bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-dose decitabine modulates myeloid-derived suppressor cell fitness via LKB1 in immune thrombocytopenia
Authors: Ni Xiaofei , Wang Lingjun , Wang Haoyi , Yu Tianshu , Xie Jie , Li Guosheng , Liu Yanfeng , Zhou Hai , Xu Miao , Hou Ming , Peng Jun , Hou Yu
Published: August 2022

Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. Metabolic fitness of MDSCs is fundamental for its suppressive activity toward effector T cells. Our previous studies showed that the number and inhibitory function of MDSCs were impaired in patients with immune thrombocytopenia (ITP) compared with healthy controls. In this study, we analyzed the effects of decitabine on MDSCs from patients with ITP, both in vitro and in vivo. We found that low-dose decitabine promoted the generation of MDSCs and enhanced their aerobic metabolism and immunosuppressive functions. Lower expression of liver kinase 1 (LKB1) was found in MDSCs from patients with ITP, which was corrected by decitabine therapy. LKB1 short hairpin RNA (shRNA) transfection effectively blocked the function of MDSCs and almost offset the enhanced effect of decitabine on impaired MDSCs. Subsequently, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient (SCID) mice to induce ITP in murine models. Passive transfer of decitabine-modulated MDSCs significantly raised platelet counts compared with that of phosphate buffered saline–modulated MDSCs. However, when LKB1 shRNA-transfected MDSCs were transferred into SCID mice, the therapeutic effect of decitabine in alleviating thrombocytopenia was quenched. In conclusion, our study suggests that the impaired aerobic metabolism of MDSCs is involved in the pathogenesis of ITP, and the modulatory effect of decitabine on MDSC metabolism contributes to the improvement of its immunosuppressive function. This provides a possible mechanism for sustained remission elicited by low-dose decitabine in patients with ITP.
Temporal in vivo platelet labeling in mice reveals age-dependent receptor expression and conservation of specific mRNAs
Authors: Armstrong Paul C. , Allan Harriet E. , Kirkby Nicholas S. , Gutmann Clemens , Joshi Abhishek , Crescente Marilena , Mitchell Jane A. , Mayr Manuel , Warner Timothy D.
Published: August 2022

The proportion of young platelets, also known as newly formed or reticulated, within the overall platelet population has been clinically correlated with adverse cardiovascular outcomes. However, our understanding of this is incomplete because of limitations in the technical approaches available to study platelets of different ages. In this study, we have developed and validated an in vivo temporal labeling approach using injectable fluorescent antiplatelet antibodies to subdivide platelets by age and assess differences in functional and molecular characteristics. With this approach, we found that young platelets (<24 hours old) in comparison with older platelets respond to stimuli with greater calcium flux and degranulation and contribute more to the formation of thrombi in vitro and in vivo. Sequential sampling confirmed this altered functionality to be independent of platelet size, with distribution of sizes of tracked platelets commensurate with the global platelet population throughout their 5-day lifespan in the circulation. The age-associated decrease in thrombotic function was accompanied by significant decreases in the surface expression of GPVI and CD31 (PECAM-1) and an increase in CD9. Platelet messenger RNA (mRNA) content also decreased with age but at different rates for individual mRNAs indicating apparent conservation of those encoding granule proteins. Our pulse-chase–type approach to define circulating platelet age has allowed timely reexamination of commonly held beliefs regarding size and reactivity of young platelets while providing novel insights into the temporal regulation of receptor and protein expression. Overall, future application of this validated tool will inform age-based platelet heterogeneity in physiology and disease.
Development of quantitative and continuous measure for severity degree of Alzheimer’s disease evaluated from MRI images of 761 human brains
Authors: Kim Sangyeol , Park Seongjun , Chang Iksoo ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2022

Background

Alzheimer’s disease affects profoundly the quality of human behavior and cognition. The very broad distribution of its severity across various human subjects requires the quantitative diagnose of Alzheimer’s disease beyond the conventional tripartite classification of cohorts such as cognitively normal (CN), mild cognitive impairment (MCI), Alzheimer’s disease (AD). The unfolding of such broad distributions by the quantitative and continuous degree of AD severity is necessary for the precise diagnose in the cross-sectional study of different stages in AD.

Results

We conducted the massive reanalysis on MRI images of 761 human brains based on the accumulated bigdata of Alzheimer’s Disease Neuroimaging Initiative. The score matrix of cortical thickness profile at cortex points of subjects was constructed by statistically learning the cortical thickness data of 761 human brains. We also developed a new and simple algebraic predictor which provides the quantitative and continuous degree of AD severity of subjects along the scale from 0 for fully CN to 1 for fully AD state. The mathematical measure of a new predictor for the degree of AD severity is presented based on a covariance correlation matrix of cortical thickness profile between human subjects. One can remove the uncertainty in the determination of different stages in AD by the quantitative degree of AD severity and thus go far beyond the tripartite classification of cohorts.

