bluuebunny/crossref_metadata_2025 huggingface dataset:
High-dose pharmaceutical-grade biotin in patients with demyelinating neuropathies: a phase 2b open label, uncontrolled, pilot study
Authors: Créange Alain , Hutin Emilie , Sedel Frédéric , Le Vigouroux Ludivine , Lefaucheur Jean-Pascal
Published: October 2023

Background

We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept.

Methods

Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks.

The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables.

Results

The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product.

Conclusions

Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory.

Trial registration

ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.
Low-dose adropin stimulates inflammasome activation of macrophage via mitochondrial ROS involved in colorectal cancer progression
Authors: Jia Linghui , Liao Liting , Jiang Yongshuai , Hu Xiangyu , Lu Guotao , Xiao Weiming , Gong Weijuan , Jia Xiaoqin
Published: October 2023

Adropin is encoded by the energy homeostasis-associated (ENHO) gene and widely present in liver, pancreas, heart, kidney, brain, and vascular tissues. Abnormal adropin is associated with metabolic, inflammatory, immune, and central nervous disorders. Whether adropin is involved in the development of colorectal cancer (CRC) is still unclear. Here, decreased adropin expression of tumor-nest cells in advanced-stage CRC was demonstrated. Adropin expressed by carcinoma cells was negatively correlated with macrophage infiltration in the matrix of CRC tissues. However, tumor macrophages enhanced adropin expression and were positively correlated with tumor invasion and metastasis. ENHO gene transfection into colon cancer (MC38) cells inhibited tumor growth in vivo, accompanying the increase of M1 macrophages. Treatment with low-dose adropin (< 100 ng/mL) on macrophages ex vivo directly increased mitochondrial reactive oxygen species for inflammasome activation. Furthermore, ENHO−/− mice had less M1 macrophages in vivo, and ENHO−/− macrophages were inert to be induced into the M1 subset ex vivo. Finally, low-dose adropin promoted glucose utilization, and high-dose adropin enhanced the expression of CPT1α in macrophages. Therefore, variations of adropin level in carcinoma cells or macrophages in tumor tissues are differently involved in CRC progression. Low-dose adropin stimulates the antitumor activity of macrophages, but high-dose adropin facilitates the pro-tumor activity of macrophages. Increasing or decreasing the adropin level can inhibit tumor progression at different CRC stages.
The role of spleen volume change in predicting immunotherapy response in metastatic renal cell carcinoma
Authors: Aslan Volkan , Karabörk Kılıç Atiye Cenay , Özet Ahmet , Üner Aytuğ , Günel Nazan , Yazıcı Ozan , Savaş Gözde , Bayrak Ahmet , Eraslan Emrah , Öksüzoğlu Berna , Kılıç Hüseyin Koray , Özdemir Nuriye
Published: October 2023

Introduction

Resistance to immune checkpoint inhibitors (ICI) is a significant issue in metastatic renal cell carcinoma (mRCC), as it is in the majority of cancer types. An important deficiency in immunooncology today is the lack of a predictive factor to identify this patient group. Myeloid-derived suppressor cells (MDSC) are a type of cell that contributes to immunotherapy resistance by inhibiting T cell activity. While it accumulates in the tumor microenvironment and blood, it can also accumulate in lymphoid organs such as the spleen and cause splenomegaly. Therefore we aimed to evaluate the effect of increase in splenic volume, which can be considered as an indirect indicator of increased MDSC cells, on survival outcomes in mRCC patients.

Methods

We analyzed 45 patients with mRCC who received nivolumab as a second-line or subsequent therapy. Splenic volume was analyzed from baseline imaging before starting nivolumab and from control imaging performed within the first 6 months of treatment initiation. Additionally, we analyzed how patients’ body mass index (BMI), IMDC risk score, ECOG performance status, nephrectomy status, neutrophil-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR) and sites of metastasis.

Results

Median splenic volume change was 10% (ranging from − 22% to + 117%) during follow-up. Change in splenic volume was found to be associated with overall survival (OS) and progression-free survival (PFS) (p = 0.025, 0.04). The median PFS in patients with increased splenic volume was 5 months, while it was 17 months in patients without increased splenic volume. (HR 2.1, 95% CI (1–4), p = 0.04). The median OS in patients with increased splenic volume was 9 months, while it was 35 months in patients without increased splenic volume (HR 2.7, 95% CI (1.1–6.2), p = 0.025). In four patients with decreased splenic volume, neither PFS nor OS could reach the median value. Log-rank p value in respectively (0.015, 0.035), The group in which an increase in volume was accompanied by a high NLR had the shortest survival rate. Basal splenic volume was analyzed separately. However, neither PFS nor OS differed significantly.

