bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex differences in the association between sleep duration and frailty in older adults: evidence from the KNHANES study
Authors: Ha Beomman , Han Mijin , So Wi-Young , Kim Seonho
Published: May 2024

Background

Frailty is a pervasive clinical syndrome among the older population. It is associated with an increased risk of diverse adverse health outcomes including death. The association between sleep duration and frailty remains unclear. Therefore, the aim of this study was to investigate the relationship between sleep duration and frailty in community-dwelling Korean older adults and to determine whether this relationship is sex-dependent.

Methods

Data on 3,953 older adults aged ≥ 65 years were obtained from the 7th (2016–2018) Korea National Health and Nutrition Examination Survey (KNHANES). Frailty was defined using the Fried phenotype with criteria customized for the KNHANES dataset. Self-reported sleep duration was classified as short sleep duration (≤ 6 h), middle sleep duration (6.1–8.9 h), and long sleep duration (≥ 9 h). Complex samples multivariate logistic regression analysis was conducted to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results

The percentage of male participants with short, middle, and long sleep durations was 34.9%, 62.1%, and 16.8%, respectively, while that of female participants was 26.1%, 59.2%, and 14.7%. The prevalence of frailty in the middle sleep duration group was lower than that in the short and long sleep duration groups in both men (short, 14.7%; middle, 14.2%; long, 24.5%; p < 0.001) and women (short, 42.9%; middle, 27.6%; long, 48.6%; p < 0.001). Both short (OR = 2.61, 95% CI = 1.91 − 4.83) and long (OR = 2.57, 95% CI = 1.36 − 3.88) sleep duration groups had a significantly higher OR for frailty than the middle sleep duration group even after adjusting for confounding variables among women, but not among men.

Conclusion

Short and long sleep durations were independently associated with frailty in community-dwelling Korean older adult women. Managing sleep problems among women should be prioritized, and effective interventions to prevent frailty should be developed accordingly.
Blood calprotectin as a biomarker for infection and sepsis – the prospective CASCADE trial
Authors: Diehl-Wiesenecker Eva , Galtung Noa , Dickescheid Johannes , Prpic Monika , Somasundaram Rajan , Kappert Kai , Bauer Wolfgang
Published: May 2024

Background

Early in the host-response to infection, neutrophils release calprotectin, triggering several immune signalling cascades. In acute infection management, identifying infected patients and stratifying these by risk of deterioration into sepsis, are crucial tasks. Recruiting a heterogenous population of patients with suspected infections from the emergency department, early in the care-path, the CASCADE trial aimed to evaluate the accuracy of blood calprotectin for detecting bacterial infections, estimating disease severity, and predicting clinical deterioration.

Methods

In a prospective, observational trial from February 2021 to August 2022, 395 patients (n = 194 clinically suspected infection; n = 201 controls) were enrolled. Blood samples were collected at enrolment. The accuracy of calprotectin to identify bacterial infections, and to predict and identify sepsis and mortality was analysed. These endpoints were determined by a panel of experts.

Results

The Area Under the Receiver Operating Characteristic (AUROC) of calprotectin for detecting bacterial infections was 0.90. For sepsis within 72 h, calprotectin’s AUROC was 0.83. For 30-day mortality it was 0.78. In patients with diabetes, calprotectin had an AUROC of 0.94 for identifying bacterial infection.

Conclusions

Calprotectin showed notable accuracy for all endpoints. Using calprotectin in the emergency department could improve diagnosis and management of severe infections, in combination with current biomarkers.

Clinical trial registration number

DRKS00020521
In vitro evaluation of two novel Escherichia bacteriophages against multiple drug resistant avian pathogenic Escherichia coli
Authors: Karami Mobina , Goudarztalejerdi Ali , Mohammadzadeh Abdolmajid , Berizi Enayat
Published: May 2024

Background

In recent years, there has been a growing interest in phage therapy as an effective therapeutic tool against colibacillosis caused by avian pathogenic Escherichia coli (APEC) which resulted from the increasing number of multidrug resistant (MDR) APEC strains.

Methods

In the present study, we reported the characterization of a new lytic bacteriophage (Escherichia phage AG- MK-2022. Basu) isolated from poultry slaughterhouse wastewater. In addition, the in vitro bacteriolytic activity of the newly isolated phage (Escherichia phage AG- MK-2022. Basu) and the Escherichia phage VaT-2019a isolate PE17 (GenBank: MK353636.1) were assessed against MDR- APEC strains (n = 100) isolated from broiler chickens with clinical signs of colibacillosis.

