bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative positive voided urine cytology predicts poor clinical outcomes in patients with upper tract urothelial carcinoma undergoing nephroureterectomy
Authors: Liu Wen , Wang Zhankun , Liu Shuai , Yao Yu , Liu Yong , Zhang Guiming
Published: November 2020

Background

Performance of urinary cytology is recommended as the part of a standard diagnostic workup and base surveillance regimens in upper tract urothelial carcinoma (UTUC). However, the effect of positive voided urine cytology (VUC) on UTUC prognosis, compared with negative VUC, has not been fully demonstrated. This study aimed to evaluate the impact of preoperative VUC on predicting intravesical recurrence, disease recurrence, and mortality in patients with UTUC who underwent nephroureterectomy (RNU).

Methods

Clinicopathological information was collected from 315 UTUC patients treated with RNU. The association between VUC and oncological outcomes was analyzed using the Kaplan–Meier method with log-rank test and Cox proportional hazards regression models. Multiple logistic regression analysis was performed to identify the influence of VUC on tumor grade.

Results

Preoperative positive VUC, presenting in 101 patients (32%), was significantly associated with tumor multifocality (P = 0.017) and higher tumor grade (P = 0.010). On multivariable Cox regression analyses, preoperative positive VUC was an independent prognostic factor of intravesical recurrence-free survival (RFS) (hazard ratio [HR] = 2.21, 95% confidence interval [CI] 1.06–4.64;P = 0.035), RFS (HR = 1.80, 95% CI 1.08–2.99;P = 0.023), and cancer-specific survival (CSS) (HR = 1.87, 95% CI 1.10–3.18;P = 0.020), but not overall survival (HR = 1.32, 95% CI 0.80–2.18;P = 0.28). Logistic regression analysis revealed that VUC was related to high tumor grade in UTUC (odds ratio = 2.23, 95%CI 1.15–4.52).

Conclusion

Preoperative positive VUC significantly increases the risk of intravesical recurrence in UTUC patients undergoing RNU. In addition, positive VUC is an adverse predictor of RFS and CSS, which might be due to the association between positive VUC and high tumor grade.
A randomized controlled trial to improve psychological detachment from work and well-being among employees: a study protocol comparing online CBT-based and mindfulness interventions
Authors: Tement Sara , Zorjan Saša , Lavrič Meta , Poštuvan Vita , Plohl Nejc
Published: November 2020

Background

The changing landscape of the work environment, which often encompasses expectations of employees being continuously available, makes it difficult to disengage from work and recover. This can have a negative impact on employees’ well-being, resulting in burnout, depression and anxiety, among other difficulties. The current study will test the effectiveness of two different online interventions (i.e., cognitive behavioral therapy; CBT and mindfulness-based stress reduction; MBSR) on employees’ psychological detachment, burnout and other variables related to general (e.g., life satisfaction) and work-specific (e.g., work engagement) well-being.

Methods/design

The study is designed as a randomized control trial with two intervention groups (i.e., CBT, MBSR) and a waitlist control group. Participants will be full-time employees from a wide range of organizations from Slovenia, who report moderate difficulties with psychological detachment from work and burnout and are not receiving any other form of treatment. The online interventions will encompass 12 sessions over 6 weeks (2 sessions per week); each session will include 1) an active audio-guided session and 2) home assignments, accompanied by handouts and worksheets. The study outcomes (i.e., psychological detachment, burnout, general and work-specific well-being), potential mechanisms (i.e., work-related maladaptive thinking patterns, mindfulness) and moderators (e.g., supervisor support for recovery) will be assessed immediately before and after the interventions (pre and post measurement) and 3 months after intervention completion (follow-up). Additionally, participants will fill out questionnaires for the assessment of the central mechanisms and study outcomes each week.

Discussion

We expect that the CBT-based intervention will lead to greater improvements in psychological detachment from work and burnout compared to the MBSR and the waitlist control group. Additionally, we expect that the CBT-based intervention will also lead to greater enhancement of both general and work-related well-being.

Trial registration

https://doi.org/10.1186/ISRCTN98347361 [May 19, 2020].
Effectiveness of an individual acceptance and commitment therapy for smoking cessation, delivered face-to-face and by telephone to adults recruited in primary health care settings: a randomized controlled trial
Authors: Mak Yim Wah , Leung Doris Y. P. , Loke Alice Yuen
Published: November 2020

Background

The aim of this study was to examine the effectiveness of delivering an individual Acceptance and Commitment Therapy (ACT) for smoking cessation among a Chinese population.

Methods

Participants were recruited from six primary health care centers. A total of 144 were eligible to take part in the study and agreed to be randomized to the intervention (ACT) group (n = 70) and control group (n = 74), respectively. Both groups received self-help materials on smoking cessation. The ACT group also underwent an initial face-to-face session and two telephone ACT sessions at 1 week and 1 month following the first session. They were re-contacted through telephone follow-ups at 3, 6, and 12 months by research assistants. The primary outcome was self-reported 7-day point-prevalence abstinence at the 12-month follow-up session. Other outcomes included biochemically validated quitting, quitting attempts, the intention to quit, the self-perception of quitting, and psychological flexibility.

Results

There was no significant difference in the self-reported 7-day point prevalence quit rate at the 12-month follow-up between the intervention group (24.3%) and the control group (21.6%) (risk ratio = 1.12; 95%CI = (0.62, 2.05); p = 0.704). Greater improvements in secondary outcomes from baseline to the 12-month follow-up were observed in the ACT group than in the control group, including a forward progression in the participants’ readiness to quit smoking (p = 0.014) and increased psychological flexibility (p = 0.022).

