Cost-effectiveness of tirofiban for acute ischemic stroke without large or medium-sized vessel occlusion: A Markov modelling analysis from the Chinese and United States perspectives.

BACKGROUND: The RESCUE BT2 trial recently showcased the efficacy of tirofiban in treating acute ischemic stroke (AIS) without large or medium-sized vessel occlusion. To further assess the value of tirofiban from the perspectives of Chinese and US healthcare system, a study was conducted to evaluate its cost-effectiveness. METHODS: A hybrid model, integrating a short-term decision tree with a long-term Markov model, was developed to assess cost-effectiveness between tirofiban and aspirin for stroke patients without large or medium-sized vessel occlusion. Efficacy data for tirofiban was sourced from the RESCUE BT2 trial, while cost information was derived from published papers. Outcomes measured included respective cost, effectiveness, and incremental cost-effectiveness ratio (ICER). We conducted a one-way sensitivity analysis to assess the robustness of the results. Additionally, we performed probabilistic sensitivity analysis (PSA) through 10,000 Monte Carlo simulations to evaluate the uncertainties associated with the results. RESULTS: The study revealed that tirofiban treatment in AIS patients without large or medium-sized vessel occlusion led to a considerable reduction of 2141 Chinese Yuan (CNY) in total cost, along with a lifetime gain of 0.14 quality-adjusted life years (QALYs). In the US settings, tirofiban also exhibited a lower cost ($197,055 versus $201,984) and higher effectiveness (4.15 QALYs versus 4.06 QALYs) compared to aspirin. One-way sensitivity analysis revealed that post-stroke care costs and stroke utility had the greatest impact on ICER fluctuation in both Chinese and US settings. However, these variations did not exceed the willingness-to-pay threshold. PSA demonstrated tirofiban's superior acceptability over aspirin in over 95% of potential scenarios. CONCLUSION: Tirofiban treatment for AIS without large or medium-sized vessel occlusion appeared dominant compared to aspirin in both China and the US.

The Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Anthracycline-Treated Patients With Cancer.

Background: Sodium glucose cotransporter-2 inhibitors (SGLT2is) are hypothesized to reduce the risk of anthracycline-associated cardiotoxicity. Objectives: This study sought to determine the association between SGLT2is and cardiovascular disease (CVD) after anthracycline-containing chemotherapy. Methods: Using administrative data sets, we conducted a population-based cohort study of people >65 years of age with treated diabetes and no prior heart failure (HF) who received anthracyclines between January 1, 2016, and December 31, 2019. After estimating propensity scores for SGLT2i use, the average treatment effects for the treated weights were used to reduce baseline differences between SGLT2i-exposed and -unexposed controls. The outcomes were hospitalization for HF, incident HF diagnoses (in- or out-of-hospital), and documentation of any CVD in future hospitalizations. Death was treated as a competing risk. Cause-specific HRs for each outcome were determined for SGLT2i-treated people relative to unexposed controls. Results: We studied 933 patients (median age 71.0 years, 62.2% female), 99 of whom were SGLT2i treated. During a median follow-up of 1.6 years, there were 31 hospitalizations for HF (0 in the SGLT2i group), 93 new HF diagnoses, and 74 hospitalizations with documented CVD. Relative to controls, SGLT2i exposure was associated with HR of 0 for HF hospitalization (P < 0.001) but no significant difference in incident HF diagnosis (HR: 0.55; 95% CI: 0.23-1.31; P = 0.18) or CVD diagnosis (HR: 0.39; 95% CI: 0.12-1.28; P = 0.12). There was no significant difference in mortality (HR: 0.63; 95% CI: 0.36-1.11; P = 0.11). Conclusions: SGLT2is may reduce the rate of HF hospitalization after anthracycline-containing chemotherapy. This hypothesis warrants further testing in randomized controlled trials.

Multimorbidity at time of death among persons with type 2 diabetes: a population-based study in Ontario, Canada.

