Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma.

High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma. SIGNIFICANCE: Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma. See related commentary by Stouth et al., p. 2091.

The evaluation of N/P fate using the SPARROW model: a case study in an arid and semi-arid region, northern China.

The assessment of nutrients' fate from source to sink is critical to water quality control. As an important ecological reserve in the arid and semi-arid regions of China, the Luanhe River Basin (LRB) has suffered from the deterioration of water quality, thus leading to the urgent management and control. However, few studies have devoted to exploring the fate of N/P contaminations for the entire watershed, due possibly to the large drainage area and heterogeneous watershed composition. Here, we attempt to illustrate N/P contaminations delivery and retention processes using the SPAtially Referenced Regression On Watershed attributes (SPARROW) model. The model reveals 97% of the spatial variability in the TN load and 81% in the TP load, verifying its availability and credibility. The results indicate that anthropogenic sources are dominating the N/P load, which account for 68.5% of N and 74.6% of P inputs. The results highlight the significant retention effects of streams and reservoirs, with 16.4% of N and 13.4% of P removals by streams and 24.3% of N and 10.7% of P removals by reservoirs, respectively. Ultimately, only 49,045.2 t yr-1 (or 16.9%) of N and 1668.7 t yr-1 (or 17.1%) of P being transported to the Bohai Sea. In addition, the analysis of influencing factors showed that regional characteristics (e.g., topography, rainfall), stream size, and delivery distance are potential factors affecting the riverine transport, whereas flow rate and surface area are primarily affecting the reservoirs attenuation. In the future, the watershed water quality management should pay more attention to source management and pollution legacy risks to achieve sustainable and healthy watershed development.

Effects of food hardness on temporomandibular joint osteoarthritis: Qualitative and quantitative micro-CT analysis of rats in vivo.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative joint disease in which quantitative analysis based on magnetic resonance image (MRI) or cone-beam computed tomography (CBCT) remains limited. Moreover, the long-term effects of soft food on the adaptive condylar remodeling process in TMJ-OA remain unclear. This study aimed to assess the effects of food hardness on adaptive condylar remodeling in a healthy TMJ, TMJ-OA, and controlled TMJ-OA. METHODS: Complete Freund's adjuvant (CFA) was used for TMJ-OA induction and Link-N (LN) for TMJ repair. Eighteen mature rats were randomly divided into six groups: (1) control/normal diet (Ctrl-N); (2) control/soft diet (Ctrl-S); (3) TMJ-OA/normal diet (CFA-N); (4) TMJ-OA/soft diet (CFA-S); (5) Link-N-controlled TMJ-OA/normal diet (LN-N); and (6) Link-N-controlled TMJ-OA/soft diet (LN-S). Micro-CT was performed 14, 21, and 28 days after CFA injection to analyze the bone volume, bone volume fraction (BVF), bone mineral density (BMD), and trabecular bone number and thickness (Tb.N, Tb.Th). MRI and histological imaging were performed to support the analysis. RESULTS: Under CFA treatment, the BVF and BMD decreased significantly (p < 0.01) and later recovered to normal. However, more significant improvements occurred in normal-diet groups than soft-diet groups. Additionally, bone volume changes were more predictable in the normal-diet groups than in the soft-diet groups. The normal-diet groups presented a significant decrease and increase in the Tb.N and Tb.Th, respectively (p < 0.05), while the Tb.N and Tb.Th in the soft-diet groups remained largely unchanged. Furthermore, a significantly higher frequency of irregularities on the condylar articular surface was found in the soft-diet groups. CONCLUSIONS: Compared with a soft diet, a normal diet may be beneficial for preserving condyle articular surface and directing bone remodeling in TMJ-OA rats.

Effect of Baihe Gujin decoction combined with Shengmai powder on the expression of IL-1ß and IL-1Ra in peripheral blood CD14+ monocytes from patients with pulmonary tuberculosis.

