Comparative pharmacokinetics of tyrosine kinase inhibitor, lapatinib, in dogs and cats following single oral administration.

Lapatinib is an orally administered tyrosine kinase inhibitor used to treat human epidermal growth factor receptor 2 (HER2) -overexpressing breast cancers in humans. Recently, the potential of lapatinib treatment against canine urothelial carcinoma or feline mammary tumor was investigated. However, the pharmacokinetic studies of lapatinib in dogs and cats are not well-defined. In the present study, the pharmacokinetic characteristics of lapatinib in both cats and dogs after a single oral administration at a dose of 25 mg/kg were compared with each other. Lapatinib was administered orally to four female laboratory cats and four female beagle dogs. Blood samples were collected over time, and the plasma lapatinib concentrations were analyzed by HPLC. Following a single dose of 25 mg/kg, the averaged maximum plasma concentration (Cmax) of lapatinib in cats was 0.47 µg/mL and achieved at 7.1 hr post-administration, while the Cmax in dogs was 1.63 µg/mL and achieved at 9.5 hr post-administration. The mean elimination half-life was 6.5 hr in cats and 7.8 hr in dogs. The average area under the plasma concentration-time curve of dogs (37.2 hr·µg/mL) was significantly higher than that of cats (7.97 hr·µg/mL). These results exhibited slow absorptions of lapatinib in both animals after oral administration. The Cmax observed in cats was significantly lower and the half-life was shorter than those observed in dogs. Based on these results, a larger dose or shorter dosing intervals might be recommended in cats to achieve similar plasma concentration as dogs.

Effects of Yizhi Tiaoshen acupuncture on learning and memory function and the expression of phosphorylated tau protein in the hippocampus of Alzheimer's disease model rats / 中国针灸

OBJECTIVE@#To observe the effects of Yizhi Tiaoshen (benefiting mental health and regulating the spirit) acupuncture on learning and memory function, and the expression of phosphorylated tubulin-associated unit (tau) protein in the hippocampus of Alzheimer's disease (AD) model rats, and explore the effect mechanism of this therapy on AD.@*METHODS@#A blank group and a sham-operation group were randomly selected from 60 male SD rats, 10 rats in each one. AD models were established in the rest 40 rats by the intraperitoneal injection of D-galactose and okadaic acid in the CA1 region of the bilateral hippocampus. Thirty successfully-replicated model rats were randomly divided into a model group, a western medication group and an acupuncture group, 10 rats in each one. In the acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Sishencong" (EX-HN 1), "Neiguan" (PC 6), "Shenmen" (HT 7), "Xuanzhong" (GB 39) and "Sanyinjiao" (SP 6); and the needles were retained for 10 min. Acupuncture was given once daily. One course of treatment was composed of 6 days, with the interval of 1 day; the completion of treatment included 4 courses. In the western medication group, donepezil hydrochloride solution (0.45 mg/kg) was administrated intragastrically, once daily; it took 7 days to accomplish one course of treatment and a completion of intervention was composed of 4 courses. Morris water maze (MWM) and novel object recognition test (NORT) were used to assess the learning and memory function of the rats. Using HE staining and Nissl staining, the morphological structure of the hippocampus was observed. With Western blot adopted, the protein expression of the tau, phosphorylated tau protein at Ser198 (p-tau Ser198), protein phosphatase 2A (PP2A) and glycogen synthase kinase-3β (GSK-3β) in the hippocampus was detected.@*RESULTS@#There were no statistical differences in all of the indexes between the sham-operation group and the blank group. Compared with the sham-operation group, in the model group, the MWM escape latency was prolonged (P<0.05), the crossing frequency and the quadrant stay time in original platform were shortened (P<0.05), and the NORT discrimination index (DI) was reduced (P<0.05); the hippocampal cell numbers were declined and the cells arranged irregularly, the hippocampal neuronal structure was abnormal and the numbers of Nissl bodies decreased; the protein expression of p-tau Ser198 and GSK-3βwas increased (P<0.05) and that of PP2A decreased (P<0.05). When compared with the model group, in the western medication group and the acupuncture group, the MWM escape latency was shortened (P<0.05), the crossing frequency and the quadrant stay time in original platform were increased (P<0.05), and DI got higher (P<0.05); the hippocampal cell numbers were elevated and the cells arranged regularly, the damage of hippocampal neuronal structure was attenuated and the numbers of Nissl bodies were increased; the protein expression of p-tau Ser198 and GSK-3β was reduced (P<0.05) and that of PP2A was increased (P<0.05). There were no statistically significant differences in the above indexes between the acupuncture group and the western medication group (P>0.05).@*CONCLUSION@#Acupuncture therapy of "benefiting mental health and regulating the spirit" could improve the learning and memory function and alleviate neuronal injure of AD model rats. The effect mechanism of this therapy may be related to the down-regulation of GSK-3β and the up-regulation of PP2A in the hippocampus, and then to inducing the inhibition of tau protein phosphorylation.

