Gemcitabine enhances pharmacokinetic exposure of the major components of Danggui Buxue Decoction in rat via the promotion of intestinal permeability and down-regulation of CYP3A for combination treatment of non-small cell lung cancer.

CONTEXT: Danggui Buxue Decoction (DBD), a traditional Chinese medicine formula, has the potential to enhance the antitumor effect of gemcitabine in non-small cell lung cancer (NSCLC) treatment by increasing gemcitabine's active metabolites. However, whether gemcitabine affects the pharmacokinetics of DBD's major components remains unclear. OBJECTIVE: This study evaluates the herb-drug interaction between DBD's major components and gemcitabine and validates the underlying pharmacokinetic mechanism. MATERIALS AND METHODS: The pharmacokinetics of 3.6 g/kg DBD with and without a single-dose administration of 50 mg/kg gemcitabine was investigated in Sprague-Dawley rats. The effects of gemcitabine on intestinal permeability, hepatic microsomal enzymes in rat tissues, and CYP3A overexpressing HepG2 cells were determined using western blot analysis. RESULTS: The combination of gemcitabine significantly altered the pharmacokinetic profiles of DBD's major components in rats. The Cmax and AUC of calycosin-7-O-ß-d-glucoside notably increased through sodium-glucose transporter 1 (SGLT-1) expression promotion. The AUC of ligustilide and ferulic acid was also significantly elevated with the elimination half-life (t1/2) prolonged by 2.4-fold and 7.8-fold, respectively, by down-regulating hepatic CYP3A, tight junction proteins zonula occludens-1 (ZO-1) and occludin expression. DISCUSSION AND CONCLUSIONS: Gemcitabine could modulate the pharmacokinetics of DBD's major components by increasing intestinal permeability, enhancing transporter expression, and down-regulating CYP3A. These findings provide critical information for clinical research on DBD as an adjuvant for NSCLC with gemcitabine and help make potential dosage adjustments more scientifically and rationally.

Poor pretransplantation minimal residual disease clearance as an independent prognostic risk factor for survival in myelodysplastic syndrome with excess blasts: A multicenter, retrospective cohort study.

BACKGROUND: Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS-EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long-term survival. MATERIALS AND METHODS: Patients with MDS-EB who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long-term survival was analyzed using univariate and multivariate logistic regression models. RESULTS: Of 220 patients with MDS-EB who underwent allo-HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5% (p = .045), respectively, whereas the 3-year OS rates were 91.3% and 66.4% (p = .035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS. CONCLUSION: Poor pretransplantation MRD clearance is an independent prognostic risk factor for long-term survival after allo-HSCT for patients with MDS-EB. PLAIN LANGUAGE SUMMARY: Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long-term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts.

Chronic radiation dermatitis induced by cardiac catheterization: a case report and literature review.

Fluoroscopy-induced chronic radiation dermatitis (FICRD) is an uncommon but increasing complication that is challenging to diagnose due to its varied symptoms and delayed onset, usually from months to years after radiation exposure. For patients undergoing cardiac catheterization, high-risk factors for radiodermatitis include obesity, the presence of complex or chronic total occlusion lesions, the use of a fixed large beam angulation, and a procedure time of more than 2 hours. We present an individual with FICRD that had an indurated plaque on his back for 7 years to familiarize physicians with high-risk groups and early recognition of the disease.

The absence of AhR in CD4+ T cells in patients with acute graft-versus-host disease may be related to insufficient CTCF expression.

BACKGROUND: Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Accumulating evidence suggests that imbalanced Treg/Th17 ratio accelerates the progression of aGVHD. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor activated through cognate ligand binding. Current evidence supports that AhR plays a critical regulatory role in the differentiation of Treg and Th17 cells. However, the relationship between AhR and aGVHD remains unclear. RESULTS: Our results showed that AhR expression was downregulated significantly in CD4+ T cells from patients with aGVHD compared with the non-aGVHD group. We also discovered that after activating AhR deficient CD4+ T cells, the expression levels of the activation markers-CD40L, CD134 and CD137 and cell proliferation activity were significantly higher than those of AhR-expressing CD4+ T cells. Restoring the expression of AhR in aGVHD CD4+ T cells resulted in significantly increased percentage of Tregs and associated gene transcripts, including Foxp3, IL-10 and CD39. In contrast, Th17 cell amounts and the transcription of related genes, including RORγt, IL-17A and IL-17F, were significantly reduced. We confirmed that CTCF recruited EP300 and TET2 to bind to the AhR promoter region and promoted AhR expression by mediating histone H3K9/K14 hyperacetylation and DNA demethylation in this region. The low expression of CTCF caused histone hypoacetylation and DNA hypermethylation of the AhR promoter, resulting in insufficient expression in aGVHD CD4+ T cells. CONCLUSIONS: CTCF is an important inducer of AhR transcription. Insufficient expression of CTCF leads to excessive AhR downregulation, resulting in substantial CD4+ T cell activation and Th17/Treg ratio increase, thereby mediating the occurrence of aGVHD.

Haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood in hematologic malignancy patients: A report of 80 cases.

The outcomes of 80 patients with hematologic malignancies who received haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) combined with unrelated cord blood (UCB) from March 2017 to June 2020 were analyzed in this retrospective study. Anti-thymocyte globulin(ATG) was administered at a dose of 7.5 mg/kg. The median time for neutrophil and platelet engraftment was 13(range: 8-22) days and 14(range: 8-103) days, respectively. The 30-day cumulative incidence of neutrophil engraftment was 100%, and the 100-day cumulative incidence of platelet engraftment was 95%. All patients achieved complete haploidentical peripheral blood stem cell engraftment, and no cord blood chimerism was observed. The cumulative incidence of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) on 100-day was 26.3%(95%CI: 17.2%-36.3%) and 5.0%(95%CI: 1.6%-11.4%), respectively. The estimated cumulative incidence of chronic GVHD (cGVHD) and moderate-severe cGVHD at 3-year was 43.3%(95%CI: 31.6%-54.4%) and 16.0%(95%CI: 8.7%-25.2%), respectively. The estimated 3-year cumulative incidence of relapse and non-relapse mortality was 18.8%(95%CI: 10.0%-29.7%) and 17.8%(95%CI: 9.9%-27.5%), respectively. The estimated 3-year probabilities of overall survival, disease-free survival, GVHD/relapse-free survival were 77.6%(95%CI: 68.3%-88.1%), 63.4%(95%CI: 52.6%-76.5%), and 55.5%(95%CI: 44.8%-68.7%), respectively. These satisfying results suggested that haplo-PBSCT combined with UCB is an alternative transplantation protocol for hematologic malignancies.

Honokiol attenuate the arsenic trioxide-induced cardiotoxicity by reducing the myocardial apoptosis.

Despite advantages of arsenic trioxide (ATO) in oncological practice, its clinical applications have been hampered by severe cardiotoxicity. The general mechanism of ATO-induced cardiotoxicity has been attributed to its damage to mitochondria, resulting in cardiac remodeling. Honokiol (HKL) is a naturally occurring compound derived from Magnolia bark. Previous studies have demonstrated that HKL exerts cardio-protective effects on ischemia/reperfusion (I/R) or chemical-induced cardiotoxicity by counteracting the toxic effects on mitochondria. The present study was conducted to investigate whether HKL pretreatment protects against ATO-induced cardiac oxidative damage and cell death. For the in vitro study, we evaluated the effects of ATO and/or Honokiol on reactive oxygen species (ROS) production and apoptosis induction in primary cultured cardiomyocytes; for the in vivo study, BALB/c mice were administrated with ATO and/or HKL for a period of 4 weeks, myocardial apoptosis, cardiac function, and cardiac remodeling (cardiac hypertrophy and cardiac fibrosis) were assessed at the end of administration. Our results demonstrated Honokiol pretreatment alleviated the ATO-induced boost in ROS concentration and the following apoptosis induction in primary cultured cardiomyocytes. In the mouse model, Honokiol pretreatment ameliorated ATO-induced myocardial apoptosis, cardiac dysfunction, and cardiac remodeling. Collectively, these results indicated that Honokiol provide a protection against ATO-induced cardiotoxicity by reducing mitochondrial damage. In addition, given that Honokiol has shown considerable suppressive effects on leukemia cells, our data also imply that ATO and Honokiol combination may possibly be a superior avenue in leukemia therapy.

Homochiral Nickel Nitrite ABX3 (X = NO2-) Perovskite Ferroelectrics.

Chiral organic-inorganic perovskites (COIPs) have recently attracted increasing interest due to their unique inherent chirality and potential applications in next-generation optoelectronic and spintronic devices. However, COIP ferroelectrics are very sparse. In this work, for the first time, we present the nickel-nitrite ABX3 COIP ferroelectrics, [(R and S)-N-fluoromethyl-3-quinuclidinol]Ni(NO2)3 ([(R and S)-FMQ]Ni(NO2)3), where the X-site is the rarely seen NO2- bridging ligand. [(R and S)-FMQ]Ni(NO2)3 display mirror-relationship in the crystal structure and vibrational circular dichroism signal. It is emphasized that [(R and S)-FMQ]Ni(NO2)3 show splendid ferroelectricity with both an extremely high phase-transition point of 405 K and a spontaneous polarization of 12 µC/cm2. To our knowledge, [(R and S)-FMQ]Ni(NO2)3 are the first examples of nickel-nitrite based COIP ferroelectrics. This finding expands the COIP family and throws light on exploration of high-performance COIP ferroelectrics.

