Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood.

Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n = 130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n = 33,735). We found brain volumetric phenotypes share substantial genetic variants (74-96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and (3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest that altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.

Comparative analysis of absorbed ingredients and metabolites, and pharmacokinetic studies of Zhimu-Huangbai herb pair in the plasma of normal and type 2 diabetes mellitus rats by UHPLC-linear trap quadrupole-orbitrap MS and LC-MS/MS.

A new rapid ultra-high-performance liquid chromatography coupled with linear trap quadrupole orbitrap mass spectrometry method was established for the qualitative analysis of absorbed ingredients and metabolites of Zhimu-Huangbai herb pair, which is used to treat type 2 diabetes mellitus. A total of 16 absorbed ingredients and 11 metabolites were identified in normal and type 2 diabetes mellitus rats, respectively. Such findings indicated that the diabetic model had no effect on the type of components in plasma. Seven absorbed ingredients and 11 metabolites were first identified after the oral administration of Zhimu-Huangbai herb pair. Thereafter, ultra-high-performance liquid chromatography coupled with linear trap quadrupole orbitrap mass spectrometry and liquid chromatography-API4000+ triple quadrupole mass spectrometer methods were established and validated for pharmacokinetic comparative studies of seven major bioactive components in normal and type 2 diabetes mellitus rats. Partial pharmacokinetic parameters in the plasma of type 2 diabetes mellitus rats were significantly different from those in normal rats. To our knowledge, this is the first comparison of absorbed ingredients and metabolites of Zhimu-Huangbai herb pair, and its use in pharmacokinetic studies between normal and type 2 diabetes mellitus rats. Ultimately, our findings provide insights into the clinical usage of Zhimu-Huangbai herb pair.

Association Between Traditional Herbal Diet and Nasopharyngeal Carcinoma Risk: A Prospective Cohort Study in Southern China.

INTRODUCTION: Prospective evidence for herbal diet and nasopharyngeal carcinoma (NPC) development is absent. We therefore evaluated the associations of herbal soup and herbal tea with NPC in a prospective cohort study in southern China. METHODS: Based on an NPC screening cohort established in 2008-2015, information on herbal diet consumption, potential confounding factors, and Epstein-Barr virus (EBV) antibody levels were collected from 10,179 individuals aged 30-69 years in Sihui city, southern China. Cox regression models were performed to examine herbal diet with NPC risk, and logistic regression models were used to examine herbal diet with EBV reactivation. RESULTS: During a median of 7.54 years of follow-up, 69 participants developed NPC. Herbal soup consumption was associated with decreased NPC risk, with HRs of 0.31 (95% confidence interval (CI): 0.15-0.62) for the highest intake frequency and 0.29 (95% CI: 0.16-0.51) for a longer duration. However, herbal tea was not significantly associated. Moreover, we identified herbal soup was inversely associated with EBV seropositivity among all the participants at baseline, with the adjusted ORs being 0.78 (95% CI: 0.65-0.93) for immunoglobulin A antibodies against EBV capsid antigens (VCA-IgA) and 0.76 (95% CI: 0.64-0.91) for nuclear antigen 1 (EBNA1-IgA) in those with the highest frequency and 0.70 (95% CI: 0.59-0.84) for VCA-IgA and 0.64 (95% CI: 0.54-0.77) for EBNA1-IgA in those with the longer duration. Inverse associations were also observed in non-NPC individuals. CONCLUSIONS: With inhibition of EBV reactivation by plants, herbal soup could significantly decrease the risk of NPC in endemic areas.

Tissue distribution study of mangiferin after intragastric administration of mangiferin monomer, Rhizoma Anemarrhenae, and Rhizoma Anemarrhenae-Phellodendron decoctions in normal or type 2 diabetic rats by LC-MS/MS.

