Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans.

Twelve new alkaloids, scolopenolines A-L (1-7, 9-11, 13, 14), along with six known analogues, were isolated from Scolopendra subspinipes mutilans, identified by analysis of spectroscopic data and quantum chemical and computational methods. Scolopenoline A (1), a unique guanidyl-containing C14 quinoline alkaloid, features a 6/6/5 ring backbone. Scolopenoline B (2) is a novel sulfonyl-containing heterodimer comprising quinoline and tyramine moieties. Scolopenoline G (7) presents a rare C12 quinoline skeleton with a 6/6/5 ring system. Alkaloids 1, 8, 10, and 15-18 display anti-inflammatory activity, while 10 and 16-18 also exhibit anti-renal-fibrosis activity. Drug affinity responsive target stability and RNA-interference assays show that Lamp2 might be a potentially important target protein of 16 for anti-renal-fibrosis activity.

Translation and adaptation of Shared Care Instrument-Revised for the older adults and their caregivers in Taiwan.

BACKGROUND: The aging population in Taiwan has resulted in an increase in the dependent population and the care load on caregivers. Shared care is an interpersonal process in which support is "traded" to "handle" chronic illnesses by home-care patients and family caregivers. The scale of shared care has received little attention in the Taiwanese cultural context. Thus, this study examined the reliability and validity of the Taiwanese versions of Shared Care Instrument-Revised (SCI-R). METHODS: The content validity, construct validity, and discriminant validity were used to test the validity of the translated questionnaires. The Cronbach's α was used to examine reliability. A total of 500 older adults and their caregivers were recruited from three counties in Taiwan. RESULTS: The reliability and validity of the Chinese version of the scale were within the acceptable range. The Cronbach's α was between 0.838 and 0.95. However, the scale's reliability was higher than that of the original version. This might be because of the inclusion of participants with less severe diseases than the participants in the original study, high social expectations in the Chinese traditional culture, and a large number of similar items. Future research should simplify the items and consider adopting diverse participant selection criteria. CONCLUSIONS: The results of this study can be used to understand shared care in Taiwan.

[Two new benzyl-benzoate glucosides from Plumeria rubra].

The components with hypoglycemic activity in Plumeria rubra were isolated and purified by various column chromatography techniques and activity tracing methods. The physical and chemical properties of all the purified monomer compounds were characterized and analyzed, and a total of six compounds were isolated and identified, including 6″-acetyl-6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside(1), 6-acetyl-6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-glucoside(2), 2-hydroxy-6-methoxy-benzyl-benzoate-2-O-ß-D-glucoside(3), 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside(4), 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-glucoside(5), and 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-xyloside(6). Compounds 1 and 2 were new compounds, and compounds 3-6 were isolated from Plumeria for the first time. The α-glucosidase inhibitory activity of six identified compounds was tested. The results show that compounds 1-6 show certain inhibitory activity with an IC_(50) value ranging from 8.2 to 33.5 µmol·L~(-1).

Rapamycin improves the survival of epilepsy model cells by blocking phosphorylation of mTOR base on computer simulations and cellular experiments.

PURPOSE: Epilepsy is a chronic brain dysfunction characterized by recurrent epileptic seizures. Rapamycin is a naturally occurring macrolide from Streptomyces hygroscopicus, and rapamycin may provide a protective effect on the nervous system by affecting mTOR. Therefore, we investigated the pharmacologic mechanism of rapamycin treating epilepsy through bioinformatics analysis, cellular experiments and supercomputer simulation. METHODS: Bioinformatics analysis was used to analyze targets of rapamycin treating epilepsy. We established epilepsy cell model by HT22 cells. RT-qPCR, WB and IF were used to verify the effects of rapamycin on mTOR at gene level and protein level. Computer simulations were used to model and evaluate the stability of rapamycin binding to mTOR protein. RESULTS: Bioinformatics indicated mTOR played an essential role in signaling pathways of cell growth and cell metabolism. Cellular experiments showed that rapamycin could promote cell survival, and rapamycin did not have an effect on mRNA expression of mTOR. However, rapamycin was able to significantly inhibit the phosphorylation of mTOR at protein level. Computer simulations indicated that rapamycin was involved in the treatment of epilepsy through regulating phosphorylation of mTOR at protein level. CONCLUSION: We found that rapamycin was capable of promoting the survival of epilepsy cells by inhibiting the phosphorylation of mTOR at protein level, and rapamycin did not have an effect on mRNA expression of mTOR. In addition to the traditional study that rapamycin affects mTORC1 complex by acting on FKBP12, this study found rapamycin could also directly block the phosphorylation of mTOR, therefore affecting the assembly of mTORC1 complex and mTOR signaling pathway.

