bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship of genetic risk score with cardiometabolic risk factors: a cross-sectional study
Authors: Gholami Fatemeh , Rasaei Niloufar , Samadi Mahsa , Yekaninejad Mir Saeid , Keshavarz Seyed Ali , Javdan Gholamali , Karimi Zahra , Mirzaei Khadijeh
Published: November 2022

Background & aims

For more than eight decades, cardiovascular disease (CVD) has remained the leading cause of death in the world. CVD risk factors are multifaceted, with genetics and lifestyle both playing a role. The aim of this study was to investigate the association between a genetic profile risk score for obesity GRS and cardio-metabolic risk factors in overweight and obese women.

Methods

The current cross-sectional study was conducted on 391 overweight and obese women. The genetic risk score was created by combining three single nucleotide polymorphisms [MC4R (rs17782313), CAV-1 (rs3807992), and Cry-1 (rs2287161)]. Anthropometric measurements, blood pressure, and some blood parameters were measured by standard protocols.

Results

A significant association between the GRS and some of cardiometabolic risk factors variables such as body mass index (β = 0. 49, 95%CI = 0.22 to 0.76, p < 0.001), waist circumference (β = 0. 86, 95%CI = 0.18 to 1.54, p = 0.01), body fat mass (β = 0. 82, 95%CI = 0.25 to 1.39, p = 0.005), %body fat (β = 0. 44, 95%CI = 0.06 to 0.82, p = 0.02), and hs-CRP (β = 0.46, 95% CI = 0.14 to 0.78, p = 0.005) was observed in crude model. After adjustment for confounding factors (age, BMI, and physical activity), a significant positive association was observed between BMI (p = 0.004), WC (p = 0.02), body fat mass (p = 0.01), %BF (p = 0.01), hs-CRP (p = 0.009), and GRS. In addition, we discovered a significant negative association between the GRS and BMC (= -0.02, 95%CI = -0.05 to -0.001, p = 0.04). But other variables did not show any significant association with GRS among obese and overweight women.

Conclusion

We found a significant positive association between GRS, including MC4R (rs17782313), CAV-1 (rs3807992), and Cry-1 (rs2287161) and cardiometabolic risk factors among overweight and obese Iranian women.
Dementia risk prediction in individuals with mild cognitive impairment: a comparison of Cox regression and machine learning models
Authors: Wang Meng , Greenberg Matthew , Forkert Nils D. , Chekouo Thierry , Afriyie Gabriel , Ismail Zahinoor , Smith Eric E. , Sajobi Tolulope T.
Published: November 2022

Background

Cox proportional hazards regression models and machine learning models are widely used for predicting the risk of dementia. Existing comparisons of these models have mostly been based on empirical datasets and have yielded mixed results. This study examines the accuracy of various machine learning and of the Cox regression models for predicting time-to-event outcomes using Monte Carlo simulation in people with mild cognitive impairment (MCI).

Methods

The predictive accuracy of nine time-to-event regression and machine learning models were investigated. These models include Cox regression, penalized Cox regression (with Ridge, LASSO, and elastic net penalties), survival trees, random survival forests, survival support vector machines, artificial neural networks, and extreme gradient boosting. Simulation data were generated using study design and data characteristics of a clinical registry and a large community-based registry of patients with MCI. The predictive performance of these models was evaluated based on three-fold cross-validation via Harrell’s concordance index (c-index), integrated calibration index (ICI), and integrated brier score (IBS).

Results

Cox regression and machine learning model had comparable predictive accuracy across three different performance metrics and data-analytic conditions. The estimated c-index values for Cox regression, random survival forests, and extreme gradient boosting were 0.70, 0.69 and 0.70, respectively, when the data were generated from a Cox regression model in a large sample-size conditions. In contrast, the estimated c-index values for these models were 0.64, 0.64, and 0.65 when the data were generated from a random survival forest in a large sample size conditions. Both Cox regression and random survival forest had the lowest ICI values (0.12 for a large sample size and 0.18 for a small sample size) among all the investigated models regardless of sample size and data generating model.

Conclusion

Cox regression models have comparable, and sometimes better predictive performance, than more complex machine learning models. We recommend that the choice among these models should be guided by important considerations for research hypotheses, model interpretability, and type of data.
Histogram-based analysis of diffusion-weighted imaging for predicting aggressiveness in papillary thyroid carcinoma
Authors: Wei Ran , Zhuang Yuzhong , Wang Lanyun , Sun Xilin , Dai Zedong , Ge Yaqiong , Wang Hao , Song Bin
Published: November 2022

Background

To assess the potential of apparent diffusion coefficient (ADC) map in predicting aggressiveness of papillary thyroid carcinoma (PTC) based on whole-tumor histogram-based analysis.

Methods

A total of 88 patients with PTC confirmed by pathology, who underwent neck magnetic resonance imaging, were enrolled in this retrospective study. Whole-lesion histogram features were extracted from ADC maps and compared between the aggressive and non-aggressive groups. Multivariable logistic regression analysis was performed for identifying independent predictive factors. Receiver operating characteristic curve analysis was used to evaluate the performances of significant factors, and an optimal predictive model for aggressiveness of PTC was developed.