Conclusions

We unfold the nature of broad distribution of AD severity of subjects even within a given cohort by the scale from 0 for fully CN to 1 for fully AD state. The quantitative and continuous degree of AD severity developed in this study would be a good practical measure for diagnosing the different stages in AD severity.
Monitoring daily well-being and meaning-making tendencies among adult child working dementia caregivers: validating an experience sampling study protocol
Authors: Chen Shuangzhou , Liu Huiying , Lou Vivian W. Q.
Published: August 2022

Background

Although the experience sampling method offers advantages for gerontological research, it has seldom been applied to examine well-being and meaning-making tendencies among adult children working caregivers of parents with dementia and thus lacks empirical support for such applications. In response, we aimed to validate the proposed protocol’s participation status, feasibility, usability, and ecological validity.

Methods

For 15 consecutive days, 100 adult child working dementia caregivers participated in our study via web-based assessments on their digital devices. The protocol was first adjusted based on a series of pilot interviews with eight volunteer dementia caregivers. Participants’ compliance and preferred times for activities along with the protocol’s feasibility, usability, and ecological validity were evaluated in a follow-up session with all participants.

Results

The protocol was adjusted in light of recruitment details, user interfaces, the reminder mechanism, and reference time for assessments. The general compliance rate was 93.3%. Preference times for assessments of work (10 a.m. to 3 p.m.), care (6–8 p.m.), and personal activities (7–10 p.m.) were identified. The protocol was generally considered to be feasible and easy to use, and ecological validity analysis indicated that the collected data adequately represented real-world data.

Conclusions

Our study provides empirical evidence to support an innovative protocol and evaluate its implementation so that future studies using it can better investigate the relationship between meaning-making tendencies and well-being among adult child working caregivers for parents with dementia.
Ultrasonographic features of cervical lymph node metastases from medullary thyroid cancer: a retrospective study
Authors: Ni Xiaofeng , Xu Shangyan , Zhan Weiwei , Zhou Wei
Published: August 2022

Background

To investigate sonographic features of cervical lymph node metastases from medullary thyroid cancer (LNM-MTC), as compared with lymph node metastases from papillary thyroid cancer (LNM-PTC).

Methods

A total of 42 MTC patients with 52 metastatic LNs and 222 PTC patients with 234 metastatic LNs who were confirmed by fine needle aspiration and post-operative pathology, were enrolled in this study. The clinical characteristics and sonographic features of LNs were compared between the two groups. Univariate analysis and multivariate logistic regression analysis were performed on the sonographic features of LNs, including short and long-axis diameter, long-axis diameter/short-axis, shape, border, hilum, echogenicity, calcifications, cystic change and vascularity pattern. The discriminating performance was assessed with the area under the receiver operating characteristic curve (AUC).

Results

The mean age of patients with LNM-MTC was older than that of patients with LNM-PTC (46.81 ± 13.05 vs 39.09 ± 12.05, P < 0.001). No differences were observed in gender, location, long-axis diameter/short-axis, shape, border, echogenicity, cystic change and vascularity pattern between LNM-MTC and LNM-PTC groups (P > 0.05, for all). However, long-axis and short-axis diameter, hilum and calcifications were statistically different between these two groups (P < 0.05, for all). The AUC of discriminate value between LNM-MTC and LNM-PTC was 0.808 (95% confidence interval 0.739–0.877).

Conclusion

Compared with LNM-PTC, LNM-MTC tended to have the sonographic characteristics of larger size, absence of hilum, and less calcifications, and awareness of these features might be helpful to in the diagnosis of LNM-MTC.
A diagnosis model in nasopharyngeal carcinoma based on PET/MRI radiomics and semiquantitative parameters
Authors: Feng Qi , Liang Jiangtao , Wang Luoyu , Ge Xiuhong , Ding Zhongxiang , Wu Haihong
Published: August 2022

Background

The staging of nasopharyngeal carcinoma (NPC) is of great value in treatment and prognosis. We explored whether a positron emission tomography/ magnetic resonance imaging (PET/MRI) based comprehensive model of radiomics features and semiquantitative parameters was useful for clinical evaluation of NPC staging.

Materials and methods

A total of 100 NPC patients diagnosed with non-keratinized undifferentiated carcinoma were divided into early-stage group (I—II) and advanced-stage group (III—IV) and divided into the training set (n = 70) and the testing set (n = 30). Radiomics features (n = 396 × 2) of the primary site of NPC were extracted from MRI and PET images, respectively. Three major semiquantitative parameters of primary sites including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) in all NPC patients were measured. After feature selection, three diagnostic models including the radiomics model, the metabolic parameter model, and the combined model were established using logistic regression model. Finally, internal validation was performed, and a nomogram for NPC comprehensive diagnosis has been made.

Results

The radiomics model and metabolic parameter model showed an area under the curve (AUC) of 0.83 and 0.80 in the testing set, respectively. The combined model based on radiomics and semiquantitative parameters showed an AUC of 0.90 in the testing set, with the best performance among the three models.