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

Nanoscale Localized Phonons at Al2O3 Grain Boundaries.

Nanoscale defects like grain boundaries (GBs) would introduce local phonon modes and affect the bulk materials' thermal, electrical, optical, and mechanical properties. It is highly desirable to correlate the phonon modes and atomic arrangements for individual defects to precisely understand the structure-property relation. Here we investigated the localized phonon modes of Al2O3 GBs by combination of the vibrational electron energy loss spectroscopy (EELS) in scanning transmission electron microscope and density functional perturbation theory (DFPT). The differences between GB and bulk obtained from the vibrational EELS show that the GB exhibited more active vibration at the energy range of <50 meV and >80 meV, and further DFPT results proved the wide distribution of bond lengths at GB are the main factor for the emergence of local phonon modes. This research provides insights into the phonon-defect relation and would be of importance in the design and application of polycrystalline materials.

Role of low-density lipoprotein electronegativity and sexual dimorphism in contributing early ventricular tachyarrhythmias following ST-elevation myocardial infarction.

Background: Early ventricular tachycardia/fibrillation (VT/VF) in patients with ST-elevation myocardial infarction (STEMI) has higher morbidity and mortality. This study examines gender-differentiated risk factors and underlying mechanisms for early onset VT/VF in STEMI. Methods: We analyzed data from 2,964 consecutive STEMI patients between January 1, 2008 and December 31, 2021. Early VT/VF was defined as occurrence of spontaneous VT/VF of ≥30 s or requirement of immediate cardioversion/defibrillation within the first 48 h after symptoms. An ex vivo ischemic-reperfusion experiments were conducted in 8-week-old ApoE-/- mice fed a high-fat diet to explore the underlying mechanisms of early VT/VF. Results: In 255 of out 2,964 STEMI patients who experienced early VT/VF, the age was younger (58.6 ± 13.8 vs. 61.0 ± 13.0 years old, P = 0.008) with a male predominance. The plasma levels of L5, the most electronegative subclass of low-density lipoprotein, was higher in early VT/VF patients compared to those without early VT/VF (n = 21, L5: 14.1 ± 22.6% vs. n = 46, L5: 4.3 ± 9.9%, P = 0.016). In the experimental setup, all male mice (n = 4) developed VT/VF post sham operation, whereas no such incidence was observed in the female mice (n = 3). Significantly, male mice exhibited considerably slower cardiac conduction velocity as compared to their female counterparts in whole heart preparations (25.01 ± 0.93 cm/s vs.42.32 ± 5.70 cm/s, P < 0.001), despite analogous action potential durations. Furthermore, isolated ventricular myocytes from male mice showed a distinctly lower sodium current density (-29.20 ± 3.04 pA/pF, n = 6) in comparison to female mice (-114.05 ± 6.41 pA/pF, n = 6, P < 0.001). This decreased sodium current density was paralleled by a reduced membrane expression of Nav1.5 protein (0.38 ± 0.06 vs. 0.89 ± 0.09 A.U., P < 0.001) and increased cytosolic Nav1.5 levels (0.59 ± 0.06 vs. 0.29 ± 0.04 A.U., P = 0.001) in male mice. Furthermore, it was observed that the overall expressions of sorting nexin 27 (SNX27) and vacuolar protein sorting 26 (VPS26) were significantly diminished in male mice as compared to female littermates (0.91 ± 0.15 vs. 1.70 ± 0.28, P = 0.02 and 0.74 ± 0.09 vs. 1.57 ± 0.13, P < 0.01, respectively). Conclusions: Our findings reveal that male STEMI patients with early VT/VF are associated with elevated L5 levels. The gender-based discrepancy in early VT/VF predisposition might be due to compromised sodium channel trafficking, possibly linked with increased LDL electronegativity.

