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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Successful application of deep machine learning could reduce time-consuming and labor-intensive clinical work of calculating the amount of radiographic bone loss (RBL) in diagnosing and treatment planning for periodontitis. This study aimed to test the accuracy of RBL classification by machine learning.A total of 236 patients with standardized full mouth radiographs were included. Each tooth from the periapical films was evaluated by three calibrated periodontists for categorization of RBL and radiographic defect morphology. Each image was pre-processed and augmented to ensure proper data balancing without data pollution, then a novel multitasking InceptionV3 model was applied.The model demonstrated an average accuracy of 0.87 ± 0.01 in the categorization of mild ( 15%) or severe (≥ 15%) bone loss with fivefold cross-validation. Sensitivity, specificity, positive predictive, and negative predictive values of the model were 0.86 ± 0.03, 0.88 ± 0.03, 0.88 ± 0.03, and 0.86 ± 0.02, respectively.Application of deep machine learning for the detection of alveolar bone loss yielded promising results in this study. Additional data would be beneficial to enhance model construction and enable better machine learning performance for clinical implementation.Higher accuracy of radiographic bone loss classification by machine learning can be achieved with more clinical data and proper model construction for valuable clinical application.

The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Here, the expression of LSM1 mRNA in breast cancer was estimated using The Cancer Genome Atlas (TCGA), Oncomine, TIMER and bc-GenExMiner databases. We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in breast cancer (BRCA) patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease-free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.

Manual titration of positive airway pressure (PAP) is a gold standard to provide an optimal pressure for the treatment of obstructive sleep apnea-hypopnea syndrome (OSAS). Since manual titration studies were costly and time-consuming, many statistical models for predicting effective PAPs were reported. However, the prediction accuracies of the models associated with nocturnal parameters still remain low. This study proposes a fuzzy neural prediction network (FNPN) with input candidate variables, selected among easily available measurements (e.g., body mass index (BMI), waist circumstance (WC), and body composition) and OSAS related questionnaires, to rapidly predict an optimal PAP. The FNPN comprises fuzzy rules and is characterized with the ability of automatic rule growing and pruning from training data. A total of 147 participants from April 2018 to April 2019 were enrolled in Taichung Veterans General Hospital, Taiwan. After two selection processes for feature extraction, WC and BMI were the significant variables for entering the FNPN to predict optimal PAP. Experimental results showed that the average successful prediction rate of the proposed method was 71.8%. This study also found that Epworth sleepiness scales (ESS) and body composition, such as visceral fat area and percent body fat, were excluded in the final prediction model. Compared with existing models, the proposed prediction approach provided a rapid prediction of optimal PAP with higher accuracy.

Few studies have assessed the efficacy and safety of reconstruction of sternal infection using a pectoralis muscle flap combined with a rectus abdominis muscle (RAM) sheath fasciocutaneous flap. We report here our experience with this procedure to reconstruct the sternal defect in patients (n = 46) with a deep sternal wound infection (DSWI) after cardiac surgery. After wound reconstruction, the proportion of prolonged mechanical ventilation use and intensive care unit (ICU) stay were 17.4% (n = 8) and 21.7% (n = 10), respectively. The 30-day all-cause mortality was 15.2%; recurrence rate was 17.4%; postoperative complications were 15.2%; and median hospital stay was 31 (0-157) days. Multivariate logistic regression analysis revealed that hypertension (β = 21.32, 95%CI 4.955-37.68, P = .014), drainage-tube use (β = 0.944, 95%CI 0.273-1.614, P = .008), and prolonged intensive care unit stay (β = 53.65, 95%CI 31.353-75.938, P .001) were significantly correlated with hospital stay. In conclusion, a procedure including surgical debridement, sternal reconstruction with bilateral PM and RAM sheath flap, long-term antibiotics, and adequate drainage is a beneficial technique in the reconstruction of deep sternal wound infection after cardiac surgery. Duration of drainage tube use may be as an index for a hospital stay or wound healing.

Kimura disease (KD) is a rare, chronic inflammatory disorder presenting with solitary or multiple masses. Treatment options include surgical excision, corticosteroids, and radiotherapy; however, optimal therapy remains to be established. Moreover, efficacy of a humanized monoclonal antibody, dupilumab (Dupixent), requires to be demonstrated. Here, we present a 36-year-old male patient with an enlarging mass in the left medial thigh and chronic eczema over the abdomen and lower legs. Kimura disease was diagnosed after surgical excision. Postoperative treatment with dupilumab was applied with an initial dose of 600 mg followed by 300 mg every 2 weeks for 8 months. No recurrence of KD was observed in the 1-year follow-up. The eczematous lesions improved greatly. To our knowledge, this is the first report of using dupilumab for treating KD.

To report the clinical outcomes of vasospasm embolization technique in treating lower gastrointestinal bleeding (LGIB).Fifty LGIB patients (32 men and 18 women; mean age, 70.4 years) with positive contrast extravasation on multidetector computed tomography were treated with pharmaco-induced vasospasm embolization by semiselective catheterization technique. Distal rectal bleeding was excluded. The bleedings in three patients were considered to be tumor related. Eighteen underwent regular hemodialysis, and 22 showed unstable hemodynamic at intervention.Forty-two bleeders were found in superior mesenteric territory and eight in the inferior mesenteric territory. Successful, immediate hemostasis was achieved in 49 (98%) patients. Early recurrent bleeding (30 days) was found in 13 (26.5%) patients with 6 local rebleeding (12.2%), 5 new-foci bleeding (10.2%), and 2 uncertain foci bleeding (4.1%). Repeated vasospasm embolization therapy was given to five patients, with successful hemostasis in four. All the three tumor-related bleeding patients undergoing vasospasm embolization had ceased bleeding and discharged. Patient-based primary and overall clinical successes were achieved in 73.5% and 83.7%, and lesion-based primary and overall clinical successes were 83.0% and 86.7%, respectively. The 30-day mortality rate was 21.3%, and the 1- and 2-year survival rates were 51.5% and 43.8%. No major procedure-related complications (eg, bowel ischemia) were encountered.This study confirmed our prior preliminary conclusion that pharmaco-induced vasospasm embolization is easy, safe, and effective for LGIB. This treatment may be considered the first-line alternative approach for LGIB, especially for patients of advanced age with complex medical problems and/or when vasa rectal embolization isn't feasible.

