Luteolin (LUT) Induces Apoptosis and Regulates Mitochondrial Membrane Potential to Inhibit Cell Growth in Human Cervical Epidermoid Carcinoma Cells (Ca Ski).

Background/Objectives: Luteolin (LUT) is a natural flavonoid with known anti-inflammatory, antioxidant, and anti-cancer properties. Cervical cancer, particularly prevalent in certain regions, remains a significant health challenge due to its high recurrence and poor response to treatment. This study aimed to investigate the anti-tumor effects of LUT on human cervical epidermoid carcinoma cells (Ca Ski), focusing on cell growth inhibition, apoptosis induction, and regulation of mitochondrial membrane potential. Methods: Ca Ski cells were treated with varying concentrations of LUT (0, 25, 50, 100 µM) for different time periods (24, 48, 72 hours). Cell viability was measured using the MTT assay, apoptosis was assessed by flow cytometry with annexin V-FITC/PI staining, and changes in mitochondrial membrane potential were evaluated using JC-1 staining. Caspase-3 activation was examined by flow cytometry, and expression of apoptosis-related proteins (caspase-3, -8, -9, AIF) was analyzed via Western blotting. Results: LUT significantly inhibited the growth of Ca Ski cells in a dose- and time-dependent manner, with the most pronounced effects observed at 100 µM over 72 hours. Flow cytometry confirmed that LUT induced apoptosis without causing necrosis. Mitochondrial membrane potential was reduced after LUT treatment, coinciding with increased caspase-3 activation. Western blot analysis revealed the upregulation of pro-apoptotic proteins caspase-3, -8, -9, and AIF, indicating that LUT induces apoptosis through the intrinsic mitochondrial pathway. Conclusions: Luteolin effectively inhibits cervical cancer cell proliferation and induces apoptosis by disrupting mitochondrial membrane potential and activating caspases. These findings suggest that LUT holds potential as a therapeutic agent for cervical cancer, with further studies needed to explore its in vivo efficacy and broader clinical applications.

Treatment outcome and germline predictive factors of ropeginterferon alpha-2b in myeloproliferative neoplasm patients.

BACKGROUND: Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. METHODS: To gain insights, targeted sequencing was performed to detect myeloid-associated mutations and SNPs in eight loci across three genes (IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha-2b (ROPEG)-treated MPN patients, among whom real-time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F-mutated cases. RESULTS: ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN-γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. CONCLUSIONS: Overall, this study provided valuable information on the ethnics- and genetics-based algorithm in the treatment of MPN.

Oral Chemotherapy Application in Elderly Patients With Diffuse Large B-Cell Lymphoma: An Alternative Regimen in Retrospective Analysis.

Background: A combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard treatment for diffuse large B-cell lymphoma (DLBCL). However, no standard treatment has been established for older patients (age ≥ 75 years). This study retrospectively analyzed different treatment strategies in older patients with DLBCL with different chemotherapy regimens and compared the survival rate of patients using oral or intravenous form cyclophosphamide and etoposide in a single center. Methods: We reviewed the records of older patients with DLBCL, aged ≥ 75 years, from January 2010 to August 2019. The different treatment combinations, clinical characteristics, response rates, and toxicity profiles were analyzed. The median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier (KM) method. Cox regression model was used to identify the risk factors. Results: Eighty-four patients were included. One-quarter of the patients received cytoreduction treatment because of their poor medical condition at the time of diagnosis. Twenty-six percent of the patients were aged ≥ 85 at the time of diagnosis and 46.7% completed the treatment course. Patients receiving non-anthracycline-containing (non-ACR) treatment had worse Charlson comorbidity index, worse PFS, lower body mass index, or were older. The mean anthracycline accumulative dose in the anthracycline-containing (ACR) group was 134 mg/m2. The median OS was 17.2 months and median PFS was 7.7 months. The PFS of R-CHOP is better than R-mini-CHOP and R-CVOP without statistical significance, but OS of R-CHOP is not better than the other regimens. Conclusion: The toxicity, efficacy, and KM curve for OS and PFS in the non-ACR group were lower compared to ACR group, without statistical significance. R-CVOP had similar OS with R-mini-CHOP in our study. The result does not mean etoposide could totally substitute for anthracycline, but etoposide did have lower early progression rate (12.5%), and it may be an option for frail patients with comorbidity. Oral form cyclophosphamide and etoposide could be considered as a substitute for intravenous administration because of the similar effect and toxic profile.