Role of Peritoneal Equilibration Test in Assessing Folate Transport During Peritoneal Dialysis.

OBJECTIVES: Low plasma folate levels have been reported in patients undergoing hemodialysis and peritoneal dialysis (PD) in clinical studies. However, folate transport has never been mentioned as a factor contributing to low plasma folate levels in patients undergoing PD. The peritoneal equilibrium test (PET) assesses the plasma creatinine level and glucose transport abilities. This study aimed to evaluate the association between plasma folate levels and folate transport during PD based on PET grades. METHODS: This study recruited 50 patients who underwent PD for ≥3 months and were categorized according to PET grades. Data regarding plasma folate levels and dialysate folate were collected. The primary outcomes were the relationship between the PET grade and plasma folate level and between the PET grade and dialysate-to-plasma folate concentration ratio (D/P folate). Furthermore, the difference in the plasma folate level and D/P folate between men and women was assessed. RESULTS: The plasma folate level and the D/P folate significantly differed among the 4 PET groups (both P < .001). PET grade was significantly negatively correlated with plasma folate levels (r = -0.56, P < .001) and positively correlated with D/P folate (r = 0.686, P < .001). In subgroup analysis, neither the plasma folate level nor the D/P folate significantly differed between men and women. CONCLUSIONS: Our study provides clinical evidence that the PET grade is associated with the plasma folate level and D/P folate, regardless of sex. Larger cohort studies are warranted to assess the importance of folate supplementation during PD based on PET grades.

Effectiveness of Chinese herbal medicine compared with angiotensin II receptor blockers in patients with diabetic kidney disease: A hospital-based matched cohort study.

Angiotensin II receptor blockers (ARBs) are one of the standard treatments for diabetic kidney disease (DKD). Some patients may opt for Chinese herbal medicine (CHM) of their own free will. However, there is no real-world evidence regarding the effectiveness and safety of CHM. We aimed to explore the effectiveness of CHM for DKD in comparison to ARBs. We enrolled 732 DKD patients (72 used only CHM and 661 used ARBs) from 2007 to 2016, and all patients were followed until December 2016 at China Medical University Hospital in Taiwan. A total of 355 ARB users and 71 CHM users were analyzed after propensity score matching. The estimated glomerular filtration rate (eGFR) after treatment was 84.9 ± 28.1 ml/min/1.73 m2 in CHM users, which was higher than that (67.8 ± 35.4 ml/min/1.73 m2) in ARB users (p < 0.001). The change in the eGFR was -6.0 ± 21.4 ml/min/1.73 m2 in CHM users and -12.9 ± 24.8 ml/min/1.73 m2 in ARB users (p = 0.029). The blood urea nitrogen (BUN) and creatinine levels of patients taking CHM were 22 ± 16 mg/dl and 0.9 ± 0.4 mg/dl, respectively, and were lower than those (30 ± 28 mg/dl and 1.7 ± 2.0 mg/dl) of patients taking ARBs (p = 0.025 and p = 0.003). Using linear regression with adjustments for age, sex, BMI, baseline eGFR, and HbA1c levels, we found that the declines in the eGFR/baseline eGFR and changes in the urine albumin-creatinine ratio (ACR) were comparable between the two groups (p = 0.86 and 0.73). This study suggests that CHM may have comparable effectiveness to ARBs, which provides insights for further investigations.

Prognostic evaluation of a multi-target magnetic bead-enriched circulating tumor cell-enriched identification system for colorectal cancer.