Conclusions

This study is the first evidence of a randomized-controlled trial on the adoption of an individual ACT for smoking cessation, delivered initially in primary health care settings and subsequently by telephone within a Chinese population. The present study found that the brief ACT intervention could not produce a significant quit rate but was promising in terms of bringing about cognitive changes, including greater psychological flexibility, and more confidence about quitting, when compared to the use of self-help materials only among the general population.

Trial registration

This trial was registered prospectively with the U.S. National Library of Medicine: (NCT01652508) on 26th July 2012.
Correction to: Cost-effectiveness of a tailored intervention designed to increase breast cancer screening among a non-adherent population: a randomized controlled trial
Authors: Ishikawa Yoshiki , Hirai Kei , Saito Hiroshi , Fukuyoshi Jun , Yonekura Akio , Harada Kazuhiro , Seki Aiko , Shibuya Daisuke , Nakamura Yosikazu
Published: November 2020

An amendment to this paper has been published and can be accessed via the original article.
Exercise/physical activity and health outcomes: an overview of Cochrane systematic reviews
Authors: Posadzki Pawel , Pieper Dawid , Bajpai Ram , Makaruk Hubert , Könsgen Nadja , Neuhaus Annika Lena , Semwal Monika
Published: November 2020

Background

Sedentary lifestyle is a major risk factor for noncommunicable diseases such as cardiovascular diseases, cancer and diabetes. It has been estimated that approximately 3.2 million deaths each year are attributable to insufficient levels of physical activity. We evaluated the available evidence from Cochrane systematic reviews (CSRs) on the effectiveness of exercise/physical activity for various health outcomes.

Methods

Overview and meta-analysis. The Cochrane Library was searched from 01.01.2000 to issue 1, 2019. No language restrictions were imposed. Only CSRs of randomised controlled trials (RCTs) were included. Both healthy individuals, those at risk of a disease, and medically compromised patients of any age and gender were eligible. We evaluated any type of exercise or physical activity interventions; against any types of controls; and measuring any type of health-related outcome measures. The AMSTAR-2 tool for assessing the methodological quality of the included studies was utilised.

Results

Hundred and fifty CSRs met the inclusion criteria. There were 54 different conditions. Majority of CSRs were of high methodological quality. Hundred and thirty CSRs employed meta-analytic techniques and 20 did not. Limitations for studies were the most common reasons for downgrading the quality of the evidence. Based on 10 CSRs and 187 RCTs with 27,671 participants, there was a 13% reduction in mortality rates risk ratio (RR) 0.87 [95% confidence intervals (CI) 0.78 to 0.96];I2 = 26.6%, [prediction interval (PI) 0.70, 1.07], median effect size (MES) = 0.93 [interquartile range (IQR) 0.81, 1.00]. Data from 15 CSRs and 408 RCTs with 32,984 participants showed a small improvement in quality of life (QOL) standardised mean difference (SMD) 0.18 [95% CI 0.08, 0.28];I2 = 74.3%; PI -0.18, 0.53], MES = 0.20 [IQR 0.07, 0.39]. Subgroup analyses by the type of condition showed that the magnitude of effect size was the largest among patients with mental health conditions.

Conclusion

There is a plethora of CSRs evaluating the effectiveness of physical activity/exercise. The evidence suggests that physical activity/exercise reduces mortality rates and improves QOL with minimal or no safety concerns.

Trial registration

Registered in PROSPERO (CRD42019120295) on 10th January 2019.
Chronic obstructive pulmonary disease prevalence and prediction in a high-risk lung cancer screening population
Authors: Goffin John R. , Pond Gregory R. , Puksa Serge , Tremblay Alain , Johnston Michael , Goss Glen , Nicholas Garth , Martel Simon , Bhatia Rick , Liu Geoffrey , Schmidt Heidi , Atkar-Khattra Sukhinder , McWilliams Annette , Tsao Ming-Sound , Tammemagi Martin C. , Lam Stephen
Published: November 2020

Background

Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition sharing risk factors with lung cancer. Lung cancer screening may provide an opportunity to improve COPD diagnosis. Using Pan-Canadian Early Detection of Lung Cancer (PanCan) study data, the present study sought to determine the following: 1) What is the prevalence of COPD in a lung cancer screening population? 2) Can a model based on clinical and screening low-dose CT scan data predict the likelihood of COPD?

Methods

The single arm PanCan study recruited current or former smokers age 50–75 who had a calculated risk of lung cancer of at least 2% over 6 years. A baseline health questionnaire, spirometry, and low-dose CT scan were performed. CT scans were assessed by a radiologist for extent and distribution of emphysema. With spirometry as the gold standard, logistic regression was used to assess factors associated with COPD.

Results

Among 2514 recruited subjects, 1136 (45.2%) met spirometry criteria for COPD, including 833 of 1987 (41.9%) of those with no prior diagnosis, 53.8% of whom had moderate or worse disease. In a multivariate model, age, current smoking status, number of pack-years, presence of dyspnea, wheeze, participation in a high-risk occupation, and emphysema extent on LDCT were all statistically associated with COPD, while the overall model had poor discrimination (c-statistic = 0.627 (95% CI of 0.607 to 0.650). The lowest and the highest risk decile in the model predicted COPD risk of 27.4 and 65.3%.

