Cardiac Dose Predicts the Response to Concurrent Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.

Definitive concurrent chemoradiation (CCRT) is the standard treatment for cervical esophageal cancer and non-surgical candidates. Initial treatment response affects survival; however, few validated markers are available for prediction. This study evaluated the clinical variables and chemoradiation parameters associated with treatment response. Between May 2010 and April 2016, 86 completed CCRT patients' clinical, dosimetric, and laboratory data at baseline and during treatment were collected. Cox regression analysis assessed the risk factors for overall survival (OS). A receiver operating characteristic curve with Youden's index was chosen to obtain the optimal cut-off value of each parameter. Treatment response was defined per Response Evaluation Criteria in Solid Tumors v.1.1 at the first post-CCRT computed tomography scan. Responders had complete and partial responses; non-responders had stable and progressive diseases. Logistic regression (LR) was used to evaluate the variables associated with responders. The Cox regression model confirmed the presence of responders (n = 50) vs. non-responders (n = 36) with a significant difference in OS. In multivariate LR, cardiac dose-volume received ≥10 Gy; the baseline hemoglobin level, highest neutrophil to lymphocyte ratio during CCRT, and cumulative cisplatin dose were significantly associated with the responders. The initial clinical treatment response significantly determines disease outcome. Cardiac irradiation may affect the treatment response.

Influence of local scale and oceanic teleconnections on regional fire danger and wildfire trends.

Studies and observations have pointed out that recent wildfires have been more severe and burned area is increasing in tropical regions. The current study aims at investigating the influence of oceanic climate modes and their teleconnection on global fire danger and trends in the 1980-2020 interval. Disentangling these trends demonstrates that across the extratropics they are primarily related to increases in temperature, whereas in the tropics changes in short-term precipitation distribution dominates the trends. Moreover, the environmental impact of short-term precipitation is dependent on local vegetation type and tightly related to oceanic temperatures far from the burned areas. Indeed, in the 2001-2020 period, a warmer tropical North Atlantic was associated with more fires in the Amazon and Africa, whereas ENSO has weakened the fire activity in equatorial Africa. The remarkable impact of oceanic modes of climate variability in inducing environmental conditions conducive to fires, has particular relevance for the seasonal spatiotemporal wildfire forecasts. Although local aspects are crucial for fire management, long-term predictions should take into account the behavior of potential climate drivers located far from the region of interest. Such teleconnections can be identified ahead of local weather anomalies.

Conformational alteration in glycan induces phospholipase Cß1 activation and angiogenesis.

BACKGROUND: In endothelial cells, phospholipase C (PLC) ß1-activated Ca2+ is a crucial second messenger for the signaling pathways governing angiogenesis. PLCß1 is inactivated by complexing with an intracellular protein called translin-associated factor X (TRAX). This study demonstrates specific interactions between Globo H ceramide (GHCer) and TRAX, which highlight a new angiogenic control through PLCß1 activation. METHODS: Globo-series glycosphingolipids (GSLs), including GHCer and stage-specific embryonic antigen-3 ceramide (SSEA3Cer), were analyzed using enzyme-linked immunosorbent assay (ELISA) and Biacore for their binding with TRAX. Angiogenic activities of GSLs in human umbilical vein endothelial cells (HUVECs) were evaluated. Molecular dynamics (MD) simulation was used to study conformations of GSLs and their molecular interactions with TRAX. Fluorescence resonance energy transfer (FRET) analysis of HUVECs by confocal microscopy was used to validate the release of PLCß1 from TRAX. Furthermore, the in vivo angiogenic activity of extracellular vesicles (EVs) containing GHCer was confirmed using subcutaneous Matrigel plug assay in mice. RESULTS: The results of ELISA and Biacore analysis showed a stable complex between recombinant TRAX and synthetic GHCer with KD of 40.9 nM. In contrast, SSEA3Cer lacking a fucose residue of GHCer at the terminal showed ~ 1000-fold decrease in the binding affinity. These results were consistent with their angiogenic activities in HUVECs. The MD simulation indicated that TRAX interacted with the glycan moiety of GHCer at amino acid Q223, Q219, L142, S141, and E216. At equilibrium the stable complex maintained 4.6 ± 1.3 H-bonds. TRAX containing double mutations with Q223A and Q219A lost its ability to interact with GHCer in both MD simulation and Biacore assays. Removal of the terminal fucose from GHCer to become SSEA3Cer resulted in decreased H-bonding to 1.2 ± 1.0 by the MD simulation. Such specific H-bonding was due to the conformational alteration in the whole glycan which was affected by the presence or absence of the fucose moiety. In addition, ELISA, Biacore, and in-cell FRET assays confirmed the competition between GHCer and PLCß1 for binding to TRAX. Furthermore, the Matrigel plug assay showed robust vessel formation in the plug containing tumor-secreted EVs or synthetic GHCer, but not in the plug with SSEA3Cer. The FRET analysis also indicated the disruption of colocalization of TRAX and PLCß1 in cells by GHCer derived from EVs. CONCLUSIONS: Overall, the fucose residue in GHCer dictated the glycan conformation for its complexing with TRAX to release TRAX-sequestered PLCß1, leading to Ca2+ mobilization in endothelial cells and enhancing angiogenesis in tumor microenvironments.