Background: Colorectal cancer (CRC) is the third most prevalent cancer in the world. Traditional tissue biopsy cannot provide dynamic monitoring of patients' tumors or reflect the characteristics of tumors in real time because the sampling process is invasive and accompanied by risks. Circulating tumor cells (CTCs) are considered a major cause of tumor metastasis, and investigating CTCs helps to understand the biology and vulnerability of malignant tumors during hematogenous metastasis. Methods: We sequentially used epithelial cell adhesion molecule (EpCAM)-coated immunoliposomal magnetic beads (Ep-IMBs) and vimentin-coated immunoliposomal magnetic beads (Vi-IMBs) to capture and characterize CTCs from 110 CRC patients. We further constructed a Cox risk regression model, optimized the model composition using backward stepwise regression, and finally applied nomograms to show the effect of each variable on survival risk. Results: The specificity of the CTCs enrichment and identification system was 100% and the sensitivity was 79.0%. Multivariate analysis indicated total CTC number was an important predictor for bad survival, whereas American Joint Committee on Cancer (AJCC) stage, lymph node metastasis, and carcinoembryonic antigen (CEA) level were associated with prognosis, and the risk of mortality was associated with the AJCC stage of the CRC. Conclusions: The CTC enrichment and identification system constructed in this research demonstrated superior accuracy. In addition, CTCs can be used as an important predictor for prognosis of patients with CRC, and the combination of other clinical predictive factors can help clinicians to better design individualized treatment regimens, which is of great clinical application value.

The Association between Acupuncture Therapy and the Risk of Disability Development in Dementia Patients: A Nationwide Cohort Study.

Purpose: Disability is the comorbidity of dementia for which there is no available preventive measure. The aim of this study was to investigate the association between acupuncture treatment and the risk of disability development in dementia patients. Patients and Methods: A cohort study was performed using a nationwide health database in Taiwan. The included dementia patients were divided into acupuncture and non-acupuncture cohorts based on whether they received acupuncture treatment during the follow-up period. The variables in the two cohorts were controlled by 1:1 propensity-score matching. The difference in disability development in dementia patients between the acupuncture and non-acupuncture cohorts was also analyzed. Subgroup analyses were performed using socioeconomic variables, comorbidities and anti-dementia agents (donepezil, rivastigmine, galantamine and memantine) used for dementia treatment. Results: A total of 9,760 dementia patients met our inclusion criteria, and patients were divided into an equal number (n=2,422) of acupuncture and non-acupuncture groups, respectively, after 1:1 propensity-score matching. The dementia patients had a lower risk of disability development after acupuncture treatment than those who did not receive acupuncture treatment (adjusted hazard ratio 0.65, 95% confidence interval 0.60-0.70, p < 0.001). The results were independent of basic variables or comorbidities in the two cohorts. Patients who did not use anti-dementia agents had a lower risk of developing disability after receiving acupuncture intervention than those who used anti-dementia agents. Conclusion: Our results revealed the relationship between acupuncture intervention and decreased risk of developing disability in dementia patients. The results are useful for dementia treatment, trial design and further planning of care programs.

The application of high-throughput sequencing technology in corneal diseases.

High-throughput sequencing technology, also known as next-generation sequencing technology, can explore new biomarkers and specific gene mutations. It has a pivotal role in promoting the gene research, which can limit the detection area, lessen the time needed for sequencing. Also, it can quickly screen out the suspected pathogenic genes of patients, gain the necessary genetic data, and provide the basis for clinical diagnosis and genetic counseling. In the research of corneal diseases, through the DNA sequencing of patients' diseased cells, it can provide a deeper understanding of corneal diseases and improve the diagnosis, classification and treatment alternatives of various corneal diseases. This article will introduce the application progress of high-throughput sequencing technology in corneal diseases, which will help to understand the application of this technology in various corneal diseases.

Risk Factors of Long-Term Sequelae After Transcatheter Closure of Perimembranous Ventricular Septal Defect in Young Children.