Conclusion

Our findings suggest that the change in splenic volume throughout immunotherapy regimens may be utilized to predict PFS and OS in mRCC patients undergoing treatment.
Non-use of diabetes medication and its associated factors: a comparative analysis of female and male patients in four Sub-Saharan African countries
Authors: Ayebeng Castro , Okyere Joshua , Dickson Kwamena Sekyi
Published: October 2023

Background

Globally, the burden of disease is shifting towards non-communicable diseases (NCDs), including diabetes. Sub-Saharan Africa (SSA) faces an increasing prevalence of diabetes, hindering the achievement of global health goals. This study investigates the determinants of non-use of diabetes medication, specifically exploring potential sex differences in four SSA countries.

Methods

This cross-sectional study analyzed recent Demographic and Health Survey (DHS) data (2017–2021) from four SSA countries (Benin, Cameroon, Madagascar, and Mauritania). Samples included 23,695 women and 25,339 men, focusing on individuals with diabetes not using medication (248 women, 162 men). Descriptive and inferential analyses, including chi-square tests and binary logistic regression models, were conducted using Stata version 14. Odds ratios were calculated with a 95% confidence interval to determine the associations.

Results

This study found that a larger proportion of female patients with diabetes (64.1%) were not using diabetes medication compared to their male counterparts (59.4%). Age influenced medication non-use in males, with older individuals exhibiting lower odds of non-usage. Higher wealth status was associated with lower odds of non-use of diabetes medications. The presence of heart disease was associated with a lower likelihood of medication non-use among females.

Conclusions

This study demonstrates sex disparities, age differences, wealth status, heart disease, and country-specific variations in medication non-use. Tailored interventions for different age groups, as well as socioeconomic support, are critical, as is integrated cardiovascular and diabetes care. These actions can improve medication use and adherence, quality of life, and long-term diabetes management outcomes.
DC/TMD axis I subtyping: generational and gender variations among East Asian TMD patients
Authors: Yap Adrian Ujin , Liu Chengge , Lei Jie , Park Ji Woon , Kim Seong Hae , Lee Byeong-min , Fu Kai Yuan
Published: October 2023

Objectives

This study examined the generational-gender distinctions in Diagnostic Criteria for Temporomandibular disorders (DC/TMD) subtypes among East Asian patients.

Methods

Consecutive “first-visit” TMD patients presenting at two university-based TMD/orofacial pain clinics in China and South Korea were enlisted. Demographic information along with symptom history was gathered and clinical examinations were performed according to the DC/TMD methodology. Axis I physical diagnoses were rendered with the DC/TMD algorithms and categorized into painful and non-painful TMDs. Patients were categorized into three birth cohorts, specifically Gen X, Y, and Z (born 1965–1980, 1981–1999, and 2000–2012 respectively) and the two genders. Data were evaluated using Chi-square/Kruskal-Wallis plus post-hoc tests and logistic regression analyses (α = 0.05).

Results

Gen X, Y, and Z formed 17.2%, 62.1%, and 20.7% of the 1717 eligible patients examined (mean age 29.7 ± 10.6 years; 75.7% women). Significant differences in prevalences of arthralgia, myalgia, headache (Gen X ≥ Y > Z), and disc displacements (Gen Z > Y > X) were observed among the three generations. Gen Z had substantially fewer pain-related and more intra-articular conditions than the other generations. Women presented a significantly greater frequency of degenerative joint disease and number of intra-articular conditions than men. After controlling for generation-gender interactions, multivariate analyses showed that “being Gen X” and female increased the risk of painful TMDs (OR = 2.20) and reduced the odds of non-painful TMDs (OR = 0.46).

Conclusions

Generational-gender diversities in DC/TMD subtypes exist and are important for guiding TMD care and future research endeavors.
Effects of simulation in improving the self-confidence of student nurses in clinical practice: a systematic review
Authors: Alrashidi Nojoud , Pasay an Eddieson , Alrashedi Maha Sanat , Alqarni Aidah Sanad , Gonzales Ferdinand , Bassuni Enas Mohammed , Pangket Petelyne , Estadilla Lorraine , Benjamin Lizy Sonia , Ahmed Kawther Elthayeb
Published: October 2023

Background

Considering the positive influence of simulation from previous literature may encourage educators to regard it as a valuable teaching strategy in nursing schools. This literature review aims to investigate whether the use of simulation improves undergraduate nurses’ self-confidence during clinical practice.

Methodology

This study employed a literature-based design. Five academic databases, including CINAHL, EBSCO, ProQuest, PubMed and Medline, were utilised to extract relevant studies using appropriate keywords and Boolean operators. Studies published in the last 15 years (2005–2020) were included in the search. Studies were retrieved using the Exclusion and Inclusion criteria. The Critical Appraisal Skills Programme (CASP) was used to critically appraise the studies.

