bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 testing protocols to guide duration of isolation: a cost-effectiveness analysis
Authors: Maya Sigal , Kahn James G.
Published: May 2023

Background

The Omicron variant of SARS-CoV-2 led to a steep rise in transmissions, and emerging variants continue to influence case rates across the US. As public tolerance for isolation abated, CDC guidance on duration of at-home isolation of COVID-19 cases was shortened to five days if no symptoms, with no laboratory test requirement, despite more cautious approaches advocated by other federal experts.

Methods

We conducted a decision tree analysis of alternative protocols for ending COVID-19 isolation, estimating net costs (direct and productivity), secondary infections, and incremental cost-effectiveness ratios. Sensitivity analyses assessed the impact of input uncertainty.

Results

Per 100 individuals, five-day isolation had 23 predicted secondary infections and a net cost of $33,000. Symptom check on day five (CDC guidance) yielded a 23% decrease in secondary infections (to 17.8), with a net cost of $45,000. Antigen testing on day six yielded 2.9 secondary infections and $63,000 in net costs. This protocol, compared to the next best protocol of antigen testing on day five of a maximum eight-day isolation, cost an additional $1,300 per secondary infection averted. Antigen or polymerase chain reaction testing on day five were dominated (more expensive and less effective) versus antigen testing on day six. Results were qualitatively robust to uncertainty in key inputs.

Conclusions

A six-day isolation with antigen testing to confirm the absence of contagious virus appears the most effective and cost-effective de-isolation protocol to shorten at-home isolation of individuals with COVID-19.
The gap height in open wedge high tibial osteotomy is not affected by the starting point of the osteotomy
Authors: Mederake Moritz , Eleftherakis Georgios , Schüll Daniel , Springer Fabian , Maffulli Nicola , Migliorini Filippo , Konrads Christian
Published: May 2023

Introduction

In open-wedge high-tibial-osteotomy (OWHTO), most surgeons use a preoperative planning software and realise that they should match the intraoperative alignment correction with the preoperative plan. We aimed to determine whether there is a difference in osteotomy gap height when starting the OWHTO either 3 or 4 cm distal to the joint line. This should help to clarify whether the osteotomy starting point must exactly match the preoperative planning.

Methods

25 patients with constitutional varus alignment were planned for OWHTO. Long-leg-standing-radiographs and mediCAD-software were used. Osteotomy was planned to a neutral Hip-Knee-Ankle angle (HKA) of 0°. The osteotomy-starting-point was either 3 or 4 cm distal to the medial joint line. The following angles were compared: mechanical medial proximal tibial angle (mMPTA), mechanical lateral distal femoral angle (mLDFA), joint line conversion angle (JCA), mechanical Tibio-Femoral angle (mTFA) or Hip Knee Ankle (HKA) angle.

Results

25 Patients (18 males, 7 females) had a mean age of 62 ± 16.6 years and showed a varus-aligned leg-axis. The HKA was − 5.96 ± 3.02° with a mMPTA of 82.22 ± 1.14°. After osteotomy-planning to a HKA of 0°, the mMPTA was 88.94 ± 3.01°. With a mean wedge height of 8.08 mm when locating the osteotomy 3 cm and a mean wedge height of 8.05 mm when locating the osteotomy 4 cm distal to the joint-line, there was no statistically significant difference (p = 0.7).

Conclusion

When performing an OWHTO aiming towards the tip of the fibula, the osteotomy starting point does not need to exactly match the planned starting-location of the osteotomy. A starting-point 1 cm more distal or proximal than previously determined through the digital planning does not alter the size of the osteotomy gap needed to produce the desired amount of correction.
Guidance of adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient derived organoids: a single center, open-label, phase II trial
Authors: Seiler Roland , Egger Martin , De Menna Marta , Wehrli Saskia , Minoli Martina , Radić Martina , Lyatoshinsky Pavel , Hösli Raphael , Blarer Jennifer , Abt Dominik , Kruithof-de Julio Marianna
Published: May 2023

Background

In intermediate-risk non-muscle invasive bladder cancer (NMIBC) clinical guidelines suggest an adjuvant instillation with a chemotherapeutic agent. However, the agent and regimen are not clearly defined. Worldwide, less than 15% of patients receive this adjuvant chemotherapeutic instillation. We recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In this phase II trial, we aim to use our in vitro pipeline to select the most effective drug for chemotherapeutic instillation in NMIBC patients.

Methods

Patients with first diagnosis of intermediate-risk NMIBC that are directed to transurethral resection of bladder tumor (TURBT) are enrolled. During TURBT, tumor is sampled, and specimens are directed to generate PDO. Once the PDO are formed, drug screens on them for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel are performed. The drug with the highest antitumor activity in vitro will then be selected for 6 adjuvant intravesical instillations once weekly. Thereafter, patients are followed according to clinical guidelines by cystoscopy.

Discussion

The aim of this trial is to use drug screens in PDO to precise treatment selection for adjuvant instillation therapies in patients with intermediate-risk NMIBC. The ultimate goal of this trial is to reduce the risk of cancer recurrence. In the future, we aim to conduct clinical multicenter trials with an increased sample size, a broader panel of compounds and a focus on the reduction of cancer recurrence by precision delivery of care.