Results

Escherichia phage AG- MK-2022. Basu belongs to the Myoviridae family and exhibits a broad host range. Furthermore, the phage showed stability under a wide range of temperatures, pH values and different concentrations of NaCl. Genome analysis of the Escherichia phage AG- MK-2022. Basu revealed that the phage possesses no antibiotic resistance genes (ARGs), mobile genetic elements (MGEs), and any E. coli virulence associated genes. In vitro bacterial challenge tests demonstrated that two phages, the Escherichia phage VaT-2019a isolate PE17 and the Escherichia phage AG- MK-2022. Basu exhibited high bactericidal activity against APEC strains and lysed 95% of the tested APEC strains.

Conclusions

The current study findings indicate that both phages could be suggested as safe biocontrol agents and alternatives to antibiotics for controlling MDR-APEC strains isolated from broilers.
A multi-view fusion lightweight network for CRSwNPs prediction on CT images
Authors: Zou Jisheng , Lyu Yi , Lin Yu , Chen Yaowen , Lai Shixin , Wang Siqi , Zhang Xuan , Zhang Xiaolei , Wu Renhua , Kang Weipiao
Published: May 2024

Accurate preoperative differentiation of the chronic rhinosinusitis (CRS) endotype between eosinophilic CRS (eCRS) and non-eosinophilic CRS (non-eCRS) is an important topic in predicting postoperative outcomes and administering personalized treatment. To this end, we have constructed a sinus CT dataset, which comprises CT scan data and pathological biopsy results from 192 patients of chronic rhinosinusitis with nasal polyps (CRSwNP), treated at the Second Affiliated Hospital of Shantou University Medical College between 2020 and 2022. To differentiate CRSwNP endotype on preoperative CT and improve efficiency at the same time, we developed a multi-view fusion model that contains a mini-architecture with each network of 10 layers by modifying the deep residual neural network. The proposed model is trained on a training set and evaluated on a test set. The multi-view deep learning fusion model achieved the area under the receiver-operating characteristics curve (AUC) of 0.991, accuracy of 0.965 and F1-Score of 0.970 in test set. We compared the performance of the mini-architecture with other lightweight networks on the same Sinus CT dataset. The experimental results demonstrate that the developed ResMini architecture contribute to competitive CRSwNP endotype identification modeling in terms of accuracy and parameter number.
Intestinal perforation due to colorectal cancer during pregnancy: case report and literature review
Authors: Gao Yan , Sun Yu
Published: May 2024

Colorectal cancer (CRC) in pregnancy is sporadic. We reported a case of a woman at 23 + 4 weeks of gestation who presented with abdominal pain. The patient underwent an ultrasound and MRI, during which a colonic mass was noted. Considering a probable incomplete intestinal obstruction, a colonoscopy, biopsy, and colonic stenting were performed by a multidisciplinary team. However, sudden hyperthermia and CT demonstrated intestinal perforation, and an emergency caesarean section and colostomy were conducted. The histological analysis confirmed moderately high-grade adenocarcinoma.
Cerebral versus cortical visual impairment: eliminating the conflict and renewing the terminology
Authors: Costa Marcelo Fernandes
Published: May 2024

The inconsistency in terminology for Cortical Visual Impairment or Cerebral Visual Impairment presents challenges: (1) different levels of changes in visual pathway and other cerebral areas do not allow discrimination; (2) different visual and oculomotor aspects are not adequately considered. We open a debate to consider a more appropriate diagnosis.
Exploring adverse events of Vilazodone: evidence from the FAERS database
Authors: Jiang Ying , Qu Yucai , Du Zhiqiang , Ou Mengmeng , Shen Yuan , Zhou Qin , Tian Lin , Zhu Haohao
Published: May 2024

Objective

This study aims to conduct an exhaustive evaluation of Vilazodone's safety in clinical application and to unearth the potential adverse event (AE) risks associated with its utilization based on FDA Adverse Event Reporting System (FAERS) database.

Methods

This research employed data spanning from the first quarter of 2011 to the third quarter of 2023 from the FAERS database. Various signal detection methodologies, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), were utilized to ascertain the correlation between Vilazodone and specific AEs.

Results

The study compiled a total of 17,439,268 reports of drug AEs, out of which 5,375 were related to Vilazodone. Through signal mining, 125 Preferred Terms (PTs) encompassing 27 System Organ Classes (SOCs) were identified. The findings indicated a higher prevalence among females and patients within the 45 to 65 age bracket. The principal categories of AEs included Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders, with prevalent incidents of Diarrhoea, Nausea, and Insomnia. Moreover, the study identified robust signals of novel potential AEs, notably in areas such as sleep disturbances (Sleep paralysis, Hypnagogic hallucination, Rapid eye movements sleep abnormal, Sleep terror, Terminal insomnia, Tachyphrenia), sexual dysfunctions (Female orgasmic disorder, Orgasm abnormal, Disturbance in sexual arousal, Spontaneous penile erection, Anorgasmia, Sexual dysfunction, Ejaculation delayed), and other symptoms and injuries (Electric shock sensation, Violence-related symptom, Gun shot wound).