Conclusion

The combined model based on PET/MRI radiomics and semiquantitative parameters is of great value in the evaluation of clinical stage (early-stage group and advanced-stage group) of NPC.
A potential link between AQP3 and SLC14A1 gene expression level and clinical parameters of maintenance hemodialysis patients
Authors: Zwiech Rafał , Bruzda-Zwiech Agnieszka , Balcerczak Ewa , Szczepańska Joanna , Krygier Adrian , Małachowska Beata , Michałek Dominika , Szmajda-Krygier Dagmara
Published: August 2022

Background

The transport of water and urea through the erythrocyte membrane is facilitated by aquaporins such as aquaglyceroporin (AQP3), and type B urea transporters (UT-B). As they may play an important role in osmotic balance of maintenance hemodialysis (HD) patients, the aim of the present study was to determine whether any relationship exists between the expression of their genes and the biochemical / clinical parameters in HD patients.

Methods

AQP3 and UT-B (SLC14A1) gene expression was evaluated using RT-qPCR analysis in 76 HD patients and 35 participants with no kidney failure.

Results

The HD group demonstrated significantly higher median expression of AQP3 and UT-B (Z = 2.16; P = 0.03 and Z = 8.82; p < 0.0001, respectively) than controls. AQP3 negatively correlated with pre-dialysis urea serum concentration (R = -0.22; P = 0.049) and sodium gradient (R = -0.31; P = 0.04); however, no significant UT-B correlations were observed. Regarding the cause of end-stage kidney disease, AQP3 expression positively correlated with erythropoietin dosages in the chronic glomerulonephritis (GN) subgroup (R = 0.6; P = 0.003), but negatively in the diabetic nephropathy subgroup (R = -0.59; P = 0.004). UT-B positively correlated with inter-dialytic weight gain% in the GN subgroup (R = 0.47; P = 0.03).

Conclusion

Maintenance hemodialysis seems significantly modify AQP3 and UT-B expression but their link to clinical and biochemical parameters needs further large-scale evaluation.
Preoperative prediction of intrahepatic cholangiocarcinoma lymph node metastasis by means of machine learning: a multicenter study in China
Authors: Huang Tingfeng , Liu Hongzhi , Lin Zhaowang , Kong Jie , Lin Kongying , Lin Zhipeng , Chen Yifan , Lin Qizhu , Zhou Weiping , Li Jingdong , Li Jiang-Tao , Zeng Yongyi
Published: August 2022

Background

Hepatectomy is currently the most effective modality for the treatment of intrahepatic cholangiocarcinoma (ICC). The status of the lymph nodes directly affects the choice of surgical method and the formulation of postoperative treatment plans. Therefore, a preoperative judgment of lymph node status is of great significance for patients diagnosed with this condition. Previous prediction models mostly adopted logistic regression modeling, and few relevant studies applied random forests in the prediction of ICC lymph node metastasis (LNM).

Methods

A total of 149 ICC patients who met clinical conditions were enrolled in the training group. Taking into account preoperative clinical data and imaging features, 21 indicators were included for analysis and modeling. Logistic regression was used to filter variables through multivariate analysis, and random forest regression was used to rank the importance of these variables through the use of algorithms. The model’s prediction accuracy was assessed by the concordance index (C-index) and calibration curve and validated with external data.

Result

Multivariate analysis shows that Carcinoembryonic antigen (CEA), Carbohydrate antigen19-9 (CA19-9), and lymphadenopathy on imaging are independent risk factors for lymph node metastasis. The random forest algorithm identifies the top four risk factors as CEA, CA19-9, and lymphadenopathy on imaging and Aspartate Transaminase (AST). The predictive power of random forest is significantly better than the nomogram established by logistic regression in both the validation group and the training group (Area Under Curve reached 0.758 in the validation group).

Conclusions

We constructed a random forest model for predicting lymph node metastasis that, compared with the traditional nomogram, has higher prediction accuracy and simultaneously plays an auxiliary role in imaging examinations.
Notch signaling mutations increase intra-tumor chemokine expression and predict response to immunotherapy in colorectal cancer
Authors: Wang Fei , Huang Chuan , Long Jie , Zhao Zhi-Bin , Ma Hai-Qing , Yao Xue-Qing , Li Liang , Lian Zhe-Xiong
Published: August 2022

Background

The Notch signaling mutation is associated with enhanced anti-tumor immune response in colorectal cancer (CRC). In this study, we aim to investigate the underlying mechanism and the predictive potential of Notch signaling mutation for responding to immunotherapy in CRC.

Methods

We analyzed the immune response associated genes in CRC with Notch signaling mutation concomitant with or without microsatellite instability (MSI) using TCGA dataset and investigated the mutation profiles of the Notch signaling pathway using cBioPortal. The Notch signaling scores and immune cell infiltration scores in different groups were calculated. We applied the Kaplan–Meier method for survival analysis in CRC patients who underwent immunotherapy, and the log-rank test to determine the statistically significant differences in survival. Notch1-knock-down cell line was constructed to detect the pathway and gene variations.