This study aimed to investigate the effectiveness of neoadjuvant chemotherapy in patients with breast cancer in different age groups and evaluate the impact of age group on survival outcome according to different treatment responses. Data were retrospectively collected from the cancer registry database of Kaohsiung Medical University Hospital in Taiwan under an approved protocol. Overall, 96 elder patients (aged >50 years) and 96 younger controls (aged ≤50 years) who received neoadjuvant chemotherapy and breast surgical treatment were examined after 1:1 matching. Logistic regression analysis was used to investigate the effectiveness of treatment response in patients of different age groups. Additionally, the Kaplan-Meier estimator and log-rank test were performed to evaluate the effect of age group and treatment response on disease-free and overall survival (OS). Although no direct significant association was found between age group and treatment response, several significant results were found in treatment response stratification analysis. Among 16 pathological complete response (pCR) patients, elder patients showed significantly greater 5-year disease-free survival (DFS) than younger patients (DFS rate, 85.7% vs. 0%, p = 0.041). However, in 176 non-pCR patients, elder patients showed poor DFS compared to younger patients (DFS rate, 16.6% vs. 32.3%; log-rank test, p = 0.031). With limited sample size and study design, our study results demonstrate that patients aged >50 years who achieved pCR after neoadjuvant chemotherapy could obtain better survival outcome than younger patients. However, the younger patients showed no survival benefits regardless of pCR status.

Background Anatomic repair of anterior talofibular ligament (ATFL) is used to manage chronic lateral ankle instability (CLAI). However, the optimal suture configuration used to repair the ATFL is not yet determined. It remains unclear whether suture configuration affects clinical outcomes in such patients. Purpose To compare the functional outcomes of all-inside arthroscopic ATFL repair using either a loop suture and or a free-edge suture configuration in CLAI patients. Study Design Cohort study; Level of evidence, 3. Methods This retrospective cohort study included 71 patients with CLAI who had undergone an all-inside arthroscopic ATFL repair procedure with either loop suture (n = 36) or free-edge suture (n = 35) from February 2016 to July 2018. Comparable pre-operatively, the Visual analogy score (VAS), American Orthopedic Foot and Ankle Society scoring system (AOFAS), Karlsson Ankle Functional Score (KAFS) scoring system, Anterior Talar Translation (ATT) and Active Joint Position Sense (AJPS) were used to evaluate postoperative ankle function. Results There were no postoperative wound complications, implant reactions, or neurological or vascular injuries. Postoperative hospitalization, VAS, AOFAS, KAFS, AJPS and the time of return to sport were similar between the loop suture group and free-edge suture group. Requiring a longer procedure time, patients with loop suture configuration achieved better ATT. Conclusion All-inside arthroscopic ATFL repair procedure for CLAI treatment provides better ATT and comparable functional outcomes when a loop suture configuration is used instead of a free-edge suture configuration. A statistical difference in ATT was observed. Given the relatively short follow-up, it is questionable whether this will have any clinical relevance.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy, which is caused by mutations mainly in genes encoding BBSome complex and IFT complex. Here, we reported a 21-year-old female with BBS characterized by three primary features including obesity, retinitis pigmentosa sine pigmento and bilateral renal cysts. She also had some secondary features such as diabetes mellitus, nonalcoholic fatty liver disease, subclinical hypothyroidism and mild conductive hearing damage. Whole exome sequencing revealed two compound heterozygous mutations in exon 2 of the BBS12 gene (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) in this patient. Sanger sequencing showed that her father and mother carried c.188delC (p.T63fs) and c.1993_1995del (p.665_665del) variants, respectively, while her parents were free of BBS-related symptoms. In conclusion, this case reported two novel mutations (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) of the BBS12 gene in a girl presented with BBS, which provides novel genetic resources for studies of the disease. Meanwhile, the BBS case shows the entire development progress from her birth to adulthood, which helps facilitate clinicians' understanding of BBS.Bardet-Biedl综合征(Bardet-Biedl syndrome, BBS)是一种罕见的常染色体隐性遗传的纤毛相关疾病,其病因主要与编码BBS蛋白复合体BBSome、鞭毛内运输复合体等基因突变有关。本文报道了1例21岁的女性BBS患者,该患者具有肥胖、视网膜色素变性、双肾囊肿的典型特征,还存在2型糖尿病、非酒精性脂肪肝、亚临床甲状腺功能减退症、轻度传导性听力下降等不典型表现。全外显子组测序发现该患者的BBS12基因2号外显子存在复合杂合突变(c.188delC, p.T63fs和c.1993_1995del, p.665_665del)。进一步通过Sanger测序发现患者的父亲和母亲分别携带c.188delC(p.T63fs)和c.1993_1995del(p.665_665del)突变,但均无相关症状。综上所述,本病例报告发现了BBS12基因的两个新的突变位点(c.188delC, p.T63fs和c.1993_1995del, p.665_665del),为该疾病的研究提供了新的遗传资源,同时该病例还展示了患者从出生到成人期间的整个疾病发展过程,能够帮助临床医生更好地理解BBS。.