Using radial pulse wave as hemodynamic measurements to quantify effects of acupuncture therapy for patients with traumatic brain injury and ischemia stroke.

Background and aim: Traumatic Brain Injury (TBI) and stroke are major sources of death and disability worldwide. Acupuncture has been used as a supplemental therapy for patients with TBI and stroke. This study was aimed to evaluate the effects of acupuncture therapy for patients with TBI and stroke by radial pulse spectrum. Experimental procedure: 22 patients (6 TBI and 16 stroke) were enrolled and underwent radial pressure wave measurement before and after acupuncture treatment at Dubi (ST-35), Zusanli (ST-36) and Jiexi (ST-41). The harmonic analysis of the radial pressure wave was calculated and transformed into Fourier series coefficients Cn, Pn and the variation coefficient CnCV. Results: After acupuncture, systolic blood pressure, heart rate, and Glasgow Coma Scale changed very slightly. The harmonic index C4, C7, C9, C10, C3CV and C5CV had significant increases. (P < 0.05) After 3-week course acupuncture treatment, systolic blood pressure, C7, C8, C9, C10 and P10 had significant increases. (P < 0.05). Conclusion: Harmonic analysis of radial pulse waves may detect earlier circulatory system changes of acupuncture treatment before they were evident with other hemodynamic readings or scale.

A non-invasive harmonic analysis to assess risk of retinopathy in type 2 diabetes mellitus.

AIMS: Assessing the hemodynamic changes of diabetic retinopathy (DR) using harmonic analysis of both non-invasively measured radial pulse and photoplethysmography (PPG) signals to propose a DR risk indicator. METHODS: A total of 1879 patients with diabetes were followed on average of 3.5 years. The radial pulse and PPG signals were measured at the beginning of the trial. Kaplan-Meier curves of the DR risk indicator was analyzed. In addition, the correlation between the measurements of the radial pulse and PPG was evaluated. RESULTS: In comparison of the patients' clinical characteristics, years of diabetes, systolic blood pressure, HbA1C, ACR, urinary albumin and fourth harmonic (C4) were higher in the DR group, and eGFR and third harmonic (C3) were lower. Patients in the high-DR risk group had a 1.8-fold higher risk of developing retinopathy than those in the low-risk group (log-rank test, p < 0.001). The correlation coefficient between radial pulse and PPG measurements for C3 and C4 were 0.727 and 0.628, respectively. CONCLUSIONS: The harmonic analysis of radial pulse and PPG signals may be used to reflect the effect of DR in hemodynamics and the derived harmonic components may predict the risk of DR of patients with type 2 diabetes.