Results

We found that Notch signaling pathway mutation was associated with activated immune response, especially in those with MSI. Such association is useful for predicting a prolonged overall survival of CRC patients who underwent immune checkpoint inhibitor treatment. The mutation resulted in the functional loss of Notch signaling and may modulate the tumor immune microenvironment by increasing the expression of chemokines that are important for recruiting immune cells.

Conclusions

The Notch signaling mutation can modulate the chemotaxis of immune cells by upregulating the chemokine levels of the tumor immune microenvironment, and CRC patients with Notch signaling pathway mutation have better overall survival after immune checkpoint inhibitor treatment.
Comparison of hyperreflective foci in macular edema secondary to multiple etiologies with spectral-domain optical coherence tomography: An observational study
Authors: Zhu Ruilin , Xiao Shiyu , Zhang Wenbo , Li Jun , Yang Menglu , Zhang Yadi , Gu Xiaopeng , Yang Liu
Published: August 2022

Background

Hyperreflective foci (HRF) features in macular edema associated with different etiologies may indicate the disease pathogenesis and help to choose proper treatment. The goal of this study is to investigate the retinal microstructural features of macular edema (ME) secondary to multiple etiologies with spectral-domain optical coherence tomography (SD-OCT) and analyze the origin of HRF in ME.

Methods

This was a retrospective study. SD-OCT images were reviewed to investigate macular microstructural features such as the number and distribution of HRF and hard exudates and the internal reflectivity of the cysts. The differences in microstructural features between groups and the correlations between the number of HRF and other parameters were analyzed.

Results

A total of 101 eyes with ME from 86 diabetic (diabetic macular edema, DME) patients, 51 eyes from 51 patients with ME secondary to branch retinal vein occlusion (branch retinal vein occlusion-macular edema, BRVO-ME), 59 eyes from 58 central retinal vein occlusion (central retinal vein occlusion-macular edema, CRVO-ME) patients, and 26 eyes from 22 uveitis (uveitic macular edema, UME) patients were included in this study. The number of HRF, the frequency of hard exudates and the enhanced internal reflectivity of the cysts were significantly different among the groups. The number of HRF in the DME group was significantly higher than that in the other groups (all P < 0.05). The frequency of hard exudates and enhanced internal reflectivity of the cysts in the DME group were significantly higher than ME secondary to other etiologies (all P < 0.001). Within the DME group, the number of HRF in the patients with hard exudates was significantly higher than that in the patients without hard exudates (P < 0.001).

Conclusion

HRF detected with SD-OCT were more frequent in DME patients than in BRVO-ME, CRVO-ME, or UME patients. The occurrence of HRF was correlated with the frequency of hard exudates. HRF may result from the deposition of macromolecular exudates in the retina, which is speculated to be a precursor of hard exudates.
Prognostic significance of immunoscore related markers in bladder cancer
Authors: Ariafar Ali , Sanati Alireza , Ahmadvand Simin , Shekarkhar Golsa , Safaei Akbar , Shayan Zahra , Faghih Zahra
Published: August 2022

Background

The significance of total and specific subpopulations of tumor-infiltrating lymphocytes (TILs) in cancer is now well-documented. In the present study, we investigated the relevance of CD3+, CD8 +, CD45RO +, and FOXP3 + TILs to the prognosis and survival of patients with bladder cancer and the disease's clinical-pathological parameters.

Methods

Infiltration of each subset was immunohistochemically evaluated in both stromal and intratumoral regions of tumor tissues from 85 patients with urothelial cell carcinoma of the bladder, with known survival.

Results

Our results indicated that intratumoral CD45RO+ lymphocytes were significantly higher in high-grade tumors than in low-grade ones (P = 0.028). The frequencies of intratumoral CD3+ (P = 0.002), CD8 + (P = 0.008), intratumoral (P = 0.002), and stromal (P = 0.017) CD45RO+ lymphocytes were also higher in patients with muscular invasion than those without invasion. The frequencies of intratumoral CD3+ (P = 0.043), CD8+ (P = 0.003), CD45RO+ (P = 0.023), and total CD45RO+ (P = 0.015), showed variation in patients with different T-stage, as well; mostly increased in T2 versus Ta and T1. Comparing patients in different stages revealed an increase in the frequencies of total CD3+ (P = 0.011), intratumoral CD3+ (P = 0.006), total CD8+ (P = 0.012), intratumoral CD8+ (P = 0.009) and stromal CD8+ (P = 0.034), as well as total and stromal CD45RO+ lymphocytes (P = 0.01 and P = 0.034, respectively) in stage II comparing to stage I, while the frequencies of stromal CD3+ (P = 0.077) and CD8+ (P = 0.053) cells tended to be decreased in stage III compared to stage II.