Different operation sequences between acupuncture and cupping therapy for lumbar muscle strain with cold and dampness: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the clinical efficacy on lumbar muscle strain with cold and dampness between the different operation sequences of acupuncture and cupping therapy.@*METHODS@#Seventy-six patients with lumbar muscle strain with cold and dampness were randomly divided into an acupuncture + cupping group (A + C group, 38 cases) and a cupping + acupuncture group (C + A group, 38 cases, 1 case dropped off). In the A + C group, cupping therapy was delivered 10 min after the end of treatment with acupuncture, while in the C + A group, acupuncture therapy was exerted 10 min after the end of treatment with cupping. Acupuncture was applied to Mingmen (GV 4), Yaoyangguan (GV 3), ashi point and bilateral Shenshu (BL 23), Dachangshu (BL 25), Weizhong (BL 40) and Yanglingquan (GB 34), and the needles were retained for 30 min in each intervention. Flash cupping was operated along the bilateral sides of the lumbar spine for 3 min, and the cups were retained for 10 min at bilateral Shenshu (BL 23), Dachangshu (BL 25) and ashi points. The intervention was delivered once every two days, 3 times weekly, for 3 weeks totally in each group. The scores of visual analogue scale (VAS) and Oswestry disability index (ODI), TCM syndrome score and the mean temperature of the lumbar region before and after treatment were compared between the two groups. The safety and the clinical efficacy were assessed for the interventions of the two groups.@*RESULTS@#Compared with the values before treatment, except for the sleep score of ODI, the VAS scores, ODI scores and TCM syndrome scores were decreased after treatment (P<0.01, P<0.05); while the mean temperature of the lumbar region was increased (P<0.01) in both groups. After treatment, the VAS score and the pain score of ODI in the C + A group were lower than those in the A + C group (P<0.05). The incidence rate of adverse reactions of the C + A group was lower than that of the A + C group (P<0.01). The effective rate in the A+C group was 92.1% (35/38), that in the C+A group was 94.6%(35/37), there was no statistical difference between the two groups (P>0.05).@*CONCLUSION@#Different operation sequences between acupuncture and cupping therapy obtain the similar efficacy on lumbar muscle strain with cold and dampness, but cupping therapy delivered prior to acupuncture has certain advantages in relieving pain and improving safety.

Microfluidized Dextran Microgels Loaded with Cisplatin/SPION Lipid Nanotherapeutics for Local Colon Cancer Treatment via Oral Administration.

Multifunctional sequential targeted delivery system is developed as an efficient therapeutic strategy against malignant tumors with selective accumulation and minimal systemic drug absorption. The therapeutic system is comprised of microfluidized dextran microgels encapsulating cisplatin/superparamagnetic iron oxide nanoparticles (SPIONs)-loaded trilaurin-based lipid nanoparticles (LNPs). The microgel system is imparted hierarchically dual targeting via dextran and folic acid (FA) residues, leading to increases both in retention of the microgels in colon and in cellular uptake of the therapeutic LNPs by colon cancer cells while being used for oral therapeutic delivery. Encapsulation of the therapeutic LNPs into dextran microgels attained by microfluidized crosslinking reaction reduces gastrointestinal adhesion and prevents the FA-modified LNPs from cellular transport by proton-coupled FA transporters in small intestine during their oral delivery to colon. Upon enzymatic degradation of the dextran microgels by dextranase present exclusively in colon, LNPs thus released become more recognizable and readily internalized by FA receptor-overexpressing colon cancer cells. The combined chemo/magnetothermal therapeutic effect of dual targeted lipid nanoparticle-loaded microgels from entrapped lipidized cisplatin and alternating magnetic field-treated SPIONs significantly inhibits tumor growth and suppresses metastatic peritoneal carcinomatosis in orthotopic colon cancer-bearing mice.