Results

A total of 15 primary research studies were extracted for review. Four major themes emerged from the review: Improved self-confidence to carry out clinical tasks, Increased ability to work in teams, Improved self-confidence to perform community work and Improved self-confidence in communicating with patients and team members.

Conclusion

Clinical simulation is a useful tool in increasing the self-confidence of nursing students to perform clinical tasks, make clinical judgements, communicate with patients and team members and improve their teamwork. To improve the quality of care received by patients, it is recommended that clinical simulations be integrated into the nursing curriculum in Saudi Arabia. Increasing the confidence of students has been shown to be associated with greater confidence in performing clinical tasks.
Dealing with missing data in laboratory test results used as a baseline covariate: results of multi-hospital cohort studies utilizing a database system contributing to MID-NET® in Japan
Authors: Komamine Maki , Fujimura Yoshiaki , Omiya Masatomo , Sato Tosiya
Published: October 2023

Background

To evaluate missing data methods applied to laboratory test results used for confounding adjustment, utilizing data from 10 MID-NET®-collaborative hospitals.

Methods

Using two scenarios, five methods dealing with missing laboratory test results were applied, including three missing data methods (single regression imputation (SRI), multiple imputation (MI), and inverse probability weighted (IPW) method). We compared the point estimates of adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) between the five methods. Hospital variability in missing data was considered using the hospital-specific approach and overall approach. Confounding adjustment methods were propensity score (PS) weighting, PS matching, and regression adjustment.

Results

In Scenario 1, the risk of diabetes due to second-generation antipsychotics was compared with that due to first-generation antipsychotics. The aHR adjusted by PS weighting using SRI, MI, and IPW by the hospital-specific-approach was 0.61 [95%CI, 0.39–0.96], 0.63 [95%CI, 0.42–0.93], and 0.76 [95%CI, 0.46–1.25], respectively. In Scenario 2, the risk of liver injuries due to rosuvastatin was compared with that due to atorvastatin. Although PS matching largely contributed to differences in aHRs between methods, PS weighting provided no substantial difference in point estimates of aHRs between SRI and MI, similar to Scenario 1. The results of SRI and MI in both scenarios showed no considerable changes, even upon changing the approaches considering hospital variations.

Conclusions

SRI and MI provide similar point estimates of aHR. Two approaches considering hospital variations did not markedly affect the results. Adjustment by PS matching should be used carefully.
Predictive value of machine learning algorithm of coronary artery calcium score and clinical factors for obstructive coronary artery disease in hypertensive patients
Authors: Wang Minxian , Sun Mengting , Yu Yao , Li Xinsheng , Ren Yongkui , Yin Da
Published: October 2023

Background

The addition of coronary artery calcium score (CACS) to prediction models has been verified to improve performance. Machine learning (ML) algorithms become important medical tools in an era of precision medicine, However, combined utility by CACS and ML algorithms in hypertensive patients to forecast obstructive coronary artery disease (CAD) on coronary computed tomography angiography (CCTA) is rare.

Methods

This retrospective study was composed of 1,273 individuals with hypertension and without a history of CAD, who underwent dual-source computed tomography evaluation. We applied five ML algorithms, coupled with clinical factors, imaging parameters, and CACS to construct predictive models. Moreover, 80% individuals were randomly taken as a training set on which 5-fold cross-validation was done and the remaining 20% were regarded as a validation set.

Results

16.7% (212 out of 1,273) of hypertensive patients had obstructive CAD. Extreme Gradient Boosting (XGBoost) posted the biggest area under the receiver operator characteristic curve (AUC) of 0.83 in five ML algorithms. Continuous net reclassification improvement (NRI) was 0.55 (95% CI (0.39–0.71), p < 0.001), and integrated discrimination improvement (IDI) was 0.04 (95% CI (0.01–0. 07), p = 0.0048) when the XGBoost model was compared with traditional Models. In the subgroup analysis stratified by hypertension levels, XGBoost still had excellent performance.

Conclusion

The ML model incorporating clinical features and CACS may accurately forecast the presence of obstructive CAD on CCTA among hypertensive patients. XGBoost is superior to other ML algorithms.
Nurses’ job crafting, work engagement, and well-being: a path analysis
Authors: Han Sujeong
Published: October 2023

Background

Nurses’ well-being is a topic of interest at both individual and organizational levels. Studies that explore the relationship between nurses’ job crafting, work engagement, and well-being are scarce. Therefore, the purpose of this study was to confirm the effect of job crafting and work engagement on nurses’ well-being.