Trial registration NCT05024734.
Stress distribution and fracture resistance of green reprocessed polyetheretherketone (PEEK) single implant crown restorations compared to unreprocessed PEEK and Zirconia: an in-vitro study
Authors: Emam Marwa , Arafa Ahmed Mohamed
Published: May 2023

Background

It is unclear which crown materials are optimum to disperse the generated stresses around dental implants. The objective of this study is to assess stress distribution and fracture resistance of green reprocessed Polyetheretherketone (PEEK) in comparison to un-reprocessed PEEK and zirconia single implant crown restorations.

Methods

Twenty crowns (n = 20) were obtained, five from zirconia and fifteen from pressed PEEK that were subdivided into 3 groups of five specimens each (n = 5) according to weight% of reprocessed material used. A 100% new PEEK was used for the first group, 50% new and 50% reprocessed PEEK were used for the second group, and a 100% reprocessed PEEK was used for the third group. Epoxy resin model with dental implant in the second mandibular premolar was constructed with strain gauges located mesially and distally to the implant to record strain while a load of 100 N was applied with 0.5 mm/min then specimens of all groups were vertically loaded till failure in a universal testing machine at cross head speed 1 mm/min. Data was statistically analyzed by using One-way Analysis of Variance (ANOVA) followed by Post-hoc test when ANOVA test is significant.

Results

No significant difference between strain values of tested groups (p = 0.174) was noticed. However, a significant difference between fracture resistance values was noticed where the zirconia group recorded a significantly higher value (p < 0.001).

Conclusions

Implant restorative materials with different moduli of elasticity have similar effects regarding stresses distributed through dental implant and their surrounding bone. Reprocessed PEEK implant restorations transmit similar stresses to dental implant and surrounding bone as non-reprocessed PEEK and zirconia restorations. Zirconia failed at higher load values than all tested PEEK restorations but all can be safely used in the posterior area as crown restorations for single implants.

Clinical relevance

Applying “green dentistry” principles may extend to include reprocessing of pressed PEEK restorative materials without affecting the material’s shock absorption properties.
Rural-urban disparities in preventive breast and cervical cancer screening among women with early-onset dementia
Authors: Xu Wendy Y. , Raver Eli , Jung Jeah , Li Yiting , Thai Gaby , Lee Sunmin
Published: May 2023

Background

The early onset of Alzheimer’s disease and related dementias (ADRD) before age 65 can introduce life and health care complications. Preserving an early-onset ADRD patient’s daily functioning longer and delaying declines in health from non-ADRD conditions become important preventive goals. This study examined the differences in utilization of preventive cancer screenings between patients with and without early-onset ADRD, and compared utilization of the screenings in rural versus urban areas among women with early-onset ADRD in the United States.

Methods

We conducted a cross-sectional study of women aged 40 to 64 years eligible for mammogram and cervical cancer screenings using commercial insurance claims from 2012 to 2018. We measured the use of biennial mammogram among women 50 to 64 years old, and the use of triennial Pap smear test among women 40 to 64 years old. We used inverse probability weighted logistic regressions to estimate the odds of receiving preventive cancer screenings by the presence of early-onset ADRD or cognitive impairments (CI). We used multivariable logistic regressions to estimate the odds of receiving preventive cancer screenings by rural or urban residence among women with early-onset ADRD/CI.

Results

Among 6,349,308 women in the breast cancer screening sample (mean [SD] age, 56.52 [4.03] years), 36,131 had early-onset ADRD/CI (mean [SD] age, 57.99 [3.98] years). Among 6,583,088 women in the cervical cancer screening sample (mean [SD] age, 52.37 [6.81] years), 30,919 had early-onset ADRD/CI (mean [SD] age, 55.79 [6.22] years). Having early-onset ADRD/CI was associated with lower utilization of mammogram (OR: 0.92, 95% CI: 0.90–0.95). No significant difference was observed in Pap smear screening (OR: 0.99, 95% CI: 0.96–1.02) between patients with and without early-onset ADRD/CI. Among patients with early-onset ADRD/CI, those in rural areas were less likely than those in urban areas to have mammograms (OR: 0.91, 95% CI: 0.85–0.97) and Pap smears (OR: 0.65, 95% CI: 0.61–0.71).

Conclusions

The observed pattern of rural-urban differences in cancer screening in our study emphasizes the need for efforts to promote evidence-based, individualized decision-making processes in the early-onset ADRD population.
Cultural competence of nursing educators at medical universities of 2nd regional planning in Iran
Authors: Majnoon Sahand , Yates Vivian M. , Asgarpour Hossein , Mirza Aghazadeh Attari Ahmad , Lotfi Mojgan
Published: May 2023

Background

One of the facets of nursing care, as a holistic profession, is cultural care. Considering the role of culture in individuals’ health behaviors, nurses are recommended to be mindful of cultural care. Since nursing educators should be culturally competent to teach cultural care to students, this study aimed to determine the cultural competence of nursing educators of medical sciences universities in the 2nd regional planning in Iran.

Methods

The current research was a descriptive and survey study framed within Campinha-Bacote’s cultural competency model. All nursing educators of universities of medical sciences in the 2nd regional planning of Iran (Tabriz, Urmia, Ardabil, Khoy, Maragheh, Sarab, and Khalkhal) were considered as research units, and the cultural diversity questionnaire for nursing faculties (CDQNE-R) was sent to them. Out of 129 questionnaires sent, 84 were turned back. The data were analyzed by the SPSS 22 software.