Clinical characteristics and disease-specific prognostic nomogram for primary gliosarcoma: a SEER population-based analysis.

Because the study population with gliosarcoma (GSM) is limited, the understanding of this disease is insufficient. In this study, the authors aimed to determine the clinical characteristics and independent prognostic factors influencing the prognosis of GSM patients and to develop a nomogram to predict the prognosis of GSM patients after craniotomy. A total of 498 patients diagnosed with primary GSM between 2004 and 2015 were extracted from the 18 Registries Research Data of the Surveillance, Epidemiology, and End Results (SEER) database. The median disease-specific survival (DSS) was 12.0 months, and the postoperative 0.5-, 1-, and 3-year DSS rates were 71.4%, 46.4% and 9.8%, respectively. We applied both the Cox proportional hazards model and the decision tree model to determine the prognostic factors of primary GSM. The Cox proportional hazards model demonstrated that age at presentation, tumour size, metastasis state and adjuvant chemotherapy (CT) were independent prognostic factors for DSS. The decision tree model suggested that age <71 years and adjuvant CT were associated with a better prognosis for GSM patients. The nomogram generated via the Cox proportional hazards model was developed by applying the rms package in R version 3.5.0. The C-index of internal validation for DSS prediction was 0.67 (95% confidence interval (CI), 0.63 to 0.70). The calibration curve at one year suggested that there was good consistency between the predicted DSS and the actual DSS probability. This study was the first to develop a disease-specific nomogram for predicting the prognosis of primary GSM patients after craniotomy, which can help clinicians immediately and accurately predict patient prognosis and conduct further treatment.

A new fluorescence "switch on" assay for heparin detection by using a functional ruthenium polypyridyl complex.

In the present study, a new strategy for heparin detection and quantification in biological media, such as fetal bovine serum (FBS), is developed by monitoring the emission change of a functional ruthenium polypyridyl complex ([Ru(phen)(2)dppz-idzo](2+), complex 1) in buffer solution. Polyanionic heparin is found to interact with a positively charged Ru-complex through electrostatic effects and/or hydrogen bonding interactions, which leads to a significant fluorescence enhancement of the Ru-complex. To get insight into this fluorescence "switch on" behavior, the binding model of the Ru-complex to heparin is established by employing molecular docking simulations based on the fluorescence and UV absorption results. The selectivity results of the fluorescence assay reveal that our complex displayed good fluorescence selectivity towards heparin over its analogues, such as chondroitin 4-sulfate (Chs) or hyaluronic acid (Hya), which have lower charge density and/or structural compatibility as compared to that of heparin. Quantification of heparin is also performed and a linear calibration curve is observed in the range of 0.01-4.87 U mL(-1) (the limit of detection is 0.01 U mL(-1)) for heparin detection in diluted FBS solution. This "one-step" fluorescence "switch on" assay for heparin detection is label-free, convenient, sensitive and selective, and has a long emission wavelength and large Stokes shift.

[Preliminary analysis of differentially expressed proteins of clear-cell renal cell carcinoma by comparative proteomic technologies].

OBJECTIVE: To explore the different expression of proteins between human clear-cell renal cell carcinoma (ccRCC) cell line RLC-310 and normal renal proximal tubule epithelial cell line HK-2, and to search new differentially expressed proteins of RCC. METHODS: RLC-310 and HK-2 cells were cultured in vitro. The total proteins were separated by ProteomeLab PF 2D protein fractionation system and the differential expression protein fractions of the two cell lines were analyzed and identified by capillary liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS). RT-PCR and Western blot were used to confirm the representative differential expression at mRNA and protein levels. RESULTS: One hundred and ninty-six differentially expressed proteins were identified. These differentially expressed proteins involved in many aspects, including cell proliferation and anti-apoptosis, energy metabolism, mitochondria reduction and oxidation, oxidative stress and resistance, cell signaling, invasion and adhesion, cytoskeleton and motion, neovascularization, etc. Except for previously reported RCC associated proteins: annexin A2, fatty acid-binding protein, vimentin, fibronectin, and so on, Septin-9 was firstly found highly expressed in RLC-310 cells when compared with that in the HK-2 cells. Moreover, the overexpression of Septin-9 was confirmed by RT-PCR and Western blot analysis at both mRNA and protein levels (P < 0.05). CONCLUSIONS: The human ccRCC cell line RLC-310 cells display differential protein profiles compared with those of the normal renal cell line HK-2 cells. The identified differential expression proteins are involved in many aspects of RCC development. It is worth further study and elucidate the molecular mechanisms of RCC. The representative differential protein Septin-9 deserves further study its role in the angiogenesis of ccRCC.