Methods

This cross-sectional survey study involved 207 nurses within a week in July 2022 across two centers, among whom the response rate was 99%. Three following instruments were used in the survey: the 14-item well-being scale, the 12-item job crafting scale, and the 9-item Utrecht Work Engagement Scores (UWES). Path analysis was performed and goodness of fit was evaluated.

Results

Job crafting and work engagement were strongly correlated with well-being, and nurses’ well-being was affected by job crafting and work engagement. Path model fit indices were adequate. The mediating effect of work engagement on the relationship between job crafting and well-being revealed that task job crafting influenced psychological well-being through work engagement (Effect: 0.15, 95% confidence interval [CI]: 0.08–0.22, p = 0.001). Furthermore, relational job crafting influenced social well-being through work engagement (Effect: 0.22, 95% CI: 0.11–0.38, p = 0.001).

Conclusion

The study’s findings can help strategize human resource management programs to enhance relational job crafting to improve nurses’ social well-being and enhance task job crafting to improve their psychological well-being. Furthermore, through job crafting, improved human resource policies can enhance work engagement and improve nurses’ well-being.
Individual- and neighborhood-level characteristics of lung cancer screening participants undergoing telemedicine shared decision making
Authors: Shusted Christine S. , Juon Hee-Soon , Ruane Brooke , Till Brian , Zeigler-Johnson Charnita , McIntire Russell K. , Grenda Tyler , Okusanya Olugbenga , Evans Nathaniel R. , Kane Gregory C. , Barta Julie A.
Published: October 2023

Background

Although lung cancer screening (LCS) for high-risk individuals reduces lung cancer mortality in clinical trial settings, many questions remain about how to implement high-quality LCS in real-world programs. With the increasing use of telemedicine in healthcare, studies examining this approach in the context of LCS are urgently needed. We aimed to identify sociodemographic and other factors associated with screening completion among individuals undergoing telemedicine Shared Decision Making (SDM) for LCS.

Methods

This retrospective study examined patients who completed Shared Decision Making (SDM) via telemedicine between May 4, 2020 – March 18, 2021 in a centralized LCS program. Individuals were categorized into Complete Screening vs. Incomplete Screening subgroups based on the status of subsequent LDCT completion. A multi-level, multivariate model was constructed to identify factors associated with incomplete screening.

Results

Among individuals undergoing telemedicine SDM during the study period, 20.6% did not complete a LDCT scan. Bivariate analysis demonstrated that Black/African-American race, Medicaid insurance status, and new patient type were associated with greater odds of incomplete screening. On multi-level, multivariate analysis, individuals who were new patients undergoing baseline LDCT or resided in a census tract with a high level of socioeconomic deprivation had significantly higher odds of incomplete screening. Individuals with a greater level of education experienced lower odds of incomplete screening.

Conclusions

Among high-risk individuals undergoing telemedicine SDM for LCS, predictors of incomplete screening included low education, high neighborhood-level deprivation, and new patient type. Future research should focus on testing implementation strategies to improve LDCT completion rates while leveraging telemedicine for high-quality LCS.
Scent detection of Brucella abortus by African giant pouched rats (Cricetomys ansorgei)
Authors: Mwampashi Raphael , Cutright Ellie , Fast Cynthia D. , Bonfoh Bassirou , Kazwala Rudovick R. , Mathew Coletha
Published: October 2023

Background

Brucellosis is a contagious zoonosis caused by bacteria of the genus Brucella. While the disease has been eradicated in most developed countries, it remains endemic in sub–Saharan Africa where access to reliable diagnostics is limited. African giant pouched rats (Cricetomys ansorgei) have been trained to detect the scent of Mycobacterium tuberculosis to increase case detection in sub-Saharan Africa. Given the similar diagnostic challenges facing brucellosis and tuberculosis, we explored the feasibility of training African giant pouched rats to detect Brucella.

Results

After 3 months of training, rats reliably identified cultured Brucella, achieving an average sensitivity of 93.56% (SD = 0.650) and specificity of 97.65% (SD = 0.016). Rats readily generalized to novel, younger Brucella cultures that presumably generated a weaker volatile signal and correctly identified at least one out of three fecal samples spiked with Brucella culture during a final test of feasibility.