BACKGROUND: Complications arising from transcatheter closure of perimembranous ventricular septal defects (pmVSD) in children, such as residual shunts and aortic regurgitation (AR), have been observed. However, the associated risk factors remain unclear. This study identified risk factors linked with residual shunts and AR following transcatheter closure of pmVSD in children aged 2-12 years.Methods and Results: The medical records of 63 children with pmVSD and a pulmonary-to-systemic blood flow ratio <2.0 who underwent transcatheter closure between 2011 and 2018 were analyzed with a minimum 3-year follow-up. The success rate of transcatheter closure was 98.4%, with no emergency surgery, permanent high-degree atrioventricular block, or mortality. Defects ≥4.5 mm had significantly higher odds of persistent residual shunt (odds ratio [OR] 6.85; P=0.03). The use of an oversize device (≥1.5 mm) showed a trend towards reducing residual shunts (OR 0.23; P=0.06). Age <4 years (OR 27.38; 95% confidence interval [CI] 2.33-321.68) and perimembranous outlet-type VSD (OR 11.94, 95% CI 1.10-129.81) were independent risk factors for AR progression after closure. CONCLUSIONS: Careful attention is crucial for pmVSDs ≥4.5 mm to prevent persistent residual shunts in transcatheter closure. Assessing AR risk, particularly in children aged <4 years, is essential while considering the benefits of pmVSD closure.

Budget Impact of Introducing Fixed-Duration Mosunetuzumab for the Treatment of Relapsed or Refractory Follicular Lymphoma After Two or More Lines of Systemic Therapy in the USA.

OBJECTIVE: This study aimed to assess the budget impact of introducing fixed-duration mosunetuzumab as a treatment option for adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies and to estimate the total cumulative costs per patient in the USA. METHODS: A 3-year budget impact model was developed for a hypothetical 1-million-member cohort enrolled in a mixed commercial/Medicare health plan. Comparators were: axicabtagene ciloleucel, tisagenlecleucel, tazemetostat, rituximab plus lenalidomide, copanlisib, and older therapies (rituximab or obinutuzumab ± chemotherapy). Costs per patient comprised treatment-associated costs including the drug, its administration, adverse events, and routine care. Dosing and safety data were ascertained from respective package inserts and clinical trial data. Drug costs (March 2023) were estimated based on the average wholesale acquisition cost reported in AnalySource®, and all other costs were based on published sources and inflated to 2022 US dollars. Market shares were obtained from Genentech internal projections and expert opinion. Budget impact outcomes were presented on a per-member per-month basis. RESULTS: Compared with a scenario without mosunetuzumab, its introduction over 3 years resulted in a budget increase of $69,812 (1% increase) and an average per-member per-month budget impact of $0.0019. Among the newer therapies, mosunetuzumab had the second-lowest cumulative per patient cost (mosunetuzumab = $202,039; axicabtagene ciloleucel = $505,845; tisagenlecleucel = $476,293; rituximab plus lenalidomide = $263,520; tazemetostat = $250,665; copanlisib = $127,293) and drug costs, and its introduction only increased total drug costs by 0.1%. By year 3, the cumulative difference in the per patient cost with mosunetuzumab was -$303,805 versus axicabtagene ciloleucel, -$274,254 versus tisagenlecleucel, -$61,481 versus rituximab plus lenalidomide, -$48,625 versus tazemetostat, and $74,747 versus copanlisib. Older therapies were less costly with 3-year cumulative costs that ranged from $36,512 to $147,885. CONCLUSIONS: Over 3 years, the estimated cumulative per patient cost of mosunetuzumab is lower than most available newer therapies, resulting in a small increase in the budget after its formulary adoption for the treatment of relapsed or refractory follicular lymphoma.

Sarcopenia Affects Liver Regeneration and Long-Term Survival Rate After Living-Donor Liver Transplantation in Patients With Hepatocellular Carcinoma.