Conclusions

COPD had a high prevalence in a lung cancer screening population. While a risk model had poor discrimination, all deciles of risk had a high prevalence of COPD, and spirometry could be considered as an additional test in lung cancer screening programs.

Trial registration

(Clinical Trial Registration: ClinicalTrials.gov, number NCT00751660, registered September 12, 2008)
Association of adipocytokines with lipid and glycemic profiles in women with normal weight obesity
Authors: Taheri Ehsaneh , Hosseini Saeed , Qorbani Mostafa , Mirmiran Parvin
Published: November 2020

Background

Individuals with normal weight obesity (NWO) are predisposed to having cardiometabolic disorders. This study aims to investigate the circulating levels of vaspin, leptin and their association with glycemic and lipid profiles in women with NWO.

Methods

Forty women with body mass index (BMI) = 18.5–24.9 kg/m2 and fat mass (FM) ≥ 30% were assigned in the NWO group. Thirty age-matched women with identical BMI range, and FM < 30% (normal weight non-obese; NWNO) were considered as a control group. In addition to anthropometric measurements, glycemic and lipid profiles and circulating levels of leptin and vaspin were measured.

Results

The mean ± standard deviation (SD) age of participants was 28.76 ± 4.76 years in the NWO group and 29.23 ± 4.50 years in the control group. The NWO group had the higher mean serum levels of insulin (9.02 ± 4.75 vs. 6.24 ± 2.51, P = 0.009), leptin (17.31 ± 8.10 vs. 9.94 ± 4.30, P < 0.001) and homeostatic model assessment of insulin resistance (HOMA-IR) (33.77 ± 20.71 vs. 23.48 ± 10.03, P = 0.009) compared to the NWNO group. The serum level of vaspin was higher in the NWO group compared to the control group (34.82 pg/ml vs. 27.72 pg/ml, respectively, P = 0.12). In NWO group, the serum levels of leptin had positive correlation with FBS (r = 0.45, P = 0.02), insulin (r = 0.51, P = 0.008), and HOMA-IR (r = 0.46, P = 0.02) and vaspin concentration was associated with insulin (r = 0.36, P = 0.02) and HOMA-IR (r = 0.30, P = 0.06), positively.

Conclusion

It is concluded that the concentration of insulin and HOMA-IR index were significantly higher in women with NWO compared to NWNO. Higher concentrations of leptin and vaspin in the NWO group were associated with glycemic profile.
Ultrasound classification-guided minimally invasive rotary cutting in granulomatous lobular mastitis
Authors: Liao Hongye , Guo Jujiang , Chen Xuming , Hua Zhipeng , Lin Juli , Weng Yiyin
Published: November 2020

Background

To summarize the clinical experience of ultrasound-guided minimally invasive surgery for granulomatous lobular mastitis (GLM), and explore the feasibility of this technique for treating GLM.

Methods

This retrospective study reviewed the clinical features and treatment outcome of 30 patients who were diagnosed pathologically as GLM from 2016.3 to 2019.5 in the Department of Breast Surgery, Women's and Children's Hospital, Xiamen University. These patients weretreated with ultrasound-guided Mammotome minimally invasive surgery, and we tried to classified the lesion into four distinct patterns (diffuse abscess mixed type, sheet hypoechoic type, localized abscess type, localized hypoechoic mass type) according to the sonographic findings and clinical symptoms to find out if these patterns correlated with treatment and recurrence rate.

Results

After a median follow-up of 12 months on average (4–42 months), 26 cases (86.7%) were cured without acute or chronic complications such as disseminated inflammation and bleeding. Post-operative bleeding occurred in 1 case, and 3 cases (10.00%) relapsed. The ultrasound classification had 0 cases of diffuse abscess mixed type, 17 cases (56.7%) of sheet hypoechoic type, 9 cases (30%) of localized abscess type, and 4 cases (13.3%) of localized hypoechoic mass type. All 3 recurrent cases were sheet hypoechoic type, which were cured after another open surgical resection and showed no recurrence during an average follow-up of 20 months (11–40 months).

Conclusions

In treating GLM patients with minimally invasive rotary cutting, ultrasound classification helps to select suitable patients, especially those with localized abscess and localized hypoechoic mass types with low recurrence rate, which is one of the safe and effective treatment methods.
Screening test accuracy of portable devices that can be used to perform colposcopy for detecting CIN2+ in low- and middle-income countries: a systematic review and meta-analysis
Authors: Taghavi Katayoun , Rohner Eliane , Basu Partha , Low Nicola , Rutjes Anne , Bohlius Julia
Published: November 2020

Background

Portable devices that can be used to perform colposcopy may improve cervical cancer screening in low- and middle-income countries (LMIC) where access to colposcopy is limited. The objective of this study was to systematically review the diagnostic test accuracy (DTA) of these devices for the detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+).

Methods

In accordance with our protocol (Prospero CRD42018104286), we searched Embase, Medline and the Cochrane Controlled Register of Trials up to 9/2019. We included DTA studies, which investigated portable devices with moderate-to-high optical magnification (≥ 6×) for colposcopy, as described in the manual for Colposcopy and Treatment by the International Agency for Research on Cancer, with a histopathological reference standard. We used the QUADAS-2 tool to assess study quality. We examined results for sensitivity and specificity in paired forest plots, stratified by stages in the clinical pathway. We pooled estimates of test accuracy for the index test, used as an add-on to other tests, using a bivariate random-effect model.

