative system dynamics modeling to understand overdose bystander behavior in the context of Connecticut’s Good Samaritan Laws and identify effective policy options
Authors: Thompson Rachel L. , Sabounchi Nasim S. , Ali Syed Shayan , Heimer Robert , D’Onofrio Gail , Heckmann Rebekah
Published: June 2024

Background

Good Samaritan Laws are a harm reduction policy intended to facilitate a reduction in fatal opioid overdoses by enabling bystanders, first responders, and health care providers to assist individuals experiencing an overdose without facing civil or criminal liability. However, Good Samaritan Laws may not be reaching their full impact in many communities due to a lack of knowledge of protections under these laws, distrust in law enforcement, and fear of legal consequences among potential bystanders. The purpose of this study was to develop a systems-level understanding of the factors influencing bystander responses to opioid overdose in the context of Connecticut’s Good Samaritan Laws and identify high-leverage policies for improving opioid-related outcomes and implementation of these laws in Connecticut (CT).

Methods

We conducted six group model building (GMB) workshops that engaged a diverse set of participants with medical and community expertise and lived bystander experience. Through an iterative, stakeholder-engaged process, we developed, refined, and validated a qualitative system dynamics (SD) model in the form of a causal loop diagram (CLD).

Results

Our resulting qualitative SD model captures our GMB participants’ collective understanding of the dynamics driving bystander behavior and other factors influencing the effectiveness of Good Samaritan Laws in the state of CT. In this model, we identified seven balancing (B) and eight reinforcing (R) feedback loops within four narrative domains: Narrative 1 - Overdose, Calling 911, and First Responder Burnout; Narrative 2 - Naloxone Use, Acceptability, and Linking Patients to Services; Narrative 3 - Drug Arrests, Belief in Good Samaritan Laws, and Community Trust in Police; and Narrative 4 - Bystander Naloxone Use, Community Participation in Harm Reduction, and Cultural Change Towards Carrying Naloxone.

Conclusions

Our qualitative SD model brings a nuanced systems perspective to the literature on bystander behavior in the context of Good Samaritan Laws. Our model, grounded in local knowledge and experience, shows how the hypothesized non-linear interdependencies of the social, structural, and policy determinants of bystander behavior collectively form endogenous feedback loops that can be leveraged to design policies to advance and sustain systems change.
Harnessing peer mentorship as a tool to turn human resource for health brain drain into brain gain: a case study of a Nigerian peer-mentored research group
Authors: Toyin-Thomas Patience , Wariri Oghenebrume , Ikhurionan Paul
Published: June 2024

Background

Peer mentorship can be a potential tool to reduce the disparities in health research capacity between high- and low- and middle-income countries. This case study describes the potential of peer mentorship to tackle two critical issues: bridging health research capacity of doctors from low- and middle-income countries (LMICs) and the transformation of human resource for health brain drain into "brain gain".

Case presentation

In 2021, a virtual peer mentorship group was established by 16 alumni of the University of Benin College of Medical Sciences' 2008 graduating class, residing across three continents. This program aimed to facilitate research collaboration and skill development among colleagues with diverse research experience levels, fostering a supportive environment for career development in research. The group relied heavily on digital technology to carry out its activities due to the different geographical locations of the group members. Led by experienced peer leaders, the group fostered a collaborative learning environment where members leveraged each other's expertise. Within 18 months, we published two research papers in high-impact peer-reviewed global health journals, launched a mixed-methods research study, and conducted training sessions on research design and implementation. Findings from our work were presented at conferences and workshops. However, logistical hurdles, competing priorities, structural constraints, and uneven participation presented challenges.

Conclusion

The peer mentorship collaboration has achieved some successes so far, and this model can be emulated by other cohorts of medical professionals across LMICs. Despite the group's success at a micro- or individual level, there remain significant structural barriers to research capacity building in LMICs that can only be addressed at the meso- and macro-levels by institutions and government, respectively. A systems-level approach is required to develop and support research capacity building and foster global research collaboration and effectively turn brain drain into brain gain.
Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop
Authors: Yao Gao-sheng , Fu Liang-min , Dai Jun-shang , Chen Jin-wei , Liu Ke-zhi , Liang Hui , Wang Zhu , Deng Qiong , Wang Jie-yan , Jin Mei-yu , Chen Wei , Fang Yong , Luo Jun-hang , Cao Jia-zheng , Wei Jin-huan
Published: June 2024

Background

Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated.

Methods

Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing.

Results

CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor.

Conclusion

A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.