Radiotherapy combined with chemotherapy increases the risk of herpes zoster in patients with gynecological cancers: a nationwide cohort study / 부인종양

Objective@#This study aimed to determine the effect of radiotherapy (RT) on the risk of herpes zoster (HZ) in patients with gynecological cancers via a nationwide population-based study. @*Methods@#Based on patient data obtained from the National Health Insurance Research Database, 1928 gynecological cancer patients were identified with 1:1 matching for RT and non-RT cohorts by age, index date, and cancer type. Another cohort consisting of 964 noncancer individuals matched was used as normal control. The incidence of HZ was compared between cancer patients with and without RT. Age, comorbidities, cancer-related surgery and chemotherapy (CT), and cancer type were adjusted as confounders. @*Results@#The risk of HZ in cancer patients was higher than that of non-cancer individuals (14.23 versus 8.34 per 1,000 person-years [PY], the adjusted hazard ratio [aHR]=1.38, p=0.044). In the cancer population, the incidence of HZ for the RT and non-RT cohorts was 20.55 versus 10.23 per 1,000 PY, respectively (aHR=1.68, p=0.009). Age >50 years was an independent factor for developing HZ. The 5-year actuarial incidence for patients receiving neither RT nor CT, RT alone, CT alone, and combined modalities was 5.4%, 6.9%, 3.7%, and 9.9%, respectively (p<0.001). In the RT cohort, the risk rose rapidly in the first year, becoming steady thereafter. @*Conclusion@#This population-based study showed that gynecological cancer patients receiving RT combined with CT had the highest cumulative risk of HZ. Health care professionals should be aware of the potential toxicities.

Research progress of antioxidant drugs in myocardial ischemia-reperfusion injury / 药学学报

Myocardial ischemia-reperfusion injury (MIRI) is one of the most difficulties in the studies of cardiovascular diseases, and excessive reactive oxygen species (ROS) accumulation in cells is the main cause of it. Reducing ROS level by antioxidant drugs to protect cardiomyocytes is being the spotlight on MIRI treatment. In this review, the research progress of antioxidant drugs in myocardial ischemia-reperfusion injury in recent years was summarized.

Identification of Potential Therapeutic Targets of Alzheimer's Disease By Weighted Gene Co-Expression Network Analysis / 中国医学科学杂志(英文版)

Objective Alzheimer's disease (AD) is the most common cause of dementia. The pathophysiology of the disease mostly remains unearthed, thereby challenging drug development for AD. This study aims to screen high throughput gene expression data using weighted co-expression network analysis (WGCNA) to explore the potential therapeutic targets.Methods The dataset of GSE36980 was obtained from the Gene Expression Omnibus (GEO) database. Normalization, quality control, filtration, and soft-threshold calculation were carried out before clustering the co-expressed genes into different modules. Furthermore, the correlation coefficients between the modules and clinical traits were computed to identify the key modules. Gene ontology and pathway enrichment analyses were performed on the key module genes. The STRING database was used to construct the protein-protein interaction (PPI) networks, which were further analyzed by Cytoscape app (MCODE). Finally, validation of hub genes was conducted by external GEO datasets of GSE 1297 and GSE 28146.Results Co-expressed genes were clustered into 27 modules, among which 6 modules were identified as the key module relating to AD occurrence. These key modules are primarily involved in chemical synaptic transmission (GO:0007268), the tricarboxylic acid (TCA) cycle and respiratory electron transport (R-HSA-1428517).

Hierarchically targetable polysaccharide-coated solid lipid nanoparticles as an oral chemo/thermotherapy delivery system for local treatment of colon cancer.

Although oral formulations of anticancer chemotherapies are clinically available, the therapeutic action relies mostly on drug absorption, being inevitably accompanied with systemic side effects. It is thus desirable to develop oral therapy systems for the local treatment of colon cancers featured with highly selective delivery to cancer cells and minimized systemic drug absorption. The present study demonstrates the effective accumulation and cell uptake of the doxorubicin and superparamagnetic iron oxide nanoparticles-loaded solid lipid nanoparticle (SLN) delivery system for chemo/magnetothermal combination therapy at tumors by hierarchical targeting of folate (FA) and dextran coated on SLN surfaces in a sequential layer-by-layer manner. Both the in vitro and in vivo characterizations strongly confirmed that the dextran shells on SLN surfaces not only retarded the cellular transport of the FA-coated SLNs by the proton-coupled FA transporter on brush border membranes in small intestine, but also enhanced the particle residence in colon by specific association with dextranase. The enzymatic degradation and removal of dextran coating led to the exposure of the FA residues, thereby further facilitating the cellular-level targeting and uptake of the SLNs by the receptor-mediated endocytosis. The evaluation of the in vivo antitumor efficacy of the hierarchically targetable SLN therapy system by oral administration showed the effective inhibition of primary colon tumors and peritoneal metastasis in terms of the ascites volume and tumor nodule number and size, along with the absence of systemic side effects.