In Western countries, breast cancer tends to occur in older postmenopausal women. However, in Asian countries, the proportion of younger premenopausal breast cancer patients is increasing. Increasing evidence suggests that the gut microbiota plays a critical role in breast cancer. However, studies on the gut microbiota in the context of breast cancer have mainly focused on postmenopausal breast cancer. Little is known about the gut microbiota in the context of premenopausal breast cancer. This study aimed to comprehensively explore the gut microbial profiles, diagnostic value, and functional pathways in premenopausal breast cancer patients. Here, we analyzed 267 breast cancer patients with different menopausal statuses and age-matched female controls. The α-diversity was significantly reduced in premenopausal breast cancer patients, and the β-diversity differed significantly between breast cancer patients and controls. By performing multiple analyses and classification, 14 microbial markers were identified in the different menopausal statuses of breast cancer. Bacteroides fragilis was specifically found in young women of premenopausal statuses and Klebsiella pneumoniae in older women of postmenopausal statuses. In addition, menopausal-specific microbial markers could exhibit excellent discriminatory ability in distinguishing breast cancer patients from controls. Finally, the functional pathways differed between breast cancer patients and controls. Our findings provide the first evidence that the gut microbiota in premenopausal breast cancer patients differs from that in postmenopausal breast cancer patients and shed light on menopausal-specific microbial markers for diagnosis and investigation, ultimately providing a noninvasive approach for breast cancer detection and a novel strategy for preventing premenopausal breast cancer., Breast cancer: gut microbes before and after menopause Women developing breast cancer before the menopause have less diverse gut microbe populations than their healthy peers, and significantly different gut microbial profiles than postmenopausal breast cancer patients. There is increasing evidence of a link between gut microbes and breast cancer, but most studies have focused on women after the menopause. The incidence of breast cancer in premenopausal women is increasing, especially in Asia. Researchers in Taiwan led by Chih-Po Chiang at Kaohsiung Medical University Hospital compared gut microbial populations in 267 breast cancer patients at different menopausal stages to matched controls. The results suggest that gut microbe profiling might offer a novel and noninvasive method for diagnosing and monitoring breast cancer. It may also lead to new strategies for prevention and treatment, as evidence emerges of a link between gut microbes and cancer.

Introduction Pituitary growth hormone-secreting (GH) pituitary adenomas (PAs) cause mass effects and dysregulated hypersecretion of GH. However, somatic mutation burden is low in PAs. While progress has been made in identifying the epigenetic changes involved in GH-PA initiation, the precise details of its tumorigenesis in GH-PA patients remains to be elucidated. As N6-methyladenosine (m6A) has been shown to often play a critical role in various tumors, it represents a possible initiation point for the tumorigenesis of pituitary adenomas. However, the role of RNA methylation in GH adenomas remains unclear. Methods Protein expression of m6A regulators was measured by immunohistochemistry. Global levels and distribution of m6A methylation were separately analyzed by m6A enzyme-linked immunosorbent assay and m6A sequencing (m6A-seq). RNA interference and lentivirus knockdown system were used to investigate the role of methyltransferase-like 3 (METTL3) and its m6A- dependent regulatory mechanism in tumor progression and GH secretion. Results We show that both METTL3 messenger RNA and protein expression are elevated in GH-PA samples when compared with both normal pituitary tissue specimens and nonsecreting pituitary adenomas. Levels of m6A modification increased in GH-PAs, and hypermethylated RNAs are involved in hormone secretion and cell development. Knockdown of METTL3 in GH3 cell line resulted in decreased cell growth and GH secretion. Importantly, we found that GNAS and GADD45γ act as the downstream targets in this process. Conclusion Our findings strongly suggest that m6A methyltransferase METTL3 promotes tumor growth and hormone secretion by increasing expression of GNAS and GADD45γ in a m6A-dependent manner. Thus, METTL3 and the methylated RNAs constitute suitable targets for clinical treatment of GH-PAs.

Background We, herein, propose an algorithm for correction of oral incontinence or/and color/texture mismatch after oromandibular reconstruction, by means of serial excision. To the best of our knowledge, this is the first case series presenting serial excision for complete removal of the free flap skin paddle to improve functional and aesthetic outcomes after free flap reconstruction of oromandibular through-and-through defects. Methods Single-centre retrospective study of all patients who underwent serial excision of the whole skin paddle, for correction of oral incontinence or/and color and texture mismatch after free flap reconstruction, in a 9-year period. We propose a treatment algorithm, based on the lip defect size. Patients with small defects undergo primary commissuroplasty, simultaneously with the free flap reconstruction and, if necessary, subsequent serial excision in local anesthesia for the color/texture mismatch. Patients with large defects undergo secondary commissuroplasty in general anesthesia. They are left to heal and, subsequently, undergo staged excision in 4-6-month intervals in local anesthesia. Results Sixteen patients were analyzed. Thirteen patients (81%) had mild oral incontinence. Eight patients (50%) required two stages of serial excision, six patients (38%) underwent three serial excisions and two patients (12%) had to be operated four times. Skin paddle surface ranged from 4 × 4 cm to 10 × 6 cm. No complications were observed and all patients were satisfied with the final outcome. Conclusion We conclude that the algorithm-based serial excision, can significantly improve the functional and aesthetic outcomes in patients with oral incontinence and color/texture mismatch after free tissue transfer for through-and-through cheek defects, involving the oral commissure.

Stroke has become the second leading cause of death in people aged higher than 60 years, with cancer being the first. Intracerebral hemorrhage (ICH) is the most lethal type of stroke. Using imaging techniques to evaluate the evolution of intracranial hematomas in patients with hemorrhagic stroke is worthy of ongoing research. The difficulty in obtaining ultra-early imaging data and conducting intensive dynamic radiographic imaging in actual clinical settings has led to the application of experimental animal models to assess the evolution of intracranial hematomas. Herein, we review the current knowledge on primary intracerebral hemorrhage mechanisms, focus on the progress of animal studies related to hematoma development and secondary brain injury, introduce preclinical therapies, and summarize related challenges and future directions.

Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's disease (CD). However, the reported remission rates of patients who received TSS vary widely between different studies, and the predictors of surgical outcomes remain controversial. The present study analyzed the early outcome of TSS in a large population of patients with CD at a single center, and identified potential predictors of initial remission of TSS in patients with CD.The clinical features and surgical outcomes of CD patients who underwent TSS between 1988 and 2018 at Peking Union Medical College Hospital (PUMCH) were collected and analyzed from their medical records.Of the 1604 CD patients who underwent TSS at PUMCH between February 1988 and October 2018, 1106 patients had complete medical data and pathological results. After surgery, the overall postoperative initial remission rate was 72.5, and 27.5% of patients maintained persistent hypercortisolism. The initial remission rate of patients with preoperative noninvasive adenoma based on MRI (77.1%), intraoperative noninvasiveness (72.5%), microadenoma (74.3%), pathological confirmation (76.4%), and first TSS (73.9%) was significantly higher than that in patients with preoperative invasive adenoma (53.0%), intraoperative invasiveness (60.7%), macroadenomas (65.9%), pathologically negative (49.7%), and repeat TSS (56.0%), respectively (all P 0.05). The initial remission rate in patients with pseudocapsule-based extracapsular resection (88.1%), MRI-visible adenoma (74.2%) was higher than that in patients without pseudocapsule-based extracapsular resection (77.1%), and with MRI-negative results (64.5%), respectively, but did not reach statistical significance (All P 0.05). Striking, there was no significant differences in initial remission rates between patients who underwent selective adenomectomy and enlarged adenomectomy (P 0.05). Whereas, the initial remission rates in patients who underwent partial hypophysectomy only was 51.0%, which was much lower than that in patients underwent selective adenomectomy and enlarged adenomectomy (P 0.05).The TSS is a safe and effective procedure for the treatment of CD. Whereas, preoperative invasiveness based on MRI, intraoperative invasiveness, macroadenomas pathologically negative, and repeat TSS are related to lower initial remission rates.

Objective To investigate the role of NudCD1 in spindle assembly checkpoint regulation and in the prognosis of colorectal cancer. Methods Immunohistochemical staining was used to detect in situ expression of NudCD1 in 100 colorectal cancer tissue samples. A chi-square test was used to analyse the correlation between the NudCD1 protein expression level of the cancer tissues and clinicopathological features. The Kaplan–Meier survival analysis was used to assess the correlation between the NudCD1 mRNA expression and the three-year survival of patients with colorectal cancer. The impact of NudCD1 on the development of colorectal cancer and the underlying molecular mechanisms were assessed by flow cytometry cell cycle and apoptosis assays after lentiviral overexpression of NudCD1 in two colorectal cancer cell lines. Quantitative real-time PCR was used to assess mRNA expression of the cellular spindle assembly checkpoint genes BUB1, BUBR1, MAD1, CDC20 and MPS1, as well as the downstream genes LIS1, DYNC1H1, and DYNLL1 in the NudC/LIS1/dynein pathway. Results Compared with normal intestinal tissue (8.00% with high expression), the expression of NudCD1 protein in colorectal cancer tissue was significantly higher (58.00% with high expression, P P P P P Conclusion NudCD1 can serve as a valuable prognostic marker for colorectal cancer. It may be involved in the regulation of spindle-assembly checkpoint-gene expression and the LIS1 pathway of colorectal cancer cells.

Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future.

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Self-monitoring for spirometry is beneficial to assess the progression of lung disease and the effect of pulmonary rehabilitation. However, home spirometry fails to meet both accuracy and repeatability criteria in a satisfactory manner. The study aimed to propose a pervasive spirometry estimation system with the six-minute walking test (6MWT), where the system with information management, communication protocol, predictive algorithms, and a wrist-worn device, was developed for pulmonary function. A total of 60 subjects suffering from respiratory diseases aged from 25 to 90 were enrolled in the study. Pulmonary function test, walking steps, and physical status were measured before and after performing the 6MWT. The significant variables were extracted to predict per step distance (PSD), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). These predicted formulas were then implemented in a wrist-worn device of the proposed pervasive estimation system. The predicted models of PSD, and FVC, FEV1 with the 6MWT were created. The estimated difference for PSD was—0.7 ± 9.7 (cm). FVC and FEV1 before performing 6MWT were 0.2 ± 0.6 (L) and 0.1 ± 0.6 (L), respectively, and with a sensitivity (Sn) of 81.8%, a specificity (Sp) of 63.2% for obstructive lung diseases, while FVC and FEV1 after performing the 6MWT were 0.2 ± 0.7 (L) and 0.1 ± 0.6 (L), respectively, with an Sn of 90.9% and an Sp of 63.2% for obstructive lung diseases. Furthermore, the developed wristband prototype of the pulmonary function estimation system was demonstrated to provide effective self-estimation. The proposed system, consisting of hardware, application and algorithms was shown to provide pervasive assessment of the pulmonary function status with the 6MWT. This is a potential tool for self-estimation on FVC and FEV1 for those who cannot conduct home-based spirometry.