Metronomic vinorelbine is an excellent and safe treatment for advanced breast cancer: a retrospective, observational study.

Advanced breast cancer (ABC) has become a chronic disease. In such a situation, an effective therapy with low toxicities and economically acceptable is needed. Metronomic vinorelbine (mVNR) has been proved to be effective on the control of MBC. The aim of this study is to evaluate the efficacy and safety of mVNR as the salvage therapy for patients with ABC. Oral vinorelbine (VNR) was administered at 70 mg/m2, fractionated on days 1, 3, and 5, for 3 weeks on and 1 week off. Once the mVNR was combined with trastuzumab, or was combined with bevacizumab, the schedule was changed to 2 weeks on and 1 week off. Clinical data of patients with ABC who had received treatment with mVNR and tumor characteristics were collected and analyzed. From Mar. 2013 to Dec, 2020, there were 90 patients with ABC received mVNR. The overall response rate was 53.3% and overall disease control rate (DCR) was 78.9% in this study, including 4 (4.4%) cases reached complete response, 44 (48.9%) cases reached partial response and 23 (25.6%) cases were table disease. The median time to treatment failure (TTF) of the Lumina A patients was 13.3 months, Lumina B patients was 9.1 months, Her-2 enrich patients was 8.9 months, and triple negative breast cancer (TNBC) patients was 5.6 months. Median overall survival time for Lumina A, Lumina B, Her-2 enrich and TNBC were 54.6 months, 53.3 months, 59.5 months and 24.5 months separately. Side effects were minimal and manageable. Metronomic VNR can be an effective treatment for ABC either works as a switch maintenance or salvage therapy. In combination with target therapy or hormonal therapy, mVNR can further improve TTF and DCR with minimal toxicities. Further study should focus on the optimal dosage, schedule and combination regimen.

A Novel Combination of Bevacizumab with Chemotherapy Improves Therapeutic Effects for Advanced Biliary Tract Cancer: A Retrospective, Observational Study.

BACKGROUND: Biliary tract cancer (BTC) is a heterogenous collection of biliary tract cancer at different primary sites, and the prognosis of advanced BTC is dismal. Systemic chemotherapy with gemcitabine and cisplatin (GC) has been the reference regimen since 2010. How to improve therapeutic effects of GC regimen is an urgent mission at present. METHODS: Bevacizumab with a reduced dosage and modified schedule (10 mg/Kg/triweekly, 1 day before GS at the first 2 cycles) was combined with standard GC for patients with advanced BTC. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 every 2 months. Kaplan-Meier curves were estimated for time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS). RESULT: A total of thirty cases of advanced BTC accepted this treatment, and the overall response rate (ORR) was 50.0%, and the disease control rate was 80.0% for all patients. The median TTF was 5.8 months, the median PFS was 8.4 months, and the median OS was 13.6 months. Most responses were noted at the first evaluation. Adverse effects (AEs) were mostly tolerable. CONCLUSIONS: After modifying the schedule, adding bevacizumab to a traditional GC regimen could increase the ORR with a shorter time-to-response, a better PFS and OS than GC alone but without the addition of AE. This regimen can be applied to patients with advanced BTC, especially those who are with a big tumor burden and who need a rapid response.

Role of quantitative hepatitis B surface antibodies in preventing hepatitis B virus-related hepatitis in patients treated with rituximab.