Results

We screened 1737 references and assessed 239 full-text articles for eligibility. Five single-gate DTA studies, including 2693 women, met the inclusion criteria. Studies evaluated two devices (Gynocular™ and Pocket) at different stages of the screening pathway. In three studies, which used the index test in an add-on capacity in 1273 women, we found a pooled sensitivity of 0.79 (95% CI 0.55–0.92) and specificity of 0.83 (95% CI 0.59–0.94). The main sources of bias were partial verification, incorporation and classification bias.

Conclusion

Few studies have evaluated portable devices able to perform colposcopy, so their accuracy for the detection of CIN2+ remains uncertain. Future studies should include patient-relevant and long-term outcomes, including missed cases, overtreatment, residual and recurrent disease. To meet the challenge of eliminating cervical cancer in LMIC, methods for visual assessment of the cervix need urgent redress.
Characteristics of prescriptions and costs for acute upper respiratory tract infections in Chinese outpatient pediatric patients: a nationwide cross-sectional study
Authors: Wang Shan , Liu Lihua , Liu Jianchao , Miao Likun , Zhuang Qian , Guo Ning , Zhao Jing , Li Quanzheng , Ren Guoquan
Published: November 2020

Background

To understand the characteristics of prescriptions and costs in pediatric patients with acute upper respiratory infections (AURI) is important for the regulation of outpatient care and reimbursement policy. This study aims to provide evidence on these issues that was in short supply.

Methods

We conducted a retrospective cross-sectional study based on data from National Engineering Laboratory of Application Technology in Medical Big Data. All outpatient pediatric patients aged 0–14 years with an uncomplicated AURI from 1 January 2015 to 31 December 2017 in 138 hospitals across the country were included. We reported characteristics of patients, the average number of medications prescribed per encounter, the categories of medication used and their percentages, the cost per visit and prescription costs of drugs. For these measurements, discrepancies among diverse groups of age, regions, insurance types, and AURI categories were compared. Kruskal-Wallis nonparametric test and Student-Newman-Keuls test were performed to identify differences among subgroups. A multinomial logistic regression was conducted to examine the independent effects of those factors on the prescribing behavior.

Results

A total of 1,002,687 clinical records with 2,682,118 prescriptions were collected and analyzed. The average number of drugs prescribed per encounter was 2.8. The most frequently prescribed medication was Chinese traditional patent medicines (CTPM) (36.5% of overall prescriptions) followed by antibiotics (18.1%). It showed a preference of CPTM over conventional medicines. The median cost per visit was 17.91 USD. The median drug cost per visit was 13.84 USD. The expenditures of antibiotics and CTPM per visit (6.05 USD and 5.87 USD) were among the three highest categories of drugs. The percentage of out-of-pocket patients reached 65.9%. Disparities were showed among subgroups of different ages, regions, and insurance types.

Conclusions

The high volume of CPTM usage is the typical feature in outpatient care of AURI pediatric patients in China. The rational and cost-effective use of CPTM and antibiotics still faces challenges. The reimbursement for child AURI cases needs to be enhanced.
Costs and its drivers for diabetes mellitus type 2 patients in France and Germany: a systematic review of economic studies
Authors: Stegbauer Constance , Falivena Camilla , Moreno Ariadna , Hentschel Anna , Rosenmöller Magda , Heise Tim , Szecsenyi Joachim , Schliess Freimut
Published: November 2020

Background

Type 2 diabetes represents an increasingly critical challenge for health policy worldwide. It absorbs massive resources from both patients and national economies to sustain direct costs of the treatment of type 2 diabetes and its complications and indirect costs related to work loss and wages. More recently, there are innovations based on remote control and personalised programs that promise a more cost-effective diabetes management while reducing diabetes-related complications. In such a context, this work attempts to update cost analysis reviews on type 2 diabetes, focusing on France and Germany, in order to explore most significant cost drivers and cost-saving opportunities through innovations in diabetes care. Although both countries approach care delivery differently, France and Germany represent the primary European markets for diabetes technologies.

Methods

A systematic review of the literature listed in MEDLINE, Embase and EconLit has been carried out. It covered interventional, observational and modelling studies on expenditures for type 2 diabetes management in France or Germany published since 2012. Included articles were analysed for annual direct, associated and indirect costs of type 2 diabetes patients. An appraisal of study quality was performed. Results were summarised narratively.

Results

From 1260 records, the final sample was composed of 24 papers selected according to predefined inclusion/exclusion criteria. Both France and Germany revealed a predominant focus on direct costs. Comparability was limited due to different study populations and cost categories used. Indirect costs were only available in Germany. According to prior literature, reported cost drivers are hospitalisation, prescriptions, higher HbA1c and BMI, treatment with insulin and complications, all indicators of disease severity. The diversity of available data and included costs limits the results and may explain the differences found.