Discussion

To our knowledge, these experiments are the first to demonstrate Brucella emits a unique odor profile that scent detection animals can be trained to identify. Importantly, cultured E. coli samples were included throughout training and test to ensure the rats learned to specifically identify Brucella bacteria rather than any bacteria in comparison to bacteria-free culture medium. E. coli controls therefore served a crucial function in determining to what extent Brucella abortus emits a unique odor signature. Further research is needed to determine if a Brucella-specific volatile signature is present within clinical samples. If confirmed, the present results suggest trained rats could serve as a valuable, novel method for the detection of Brucella infection.
A novel protein purification scheme based on salt inducible self-assembling peptides
Authors: Zeng Guang , Zheng Yinzhen , Xiang Ya , Liu Run , Yang Xiaofeng , Lin Zhanglin
Published: October 2023

Background

Protein purification remains a critical need for biosciences and biotechnology. It frequently requires multiple rounds of chromatographic steps that are expensive and time-consuming. Our lab previously reported a cleavable self-aggregating tag (cSAT) scheme for streamlined protein expression and purification. The tag consists of a self-assembling peptide (SAP) and a controllable self-cleaving intein. The SAP drives the target protein into an active aggregate, then by intein-mediated cleavage, the target protein is released. Here we report a novel cSAT scheme in which the self-assembling peptide is replaced with a salt inducible self-assembling peptide. This allows a target protein to be expressed first in the soluble form, and the addition of salt then drives the target protein into the aggregated form, followed by cleavage and release.

Results

In this study, we used MpA (MKQLEDKIEELLSKAAMKQLEDKIEELLSK) as a second class of self-assembling peptide in the cSAT scheme. This scheme utilizes low salt concentration to keep the fusion protein soluble, while eliminating insoluble cellular matters by centrifugation. Salt then triggers MpA-mediated self-aggregation of the fusion, removing soluble background host cell proteins. Finally, intein-mediated cleavage releases the target protein into solution. As a proof-of-concept, we successfully purified four proteins and peptides (human growth hormone, 22.1 kDa; LCB3, 7.7 kDa; SpyCatcherΔN-ELP-SpyCatcherΔN, 26.2 kDa; and xylanase, 45.3 kDa) with yields ranging from 12 to 87 mg/L. This was comparable to the classical His-tag method both in yield and purity (72–97%), but without the His-tag. By using a further two-step column purification process that included ion-exchange chromatography and size-exclusion chromatography, the purity was increased to over 99%.

Conclusion

Our results demonstrate that a salt-inducible self-assembling peptide can serve as a controllable aggregating tag, which might be advantageous in applications where soluble expression of the target protein is preferred. This work also demonstrates the potential and advantages of utilizing salt inducible self-assembling peptides for protein separation.
Magnesium intake and all-cause mortality after stroke: a cohort study
Authors: Wang Mengyan , Peng Jianhong , Yang Caili , Zhang Wenyuan , Cheng Zicheng , Zheng Haibin
Published: October 2023

Background

Population-based studies have shown that adequate magnesium intake is associated with a lower risk of stroke and all-cause mortality. Whether adequate magnesium intake is important for reducing all-cause mortality risk after stroke remains unclear.

Methods

We analyzed data from 917 patients with a self-reported history of stroke from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. The total magnesium intake was calculated by summing the magnesium intake from dietary and dietary supplements, and then adjusting for total energy intake according to the nutrient density method. Mortality status was determined using public-use linked mortality files from 2019. Cox regression model and restricted cubic splines were used to explore the relationship between magnesium intake and all-cause mortality.

Results

The average total magnesium intake across all patients was 251.0 (184.5–336.5) mg/d, and 321 (70.2%) males and 339 (73.7%) females had insufficient magnesium intake. During a median follow-up period of 5.3 years, 277 deaths occurred. After fully adjusting for confounding factors, total magnesium intake levels were inversely associated with all-cause mortality risk (HR per 1-mg/(100 kcal*d) increase, 0.97; 95% CI, 0.94–1.00; p = 0.017). Participants with the highest quartile of total magnesium intake (≥ 18.5 mg/(100 kcal*d)) had a 40% reduction in all-cause mortality risk compared to those with the lowest quartile (≤ 12.0 mg/(100 kcal*d)) (HR, 0.60; 95% CI, 0.38–0.94; p = 0.024). Stratified analyses showed that this inverse association was statistically significant in those who were older, female, without hypertension, and had smoking, normal renal function, and adequate energy intake. Dietary magnesium intake alone might be not related to all-cause mortality.