Hepatitis B virus (HBV) reactivation is a well-known complication after rituximab-based chemotherapy in patients with B cell lymphoma (BCL) who have resolved HBV infection. This retrospective cohort study used electronic medical records from the Kaohsiung Chang Gung Memorial Hospital. There were 128 patients with BCL and resolved HBV infection treated with 1st-line rituximab-containing therapy from 2008 to 2013. No patient received antiviral prophylaxis. Patients with high pretreatment hepatitis B surface antibody (anti-HBs titer ≥100 mIU/mL), had significantly less HBV reactivation (2.0%, 1/49) than patients with low (10-100 mIU/mL, 10.8%, 4/37) or negative anti-HBs (<10 mIU/mL, 23.8%, 10/42) (p = 0.001). No patient in the high group vs. 1 (2.7%) low group vs. 6 (14.3%) negative group developed HBV-related hepatitis (p = 0.002). Patients with high pretreatment anti-HBs have a low risk of HBV-related complications and may not require antiviral prophylaxis. We propose an algorithm for the management of HBV reactivation risk in BCL.

A comprehensive retrospective cohort study of the journey of B-cell lymphoma in Taiwan.

Complete disease journey and risk factors for poor outcomes are needed to facilitate effectiveness evaluations of new therapies and clinical decision-making in B-cell Non-Hodgkin lymphoma (B-NHL), particularly in Asia where such data are lacking. This retrospective cohort study used electronic medical records from a regional medical centre in southern Taiwan to follow-up 441 patients newly diagnosed with common B-NHL subtypes: Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone Lymphoma (MZL), Mantle Cell Lymphoma (MCL), and Waldenström macroglobulinemia (WM), between 01-Jan-2008 and 31-Dec-2013, until 31-Dec-2017. Treatment pathways were modelled using a Markov approach. Stage III/IV disease at diagnosis was frequent for patients with DLBCL, FL, MCL and WM. Hepatitis B surface antigen/hepatitis C virus seropositivity was 18.6%/12.3%. Clinical responses to 1st-line treatment were observed in 76.0% (DLBCL), 87.3% (FL), 86.0% (MZL), 60.0% (MCL), and 42.9% (WM) of patients. For DLBCL, disease control was achieved by ~ 50% after 1st-line, ~ 24% after 2nd-line, ~ 17% after 3rd-line. Patients with Stage III/IV DLBCL or age > 65 years at diagnosis had lower rates of active treatment, poorer disease control and higher mortality than patients with early stage disease or age ≤ 65 years. Disease flare < 6 months after 1st-line treatment was significantly associated with mortality. Despite good clinical response rates for some sub-types, survival remains poor. New treatments are needed to improve the outcome of B-NHL.

The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption - a stable iron isotope study in Taiwanese women.

Genome wide studies have associated TMPRSS6 rs855791 (2321 C>T) with iron status and hepcidin. It is unclear whether this polymorphism affects iron absorption. In nonanemic Taiwanese women (n=79, 44 TT variant, 35 CC variant), we administered standardized rice-based test meals containing 4 mg of labeled 57Fe or 58Fe as FeSO4 on alternate days. Fractional iron absorption was measured by erythrocyte incorporation of the tracers 14 days after administration. Compared to the CC variant, in the TT variant serum iron and transferrin saturation were lower (P=0.001; P<0.001, respectively) and serum hepcidin/transferrin saturation and serum hepcidin/serum iron ratios were higher (P=0.042; P=0.088, respectively). Serum hepcidin did not differ between groups (P=0.862). Geometric mean (95% CI) fractional iron absorption, corrected to a serum ferritin of 15 µg/L, was 26.6% (24.0, 29.5) in the CC variant and 18.5% (16.2, 21.1) in the TT variant (P=0.002). Overall, predictors of iron absorption were: serum ferritin (P<0.001); genetic variant (P=0.032); and hepcidin (P<0.001). In the models by variant, in the CC variant the model explained 67-71% of variability in absorption and serum ferritin was the only significant predictor (P<0.001); in the TT variant, the model explained only 35-43% of variability, and hemoglobin (P=0.032), soluble transferrin receptor (P=0.004) and hepcidin (P<0.001) were significant predictors. Women with the TMPRSS6 rs855791 (2321 C>T) polymorphism show altered iron homeostasis which affects oral iron absorption and may increase their risk for iron deficiency. The trial was registered at www.clinicaltrials.gov as NCT03317873, and funded by the Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, (grant CMRPG8F0721) and ETH Zurich, Switzerland.