Conclusions

Complication prevention and glycaemic control are widely recognized as the most effective ways to control diabetes treatment costs. The value propositions of self-based supports, such as hybrid closed-loop metabolic systems, already implemented in type 1 diabetes management, are the key points for further debates and policymaking, which should involve the perspectives of caregivers, patients and payers.
Correction to: Genome-enabled insights into the biology of thrips as crop pests
Authors: Rotenberg Dorith , Baumann Aaron A. , Ben-Mahmoud Sulley , Christiaens Olivier , Dermauw Wannes , Ioannidis Panagiotis , Jacobs Chris G. C. , Vargas Jentzsch Iris M. , Oliver Jonathan E. , Poelchau Monica F. , Rajarapu Swapna Priya , Schneweis Derek J. , Snoeck Simon , Taning Clauvis N. T. , Wei Dong , Widana Gamage Shirani M. K. , Hughes Daniel S. T. , Murali Shwetha C. , Bailey Samuel T. , Bejerman Nicolas E. , Holmes Christopher J. , Jennings Emily C. , Rosendale Andrew J. , Rosselot Andrew , Hervey Kaylee , Schneweis Brandi A. , Cheng Sammy , Childers Christopher , Simão Felipe A. , Dietzgen Ralf G. , Chao Hsu , Dinh Huyen , Doddapaneni Harsha Vardhan , Dugan Shannon , Han Yi , Lee Sandra L. , Muzny Donna M. , Qu Jiaxin , Worley Kim C. , Benoit Joshua B. , Friedrich Markus , Jones Jeffery W. , Panfilio Kristen A. , Park Yoonseong , Robertson Hugh M. , Smagghe Guy , Ullman Diane E. , van der Zee Maurijn , Van Leeuwen Thomas , Veenstra Jan A. , Waterhouse Robert M. , Weirauch Matthew T. , Werren John H. , Whitfield Anna E. , Zdobnov Evgeny M. , Gibbs Richard A. , Richards Stephen
Published: November 2020

An amendment to this paper has been published and can be accessed via the original article.
EZH2 promotes the expression of LPA1 by mediating microRNA-139 promoter methylation to accelerate the development of ovarian cancer
Authors: Wu Dongbo , Wu Fanglan , Li Birong , Huang Wei , Wang Donglian
Published: November 2020

Background

It has been known that ovarian cancer (OC) is a leading cause for women mortality globally. We aimed to analyze the underlying mechanism supporting that enhancer of zeste homolog 2 (EZH2) affected the development of OC via the involvement of microRNA-139 (miR-139)/transforming growth factor beta (TGF-β)/lysophosphatidic acid-1 (LPA1) axis.

Methods

High expression patterns of EZH2 and miR-139 and low LPA1 expression pattern in OC were evaluated using RT-qPCR and immunoblotting, while their correlation was assessed by the Spearman’s rank and Pearson’s correlation coefficient. Subsequently, dual-luciferase reporter gene assay was applied to validate the binding relationship between miR-139 and LPA1, while H3K27me enrichment was assessed by ChIP assay. After that, the effects of altered expression of EZH2, miR-194, or LPA1 on the cell biological functions and the expression pattern of TGF-related factors were evaluated.

Results

We found that EZH2 repressed the miR-139 expression pattern by recruiting H3K27me3 to promote miR-139 promoter methylation, while silencing of EZH2 suppressed in vitro cancer progression by increasing miR-139. LPA1 was a target of miR-139, and could activate the TGF-β signaling pathway, which hastened the OC progression. miR-139-targeted inhibition of LPA1 and LPA1-activated TGF-β signaling pathway were evidenced to be critical mechanisms underlying the effects of EZH2 on OC cells. Lastly, silencing of EZH2 inhibited the xenograft growth in vivo.

Conclusions

EZH2 could down-regulate miR-139 expression pattern by recruiting H3K27me3 to promote the miR-139 promoter methylation and activate the TGF-β pathway by up-regulating LPA1, which contributed to the progression of OC. The current study may possess potentials for OC treatment.
The double-edged sword effect of macrophage targeting delivery system in different macrophage subsets related diseases
Authors: Yuan Yuchuan , Long Ling , Liu Jiaxing , Lin Yongyao , Peng Cuiping , Tang Yue , Zhou Xuemei , Li Shuhui , Zhang Chengyuan , Li Xiaohui , Zhou Xing
Published: November 2020

Background

Monocyte/macrophage-targeting delivery systems (MTDSs) have been focused upon as an emerging routine for delivering drugs to treat various macrophage-related diseases. However, the ability of MTDSs to distinguish different macrophage-related diseases and their impact on macrophage function and disease progression have not been systematically revealed, which is important for actively targeted therapeutic or diagnostic strategies.

Results

Herein, we used dextran-modified polystyrene nanoparticles (DEX-PS) to demonstrate that modification of nanoparticles by dextran can specifically enhance their recognition by M2 macrophages in vitro, but it is obstructed by monocytes in peripheral blood according to in vivo assays. DEX-PS not only targeted and became distributed in tumors, an M2 macrophage-related disease, but was also highly distributed in an M1 macrophage-related disease, namely acute peritonitis. Thus, DEX-PS acts as a double-edged sword in these two different diseases by reeducating macrophages to a pro-inflammatory phenotype.

Conclusions

Our results suggest that MTDSs, even those designed based on differential expression of receptors on specific macrophage subtypes, lack the ability to distinguish different macrophage subtype-related diseases in vivo. In addition to the potential impact of these carrier materials on macrophage function, studies of MTDSs should pay greater attention to the distribution of nanoparticles in non-target macrophage-infiltrated disease sites and their impact on disease processes.
The tail of cryptochromes: an intrinsically disordered cog within the mammalian circadian clock
Authors: Parico Gian Carlo G. , Partch Carrie L.
Published: November 2020