OBJECTIVE: Individuals with Type 2 Diabetes are likely to experience multimorbidity and accumulate multiple chronic conditions over their life. We aimed to identify causes of death and chronic conditions at the time of death in a population-based cohort, and to analyze variations in the presence of diabetes at the time of death overall and across income and immigrant status. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study of 2,199,801 adult deaths from 1992 to 2017 in Ontario, Canada. We calculated the proportion of decedents with chronic conditions at time of death and causes of death. The risk of diabetes at the time of death was modeled across sociodemographic variables with a log binomial regression adjusting for sex, age, immigrant status, area-level income. comorbiditiesand time. RESULTS: The leading causes of death in the cohort were cardiovascular and cancer. Decedents with diabetes had a higher prevalence of most chronic conditions than decedents without diabetes, including hypertension, osteo and other arthritis, chronic coronary syndrome, mood disorder, and congestive heart failure. The risk of diabetes at the time of death was 19% higher in immigrants (95%CI 1.18-1.20) and 15% higher in refugees (95%CI 1.12-1.18) compared to long-term residents, and 19% higher in the lowest income quintile (95%CI 1.18-1.20) relative to the highest income quintile, after adjusting for other covariates. CONCLUSIONS: Individuals with diabetes have a greater multimorbidity burden at the time of death, underscoring the importance of multiple chronic disease management among those living with diabetes and further considerations of the social determinants of health.

Variations in all-cause mortality, premature mortality and cause-specific mortality among persons with diabetes in Ontario, Canada.

INTRODUCTION: Patients with diabetes have a higher risk of mortality compared with the general population. Large population-based studies that quantify variations in mortality risk for patients with diabetes among subgroups in the population are lacking. This study aimed to examine the sociodemographic differences in the risk of all-cause mortality, premature mortality, and cause-specific mortality in persons diagnosed with diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cohort study of 1 741 098 adults diagnosed with diabetes between 1994 and 2017 in Ontario, Canada using linked population files, Canadian census, health administrative and death registry databases. We analyzed the association between sociodemographics and other covariates on all-cause mortality and premature mortality using Cox proportional hazards models. A competing risk analysis using Fine-Gray subdistribution hazards models was used to analyze cardiovascular and circular mortality, cancer mortality, respiratory mortality, and mortality from external causes of injury and poisoning. RESULTS: After full adjustment, individuals with diabetes who lived in the lowest income neighborhoods had a 26% (HR 1.26, 95% CI 1.25 to 1.27) increased hazard of all-cause mortality and 44% (HR 1.44, 95% CI 1.42 to 1.46) increased risk of premature mortality, compared with individuals with diabetes living in the highest income neighborhoods. In fully adjusted models, immigrants with diabetes had reduced risk of all-cause mortality (HR 0.46, 95% CI 0.46 to 0.47) and premature mortality (HR 0.40, 95% CI 0.40 to 0.41), compared with long-term residents with diabetes. Similar HRs associated with income and immigrant status were observed for cause-specific mortality, except for cancer mortality, where we observed attenuation in the income gradient among persons with diabetes. CONCLUSIONS: The observed mortality variations suggest a need to address inequality gaps in diabetes care for persons with diabetes living in the lowest income areas.

Spinning thermal radiation from twisted two different anisotropic materials.

Thermal radiation has applications in numerous fields, such as radiation cooling, thermal imaging, and thermal camouflage. Micro/nanostructures such as chiral metamaterials with polarization-dependent or symmetry-breaking properties can selectively emit circularly (spin) polarized polarization waves. In this paper, we propose and demonstrate the spinning thermal radiation from two twisted different anisotropic materials. Taking industrial polymer and biaxial hyperbolic material α-MoO3 as an example, it is found that broadband spinning thermal radiation can be obtained from 13 µm to 18 µm. The spin thermal radiation of the proposed twisted structure originates from the combined effect of polarization conversion of circularly polarized wave and selective absorption of linearly polarized wave by the top and bottom layers of anisotropic materials, respectively. Besides, the narrowband spinning thermal radiation with 0.9 circular dichroism is achieved at wavelength of 12.39 µm and 18.93 µm for finite thickness α-MoO3 due to the epsilon-near-zero mode, and the magnetic field distribution can confirm the phenomenon. This work achieves broadband and narrowband spin thermal radiation and significantly enhances circular dichroism, which may have applications in biological sensing and thermal detection.