This experiment was conducted to investigate the effect of taking Baihe Gujin decoction combined with Shengmai powder on IL-1ß and IL-1Ra expression in peripheral blood CD14+ monocytes from patients with pulmonary tuberculosis. For this purpose, one hundred adult patients with primary pulmonary tuberculosis were selected for the study. The age of the enrolled cases ranged from 18 to 60 years old, with a controlled male to the female sex ratio of about 1:1. The Chinese medical evidence was considered to be a qi-yin deficiency type of pulmonary consumption. The patients were randomly divided into experimental and control groups, 50 cases each. In addition, 50 cases of healthy people were selected as a healthy control group, totaling 150 cases. In the experimental group, patients were given Baihe gujin decoction and Shengmai powder based on conventional western medicine, 1 dose for 1 day, 150mL/time for 2 times. The control group was treated with conventional Western medicine. 2 mL of fasting elbow venous blood from the subjects was taken in the morning. Peripheral blood mononuclear cells were isolated by density centrifugation. Monocytes were obtained after incubation with 5 µL of CD14+ immune magnetic beads at 4°C. The relative expression of IL1ß and IL1R genes were measured using real-time quantitative PCR (RT-PCR), respectively. Results showed that the relative expression of IL1ß and IL1R genes was significantly lower in the experimental group after 3 months compared with the control group, and the statistical difference was highly significant (p<0.01). It was concluded that the administration of Baihe gujin decoction and Shengmai powder was closely related to the relative expression of IL1ß and IL1R genes in patients' serum, indicating that Baihe gujin decoction and Shengmai powder have an important role in improving the clinical symptoms of pulmonary tuberculosis.

Postoperative hypothalamic damage predicts postoperative weight gain in patients with adult-onset craniopharyngioma.

OBJECTIVE: This study aimed to recapitulate the change trajectory of postoperative weight and investigate the association between postoperative hypothalamic damage and weight gain and hypothalamic obesity (HO) in patients with adult-onset craniopharyngioma. METHODS: The data of 96 patients with surgically treated primary adult-onset craniopharyngioma were retrospectively analyzed. The association between postoperative hypothalamic damage based on magnetic resonance images or endoscopic observation and postoperative weight gain and HO was determined by multivariable logistic regression. RESULTS: Forty-seven (49.0%) patients and 18 (18.8%) patients experienced clinically meaningful weight gain (≥5%) and HO at last follow-up, respectively. Postoperative weight significantly increased during the first 6 months following surgery, followed by stabilization. Both grade 2 postoperative hypothalamus damage, as evaluated by the magnetic resonance imaging classification system of Müller et al., and higher scores based on the Roth et al. hypothalamic lesion score were significantly associated with postoperative weight gain of ≥5% (p = 0.005 and p = 0.002) and with HO (p = 0.001 and p = 0.008). Additionally, bilateral hypothalamic injury as evaluated by the Hong et al. hypothalamic injury pattern based on endoscopic observation (p = 0.008) could predict postoperative weight gain ≥5%. CONCLUSIONS: Significant postoperative weight gain is common in patients with adult-onset craniopharyngioma. Postoperative hypothalamic damage can predict clinically meaningful weight gain and HO.

Translational and pharmacokinetic-pharmacodynamic application for the clinical development of GDC-0334, a novel TRPA1 inhibitor.

GDC-0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC-0334 were evaluated in this first-in-human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC-0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK-PD of GDC-0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC-0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target-engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose-concentration-effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC-0334 was administered with food. The inhibitory effect of GDC-0334 on the AITC-induced DBF biomarker exhibited a clear sigmoid-Emax relationship with GDC-0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC-0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GDC-0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic-pharmacodynamic (PK-PD) modeling strategy could be implemented in a systematic and step-wise manner to build and learn from emerging data for early clinical development. WHAT QUESTION DID THIS STUDY ADDRESS? Can noncompartmental and population-based analyses be used to describe the PK and PD characteristics of GDC-0334 in preclinical and clinical studies? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? GDC-0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC-0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC-0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK-PD relationship. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The models developed based on TRPA1 agonist-induced dermal blood flow inhibition data can be used to predict PK-PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.

Hypothalamic injury patterns after resection of craniopharyngiomas and correlation to tumor origin: A study based on endoscopic observation.