Conclusion

Although Vilazodone presents a positive prospect in the management of MDD, the discovery of AEs linked to its use, particularly the newly identified potential risks such as sleep and sexual dysfunctions, necessitates heightened vigilance among clinicians.
Borderline personality traits mediate the relationship between negative life events and nonsuicidal self-injury in a clinical sample with youth depression
Authors: Chen Wangni , Yuan Ting , Pan Yuwen , Ma Yarong , Sun Bin , Yu Min , Lin Xiaoming , He Hongbo , Zhang Jie
Published: May 2024

Background

Borderline personality traits play a significant role in nonsuicidal self-injury (NSSI), particularly in depressed youths. NSSI is also highly correlated with negative life events. This research aimed to explore the connections between negative life events, borderline personality traits, and NSSI.

Methods

The study included 338 depressed youth aged 13 to 25 years. Self-reported measures and clinical interviews were utilized to evaluate the depressive symptoms, borderline personality traits, negative life events, and NSSI behaviours of these participants. Identifying variables linked to NSSI was the aim of our analysis, and we also conducted a mediation analysis to look into the influence of borderline traits on the connection between negative life events and NSSI.

Results

Of the 338 depressed youth, approximately 59.47% (201/338) displayed NSSI, which was associated with greater clinical severity. Borderline traits had an independent influence on NSSI and it partially explained the connection between negative life events and NSSI, even when accounting for depression symptoms. Depressed youth who were more vulnerable to NSSI behaviours often experienced negative life events such as interpersonal relationships, academic pressure, being punished, and loss.

Conclusions

Our research suggests that depressed youth who experience more negative life events are more likely to experience NSSI, and negative life events indirectly influence nonsuicidal self-injury through borderline personality traits. Implementing interventions focused on mitigating borderline symptoms could be a promising therapeutic approach for addressing NSSI in young people.
Sociodemographic determinants of vaccination and willingness to pay for COVID-19 vaccines in Hungary, results of a cross-sectional online questionnaire
Authors: Beretzky Zsuzsanna , Brodszky Valentin
Published: May 2024

Background

Several different coronavirus disease (COVID-19) vaccines were authorized and distributed all over the world, including Hungary, but vaccination rates and acceptance of the different vaccines varied through 2021 and subsequent years. In Hungary Western vaccines and the Chinese and Russian vaccines were available in early 2021. Understanding preference and willingness to pay (WTP) for the COVID-19 vaccine could provide information for policy decision making to control the COVID-19 pandemic. We aimed to assess the socio-demographic factors influencing the COVID-19 vaccination and to analyse individual preferences for the available COVID-19 vaccines in Hungary.

Methods

A cross-sectional online questionnaire survey was conducted between 25–05-2021 and 08–06-2021 exploring the vaccine acceptance and WTP for vaccination in the Hungarian general population. To assess the preferences towards the different vaccines available in Hungary at the time of the study, we used a multi-step WTP task.

Results

Altogether 2,000 respondents filled out our survey, with the average age of 49.1 (SD = 15.3), out of whom 370 respondents (18.5%) stated that they already had a COVID-19 infection. Age above 65 years, male gender, higher level of education, higher income and residence in the capital or county seats were associated with a higher probability of vaccination. The average WTP ranged from 14.2 to 30.3 EUR for the different vaccine types.

Conclusions

Males, respondents with higher education and income stated a higher WTP value for all vaccines. Better socioeconomic status increased both vaccination coverage and willingness to pay for vaccines.
3D-Printed custom-made hemipelvic endoprosthetic reconstruction following periacetabular tumor resection: utilizing a novel classification system
Authors: Hu Xin , Lu Minxun , Wang Yitian , Luo Yi , Zhou Yong , Yang Xiao , Min Li , Tu Chongqi
Published: May 2024

Background

Customized 3D-printed pelvic implants with a porous structure have revolutionized periacetabular pelvic defect reconstruction after tumor resection, offering improved osteointegration, long-term stability, and anatomical fit. However, the lack of an established classification system hampers implementation and progress.

Methods

We formulated a novel classification system based on pelvic defect morphology and 3D-printed hemipelvis endoprostheses. It integrates surgical approach, osteotomy guide plate and prosthesis design, postoperative rehabilitation plans, and perioperative processes.