Results

The results of this study showed that the research participants agreed with the subscales of cultural awareness, cultural knowledge, cultural skill, and cultural desire according to Sealey and Yates’ interpretation scale. Also, the research units cast doubts on the cultural encounter subscale. The mean scores of the participants’ responses to the questions of every subscale equaled 4.11, 3.52, 3.71, 3.38, and 3.93 for the subscales of cultural awareness, cultural knowledge, cultural skill, cultural encounter, and cultural desire, respectively. Likewise, the mean scores of participants’ responses to the subscales of transcultural educational behaviors and general cultural competence equaled 3.90 and 3.73.

Conclusions

The nursing faculties participating in the present study agreed with the 4 sub-models of Campinha-Bacote cultural care and the presence of cultural competence criteria. Also, the research units had doubts about the cultural encounter subscale. This result means that the research participants were undecided about their level of participation in face-to-face interactions with people from different cultural, racial, and ethnic groups. According to the results of the study, it is important to hold transcultural nursing training workshops and courses to maintain and improve the level of cultural competence of nursing faculties at universities of medical sciences in the 2nd regional planning in Iran.
The relationship between succession and intellectual capital with entrepreneurship in hospitals
Authors: Rafiei Shoaib , Mehrtak Mohammad , Amerzadeh Mohammad , Rafiei Sima , Moosavi Saeideh , Kalhor Rohollah
Published: May 2023

Background

The hospital environment is very dynamic and faces many internal and external changes. Healthcare knowledge and technology are developing at a swift pace. This study investigated the relationship between succession and intellectual capital with entrepreneurship at the Qazvin University of Medical Sciences hospital, Iran.

Methods

The number of employees working in six hospitals was 2256, and according to Morgan’s table, the required number of samples was 331. We distributed three hundred sixty-five questionnaires considering 10% of sample loss. We used a multi-stage stratified sampling method. In the first stage, each hospital was considered a stratum. After that, occupational groups were considered the next stratum within each hospital, and based on the ratio, the required number of samples for each occupational group was randomly selected. We used the Sobel test to investigate the mediating role of intellectual capital and the structural equation model to fit the research model.

Results

Succession aspects, including culturalization, meritocracy, job promotion path, and the role of senior managers, have a positive and significant effect on intellectual capital. Succession is only effective on intellectual capital and does not affect the personnel’s entrepreneurship directly or through intellectual capital.

Conclusion

Conducting training classes and intervention programs and using localized succession models can create a suitable platform for increasing organizational creativity and entrepreneurship, motivating the hospitals’ personnel, and increasing intellectual capital.
Feasibility and acceptability of involving bilingual community navigators to improve access to health and social care services in general practice setting of Australia
Authors: Mistry Sabuj Kanti , Harris Elizabeth , Li Xue , Harris Mark F.
Published: May 2023

Background

Patients from culturally and linguistically diverse (CALD) backgrounds often face difficulties in accessing health and social care services. This study explored the feasibility and acceptability of involving community health workers (CHWs) as bilingual community navigators (BCNs) in general practice setting, to help patients from CALD backgrounds access health and social care services in Australia.

Methods

This research was conducted in two general practices in Sydney where most patients are from specific CALD backgrounds (Chinese in one practice and Samoan in other). Three CHWs trained as BCNs were placed in these practices to help patients access health and social care service. A mixed-method design was followed to explore the feasibility and acceptability of this intervention including analysis of a record of services provided by BCNs and post-intervention qualitative interviews with patients, practice staff and BCNs exploring the feasibility and acceptability of the BCNs’ role. The record was analyzed using descriptive statistics and interviews were audio-recorded, transcribed, and thematically analyzed.

Results

BCNs served a total of 95 patients, providing help with referral to other services (52.6%), information about appointments (46.3%), local resources (12.6%) or available social benefits (23.2%). Most patients received one service from BCNs with the average duration of appointments being half an hour. Overall, BCNs fitted in well within the practices and patients as well as staff of participating practices accepted them well. Their role was facilitated by patients’ felt need for and acceptance of BCNs’ services, recruitment of BCNs from the patient community, as well as BCNs’ training and motivation for their role. Major barriers for patients to access BCNs’ services included lack of awareness of the BCNs’ roles among some patients and practice staff, unavailability of information about local culture specific services, and inadequate time and health system knowledge by BCNs. Limited funding support and the short timeframe of the project were major limitations of the project.