Efficacy of brain natriuretic peptide vs. nicorandil in preventing contrast-induced nephropathy: a network meta-analysis.

This study aimed to conduct a network meta-analysis (NMA) to compare the efficacy of brain natriuretic peptide (BNP) vs nicorandil for preventing contrast-induced nephropathy (CIN). Databases of Pubmed, Cochrane, Embase, Web of Science were searched by keywords for eligible studies of randomized controlled trials investigating different agents (BNP, nicorandil, nitroglycerin, intravenous saline) for preventing CIN. The outcomes included a change in serum creatinine level at 48 h and the incidence of CIN after percutaneous coronary intervention (PCI) or coronary angiography (CAG). A total of 13 studies with 3,462 patients were included. Compared with intravenous saline alone, except for nitroglycerin (odds ratio [OR]: 1.02, 95% CI [0.36-2.88]), the other drugs significantly reduced the CIN incidence with OR of 0.35 (95% CI [0.24-0.51]) for BNP, 0.52 (0.29, 0.94) for usual-dose nicorandil, 0.28 (0.19, 0.43) for double-dose nicorandil. BNP and double-dose nicorandil significantly decreased the change of serum creatinine (SCr) levels with mean difference (MD) of -6.98, (-10.01, -3.95) for BNP, -8.78, (-11.63, -5.93) for double-dose nicorandil. No significant differences were observed in the change of SCr levels for nitroglycerin (-4.97, [-11.46, 1.52]) and usual-dose nicorandil (-2.32, [-5.52, 0.89]) compared with intravenous saline alone. For double-dose nicorandil, the CIN incidence and the change of SCr level in group of 4-5 days treatment course were more than group of less than or equal to 24 h treatment course (OR of 1.48, [0.63-3.46] and MD of 2.48, [-1.96, 6.91]). In conclusion, BNP and double-dose nicorandil can have effects on preventing the incidence of CIN and double-dose nicorandil performed better than BNP. In double-dose nicorandil groups, a course of less than or equal to 24 h before and after procedure performed with better efficacy than a course of 4-5 days.

Exosome-Mediated Transfer of miR-1323 from Cancer-Associated Fibroblasts Confers Radioresistance of C33A Cells by Targeting PABPN1 and Activating Wnt/ß-Catenin Signaling Pathway in Cervical Cancer.

Plenty of pieces of evidence suggest that the resistance to radiotherapy greatly influences the therapeutic effect in cervical cancer (CCa). MicroRNAs (miRNAs) have been reported to regulate cellular processes by acting as tumor suppressors or promoters, thereby driving radioresistance or radiosensitivity. Meanwhile, it has been reported that microRNA-1323 (miR-1323) widely participates in cancer progression and radiotherapy effects. However, the role of miR-1323 is still not clear in CCa. Hence, in this study, we are going to investigate the molecular mechanism of miR-1323 in CCa cells. In the beginning, miR-1323 was found aberrantly upregulated in CCa cells via RT-qPCR assay. Functional assays indicated that miR-1323 was transferred by cancer-associated fibroblasts-secreted (CAFs-secreted) exosomes and miR-1323 downregulation suppressed cell proliferation, migration, invasion, and increased cell radiosensitivity in CCa. Mechanism assays demonstrated that miR-1323 targeted poly(A)-binding protein nuclear 1 (PABPN1). Besides, PABPN1 recruited insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to regulate glycogen synthase kinase 3 beta (GSK-3ß) and influenced Wnt/ß-catenin signaling pathway. Therefore, rescue experiments were implemented to validate that PABPN1 overexpression rescued the inhibited cancer development and radioresistance induced by the miR-1323 inhibitor. In conclusion, miR-1323 was involved in CCa progression and radioresistance which might provide a novel insight for CCa treatment.

Multifunctional Irrigation-Assisted Vacuum Drainage versus Traditional Drainage in the Treatment of Odontogenic Deep Fascial Infection: A Retrospective Cohort Study.