In vivo reflectance confocal microscopy of Basal cell carcinoma: feasibility of preoperative mapping of cancer margins.

BACKGROUND: Reflectance confocal microscopy (RCM) images skin at cellular resolution and has shown utility for the diagnosis of nonmelanoma skin cancer in vivo. It has the potential to define lesion margins before surgical therapy. OBJECTIVES: To investigate the feasibility of RCM in defining the margins of basal cell carcinoma before surgery. METHODS: The margins of 10 lesions were evaluated using RCM. Biopsies of the margins were used to confirm the results. A protocol was constructed to define margins. RCM was used to delineate preoperative surgical margins in 13 patients. Intraoperative frozen biopsy was used to confirm the margins. RESULTS: In seven of 10 (70.0%) cases, the margins of the cancer were identified suing RCM. The tumor island was the critical feature in identifying the margins. In 12 of 13 (92.3%) cases, frozen biopsy corroborated that the surgical margins delineated by RCM were clear. CONCLUSION: RCM imaging of the margins is feasible and demonstrates the possibility of preoperative mapping of cancer margins.

[The expression and clinical significance of Annexin II in clear-cell renal cell carcinoma].

AIM: To discuss the difference of annexinII expression between the Clear-Cell Renal Cell Carcinoma(ccRCC) and the corresponding normal renal tissues, and to reveal the clinical significance of Annexin II expression in ccRCC. METHODS: Western blotting was used to detect the expression of Annexin II in 29 samples of fresh ccRCC and the corresponding normal renal tissues. Annexin II expression was examined in 120 samples of paraffin-embedding ccRCC and the corresponding normal renal tissues using immunohistochemistry. Correlations with Annexin IIexpression and clinic-pathological parameters were analyzed. RESULTS: There was expression of Annexin II in both ccRCC and the corresponding normal renal tissues. In ccRCC tissues, the total levels of Annexin II proteins were significantly higher than that in the corresponding normal renal tissues (P<0.01). The positive rate of AnnexinII expression in immunohistochemistry was 67.5% in the ccRCC tissues, existing significant difference compared with the corresponding normal renal tissues (P<0.01). Expression of Annexin II in ccRCC mainly showed membranous staining. Annexin II expression level was positively correlated with TNM stage (P<0.05), histology grade (P<0.05), renal capsule infiltration (P<0.01) and distant metastasis (P<0.01) of ccRCC. Moreover, Annexin II expression level was significantly correlated with ccRCC patients'5-years survival rate(P<0.01). CONCLUSION: Overexpression of AnnexinII in the ccRCC is closely correlated with the ccRCC development. It may play an important role in the process of ccRCC invasion and metastasis.

Effects of exogenous hydrogen sulfide on apoptosis proteins and oxidative stress in the hippocampus of rats undergoing heroin withdrawal.

In this study, the mechanism of H(2)S protection in the hippocampus of heroin-treated rats was investigated. Male Sprague-Dawley rats were randomly divided into three groups: a saline group, a heroin and saline group, and a heroin and sodium hydrosulfide group. According to the principle of increasing heroin dosage daily, heroin withdrawal was precipitated on day 9 with an injection of naloxone (5 mg/kg, i.p.), and withdrawal symptoms were scored. The levels of cystathionine-ß-synthase, H2S, reduced glutathione and malondialdehyde, as well as the levels of cleaved caspase-3, Bax, and Bcl-2 proteins and the activities of superoxide dismutase, catalase, and glutathione peroxidase were assayed in the hippocampus. The results showed that exogenous H(2)S alleviated heroin withdrawal symptoms. Moreover, exogenous H(2)S not only increased cellular H(2)S and the cystathionine-ß-synthase protein level activity but also significantly improved heroin-induced oxidative stress. Protein expression of cleaved caspase-3 and Bax decreased, whereas Bcl-2 protein levels in hippocampus increased with exogenous H(2)S. Exogenous H(2)S alleviated heroin-induced rat hippocampal damage through antioxidant and antiapoptosis effects.