Conclusion

BCNs’ placement in general practice was feasible and acceptable to patients and staff in these practices. This first step needs to be followed by accredited training, development of the workforce and establishing systems for supervision in order to sustain the program. Future research is needed on the extension of the intrevention to other practices and culture groups.
Evolution of loss of heterozygosity patterns in hybrid genomes of Candida yeast pathogens
Authors: Mixão Verónica , Nunez-Rodriguez Juan Carlos , del Olmo Valentina , Ksiezopolska Ewa , Saus Ester , Boekhout Teun , Gacser Attila , Gabaldón Toni
Published: May 2023

Background

Hybrids are chimeric organisms with highly plastic heterozygous genomes that may confer unique traits enabling the adaptation to new environments. However, most evolutionary theory frameworks predict that the high levels of genetic heterozygosity present in hybrids from divergent parents are likely to result in numerous deleterious epistatic interactions. Under this scenario, selection is expected to favor recombination events resulting in loss of heterozygosity (LOH) affecting genes involved in such negative interactions. Nevertheless, it is so far unknown whether this phenomenon actually drives genomic evolution in natural populations of hybrids. To determine the balance between selection and drift in the evolution of LOH patterns in natural yeast hybrids, we analyzed the genomic sequences from fifty-five hybrid strains of the pathogenic yeasts Candida orthopsilosis and Candida metapsilosis, which derived from at least six distinct natural hybridization events.

Results

We found that, although LOH patterns in independent hybrid clades share some level of convergence that would not be expected from random occurrence, there is an apparent lack of strong functional selection. Moreover, while mitosis is associated with a limited number of inter-homeologous chromosome recombinations in these genomes, induced DNA breaks seem to increase the LOH rate. We also found that LOH does not accumulate linearly with time in these hybrids. Furthermore, some C. orthopsilosis hybrids present LOH patterns compatible with footprints of meiotic recombination. These meiotic-like patterns are at odds with a lack of evidence of sexual recombination and with our inability to experimentally induce sporulation in these hybrids.

Conclusions

Our results suggest that genetic drift is the prevailing force shaping LOH patterns in these hybrid genomes. Moreover, the observed LOH patterns suggest that these are likely not the result of continuous accumulation of sporadic events—as expected by mitotic repair of rare chromosomal breaks—but rather of acute episodes involving many LOH events in a short period of time.
Correlation analysis of lung mucosa-colonizing bacteria with clinical features reveals metastasis-associated bacterial community structure in non-small cell lung cancer patients
Authors: Wang Wenxue , Liang Xiao , Kong Hui , Yang Yun , Xia Yilan , Wang Qiongjiao , Xia Andong , Geng Jiawei
Published: May 2023

Background

Microbes colonizing lower airways can regulate the host immune profile and consequently participate in lung disease. Increasing evidence indicate that individual microbes promote lung cancer progression and are involved in metastasis incidence. To date, however, no study has revealed the community structure of lung bacteria in metastatic non-small cell lung cancer (NSCLC) patients.

Methods

We prospectively enrolled 50 healthy subjects and 57 NSCLC patients. All healthy subjects and NSCLC patients underwent bronchoscope procedures for brush specimen collection. The 16 S ribosomal RNA gene was sequenced to characterize the community structure of lung mucosa-colonizing bacteria. The peripheral blood of NSCLC patients was also measured for leukocytes and cancer markers.

Results

The lung bacteria of healthy subjects and NSCLC patients were divided into four communities. All community 2 members showed increased abundance in NSCLC patients compared with healthy subjects, and most community 2 members showed increased abundance in the metastatic NSCLC patients compared with the non-metastatic group. These bacteria were significantly and positively correlated with eosinophils, neutrophils and monocytes in the metastatic NSCLC group. In addition, the correlation between lung bacteria and cancer markers differed between the metastatic and non-metastatic NSCLC patients. Furthermore, bronchoalveolar lavage fluid from lung adenocarcinoma patients directly promoted NSCLC cell migration.

Conclusions

The community structure of lung mucosa-colonizing bacteria was relatively stable, but changed from the healthy population to NSCLC patients, especially the metastatic group. This distinct community structure and specific correlation with immune cells and cancer markers could help to distinguish NSCLC patients with or without metastasis.
Comparative efficacy and safety of PD-1/PD-L1 inhibitors in triple negative breast cancer: a systematic review and network meta-analysis of randomized controlled trials
Authors: Elmakaty Ibrahim , Abdo Ruba , Elsabagh Ahmed , Elsayed Abdelrahman , Malki Mohammed Imad
Published: May 2023

Background

Triple-Negative Breast Cancer (TNBC) is a lethal subtype of breast cancer with limited treatment options. The purpose of this Network Meta-Analysis (NMA) is to compare the efficacy and safety of inhibitors of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in treating TNBC.

Methods

Our search strategy was used in six databases: PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature database, Embase, Scopus, and Web of Science up to November 2nd, 2022, as well as a thorough search in the most used trial registries. We included phase II and III randomized controlled trials that looked at the efficacy of PD-1/PD-L1 inhibitors in the treatment of TNBC and reported either Overall Survival (OS), Progression-Free Survival (PFS), or pathological Complete Response (pCR). The risk of bias was assessed utilizing Cochrane's risk of bias 2 tool, and the statistical analysis was performed using a frequentist contrast-based method for NMA by employing standard pairwise meta-analysis applying random effects model.

Results

12 trials (5324 patients) were included in our NMA including seven phase III trials. Pembrolizumab in a neoadjuvant setting achieved a pooled OS of 0.82 (95% Confidence Interval (CI) 0.65 to 1.03), a PFS of 0.82 (95% CI 0.71 to 0.94) and a pCR 2.79 (95% CI 1.07 to 7.24) compared to Atezolizumab’s OS of 0.92 (95% CI 0.74 to 1.15), PFS of 0.82 (95% CI 0.69 to 0.97), and pCR of 1.94 (95% CI 0.86 to 4.37). Atezolizumab had less grade ≥ 3 adverse events (OR 1.48, 95% CI 0.90 to 2.42) than Pembrolizumab (OR 1.90, 95% CI 1.08 to 3.33) in the neoadjuvant setting.