The precise understanding of hypothalamic injury (HI) patterns and their relationship with different craniopharyngioma (CP) classifications remains poorly addressed. Here, four HI patterns after CP resection based on endoscopic observation were introduced. A total of 131 CP cases treated with endoscopic endonasal approach (EEA) were reviewed retrospectively and divided into four HI patterns: no-HI, mild-HI, unilateral-HI and bilateral-HI, according to intraoperative findings. The outcomes were evaluated and compared between groups in terms of weight gain, endocrine status, electrolyte disturbance and neuropsychological function before and after surgery. A systematic correlation was found between CP origin and subsequent HI patterns. The majority of intrasellar and suprasellar stalk origins lead to a no-HI pattern, the central-type CP mainly develops a mild or bilateral HI pattern, and the majority of tumors with hypothalamic stalk origins result in unilateral HI and sometimes bilateral HI patterns. The proportion of tumors with a maximum diameter >3 cm in the no-HI group was higher than that in the mild-HI group, BMI and quality of life in the no-HI group showed better results than those in the other groups. The incidence of new-onset diabetes insipidus in the bilateral-HI group was significantly higher than that in the other groups. Memory difficulty was observed mainly in the unilateral-HI and bilateral-HI groups. However, the outcomes of electrolyte disturbance, sleep, and cognitive disorder in the unilateral-HI group were significantly better than those in the bilateral-HI group. This study suggests the possibility of using pre- and intraoperative observation of CP origin to predict four HI patterns and even subsequent outcomes after tumor removal.

Associated Factors for Osteoporosis and Fracture in Chinese Elderly.

BACKGROUND The factors associated with osteoporosis are poorly understood in the Chinese population. This study aimed to examine the factors associated with osteoporosis and with fractures in a Chinese elderly population. MATERIAL AND METHODS This was a cross-sectional study of elderly people living in Tianjin between 2012 and 2014. Bone mineral density was measured by dual X-ray absorptiometry. The subjects completed a questionnaire about lifestyle habits, personal and family medical history, calcium intake, and exercising. Data were gathered on occurrence of fracture at 5 years or August 2018, whichever occurred first. RESULTS There were 298 individuals with osteoporosis (18.5% male, median age 67 years) and 397 without (46.3% male, median age 62 years). Male sex (OR=0.051, 95% CI: 0.021-0.126), age (OR=1.049, 95% CI: 1.099-1.202), being divorced/widowed (OR=2.445, 95% CI: 1.219-4.904), digestive ulcer history (OR=3.805, 95% CI: 1.539-9.405), family history of hunchback (OR=2.659, 95% CI: 1.145-6.175), family history of osteoarthropathy (OR=4.222, 95% CI: 2.128-8.375), fracture history (OR=2.138, 95% CI: 1.307-3.496), drinking green tea (OR=0.352, 95% CI: 0.217-0.574), and exercising (OR=0.303, 95% CI: 0.193-0.475) were independently associated with osteoporosis. Digestive ulcer history (OR=3.183, 95% CI: 1.178-8.5992), exercising (OR=0.354, 95% CI: 0.139-0.903), and taking calcium supplements during follow-up (OR=0.262, 95% CI: 0.112-0.611) were independently associated with fractures in patients with osteoporosis. CONCLUSIONS Female sex, age, marital status, history of digestive ulcer and fracture, and family history of hunchback and osteoarthropathy are associated with osteoporosis among elderly subjects, while drinking green tea and exercising are inversely associated. Among the patients with osteoporosis, a history of digestive ulcer is associated with fractures, while exercising and taking calcium supplements are inversely associated.

Potential Mechanisms of Action of Curcumin for Cancer Prevention: Focus on Cellular Signaling Pathways and miRNAs.

Despite significant progressions in treatment modalities over the last decade, either cancer incidence or mortality is continuously on the rise throughout the world. Current anticancer agents display limited efficacy, accompanied by severe side effects. In order to improve therapeutic outcomes in patients with cancer, it is crucial to identify novel, highly efficacious pharmacological agents. Curcumin, a hydrophobic polyphenol extracted from turmeric, has gained increasing attention due to its powerful anticancer properties. Curcumin can inhibit the growth, invasion and metastasis of various cancers. The anticancer mechanisms of curcumin have been extensively studied. The anticancer effects of curcumin are mainly mediated through its regulation of multiple cellular signaling pathways, including Wnt/ß-catenin, PI3K/Akt, JAK/STAT, MAPK, p53 and NF-ĸB signaling pathways. Moreover, curcumin also orchestrates the expression and activity of oncogenic and tumor-suppressive miRNAs. In this review, we summarized the regulation of these signaling pathways by curcumin in different cancers. We also discussed the modulatory function of curcumin in the downregulation of oncogenic miRNAs and the upregulation of tumor-suppressive miRNAs. An in-depth understanding of the anticancer mechanisms of curcumin will be helpful for developing this promising compound as a therapeutic agent in clinical management of cancer.