A model for predicting responsiveness to immunotherapy in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) has not been well established. We aimed to establish a new classifier for CIDP patients based on clinical characteristics, laboratory findings, and electrophysiological features.The clinical, laboratory, and electrophysiological features of 172 treatment-naïve patients with CIDP between 2003 and 2019 were analyzed using an unsupervised hierarchical clustering. The identified pivotal features were used to establish simple classifications using a tree-based model.Three clusters were identified: 1, n = 65; 2, n = 70; and 3, n = 37. Patients in Cluster 1 scored lower on the disability assessment score before treatment. More patients in Clusters 2 (90.0%) fulfilled demyelinating criteria than patients in Cluster 1 (30.8%, p lt; .001). Cluster 3 had more patients with chronic kidney disease (CKD) (27.0%) and hypoalbuminemia (3.40 g/dL) than did Cluster 2 (CKD: 0%, p lt; .001; hypoalbuminemia: 4.09 g/dL, p lt; .001). The responsiveness to pulse steroid therapy was higher in Cluster 2 (70.0%) than in Clusters 1 (31.8%; p = .043) and 3 (25.0%; p = .014). A tree-based model with four pivotal features classified patients in our cohort into new clusters with high accuracy (89.5%).The established hierarchical clustering with the tree-based model identified key features contributing to differences in disease severity and response to pulse steroid therapy. This classification system could assist clinicians in the selection of treatments and could also help researchers by clustering patients for clinical treatment trials.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high‐risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is the only curative option for patients suffering from high‐risk AML/MDS. However, many patients relapse after allo‐HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL‐2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft‐versus‐host disease (GVHD) and boost the graft‐versus‐leukemia (GVL) effect post‐transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low‐dose decitabine (LDEC) plus VEN to prevent relapse after allo‐HSCT for high‐risk AML/MDS patients. Twenty patients with high‐risk AML (n = 17) or high‐risk MDS (n = 3) post‐transplantation were recruited. Approximately day 100 post‐transplantation, all patients received LDEC (15 mg/m2 for 3 d) followed by VEN (200 mg) on d 1‐21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event‐free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo‐HSCT. Survival outcomes were assessed using Kaplan‐Meier analysis. The median follow‐up was 598 (149‐1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2‐y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2‐y EFS time was 525 (149‐1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo‐HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high‐risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high‐risk AML/MDS patients., The results of the current study suggest that maintenance treatment with LDEC combined with VEN introduced nearly 3 mo after allo‐HSCT is efficacious, with an acceptable toxicity profile and impressive long‐term disease control.

Background Bypass grafting is the standard of care for chronic aorto-iliac occlusive disease (AIOD, aka Leriche Syndrome) but is associated with mortality rates of up to 25% if surgical re-intervention is necessary. Despite a recent shift towards an endovascular-first strategy for TransAtlantic InterSociety Consensus II (“TASC II”) C and D lesions, reports from Leriche Syndrome are still limited. Patients and methods 15 high-risk patients (11 male, 4 female), mean age of 60.6 years, with chronic aorto-iliac occlusive disease were retrospectively reviewed. Retrograde approaches via the bilateral femoral arteries for aortic occlusion less than 4 cm in length and/or antegrade fashion from the brachial artery for juxtarenal type lesions were made. For the latter, thrombolysis prior to angioplasty was also performed. Intraluminal or if necessary, subintimal angioplasty was performed with deployment of either bare metal stents or stentgrafts in a kissing-stent fashion. Results A total of 28 iliac arteries and 14 occluded abdominal aorta were treated with 100% technical success, of which 25% success were achieved by using subintimal technique. Two minor complications occurred, including vascular rupture and distal emboli in one patient apiece, which were successfully managed via endovascular fashion. There were no complications of renal artery emboli. Primary and secondary patency rates at 1, 3 and 5 years were 92.3% and 100%; 83.9% and 100%; and 83.9% and 100%, respectively. Conclusion Endovascular therapy for chronic aorto-iliac occlusion has a high technical success rate, with good short- and mid-term primary and secondary patency rates and may provide a valid alternative to surgery for high-risk patients.

Context The resection plan of pituitary adenoma (PA) needs preoperative observation of the sellar region. Radiomics prediction requires high-quality segmentations. Manual delineation is time-consuming and subject to rater variability. Objective This work aims to create an automated segmentation method for the sellar region, several tools to extract invasiveness-related features, and evaluate their clinical usefulness by predicting the tumor consistency. Methods Patients included were diagnosed with pituitary adenoma at Peking Union Medical College Hospital. A deep convolutional neural network, called gated-shaped U-net (GSU-Net), was created to automatically segment the sellar region into 8 classes. Five magnetic resonance imaging (MRI) features were extracted from the segmentation results, including tumor diameters, volume, optic chiasma height, Knosp grading system, and degree of internal carotid artery contact. The clinical usefulness of the proposed methods was evaluated by the diagnostic accuracy of the tumor consistency. Results A total of 163 patients with confirmed pituitary adenoma were included as the first group and were randomly divided into a training data set and test data set (131 and 32 patients, respectively). Fifty patients with confirmed acromegaly were included as the second group. The Dice coefficient of pituitary adenoma in important image slices was 0.940. The proposed methods achieved accuracies of more than 80% for the prediction of 5 invasive-related MRI features. Methods derived from the automatic segmentation showed better performance than original methods and achieved areas under the curve of 0.840 and 0.920 for clinical models and radiomics models, respectively. Conclusion The proposed methods could automatically segment the sellar region and extract features with high accuracy. The outstanding performance of the prediction of the tumor consistency indicates the methods’ clinical usefulness for supporting neurosurgeons in judging patients’ conditions, predicting prognosis, and other downstream tasks during the preoperative period.

Oxidative stress and neuroinflammatory response after the ischemic injury are important pathophysiologic mechanisms that cause brain tissue loss and neurological deficit. This study aims to observe the expression and role of carbonyl reductase 1 (CBR1), an NADPH-dependent oxidoreductase with specificity for carbonyl compounds such as 4-hydroxynonenal (4-HNE), in the brain after ischemic injury and to investigate the influence of CBR1 on ischemia-induced neuroinflammation. CBR1 expresses in the neurons, astrocyte, and microglia in the normal brain. The expression of CBR1 decreased in the ischemic regions following cerebral ischemia, and also reduced in primary neurons after OGD (oxygen-glucose deprivation); however, the expression of CBR1 significantly increased in microglia in the ischemic penumbra. Furthermore, TAT-CBR1 fusion protein played neuroprotective effects in reducing the infarct volume and improving neurological outcomes after ischemic injury. Mechanistically, CBR1 decreased the levels of 4-HNE in the brain after stroke; it also modulated microglial polarization toward the M2 phenotype, which was well-known to confer neuroprotection after ischemic injury. Our results demonstrate that CBR1 provides neuroprotection against ischemic injury by reducing oxidative stress and neuroinflammation, making a promising agent for cerebral ischemia treatment.

Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis., Human ribonuclease 1 (hRNase 1) regulates innate immunity, hemostasis and RNA clearance. Here, the authors report an alternative function of hRNase 1 as a secretory ligand of Eph receptor EphA4 to enhance breast cancer stemness and promote breast tumour initiation.

OBJECTIVE This study aimed to increase workers' awareness of betel quid cessation. Methods: Using community and workplace resources, a workplace health promotion program was developed in accordance with the five action areas of the Ottawa Charter. Questionnaires were administered to examine the changes in the knowledge and attitudes of 714 workers in different occupations before and three months after the intervention. Results: Regardless of subjects' pre-intervention chewing status, their knowledge and attitude scores relating to betel quid cessation increased significantly after the intervention. The effect of occupation was significant on the post-intervention knowledge and attitude scores among chewers. Furthermore, 16 (11.6%) of the 138 study subjects who chewed betel quid before the intervention and had no willingness to quit, did quit betel quid chewing following the intervention. The factors contributing to an unwillingness to quit among chewers with no intention to quit before the intervention were examined. Workers in the electronic material manufacturing industry had a greater willingness to quit compared to those in the metal, machinery, and related trades (odds ratio [OR] = 0.15; 95% confidence interval [CI] = 0.02-0.94). Travel attendants, tour guides, cleaners, and helpers were the least willing to quit (OR = 21.29; 95% CI = 2.51-180.81). Conclusions: This study promoted workers' awareness of betel quid cessation by adopting the five action areas of the Ottawa Charter framework, the effectiveness of the intervention varied in different occupations. Workers with a high-income and better education level had a higher awareness of betel quid cessation.

Excessive glutamate leading to excitotoxicity worsens brain damage after SAH and contributes to long-term neurological deficits. The drug ifenprodil is a non-competitive antagonist of GluN1-GluN2B N-methyl-d-aspartate (NMDA) receptor, which mediates excitotoxic damage in vitro and in vivo. Here, we show that cerebrospinal fluid (CSF) glutamate level within 48 h was significantly elevated in aSAH patients who later developed poor outcome. In rat SAH model, ifenprodil can improve long-term sensorimotor and spatial learning deficits. Ifenprodil attenuates experimental SAH-induced neuronal death of basal cortex and hippocampal CA1 area, cellular and mitochondrial Ca2+ overload of basal cortex, blood-brain barrier (BBB) damage, and cerebral edema of early brain injury. Using in vitro models, ifenprodil declines the high-concentration glutamate-mediated intracellular Ca2+ increase and cell apoptosis in primary cortical neurons, reduces the high-concentration glutamate-elevated endothelial permeability in human brain microvascular endothelial cell (HBMEC). Altogether, our results suggest ifenprodil improves long-term neurologic deficits through antagonizing glutamate-induced excitotoxicity.

Deregulated metabolism is one of the characteristics of hepatocellular carcinoma. Sex hormone receptor signalling has been involved in the marked gender dimorphism of hepatocellular carcinoma pathogenesis. Oestrogen receptor (ER) has been reported to reduce the incidence of liver cancer. However, it remains unclear how oestrogen and ER regulate metabolic alterations in liver tumour cells. Our previous work revealed that ERα interacted with carbohydrate responsive element binding protein (ChREBP), which is a transcription factor promoting aerobic glycolysis and proliferation of hepatoma cells. Here, the data showed that ERα overexpression with E2 treatment reduced aerobic glycolysis and cell proliferation of hepatoma cells. In addition to modestly down‐regulating ChREBP transcription, ERα promoted ChREBP degradation. ERα co‐immunoprecipitated with both ChREBP‐α and ChREBP‐β, the two known subtypes of ChREBP. Although E2 promoted ERα to translocate to the nucleus, it did not change subcellular localization of ChREBP. In addition to interacting with ChREBP‐β and promoting its degradation, ERα decreased ChREBP‐α–induced ChREBP‐β transcription. Taken together, we confirmed an original role of ERα in suppressing aerobic glycolysis in liver cancer cells and elucidated the mechanism by which ERα and ChREBP‐α together regulated ChREBP‐β expression.

BACKGROUND Although transsphenoidal adenomectomy is the first treatment choice for Cushing's disease (CD), tumor recurrence rates are as high as 45%, resulting in a therapeutic challenge for endocrinologists and neurosurgeons. For recurrent/persistent CD (RCD/PCD), Repeat transsphenoidal surgery (RTSS), radiotherapy, gamma knife radiosurgery (GKRS) or bilateral adrenalectomy may be considered. The purpose of the study was to report the treatments and outcomes of RCD/PCD in a single center. METHODS A retrospective study was performed on 55 RCD/PCD patients from a single center between 2000 and 2012 at Peking Union Medical College Hospital (PUMCH). RESULTS Among the 55 RCD/PCD patients, 43 achieved remission (78%), and 11 maintained a PCD status (20%). The average times to recurrence after the initial treatment and Repeated treatment were 43.25±10.3 and 5.13±4.7 months, respectively (P=0.006); 17.6% of the patients experienced recurrence within the first year, and 52.9% of the patients experienced recurrence within 1.1-5.0 years. For the Repeated treatments, surgery was more effective for the biochemical remission of serum cortisol and adrenocorticotrophic hormone (ACTH) levels than radiotherapy. Delayed remission occurred in 28.9% (11/38) of the patients after Repeated surgery. Considering the previous biochemical levels after the initial surgery in RCD patients, 19.75% of patients experienced recurrence when serum cortisol levels were less than