PURPOSE: Odontogenic deep fascial space infection in the head and neck is a common potentially fatal clinical problem. Traditional drainage method is considered laborious and gravity-dependent. In this study, we aimed to evaluate the clinical effect of a modified multifunctional irrigation-assisted vacuum drainage (MIVD) by comparing it with the traditional drainage method in the treatment of odontogenic deep fascial infection. PATIENTS AND METHODS: Patients diagnosed with odontogenic deep fascial space infection in the Second Affiliated Hospital, Zhejiang University School of Medicine, China between March 2018 and March 2021 were studied. We divided the patients into two groups based on the drainage method they received: patients with the MIVD device were included in the MIVD group, patients with traditional drainage were included in the traditional group. Data were collected retrospectively including baseline characteristics and treatment outcome variables. RESULTS: A total of 65 patients were included. All the patients were eventually cured. There were no significant differences in age, gender, diabetes, end stage renal disease, autoimmune diseases, other systemic diseases, tobacco use, number of the infected spaces, preoperative white blood cell count and C-reactive protein between the two groups. The number and frequency of manual irrigation by clinicians (MIC), time required for white blood cell count to return to normal levels (TWBC), time required for C-reactive protein to return to normal levels (TCRP), the length of hospitalization and the length and total cost of antibiotics use were significantly less in the MIVD group. There was no significant difference in the cost of hospitalization between the 2 groups. CONCLUSION: The MIVD device significantly reduced the number and frequency of MIC, TWBC, TCRP, the length of hospitalization and the length and total cost of antibiotics use in comparison with the traditional drainage method. It provided a favorable treatment method for patients with odontogenic deep fascial space infection in the head and neck.

Statin Exposure and Risk of Heart Failure After Anthracycline- or Trastuzumab-Based Chemotherapy for Early Breast Cancer: A Propensity Score‒Matched Cohort Study.

Background Statins are hypothesized to reduce the risk of cardiotoxicity associated with anthracyclines and trastuzumab. Our aim was to study the association of statin exposure with hospitalization or emergency department visits (hospital presentations) for heart failure (HF) after anthracycline- and/or trastuzumab-containing chemotherapy for early breast cancer. Methods and Results Using linked administrative databases, we conducted a retrospective cohort study of women aged ≥66 years without prior HF who received anthracyclines or trastuzumab for newly diagnosed early breast cancer in Ontario between 2007 to 2017. Statin-exposed and unexposed women were matched 1:1 using propensity scores. Trastuzumab-treated women were also matched on anthracycline exposure. We matched 666 statin-discordant pairs of anthracycline-treated women and 390 pairs of trastuzumab-treated women (median age, 69 and 71 years, respectively). The 5-year cumulative incidence of HF hospital presentations after anthracyclines was 1.2% (95% CI, 0.5%-2.6%) in statin-exposed women and 2.9% (95% CI, 1.7%-4.6%) in unexposed women (P value, 0.01). The cause-specific hazard ratio associated with statins in the anthracycline cohort was 0.45 (95% CI, 0.24-0.85; P value, 0.01). After trastuzumab, the 5-year cumulative incidence of HF hospital presentations was 2.7% (95% CI, 1.2%-5.2%) in statin-exposed women and 3.7% (95% CI, 2.0%-6.2%) in unexposed women (P value 0.09). The cause-specific hazard ratio associated with statins in the trastuzumab cohort was 0.46 (95% CI, 0.20-1.07; P value, 0.07). Conclusions Statin-exposed women had a lower risk of HF hospital presentations after early breast cancer chemotherapy involving anthracyclines, with non-significant trends towards lower risk following trastuzumab. These findings support the development of randomized controlled trials of statins for prevention of cardiotoxicity.

e5NT inhibitor protects acute restraint stress-induced depression by regulating nucleoside release in mice.