Results

The aggressive and non-aggressive groups comprised 67 (mean age, 44.03 ± 13.99 years) and 21 (mean age, 43.86 ± 12.16 years) patients, respectively. Five histogram features were included into the final predictive model. ADC_firstorder_TotalEnergy had the best performance (area under the curve [AUC] = 0.77). The final combined model showed an optimal performance, with AUC and accuracy of 0.88 and 0.75, respectively.

Conclusions

Whole-lesion histogram analysis based on ADC maps could be utilized for evaluating aggressiveness in PTC.
SOX-1 antibodies in a patient with Crohn’s disease: a case report
Authors: Polilli Ennio , Frattari Antonella , Esposito Jessica Elisabetta , Angelini Gilda , Di Risio Annalisa , Mazzotta Elena , Coladonato Simona , Di Iorio Giancarlo , Parruti Giustino , Tocco Pierluigi
Published: November 2022

Background

The anti-SOX-1 antibodies have been mainly associated with Lambert-Eaton Myasthenic Syndrome (LETMS) and Small-Cell Lung Cancer (SCLC). In this report, we describe the interesting case of a patient with serum anti-SOX-1 antibodies and Crohn’s Disease (CD) with ensuing neurological symptoms.

Case presentation

A Caucasian 67-year-old female was admitted to the Emergency Department with seizures, vertigo, emesis, nausea, postural instability and recurrent falls, over a period of 10 days. She had been affected by Crohn’s Disease since 1991. A CT scan failed to detect any ischemic or haemorrhagic lesion. A brain MRI revealed signs of leukoencephalopathy. Western blot analysis of her serum revealed a high titre of the onconeural antibody anti-SOX1, consistent with a neurological, cerebellar type, paraneoplastic syndrome. In spite of multiple efforts to unmask a possible underlying malignancy, no neoplastic lesion cropped up during hospitalization. Her clinical conditions progressively deteriorated, up to respiratory failure; a few days later she died, due to ensuing septic shock and Multiple Organ Failure.

Conclusions

Our experience may usher and reveal a new role of anti-neural antibodies, so far reckoned an early indicator of associated malignancy, suggesting that neurological syndromes associated with such antibodies may complicate also chronic Gastrointestinal (GI) diseases. As of now, testing for anti-neuronal antibodies appeared unnecessary within the diagnostic assessment of gastroenterological disorders, which may lead to overlooking incident neurologic autoimmune diseases. Further exploration of such research hypothesis in clinical grounds appears intriguing.
Study protocol of transcranial electrical stimulation at alpha frequency applied during rehabilitation: A randomized controlled trial in chronic stroke patients with visuospatial neglect
Authors: Middag-van Spanje Marij , Schuhmann Teresa , Nijboer Tanja , van der Werf Olof , Sack Alexander T. , van Heugten Caroline
Published: November 2022

Background

A frequent post stroke disorder in lateralized attention is visuospatial neglect (VSN). As VSN has a strong negative impact on recovery in general and independence during daily life, optimal treatment is deemed urgent. Next to traditional stroke treatment, non-invasive brain stimulation offers the potential to facilitate stroke recovery as a complementary approach. In the present study, visual scanning training (VST; the current conventional treatment) will be combined with transcranial alternating current stimulation (tACS) to evaluate the additive effects of repeated sessions of tACS in combination with six-weeks VST rehabilitation.

Methods

In this double-blind randomized placebo-controlled intervention study (RCT), we will compare the effects of active tACS plus VST to sham (placebo) tACS plus VST, both encompassing 18 VST training sessions, 40 minutes each, during 6 weeks. Chronic stroke patients with VSN (> 6 months post-stroke onset) are considered eligible for study participation. In total 22 patients are needed for the study. The primary outcome is change in performance on a cancellation task. Secondary outcomes are changes in performance on a visual detection task, two line bisection tasks, and three measures to assess changes in activities of daily living. Assessment is at baseline, directly after the first and ninth training session, after the last training session (post training), and 1 week and 3 months after termination of the training (follow-up).

Discussion

If effective, a tACS-VST rehabilitation program could be implemented as a treatment option for VSN.

Trial registration

ClinicalTrials.gov; registration number: NCT05466487; registration date: July 18, 2022 retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT05466487
Investigation of the role of X chromosome inactivation and androgen receptor CAG repeat polymorphisms in patients with recurrent pregnancy loss: a prospective case–control study
Authors: Sui Yilun , Fu Jing , Zhang Shuo , Li Lu , Sun Xiaoxi
Published: November 2022

Background

Previous research has revealed that skewed X chromosome inactivation (SXCI) and androgen receptor (AR) CAG polymorphisms are associated with increased risk of recurrent pregnancy loss (RPL); however, the results are conflicting, and the underlying mechanisms remain unclear. This study investigated the role of SXCI and AR CAG polymorphisms in patients with RPL and explored whether the underlying mechanisms were related to the ovarian reserve and preimplantation embryo aneuploidy.