Loss of core-fucosylation of SPARC impairs collagen binding and contributes to COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with high morbidity and mortality worldwide. Although several mechanisms to account for deleterious immune effects were proposed, molecular description for the underlying alveolar structural alterations for COPD is lacking. Here, silencing of α1,6-fucosyltransferase (Fut8), the enzyme for core-fucosylation and highly expressed in lung stem cells, resulted in alveolar structural changes in lung organoids, recapitulating COPD. Site-specific mass spectrometry analysis demonstrated that the secreted protein acidic and rich in cysteine (SPARC), which binds collagen, contains a core-fucosylation site in its VCSNDNcfK glycopeptide. Biacore assay showed markedly reduced collagen binding of SPARC lacking core fucosylation. Molecular dynamics analysis revealed that core fucosylation of SPARC-induced dynamic conformational changes in its N-glycan, allowing terminal galactose and N-acetylglucosamine to interact with K150, P261 and H264 residues, thereby promoting collagen binding. Site-specific mutagenesis of these residues also resulted in low affinity for collagen binding. Moreover, loss of collagen and decline of core fucosylation were observed in COPD lung tissues. These findings provide a new mechanistic insight into the role of core fucosylation of SPARC in cell-matrix communication and contribution to the abnormal alveolar structures in COPD.

Puf-A promotes cancer progression by interacting with nucleophosmin in nucleolus.

Previously, we identified Puf-A as a novel member of Puf-family RNA-binding proteins; however, its biological functions remain obscure. Analysis of tumor samples of non-small cell lung cancer (NSCLC) showed that high Puf-A expression correlated with high histology grade and abnormal p53 status. Kaplan-Meier curve for overall survival revealed high expression of Puf-A to predict poor prognosis in stage I NSCLC. Among patients with colorectal cancer, high Puf-A expression also showed an adverse impact on overall survival. In lung cancer cell lines, downregulation of p53 increased Puf-A expression, and upregulation of p53 dampened its expression. However, luciferase reporter assays indicated that PUF-A locus harbored the p53-response element, but regulated Puf-A transcription indirectly. In vivo suppression of p53 in CCSP-rtTA/TetO-Cre/LSL-KrasG12D/p53flox/flox conditional mutant mice accelerated the progression of the KrasG12D-driven lung cancer, along with enhanced expression of Puf-A. Importantly, intranasal delivery of shPuf-A to the inducible KrasG12D/p53flox/flox mice suppressed tumor progression. Puf-A silencing led to marked decreases in the 80S ribosomes, along with decrease in S6 and L5 in the cytoplasm and accumulation in the nucleolus. Based on immunofluorescence staining and immunoprecipitation studies, Puf-A interacted with NPM1 in nucleolus. Puf-A silencing resulted in NPM1 translocation from nucleolus to nucleoplasm and this disruption of NPM1 localization was reversed by a rescue experiment. Mechanistically, Puf-A silencing altered NPM1 localization, leading to the retention of ribosomal proteins in nucleolus and diminished ribosome biogenesis, followed by cell-cycle arrest/cell death. Puf-A is a potential theranostic target for cancer therapy and an important player in cancer progression.

Non-Invasive radial pressure wave analysis may digitally predict women's risks of type 2 diabetes (T2DM): A case and control group study.

BACKGROUND: Women not only have worse diabetes complications, but also have menstrual cycle, pregnancy, and menopause which can make managing diabetes more difficult. The aim of this study was to investigate if radial pressure wave analysis may non-invasively screen for women's risk of type 2 diabetes. METHODS: Spectrum analysis of the radial pressure wave was performed to evaluate the first five harmonic components, C1 to C5. The study consisted of a total of 808 non-pregnant female subjects aged 20-95 over the period of 4 years, and 404 of them were diagnosed with Type 2 diabetes as the case group. RESULT: The first five harmonic components are significantly different in a comparison of the case group and the control group. In the logistic regression analysis, T2DM was found to be associated with C1 (OR = 1.055, CI = 1.037-1.074, p < 0.001), C2 (OR = 1.051, CI = 1.019-1.085, p = 0.002), and C3 (OR = 0.972, CI = 0.950-0.994, p = 0.013). In the Receiver Operating Characteristic curve analysis, the Area Under Curve of using C3 only (70%, p <0.05), weighted C1, C2 and C3, (75%, p < 0.05), and weighted C1, C2 and C3 and Body mass Index (84%, p <0.05) were tested for the accuracy on how well these tests separate the women into the groups with and without the T2DM. CONCLUSION: We thus concluded that pulse spectrum was a non-invasive predictor for women's risk of T2DM.