Cryptochrome (CRY) proteins play an essential role in regulating mammalian circadian rhythms. CRY is composed of a structured N-terminal domain known as the photolyase homology region (PHR), which is tethered to an intrinsically disordered C-terminal tail. The PHR domain is a critical hub for binding other circadian clock components such as CLOCK, BMAL1, PERIOD, or the ubiquitin ligases FBXL3 and FBXL21. While the isolated PHR domain is necessary and sufficient to generate circadian rhythms, removing or modifying the cryptochrome tails modulates the amplitude and/or periodicity of circadian rhythms, suggesting that they play important regulatory roles in the molecular circadian clock. In this commentary, we will discuss how recent studies of these intrinsically disordered tails are helping to establish a general and evolutionarily conserved model for CRY function, where the function of PHR domains is modulated by reversible interactions with their intrinsically disordered tails.
Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK
Authors: Liu Ying , Yu Lijia , Xu Yaling , Tang Xiaohui , Wang Xijin
Published: November 2020

Background

Smad3 signaling is indicated to regulate microglia activity. Parkinson’s disease (PD) neurodegeneration is shown to be associated with aging and neuroinflammation. However, it remains unclear about the relationship among Smad3 signaling, aging, neuroinflammation, and PD.

Methods

Rats were treated with SIS3 (a specific inhibitor of Smad3, intranigal injection) and/or lipopolysaccharide (intraperitoneal injection). We investigated the effect of SIS3 and lipopolysaccharide and their mechanism of action on motor behavior and nigrostriatal dopaminergic system in the rats. Furthermore, we explored the effect of SIS3 and LPS and their potential signaling mechanism of action on inflammatory response by using primary microglial cultures. Finally, we investigated the relationship among aging, Smad3 signaling, and neuroinflammation using animals of different ages.

Results

Both SIS3 and lipopolysaccharide induced significant behavior deficits and nigrostriatal dopaminergic neurodegeneration in the rats compared with the vehicle-treated (control) rats. Significantly increased behavior deficits and nigrostriatal dopaminergic neurodegeneration were observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the rats treated with vehicle, SIS3, or lipopolysaccharide. Furthermore, both SIS3 and lipopolysaccharide induced significant microglia activation and proinflammatory factor (IL-1β, IL-6, iNOS, and ROS) level increase in the SN of rats compared with the control rats. Significantly enhanced microglial inflammatory response was observed in the rats co-treated with SIS3 and lipopolysaccharide compared with the other three groups. For our in vitro study, both SIS3 and lipopolysaccharide induced significant proinflammatory factor level increase in primary microglia cultures compared with the control cultures. Significantly increased inflammatory response was observed in the cultures co-treated with SIS3 and lipopolysaccharide compared with the other three groups. MAPK (ERK/p38) contributed to microglial inflammatory response induced by co-treatment with SIS3 and lipopolysaccharide. Interestingly, there was decrease in Smad3 and pSmad3 expression (protein) and enhancement of neuroinflammation in the mouse SN with aging. Proinflammatory factor levels were significantly inversely correlated with Smad3 and pSmad3 expression.

Conclusion

Our study strongly indicates the involvement of SN Smad3 signaling deficiency in aging and PD neurodegeneration and provides a novel molecular mechanism underlying the participation of aging in PD and helps to elucidate the mechanisms for the combined effect of multiple factors in PD.
Dosimetric analysis of local failures in skull-base chordoma and chondrosarcoma following pencil beam scanning proton therapy
Authors: Basler Lucas , Poel Robert , Schröder Christina , Bolsi Alessandra , Lomax Antony , Tanadini-Lang Stephanie , Guckenberger Matthias , Weber Damien C.
Published: November 2020

Background

Despite combined modality treatment involving surgery and radiotherapy, a relevant proportion of skull-base chordoma and chondrosarcoma patients develop a local recurrence (LR). This study aims to analyze patterns of recurrence and correlate LR with a detailed dosimetric analysis.

Methods

222 patients were treated with proton radiotherapy for chordoma (n = 151) and chondrosarcoma (n = 71) at the PSI between 1998 and 2012. All patients underwent surgery, followed by pencil-beam scanning proton therapy to a mean dose of 72.5 ± 2.2GyRBE. A retrospective patterns of recurrence analysis was performed: LR were contoured on follow-up MRI, registered with planning-imaging and the overlap with initial target structures (GTV, PTVhigh-dose, PTVlow-dose) was calculated. DVH parameters of planning structures and recurrences were calculated and correlated with LR using univariate and multivariate cox regression.

Results

After a median follow-up of 50 months, 35 (16%) LR were observed. Follow-up MRI imaging was available for 27 (77%) of these recurring patients. Only one (3.7%) recurrence was located completely outside the initial PTV (surgical pathway recurrence). The mean proportions of LR covered by the initial target structures were 48% (range 0–86%) for the GTV, 70% (range 0–100%) for PTVhigh and 83% (range 0–100%) for PTVlow. In the univariate analysis, the following DVH parameters were significantly associated with LR: GTV(V < 66GyRBE, p = 0.01), GTV(volume, p = 0.02), PTVhigh(max, p = 0.02), PTVhigh(V < 66GyRBE, p = 0.03), PTVhigh(V < 59GyRBE, p = 0.02), PTVhigh(volume, p = 0.01) and GTV(D95, p = 0.05). In the multivariate analysis, only histology (chordoma vs. chondrosarcoma, p = 0.01), PTVhigh(volume, p = 0.05) and GTV(V < 66GyRBE, p = 0.02) were independent prognostic factors for LR.