Methods

This was a prospective case-control study carried out in a tertiary hospital-based reproductive medicine center. An external validation RPL cohort was recruited during the study period. Data on baseline and cycle characteristics were collected. X-chromosome inactivation (XCI) was measured using a human AR assay. AR polymorphisms were assessed using quantitative fluorescent polymerase chain reactions and direct sequencing. Blastocysts of the patients with RPL were tested by single nucleotide polymorphism microarray based preimplantation genetic testing for aneuploidy.

Results

In total, 131 patients with idiopathic RPL and 126 controls were included for the case-control study. Patients with RPL exhibited a significantly more skewed XCI distribution pattern (67.71 ± 10.50 vs. 64.22 ± 10.62, p = 0.011), as well as significantly shorter bi-allelic mean (18.56 ± 1.97 vs. 19.34 ± 2.38, p = 0.005) and X-weighted bi-allelic mean (18.46 ± 2.02 vs. 19.38 ± 2.53, p = 0.001) of AR CAG repeats. Multivariate logistic regression models indicated that CAG repeat < 20, SXCI, and duration of stimulation were independently associated with the risk of RPL. However, SXCI and AR CAG polymorphisms were not associated with ovarian reserve or preimplantation embryo aneuploidy in the RPL group, and the same results were attained in a separate validation cohort of 363 patients with RPL.

Conclusion

SXCI and AR CAG polymorphisms are related to RPL; however, these two factors do not lead to RPL by affecting the ovarian reserve or increasing embryo aneuploidy. The roles of SXCI and AR CAG in RPL may involve other mechanisms that require further investigation.

Trial registration:

NCT02504281, https://www.clinicaltrials.gov (Date of registration, 21/07/2015; date of enrolment of the first subject, 30/07/2015).
B7-H3 targeted CAR-T cells show highly efficient anti-tumor function against osteosarcoma both in vitro and in vivo
Authors: Zhang Qian , Zhang Zhiqiang , Liu Guodi , Li Dehua , Gu Zhangjie , Zhang Linsong , Pan Yingjiao , Cui Xingbing , Wang Lu , Liu Guoping , Tian Xiaoli , Zhang Ziming
Published: November 2022

Background

Osteosarcoma (OS) mainly happens in children and youths. Surgery, radiotherapy and chemotherapy are the common therapies for osteosarcoma treatment but all their anti-tumor effects are limited. In recent years, a new cellular therapy, CAR-T, a cellular immunotherapy with genetically engineered T cells bearing chimeric antigen receptor targeting specific tumor-associated antigen, has been proved to be an effective therapy against acute lymphoblastic leukemia. Thus, CAR-T is a potentially effective therapy for osteosarcoma treatment.

Methods

A CAR gene targeting B7-H3 antigen was constructed into lentiviral vector through molecular biology techniques. Then, the CAR gene was transferred to T cells through lentiviral delivery system, and the CAR-T cells were largely expanded using in vitro culture technology. The in vitro anti-tumor effect of CAR-T cells was evaluated through Real Time Cell Analysis system (RTCA) and ELISA assay. The in vivo anti-tumor capabilities of CAR-T cells were evaluated using the patient-derived xenografts (PDX) model of osteosarcoma.

Results

The third-generation CAR-T cells we constructed could target the B7-H3 antigen, and the phenotype of CAR-T cells was consistent with normal T cells; The CAR-T cells showed superior antitumor effects both in vitro and in vivo.

Conclusion

Our study showed that B7-H3 targeted CAR-T cells had high anti-tumor efficacy against osteosarcoma both in vitro and in vivo, which proved that B7-H3 targeted CAR-T therapy is potentially effective for osteosarcoma treatment.
Observation, laser photocoagulation or anti-VEGF therapy in the management of retinal arterial macroaneurysms
Authors: Wang Yuelin , Du Hong , Zhao Xinyu , Meng Lihui , Chen Youxin
Published: November 2022

Background

To explore the efficacy of observation, laser photocoagulation, and anti-VEGF in the management of retinal arterial macroaneurysm (RAM).

Methods

We retrospectively included patients diagnosed with RAM at the Peking Union Medical College Hospital (PUMCH) from 2003 to 2021, and comprehensively reviewed cases documented in the literature from multiple databases (PROSPERO protocol CRD42022310417). Patients were categorized into 3 groups: the observation group, anti-VEGF group, and laser photocoagulation group. LogMAR visual acuity (VA) and central retinal thickness (CMT) at the end of the follow-up were analyzed.

Results

A total of 14 patients from the PUMCH and 210 patients from the literature review were included. VA and CMT in patients who underwent observation, laser photocoagulation, and anti-VEGF therapies were significantly improved from baseline (p < 0.05), with changes in LogMAR VA improved by -0.34 ± 0.68, -0.17 ± 0.58, and -0.45 ± 0.62 and changes in CMT improved by -148.26 ± 138.99 µm, -185.61 ± 130.37 µm, and -287.45 ± 171.87 µm, respectively. Subgroup analysis revealed that anti-VEGF therapy was used in patients with worse VA than patients who underwent laser photocoagulation (p = 0.010), but achieved better improvement in VA than the laser photocoagulation group (p = 0.049). Patients treated with anti-VEGF also had thicker CMT than the observation group (p = 0.013), and experienced better changes in CMT than the observation, as well as laser photocoagulation groups (p = 0.005; p = 0.047).