Effects of Niaoduqing Particles () on Delaying Progression of Renal Dysfunction: A Post-trial, Open-Label, Follow-up Study.

OBJECTIVE: To follow up the participants of the randomized clinical trial "Efficacy and Safety of Niaoduqing Particles () for Delaying Moderate-to-Severe Renal Dysfunction", and assess the long-term effects of Niaoduqing Particles on delaying the progression of renal dysfunction. METHODS: Participants, who had previously been randomly assigned to receive Niaoduqing Particles or placebo for 24 weeks (146 cases in each group), were invited to follow-up and all were administered Niaoduqing Particles 5 g thrice daily and 10 g before bedtime for 24 weeks. The primary endpoints were changes in baseline serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) after completion of the open-label treatment period. RESULTS: After the double-blind period, the median (interquartile range) changes in Scr were 1.1 (-13.0-24.1) and 11.7 (-2.6-42.9) µmol/L for the Niaoduqing Particle and placebo groups, respectively (P=0.008), and the median changes in eGFRs were-0.2 (-4.3-2.7) and-2.21 (-5.7-0.8) mL•min-1•1.73 m-2, respectively (P=0.016). There were significant differences in the double-blind period changes in renal function between groups. After the open-label period, the median changes in Scr were 9.0 (-10.0-41.9) and 17.5 (-6.0-50.0) µmol/L for the Niaoduqing Particle and placebo groups according to baseline grouping, respectively (P=0.214), and the median changes in eGFRs were-2.3 (-6.4-1.9) and-3.7 (-7.5-1.1) mL•min-1•1.73 m-2, respectively (P=0.134). There were no statistical differences in the open-label period changes in renal function between groups. The eGFR reduction of participants who accepted Niaoduqing Particle treatment for 48 weeks was projected to 2.5 mL•min-1•1.73 m-2 per year. CONCLUSION: Niaoduqing Particles appear to have long-term efficacy for patients with moderate-to-severe renal dysfunction. Although there was no statistical difference, the early use of Niaoduqing Paticles seems to ameliorate the worsening of renal function. (Trial registration No. ChiCTR-TRC-12002448).

Resource Investigation and Conservation of Medicinal Plants in Hasi Mountain Nature Reserve of Gansu Province / 中国实验方剂学杂志

Objective:To explore the wild medicinal plant species and utilization of Hasi mountain nature reserve,in order to provide the references for reasonable utilization and protection of the medicinal plant resources in this area. Method:The survey was conducted based on the technical scheme of the Fourth National Survey on Chinese Material Medica Resources. By consulting literature,collecting medicinal plants specimen and visiting survey area,researchers collected and summarized the wild medicinal plant species, and analyzed the results of reserves. Result:The results showed 7 varieties in 247 kinds of wild medicinal plants in Hasi mountain nature reserve,which belonged to 161 genera in 61 families;by the medicinal parts of all wild medicinal plants,the whole plant of a total of 124 species could be used,accounting for 48.82% of the total species,by traditional Chinese medicine efficacy, antipyretic herbs were the majority,accounting for 32.68% of the total. In addition,there were 8 kinds of rare and endangered wild medicinal plants,such as Ephedra sinica,Gentiana dahurica and Epipactis helleborine. Conclusion:Hasi mountain nature reserve has rich wild medicinal plant resources,and is an important part of medicinal plant resources and protection areas of Jingyuan county and Loess Plateau. However, because they are serious affected by incontinent excavation and insect pest,efforts shall be made in scientific protection and rational development.

Efficacy and Safety of Niaoduqing Particles for Delaying Moderate-to-severe Renal Dysfunction: A Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Study.