Conclusions

We collectively observed that the frequency of immune cells, especially CD45RO+, CD3+, and CD8+ lymphocytes, were significantly higher in early-progressed tumors. This observation could be explained by continuous and prolonged stimulation of immune cells with tumor antigens during tumor progression or an increase in the recruiting factors, especially in the early stages, to eliminate tumor cells. However, with tumor progression to the late stages, the inhibitory microenvironment provided by tumor cells suppresses or changes the functionality of the effector and memory immune cells to help tumor growth. However, more functional studies with larger sample sizes are needed to reveal the real status of the immune system in patients with bladder cancer.
Psychological safety between pediatric residents and nurses and the impact of an interdisciplinary simulation curriculum
Authors: Haviland Courtney , Green Janet , Dzara Kristina , Hardiman Wendy O. , Petrusa Emil R. , Park Yoon Soo , Frey-Vogel Ariel S.
Published: August 2022

Background

Effective teamwork in interdisciplinary healthcare teams is necessary for patient safety. Psychological safety is a key component of effective teamwork. The baseline psychological safety on pediatric inpatient healthcare teams is unknown. The purpose of this study is to determine the baseline psychological safety between pediatric nurses and residents and examine the impact of an interdisciplinary nighttime simulation curriculum.

Methods

A convergent, multistage mixed methods approach was used. An interprofessional simulation curriculum was implemented fall 2020 to spring 2021. Qualitative focus group data and quantitative survey data on team psychological safety were collected and compared, both pre- and post-intervention and across nurses and residents. Thematic analysis of the qualitative data was conducted, and themes integrated with survey findings.

Results

Data were collected from 30 nurses and 37 residents pre-intervention and 32 and 38 post-intervention, respectively. Residents and nurses negatively rated psychological safety (pre-intervention mean = 3.40 [SD = 0.72]; post-intervention mean = 3.35 [SD = 0.81]). At both times psychological safety was rated significantly lower for residents (pre-intervention mean = 3.11 [SD = 0.76], post-intervention mean = 2.98 [SD = 0.84]) than nurses (pre-intervention mean = 3.76 [SD = 0.45], post-intervention mean = 3.79 [SD = 0.50]), all P < .001. Qualitative analysis identified six integrated themes: (1) influence of existing relationships on future interactions, (2) unsatisfactory manner and frequency of communication, (3) unsatisfactory resolution of disagreements (4) overwhelming resident workload impairs collaboration, (5) interpersonal disrespect disrupts teamwork, and (6) interprofessional simulation was useful but not sufficient for culture improvement.

Conclusion

Resident-nurse team psychological safety ratings were not positive. While interprofessional simulation curriculum shows promise, additional efforts are needed to improve psychological safety among residents and nurses.
Evaluation of an individual anamnesis tool for teaching risk-oriented prevention – a pilot study in undergraduate dental students
Authors: Schmalz Gerhard , Lange Jacqueline , Krause Felix , Haak Rainer , Lethaus Bernd , Zimmerer Rüdiger , Ziebolz Dirk
Published: August 2022

Background

A comprehensive medical history is needed to establish and ensure a high standard in dental care; however, it is challenging to draw clinical consequences on the variety of potential diseases and medications, especially for dental students. Aim of this observational study was to investigate, whether undergraduate dental students using an analog anamnesis tool for risk classification would be more confident and have more knowledge in risk classification than other students in the same year of study.

Methods

A cohort of 48 fifth year dental students was included and allocated into two groups based on their curriculum-related division (group A: n = 25, group B: n = 23). Group A received a teaching event and provision of an analog anamnesis tool for risk classification; group B received neither a teaching event nor the anamnesis tool. At baseline and after two weeks (follow-up), questionnaires regarding self-perceived confidence with risk classification, questions on different disease, medications and lifestyle factors and a task with 15 medical histories of prepared patient cases were applied. The data was statistically analyzed using Mann–Whitney or Wilcoxon test.

Results

In group comparison of the differences between baseline and follow-up regarding self-perceived confidence, significantly higher improvement was noted in group A compared to group B for all questions (p < 0.05). With regard to knowledge, the group comparison revealed that the differences in all of the four tasks were significantly higher in group A compared to group B (pi ≤ 0.01). Thereby, the different tasks in group A differed between baseline and follow-up as follows: Risk of complications: 49.04 ± 13.59 vs. 67.96 ± 17.22, p < 0.01, Risk of oral diseases: 48.77 ± 13.57 vs. 63.44 ± 16.78, p = 0.01, Indication of antibiotic prophylaxis: 75.70 ± 13.45 vs. 87.97 ± 10.37, p < 0.01 and the Medical history task on 15 patient cases: 58.45 ± 4.74 vs. 71.47 ± 9.54, p < 0.01.

Conclusion

The applied analog anamnesis tool supported an increase in students´ confidence with issues related to at-risk patients alongside with their knowledge in risk classification. The applied anamnesis tool can be recommended for improving teaching of risk management for undergraduate dental students.
Barriers and facilitators to scaling up Healthy Choices, a motivational interviewing intervention for youth living with HIV
Authors: MacDonell Karen , Dinaj-Koci Veronica , Koken Juline , Naar Sylvie
Published: August 2022

Background

This study included Community Health Workers and their supervisors from HIV clinical care teams who participated in the Healthy Choices intervention program. Healthy Choices is a Motivational Interviewing-based intervention aimed at improving medication adherence and reducing alcohol use for adolescents and emerging adults ages 16—24 living with HIV. In this study, the intervention was “scaled up” for delivery by local HIV care providers in real-world clinic settings.