Conclusions

PD-1/PD-L1 inhibitors exhibited varying efficacy in terms of OS, PFS, and pCR. They were associated with an increase in immune-related adverse effects. When used early in the course of TNBC, PD-1/PD-L1 inhibitors exert their maximum benefit. Durvalumab as a maintenance treatment instead of chemotherapy has shown promising outcomes. Future studies should focus on PD-L1 expression status and TNBC subtypes, since these factors may contribute to the design of individualized TNBC therapy regimens.

Systematic review registration PROSPERO Identifier: CRD42022380712.
PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin
Authors: Wilson Mike R. , Harkins Shannon , Reske Jake J. , Siwicki Rebecca A. , Adams Marie , Bae-Jump Victoria L. , Teixeira Jose M. , Chandler Ronald L.
Published: May 2023

Endometrial epithelia are known to harbor cancer driver mutations in the absence of any pathologies, including mutations in PIK3CA. Insulin plays an important role in regulating uterine metabolism during pregnancy, and hyperinsulinemia is associated with conditions impacting fertility. Hyperinsulinemia also promotes cancer, but the direct action of insulin on mutated endometrial epithelial cells is unknown. Here, we treated 12Z endometriotic epithelial cells carrying the PIK3CAH1047R oncogene with insulin and examined transcriptomes by RNA-seq. While cells naively responded to insulin, the magnitude of differential gene expression (DGE) was nine times greater in PIK3CAH1047R cells, representing a synergistic effect between insulin signaling and PIK3CAH1047R expression. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in wild-type cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CAH1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CAH1047R expression alone resulted in overexpression (OE) of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CAH1047R cells were rescued by knockdown of Viperin, while Viperin OE alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CAH1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CAH1047R mutant cells. These results suggest that response to insulin signaling is altered in mutated endometriotic epithelial cells.
Stress and polycystic ovarian morphology in functional hypothalamic amenorrhea: a retrospective cohort study
Authors: Hager Marlene , Dewailly Didier , Marculescu Rodrig , Ghobrial Stefan , Parry John Preston , Ott Johannes
Published: May 2023

Background

Women with functional hypothalamic amenorrhea (FHA) reveal polycystic ovarian morphology (PCOM) in up to 50%. If stress sensitivity in women with polycystic ovary syndrome (PCOS) is the reason why PCOS women are prone to develop FHA, patients with FHA caused by stress should reveal PCOM more often.

Methods

In a retrospective cohort study, 38 stress-associated and 38 excessive exercise-induced FHA women were included. The main outcome parameter was PCOM. In addition, the focus was on general patient characteristics as well as on prolactin, dehydroepiandrosterone-sulphate (DHEAS), and anti-Mullerian hormone (AMH).

Results

PCOM was found in 34/76 patients (44.7%). The stress group showed a higher prevalence of PCOM than the excessive exercise group (57.9% versus 31.6%, p = 0.019) as well as higher prolactin levels (median 13.2ng/mL versus 11.7ng/mL, p = 0.008) and a trend towards higher DHEAS levels (p = 0.058).

Conclusions

In FHA women, the PCOM prevalence was significantly higher in the stress-group than in the excessive exercise-group. The well-known stress sensitivity in women with PCOS might explain why PCOS women are prone to develop FHA as well as the high PCOM prevalence in FHA women.
Human pancreatic cancer patients with Epithelial-to-Mesenchymal Transition and an aggressive phenotype show a disturbed balance in Protein Phosphatase Type 2A expression and functionality
Authors: van Pelt Jos , Meeusen Bob , Derua Rita , Guffens Liesbeth , Van Cutsem Eric , Janssens Veerle , Verslype Chris
Published: May 2023

Background

Pancreatic ductal adenocarcinoma (PDAC) has a low survival, its incidence is rising and little therapeutic improvements are expected in the near future. It has been observed that Epithelial-to-Mesenchymal transition (EMT) contributes (including in PDAC) to a more aggressive cancer phenotype. Additionally, largely unexplored, studies indicate a mechanistic interplay between Protein Phosphatase Type 2A (PP2A) enzymes and EMT that could offer treatment opportunities. The aim was to investigate the relation of a PP2A expression signature (encompassing all PP2A subunits, endogenous inhibitors and activators) with EMT and aggressive pancreatic cancer, and to discuss possible implications.

Methods

We retrieved different PDAC expression datasets from NCBI to capture the variation in patients, and analyzed these using datamining, survival analysis, differential gene and protein expression. We determined genes highly associated with aggressive PDAC. For in vitro evaluation, Panc-1 cells were treated with the pharmacologic PP2A inhibitor Okadaic Acid (OA). Additionally, two OA-resistant Panc-1 clones were developed and characterized.