Conclusion

This study identified DVH parameters, which are associated with the risk of local recurrence after proton therapy using pencil-beam scanning for patients with skull-base chordoma and chondrosarcoma.
Metachronous cutaneous squamous cell carcinoma in a young patient as the only presenting symptom to uncover Lynch syndrome with MLH1 Germline mutation
Authors: Khaddour Karam , Fields Ryan C. , Ansstas Michael , Rosman Ilana S. , Ansstas George
Published: November 2020

Background

Cutaneous malignancies are rare complications of Lynch syndrome and can include Muir-Torre and Turcot syndromes that are associated with sebaceous gland tumors and keratoacanthomas. The incidence and clinical course of cutaneous squamous cell carcinoma have not been well documented in Lynch syndrome due to its rarity.

Case presentation

A 49-year male presented with an enlarging groin skin lesion that was biopsed and demonstrated cutaneous squamous cell carcinoma for which he underwent a surgical resection. The patient experienced later a recurrence of cutaneous squamous cell carcinoma around the resected margins. Next generation sequencing of tumor tissue revealed mutations in MSH6 and MLH1, in addition to high microsatellite instability. The patient underwent pembrolizumab treatment with complete resolution of the cutaneous lesion in the groin, but subsequently developed a new mass in the right antecubital fossa shortly after discontinuation of pembrolizumab. Repeat biopsy of the antecubital fossa lesion revealed a recurrence of cutaneous squamous cell carcinoma. Germline mutation testing revealed MLH1 mutation, compatible with Lynch syndrome, and the patient restarted pembrolizumab which was associated with a complete response. The patient was referred for genetic counseling and cancer screening.

Conclusions

Cutaneous squamous cell carcinoma, although rare, can be the initial presenting symptom in patients with Lynch syndrome. This association has been described in patients with germline mutations in MLH1. Lynch syndrome should be considered when evaluating young patients presenting with recurrent cutaneous squamous cell carcinoma with positive family history of malignancy and/ or without any identifiable risk factors for skin cancers, including those with a durable and rapid response to immunotherapy.
Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer
Authors: Giannoudis Athina , Malki Mohammed Imad , Rudraraju Bharath , Mohhamed Hisham , Menon Suraj , Liloglou Triantafillos , Ali Simak , Carroll Jason S. , Palmieri Carlo
Published: November 2020

Background

Activating transcription factor-2 (ATF2), a member of the leucine zipper family of DNA binding proteins, has been implicated as a tumour suppressor in breast cancer. However, its exact role in breast cancer endocrine resistance is still unclear. We have previously shown that silencing of ATF2 leads to a loss in the growth-inhibitory effects of tamoxifen in the oestrogen receptor (ER)-positive, tamoxifen-sensitive MCF7 cell line and highlighted that this multi-faceted transcription factor is key to the effects of tamoxifen in an endocrine sensitive model. In this work, we explored further the in vitro role of ATF2 in defining the resistance to endocrine treatment.

Materials and methods

We knocked down ATF2 in TAMR, LCC2 and LCC9 tamoxifen-resistant breast cancer cell lines as well as the parental tamoxifen sensitive MCF7 cell line and investigated the effects on growth, colony formation and cell migration. We also performed a microarray gene expression profiling (Illumina Human HT12_v4) to explore alterations in gene expression between MCF7 and TAMRs after ATF2 silencing and confirmed gene expression changes by quantitative RT-PCR.

Results

By silencing ATF2, we observed a significant growth reduction of TAMR, LCC2 and LCC9 with no such effect observed with the parental MCF7 cells. ATF2 silencing was also associated with a significant inhibition of TAMR, LCC2 and LCC9 cell migration and colony formation. Interestingly, knockdown of ATF2 enhanced the levels of ER and ER-regulated genes, TFF1, GREB1, NCOA3 and PGR, in TAMR cells both at RNA and protein levels. Microarray gene expression identified a number of genes known to mediate tamoxifen resistance, to be differentially regulated by ATF2 in TAMR in relation to the parental MCF7 cells. Moreover, differential pathway analysis confirmed enhanced ER activity after ATF2 knockdown in TAMR cells.

Conclusion

These data demonstrate that ATF2 silencing may overcome endocrine resistance and highlights further the dual role of this transcription factor that can mediate endocrine sensitivity and resistance by modulating ER expression and activity.
Behavioral, neuromorphological, and neurobiochemical effects induced by omega-3 fatty acids following basal forebrain cholinergic depletion in aged mice
Authors: Cutuli Debora , Landolfo Eugenia , Nobili Annalisa , De Bartolo Paola , Sacchetti Stefano , Chirico Doriana , Marini Federica , Pieroni Luisa , Ronci Maurizio , D’Amelio Marcello , D’Amato Francesca Romana , Farioli-Vecchioli Stefano , Petrosini Laura
Published: November 2020

Background

In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer’s disease (AD) confined especially in the early or prodromal stages of the pathology.

In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology.

Methods

Aged mice first underwent mu-p75-saporin immunotoxin intraventricular lesions to obtain a massive cholinergic depletion and then were orally supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks. Four weeks after the beginning of the dietary supplementation, anxiety levels as well as mnesic, social, and depressive-like behaviors were evaluated. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were carried out.

Results

The n-3 PUFA treatment regulated the anxiety alterations and reverted the novelty recognition memory impairment induced by the cholinergic depletion in aged mice. Moreover, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA were positively related to mnesic abilities.