Noninvasively measured radial pressure wave analysis provides insight into cardiovascular changes during pregnancy and menopause.

OBJECTIVE: Pregnancy and menopause are significant life events associated with major changes in female hormone levels and changes in cardiovascular health. The role of estrogen in influencing cardiovascular risk is an ongoing research topic. Many studies have provided evidence that radial pressure wave characteristics are an important indicator to consistently and independently predict cardiovascular events. The aim of this study was to investigate if radial pressure wave analysis provided statistical insights into the physiological variations due to pregnancy and menopause. Furthermore, the study investigated how these variations could serve as an indicator for cardiovascular risks. As the radial pulse measurement is non-invasive and speedy, it may be helpful in evaluating cardiovascular changes and risk during these transitions. MATERIALS AND METHOD: A total of 702 randomly selected female subjects (90 pregnant and 97 post-menopausal), aged 20-59, enrolled in the study. The visit measured the subject's hemodynamic parameters including heart rate, systolic blood pressure (SBP), diastolic blood pressure (DBP) and radial pressure waves. SBP and DBP were evaluated by an automatic blood pressure monitor. Radial pressure wave data were continuously recorded for 12-s using a TD01C pulse measuring instrument. Spectrum analysis of the radial pressure wave was performed to evaluate the first five harmonic components (C1-C5). RESULTS: A comparison of pregnant women to non-pregnant women showed C3 and C5 were lower. Heart rate C2 and C4 were higher in pregnant women. A comparison of women pre-menopausal and post-menopausal showed no significant difference in SBP or DBP. Menopause significantly changed the C1 and C4 radial pressure wave harmonics. An increase in C1 and a decrease in C4 were observed. CONCLUSION AND DISCUSSION: This study provided further clinical evidence to support the hemodynamic model that describes the cardiovascular changes and risks related to the harmonic components of the pulse spectrum. Beyond blood pressure, the effects of menopause on the radial pressure wave, especially on hemodynamic index C4, independent of age and BMI, may explain increased post-menopausal cardiovascular risk. This and past studies collectively suggest that radial pressure wave components may be an indicator of a female body's ability to supply oxygen and nutrients. Harmonic analysis of the radial pressure wave may provide additional insights into the underlying mechanism of the cardiovascular changes over the lifespan of a woman.

Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT activation.

Cancer stem cells (CSC) play a pivotal role in cancer metastasis and resistance to therapy. Previously, we compared the phosphoproteomes of breast cancer stem cells (BCSCs) enriched subpopulation and non-BCSCs sorted from breast cancer patient-derived xenograft (PDX), and identified a function unknown protein, transmembrane and coiled-coil domain family 3 (TMCC3) to be a potential enrichment marker for BCSCs. We demonstrated greater expression of TMCC3 in BCSCs than non-BCSCs and higher expression of TMCC3 in metastatic lymph nodes and lungs than in primary tumor of breast cancer PDXs. TMCC3 silencing suppressed mammosphere formation, ALDH activity and cell migration in vitro, along with reduced tumorigenicity and metastasis in vivo. Mechanistically, we found that AKT activation was reduced by TMCC3 silencing, but enhanced by TMCC3 overexpression. We further demonstrated that TMCC3 interacted directly with AKT through its 1-153 a.a. domain by cell-free biochemical assay in vitro and co-immunoprecipitation and interaction domain mapping assays in vivo. Based on domain truncation studies, we showed that the AKT-interacting domain of TMCC3 was essential for TMCC3-induced AKT activation, self-renewal, and metastasis. Clinically, TMCC3 mRNA expression in 202 breast cancer specimens as determined by qRT-PCR assay showed that higher TMCC3 expression correlated with poorer clinical outcome of breast cancer, including early-stage breast cancer. Multivariable analysis identified TMCC3 expression as an independent risk factor for survival. These findings suggest that TMCC3 is crucial for maintenance of BCSCs features through AKT regulation, and TMCC3 expression has independent prognostic significance in breast cancer. Thus, TMCC3 may serve as a new target for therapy directed against CSCs.