Results

In patients, there is a strong correlation between EMT and aggressive PDAC, and between aggressive PDAC and PP2A, with a significant upregulation of PP2A inhibitor genes. Several PP2A genes significantly correlated with decreased survival. In vitro, short-term exposure to OA induced EMT in Panc-1 cells. This shift towards EMT was further pronounced in the OA-resistant Panc-1 clones, morphologically and by pathway analysis. Proteomic analysis and gene sequencing showed that the advanced OA-resistant model most resembles the clinical PDAC presentation (with EMT signature, and with several specific PP2A genes upregulated, and others downregulated).

Conclusions

We demonstrated a strong association between EMT, altered PP2A expression and aggressive PDAC in patients. Also, in vitro, PP2A inhibition induces EMT. Overall, statistics suggests the mechanistic importance of PP2A dysregulation for PDAC progression. Translationally, our observations indicate that pharmacologic restoration of PP2A activity could be an attractive therapeutic strategy to block or reverse progression.
Potential clinical implications of CD4+CD26high T cells for nivolumab treated melanoma patients
Authors: Galati Domenico , Zanotta Serena , Capone Mariaelena , Madonna Gabriele , Mallardo Domenico , Romanelli Marilena , Simeone Ester , Festino Lucia , Sparano Francesca , Azzaro Rosa , De Filippi Rosaria , Pinto Antonio , Paulos Chrystal M. , Ascierto Paolo A.
Published: May 2023

Background

Nivolumab is an anti-PD1 antibody that has dramatically improved metastatic melanoma patients’ outcomes. Nevertheless, many patients are resistant to PD-1 inhibition, occasionally experiencing severe off-target immune toxicity. In addition, no robust and reproducible biomarkers have yet been validated to identify the correct selection of patients who will benefit from anti-PD-1 treatment avoiding unwanted side effects. However, the strength of CD26 expression on CD4+ T lymphocytes permits the characterization of three subtypes with variable degrees of responsiveness to tumors, suggesting that the presence of CD26-expressing T cells in patients might be a marker of responsiveness to PD-1-based therapies.

Methods

The frequency distribution of peripheral blood CD26-expressing cells was investigated employing multi-parametric flow cytometry in 69 metastatic melanoma patients along with clinical characteristics and blood count parameters at baseline (W0) and compared to 20 age- and sex-matched healthy controls. Percentages of baseline CD4+CD26high T cells were correlated with the outcome after nivolumab treatment. In addition, the frequency of CD4+CD26high T cells at W0 was compared with those obtained after 12 weeks (W1) of therapy in a sub-cohort of 33 patients.

Results

Circulating CD4+CD26high T cells were significantly reduced in melanoma patients compared to healthy subjects (p = 0.001). In addition, a significant association was observed between a low baseline percentage of CD4+CD26high T cells (< 7.3%) and clinical outcomes, measured as overall survival (p = 0.010) and progression-free survival (p = 0.014). Moreover, patients with clinical benefit from nivolumab therapy had significantly higher frequencies of circulating CD4+CD26high T cells than patients with non-clinical benefit (p = 0.004) at 12 months. Also, a higher pre-treatment proportion of circulating CD4+CD26high T cells was correlated with Disease Control Rate (p = 0.014) and best Overall Response Rate (p = 0.009) at 12 months. Interestingly, after 12 weeks (W1) of nivolumab treatment, percentages of CD4+CD26high T cells were significantly higher in comparison with the frequencies measured at W0 (p < 0.0001), aligning the cell counts with the ranges seen in the blood of healthy subjects.

Conclusions

Our study firstly demonstrates that peripheral blood circulating CD4+CD26high T lymphocytes represent potential biomarkers whose perturbations are associated with reduced survival and worse clinical outcomes in melanoma patients.
β-arrestin1 regulates astrocytic reactivity via Drp1-dependent mitochondrial fission: implications in postoperative delirium
Authors: Hua Fuzhou , Zhu Hong , Yu Wen , Zheng Qingcui , Zhang Lieliang , Liang Weidong , Lin Yue , Xiao Fan , Yi Pengcheng , Xiong Yanhong , Dong Yao , Li Hua , Fang Lanran , Liu Hailin , Ying Jun , Wang Xifeng
Published: May 2023

Postoperative delirium (POD) is a frequent and debilitating complication, especially amongst high risk procedures, such as orthopedic surgery. This kind of neurocognitive disorder negatively affects cognitive domains, such as memory, awareness, attention, and concentration after surgery; however, its pathophysiology remains unknown. Multiple lines of evidence supporting the occurrence of inflammatory events have come forward from studies in human patients’ brain and bio-fluids (CSF and serum), as well as in animal models for POD. β-arrestins are downstream molecules of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). As versatile proteins, they regulate numerous pathophysiological processes of inflammatory diseases by scaffolding with inflammation-linked partners. Here we report that β-arrestin1, one type of β-arrestins, decreases significantly in the reactive astrocytes of a mouse model for POD. Using β-arrestin1 knockout (KO) mice, we find aggravating effect of β-arrestin1 deficiency on the cognitive dysfunctions and inflammatory phenotype of astrocytes in POD model mice. We conduct the in vitro experiments to investigate the regulatory roles of β-arrestin1 and demonstrate that β-arrestin1 in astrocytes interacts with the dynamin-related protein 1 (Drp1) to regulate mitochondrial fusion/fission process. β-arrestin1 deletion cancels the combination of β-arrestin1 and cellular Drp1, thus promoting the translocation of Drp1 to mitochondrial membrane to provoke the mitochondrial fragments and the subsequent mitochondrial malfunctions. Using β-arrestin1-biased agonist, cognitive dysfunctions of POD mice and pathogenic activation of astrocytes in the POD-linked brain region are reduced. We, therefore, conclude that β-arrestin1 is a promising target for the understanding of POD pathology and development of POD therapeutics.
Hemagglutinin virus-like particles incorporated with membrane-bound cytokine adjuvants provide protection against homologous and heterologous influenza virus challenge in aged mice
Authors: Park Bo Ryoung , Bommireddy Ramireddy , Chung David Hyunjung , Kim Ki-Hye , Subbiah Jeeva , Jung Yu-Jin , Bhatnagar Noopur , Pack Christopher D. , Ramachandiran Sampath , Reddy Shaker J.C. , Selvaraj Periasamy , Kang Sang-Moo
Published: May 2023