Conclusions

Stroke survivors who consumed adequate amounts of magnesium from diet and supplements had a lower risk of all-cause mortality.
Radiotherapy combined with nano-biomaterials for cancer radio-immunotherapy
Authors: Dong Qingrong , Xue Tingyu , Yan Haili , Liu Fang , Liu Ruixue , Zhang Kun , Chong Yu , Du Jiangfeng , Zhang Hui
Published: October 2023

Radiotherapy (RT) plays an important role in tumor therapy due to its noninvasiveness and wide adaptation. In recent years, radiation therapy has been discovered to induce an anti-tumor immune response, which arouses widespread concern among scientists and clinicians. In this review, we highlight recent advances in the applications of nano-biomaterials for radiotherapy-activated immunotherapy. We first discuss the combination of different radiosensitizing nano-biomaterials and immune checkpoint inhibitors to enhance tumor immune response and improve radiotherapy efficacy. Subsequently, various nano-biomaterials-enabled tumor oxygenation strategies are introduced to alleviate the hypoxic tumor environment and amplify the immunomodulatory effect. With the aid of nano-vaccines and adjuvants, radiotherapy refreshes the host's immune system. Additionally, ionizing radiation responsive nano-biomaterials raise innate immunity-mediated anti-tumor immunity. At last, we summarize the rapid development of immune modulatable nano-biomaterials and discuss the key challenge in the development of nano-biomaterials for tumor radio-immunotherapy. Understanding the nano-biomaterials-assisted radio-immunotherapy will maximize the benefits of clinical radiotherapy and immunotherapy and facilitate the development of new combinational therapy modality.

Graphical Abstract
A novel comorbidity index in Italy based on diseases detected by the surveillance system PASSI and the Global Burden of Diseases disability weights
Authors: Andreella Angela , Monasta Lorenzo , Campostrini Stefano
Published: October 2023

Background

Understanding comorbidity and its burden characteristics is essential for policymakers and healthcare providers to allocate resources accordingly. However, several definitions of comorbidity burden can be found in the literature. The main reason for these differences lies in the available information about the analyzed diseases (i.e., the target population studied), how to define the burden of diseases, and how to aggregate the occurrence of the detected health conditions.

Methods

In this manuscript, we focus on data from the Italian surveillance system PASSI, proposing an index of comorbidity burden based on the disability weights from the Global Burden of Disease (GBD) project. We then analyzed the co-presence of ten non-communicable diseases, weighting their burden thanks to the GBD disability weights extracted by a multi-step procedure. The first step selects a set of GBD weights for each disease detected in PASSI using text mining. The second step utilizes an additional variable from PASSI (i.e., the perceived health variable) to associate a single disability weight for each disease detected in PASSI. Finally, the disability weights are combined to form the comorbidity burden index using three approaches common in the literature.

Results

The comorbidity index (i.e., combined disability weights) proposed allows an exploration of the magnitude of the comorbidity burden in several Italian sub-populations characterized by different socioeconomic characteristics. Thanks to that, we noted that the level of comorbidity burden is greater in the sub-population characterized by low educational qualifications and economic difficulties than in the rich sub-population characterized by a high level of education. In addition, we found no substantial differences in terms of predictive values of comorbidity burden adopting different approaches in combining the disability weights (i.e., additive, maximum, and multiplicative approaches), making the Italian comorbidity index proposed quite robust and general.
Neutral sphingomyelinase inhibition promotes local and network degeneration in vitro and in vivo
Authors: Risner Michael L. , Ribeiro Marcio , McGrady Nolan R. , Kagitapalli Bhanu S. , Chamling Xitiz , Zack Donald J. , Calkins David J.
Published: October 2023

Background

Cell-to-cell communication is vital for tissues to respond, adapt, and thrive in the prevailing milieu. Several mechanisms mediate intercellular signaling, including tunneling nanotubes, gap junctions, and extracellular vesicles (EV). Depending on local and systemic conditions, EVs may contain cargoes that promote survival, neuroprotection, or pathology. Our understanding of pathologic intercellular signaling has been bolstered by disease models using neurons derived from human pluripotent stems cells (hPSC).

Methods

Here, we used hPSC-derived retinal ganglion cells (hRGC) and the mouse visual system to investigate the influence of modulating EV generation on intercellular trafficking and cell survival. We probed the impact of EV modulation on cell survival by decreasing the catabolism of sphingomyelin into ceramide through inhibition of neutral sphingomyelinase (nSMase), using GW4869. We assayed for cell survival in vitro by probing for annexin A5, phosphatidylserine, viable mitochondria, and mitochondrial reactive oxygen species. In vivo, we performed intraocular injections of GW4869 and measured RGC and superior colliculus neuron density and RGC anterograde axon transport.