Background The main purpose of this study was to describe the all-inside arthroscopic technique for repairing anterior talofibular ligament (ATFL) avulsion fractures at the attachment points of the fibula and talus, and to evaluate the functional outcomes during long-term follow-up. Methods The data of 78 patients with ATFL avulsion fracture treated in our hospital from August 2013 to November 2016 were analyzed retrospectively. All patients underwent surgery. Patients were divided into two groups according to whether they had undergone all-inside arthroscopic treatment or open treatment. The American Orthopedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), Foot and Ankle Outcome Score (FAOS) and a 36-item Short Form Health Survey questionnaire (SF-36) were used to evaluate functional outcomes. Results The postoperative follow-up period was 24–48 months. All patients reported subjective improvements to ankle stability without any nerve, blood vessel or tendon complications. At the final follow-up, there was no significant difference in the AOFAS, SF-36 or sport participation rate between the arthroscopic group and the open group; however, the KAFS and FAOS were significantly higher in the arthroscopic group than in the open group. Conclusions For ATFL avulsion fractures, the all-inside ankle arthroscopic procedure produced better outcomes than did the open procedure. The all-inside ankle arthroscopic procedure provides a minimally invasive technique with acceptable long-term functional outcomes.

The tumor microenvironment represents one of the main obstacles in breast cancer treatment owing to the presence of heterogeneous stromal cells, such as adipose-derived stem cells (ADSCs), that may interact with breast cancer cells and promote cancer development. Resistin is an adipocytokine associated with adverse breast cancer progression; however, its underlying mechanisms in the context of the breast tumor microenvironment remain largely unidentified. Here, we utilized a transwell co-culture model containing patient-derived ADSCs and breast cancer cell lines to investigate their potential interaction, and observed that breast cancer cells co-cultured with resistin-treated ADSCs (R-ADSCs) showed enhanced cancer cell growth and metastatic ability. Screening by proteome arrays revealed that C-X-C motif chemokine ligand 5 (CXCL5) was released in the conditioned medium of the co-culture system, and phosphorylated ERK was increased in breast cancer cells after co-culture with R-ADSCs. Breast cancer cells treated with the recombinant proteins of CXCL5 showed similarly enhanced cell migration and invasion ability as occurred in the co-culture model, whereas application of neutralizing antibodies against CXCL5 reversed these phenomena. The orthotopic xenograft in mice by breast cancer cells after co-culture with R-ADSCs had a larger tumor growth and more CXCL5 expression than control. In addition, clinical analysis revealed a positive correlation between the expression of resistin and CXCL5 in both tumor tissues and serum specimens of breast cancer patients. The current study suggests that resistin-stimulated ADSCs may interact with breast cancer cells in the tumor microenvironment via CXCL5 secretion, leading to breast cancer cell malignancy.

The use of hematoma expansion (HE) in intracerebral hemorrhage (ICH) patients is limited due to its low sensitivity. Perihematomal edema (PHE) has been considered an important marker of secondary brain injury after ICH. Enrolling PHE expansion to redefine traditional ICH expansion merits exploration.This study analyzed a cohort of patients with spontaneous ICH. The hematoma and PHE were manually segmented. Logistic regression analysis was utilized to identify risk factors for poor outcomes. Receiver operating characteristic curve analysis was performed to calculate the predictive values of PHE expansion and HE. Poor neurological outcome was defined as a modified Rankin Scale score of 4-6 at 90 days.Overall, 223 target patients were enrolled in the study. Multivariable analysis showed the larger PHE expansion is the independent risk factors for poor prognosis. The predictive value of absolute PHE expansion (AUC=0.776, sensitivity=67.9%, specificity=77.0%) was higher than that of absolute HE (AUC=0.573, sensitivity=41.7%, specificity=87.1%) and HE (6 ml) (AUC=0.594, sensitivity=23.8%, specificity=95.0%). The best cutoff for early absolute/relative PHE expansion resulting in a poor outcome was 5.96 ml and 31%.Early PHE expansion was associated with a poor outcome, characterized by a better predictive value than HE.

This study aimed to examine the reliability of existing Knosp grade (KG) and modified KG for cavernous sinus invasion (CSI). A thorough search of literature from 1993 to 2020 in six databases was performed. Studies that reported the intraoperative confirmation of CSI using KG and/or modified KG were included. The pooled estimates were calculated by meta-analysis with a bivariate mixed-effect model and the assessment of heterogeneity with I2 statistic. The final search yielded 12 eligible studies, which enrolled 3006 patients assessed with KG and 1315 patients assessed with modified KG. The results of the area under the receiver operating characteristic curve showed the good discriminative abilities of grades 2–4 (0.90), 3–4 (0.86) and 3B–4 (0.91) in predicting CSI. Grade 3A showed a remarkably lower CSI rate (44% versus 81%) and incomplete resection rate (26% versus 52%) than grade 3B. Grades 0 and 1 showed a low CSI rate. CSI and incomplete resection rates in grade 2 (30% and 21%, respectively) were close to those in grade 3A. Modifying the KG improved its prognostic role in CSI and gross total resection. However, these grading systems cannot be used as the group standard for invasive and non-invasive pituitary adenomas (PAs) because of the weak reliability of the scale’s middle grades (grades 2 and 3A). Authors of future PA studies should consider reporting KG as high (grades 3B and 4), medium (grades 2 and 3A) and low (grades 0 and 1) to optimise the application of the scale.