Background

Current influenza vaccines deliver satisfactory results in young people but are less effective in the elderly. Development of vaccines for an ever-increasing aging population has been an arduous challenge due to immunosenescence that impairs the immune response in the aged, both quantitatively and qualitatively.

Results

To potentially enhance vaccine efficacy in the elderly, we investigated the immunogenicity and cross-protection of influenza hemagglutinin virus-like particles (HA-VLP) incorporated with glycosylphosphatidylinositol (GPI)-anchored cytokine-adjuvants (GPI-GM-CSF and GPI-IL-12) via protein transfer in aged mice. Lung viral replication against homologous and heterologous influenza viruses was significantly reduced in aged mice after vaccination with cytokine incorporated VLPs (HA-VLP-Cyt) in comparison to HA-VLP alone. Enhanced IFN-γ+CD4+ and IFN-γ+CD8+ T cell responses were also observed in aged mice immunized with HA-VLP-Cyt when compared to HA-VLP alone.

Conclusions

Cytokine-adjuvanted influenza HA-VLP vaccine induced enhanced protective response against homologous influenza A virus infection in aged mice. Influenza HA-VLP vaccine with GPI-cytokines also induced enhanced T cell responses correlating with better protection against heterologous infection in the absence of neutralizing antibodies. The results suggest that a vaccination strategy using cytokine-adjuvanted influenza HA-VLPs could be used to enhance protection against influenza A virus in the elderly.
Single-cell RNA sequencing reveals the local cell landscape in mouse epididymal initial segment during aging
Authors: Zhuang Jintao , Li Xiangping , Yao Jiahui , Sun Xiangzhou , Liu Jiumin , Nie Hua , Hu Yang , Tu Xiangan , Liu Huang , Qin Weibing , Xie Yun
Published: May 2023

Background

Morphological and functional alterations in aging reproductive organs result in decreased male fertility. The epididymis functions as the transition region for post-testicular sperm maturation. And we have previously demonstrated that the epididymal initial segment (IS), a region of the reproductive tract essential for sperm maturation and capacitation, undergoes considerable histological changes and chronic immune activation in mice during aging. However, the local aging-associated cellular and molecular changes in the aged epididymal IS are poorly understood.

Results

We conducted single-cell RNA sequencing analysis on the epididymal IS of young (3-month-old) and old (21-month-old) mice. In total, 10,027 cells from the epididymal IS tissues of young and old mice were obtained and annotated. The cell composition, including the expansion of a principal cell subtype andMs4a4bHiMs4a6bHiT cells, changed with age. Aged principal cells displayed multiple functional gene expression changes associated with acrosome reaction and sperm maturation, suggesting an asynchronous process of sperm activation and maturation during epididymal transit. Meanwhile, aging-related altered pathways in immune cells, especially the “cell chemotaxis” inCx3cr1Hiepididymal dendritic cells (eDCs), were identified. The monocyte-specific expression of chemokineCcl8increased with age in eDCs. And the aged epididymal IS showed increased inflammatory cell infiltration and cytokine secretion. Furthermore, cell–cell communication analysis indicated that age increased inflammatory signaling in the epididymal IS.

Conclusion

Contrary to the general pattern of lower immune responses in the male proximal genital tract, we revealed an inflammaging status in mouse epididymal initial segment. These findings will allow future studies to enable the delay of male reproductive aging via immune regulation.
Age, dose, and binding to TfR on blood cells influence brain delivery of a TfR-transported antibody
Authors: Faresjö Rebecca , Sehlin Dag , Syvänen Stina
Published: May 2023

Background

Transferrin receptor 1 (TfR1) mediated brain delivery of antibodies could become important for increasing the efficacy of emerging immunotherapies in Alzheimer's disease (AD). However, age, dose, binding to TfR1 on blood cells, and pathology could influence the TfR1-mediated transcytosis of TfR1-binders across the blood–brain barrier (BBB). The aim of the study was, therefore, to investigate the impact of these factors on the brain delivery of a bispecific TfR1-transported Aβ-antibody, mAb3D6-scFv8D3, in comparison with the conventional antibody mAb3D6.