Results

Following twenty-four hours of dosing hRGCs with GW4869, we found that inhibition of nSMase decreased ceramide and enhanced GM1 ganglioside accumulation. This inhibition also reduced the density of small EVs, increased the density of large EVs, and enriched the pro-apoptotic protein, annexin A5. Reducing nSMase activity increased hRGC apoptosis initiation due to enhanced density and uptake of apoptotic particles, as identified by the annexin A5 binding phospholipid, phosphatidylserine. We assayed intercellular trafficking of mitochondria by developing a coculture system of GW4869-treated and naïve hRGCs. In treated cells, inhibition of nSMase reduced the number of viable mitochondria, while driving mitochondrial reactive oxygen species not only in treated, but also in naive hRGCs added in coculture. In mice, 20 days following a single intravitreal injection of GW4869, we found a significant loss of RGCs and their axonal recipient neurons in the superior colliculus. This followed a more dramatic reduction in anterograde RGC axon transport to the colliculus.

Conclusion

Overall, our data suggest that perturbing the physiologic catabolism of sphingomyelin by inhibiting nSMase reorganizes plasma membrane associated sphingolipids, alters the profile of neuron-generated EVs, and promotes neurodegeneration in vitro and in vivo by shifting the balance of pro-survival versus -degenerative EVs.
Intracellular remodeling associated with endoplasmic reticulum stress modifies biomechanical compliance of bladder cells
Authors: Gruber Livia , Jobst Maximilian , Kiss Endre , Karasová Martina , Englinger Bernhard , Berger Walter , Del Favero Giorgia
Published: October 2023

Bladder cells face a challenging biophysical environment: mechanical cues originating from urine flow and regular contraction to enable the filling voiding of the organ. To ensure functional adaption, bladder cells rely on high biomechanical compliance, nevertheless aging or chronic pathological conditions can modify this plasticity. Obviously the cytoskeletal network plays an essential role, however the contribution of other, closely entangled, intracellular organelles is currently underappreciated. The endoplasmic reticulum (ER) lies at a crucial crossroads, connected to both nucleus and cytoskeleton. Yet, its role in the maintenance of cell mechanical stability is less investigated. To start exploring these aspects, T24 bladder cancer cells were treated with the ER stress inducers brefeldin A (10-40nM BFA, 24 h) and thapsigargin (0.1-100nM TG, 24 h). Without impairment of cell motility and viability, BFA and TG triggered a significant subcellular redistribution of the ER; this was associated with a rearrangement of actin cytoskeleton. Additional inhibition of actin polymerization with cytochalasin D (100nM CytD) contributed to the spread of the ER toward cell periphery, and was accompanied by an increase of cellular stiffness (Young´s modulus) in the cytoplasmic compartment. Shrinking of the ER toward the nucleus (100nM TG, 2 h) was related to an increased stiffness in the nuclear and perinuclear areas. A similar short-term response profile was observed also in normal human primary bladder fibroblasts. In sum, the ER and its subcellular rearrangement seem to contribute to the mechanical properties of bladder cells opening new perspectives in the study of the related stress signaling cascades.
NFAT1 and NFκB regulates expression of the common γ-chain cytokine receptor in activated T cells
Authors: Shim Ju A , Lee So Min , Jeong Jin Woo , Kim Hyori , Son Woo Jae , Park Jun Hong , Song Parkyong , Im Sin-Hyeog , Bae Sangsu , Park Jung-Hyun , Jo Yuna , Hong Changwan
Published: October 2023

Introduction

Cytokines of the common γ chain (γc) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, autoimmune diseases, allergies, and cancer. Although γc is considered an assistant receptor to transmit cytokine signals and is an indispensable receptor in the immune system, its regulatory mechanism is not yet well understood.

Objective

This study focused on the molecular mechanisms that γc expression in T cells is regulated under T cell receptor (TCR) stimulation.

Methods

The γc expression in TCR-stimulated T cells was determined by flow cytometry, western blot and quantitative RT-PCR. The regulatory mechanism of γc expression in activated T cells was examined by promoter-luciferase assay and chromatin immunoprecipitation assays. NFAT1 and NFκB deficient cells generated using CRISPR-Cas9 and specific inhibitors were used to examine their role in regulation of γc expression. Specific binding motif was confirmed by γc promotor mutant cells generated using CRISPR-Cas9. IL-7TgγcTg mice were used to examine regulatory role of γc in cytokine signaling.

Results

We found that activated T cells significantly upregulated γc expression, wherein NFAT1 and NFκB were key in transcriptional upregulation via T cell receptor stimulation. Also, we identified the functional binding site of the γc promoter and the synergistic effect of NFAT1 and NFκB in the regulation of γc expression. Increased γc expression inhibited IL-7 signaling and rescued lymphoproliferative disorder in an IL-7Tg animal model, providing novel insights into T cell homeostasis.