Results

Retrospectively analyzing 60 patients (31 males, 29 females), we classified them into Type A (15 patients: Aa = 6, Ab = 9), Type B (27 patients: Ba = 15, Bb = 12), Type C (17 patients). All underwent customized osteotomy guide plate-assisted tumor resection and 3D-printed hemipelvic endoprosthesis reconstruction. Follow-up duration was median 36.5 ± 15.0 months (range, 6 to 74 months). The mean operating time was 430.0 ± 106.7 min, intraoperative blood loss 2018.3 ± 1305.6 ml, transfusion volume 2510.0 ± 1778.1 ml. Complications occurred in 13 patients (21.7%), including poor wound healing (10.0%), deep prosthesis infection (6.7%), hip dislocation (3.3%), screw fracture (1.7%), and interface loosening (1.7%). VAS score improved from 5.5 ± 1.4 to 1.7 ± 1.3, MSTS-93 score from 14.8 ± 2.5 to 23.0 ± 5.6. Implant osseointegration success rate was 98.5% (128/130), with one Type Ba patient experiencing distal prosthesis loosening.

Conclusion

The West China classification may supplement the Enneking and Dunham classification, enhancing interdisciplinary communication and surgical outcomes. However, further validation and wider adoption are required to confirm clinical effectiveness.
Prevention of malnutrition after one anastomosis gastric bypass: value of the common channel limb length
Authors: Mostafapour Elyas , Shahsavan Masoumeh , Shahmiri Shahab Shahabi , Jawhar Noura , Ghanem Omar M. , Kermansaravi Mohammad
Published: May 2024

Purpose

Hypoalbuminemia and anemia are commonly observed indications for one anastomosis gastric bypass (OAGB) reversal and remain significant concerns following the procedure. Sufficient common channel limb length (CCLL) is crucial to minimize nutritional complications. However, limited literature exists regarding the impact of CCLL on OAGB outcomes. This study aimed to assess the effect of CCLL on weight loss and nutritional status in patients who underwent OAGB.

Methods

A prospective cohort study was conducted from August 2021 to July 2022, involving 64 patients with a body mass index of 40–50 kg/m2. The standardized length of the biliopancreatic limb (BPLL) for all patients in this study was set at 175 cm. Additionally, the measurement of the common channel limb length (CCLL) was performed consistently by the same surgeon for all included patients.

Results

The mean age and BMI of the patients were 39.91 ± 10.03 years and 43.13 ± 2.43 kg/m2, respectively, at the time of surgery. There was a statistically significant negative correlation between CCLL and percent total weight loss (%TWL) at the 12-month mark after OAGB (P = 0.02). Hypoalbuminemia was observed in one patient (1.6%), while anemia was present in 17 patients (26.6%) at the one-year follow-up. Statistical analysis revealed no significant difference in the incidence of anemia and hypoalbuminemia between patients with CCLL < 4 m and those with CCLL ≥ 4 m.

Conclusion

A CCLL of 4 m does not appear to completely prevent nutritional complications following OAGB. However, maintaining a CCLL of at least 4 m may be associated with a reduced risk of postoperative nutritional deficiencies.
Generalist, specialist, or expert in palliative care? A cross-sectional open survey on healthcare professionals’ self-description
Authors: van Zuilekom Ingrid , Metselaar Suzanne , Godrie Fleur , Onwuteaka-Philipsen Bregje , van Os-Medendorp Harmieke
Published: May 2024

Background

In the Netherlands, palliative care is provided by generalist healthcare professionals (HCPs) if possible and by palliative care specialists if necessary. However, it still needs to be clarified what specialist expertise entails, what specialized care consists of, and which training or work experience is needed to become a palliative care specialist. In addition to generalists and specialists, ‘experts’ in palliative care are recognized within the nursing and medical professions, but it is unclear how these three roles relate. This study aims to explore how HCPs working in palliative care describe themselves in terms of generalist, specialist, and expert and how this self-description is related to their work experience and education.

Methods

A cross-sectional open online survey with both pre-structured and open-ended questions among HCPs who provide palliative care. Analyses were done using descriptive statistics and by deductive thematic coding of open-ended questions.

Results

Eight hundred fifty-four HCPs filled out the survey; 74% received additional training, and 79% had more than five years of working experience in palliative care. Based on working experience, 17% describe themselves as a generalist, 34% as a specialist, and 44% as an expert. Almost three out of four HCPs attributed their level of expertise on both their education and their working experience. Self-described specialists/experts had more working experience in palliative care, often had additional training, attended to more patients with palliative care needs, and were more often physicians as compared to generalists. A deductive analysis of the open questions revealed the similarities and distinctions between the roles of a specialist and an expert. Seventy-six percent of the respondents mentioned the importance of having both specialists and experts and wished more clarity about what defines a specialist or an expert, how to become one, and when you need them. In practice, both roles were used interchangeably. Competencies for the specialist/expert role consist of consulting, leadership, and understanding the importance of collaboration.