PURPOSE: Despite technological and immunologic innovations, some living-donor liver transplant (LDLT) recipients still face poor liver regeneration. Sarcopenia is often recognized as a biomarker for poor outcomes in surgical patients. This study aimed to evaluate associations between sarcopenia and liver regeneration in LDLT recipients. MATERIALS AND METHODS: This retrospective review included consecutive patients who had received LDLT at Chang Gung Memorial Hospital between 2005 and 2017. Sarcopenia was assessed using the psoas muscle index (PMI) in cross-sectional images. Receiver operating characteristic curve analysis was used to determine the ability of PMI to predict relatively poor survival rates. Correlations between liver regeneration and sarcopenia were evaluated using regression analysis. RESULTS: A total of 109 LDLT recipients were included. The 1-, 3-, 5, 10-, and 15-year survival rates were 93.7%, 84.8%, 79.7%, 74.7%, and 73.3% in males and 93.3%, 83.3%, 83.3%, 71.4%, and 71.4% in females. PMIs were significantly different based on 10- and 15-year overall survival rates (P = .001 and P = .000) in male patients. Receiver operating characteristic curve analysis revealed the PMI cutoff point at 6.7 cm2/m2 (sensitivity = 48.3%, specificity = 81%, AUC (area under the ROC curve) = 0.685) based on 10-year survival. Linear regression analysis revealed that PMI was significantly associated with liver regeneration in males (P = .013). CONCLUSIONS: Sarcopenia and low PMI are associated with poor liver regeneration and long-term survival after LDLT in male patients. Further studies, including sarcopenia with conventional scores, may help to more reliably predict liver regeneration and mortality among LDLT patients with hepatocellular carcinoma.

Upregulation of vesicle-associated membrane protein 7 in breast cancer tissues.

BACKGROUND: Vesicle-associated membrane protein 7 (VAMP7) plays oncogenic roles in cancers. However, its clinical significance in breast cancer (BC) tissues remains unknown. OBJECTIVE: To elucidate the clinical implications of VAMP7, as well as its involvement in the tumor microenvironment and molecular pathways of breast cancer. METHODS: BC (n=100) and non-cancerous breast tissues (n= 100) were collected for an immunohistochemical experiment (1:200). The protein expression level of VAMP7 was determined by using a semi-quantitative scoring method. High-throughput RNA-sequencing data of BC tissues were analyzed to confirm the mRNA expression trend of VAMP7. Additionally, the largest BC prognosis cohort data were collected to mine the potential impact VAMP7 has on BC progression. The association between VAMP7 and the microenvironment of BC was evaluated by using a CIBERSORT algorithm. Moreover, we explored the co-expressed molecular mechanisms of VAMP7 in BC by calculating Pearson correlation coefficients and overexpressed genes. Finally, the biological mechanism underlying the relationship between VAMP7 and the key pathways was also explored using gene set enrichment analysis (GSEA). Potential therapeutic strategies were predicted targeting VAMP7. RESULTS: VAMP7 protein was significantly over-expressed in BC tissue than that in controls (p< 0.001). Compared with 459 normal breast tissues and 113 non-cancerous breast tissues, the expression level of VAMP7 mRNA was significantly increased in 1111 BC tissues. CD4+T cells, macrophages, and naïve B cells had a higher infiltration rate in BC tissues with high VAMP7 expression, while regulatory T cells and CD8+T cells had a lower infiltration rate. Over-expressed VAMP7 was associated with macrophages activation and transition from M1 to M2 polarization. Upregulated VAMP7 could predicted poorer OS, DMFS, PPS, and RFS outcomes. Upregulated VAMP7 co-expressed genes were significantly enriched in the cell cycle checkpoints. GSEA confirmed that over-expressed VAMP7 are markedly associated with functional enrichment in cell cycle related categories, including mitotic spindle, G2M checkpoint, and E2F targets. KU-55933 was predicted as a putative therapeutic drug for BC targeting VAMP7. CONCLUSIONS: VAMP7 was upregulated in BC tissue and correlated with poor prognosis of BC patients. VAMP7 may promote BC progression by targeting the cell cycle pathway.

Effect of acupuncture on ischaemic stroke in patients with rheumatoid arthritis: a nationwide propensity score-matched study.