S1 versus Doublet Regimens as Adjuvant Chemotherapy in Patients with Advanced Gastric Cancer after Radical Surgery with D2 Dissection-A Propensity Score Matching Analysis.

BACKGROUND: Fluoropyrimidine- and platinum-based doublet regimen is the standard treatment of adjuvant chemotherapy (AC) for gastric cancer (GC). Our study aims to compare S1 with doublet regimens as AC in patients with advanced GC after radical surgery with D2 dissection. METHODS: Patients who were diagnosed with GC and underwent a curative surgery with D2 dissection followed by AC were enrolled into our study. A propensity score matching analysis was performed to reduce the selection bias. Kaplan-Meier curves were estimated for recurrence-free survival (RFS) and overall survival (OS). Cox regression models were conducted for survival. RESULTS: After propensity sore matching, 64 patients with S1 and 64 patients with doublet regimens were identified. The median RFS (p = 0.355) and OS (p = 0.309) were both insignificant between S1 and ST. Cox regression analysis demonstrated that pathologic stage and lymph node ratio (LNR) were independently correlated with survival. Patients were then stratified into low risk and high risk groups. The median RFS (p < 0.001) and OS (p < 0.001) had significant differences between low risk and high risk. In the high-risk group, doublet regimens were strongly associated with survival (p = 0.020) as compared with S1. While in the low-risk group, doublet regimen and S1 did not have statistically different survival benefits. CONCLUSIONS: Our study demonstrated that doublet regimens are superior to S1 in high-risk groups, and that survival outcomes are similar between doublet regimens and S1 in low-risk groups. Our prognostic model might have clinical implications for AC.

Intracoronary Injection of Autologous CD34+ Cells Improves One-Year Left Ventricular Systolic Function in Patients with Diffuse Coronary Artery Disease and Preserved Cardiac Performance-A Randomized, Open-Label, Controlled Phase II Clinical Trial.

This phase II randomized controlled trial tested whether intracoronary autologous CD34+ cell therapy could further improve left ventricular (LV) systolic function in patients with diffuse coronary artery disease (CAD) with relatively preserved LV ejection fraction (defined as LVEF >40%) unsuitable for coronary intervention. Between December 2013 and November 2017, 60 consecutive patients were randomly allocated into group 1 (CD34+ cells, 3.0 × 107/vessel/n = 30) and group 2 (optimal medical therapy; n = 30). All patients were followed for one year, and preclinical and clinical parameters were compared between two groups. Three-dimensional echocardiography demonstrated no significant difference in LVEF between groups 1 and 2 (54.9% vs. 51.0%, respectively, p = 0.295) at 12 months. However, compared with baseline, 12-month LVEF was significantly increased in group 1 (p < 0.001) but not in group 2 (p = 0.297). From baseline, there were gradual increases in LVEF in group 1 compared to those in group 2 at 1-month, 3-months, 6-months and 12 months (+1.6%, +2.2%, +2.9% and +4.6% in the group 1 vs. -1.6%, -1.5%, -1.4% and -0.9% in the group 2; all p < 0.05). Additionally, one-year angiogenesis (2.8 ± 0.9 vs. 1.3 ± 1.1), angina (0.4 ± 0.8 vs. 1.8 ± 0.9) and HF (0.7 ± 0.8 vs. 1.8 ± 0.6) scores were significantly improved in group 1 compared to those in group 2 (all p < 0.001). In conclusion, autologous CD34+ cell therapy gradually and effectively improved LV systolic function in patients with diffuse CAD and preserved LVEF who were non-candidates for coronary intervention (Trial registration: ISRCTN26002902 on the website of ISRCTN registry).