Methods

Providers (N = 21) completed semi-structured interviews (N = 29) about their experiences with intervention scale-up. Rigorous thematic analyses were conducted within discussions of barriers and facilitators of intervention implementation.

Results

Three dominant thematic areas emerged from the data: (1) perceptions of the Healthy Choices intervention, (2) engaging high risk YLH in in-person behavior interventions, and (3) perspectives on implementation of the intervention using local staff. Results offer insights into implementation of MI-based interventions for adolescents and emerging adults in clinic settings using local clinical staff instead of dedicated research staff.

Conclusions

Overall, scaled-up intervention programs for youth are challenged to maintain scientific rigor, provide rigorous training and supports, and offer an attractive and engaging program.
Pyrotinib combined with apatinib for targeting metastatic non-small cell lung cancer with HER2 alterations: a prospective, open-label, single-arm phase 2 study (PATHER2)
Authors: Yang Guangjian , Xu Haiyan , Yang Yaning , Zhang Shuyang , Xu Fei , Hao Xuezhi , Li Junling , Xing Puyuan , Hu Xingsheng , Liu Yutao , Wang Lin , Lin Lin , Wang Zhijie , Duan Jianchun , Wang Jie , Wang Yan
Published: August 2022

Background

Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients.

Methods

HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR).

Results

Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported.

Conclusions

Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients.

Trial registration

Chinese Clinical Trial Registry Identifier: ChiCTR1900021684.
Impact of the interaction between the polymorphisms and hypermethylation of the CD36 gene on a new biomarker of type 2 diabetes mellitus: circulating soluble CD36 (sCD36) in Senegalese females
Authors: Touré Maïmouna , Samb Abdoulaye , Sène Mbaye , Thiam Souleymane , Mané Cheikh A. B. , Sow Abdou K. , Ba-Diop Awa , Kane Modou O. , Sarr Mamadou , Ba Abdoulaye , Gueye Lamine
Published: August 2022

Background

Several predisposing factors for diabetes mellitus have been identified, including cluster determinant 36 (CD36) receptor expression. We aimed to determine the effects of CD36 gene polymorphisms and hypermethylation on the plasma CD36 protein levels in type 2 diabetes.

Materials and methods

We conducted a cross-sectional study involving 100 females (lean healthy control subjects and subjects with type 2 diabetes). This study was conducted at the Human Physiology Laboratory at the Dakar Faculty of Medicine in Senegal. Circulating sCD36 levels and DNA methyltransferase 3a levels were determined by enzyme-linked immunosorbent assay. The other biological parameters were evaluated in a biochemical laboratory. CD36 gene polymorphisms and methylation were explored by real-time polymerase chain reaction and methylation-specific polymerase chain reaction, respectively.

Results

sCD36 was negatively correlated with HDL-cholesterol levels (r =  − 0.52 p = 0.0001) and triglyceride levels (r =  − 0.36 p = 0.01) in control subjects. However, in the type 2 diabetes group, sCD36 levels were positively correlated with total cholesterol levels (r = 0.28 p = 0.04). For rs3211867, control subjects harboring the CC genotypes had significantly higher sCD36 levels than control subjects harboring the AA/AC genotype (p = 0.02); in the type 2 diabetes group, the sCD36 level was not significantly lower in subjects harboring the AA/AC genotype than in subjects harboring the CC genotype (p = 0.27). CD36 gene methylation reduced the sCD36 level in the control subjects compared to control subjects without CD36 gene methylation (p = 0.03). This difference was not significant in the type 2 diabetes group comparing subjects with diabetes with CD36 gene methylation to subjects with diabetes without CD36 gene methylation (p = 0.09). We noted a nonsignificant increase in sCD36 levels in subjects with diabetes with CD36 gene methylation compared to control subjects with CD36 gene methylation (p = 0.27). A combination of the CD36 polymorphism effect and the CD36 methylation effect did not significantly reduce sCD36 levels in subjects with type 2 diabetes.

Conclusion

CD36 gene polymorphisms and CD36 gene methylation separately reduce sCD36 levels. Their impacts are compensated for in subjects with type 2 diabetes by an increase in sCD36 levels, the mechanism of which needs to be elucidated.
Novel flavonoid C-8 hydroxylase from Rhodotorula glutinis: identification, characterization and substrate scope
Authors: Dulak Kinga , Sordon Sandra , Matera Agata , Kozak Bartosz , Huszcza Ewa , Popłoński Jarosław
Published: August 2022

Background

The regioselective hydroxylation of phenolic compounds, especially flavonoids, is still a bottleneck of classical organic chemistry that could be solved using enzymes with high activity and specificity. Yeast Rhodotorula glutinis KCh735 in known to catalyze the C-8 hydroxylation of flavones and flavanones. The enzyme F8H (flavonoid C8-hydroxylase) is involved in the reaction, but the specific gene has not yet been identified. In this work, we present identification, heterologous expression and characterization of the first F8H ortho-hydroxylase from yeast.