Low cardiac dose and neutrophil-to-lymphocyte ratio predict overall survival in inoperable esophageal squamous cell cancer patients after chemoradiotherapy.

We aimed to determine the prognostic significance of cardiac dose and hematological immunity parameters in esophageal cancer patients after concurrent chemoradiotherapy (CCRT). During 2010-2015, we identified 101 newly diagnosed esophageal squamous cell cancer patients who had completed definitive CCRT. Patients' clinical, dosimetric, and hematological data, including absolute neutrophil count, absolute lymphocyte count, and neutrophil-to-lymphocyte ratio (NLR), at baseline, during, and post-CCRT were analyzed. Cox proportional hazards were calculated to identify potential risk factors for overall survival (OS). Median OS was 13 months (95% confidence interval [CI]: 10.38-15.63). Univariate analysis revealed that male sex, poor performance status, advanced nodal stage, higher percentage of heart receiving 10 Gy (heart V10), and higher NLR (baseline and follow-up) were significantly associated with worse OS. In multivariate analysis, performance status (ECOG 0 & 1 vs. 2; hazard ratio [HR] 3.12, 95% CI 1.30-7.48), heart V10 (> 84% vs. ≤ 84%; HR 2.24, 95% CI 1.26-3.95), baseline NLR (> 3.56 vs. ≤ 3.56; HR 2.36, 95% CI 1.39-4.00), and follow-up NLR (> 7.4 vs. ≤ 7.4; HR 1.95, 95% CI 1.12-3.41) correlated with worse OS. Volume of low cardiac dose and NLR (baseline and follow-up) were associated with worse patient survival.

Yulink, predicted from evolutionary analysis, is involved in cardiac function.

BACKGROUND: The comparative evolutionary genomics analysis was used to study the functions of novel Ka/Ks-predicted human exons in a zebrafish model. The Yulink (MIOS, Entrez Gene: 54,468), a conserved gene from zebrafish to human with WD40 repeats at N-terminus, was identified and found to encode an 875 amino acid in human. The biological function of this Yulink gene in cardiomyocytes remains unexplored. The purpose of this study is to determine the involvement of Yulink in the functions of cardiomyocytes and to investigate its molecular regulatory mechanism. METHODS: Knockdown of Yulink was performed using morpholino or shRNA in zebrafish, mouse HL-1 cardiomyocytes, and human iPSC-derived cardiomyocytes. The expression levels of mRNA and protein were quantified by qPCR and western blots. Other methods including DNA binding, ligand uptake, agonists treatment and Ca2+ imaging assays were used to study the molecular regulatory mechanism by Yulink. Statistical data were shown as mean ± SD or mean ± standard error. RESULTS: The knockdown of yulink with three specific morpholinos in zebrafish resulted in cardiac dysfunctions with pericardial edema, decreased heart beats and cardiac output. The Yulink knockdown in mouse HL-1 cardiomyocytes disrupted Ca2+ cycling, reduced DNA binding activity of PPARγ (peroxisome proliferator-activated receptor gamma) and resulted in a reduction of Serca2 (sarcoplasmic reticulum Ca2+ ATPase 2) expression. Expression of Serca2 was up-regulated by PPARγ agonists and down-regulated by PPARγ-shRNA knockdown, suggesting that Yulink regulates SERCA2 expression through PPARγ in mouse HL-1 cardiomyocytes. On the other hand, YULINK, PPARγ or SERCA2 over-expression rescued the phenotypes of Yulink KD cells. In addition, knockdown of YULINK in human iPSC-derived cardiomyocytes also disrupted Ca2+ cycling via decreased SERCA2 expression. CONCLUSIONS: Overall, our data showed that Yulink is an evolutionarily conserved gene from zebrafish to human. Mechanistically Yulink regulated Serca2 expression in cardiomyocytes, presumably mediated through PPARγ nuclear entry. Deficiency of Yulink in mouse and human cardiomyocytes resulted in irregular Ca2+ cycling, which may contribute to arrhythmogenesis.