OBJECTIVES: To determine whether ecto-5'-nucleotidase (e5NT) contributes to the release of adenosine and uridine and whether is establishes the role of e5NT in acute restraint stress-induced depression and anxiety-like behaviours in mice. METHODS: Acute restraint stress was induced to detect the level of nucleoside in the hippocampus. Mouse hippocampal brain proteins were isolated and subjected to Western blotting (WB) experiments to examine the protein expression levels of proteins that affect nucleoside release. Adenosine 5'-(α,ß-methylene)diphosphate (APCP), an e5NT inhibitor, was intraventricularly injected to investigate the regulatory effect of e5NT on nucleoside levels and behavioural changes caused by acute restraint stress in mice. KEY FINDINGS: Acute restraint stress increased the level of extracellular adenosine and uridine levels in the hippocampus of mice and significantly increased the expression of extracellular nucleoside-metabolizing enzymes were significantly increased. By administering APCP, the increase in adenosine and uridine levels caused by acute restraint stress could be suppressed. APCP inhibited behavioural changes, which were induced by acute restraint stress. CONCLUSIONS: These data suggest that acute restraint stress may alter extracellular adenosine and uridine levels content in the hippocampus of mice via e5NT, and thus, the inhibition of e5NT may improve the anxiety behaviour in mice. Therefore, e5NT may therefore be a potential therapeutic target for the treatment of anxiety in mice.

Fractionation and antioxidant activities of the water-soluble polysaccharides from Lonicera japonica Thunb.

L. japonica has been used as food and healthy beverage due to the good nutrition. Although the chemical compounds have been extensively studied, polysaccharide compositions remain unclear. In this study, water-soluble polysaccharides of L. japonica were fractionated into one neutral fraction (LJP-N) and four acidic fractions (LJP-A-1 ~ LJP-A-4) by a combination of ion-exchange and gel permeation chromatographies. The structures and antioxidant activities of these factions were determined by HPLC, FT-IR and the radical scavenging activities, anti-hemolysis inhibitory ability, protective effect against DNA damage. Results showed that LJP-N was a starch-like glucan with some arabinogalactan; acidic fractions were all pectic polysaccharide, with the average molecular weights approximately ranging from 19.0 to 383.8 kDa. LJP-A-2 ~ LJP-A-4 were similar to each other, mainly composed of GalA (>50%) with some Gal and Ara residues, while LJP-A-1 mainly composed of Gal and Ara (>70%). LJP-A-3 was defined as HG-type pectic polysacchride, with a trace of RG-I domain by NMR experiment. The antioxidant activity of LJP fractions showed different activities, and LJP-A-3 and LJP-A-4 exhibited noticeable antioxidant activities by six kinds of evaluated methods comparable with others. The results indicated that LJP-A-3 and LJP-A-4 could be used as a potential natural source of antioxidant.

Absolute cross sections for chemoradiation therapy: Damages to cisplatin-DNA complexes induced by 10 eV electrons.

In chemoradiation therapy, the synergy between the radiation and the chemotherapeutic agent (CA) can result in a super-additive treatment. A priori, this increased effectiveness could be estimated from model calculations, if absolute cross sections (ACSs) involved in cellular damage are substantially higher, when the CA binds to DNA. We measure ACSs for damages induced by 10 eV electrons, when DNA binds to the CA cisplatin as in chemotherapy. At this energy, DNA is damaged essentially by the decay of core-excited transient anions into bond-breaking channels. Films of cisplatin-DNA complexes of ratio 5:1 with thicknesses 10, 15, and 20 nm were irradiated in vacuum during 5-30 s. Conformation changes were quantified by electrophoresis and yields extrapolated from exposure-response curves. Base damages (BDs) were revealed and quantified by enzymatic treatment. The ACSs were generated from these yields by two mathematical models. For 3197 base-pair plasmid DNA, ACS for single strand breaks, double strand breaks (DSBs), crosslinks, non-DSB cluster damages, and total BDs is 71 ± 2, 9.3 ± 0.4, 10.1 ± 0.3, 8.2 ± 0.3, and 115 ± 2 ×10-15 cm2, respectively. These ACSs are higher than those of nonmodified DNA by factors of 1.6 ± 0.1, 2.2 ± 0.1, 1.3 ± 0.1, 1.3 ± 0.3, and 2.1 ± 0.4, respectively. Since LEEs are produced in large quantities by radiolysis and strongly interact with biomolecules, we expect such enhancements to produce substantial additional damages in the DNA of the nucleus of cancer cells during concomitant chemoradiation therapy. The increase damage appears sufficiently large to justify more elaborate simulations, which could provide a quantitative evaluation of molecular sensitization by Pt-CAs.