Conclusions

Although the grounds on which HCPs describe themselves as generalist, specialist, or experts differ, HCPs who describe themselves as specialists or experts mostly do so based on both their post-graduate education and their work experience. HCPs find it important to have specialists and experts in palliative care in addition to generalists and indicate more clarity about (the requirements for) these three roles is needed.
Luteolin attenuates CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11
Authors: Han Zhiqiang , Batudeligen  , Chen Hongmei , Narisu  , Anda  , Xu Yanhua , Xue Lan
Published: May 2024

Background

Luteolin (3,4,5,7-tetrahydroxy flavone) is reported to strongly protect from acute carbon tetrachloride (CCl4) -induced liver injury or fibrosis. Ferroptosis can be induced by hepatic injury, and contributes to liver fibrosis development. The exact functional mechanism underlying luteolin inhibition of hepatic injury and whether ferroptosis is involved are unclear.

Methods

Mice model and cell model of liver injury were constructed or induced to explore the effect and molecular mechanisms of Luteolin in the treatment of hepatic injury using CCl4. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to evaluate HepG2 cell viability and apoptosis. The differential expressed genes involved in liver injury were scanned using RNA-seq and confirmed using functional study. Western blot was used to detect the indicators related to ferroptosis.

Results

Luteolin attenuated hepatic injury by alleviating cell morphology and decreasing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels in vivo mice models, and increasing cell viability, downregulating arachidonate 12-lipoxygenase (ALOX12), cyclooxygenase-2 (COX-2) and P21 protein expression, suppressing apoptosis in vitro cell models. Luteolin also inhibited ferroptosis by stimulating glutathione peroxidase 4 (GPX4) and mitochondrial ferritin (FTMT) protein expression, increasing glutathione (GSH) content, and minimizing Fe2+ and malondialdehyde (MDA) levels. Solute carrier family 7a member 11 (SLC7A11) was identified to be a key regulatory gene that participated in luteolin attenuation of CCl4-induced hepatic injuries in HepG2 cells using Microarray assay. Functional study showed that SLC7A11 can alleviate hepatic injury and ferroptosis.

Conclusion

Luteolin attenuated CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11. SLC7A11 may serve as a novel alternative therapeutic target for hepatic injury.
Refusal of patients: care for people without health insurance in German emergency departments
Authors: Zimmer Matthias
Published: May 2024

In case of an emergency, health insurance in Germany provides easy access to medical care in emergency departments. Over 100,000 people do not have health insurance for various reasons. They are repeatedly refused treatment in emergency rooms as their right to care outside of regular insurance is often unknown or ignored.
Comparison of barriers to effective nurse-patient communication in COVID-19 and non-COVID-19 wards
Authors: Bakhshi Hamed , Shariati Mohammad Javad , Basirinezhad Mohammad Hasan , Ebrahimi Hossein
Published: May 2024

Background

Communication is a basic need of humans. Identifying factors that prevent effective nurse-patient communication allows for the better implementation of necessary measures to modify barriers. This study aims to compare the barriers to effective nurse-patient communication from the perspectives of nurses and patients in COVID-19 and non-COVID-19 wards.

Materials and methods

This cross-sectional descriptive study was conducted in 2022. The participants included 200 nurses (by stratified sampling method) and 200 patients (by systematic random sampling) referred to two conveniently selected hospitals in Shahroud, Iran. The inclusion criteria for nurses were considered having at least a bachelor’s degree and a minimum literacy level for patients to complete the questionnaires. Data were collected by the demographic information form and questionnaire with 30 and 15 questions for nurses and patients, which contained similar questions to those for nurses, based on a 5-point Likert scale. Data were analysis using descriptive indices and inferential statistics (Linear regression) in SPSS software version 18.

Results

The high workload of nursing, excessive expectations of patients, and the difficulty of nursing work were identified by nurses as the main communication barriers. From the patients’ viewpoints, the aggressiveness of nurses, the lack of facilities (welfare treatment), and the unsanitary conditions of their rooms were the main communication barriers. The regression model revealed that the mean score of barriers to communication among nurses would decrease to 0.48 for each unit of age increase. Additionally, the patient’s residence explained 2.3% of the nurses’ barriers to communication, meaning that native participants obtained a mean score of 2.83 units less than non-native nurses, and there was no statistically significant difference between the COVID and non-COVID wards.

Conclusion

In this study, the domain of job characteristics was identified by nurses as the major barrier, and patients emphasized factors that were in the domain of individual/social factors. There is a pressing need to pay attention to these barriers to eliminate them through necessary measures by nursing administrators.
GPS2 ameliorates cigarette smoking-induced pulmonary vascular remodeling by modulating the ras-Raf-ERK axis
Authors: Hu Ting , Mu Chaohui , Li Yanmiao , Hao Wanming , Yu Xinjuan , Wang Yixuan , Han Wei , Li Qinghai
Published: May 2024

Background

Mitogen-activated protein kinase (MAPK)signaling-mediated smoking-associated pulmonary vascular remodeling (PVR) plays an important role in the pathogenesis of group 3 pulmonary hypertension (PH). And G protein pathway suppressor 2 (GPS2) could suppress G-protein signaling such as Ras and MAPK, but its role in cigarette smoking -induced PVR (CS-PVR) is unclear.