BACKGROUND: Chronic kidney disease (CKD) with moderate-to-severe renal dysfunction usually exhibits an irreversible course, and available treatments for delaying the progression to end-stage renal disease are limited. This study aimed to assess the efficacy and safety of the traditional Chinese medicine, Niaoduqing particles, for delaying renal dysfunction in patients with stage 3b-4 CKD. METHODS: The present study was a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial. From May 2013 to December 2013, 300 CKD patients with an estimated glomerular filtration rate (eGFR) between 20 and 45 ml·min-1·1.73 m-2, aged 18-70 years were recruited from 22 hospitals in 11 Chinese provinces. Patients were randomized in a 1:1 ratio to either a test group, which was administered Niaoduqing particles 5 g thrice daily and 10 g before bedtime for 24 weeks, or a control group, which was administered a placebo using the same methods. The primary endpoints were changes in baseline serum creatinine (Scr) and eGFR after completion of treatment. The primary endpoints were analyzed using Student's t-test or Wilcoxon's rank-sum test. The present study reported results based on an intention-to-treat (ITT) analysis. RESULTS: A total of 292 participants underwent the ITT analysis. At 24 weeks, the median (interquartile range) change in Scr was 1.1 (-13.0-24.1) and 11.7 (-2.6-42.9) µmol/L for the test and control groups, respectively (Z = 2.642, P = 0.008), and the median change in eGFR was -0.2 (-4.3-2.7) and -2.2 (-5.7-0.8) ml·min-1·1.73 m-2, respectively (Z = -2.408, P = 0.016). There were no significant differences in adverse events between the groups. CONCLUSIONS: Niaoduqing particles safely and effectively delayed CKD progression in patients with stage 3b-4 CKD. This traditional Chinese medicine may be a promising alternative medication for patients with moderate-to-severe renal dysfunction. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR-TRC-12002448; http://www.chictr.org.cn/showproj.aspx?proj=7102.

Observation of proper nutritional therapy in critically ill patients guided by indirect caloimetry / 中国基层医药

Objective To evaluate the effect of proper nutritional therapy guided by indirect caloimetry . Methods According to the digitaltable ,70 critically ill patients whose APACHE II >5 were randomly divided into oberserving ( nutritional therapy guided by indirect caloimetry ) and control groups ( nutritional therapy guided by harris-benedict formula),each group 35 cases.The results of nutrition support were analysed .Results TP,MAMC,ALB were higher than that before treatment in oberserving group (all P0.05).Conclusion The nutritional therapy guided by indirect caloimetry by harris-benedict formula have the some nutritional effect in critically ill patients .

[Efficacy of hirudin in treating immunoglobulin A nephropathy with hematuria: a randomized controlled trial].

OBJECTIVE: To investigate the curative effects and side effects of hirudin in treating immunoglobulin A nephropathy (IgAN) with hematuria and minimal proteinuria in a short-term. METHODS: Two hundred and sixty-two histologically confirmed cases of IgAN with hematuria and minimal proteinuria from 1998 to 2007 were randomly divided into hirudin-treated group (peroral administration of Maixuekang capsules) and dipyridamole-treated group (peroral administration of dipyridamole). In the two groups, contrast analysis of conformation and counts of erythrocytes in urine, urine protein quantitation in 24 hours, levels of serum creatinine (Scr) and creatinine clearance rate (Ccr), blood lipid, five items of blood clotting and side effects was performed. RESULTS: After six-month treatment, the anisotrophy rate and the counts of erythrocytes in urine, and the urine protein quantitation in 24 hours in hirudin-treated group were decreased distinctly as compared with pre-treatment (P<0.01) and dipyridamole-treated group (P<0.05). On the other hand, Ccr was increased obviously in hirudin-treated group as compared with pre-treatment and dipyridamole-treated group (P<0.01). The blood lipid was also ameliorated in hirudin-treated group, but there was no significant difference. The anticoagulation effect of hirudin was better than dipyridamole (P<0.01). Efficacy assessment showed that the total response rate, complete remission rate and predominance remission rate in hirudin-treated group were higher than those in dipyridamole-treated group. Few side effects were found in both groups, and the rate of adverse reaction in gastrointestinal tract was lower in hirudin-treated group as compared with that in dipyridamole-treated group (P<0.05). CONCLUSION: Compared with dipyridamole, hirudin has superiority in kidney protection and decreasing the anisotrophy rate, counts of erythrocytes in urine and the urine protein.