Upregulation of long non-coding RNA OGFRP1 facilitates endometrial cancer by regulating miR-124-3p/SIRT1 axis and by activating PI3K/AKT/GSK-3ß pathway.

We planned to investigate the possible influences of long non-coding RNA (opioid growth factor receptor pseudogene 1) OGFRP1 in endometrial cancer and its potential regulatory mechanism. We measured the level of OGFRP1 in endometrial cancer tissues and evaluated the influences of OGFRP1 dysregulation on the tumour cell biological processes of endometrial cancer cells. Further, the regulatory relationships between OGFRP1 and miR-124-3p, between miR-124-3p and Sirtuin1 (SIRT1) were, respectively, investigated. The interaction between OGFRP1 dysregulation and activation of PI3K/AKT/GSK-3ß pathway was revealed by Western blotting. OGFRP1 was up-regulated in endometrial cancer tissues and cells. OGFRP1 suppression inhibited the malignant behaviour (inhibited cell viability, promoted cell apoptosis, and suppressed cell migration and invasion) of the Ishikawa cells via negatively regulating miR-124-3p. SIRT1 was a target gene of miR-124-3p, and miR-124-3p regulated tumour growth and metastasis by the down-stream signal of SIRT1. Moreover, suppression of OGFRP1 restrained the activation of PI3K/AKT/GSK-3ß signals in the Ishikawa cells via miR-124-3p/SIRT1 axis. Our experiments revealed that upregulation of OGFRP1 may enhance the progression of endometrial cancer by regulating miR-124-3p/SIRT1 axis and by activating PI3K/AKT/GSK-3ß pathway. OGFRP1 may be of significance in illustrating the biology of endometrial cancer.

LINC00657 expedites neuropathic pain development by modulating miR-136/ZEB1 axis in a rat model.

Long non-coding RNAs (lncRNAs) are involved in the progression of several diseases. The interactions among lncRNAs, microRNA (miRNAs) or their targeting genes are reported to play crucial roles in the development of diseases. LINC00657 is observed to be upregulated in several cancers. However, the biological role of LINC00657 in neuropathic pain progress is unclear. Hence, in our study, we aimed to investigate the function of LINC00657 in neuropathic pain development. A chronic constriction injury (CCI) rat model was established, and we found that LINC00657 was greatly increased in CCI rats associated with a decrease of miR-136. Inhibition of LINC00657 suppressed neuropathic pain via alleviating mechanical and thermal hyperalgesia. In addition, miR-136 overexpression can also inhibit the neuropathic pain development. MiR-136 was predicted to serve as a miRNA target of LINC00657, and dual-luciferase reporter assay confirmed the correlation between LINC00657 and miR-136. Moreover, we observed that the decrease of LINC00657 was able to inhibit the neuroinflammation of CCI rats by targeting expression of cyclooxygenase-2, tumor necrosis factor-α and interleukin-1ß while miR-136 inhibitors reversed this phenomenon. Next, by using bioinformatics analysis, ZEB1 was predicted as a direct target of miR-136, and miR-136 could negatively modulate ZEB1 expression. Besides these, ZEB1 was remarkably increased in the CCI rats. Knockdown of ZEB1 can inhibit neuropathic pain development, while miR-136 inhibitors can reverse it. In conclusion, it was implied that LINC00657 can induce the neuropathic pain development via regulating miR-136/ZEB1 axis.

Including the Ductal Carcinoma-In-Situ (DCIS) Score in the Development of a Multivariable Prediction Model for Recurrence After Excision of DCIS.