Methods

Young (3–5 months) and aged (17–20 months) WT and tg-ArcSwe mice (AD model) were injected with 125I-labeled mAb3D6-scFv8D3 or mAb3D6. Three different doses were used in the study, 0.05 mg/kg (low dose), 1 mg/kg (high dose), and 10 mg/kg (therapeutic dose), with equimolar doses for mAb3D6. The dose-corrected antibody concentrations in whole blood, blood cells, plasma, spleen, and brain were evaluated at 2 h post-administration. Furthermore, isolated brains were studied by autoradiography, nuclear track emulsion, and capillary depletion to investigate the intrabrain distribution of the antibodies, while binding to blood cells was studied in vitro using blood isolated from young and aged mice.

Results

The aged WT and tg-ArcSwe mice showed significantly lower brain concentrations of TfR-binding [125I]mAb3D6-scFv8D3 and higher concentrations in the blood cell fraction compared to young mice. For [125I]mAb3D6, no significant differences in blood or brain delivery were observed between young and aged mice or between genotypes. A low dose of [125I]mAb3D6-scFv8D3 was associated with increased relative parenchymal delivery, as well as increased blood cell distribution. Brain concentrations and relative parenchymal distribution of [125I]mAb3D6-scFv8D6 did not differ between tg-ArcSwe and WT mice at this early time point but were considerably increased compared to those observed for [125I]mAb3D6.

Conclusion

Age-dependent differences in blood and brain concentrations were observed for the bispecific antibody mAb3D6-scFv8D3 but not for the conventional Aβ antibody mAb3D6, indicating an age-related effect on TfR1-mediated brain delivery. The lowest dose of [125I]mAb3D6-scFv8D3 was associated with higher relative BBB penetration but, at the same time, a higher distribution to blood cells. Overall, Aβ-pathology did not influence the early brain distribution of the bispecific antibody. In summary, age and bispecific antibody dose were important factors determining brain delivery, while genotype was not.
Intra-articular injection of bone marrow aspirate concentrate (BMAC) or adipose-derived stem cells (ADSCs) for knee osteoarthritis: a prospective comparative clinical trial
Authors: Pintore Andrea , Notarfrancesco Donato , Zara Arnaldo , Oliviero Antonio , Migliorini Filippo , Oliva Francesco , Maffulli Nicola
Published: May 2023

Background

We determined whether autologous mesenchymal stem cells (MSCs) injections provide clinical and functional improvements in knee osteoarthritis (KOA) patients, and whether the results differ between autologous bone marrow cells (BMAC) and adipose-derived stromal cells (ADSCs).

Methods

Between January 2021 and April 2022, 51 patients undergoing intra-articular injection of BMAC and 51 patients undergoing intra-articular injection of ADSCs were prospectively recruited. The Kellgren and Lawrence (K–L) classification was used to grade the severity of osteoarthritis. Knee Injury and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score (OKS), and visual analog scale (VAS) were collected for all 102 patients in the previous week before the procedures, and at the one and 6 months from injection.

Results

Knee KOOS scores, knee OKS scores, and VAS pain scores changed in similar ways in the two treatment groups. Both treatment groups demonstrated significant improvement pre-procedure to post-procedure in knee KOOS scores (p < 0.0001), knee OKS scores (p < 0.0001), and VAS pain scores (p < 0.0001). Patients with K–L grade 2 showed better functional and clinical outcomes than patients with K–L grades 3 and 4 (p < 0.0001).

Conclusion

Both intra-articular BMAC and ADSC injections significantly improved pain and functional outcomes at 6-month follow-up in patients with KOA. The difference between BMAC and ADCSs groups as tissue sources of MSCs was not statistically significant in terms of clinical and functional outcomes.
Exploring the effect of Yinzhihuang granules on alcoholic liver disease based on pharmacodynamics, network pharmacology and molecular docking
Authors: Tan Yingying , Zhang Fanqin , Fan Xiaotian , Lu Shan , Liu Yingying , Wu Zhishan , Huang Zhihong , Wu Chao , Cheng Guoliang , Li Bing , Huang Jiaqi , Stalin Antony , Zhou Wei , Wu Jiarui
Published: May 2023

Background

Yinzhihuang granules (YZHG) is a commonly used Chinese patent medicine for the treatment of liver disease. However, the mechanism of YZHG in alcoholic liver disease (ALD) is still unclear.

Methods

This study combined liquid chromatography-mass spectrometry technology, pharmacodynamics, network pharmacology and molecular docking methods to evaluate the potential mechanism of YZHG in the treatment of ALD.

Results

A total of 25 compounds including 4-hydroxyacetophenone, scoparone, geniposide, quercetin, baicalin, baicalein, chlorogenic acid and caffeic acid in YZHG were identified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The pharmacodynamic investigations indicated that YZHG could improve liver function and the degree of liver tissue lesions, and reduce liver inflammation and oxidative stress in ALD mice. Network pharmacology analysis showed that YZHG treated ALD mainly by regulating inflammation-related signaling pathways such as the PI3K-Akt signaling pathway. The results of the PPI network and molecular docking showed that the targets of SRC, HSP90AA1, STAT3, EGFR and AKT1 could be the key targets of YZHG in the treatment of ALD.

Conclusion

This study explored the potential compounds, potential targets and signaling pathways of YZHG in the treatment of ALD, which is helpful to clarify the efficacy and mechanism of YZHG and provide new insights for the clinical application of YZHG.