Methods

An in vivo model of smoke-exposed rats was constructed to assess the role of GPS2 in smoking-induced PH and PVR. In vitro, the effects of GPS2 overexpression and silencing on the function of human pulmonary arterial smooth cells (HPASMCs) and the underlying mechanisms were explored.

Results

GPS2 expression was downregulated in rat pulmonary arteries (PAs) and HPASMCs after CS exposure. More importantly, CS-exposed rats with GPS2 overexpression had lower right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and wall thickness (WT%) than those without. And enhanced proliferation and migration of HPASMCs induced by cigarette smoking extract (CSE) can be evidently inhibited by overexpressed GPS2. Besides, GPS2siRNA significantly enhanced the proliferation, and migration of HPASMCs as well as activated Ras and Raf/ERK signaling, while these effects were inhibited by zoledronic acid (ZOL). In addition, GPS2 promoter methylation level in rat PAs and HPASMCs was increased after CS exposure, and 5-aza-2-deoxycytidine (5-aza) inhibited CSE-induced GPS2 hypermethylation and downregulation in vitro.

Conclusions

GPS2 overexpression could improve the CS-PVR, suggesting that GPS2 might serve as a novel therapeutic target for PH-COPD in the future.

Graphical Abstract
Evidence of Plasmodium vivax circulation in western and eastern regions of Senegal: implications for malaria control
Authors: Badiane Aida S. , Ngom Bassirou , Ndiaye Tolla , Cunningham Deirdre , Campbell James , Gaye Amy , Sène Aita , Sy Mouhamad , Ndiaye Daouda , Nwakanma Davis , Langhorne Jean
Published: May 2024

Background

Malaria elimination in Senegal requires accurate diagnosis of all Plasmodium species. Plasmodium falciparum is the most prevalent species in Senegal, although Plasmodium malariae, Plasmodium ovale, and recently Plasmodium vivax have also been reported. Nonetheless, most malaria control tools, such as Histidine Rich Protein 2 rapid diagnosis test (PfHRP2-RDT,) can only diagnose P. falciparum. Thus, PfHRP2-RDT misses non-falciparum species and P. falciparum infections that fall below the limit of detection. These limitations can be addressed using highly sensitive Next Generation Sequencing (NGS). This study assesses the burden of the four different Plasmodium species in western and eastern regions of Senegal using targeted PCR amplicon sequencing.

Methods

Three thousand samples from symptomatic and asymptomatic individuals in 2021 from three sites in Senegal (Sessene, Diourbel region; Parcelles Assainies, Kaolack region; Gabou, Tambacounda region) were collected. All samples were tested using PfHRP2-RDT and photoinduced electron transfer polymerase chain reaction (PET-PCR), which detects all Plasmodium species. Targeted sequencing of the nuclear 18S rRNA and the mitochondrial cytochrome B genes was performed on PET-PCR positive samples.

Results

Malaria prevalence by PfHRP2-RDT showed 9.4% (94/1000) and 0.2% (2/1000) in Diourbel (DBL) and Kaolack (KL), respectively. In Tambacounda (TAM) patients who had malaria symptoms and had a negative PfHRP2-RDT were enrolled. The PET-PCR had a positivity rate of 23.5% (295/1255) overall. The PET-PCR positivity rate was 37.6%, 12.3%, and 22.8% in Diourbel, Kaolack, and Tambacounda, respectively. Successful sequencing of 121/295 positive samples detected P. falciparum (93%), P. vivax (2.6%), P. malariae (4.4%), and P. ovale wallikeri (0.9%). Plasmodium vivax was co-identified with P. falciparum in thirteen samples. Sequencing also detected two PfHRP2-RDT-negative mono-infections of P. vivax in Tambacounda and Kaolack.

Conclusion

The findings demonstrate the circulation of P. vivax in western and eastern Senegal, highlighting the need for improved malaria control strategies and accurate diagnostic tools to better understand the prevalence of non-falciparum species countrywide.
DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma
Authors: Liu Yangfan , Sun Yu , Yang Jin , Wu Deyang , Yu Shuang , Liu Junjiang , Hu Tao , Luo Jingjing , Zhou Hongmei
Published: May 2024

Background

The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear.

Methods

The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation.

Results

We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3β collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback.