Conclusion

Observation, anti-VEGF, and laser photocoagulation are effective therapeutic methods for the management of RAM, and anti-VEGF therapy is intended to better improve patients with severe VA and CMT.
Development and application of the TFA macrosimulation model: a case study of modelling the impact of trans fatty acid (TFA) elimination policies in Brazil
Authors: Nilson Eduardo Augusto Fernandes , Khandpur Neha , da Silva Gomes Fabio
Published: November 2022

Introduction

The consumption of trans-fatty acids (TFA) is directly associated with cardiovascular disease risk and is responsible for a significant health burden globally. The policy strategies for reducing TFA include limiting their content in foods and eliminating partially hydrogenated oils (PHO) in the market. This study aims to describe a comparative risk assessment macrosimulation model and to apply this tool to estimate the potential reductions in CVD mortality gained from the compared scenarios of TFA reduction/elimination in Brazil.

Methodology

We developed and implemented a comparative risk assessment macrosimulation model estimates the potential CVD mortality reduction (coronary heart disease – CHD- and stroke) if TFA intake is reduced in diets. The TFA macrosimulation model estimates the change in the annual number of NCD deaths between baseline with current TFA consumption levels and alternate or counterfactual scenarios, such as considering different limits to TFA content in foods and the elimination of PHO in Brazil in 2018. The model incorporated additional outputs related to other impacts of TFA reduction on DPP, such as Years of Life Lost, Years of Productive Life Lost, and related economic impacts of premature deaths.

Results

In 2018, a 2% limit for TFA in the oils and fats and a 5% limit of TFAs for other foods could avert or postpone approximately 2,000 deaths (UI 95% 1,899-2,142) and save US$ 32.1 million savings in productivity losses to the economy associated to premature deaths. An intermediate scenario, applying a 2% limit of TFA in all food products In Brazil could prevent or postpone approximately 6,300 deaths (UI 95% 5,925-6,684) and the premature deaths prevented would represent US$ 100.2 million in economic saving. Finally, by banning PHO, approximately 10,500 deaths could be prevented or postponed (UI 95% 9,963 − 10,909), corresponding to US$ 166.7 million in savings to the economy because of premature deaths.

Conclusion

The TFA macrosimulation model can efficiently compare different policy scenarios for trans fats reduction policies at the country level and proves that the elimination of PHOs from the food market in Brazil may significantly reduce the health burden of trans fatty acids in the country compared to other policy options. The model also represents a useful public health tool to support TFA reduction and elimination policies in other countries.
A randomized controlled trial to evaluate the effectiveness of a novel mouth rinse in patients with gingivitis
Authors: Newman Bianca A. , Rosebrough Claire N. , Tamashiro Ryan A. , Dias Ribeiro Ana P. , Whitlock Joan A. , Sidhu Gurjit , Aukhil Ikramuddin , Porral Dianne Y. , Progulske-Fox Ann , Myntti Matthew F. , Wang Gary P.
Published: November 2022

Background

This single-center, randomized controlled trial aimed to determine the effectiveness of a novel, biofilm-disrupting, mouth rinse that combines Cetylpyridinium chloride (CPC) and essential oils in preventing re-accumulation of supragingival plaque and supragingival microbiome in patients with gingivitis after dental prophylaxis.

Methods

One hundred eighteen participants were randomly assigned in a 1:1 ratio to receive twice-daily test mouth rinse (59) or carrier rinse control (59) for 12 weeks after dental prophylaxis.

Results

In a per-protocol analysis that included patients who completed the intervention, the treatment group (39) had significantly lower supragingival plaque scores at 6 and 12 weeks compared to the control group (41; p = 0.022). Both groups showed similar improvement in gingivitis score, but neither group had improvement in bleeding score or probing depth. Thirty-eight (29%) patients did not complete the study due to loss of follow-up (17) or early discontinuation of the assigned intervention (21). Microbiome sequencing showed that the treatment rinse significantly depleted abundant and prevalent members of the supragingival plaque microbiome consortium.

Conclusions

Among patients with gingivitis, the novel mouth rinse significantly reduced re-accumulation of supragingival plaque following dental prophylaxis by depleting supragingival plaque microbiome. However, long-term adherence to the rinse may be limited by adverse effects (ClinicalTrials.gov number, NCT03154021).
The decisional balance, attitudes, and practice behaviors, its predicting factors, and related experiences of advance care planning in Taiwanese patients with advanced cancer
Authors: Chen Yueh-Chun , Huang Hsiang-Ping , Tung Tao-Hsin , Lee Ming-Yang , Beaton Randal D. , Lin Yung-Chang , Jane Sui-Whi
Published: November 2022

Background

Patients with advanced cancer are prone to experience burdensome physical, psychological, and financial consequences. Healthcare providers may not fully appreciate advanced cancer patients’ medical care autonomy, such as at that emboded by Advance Care Planning (ACP), and by doing so may compromise their quality of end-of-life (EOL). Hence, it is essential for healthcare providers to effectively assess and communicate with patients’ regarding their medical decisions before their patients are incapacitated by their disease progression. The purpose of this investigation was to describe the decisional balance, attitudes, and practice behaviors of ACP and its predictors of ACP-related experiences in Taiwanese patients with advanced cancer.