Liraglutide, a glucagon-like peptide 1 (GLP1) receptor agonist, is known to inhibit the atherosclerosis of apoE mice and suppress the cellular behaviors of VSMCs induced by AngII. This study aimed to explore whether liraglutide can reduce the proliferation, invasion and phenotypic transformation of VSMCs induced by Hcy and the underlying mechanism. Hcy was used to induce the proliferation of VSMCs, and liraglutide was then used to expose the cells for assessing cell proliferation. Afterward, the cell migration and phenotypic switch were evaluated to observe the effects of liraglutide. Meanwhile, the expression of PCSK9 and LDLR was detected. After overexpressing PCSK9, the changes in proliferation, cell migration and phenotypic switch were estimated again. Hcy promoted cell proliferation of VSMCs, whereas liraglutide blocked the proliferation, migration and phenotypic switch of Hcy-induced VSMCs. Furthermore, the expression of PCSK9 was downregulated and LDLR expression was upregulated after liraglutide administration in Hcy-induced VSMCs. After overexpressing PCSK9, the proliferation, migration and phenotypic switch of Hcy-induced VSMCs were enhanced. Liraglutide blocked the proliferation, migration and phenotypic switching of Hcy-induced VSMCs by suppressing PCSK9/LDLR. This finding provided the basis for the future application of liraglutide as an effective drug for therapeutic strategy in targeting AS.

Background aims Mesenchymal stem cells (MSCs) use multiple mechanisms to constrain both innate and adaptive immune responses to prevent graft-versus-host disease (GVHD). Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of early myeloid progenitor cells originating from bone marrow, are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses, indicating their potential for GVHD therapy. There is accumulating evidence that MSCs and MDSCs do not act independently, but rather establish crosstalk. However, the role of MSCs in MDSC expansion and activation in GVHD remains unexplored. Methods In vitro experiments included 2 groups: peripheral blood mononuclear cells (PBMCs) after mobilization and human umbilical cord blood-derived MSCs (UCB-MSCs) co-cultured with PBMCs. The number and functional difference of MDSCs in PBMCs were determined by flow cytometry. The culture supernatants of co-cultured cells were analyzed to identify cytokines involved in MDSC proliferation. The relationship between MSCs and MDSCs was clarified in GVHD and graft-versus-leukemia (GVL) animal models. Results In vitro experiments confirmed that UCB-MSCs secreted HLA-G protein to promote and maintain the proliferation of MDSCs in peripheral blood after granulocyte colony-stimulating factor mobilization, and UCB-MSCs mediated the function of MDSCs to inhibit the proliferation of T cells and promote the proliferation of regulatory T cells. UCB-MSCs overexpressing HLA-G induced MDSC production in recipient mice, improved the ability of MDSCs to suppress T cells and further reduced acute GVHD (aGVHD) symptoms and survival time without influencing GVL effects. Conclusions UCB-MSCs expanded MDSCs via HLA-G/Ig-like transcript 4, reducing the severity of aGVHD without affecting GVL. The immunosuppressive potential of MSCs for the treatment of aGVHD significantly affects the development of MDSCs, thereby consolidating the position of MSCs in the prevention and treatment of aGVHD.

Glioblastoma (GBM) is the deadliest primary brain tumor that is highly resistant to current treatments. Polo-like kinase 1 (PLK1) and signal transducer and activator of transcription 3 (STAT3) are highly expressed in gliomas, especially GBM. Previous studies have shown reciprocal activation between PLK1 and STAT3 and that they regulate the same pools of MYC downstream. We have demonstrated that PLK1 and STAT3 levels are elevated in gliomas compared with those in normal brain tissues, and high expression of both PLK1 and STAT3 is associated with poor prognosis in TCGA. Moreover, there was direct or indirect reciprocal regulation between PLK1 and STAT3. Furthermore, we found that PLK1 and STAT3 can regulate the same pools of MYC downstream. Compared to monotherapy, combined treatment of glioma cells with PLK1 and STAT3 inhibitors, BI2536 and Stattic, respectively, showed lower expression of MYC, synergistic induction of cell invasion and apoptosis in vitro, and tumor inhibition in xenografts. PLK1 and STAT3 were able to directly regulate the expression of MYC and induce apoptosis of glioma cells through the regulation of MYC. These findings may help develop a therapeutic strategy for dual inhibition of PLK1 and STAT3 against the tumorigenesis of glioma.

Purpose The Broström-Gould procedure, with the repair of the anterior talofibular ligament (ATFL) combined with the transfer of the extensor retinaculum, is considered the gold standard procedure for the management of chronic lateral ankle instability (CLAI). Lateral ligament reconstruction is considered if the ATFL remnant quality is poor or the ATFL has been damaged beyond the ability to suture it. It remains unclear whether not repairing the ATFL remnant produces comparable functional outcomes to the classical Broström-Gould procedure. Methods This retrospective cohort study included 84 patients with CLAI undergoing either repair or non-repair of the ATFL remnant using an all-inside arthroscopic Broström-Gould procedure from 2015 to 2018. The Visual Analogue Scale (VAS) scores, American Orthopedic Foot and Ankle Society (AOFAS) scores, Karlsson Ankle Functional Score (KAFS), Anterior Talar Translation (ATT), Active Joint Position Sense (AJPS), and the rate of return to sports were compared in both groups. Results All the functional scores (VAS, AOFAS, KAFS, ATT, AJPS) significantly improved in both groups at 1 and 2 years after surgery. At all the follow-up time points, the VAS, AOFAS, KAFS, ATT, AJPS, and the rate of return to sport scores were comparable between the repair and non-repair group. Conclusion There are no statistically significant differences in postoperative outcomes between ATFL remnant repair and non-repair for the management of CLAI using the all-inside arthroscopic Broström-Gould procedure. From the clinical viewpoint, the present study shows that the potential differences in clinical outcomes between ATFL remnant repair and non-repair are likely not relevant when performing an all-inside arthroscopic Broström-Gould procedure for CLAI. Level of evidence III.