Conclusion

Our results indicate functional cooperation between NFAT1 and NFκB in upregulating γc expression in activated T cells. As γc expression also regulates γc cytokine responsiveness, our study suggests that γc expression should be considered as one of the regulators in γc cytokine signaling and the development of T cell immunotherapies.
SARS-CoV-2 primed platelets–derived microRNAs enhance NETs formation by extracellular vesicle transmission and TLR7/8 activation
Authors: Liao Tsai-Ling , Liu Hung-Jen , Chen Der-Yuan , Tang Kuo-Tung , Chen Yi-Ming , Liu Po-Yu
Published: October 2023

Background

Hyperactive neutrophil extracellular traps (NETs) formation plays a key role in the pathogenesis of severe COVID-19. Extracellular vesicles (EVs) are vehicles which carry cellular components for intercellular communication. The association between COVID-19 patients-derived EVs and NETs formation remains elusive.

Methods

We explored the roles of EVs in NETs formation from 40 COVID-19 patients with different disease severities as well as 30 healthy subjects. The EVs-carried microRNAs profile was analyzed using next generation sequencing approach which was validated by quantitative reverse transcription PCR. The regulatory mechanism of EVs on NETs formation was investigated by using an in vitro cell-based assay, including immunofluorescence assay, flow cytometry, and immunoblotting.

Results

COVID-19 patient–derived EVs induced NETs formation by endocytosis uptake. SARS-CoV-2 spike protein-triggered NETs formation was significantly enhanced in the presence of platelet–derived EVs (pEVs) and this effect was Toll-like receptor (TLR) 7/8- and NADPH oxidase-dependent. Increased levels of miR-21/let-7b were revealed in EVs from COVID-19 patients and were associated with disease severity. We demonstrated that the spike protein activated platelets directly, followed by the subsequent intracellular miR-21/let-7b upregulation and then were loaded into pEVs. The pEVs-carried miR-21 interacted with TLR7/8 to prime p47phox phosphorylation in neutrophils, resulting in NADPH oxidase activation to promote ROS production and NETs enhancement. In addition, miR-21 modulates NF-κB activation and IL-1β/TNFα/IL-8 upregulation in neutrophils upon TLR7/8 engagement. The miR-21 inhibitor and TLR8 antagonist could suppress efficiently spike protein-induced NETs formation and pEVs primed NETs enhancement.

Conclusions

We identified SARS-CoV-2 triggered platelets–derived GU-enriched miRNAs (e.g., miR-21/let-7b) as a TLR7/8 ligand that could activate neutrophils through EVs transmission. The miR-21-TLR8 axis could be used as a potential predisposing factor or therapeutic target for severe COVID-19.
Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial
Authors: Smit Lisa , Slooter Arjen J. C. , Devlin John W. , Trogrlic Zoran , Hunfeld Nicole G. M. , Osse Robert Jan , Ponssen Huibert H. , Brouwers Arjen J. B. W. , Schoonderbeek Jeannette F. , Simons Koen S. , van den Boogaard Mark , Lens Judith A. , Boer Dirk P. , Gommers Diederik A. M. P. J. , Rietdijk Wim J. R. , van der Jagt Mathieu ,   the EuRIDICE study group
Published: October 2023

Background

The role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae.

Methods

This multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization.

Results

The trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients [mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%]. Haloperidol did not increase DCFDs (adjusted RR 0.98 [95% CI 0.73–1.31], p = 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 [95% CI 0.18–0.89], p = 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol [OR 0.43 (95% CI 0.12–1.56)] and other antipsychotics [OR 0.63 (95% CI 0.29–1.32)], self-extubation or invasive device removal [OR 0.70 (95% CI 0.22–2.18)]) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study.

Conclusions

Haloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation.

Trial registration: ClinicalTrials.gov (#NCT03628391), October 9, 2017.
mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers
Authors: Bouamar Hakim , Broome Larry Esteban , Lathrop Kate Ida , Jatoi Ismail , Brenner Andrew Jacob , Nazarullah Alia , Gorena Karla Moncada , Garcia Michael , Chen Yidong , Kaklamani Virginia , Sun Lu-Zhe
Published: October 2023

Background

Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers.

Methods

We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5–7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry.

Results

Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression.

Conclusion

Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression.

Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.
Landscape of enhancer disruption and functional screen in melanoma cells
Authors: Wang Zhao , Luo Menghan , Liang Qian , Zhao Ke , Hu Yuelin , Wang Wei , Feng Xiangling , Hu Bolang , Teng Jianjin , You Tianyi , Li Ran , Bao Zhengkai , Pan Wenhao , Yang Tielong , Zhang Chao , Li Ting , Dong Xiaobao , Yi Xianfu , Liu Ben , Zhao Li , Li Miaoxin , Chen Kexin , Song Weihong , Yang Jilong , Li Mulin Jun
Published: October 2023

Background

The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma.

Results

Here, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions.

Conclusions

Our study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.