Methods

This cross-sectional, descriptive study employed a mixed-methodsquantitative and qualitative design with a sample of 166 patients that were purposely recruited from in-patient oncology units at a regional teaching hospital in southern Taiwan. Study data consisted of patient replies to a 34-item self-report tool, Decisional Balance, Attitudes, Practice Behaviors of ACP (DAP-ACP) and 4 semi-structured questions.

Result

Findings indicated that, in general, study participants exhibited favorable ACP-decisional balance and positive ACP-attitudes & practice behaviors. The results also indicated that gender, educational level, and cancer diagnosis were associated with significant differences on the “ACP-decisional balance” and “ACP-attitudes” scales. In addition, our findings documented that the participants’ gender and educational level were significant predictors of both ACP-decisional balance and ACP-attitudes. Furthermore the participants’ ACP-practice behaviors were predicted by ACP-decisional balance, but not with their ACP-attitudes. The qualitative analysis of the semi-structured questions identified six themes in responses to current medical decision making (e.g., compliance with physician instructions, family engagement in treatment decision-making); and eight themes pertaining to future ACP-related concerns were identified (e.g., family conflict, effectiveness of time-limited trials).

Conclusion

To promote patients’ engagement in ACP, the healthcare professional need to assess and advocate patients’ concerns or attitudes regarding ACP in a timely manner. In addition, factors or concerns that might influence patients’ responses to ACP derived from both the quantitative and qualitative findings of this current study need to be considered especially in initiating the dialogue regarding ACP with patients with advanced cancer.

Trial registration

No. CYCH 2,019,072, Date of registration 5 Dec 2019.
Methadone switching for refractory cancer pain
Authors: Ding Haiying , Song Yu , Xin Wenxiu , Sun Jiao , Zhong Like , Zhou Qinfei , He Chaoneng , Gong Liyan , Fang Luo
Published: November 2022

Background

Methadone is commonly considered an alternative opioid treatment for refractory cancer pain. This study aims to investigate the efficacy, safety, and cost of methadone in the treatment of refractory cancer pain.

Methods

A retrospective study was conducted in patients who used methadone for refractory cancer pain from April 2016 to December 2020 at a cancer specialized hospital. Pain control, evaluated via pain score and breakthrough pain frequency, and adverse events of methadone were compared with analgesic regimens prior to methadone administration. The factors potentially affecting the switching outcome were analyzed via multivariate analysis. Moreover, the cost of pain control was estimated.

Results

Ninety patients received methadone for poor pain control (74.4%), intolerable adverse events (10.0%), or both (15.6%) after prior opioid treatments. Sixty-four patients (71.1%) were successfully switched to methadone with median pain score significantly decreased from 4.0 to 2.0 (p < 0.001) and median daily frequency of breakthrough pain from 3.0 to 0.0 (p < 0.001) at a maintained median conversion ratio of 6.3 [interquartile range (IQR): 4.0–10.0] to prior opioid treatment. Similar adverse event profiles of constipation, nausea, vomiting, and dizziness were observed between methadone and prior opioid regimens. The median daily cost of analgesic regimens was significantly reduced from $19.5 (IQR: 12.3–46.2) to $10.8 (IQR: 7.1–18.7) (p < 0.01) after switching to methadone. The 3-day switch method significantly improved the rate of successful switching compared with the stop and go method (odds ratio = 3.37, 95% CI: 1.30–8.76, p = 0.013).

Conclusion

Methadone is an effective, safe, and cost-saving treatment for patients with refractory cancer pain.
Investigation of the causal relationship between ALS and autoimmune disorders: a Mendelian randomization study
Authors: Alipour Paria , Senkevich Konstantin , Ross Jay P. , Spiegelman Dan , Manousaki Despoina , Dion Patrick A. , Rouleau Guy A.
Published: November 2022

Background

Epidemiological studies have reported an association between amyotrophic lateral sclerosis (ALS) and different autoimmune disorders. This study aims to explore the causal relationship between autoimmune disorders and ALS using Mendelian randomization (MR).

Methods

To test the genetically predicted effects of liability towards immune-related outcomes on ALS risk, we used summary statistics from the largest European genome-wide association studies (GWAS) for these disorders in a two-sample MR setting. To do this, we extracted single nucleotide polymorphisms (SNPs) from the GWAS, which strongly associated with the 12 traits, and queried their effects in a large European ALS GWAS (27,265 cases and 110,881 controls). To avoid bias in our MR instruments related to the complex linkage disequilibrium structure of the human leukocyte antigen (HLA) region, we excluded SNPs within this region from the analyses. We computed inverse-variance weighted (IVW) MR estimates and undertook sensitivity analyses using MR methods robust to horizontal pleiotropy. We also performed a reverse MR analysis testing the causal effects of ALS on the above autoimmune traits.