Conclusions

The demonstration that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD.
Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: off-the-shelf GMP-manufactured donor-independent ATMP
Authors: Ballikaya Seda , Sadeghi Samar , Niebergall-Roth Elke , Nimtz Laura , Frindert Jens , Norrick Alexandra , Stemler Nicole , Bauer Nicole , Rosche Yvonne , Kratzenberg Vanessa , Pieper Julia , Ficek Tina , Frank Markus H. , Ganss Christoph , Esterlechner Jasmina , Kluth Mark A.
Published: November 2020

Background

Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an easily accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated not only with skin-related but also systemic inflammatory and/or degenerative processes.

Methods

We have developed a validated Good Manufacturing Practice-compliant expansion and manufacturing process by which ABCB5+ MSCs derived from surgical discard skin tissues are processed to an advanced-therapy medicinal product (ATMP) for clinical use. Enrichment for ABCB5+ MSCs is achieved in a three-step process involving plastic adherence selection, expansion in a highly efficient MSC-selecting medium, and immunomagnetic isolation of the ABCB5+ cells from the mixed culture.

Results

Product Quality Review data covering 324 cell expansions, 728 ABCB5+ MSC isolations, 66 ABCB5+ MSC batches, and 85 final drug products reveal high process robustness and reproducible, reliable quality of the manufactured cell therapy product.

Conclusion

We have successfully established an expansion and manufacturing process that enables the generation of homogenous ABCB5+ MSC populations of proven biological activity manufactured as a standardized, donor-independent, highly pure, and highly functional off-the-shelf available ATMP, which is currently tested in multiple clinical trials.
Momordica charantia polysaccharides modulate the differentiation of neural stem cells via SIRT1/Β-catenin axis in cerebral ischemia/reperfusion
Authors: Hu Zhaoli , Li Fengying , Zhou Xiaoling , Zhang Feng , Huang Linyan , Gu Bing , Shen Jiangang , Qi Suhua
Published: November 2020

Background

Stroke is the leading cause of long-term motor disability and cognitive impairment. Recently, neurogenesis has become an attractive strategy for the chronic recovery of stroke. It is important to understand the molecular mechanism that promotes neural stem cell (NSC) neurogenesis for future NSC-based therapies. Our previous study showed that Momordica charantia polysaccharides (MCPs) exerted neuroprotective effects on stroke via their anti-oxidant and anti-inflammation activities. However, it remains unknown whether MCPs promote NSC neurogenesis after cerebral ischemic/reperfusion injury (IRI).

Methods

We investigated MCPs’ function in differentiation of neural stem cells (NSCs) in vivo and in vitro experiments. Based on a middle cerebral artery occlusion (MCAO) rat model, the effect of MCPs on neuronal differentiation after MCAO was analyzed. Primary NSCs and neural stem cell line C17.2 were cultured and subjected to glutamate stimulation to establish the cell model of IRI. We evaluated the effect of MCPs on NSC differentiation in IRI cell model by Western blot and immunofluorescence staining. The SIRT1 activity of NSCs post glutamate stimulation was also evaluated by CELL SIRT1 COLORIMETRY ASSAY KIT. In addition, molecular mechanism was clarified by employing the activator and inhibitor of SIRT1.

Results

MCPs had no effects on the differentiation of neural stem cells under physiological conditions while shifted NSC differentiation potential from the gliogenic to neurogenic lineage under pathological conditions. Activation of SIRT1 with MCPs was responsible for the neuronal differentiation of C17.2-NSCs. The neuronal differentiation effect of MCPs was attributed to upregulation SIRT1-mediated deacetylation of β-catenin. MCP-induced deacetylation via SIRT1 promoted nuclear accumulation of β-catenin in NSCs.

Conclusion

Our findings indicate that the deacetylation of β-catenin by SIRT1 represents a critical mechanism of action of MCPs in promoting NSC neuronal differentiation. It provides an improved understanding of molecular mechanism underlying neuroprotective effects of MCPs in IRI, indicating its potential role on treating ischemic stroke especially chronic recovery.
Moderate SMFs attenuate bone loss in mice by promoting directional osteogenic differentiation of BMSCs
Authors: Chen Guilin , Zhuo Yujuan , Tao Bo , Liu Qian , Shang Wenlong , Li Yinxiu , Wang Yuhong , Li Yanli , Zhang Lei , Fang Yanwen , Zhang Xin , Fang Zhicai , Yu Ying
Published: November 2020

Background

Osteoporosis is a common metabolic bone disease without effective treatment. Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to differentiate into multiple cell types. Increased adipogenic differentiation or reduced osteogenic differentiation of BMSCs might lead to osteoporosis. Whether static magnetic fields (SMFs) might influence the adipo-osteogenic differentiation balance of BMSCs remains unknown.

Methods

The effects of SMFs on lineage differentiation of BMSCs and development of osteoporosis were determined by various biochemical (RT-PCR and Western blot), morphological (staining and optical microscopy), and micro-CT assays. Bioinformatics analysis was also used to explore the signaling pathways.

Results

In this study, we found that SMFs (0.2–0.6 T) inhibited the adipogenic differentiation of BMSCs but promoted their osteoblastic differentiation in an intensity-dependent manner. Whole genomic RNA-seq and bioinformatics analysis revealed that SMF (0.6 T) decreased the PPARγ-mediated gene expression but increased the RUNX2-mediated gene transcription in BMSCs. Moreover, SMFs markedly alleviated bone mass loss induced by either dexamethasone or all-trans retinoic acid in mice.

Conclusions

Taken together, our results suggested that SMF-based magnetotherapy might serve as an adjunctive therapeutic option for patients with osteoporosis.