Results

Differential transcriptome analysis and homology to bacterial monooxygenases, including also a FAD-dependent motif and a GD motif characteristic for flavin-dependent monooxygenases, provided a set of coding sequences among which RgF8H was identified. Phylogenetic analysis suggests that RgF8H is a member of the flavin monooxygenase group active on flavonoid substrates. Analysis of recombinant protein showed that the enzyme catalyzes the C8-hydroxylation of naringenin, hesperetin, eriodyctiol, pinocembrin, apigenin, luteolin, chrysin, diosmetin and 7,4ʹ-dihydroxyflavone. The presence of the C7-OH group is necessary for enzymatic activity indicating ortho-hydroxylation mechanism. The enzyme requires the NADPH coenzyme for regeneration prosthetic group, displays very low hydroxyperoxyflavin decupling rate, and addition of FAD significantly increases its activity.

Conclusions

This study presents identification of the first yeast hydroxylase responsible for regioselective C8-hydroxylation of flavonoids (F8H). The enzyme was biochemically characterized and applied in in vitro cascade with Bacillus megaterium glucose dehydrogenase reactions. High in vivo activity in Escherichia coli enable further synthetic biology application towards production of rare highly antioxidant compounds.
Sociodemographic inequalities in the trends of different types of leisure-time physical activity among Brazilian adults between 2006 and 2019
Authors: Araujo Raphael H. O. , Werneck André O. , Silva Danilo R. , Jesus Gilmar M.
Published: August 2022

Background

The current study aimed to describe the trends in gender, ethnicity, and education inequalities of types of leisure-time physical activity (LTPA) practiced by Brazilian adults from 2006 to 2019.

Methods

We used data from 2006 to 2019 of the Brazilian Surveillance System for Risk and Protective Factors for Chronic Diseases by Telephone Survey, which is an annual survey with a representative sample of adults (≥ 18y) living in state capital cities. The types of LTPA considered were walking, running, strength/gymnastics, sports, other LTPA, and no LTPA participation. Gender (women or men), ethnicity (white, black, brown, or yellow/indigenous), and years of formal education were also self-reported. We used relative frequencies and their respective 95% confidence intervals to analyze trends. The absolute and relative differences between the proportions were used to assess the inequalities.

Results

We observed increases in inequalities related to gender and education (running and strength/gymnastics), while gender inequalities for sports, other types, and no LTPA participation decreased. There were persistent inequalities related to gender (walking) and education (sports, other types, and no LTPA participation). Considering ethnicity, we noted increases in inequality for strength/gymnastics, where white adults were more active than black and brown adults. In addition, white adults reported more access to LTPA than brown adults over the years analyzed.

Conclusion

Women, black and brown people, and subjects with less schooling were the most unfavored groups. While some inequalities persisted over the years, others increased, such as ethnicity and education inequalities for strength/gymnastics.
A novel antibiotic combination of linezolid and polymyxin B octapeptide PBOP against clinical Pseudomonas aeruginosa strains
Authors: Huang Ting , Zeng Mao , Fu Huiyao , Zhao Kelei , Song Tao , Guo Yidong , Zhou Jingyu , Zhai Longfei , Liu Chaolan , Prithiviraj Balakrishnan , Wang Xinrong , Chu Yiwen
Published: August 2022

Background

Antibiotic-resistant Gram-negative bacteria are becoming a major public health threat such as the important opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa). The present study investigated enhancement of the linezolid spectrum, which is normally used to treat Gram-positive bacteria, at inhibiting P. aeruginosa growth.

Methods

The checkerboard test or time-kill assay were carried out to determine the antibacterial effects of linezolid in cooperation with polymyxin B octapeptide PBOP (LP) against P. aeruginosa based on in vitro model. The protective effect of LP against P. aeruginosa infection was assessed based on a Caenorhabditis elegans (C. elegans) model.

Results

The synergistic activity and antibacterial effects were significantly increased against P. aeruginosa by LP treatment, while linezolid and PBOP as monotherapies exhibited no remarkably bactericidal activity against the clinical strains. Additionally, LP treatment modified biofilm production, morphology, swimming motility of P. aeruginosa, and protected C. elegans from P. aeruginosa infection.

Conclusions

This research demonstrates that LP combination has significant synergistic activity against P. aeruginosa, and PBOP is potential to be an activity enhancer. Notably, this strategy improved the antibacterial activity spectrum of linezolid and other anti-Gram-positive agents and represents an effective choice to surmount the antibiotic resistance of bacteria in the long term.
Immune system-related soluble mediators and COVID-19: basic mechanisms and clinical perspectives
Authors: Soltani-Zangbar Mohammad Sadegh , Parhizkar Forough , Abdollahi Mojtaba , Shomali Navid , Aghebati-Maleki Leili , Shahmohammadi Farid Sima , Roshangar Leila , Mahmoodpoor Ata , Yousefi Mehdi
Published: August 2022