Human Umbilical Cord-Derived Mesenchymal Stem Cells for Acute Respiratory Distress Syndrome.

OBJECTIVES: To investigate the safety, feasibility, and possible adverse events of single-dose human umbilical cord-derived mesenchymal stem cells in patients with moderate-to-severe acute respiratory distress syndrome. DESIGN: Prospective phase I clinical trial. SETTING: Medical center in Kaohsiung, Taiwan. PATIENTS: Moderate-to-severe acute respiratory distress syndrome with a PaO2/FIO2 ratio less than 200. INTERVENTIONS: Scaling for doses was required by Taiwan Food and Drug Administration as follows: the first three patients received low-dose human umbilical cord-derived mesenchymal stem cells (1.0 × 10 cells/kg), the next three patients with intermediate dose (5.0 × 10 cells/kg), and the final three patients with high dose (1.0 × 10 cells/kg) between December 2017 and August 2019. MEASUREMENTS AND MAIN RESULTS: Nine consecutive patients were enrolled into the study. In-hospital mortality was 33.3% (3/9), including two with recurrent septic shock and one with ventilator-induced severe pneumomediastinum and subcutaneous emphysema. No serious prespecified cell infusion-associated or treatment-related adverse events was identified in any patient. Serial flow-cytometric analyses of circulating inflammatory biomarkers (CD14CD33/CD11b+CD16+/CD16+MPO+/CD11b+MPO+/CD14CD33+) and mesenchymal stem cell markers (CD26+CD45-/CD29+CD45-/CD34+CD45-/CD44+CD45-/CD73+CD45-/CD90+CD45-/CD105+CD45-/CD26+CD45-) were notably progressively reduced (p for trend < 0.001), whereas the immune cell markers (Helper-T-cell/Cytotoxity-T-cell/Regulatory-T-cell) were notably increased (p for trend < 0.001) after cell infusion. CONCLUSIONS: The result of this phase I clinical trial showed that a single-dose IV infusion of human umbilical cord-derived mesenchymal stem cells was safe with favorable outcome in nine acute respiratory distress syndrome patients.

Molecular heterogeneity unravelled by single-cell transcriptomics in patients with essential thrombocythaemia.

Significant phenotypic heterogeneity exists in patients with all subtypes of myeloproliferative neoplasms (MPN), including essential thrombocythaemia (ET). Single-cell RNA sequencing (scRNA-Seq) holds the promise of unravelling the biology of MPN at an unprecedented level of resolution. Herein we employed this approach to dissect the transcriptomes in the CD34+ cells from the peripheral blood of seven previously untreated ET patients and one healthy adult. The mutational profiles in these patients were as follows: JAK2 V617F in two, CALR in three (one type I and two type II) and triple-negative (TN) in two. Our results reveal substantial heterogeneity within this enrolled cohort of patients. Activation of JAK/STAT signalling was recognized in discrepant progenitor lineages among different samples. Significantly disparate molecular profiling was identified in the comparison between ET patients and the control, between patients with different driver mutations (JAK2 V617F and CALR exon 9 indel), and even between patients harbouring the same driver. Intra-individual clonal diversity was also found in the CD34+ progenitor population of a patient, possibly indicating the presence of multiple clones in this case. Estimation of subpopulation size based on cellular immunophenotyping suggested differentiation bias in all analysed samples. Furthermore, combining the transcriptomic information with data from targeted sequencing enabled us to unravel key somatic mutations that are molecularly relevant. To conclude, we demonstrated that scRNA-Seq extended our knowledge of clonal diversity and inter-individual heterogeneity in patients with ET. The obtained information could potentially leapfrog our efforts in the elucidation of the pathogenesis of the disease.

Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation.

Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non-mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was characterized by mitochondrial ROS generation, p38 MAPK activation, TNF-α upregulation and activation of the death receptor-mediated pathway. Meanwhile, ABZ induced tubulin depolymerization and G2/M cell cycle arrest. ABZ-induced SIRT3 degradation elicited ROS-mediated p38 MAPK activation, leading to pyruvate kinase M2-mediated tristetraprolin (TTP) degradation. Inhibition of TTP-mediated TNF-α mRNA decay elicited TNF-α upregulation in ABZ-treated cells. Either the overexpression of SIRT3 or abolishment of ROS/p38 MAPK activation suppressed TNF-α upregulation and rescued the viability of ABZ-treated cells. In contrast to the inhibition of ROS/p38 MAPK pathway, SIRT3 overexpression attenuated tubulin depolymerization and G2/M arrest in ABZ-treated cells. Treatment with a SIRT3 inhibitor induced TNF-α upregulation and cell death without the induction of G2/M arrest in U937 cells. Taken together, our data indicate that ABZ-induced SIRT3 downregulation promotes its microtubule-destabilizing effect, and that the non-mitotic effect of ABZ largely triggers apoptosis of U937 cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation. Notably, the same pathway is involved in the ABZ-induced death of HL-60 cells.

Autologous stem cell transplantation in multiple myeloma: Post-transplant outcomes of Taiwan Blood and Marrow Transplantation Registry.

BACKGROUND/PURPOSE: Multiple myeloma (MM) is a monoclonal plasma cell malignancy. The primary choice of treatment for MM is induction therapy followed by autologous stem cell transplantation (ASCT). This study aimed to analyze the treatment efficacy of ASCT in a Taiwanese cohort and evaluate possible prognostic factors. METHODS: From the database of the Taiwan Blood and Marrow Transplantation registry, data on 396 patients with MM who underwent ASCT were reviewed. RESULTS: The average age of participants was 54.8 years, and there were more men than women (57.6% vs. 42.4%). Most patients were diagnosed with IgG-type myeloma (52.4%), followed by IgA-type (23.2%) and light-chain type (21.4%). Patients with Durie Salmon Staging System (DSS) III disease accounted for 61.9% of the study cohort, while 23.7% had stage II and 14.4% had stage I disease. The median progression-free survival (PFS) and overall survival (OS) after ASCT were 46.5 months and 70.4 months, respectively. DSS III was a poor prognostic factor affecting both PFS and OS with a duration of 35.9 months and 69.0 months, respectively, compared with the other two stages (p = 0.006 and p = 0.03, respectively). In addition, patients with better treatment response before ASCT had better PFS and OS compared with those who did not show a response (both p < 0.0001). The overall incidence of organ toxicities associated with transplantation was low. CONCLUSION: In conclusion, our cohort showed that myeloma patients with early DSS and better treatment response before ASCT had better long-term survival outcomes.

Intra-carotid arterial transfusion of autologous circulatory derived CD34+ cells for old ischemic stroke patients - a phase I clinical trial to evaluate safety and tolerability.

This phase I clinical trial tested the hypothesis that circulatory CD34+ cell therapy might be safe for old ischemic stroke (IS) (defined as IS>6 months) patients and also to evaluate the neurological function after the therapy. Nine old IS patients (with mean IS interval: 8.6 ± 6.4 years) were consecutively enrolled and received intra-carotid artery transfusion of circulatory-derived autologous CD34+ cells (3.0×107 cells/patient) into the ipsilateral brain infarct area at catheterization room by Catheter Looping Technique, after subcutaneous G-CSF injection (5 µg/kg twice a day for 4 days). The results showed that procedural safety was 100% with all patients uneventfully discharged. The circulating number of EPCs and angiogenesis (i.e., by Matrigel assay) were significantly higher at post than at prior to G-CSF treatment (all P<0.001). Time courses (0/5/10/30 minutes) of blood samplings from right-internal jugular vein exhibited significantly increased in levels of SDF-1α and EPCs numbers in time points of 5/10/30 minutes than in the baseline (0 minute) (all P<0.05). Barthel index was increased (defined as ≥5 scores) in 44.4% (4/9) and CASI score was notably improved (all P<0.01) at 6-month follow-up after the cell therapy as compared to the baseline. No recurrent IS or any tumorigenesis was found in these patients with a mean follow-up time interval of 16.5 ± 6.2 months. All of these patients remain survive and are followed up at outpatient department. In conclusion, CD34+ cell therapy is safe and might offer some benefit to old IS patients.

Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection.

BACKGROUND & AIMS: Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection. This study investigated whether baseline anti-HBc and anti-HBs levels may better predict HBV reactivation. METHODS: We prospectively measured the HBV DNA levels of patients with lymphoma and resolved HBV infection receiving rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone-based chemotherapy and started an antiviral therapy upon HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels. Anti-HBs and anti-HBc were quantified by a double-sandwich assay. Receiver-operating-characteristic-curve analysis was used to determine the optimal baseline anti-HBc/anti-HBs levels for predicting HBV reactivation. RESULTS: HBV reactivation occurred in 24 of the 197 patients enrolled, with an incidence of 11.6/100 person-years. For the 192 patients with enough serum samples for analysis, low anti-HBs (<56.48 mIU/ml) and high anti-HBc (≥6.41 IU/ml) at baseline were significantly associated with high risk of HBV reactivation (hazard ratio [HR] 8.48 and 4.52, respectively; p <0.01). The multivariate analysis indicated that (1) patients with both high anti-HBc and low anti-HBs at baseline (36 of 192 patients) had an HR of 17.29 for HBV reactivation (95% CI 3.92-76.30; p <0.001), and (2) HBV reactivation may be associated with inferior overall survival (HR 2.41; 95% CI 1.15-5.05; p = 0.02). CONCLUSIONS: Baseline anti-HBc/anti-HBs levels may predict HBV reactivation in these patients with lymphoma and help optimize prophylactic antiviral therapy for high-risk patients. LAY SUMMARY: In this study, we identified a subgroup of patients with lymphoma and resolved hepatitis B virus infection that had a high risk of hepatitis B virus reactivation after receiving rituximab-containing chemotherapy. These findings will help optimize a preventive strategy, especially in hepatitis B virus endemic regions with limited healthcare resources. Clinical trial number: NCT 00931229.

The Five-Year Clinical and Angiographic Follow-Up Outcomes of Intracoronary Transfusion of Circulation-Derived CD34+ Cells for Patients With End-Stage Diffuse Coronary Artery Disease Unsuitable for Coronary Intervention-Phase I Clinical Trial.

OBJECTIVES: This study investigated the clinical and angiographic long-term outcomes of intracoronary transfusion of circulation-derived CD34+ cells for patients with end-stage diffuse coronary artery disease unsuitable for coronary intervention. DESIGN AND SETTING: A single-center prospective randomized double-blinded phase I clinical trial. Thirty-eight patients undergoing CD34+ cell therapy were allocated into groups 1 (1.0 × 10 cells/each vessel; n = 18) and 2 (3.0 × 10 cells/each vessel; n = 20). PATIENTS: Those with end-stage diffuse coronary artery disease were unsuitable for percutaneous and surgical coronary revascularization. INTERVENTIONS: Intracoronary delivery of circulation-derived CD34+ cells. MEASUREMENTS AND MAIN RESULTS: We prospectively evaluated long-term clinical and echocardiographic/angiographic outcomes between survivors and nonsurvivors. By the end of 5-year follow-up, the survival rate and major adverse cardio/cerebrovascular event were 78.9% (30/38) and 36.8% (14/38), respectively. During follow-up period, 31.6% patients (12/38) received coronary stenting for reason of sufficient target vessel size grown-up after the treatment. Endothelial function was significantly reduced in the nonsurvivors than the survivors (p = 0.039). Wimasis image analysis of angiographic findings showed that the angiogenesis was significantly and progressively increased from baseline to 1 and 5 years (all p < 0.001). The 3D echocardiography showed left ventricular ejection fraction increased from baseline to 1 year and then remained stable up to 5 years, whereas left ventricular chamber diameter exhibited an opposite pattern to left ventricular ejection fraction among the survivors. The clinical scores for angina and heart failure were significantly progressively reduced from baseline to 1 and 5 years (all p < 0.001). CONCLUSIONS: CD34+ cell therapy for end-stage diffuse coronary artery disease patients might contribute to persistently long-term effects on improvement of left ventricular function, angina/heart failure, and amelioration of left ventricular remodeling.