A simple, accurate, and reliable liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for the determination of mangiferin in rat plasma and tissue homogenates using rutin as an internal standard (IS). Chromatographic separation was achieved on a Shiseido CAPCELL PAK C18 column (150 × 2.0 mm, 5 µm) using a gradient elution of 1% acetic acid in water and methanol at a flow rate of 300 µL·min-1. Quantification was performed on an API 4000+ triple-quadrupole mass spectrometer equipped with a turbo electrospray ionization (ESI) source in positive ion multiple reaction monitoring (MRM) mode. Selected ion monitoring transitions of 423.1 → 273.1 and 611.4 → 303.3 were chosen to quantify mangiferin and IS. Biological samples were pretreated via protein precipitation with acetonitrile-acetic acid. The standard calibration curves were above the ranges of 2 to 500 ng·mL-1 and 5 to 2000 ng·mL-1 for tissues, and 1 to 600 ng·mL-1 for plasma. All calibration curves for tissue and plasma samples showed good linearity (r ≥ 0.9974) over the concentration ranges. Intra- and inter-day precisions were <14.0%, and accuracy ranged from 97.2% to 111.7%. The established method was successfully applied on mangiferin tissue distribution following the intragastric administration of mangiferin, Rhizoma Anemarrhenae (A. Rhizoma) decoction, or Rhizoma Anemarrhenae-Phellodendron (herb pair, HP) decoction under healthy or diabetic conditions. Mangiferin was detected from all the tested tissues (except for brain) after monomer administration, and the concentrations were lower compared with the decoction groups. Distributions in the HP group were lower than those in the A. Rhizoma group, but mangiferin content in pancreas was obviously higher than in other tissues and in the A. Rhizoma group. Compared with healthy rats, mangiferin distributions in pancreas and intestine were lower in diabetic rats administered with the same dose of the herb pair, but still higher than those in other tissues. In addition, distributions in liver, spleen, lung, kidney, stomach, and plasma were higher than those in the normal group.

A network meta-analysis in comparing prophylactic treatments of radiotherapy-induced oral mucositis for patients with head and neck cancers receiving radiotherapy.

OBJECTIVES: The objective of this network meta-analysis is to optimize the prophylactic treatment for radiotherapy-induced oral mucositis in patients with head and neck cancer (HNSCC) receiving postoperative or definitive radiotherapy with or without chemotherapy. MATERIALS AND METHODS: We searched electronic databases to identify all eligible randomized clinical trials on oral mucositis. The endpoint was grade 0-2 oral mucositis. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were extracted. Network meta-analysis was performed using the frequentist approach to conduct multiple treatment comparisons. RESULTS: In total, 57 trials with 5261 patients were eligible for this study. Both direct and network meta-analysis revealed that low-level laser additional to standard oral care (SOC) was better than most of the other treatments and achieved the highest effect on grade 0-2 oral mucositis, with a surface under the cumulative ranking curve (SUCRA) of 95.8%; however, SOC with or without placebo had worse effect than most of the other treatments and was ranked worst (SUCRA = 0.4%). Moreover, sensitivity analysis performed after we had combined the SOC and placebo groups (non-medication treatment, NMT) yielded similar results, with SUCRA of 91.3% and 3.5% for low-level laser and NMT, respectively. CONCLUSIONS: Low-level laser additional to SOC may be a more effective prophylactic treatment for reducing severe radiotherapy-induced oral mucositis; SOC alone is insufficient for patients with HNSCC receiving postoperative or definitive radiotherapy with or without chemotherapy.

Anticancer Effects of Baicalein in Pancreatic Neuroendocrine Tumors In Vitro and In Vivo.