Results

After applying Bonferroni correction for multiple testing, our MR analyses showed that the liability to autoimmune disorders does not affect ALS risk. Our reverse MR analysis also did not support the effects of liability to ALS on other autoimmune disorders. The results of the main IVW MR analyses were generally supported by our sensitivity MR analyses. The variance in the exposures explained by the sets of SNPs used as MR instruments ranged from 8.1 × 10−4 to 0.31. Our MR study was well-powered to detect effects as small as an odds ratio (OR) of 1.045 for ALS in the main MR and as small as an OR of 1.32 in the reverse MR.

Conclusion

Our MR study does not support a relationship between liability to autoimmune disorders and ALS risk in the European population. The associations observed in epidemiological studies could be partly attributed to shared biology or environmental confounders.
Gender differences in changes in metabolic syndrome status and its components and risk of cardiovascular disease: a longitudinal cohort study
Authors: Ramezankhani Azra , Azizi Fereidoun , Hadaegh Farzad
Published: November 2022

Background

We aimed to investigate the gender difference in the association between changes in metabolic syndrome (MetS) and its components with the risk of cardiovascular disease (CVD) and coronary heart disease (CHD) among adult participants in the Tehran lipid and glucose study cohort.

Methods

A total of 4624 adults (aged ≥ 30 years) who participated in two Phases 2 (2002–2005) and 3 (2005–2008) were included and followed up until 2018. Based on the status of MetS and its components in two phases, we divided participants into four groups: MetS-free, MetS-developed, MetS-recovery and MetS-stable groups, and similar categories were defined for MetS components. Multiple Cox regression models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs), and women-to-men ratios of HRs (RHRs).

Results

During a median follow-up of 11.6 years, 619 CVD events (292 women) and 512 CHD events (230 women) occurred. In both genders, the MetS-stable group had the highest risk of CVD and CHD, compared with the MetS-free group, but the associations were stronger in women than men: the HR (95% CI) were (2.76, 2.00-3.82) and (3.08, 2.15–4.40) for CVD and CHD, respectively, in women, and (1.60, 1.23–2.09) and (1.74, 1.30–2.31) for men. The multivariate adjusted women-to-men RHRs were (1.72, 1.16–2.56) for CVD and (1.77, 1.14–2.73) for CHD. Only among women, the risks for CVD in MetS-recovery group (1.67, 1.06–2.63) and MetS-developed group (1.89, 1.16–3.06|) were higher than MetS-free group. For CHD, women in MetS-developed group (1.86, 1.07–3.22) had higher risk than MetS-free group. However, no evidence of gender difference was observed in these associations. Among MetS components, persistent high blood pressure (BP) conferred greater risk for CVD and CHD in women than men; the women-to-men RHRs of CVD and CHD for high BP-stable groups were 1.54 (1.05–2.26) and 1.62 (1.07–2.47), respectively. For CHD events, persistent high fasting plasma glucose was associated with greater risk in women than men with women-to-men RHRs of 1.62 (1.09–2.40).

Conclusion

Change in MetS and its key components were associated with different risks for CVD events in both genders, with generally stronger associations in women than men.
Targeting the tumor stroma for cancer therapy
Authors: Xu Maosen , Zhang Tao , Xia Ruolan , Wei Yuquan , Wei Xiawei
Published: November 2022

Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.
Low-density lipoprotein cholesterol goal attainment in patients with clinical evidence of familial hypercholesterolemia and elevated Lp(a)
Authors: Schwarz Andrea , Demuth Ilja , Landmesser Ulf , Haghikia Arash , König Maximilian , Steinhagen-Thiessen Elisabeth
Published: November 2022

Background

Although potent lipid-lowering therapies are available, patients commonly fall short of recommended low-density lipoprotein cholesterol (LDL-C) levels. The aim of this study was to examine the relationship between familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] and LDL-C goal attainment, as well as the prevalence and severity of coronary artery disease (CAD). Moreover, we characterized patients failing to meet recommended LDL-C goals.

Methods

We performed a cross-sectional analysis in a cohort of patients undergoing cardiac catheterization. Clinical FH was determined by the Dutch Clinical Lipid Network Score, and Lp(a) ≥ 50 mg/dL (≈ 107 nmol/L) was considered elevated.

Results

A total of 838 participants were included. Overall, the prevalence of CAD was 72%, and 62% received lipid-lowering treatment. The prevalence of clinical FH (probable and definite FH) was 4%, and 19% had elevated Lp(a) levels. With 35%, LDL-C goal attainment was generally poor. Among the participants with clinical FH, none reached their LDL-C target. Among patients with elevated Lp(a), LDL-C target achievement was only 28%. The prevalence and severity of CAD were higher in participants with clinical FH (86% prevalence) and elevated Lp(a) (80% prevalence).

Conclusion

Most participants failed to meet their individual LDL-C goals according to the ESC 2016 and 2019 guidelines. In particular, high-risk patients with clinical FH or elevated Lp(a) rarely met their target for LDL-C. The identification of these patients and more intense treatment approaches are crucial for the improvement of CAD primary and secondary prevention.
The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis
Authors: Feng Yun , Li Wenhua , Wang Zhuoya , Zhang Ruling , Li Yan , Zang Lijuan , Wang Peiwen , Li Zhenghong , Dong Yuwei
Published: November 2022

Background

To explore the roles of Annexin A2 (ANXA2) on hepatocyte pyroptosis and hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and underlying molecular mechanism.