During SARS-CoV-2 infection, an effective immune response provides the first line of defense; however, excessive inflammatory innate immunity and impaired adaptive immunity may harm tissues. Soluble immune mediators are involved in the dynamic interaction of ligands with membrane-bound receptors to maintain and restore health after pathological events. In some cases, the dysregulation of their expression can lead to disease pathology. In this literature review, we described current knowledge of the basic features of soluble immune mediators and their dysregulation during SARS-CoV-2 infections and highlighted their contribution to disease severity and mortality.
Establishment and evaluation of ectopic and orthotopic prostate cancer models using cell sheet technology
Authors: Zhang Dongliang , Wang Ying , Liu Lei , Li Zeng , Yang Shengke , Zhao Weixin , Wang Xiang , Liao Hong , Zhou Shukui
Published: August 2022

Background

The traditional prostate cancer (PCa) model is established by injecting cell suspension and is associated with a low tumor formation rate. Cell sheet technology is one of the advancements in tissue engineering for 3D cell-based therapy. In this study, we established ectopic and orthotopic PCa models by cell sheet technology, and then compared the efficiency of tumor formation with cell suspension injection.

Methods

DU145 cells were seeded on 35 mm temperature-sensitive dishes to form PCa cell sheets, while the cell suspension with the same cell density was prepared. After transplanting into the nude mice, the tumor volumes were measured every 3 days and the tumor growth curves were conducted. At the time points of 2 weeks and 4 weeks after the transplantation, magnetic resonance imaging (MRI) was used to evaluate the transplanting site and distant metastasis. Finally, the mice were sacrificed, and the related tissues were harvested for the further histological evaluation.

Results

The orthotopic tumor formation rate of the cell sheet injection group was obviously better than that in cell suspension injection group (100% vs 67%). Compared with cell suspension injection, the tumors of DU145 cell sheet fragments injection had the higher density of micro-vessels, more collagen deposition, and lower apoptosis rate. There was no evidence of metastasis in forelimb, lung and liver was found by MRI and histological tests.

Conclusion

We successfully cultured the DU145 cell sheet and can be used to establish ectopic and orthotopic PCa tumor-bearing models, which provide an application potential for preclinical drug development, drug-resistance mechanisms and patient individualized therapy.
Markers of endothelial glycocalyx dysfunction in Clarkson disease
Authors: Xie Zhihui , Børset Magne , Svéen Kjell , Bøe Ole Wilhelm , Chan Eunice C. , Lack Justin B. , Hornick Katherine M. , Verlicchi Franco , Eisch A. Robin , Melchio Remo , Dudek Arkadiusz Z. , Druey Kirk M.
Published: August 2022

Background

Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia.

Methods

We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining.

Results

Serum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells.

Conclusions

eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS.

Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses.
Prior episode of colitis impairs contextual fear memory
Authors: Wu Chia-Shan , Endres Valerie
Published: August 2022

Accumulating evidence has shown that intestinal inflammations in inflammatory bowel disease (IBD) also drive pathological responses in organs outside the intestine, including the brain. Previous studies using the dextran sodium sulfate (DSS)-induced colitis model have shown that colonic inflammation contributes to the development of anxiety- and depression-related behaviors; however, little is known about whether memory function is affected. Here, we subjected male and female C57BL/6J mice to DSS-induced colitis for 6 days, followed by Pavlovian conditioned fear (CF) tests 15 days after the start of inflammation, when local colonic inflammation has receded. The contextual and cued CF tests were used to assess associative fear memory. We found that DSS-induced colitis led to significant impairment in contextual fear memory in both male and female mice; on the other hand, auditory cued fear memories were comparable between control and DSS-treated mice. There were marked signs of astrogliosis in the hippocampal regions 17 days (D17) after colitis induction. Furthermore, molecular characterization of hippocampi showed marked but transient increases in the expression of inflammatory genes Nfkb, Trem2 (microglial marker), GFAP (astrocyte marker), Il1b, and S100a8 in DSS-treated mice. While the expression of Nfkb, Trem2, and GFAP showed a peak on day 10, the S100a8 expression was high on days 10 and 17 and subsided on day 42. Interestingly, expression of Bdnf remained elevated in the times assessed (D10, 17, 42). Together, these results demonstrated that DSS-induced colitis could induce prolonged neuroinflammation and impaired contextual fear memory.
Recent advances in therapeutic strategies for triple-negative breast cancer
Authors: Li Yun , Zhang Huajun , Merkher Yulia , Chen Lin , Liu Na , Leonov Sergey , Chen Yongheng
Published: August 2022

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC) with a poor prognosis. Current treatment options are limited to surgery, adjuvant chemotherapy and radiotherapy; however, a proportion of patients have missed the surgical window at the time of diagnosis. TNBC is a highly heterogeneous cancer with specific mutations and aberrant activation of signaling pathways. Hence, targeted therapies, such as those targeting DNA repair pathways, androgen receptor signaling pathways, and kinases, represent promising treatment options against TNBC. In addition, immunotherapy has also been demonstrated to improve overall survival and response in TNBC. In this review, we summarize recent key advances in therapeutic strategies based on molecular subtypes in TNBC.