OBJECTIVES: Baicalein is a Chinese traditional medicine that inhibits tumor migration and growth. Pancreatic neuroendocrine tumors (pNETs) have a high incidence in China, but there are still no effective treatments. The aim of our study was to investigate whether baicalein could inhibit pNETs. METHODS: In vitro, we used BON1-a cell line of pNETs-to analyze the apoptosis and migration and invasion after baicalein treatment via flow cytometry and Western blot. In vivo, we used a xenograft tumors model to evaluate the size of tumors after baicalein treatment. Western blot was used to analyze the expression of apoptosis and migration-related protein. RESULTS: In vitro, the Cell Counting Kit 8 assay showed that baicalein decreased BON1 viability, and flow cytometry demonstrated that baicalein induced BON1 apoptosis and protein changes. In addition, baicalein inhibited BON1 migration and invasion as shown via a Transwell assay. In vivo, baicalein inhibited tumor growth and migration and also increased apoptosis-related protein expression. CONCLUSIONS: Baicalein could increase caspase-3 and Bax expression and decrease survivin and Bcl-2 to induce apoptosis. It inhibits migration and invasion by decreasing expression of vascular endothelial growth factor and matrix metalloproteinases 2 and 9.

Refining the Role of Lymph Node Biopsy in Survival for Patients with Nasopharyngeal Carcinoma: Population-Based Study from the Surveillance Epidemiology and End-Results Registry.

BACKGROUND: The updated version of the National Comprehensive Cancer Network (NCCN) guidelines revised pretreatment workup for nasopharyngeal carcinoma (NPC) into "biopsy of the primary site or neck." Despite provision of important diagnostic information, concerns regarding tumor cell dissemination limit the application of lymph node biopsy. This study aimed to investigate whether biopsy of the neck is associated with impaired survival in NPC. METHODS: A propensity score-matched, population-based cohort identified from the Surveillance, Epidemiology, and End Results database was used to compare overall survival (OS) and disease-specific survival (DSS) of patients who underwent pretreatment cervical lymph node biopsy without subsequent neck dissection or removal of node compared with patients who did not undergo node biopsy. RESULTS: Of 2910 eligible patients, 416 (14.3%) underwent pretreatment lymph node biopsy. After use of control for patient, tumor, and demographic characteristics, biopsy was not associated with impaired OS (hazard ratio [HR], 1.15; 95% confidence interval [CI] 0.89-1.47; P = 0.29) or DSS (HR, 1.07; 95% CI 0.81-1.40; P = 0.63). Interestingly, in the subgroup analysis, the unfavorable effect of biopsy was observed for patients with differentiated non-keratinizing squamous cell carcinoma (but not other histologic types). Race did not positively alter the survival outcomes. CONCLUSIONS: The findings provide reference for clinical practice, showing that pretreatment cervical lymph node biopsy is not associated with impaired survival in NPC, except for patients with differentiated non-keratinizing squamous cell carcinoma. The recommended NCCN guidelines would be more specific by adding details to the general recommendation that neck biopsy is safe for all patients. Future prospective studies are needed to verify the study findings.

Brucine-loaded liposomes composed of HSPC and DPPC at different ratios: in vitro and in vivo evaluation.

OBJECTIVE: The objective of this study is to test the hypothesis that the phase transition temperature (T(m)), the main property of liposomes, can be easily controlled by changing the molar ratio of hydrogenated soy phosphatidylcholine (HSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphacholine (DPPC) after drug encapsulation. MATERIALS AND METHODS: Brucine, an antitumor alkaloid, was encapsulated into the liposomes with different HSPC/DPPC compositions. The T(m)s of the brucine-loaded liposomes (BLs) were determined by differential scanning calorimetry (DSC). Then the physicochemical properties and pharmacokinetics of the BLs with different HSPC/DPPC compositions were investigated and compared. RESULTS: The results of DSC revealed that HSPC and DPPC can combine into one phase. The findings of molecular modeling study suggested that HSPC interacts with DPPC via electrostatic interaction. The molar ratio of HSPC/DPPC influenced the sizes of BLs but had little effect on the entrapment efficiency (EE). The stability of BLs was improved with the increase of the HSPC ratios, especially with the presence of plasma. Following i.v. administration, it was found that AUC values of BLs in vivo were directly related to the HSPC/DPPC ratios of BLs, namely the T(m)s of BLs. DISCUSSION: The behavior of liposomes, especially in vivo pharmacokinetic behavior, can be controlled by the modification of T(m). CONCLUSION: The characterization of BLs in vitro and in vivo had demonstrated that the Tm could be flexibly modified for liposomes composed of both HSPC and DPPC. Using HSPC/DPPC composition may be an efficient strategy to control the T(m), thus control the in vivo pharmacokinetic behavior, of BLs.

Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China.

BACKGROUND: The objective of this study was to evaluate the long-term survival and late toxicities of concurrent-adjuvant chemotherapy in patients with stage III through IVB nasopharyngeal carcinoma (NPC) from endemic regions of China. METHODS: Patients with stage III to IVB NPC were assigned randomly to receive radiotherapy (RT) alone (the RT group) or RT plus concurrent adjuvant chemotherapy (the CRT group). CRT patients received concurrent cisplatin (40 mg/m2) weekly during RT followed by cisplatin (80 mg/m2) and fluorouracil (800 mg/m(2) daily for 5 days) every 4 weeks for 3 cycles. The primary endpoint was overall survival. RESULTS: In total, 316 patients underwent randomization, with 158 to each group. At a median follow-up of 70 months, the 5-year overall survival rate was 72% for the CRT group and 62% for the RT group (hazard ratio, 0.69; 95% confidence interval, 0.48-0.99; P = .043). Failure-free survival was significantly higher in the CRT group (P = .020). Most late toxicities were similar (33% vs. 26%; P = .089), except for cranial neuropathy (P = .042), peripheral neuropathy (P = .041), and ear damage (P = .048), which were significantly increased in the CRT group. CONCLUSIONS: The addition of concurrent adjuvant chemotherapy to RT provides survival benefits to patients with stage III through IVB NPC in endemic regions of China, and it does not increase most late toxicities apart from cranial neuropathy, peripheral neuropathy, and ear damage.

Two new chalcone glycosides from the stems of Entada phaseoloides.

Two new chalcone glycosides 4'-O-(6″-O-galloyl-ß-d-glucopyranosyl)-2',4-dihydroxychalcone (1) and 4'-O-(6″-O-galloyl-ß-d-glucopyranosyl)-2'-hydroxy-4-methoxychalcone (2) together with one known chalcone glycoside 4'-O-ß-d-glucopyranosyl-2'-hydroxy-4-methoxychalcone (3) were isolated from the stems of Entada phaseoloides. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis, including HSQC, HMBC, (1)H-(1)H COSY, and chemical evidences. This is the first report of chalcone-type compounds isolated from the genus Entada.

Ammonium sulfate gradient loading of brucine into liposomes: effect of phospholipid composition on entrapment efficiency and physicochemical properties in vitro.

BACKGROUND: Brucine, the major active alkaloid constituent extracted from traditional Chinese herbal medicine Nux vomica, had been found to possess remarkable antitumor, analgesic, and anti-inflammatory activities. In this study, we attempted to encapsulate brucine into liposomes to improve its therapeutic effects. The entrapment efficiency (EE) and the stability of liposomes are two key factors associated with the therapeutic effects of liposomal drugs. We developed a novel liposome-based brucine formulation that was composed of soybean phosphatidylcholine (SPC) and hydrogenated soybean phosphatidylcholine (HSPC). METHOD: The liposomes with different phospholipid composition were characterized for their EE, vesicle size, drug release profile, and leakage in vitro. RESULTS: The molar ratio of HSPC/SPC = 1:9 was determined as the optimum ratio. Compared with conventional liposomes composed of only SPC or HSPC, EE of the brucine-loaded novel liposomes was increased markedly, especially at high drug/lipid molar ratios. The results of drug release showed that the novel liposomes were more stable than the conventional SPC liposomes in the presence of fetal calf serum. In addition, the results of the leakage experiments revealed that the novel liposomes also had better stability in phosphate buffer solution (PBS) with respect to drug retention. Although the conventional HSPC liposomes is more stable than the novel liposomes, the novel liposomes composed of 10% HSPC and 90% SPC may still have promising application potential because HSPC is much more expensive than SPC. CONCLUSION: Taken together, efficient encapsulation of brucine into the novel liposomes, their improved stability, and the price of phospholipids indicate that the novel liposomes may act as promising carriers for active alkaloids such as brucine.

Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china.

PURPOSE: A prospective randomized trial was performed to evaluate the efficacy of concurrent chemotherapy and adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) in endemic regions of China. METHODS AND MATERIALS: Between July 2002 and September 2005, 316 eligible patients were randomly assigned to receive either radiotherapy alone (RT) or chemoradiotherapy concurrent with adjuvant chemotherapy (CRT). All patients received 70 Gy in 7 weeks using standard RT portals and techniques. The CRT patients were given concurrent cisplatin (40 mg/m(2) on Day 1) weekly during RT, followed by cisplatin (80 mg/m(2) on Day 1) and fluorouracil (800 mg/m(2) on Days 1-5) every 4 weeks (Weeks 5, 9, and 13) for three cycles after completion of RT. All patients were analyzed by intent-to-treat analysis. RESULTS: The two groups were well-balanced in all prognostic factors and RT parameters. The CRT group experienced significantly more acute toxicity (62.6% vs. 32%, p = 0.000). A total of 107 patients (68%) and 97 patients (61%) completed all cycles of concurrent chemotherapy and adjuvant chemotherapy, with a median follow-up time of 29 months. The 2-year overall survival rate, failure-free survival rate, distant failure-free survival rate, and locoregional failure-free survival rate for the CRT and RT groups were 89.8% vs. 79.7% (p = 0.003), 84.6% vs. 72.5% (p = 0.001), 86.5% vs. 78.7% (p = 0.024), and 98.0% vs. 91.9% (p = 0.007), respectively. CONCLUSIONS: This trial demonstrated the significant survival benefits of concurrent chemotherapy plus adjuvant chemotherapy in patients with locoregionally advanced NPC in endemic regions of China.

Anti-endotoxic effects of syringic acid of Radix Isatidis.

The anti-endotoxic effect of syringic acid (SA) isolated from Radix Isatidis (Banlangen, BLG) was studied. SA was extracted and isolated from BLG and diluted into 1% solution. The content of SA-pretreated endotoxin (ET) was quantitatively determined using Limulus test. The ability of fever induction of ET pretreated with SA was measured using endotoxin-induced fever test in rabbits. The LPS-induced death in mice pretreated with and without SA was compared. Results showed that after pretreatment with SA, 83.16% of ET was destroyed, the ET-induced fever in rabbits relieved markedly and the LPS-induced death rate in mice dropped from 68% to 20%. It was concluded that SA isolated from BLG had anti-endotoxic effects.

[Studies on anti-endotoxin activity of F022 from Radix Isatidis].

OBJECTIVE: To study the anti-endotoxin activity and mechanism of F022 from Radix Isatidis. METHOD: The production of TNF-alpha and IL-6 of murine peritoneal macrophages stimulated by LPS was measured by ELISA. The temperature in rabbits was tested after i.v. administration of LPS. The lethality of BCG-primed mice was induced by LPS. RESULT: If F022 was added to macrophages culture simultaneously with LPS or 1 h before addition of LPS, production of TNF-alpha and IL-6 by macrophages was remarkably inhibited in vitro. F022 inhibited the fever induced by LPS in rabbits and protected BCG-primed mice from LPS induced lethality if given before administration of LPS. CONCLUSION: The anti-endotoxin effect of F022 may inhibit LPS binding to its receptor, and it may be a LPS receptor antagonist.