Conclusions

Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.
RICTOR/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition
Authors: Ponzone Luca , Audrito Valentina , Landi Claudia , Moiso Enrico , Levra Levron Chiara , Ferrua Sara , Savino Aurora , Vitale Nicoletta , Gasparrini Massimiliano , Avalle Lidia , Vantaggiato Lorenza , Shaba Enxhi , Tassone Beatrice , Saoncella Stefania , Orso Francesca , Viavattene Daniele , Marina Eleonora , Fiorilla Irene , Burrone Giulia , Abili Youssef , Altruda Fiorella , Bini Luca , Deaglio Silvia , Defilippi Paola , Menga Alessio , Poli Valeria , Porporato Paolo Ettore , Provero Paolo , Raffaelli Nadia , Riganti Chiara , Taverna Daniela , Cavallo Federica , Calautti Enzo
Published: May 2024

Background

The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM.

Methods

After analyzing The Cancer Genome Atlas MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600EMM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo.

Results

Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600Ecells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi.

Conclusions

Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600Emelanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner.
Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis
Authors: Boulestreau Jérémy , Maumus Marie , Bertolino Giuliana M. , Toupet Karine , Jorgensen Christian , Noël Daniéle
Published: May 2024

Age is the most important risk factor in degenerative diseases such as osteoarthritis (OA), which is associated with the accumulation of senescent cells in the joints. Here, we aimed to assess the impact of senescence on the therapeutic properties of extracellular vesicles (EVs) from human fat mesenchymal stromal cells (ASCs) in OA. We generated a model of DNA damage-induced senescence in ASCs using etoposide and characterized EVs isolated from their conditioned medium (CM). Senescent ASCs (S-ASCs) produced 3-fold more EVs (S-EVs) with a slightly bigger size and that contain 2-fold less total RNA. Coculture experiments showed that S-ASCs were as efficient as healthy ASCs (H-ASCs) in improving the phenotype of OA chondrocytes cultured in resting conditions but were defective when chondrocytes were proliferating. S-EVs were also impaired in their capacity to polarize synovial macrophages towards an anti-inflammatory phenotype. A differential protein cargo mainly related to inflammation and senescence was detected in S-EVs and H-EVs. Using the collagenase-induced OA model, we found that contrary to H-EVs, S-EVs could not protect mice from cartilage damage and joint calcifications, and were less efficient in protecting subchondral bone degradation. In addition, S-EVs induced a pro-catabolic and pro-inflammatory gene signature in the joints of mice shortly after injection, while H-EVs decreased hypertrophic, catabolic and inflammatory pathways. In conclusion, S-EVs are functionally impaired and cannot protect mice from developing OA.
A novel conductive microtubule hydrogel for electrical stimulation of chronic wounds based on biological electrical wires
Authors: Fan Weijing , Yang Xiao , Hu Xiaoming , Huang Renyan , Shi Hongshuo , Liu Guobin
Published: May 2024

Electrical stimulation (ES) is considered a promising therapy for chronic wounds via conductive dressing. However, the lack of a clinically suitable conductive dressing is a serious challenge. In this study, a suitable conductive biomaterial with favorable biocompatibility and conductivity was screened by means of an inherent structure derived from the body based on electrical conduction in vivo. Ions condensed around the surface of the microtubules (MTs) derived from the cell’s cytoskeleton are allowed to flow in the presence of potential differences, effectively forming a network of biological electrical wires, which is essential to the bioelectrical communication of cells. We hypothesized that MT dressing could improve chronic wound healing via the conductivity of MTs applied by ES. We first developed an MT-MAA hydrogel by a double cross-linking method using UV and calcium chloride to improve chronic wound healing by ES. In vitro studies showed good conductivity, mechanical properties, biocompatibility, and biodegradability of the MT-MAA hydrogel, as well as an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to ES. The in vivo experimental results from a full-thickness diabetic wound model revealed rapid wound closure within 7d in C57BL/6J mice, and the wound bed dressed by the MT-MAA hydrogel was shown to have promoted re-epithelization, enhanced angiogenesis, accelerated nerve growth, limited inflammation phases, and improved antibacterial effect under the ES treatment. These preclinical findings suggest that the MT-MAA hydrogel may be an ideal conductive dressing for chronic wound healing. Furthermore, biomaterials based on MTs may be also promising for treating other diseases.
A descriptive study on diagnostic timelines, and factors influencing delayed diagnosis among adult head and neck cancer patients at Uganda cancer institute
Authors: Lalango Fiona , Kabagenyi Fiona , Seguya Amina , Byaruhanga Richard , Otiti Jeff
Published: May 2024

Background

Many patients with head and neck cancer (HNC) often present with advanced disease. This may result from delay in deciding to seek care, delay in reaching the healthcare facility and or delay in accessing care in the healthcare facility. We therefore set out to determine the time to definitive diagnosis and factors associated with delayed diagnosis among patients with HNC at the Uganda Cancer Institute (UCI).

Methods

A cross-sectional study was conducted at UCI, patients with HNC were recruited. An interviewer administered questionnaire was used to collect data on sociodemographic factors and clinical characteristics, including timelines in months, from symptom onset to deciding to seek care, to reaching the health care facility and to definitive diagnosis. Multivariate Poisson regression analysis was used to calculate odds ratios (ORs) for the factors of association with delayed diagnosis.