Sialylation of CD55 by ST3GAL1 Facilitates Immune Evasion in Cancer.

Altered glycosylations, which are associated with expression and activities of glycosyltransferases, can dramatically affect the function of glycoproteins and modify the behavior of tumor cells. ST3GAL1 is a sialyltransferase that adds sialic acid to core 1 glycans, thereby terminating glycan chain extension. In breast carcinomas, overexpression of ST3GAL1 promotes tumorigenesis and correlates with increased tumor grade. In pursuing the role of ST3GAL1 in breast cancer using ST3GAL1-siRNA to knockdown ST3GAL1, we identified CD55 to be one of the potential target proteins of ST3GAL1. CD55 is an important complement regulatory protein, preventing cells from complement-mediated cytotoxicity. CD55 had one N-linked glycosylation site in addition to a Ser/Thr-rich domain, which was expected to be heavily O-glycosylated. Detailed analyses of N- and O-linked oligosaccharides of CD55 released from scramble or ST3GAL1 siRNA-treated breast cancer cells by tandem mass spectrometry revealed that the N-glycan profile was not affected by ST3GAL1 silencing. The O-glycan profile of CD55 demonstrated a shift in abundance to nonsialylated core 1 and monosialylated core 2 at the expense of the disialylated core 2 structure after ST3GAL1 silencing. We also demonstrated that O-linked desialylation of CD55 by ST3GAL1 silencing resulted in increased C3 deposition and complement-mediated lysis of breast cancer cells and enhanced sensitivity to antibody-dependent cell-mediated cytotoxicity. These data demonstrated that ST3GAL1-mediated O-linked sialylation of CD55 acts like an immune checkpoint molecule for cancer cells to evade immune attack and that inhibition of ST3GAL1 is a potential strategy to block CD55-mediated immune evasion.

Dissecting the conformation of glycans and their interactions with proteins.

The use of in silico strategies to develop the structural basis for a rational optimization of glycan-protein interactions remains a great challenge. This problem derives, in part, from the lack of technologies to quantitatively and qualitatively assess the complex assembling between a glycan and the targeted protein molecule. Since there is an unmet need for developing new sugar-targeted therapeutics, many investigators are searching for technology platforms to elucidate various types of molecular interactions within glycan-protein complexes and aid in the development of glycan-targeted therapies. Here we discuss three important technology platforms commonly used in the assessment of the complex assembly of glycosylated biomolecules, such as glycoproteins or glycosphingolipids: Biacore analysis, molecular docking, and molecular dynamics simulations. We will also discuss the structural investigation of glycosylated biomolecules, including conformational changes of glycans and their impact on molecular interactions within the glycan-protein complex. For glycoproteins, secreted protein acidic and rich in cysteine (SPARC), which is associated with various lung disorders, such as chronic obstructive pulmonary disease (COPD) and lung cancer, will be taken as an example showing that the core fucosylation of N-glycan in SPARC regulates protein-binding affinity with extracellular matrix collagen. For glycosphingolipids (GSLs), Globo H ceramide, an important tumor-associated GSL which is being actively investigated as a target for new cancer immunotherapies, will be used to demonstrate how glycan structure plays a significant role in enhancing angiogenesis in tumor microenvironments.

Targeting glycosphingolipids for cancer immunotherapy.

Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor progression remains largely unclear, anticancer immunotherapies directed against GSLs are attracting growing attention. Here, we focus on GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and Globo H ceramide (GHCer), the most prevalent cancer-associated GSL overexpressed in a variety of epithelial cancers. We first summarize recent advances on our understanding of GD2 and GHCer biology and then discuss the clinical development of the first immunotherapeutic agent targeting a glycolipid, the GD2-specific antibody dinutuximab, its approved indications, and new strategies to improve its efficacy for neuroblastoma. Next, we review ongoing clinical trials on Globo H-targeted immunotherapeutics. We end with highlighting how these studies provide sound scientific rationales for targeting GSLs in cancer and may facilitate a rational design of new GSL-targeted anticancer therapeutics.

Risk assessment of macrovascular and microvascular events in patients with type 2 diabetes by analyzing the amplitude variation of the fourth harmonic component of radial pulse wave.