OBJECTIVE: To demonstrate that acupuncture is beneficial for decreasing the risk of ischaemic stroke in patients with rheumatoid arthritis (RA). DESIGN: A propensity score-matched cohort study. SETTING: A nationwide population-based study. PARTICIPANTS: Patients with RA diagnosed between 1 January 1997 and 31 December 2010, through the National Health Insurance Research Database in Taiwan. INTERVENTIONS: Patients who were administered acupuncture therapy from the initial date of RA diagnosis to 31 December 2010 were included in the acupuncture cohort. Patients who did not receive acupuncture treatment during the same time interval constituted the no-acupuncture cohort. PRIMARY OUTCOME MEASURES: A Cox regression model was used to adjust for age, sex, comorbidities, and types of drugs used. We compared the subhazard ratios (SHRs) of ischaemic stroke between these two cohorts through competing-risks regression models. RESULTS: After 1:1 propensity score matching, a total of 23 226 patients with newly diagnosed RA were equally subgrouped into acupuncture cohort or no-acupuncture cohort according to their use of acupuncture. The basic characteristics of these patients were similar. A lower cumulative incidence of ischaemic stroke was found in the acupuncture cohort (log-rank test, p<0.001; immortal time (period from initial diagnosis of RA to index date) 1065 days; mean number of acupuncture visits 9.83. In the end, 341 patients in the acupuncture cohort (5.95 per 1000 person-years) and 605 patients in the no-acupuncture cohort (12.4 per 1000 person-years) experienced ischaemic stroke (adjusted SHR 0.57, 95% CI 0.50 to 0.65). The advantage of lowering ischaemic stroke incidence through acupuncture therapy in RA patients was independent of sex, age, types of drugs used, and comorbidities. CONCLUSIONS: This study showed the beneficial effect of acupuncture in reducing the incidence of ischaemic stroke in patients with RA.

Development of a live-attenuated chimeric vaccine against the emerging Usutu virus.

Usutu virus (USUV) is an emerging arthropod-borne flavivirus that has expanded into multiple European countries during the past several decades. USUV infection in human has been linked to severe neurological complications, and no vaccine is now available against USUV. In this work, we develop a live-attenuated chimeric USUV vaccine (termed ChinUSUV) based on the full-length infectious cDNA clone of the licensed Japanese encephalitis virus (JEV) vaccine strain SA14-14-2. In vitro studies demonstrate that ChinUSUV replicates efficiently and maintains its genetic stability. Remarkably, ChinUSUV exhibits a significant attenuation phenotype in multiple mouse models even compared with the licensed JEV vaccine. A single immunization with ChinUSUV elicits potent IgG and neutralizing antibody responses as well as T cell response. Passive transfer of sera from ChinUSUV-immunized mice confers significant protection against lethal homologous challenge in suckling mice. Taken together, our results suggest that ChinUSUV represents a potential USUV vaccine candidate that merits further development.

Use of artificial intelligence and I-Score for prediction of recurrence before catheter ablation of atrial fibrillation.

BACKGROUND: Based solely on pre-ablation characteristics, previous risk scores have demonstrated variable predictive performance. This study aimed to predict the recurrence of AF after catheter ablation by using artificial intelligence (AI)-enabled pre-ablation computed tomography (PVCT) images and pre-ablation clinical data. METHODS: A total of 638 drug-refractory paroxysmal atrial fibrillation (AF) patients undergone ablation were recruited. For model training, we used left atria (LA) acquired from pre-ablation PVCT slices (126,288 images). A total of 29 clinical variables were collected before ablation, including baseline characteristics, medical histories, laboratory results, transthoracic echocardiographic parameters, and 3D reconstructed LA volumes. The I-Score was applied to select variables for model training. For the prediction of one-year AF recurrence, PVCT deep-learning and clinical variable machine-learning models were developed. We then applied machine learning to ensemble the PVCT and clinical variable models. RESULTS: The PVCT model achieved an AUC of 0.63 in the test set. Various combinations of clinical variables selected by I-Score can yield an AUC of 0.72, which is significantly better than all variables or features selected by nonparametric statistics (AUCs of 0.66 to 0.69). The ensemble model (PVCT images and clinical variables) significantly improved predictive performance up to an AUC of 0.76 (sensitivity of 86.7% and specificity of 51.0%). CONCLUSIONS: Before ablation, AI-enabled PVCT combined with I-Score features was applicable in predicting recurrence in paroxysmal AF patients. Based on all possible predictors, the I-Score is capable of identifying the most influential combination.