Results

We recruited 160 HNC patients, and 134 patients were analyzed. The median age was 49.5 years (IQR 26.5), 70% (94 of 134) were male, 48% (69 of 134) had below secondary school education, 49% (65 of 134) had a household income < 54 USD. 56% (76 of 134) were sole bread winners, 67% (89 of 134) had good access road condition to the nearest health unit and 70% (91 of 134) presented with tumor stage 4. Median time from onset of symptoms to definitive diagnosis was 8.1 months (IQR 15.1) and 65% (87 of 134) of patients had delayed diagnosis. Good access roads (aOR: 0.26, p = 0.006), secondary school education (aOR: 0.17, p = 0.038), and household income > 136 USD (aOR: 0.27, p = 0.043) were associated with lower odds of delayed diagnosis. Being the sole bread winner (aOR: 2.15, p = 0.050) increased the odds of delayed diagnosis.

Conclusion

Most of HNC patients (65%) at UCI had delayed diagnosis. A national care pathway for individuals with suspected HNC should be established and consider rotation of Ear, Nose and Throat surgeons to underserved regions, to mitigate diagnostic delay.
Emerging roles of lactate in acute and chronic inflammation
Authors: Fang Yunda , Li Zhengjun , Yang Lili , Li Wen , Wang Yutong , Kong Ziyang , Miao Jia , Chen Yanqi , Bian Yaoyao , Zeng Li
Published: May 2024

Traditionally, lactate has been considered a ‘waste product’ of cellular metabolism. Recent findings have shown that lactate is a substance that plays an indispensable role in various physiological cellular functions and contributes to energy metabolism and signal transduction during immune and inflammatory responses. The discovery of lactylation further revealed the role of lactate in regulating inflammatory processes. In this review, we comprehensively summarize the paradoxical characteristics of lactate metabolism in the inflammatory microenvironment and highlight the pivotal roles of lactate homeostasis, the lactate shuttle, and lactylation (‘lactate clock’) in acute and chronic inflammatory responses from a molecular perspective. We especially focused on lactate and lactate receptors with either proinflammatory or anti-inflammatory effects on complex molecular biological signalling pathways and investigated the dynamic changes in inflammatory immune cells in the lactate-related inflammatory microenvironment. Moreover, we reviewed progress on the use of lactate as a therapeutic target for regulating the inflammatory response, which may provide a new perspective for treating inflammation-related diseases.
Bcl-2 dependent modulation of Hippo pathway in cancer cells
Authors: D’Aguanno Simona , Brignone Matteo , Scalera Stefano , Chiacchiarini Martina , Di Martile Marta , Valentini Elisabetta , De Nicola Francesca , Ricci Alessia , Pelle Fabio , Botti Claudio , Maugeri-Saccà Marcello , Del Bufalo Donatella
Published: May 2024

Introduction

Bcl-2 and Bcl-xL are the most studied anti-apoptotic members of Bcl-2 family proteins. We previously characterized both of them, not only for their role in regulating apoptosis and resistance to therapy in cancer cells, but also for their non-canonical functions, mainly including promotion of cancer progression, metastatization, angiogenesis, and involvement in the crosstalk among cancer cells and components of the tumor microenvironment. Our goal was to identify transcriptional signature and novel cellular pathways specifically modulated by Bcl-2.

Methods

We performed RNAseq analysis of siRNA-mediated transient knockdown of Bcl-2 or Bcl-xL in human melanoma cells and gene ontology analysis to identify a specific Bcl-2 transcriptional signature. Expression of genes modulated by Bcl-2 and associated to Hippo pathway were validated in human melanoma, breast adenocarcinoma and non-small cell lung cancer cell lines by qRT-PCR. Western blotting analysis were performed to analyse protein expression of upstream regulators of YAP and in relation to different level of Bcl-2 protein. The effects of YAP silencing in Bcl-2 overexpressing cancer cells were evaluated in migration and cell viability assays in relation to different stiffness conditions. In vitro wound healing assays and co-cultures were used to evaluate cancer-specific Bcl-2 ability to activate fibroblasts.

Results

We demonstrated the Bcl-2-dependent modulation of Hippo Pathway in cancer cell lines from different tumor types by acting on upstream YAP regulators. YAP inhibition abolished the ability of Bcl-2 to increase tumor cell migration and proliferation on high stiffness condition of culture, to stimulate in vitro fibroblasts migration and to induce fibroblasts activation.

Conclusions

We discovered that Bcl-2 regulates the Hippo pathway in different tumor types, promoting cell migration, adaptation to higher stiffness culture condition and fibroblast activation. Our data indicate that Bcl-2 inhibitors should be further investigated to counteract cancer-promoting mechanisms.