Methods

Bioinformatics analyses were performed on transcriptome data of liver tissues from mice and patients with liver fibrosis for screening the hepatocyte pyroptosis-related differential genes. The in vivo NASH mouse model and in vitro NASH cellular model were established. The expression levels of Anxa2/ANXA2 were quantified. Then, the upstream transcription factor of Anxa2 was screened by ChIP-Seq and experimentally verified. The effects of the p-STAT3/ANXA2 axis on Caspase-1 mediated pyroptosis and fibrosis were explored by in vivo and in vitro experiments.

Results

Bioinformatics analyses suggested that the expression of Anxa2/ANXA2 was significantly up-regulated in liver tissues of both NASH mice and patients scoring with high pyroptotic activity. Experimental data showed that the ANXA2 expression was positively associated with the development of hepatocyte pyroptosis and fibrosis. As a transcription factor of ANXA2, p-STAT3 can bind to the promoter of Anxa2 and promote its transcription. The inhibition of p-STAT3 can significantly suppress hepatocyte pyroptosis and fibrosis, which was significantly reversed after the over-expression of Anxa2. Caspase-1 was verified as the player of the p-STAT3/ANXA2 axis to promote pyroptosis and fibrosis. By specifically inhibiting Caspase-1, the promotion effect of the p-STAT3/ANXA2 axis on pyroptosis and fibrosis can be significantly weakened.

Conclusion

The p-STAT3 promoted Anxa2 expression at the transcription level, thus activating the Caspase-1 mediated hepatocyte pyroptosis and fibrosis in NASH.
Long-term Prophylaxis with Androgens in the management of Hereditary Angioedema (HAE) in emerging countries
Authors: Guo Yinshi , Zhang Huanping , Lai He , Wang Huiying , Chong-Neto Herberto J. , Valle Solange O. R. , Zhu Rongfei
Published: November 2022

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by repetitive subcutaneous or submucosal angioedema, activation of the kinin system, and increased vascular permeability. C1-inhibitor (C1-INH) deficiency, the main mechanism of HAE pathogenesis, occurs when abnormal activation of plasma kallikrein, bradykinin, and factor XII, or mutation of genes such as SERPING1 cause quantitative or functional C1-INH defects. Although androgens are not approved for HAE treatment in many countries, they are widely used in China and Brazil to reduce the frequency and severity of HAE attacks. The long-term adverse effects of androgen treatment are concerning for both physicians and patients. Virilization, weight gain, acne, hirsutism, liver damage, headache, myalgia, hematuria, menstrual disorders, diminished libido, arterial hypertension, dyslipidemia, and anxiety/depression are commonly observed during long-term treatment with androgens. These adverse effects can affect the quality of life of HAE patients and often lead to treatment interruption, especially in women and children. In-depth studies of the pathogenesis of HAE have led to the approval of alternative treatment strategies, including plasma-derived C1 inhibitor, recombinant human C1 inhibitor, plasma Kallikrein inhibitor (ecallantide; lanadelumab), and bradykinin B2 receptor antagonist (icatibant), some of which have achieved satisfactory results with mostly non-serious side effects. Therefore, a new standard of medical care may expand possibilities for the management of HAE in emerging countries.
Retraction Note: Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma
Authors: Liu Zhikui , Wang Yufeng , Wang Liang , Yao Bowen , Sun Liankang , Liu Runkun , Chen Tianxiang , Niu Yongshen , Tu Kangsheng , Liu Qingguang
Published: November 2022

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13046-019-1188-x.
Identification and validation of a novel signature as a diagnostic and prognostic biomarker in colorectal cancer
Authors: Wang Di , Liufu Junye , Yang Qiyuan , Dai Shengqun , Wang Jiaqi , Xie Biao
Published: November 2022

Background

Colorectal cancer (CRC) is one of the most common malignant neoplasms worldwide. Although marker genes associated with CRC have been identified previously, only a few have fulfilled the therapeutic demand. Therefore, based on differentially expressed genes (DEGs), this study aimed to establish a promising and valuable signature model to diagnose CRC and predict patient’s prognosis.

Methods

The key genes were screened from DEGs to establish a multiscale embedded gene co-expression network, protein-protein interaction network, and survival analysis. A support vector machine (SVM) diagnostic model was constructed by a supervised classification algorithm. Univariate Cox analysis was performed to construct two prognostic signatures for overall survival and disease-free survival by Kaplan–Meier analysis, respectively. Independent clinical prognostic indicators were identified, followed by univariable and multivariable Cox analysis. GSEA was used to evaluate the gene enrichment analysis and CIBERSORT was used to estimate the immune cell infiltration. Finally, key genes were validated by qPCR and IHC.