Febuxostat-induced agranulocytosis in an end-stage renal disease patient: A case report.

INTRODUCTION: Febuxostat, a nonpurine xanthine oxidase inhibitor, is approved as the first-line urate-lowering therapy in gout patients with normal renal function or mild to moderate renal impairment. The most common adverse effects of febuxostat are liver function test abnormalities, diarrhea, and skin rash. However, there is insufficient data in patients with severe renal impairment and end-stage renal disease (ESRD). We report the first case, to our knowledge, in which agranulocytosis developed after febuxostat treatment in an ESRD patient. CLINICAL PRESENTATION: A 67-year-old woman with gout and ESRD received febuxostat 40 mg a day for 2.5 months. She subsequently complicated with febrile neutropenia and the absolute neutrophil count was only 14/µL. After broad-spectrum antibiotics treatment and no more exposure to febuxostat for 17 days, her infection and neutrophil count recovered. Bone marrow study during neutropenic period showed myeloid hypoplasia without evidence of hematologic neoplasms. CONCLUSION: As febuxostat use may become more common in the population of advanced renal failure, clinicians should be aware of this rare but potentially life-threatening adverse effect. Based on our experience, close monitoring hemogram and immediate discontinuation of this medication may prevent serious consequences.

Indoxyl Sulfate Downregulates Mas Receptor via Aryl Hydrocarbon Receptor/Nuclear Factor-kappa B, and Induces Cell Proliferation and Tissue Factor Expression in Vascular Smooth Muscle Cells.

BACKGROUND/AIM: Angiotensin converting enzyme-related carboxypeptidase 2/angiotensin (Ang)-(1-7)/Mas receptor axis is protective in the development of chronic kidney disease and cardiovascular disease. This study is aimed at investigating whether indoxyl sulfate (IS) affects Mas receptor expression, cell proliferation and tissue factor expression in vascular smooth muscle cells, and if Ang-(1-7), an activator of Mas receptor, counteracts the IS-induced effects. METHODS: IS was administered to normotensive and hypertensive rats. Human aortic smooth muscle cells (HASMCs) were cultured with IS. RESULTS: IS reduced the expression of Mas receptor in the aorta of normotensive and hypertensive rats. IS downregulated the Mas receptor expression in a time- and dose-dependent manner in HASMCs. Knockdown of aryl hydrocarbon receptor (AhR) and nuclear factor-kappa B (NF-x03BA;B) inhibited IS-induced downregulation of Mas receptor. Further, IS stimulated cell proliferation and tissue factor expression in HASMCs. Ang-(1-7) attenuated IS-induced cell proliferation and tissue factor expression in HASMCs. Ang-(1-7) suppressed phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and NF-x03BA;B in HASMCs. CONCLUSION: IS downregulated the expression of Mas receptor via AhR/NF-x03BA;B, and induced cell proliferation and tissue factor expression in HASMCs. Ang-(1-7) inhibited IS-induced cell proliferation and tissue factor expression by suppressing the phosphorylation of ERK1/2 and NF-x03BA;B p65.