INTRODUCTION: Individual prediction of local recurrence (LR) risk after breast-conserving surgery (BCS) for ductal carcinoma-in-situ (DCIS) is needed to identify women at low risk, for whom radiotherapy may be omitted. PATIENTS AND METHODS: Three predictive models of LR-clinicopathologic factors (CPF) alone; CPF + estrogen receptor (ER) + human epidermal growth factor receptor 2 (HER2); and CPF + DCIS score (DS)-were developed among 1102 cases of DCIS in patients with complete covariate and outcome data. Categorizations of discrete variables and transformations of continuous variables were examined in Cox models; 2-way interactions and interactions with time were assessed. Internal validation was performed by bootstrapping. Individual predicted 10-year LR risks were computed from covariate values, estimated regression parameters, and estimated baseline survival function. Accuracy was assessed by c statistics and calibration plots. RESULTS: The strongest prediction model incorporated CPF + DS. The c statistics for CPF + DS, CPF + ER + HER2, or CPF-alone models were 0.7025, 0.6879, and 0.6825, respectively. The CPF + DS model was better calibrated at predicting low (≤ 10%) individual 10-year LR risks after BCS alone than those incorporating CPF + ER + HER2 or CPF alone, evidenced by c statistics and plots of observed by predicted risks. Among women aged ≥ 50 with no adverse CPF, the CPF + DS model identified the greatest proportion of women (62.3%) with predicted individual 10-year LR ≤ 10% without radiotherapy compared to the CPF + ER + HER2 (50.9%) or CPF alone (46.5%) models. CONCLUSION: Individual prediction of LR incorporating DS is more accurate and identifies a higher proportion of women with low predicted risk of LR after BCS alone, for whom radiotherapy may be omitted.

Identification of CD28 and PTEN as novel prognostic markers for cervical cancer.

Cervical cancer (CC) is the most common malignant tumor with poor clinical outcome among women. Identification of novel biomarkers could be beneficial for the clinical diagnosis and treatment of CC. This study aimed to identify prognostic biomarkers for the prediction of prognostic status of CC patients, and explore the effect of the corresponding methylated genes in the occurrence and development of CC. The methylation microarray data of CC was extracted from The Cancer Genome Atlas (TCGA) dataset. The methylation genes associated with the prognostic status were identified based on the information of the relapse-free survival (RFS) of the CC patients. The prognostic gene pairs were further identified. Then, the prognostic signature was identified by the forward search algorithm based on the C-index method. The results were validated by independent dataset. Finally, the functional analysis was performed on the methylation genes. A total of 276 methylation genes and 2508 gene pairs associated with the prognostic status of the CC were identified. A signature composed of eight methylation gene pairs was obtained to predict the prognostic status of cervical patients. A series of genes that played an important role in the occurrence and development of CC were obtained by the functional enrichment analysis. To summary, a prognostic signature consisting of eight methylation gene pairs was obtained. Of note, the CD28 and PTEN gene pair were found to play important roles in the occurrence and development of CC.

Overexpression of MALAT1 contributes to cervical cancer progression by acting as a sponge of miR-429.

Cervical cancer remains a malignant type of tumor and is the fourth leading cause of cancer-related death among females. MALAT1 has been identified as a tumor oncogene in various cancers. Our present study aimed to explore the biological role of MALAT1 in cervical cancer. We observed that MALAT1 was significantly upregulated in human cervical cancer cell lines compared with the ectocervical epithelial cells. MALAT1 was repressed by transfection with LV-shMALAT1, whereas increased by LV-MALAT1 in HeLa and Caski cells. Silencing of MALAT1 obviously reduced cervical cell viability, induced cell apoptosis, and repressed cell invasion capacity. Conversely, overexpression of MALAT1 exhibited an opposite phenomenon. Furthermore, miR-429 was predicted as a direct target of MALAT1, and it was dramatically decreased in cervical cancer cells. It has been shown that miR-429 plays a crucial role in cervical cancer progression. In our current study, the targeting correlation between MALAT1 and miR-429 was confirmed by luciferase reporter assays and RIP experiments. Finally, in vivo animal models were established, and we indicated that MALAT1 inhibited cervical cancer progression via targeting miR-429. These findings revealed that MALAT1 can sponge miR-429 and regulate cervical cancer pathogenesis in vivo and in vitro. In conclusion, we indicated that the MALAT1/miR-429 axis was involved in cervical cancer development.

Molecular efficacy of radio- and chemotherapy sequences from direct DNA damage measurements.