This investigation explored the hypothesis that whether the coefficient of variation of the fourth harmonic amplitude of the radial pulse wave (C4CV) predicts the risk of macrovascular and microvascular events in patients with type 2 diabetes mellitus (T2DM). Radial pulse wave and brachial blood pressure were measured at baseline in 2324 patients with T2DM and C4CV was calculated using the Fourier series method. Macrovascular and microvascular events during follow-up were determined by medical records. We plotted the Kaplan-Meier curve and performed a Cox proportional hazard model and a log-rank test to estimate the effectiveness of C4CV as a risk predictor. We divided patients into quartile groups based on C4CV (<4.3%, 4.3% to 6.8%, 6.8% to 11.4%, and >11.4%). Compared with patients with C4CV < 4.3%, patients with C4CV> 11.4% had a double incidence of macrovascular events (hazard ratio, 2.13; 95% CI, 1.70-2.67) and microvascular events (hazard ratio, 2.08; 95% CI, 1.67-2.58), and the incidence of cardiovascular death was three times (hazard ratio, 3.03; 95% CI, 1.10-8.83). The Cox regression analysis demonstrated that the risk of both macrovascular and microvascular outcomes increases with the increase in quartile level of C4CV value (P < 0.0001). These associations remained after adjustment for age, gender, smoking, systolic blood pressure, diastolic blood pressure, dyslipidemia, diabetes duration, Hba1c, and cardiovascular disease (P < 0.0001). C4CV is a novel independent predictor of cardiovascular mortality, macrovascular events, and microvascular events in patients with T2DM.

The first harmonic of radial pulse wave predicts major adverse cardiovascular and microvascular events in patients with type 2 diabetes.

This brief report take a further look on the first harmonic of radial pulse wave (C1) after the 1.8 ±â€¯0.5 years follow-up and demonstrated that the quartile level of C1 independently predicts the risk of cardiovascular death, major adverse cardiovascular events, and microvascular outcomes in 2324 patients with type 2 diabetes.

FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding.

BACKGROUND: The transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2 has been considered as a key pharmacological target. Unfortunately, there are no specific Nrf2 inhibitors for therapeutic application. Moreover, high Nrf2 activity in many tumors without Keap1 or Nrf2 mutations suggests that alternative mechanisms of Nrf2 regulation exist. METHODS: Interaction of FAM129B with Keap1 is demonstrated by immunofluorescence, colocalization, co-immunoprecipitation and mammalian two-hybrid assay. Antioxidative function of FAM129B is analyzed by measuring ROS levels with DCF/flow cytometry, Nrf2 activation using luciferase reporter assay and determination of downstream gene expression by qPCR and wester blotting. Impact of FAM129B on in vivo chemosensitivity is examined in mice bearing breast and colon cancer xenografts. The clinical relevance of FAM129B is assessed by qPCR in breast cancer samples and data mining of publicly available databases. FINDINGS: We have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer. INTERPRETATION: These findings demonstrate the important role of FAM129B in Nrf2 activation and antioxidative response, and identify FMA129B as a potential therapeutic target. FUND: The Chang Gung Medical Foundation (Taiwan) and the Ministry of Science and Technology (Taiwan).

Fourth harmonic of radial pulse wave predicts adverse cardiac events in asymptomatic patients with type 2 diabetes.

AIMS: Studies have shown that the fourth harmonic of the radial pulse wave (C4) is associated with atherosclerotic processes and myocardial ischemia. We sought to investigate whether C4 is an independent predictor of adverse cardiac events (ACE). METHODS: The baseline C4 is calculated using the Fourier series method. 1968 asymptomatic patients with type 2 diabetes were followed up for 1.8 ±â€¯0.4 years and survival analysis were performed using Cox proportional hazard model. RESULTS: The Cox regression analysis showed that the C4 value is independent and inversely related to ACE both before and after adjusting for age, sex, smoke, systolic blood pressure, dyslipidemia, and Hba1c. (P for trend < 0.001) CONCLUSIONS: Decreasing C4 is associated with an increased risk of ACE in asymptomatic patients with type 2 diabetes.