Results

In this study, four key genes (DKC1, FLNA, CSE1L and NSUN5) were screened. The SVM diagnostic model, consisting of 4-gene signature, showed a good performance for the diagnostic (AUC = 0.9956). Meanwhile, the four-gene signature was also used to construct a risk score prognostic model for disease-free survival (DFS) and overall survival (OS), and the results indicated that the prognostic model performed best in predicting the DFS and OS of CRC patients. The risk score was validated as an independent prognostic factor to exhibit the accurate survival prediction for OS according to the independent prognostic value. Furthermore, immune cell infiltration analysis demonstrated that the high-risk group had a higher proportion of macrophages M0, and T cells CD4 memory resting was significantly higher in the low-risk group than in the high-risk group. In addition, functional analysis indicated that WNT and other four cancer-related signaling pathways were the most significantly enriched pathways in the high-risk group. Finally, qRT-PCR and IHC results demonstrated that the high expression of DKC1, CSE1L and NSUN5, and the low expression of FLNA were risk factors of CRC patients with a poor prognosis.

Conclusion

In this study, diagnosis and prognosis models were constructed based on the screened genes of DKC1, FLNA, CSE1L and NSUN5. The four-gene signature exhibited an excellent ability in CRC diagnosis and prognostic prediction. Our study supported and highlighted that the four-gene signature is conducive to better prognostic risk stratification and potential therapeutic targets for CRC patients.
PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ in the joint microenvironment
Authors: Yao Yao , Cai Xiaoyu , Zhang Meng , Zhang Xiao , Ren Fujia , Zheng Yan , Fei Weidong , Zhao Mengdan , Zheng Caihong
Published: November 2022

Background

The cytoskeletal protein, PSTPIP2, is associated with inflammation and is predominantly expressed in macrophages. Previous data have shown that PSTPIP2 inhibits articular bone damage in arthritic rats. The aim of this study is to explore the molecular mechanism of PSTPIP2’s resistance to bone erosion.

Methods

In the current study, peripheral blood and surgically excised synovial tissue from RA patients, DBA/1 mice, Pstpip2CreR26-ZsGreen reporter mice, and Esr2fl/fl/Adgre-Cre tool mice were used for in vivo studies. Adeno-associated viral vector was used to overexpress PSPTIP2 protein in vivo.

Results

We found that The level of PSTPIP2 in synovial macrophages is negatively correlated with RA disease activity, which is mediated by synovial macrophages polarization. PSTPIP2hi synovial macrophages form a tight immunological barrier in the lining layer. Notably, the ability of PSTPIP2 to regulate synovial macrophages polarization is dependent on ERβ. Additionally, PSTPIP2 regulates the dynamics of synovial macrophages via ERβ.

Conclusions

Together, this study reveals that PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form an immunological barrier (F4/80+PSTPIP2hi cell-enriched zone) for the joints. Thus, local modulation of PSTPIP2 expression in the joint microenvironment may be a potential strategy for controlling bone erosion in rheumatoid arthritis.

Graphical Abstract

PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form F4/80+PSTPIP2hi cellular barrier in joint microenvironment.
Sex differences in Alzheimer’s disease: plasma MMP-9 and markers of disease severity
Authors: Tsiknia Amaryllis A. , Sundermann Erin E. , Reas Emilie T. , Edland Steven D. , Brewer James B. , Galasko Douglas , Banks Sarah J. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2022

Background

Studies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.

Methods

Our sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.

Results

Total and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [−0.11 to −0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = −14.98 [−27.37 to −2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = −2.10 [−3.97 to −0.27], p = 0.027 and β = −2.24 [−4.32 to −0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).

Conclusions

MMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women’s elevated susceptibility to AD.
Impact of nano silver composite structure on cadmium neurotoxicity in albino rats
Authors: El-Sherbiny Emad Mohamed , Abdel-Gawad Eman Ismail , Osman Hala Fawzy
Published: November 2022

The present study was planned to investigate the possible therapeutic effects of silver/hydroxyapatite nanocomposite (nAg/HAp) on neurotoxicity induced by cadmium chloride (CdCl2) in albino rats. The nanocomposite has been formulated by a chemical route and characterized by scanning electron microscope (SEM), Transmission Electron Microscopy (TEM), and energy-dispersive X-ray Analysis spectroscopy (EDAX). A population of rats was randomly assorted into three groups; the animals were subjected to intraperitoneal CdCl2administration every 2 days at a dose level of 1.0 mg/kg b.wt. for 3 months while the treatment with nAg/HAp was performed via intravenous injection at a dose level of 50 mg/kg b,wt. once a week for 4 weeks. Quantitative DNA fragmentation and biochemical analysis including the content of γ-aminobutyric acid (GABA), noradrenaline (NA), dopamine (DA), caspase-3, calmodulin (CaM), calcium adenosine 5′-triphosphatase (Ca++ATPase), tau protein, glutathione (GSH) and malondialdehyde (MDA) were measured in brain tissue. The results revealed the potent efficacy of nAg/HAp in attenuating DNA fragmentation and partially recovering most of the investigated parameters manifested by a significant elevation in GABA, NA, DA, Ca++ATPase, and GSH levels and a decrease in tau protein, caspase-3, CaM and MDA tissue content in comparison with Cd—intoxicated groups. Accordingly, the synthesized nAg/HAp at the selected dose can be used as a biosafe intravenous injection in neurodegenerative diseases.