PURPOSE: To investigate the molecular aspects of the synergy between ionizing radiation and platinum (Pt) chemotherapeutic agents in cancer treatment with chemoradiation therapy (CRT) by measuring damages induced by low-energy electrons (LEE) to DNA bound to cisplatin. LEE are produced abundantly by any type of ionizing radiation and cisplatin represents a typical Pt-chemotherapeutic agents. MATERIALS AND METHODS: Our strategy involves two parallel administrations of cisplatin and irradiation with a 4.6 and 9.6 eV electron fluence of 1.1 × 1012: (1) LEE bombardment of supercoiled DNA and its subsequent reaction with cisplatin; (2) the reaction of DNA with cisplatin followed by LEE irradiation. The damage yields for the loss of supercoiled (LS), single-strand breaks (SSB) and double-strand breaks (DSB) were obtained from gel electrophoresis analysis. Base modifications were revealed by treating the samples with Escherichia coli base excision repair endonuclease (Nth and Fpg). RESULTS: The yields were deduced from the respective time-response for the reaction of DNA with cisplatin. The results show that binding cisplatin to DNA followed by LEE irradiation, consistently yields more DNA damages than the reverse order. In comparison to non-treated DNA, administration (2) results in an increase of LS and SSB of 1.4-3.3 folds and of DSB by more than an order of magnitude. Furthermore, after enzyme treatment, the yields of DSB rise by factors of 5.3-15.4, indicating a large increase of clustered damages, which should at least partially translate into an increase of lethal damages in cancer cells during the CRT. CONCLUSIONS: Our results demonstrate that a strong synergy between radiation and cisplatin can only be achieved at the molecular level, if the drug is present at the time of irradiation. Furthermore, this work confirms the LEE mechanism previously proposed to explain the synergy between radiation and Pt drugs in CRT. It involves chemical sensitization of DNA prior to irradiation, to facilitate strand breaks and clustered damages induced by the highly reactive LEE.

Has-miR-30a regulates autophagic activity in cervical cancer upon hydroxycamptothecin exposure.

Cervical cancer is a leading cause of morbidity and mortality in women worldwide. Hydroxycamptothecin (HCPT) represents a new generation of antitumor agents targeting DNA topoisomerase I, which has been applied to treat various cancers with fewer side effects. Autophagy is emerging as an important biological mechanism in targeting human cancers, including cervical cancer. In this study, We have reported that HCPT could induce autophagy in Hela cells. Our investigation of the underlying mechanisms revealed that the decreased expression of miR-30a is involved in HCPT-induced autophagy. Futhermore, we showed that miR-30a could directly target a specific fragment in the 3' untranslated region of Beclin-1 as demonstrated by luciferase assay and overexpression of hsa-miR-30a by transfecting with miR-30a mimic could block HCPT-induced autophagic activity. It is the first time provide a deeper understanding of the mechanisms underlying cellular and molecular mechanisms by which HCPT affect cervical cancer.

Pulmonary embolism in ischemic stroke: clinical presentation, risk factors, and outcome.

BACKGROUND: Limited information is available on the frequency of pulmonary embolism (PE) in patients with an acute ischemic stroke (AIS). We evaluated clinical characteristics, predisposing factors, and outcomes in AIS patients with PE. METHODS AND RESULTS: We included all AIS patients admitted to participating institutions in the Registry of the Canadian Stroke Network. Clinically PE was documented by a physician and confirmed by computed tomography pulmonary angiography within 30 days of the stroke case index. The primary outcome was death or disability at discharge. Secondary outcomes included disposition, length of hospital stay, mortality at 3 months and 1 year. Among 11 287 patients with AIS, PE was found in 89 (0.78%) patients. History of cancer, deep vein thrombosis (DVT)/PE, and DVT during the hospitalization were associated with PE. PE was associated with higher risk of death at 30 days (25.8% versus 13.6%; P<0.001), at 1 year (47.2% versus 24.6%; P<0.001), and disability at discharge (85.4% versus 63.6%; P<0.001). Mean length of stay was longer in stroke patients with PE (36 versus 16 days; P=0.001). After adjusting for age, sex, and stroke severity, PE remained associated with lower survival at 30 days and 1 year, and death or disability at discharge (OR 3.02; 95% CI 1.56 to 5.83). CONCLUSIONS: In this large cohort study, PE occurred in nearly 1% of AIS patients. PE was more common in patients with severe stroke, history of cancer, previous DVT/PE or acute DVT and associated with lower short- and long-term survival, greater disability, and longer length of stay.