Effects of Different Stimulation of Electroacupuncture on Protein Expressions of SOCS1 and SOCS3 in Rabbits with Acute Facial Nerve Injury / 中国中医药信息杂志

Objective To investigate the effects of different stimulation of electroacupuncture on the protein expressions of SOCS1 and SOCS3 in rabbits with acute facial nerve injury; To determine the better stimulation. Methods New Zealand rabbits were treated with special hemostatic forceps for 5 min, and the length of the lesion was about 2.5 cm. The model of facial nerve injury was induced. The experiment was divided into blank group, sham-operation group, model group, and electoracupuncture weak-, medium-, and strong-stimulation group. The model group received no intervention after surgery. After treatment, the damaged facial nerve of each group was intercepted. The protein expressions of SOCS1 and SOCS3 mediated by negative feedback regulation of JAK-STAT were detected by ABC-ELISA. Results Compared with the blank group, the protein expressions of SOCS1 and SOCS3 in the model group increased (P<0.01). Compared with the model group, the protein expressions of SOCS1 and SOCS3 protein in electroacupuncture weak- stimulation group decreased (P<0.01). Conclusion Electroacupuncture can make SOCS1, SOCS3 protein expressions normal for acute facial nerve injury, and acupuncture treatment effect does not increase with the increase of stimulation.

Effect of liver-soothing and mind-regulating acupuncture on resting-state electroencephalographic signals in rats with post-traumatic stress disorder / 针灸推拿医学（英文版）

Objective:To observe the effect of liver-soothing and mind-regulating acupuncture method on the resting-state electroencephalography (EEG) in rats with post-traumatic stress disorder (PTSD),and to provide evidence for the effect mechanism study and clinical application of acupuncture intervention for PTSD.Methods:Sixty Sprague-Dawley (SD) rats were randomly divided into a blank control group,a model group,a grasping group,a paroxetine group and an acupuncture group,with 12 rats in each group.Except for rats in the blank control group,rats in the other groups were subjected to preparing the PTSD models using 'incarceration plus electric shock' method.After interventions,changes in rat behavior of each group were observed;changes in resting-state EEG were collected and analyzed with multichannel EEG acquisition and analysis system,and image analysis and statistical processing were performed.Results:Compared with the blank control group,the average escape latency in the model group was significantly longer (P＜0.05),and the times of crossing the platform and the effective areas were all significantly reduced (P＜0.01).Compared with the grasping group,the average escape latencies in the paroxetine group and acupuncture group were significantly shortened (P＜0.05),and the times of crossing the platform and the effective areas were all significantly increased (P＜0.05).There were no significant differences in the average escape latency,the times of crossing the platform and the effective areas between the acupuncture group and paroxetine group (all P＞0.05).Compared with the blank control group,the α-wave power spectrum value in the model group was significantly decreased,and the power spectrum values of β-wave,δ-wave and a-wave were significantly increased (all P＜0.01);compared with the grasping group,α-wave power spectrum values in the paroxetine group and acupuncture group were significantly increased (both P＜0.01),and the power spectrum values of β-wave,δ-wave and a-wave were decreased significantly (all P＜0.01).The power spectrum values of α-wave,β-wave,δ-wave and (e)-wave of rats in the acupuncture group were not significantly different from those in the paroxetine group (all P＞0.05).Conclusion:Liver-soothing and mind-regulating acupuncture method can significantly improve the abnormal EEG activity in PTSD rats,which may be one mechanism of liver-soothing and mind-regulating acupuncture method in effectively affecting the brain function in PTSD rats.

Influence of acupuncture on pulmonary function of patients with asthma: a review / 针灸推拿医学（英文版）

Asthma is a common disease with recurrent onset which severely affects patients' quality of life.Acupuncture can improve pulmonary functions in asthma patients and thus treat this disorder.To summarize the status of acupuncture treatment for asthma,we have collected clinical literatures published in the recent 10 years and analyzed the influence of acupuncture on pulmonary functions in asthma patients from the aspects of frequently used points,needling techniques,manipulation and mechanisms to provide references for treating asthma with acupuncture.

Erratum: Active Tumor Permeation and Uptake of Surface Charge-Switchable Theranostic Nanoparticles for Imaging-Guided Photothermal/Chemo Combinatorial Therapy: Erratum.

[This corrects the article on p. 302 in vol. 6, PMID: 26909107.].

Point-selection Rules Analysis in Acupuncture-moxibustion Treatment of Asthma Based on the Evaluation of Pulmonary Function / 上海针灸杂志

Objective To discuss and summarize the point-selection rules in acupuncture-moxibustion treatment of asthma,by arranging and analyzing the relevant clinical studies with pulmonary function as the evaluation index.Method A total of 264 eligible articles of clinical trials about acupuncture-moxibustion treatment of asthma published in the last 10 years were analyzed by using frequency statistical method.Result and Conclusion In acupuncturemoxibustion treatment of asthma,acupoints frequently used majorly included Feishu (BL 13),Dingchuan (EX-B 1),Danzhong (CV 17),Pishu (BL 20),and Shenshu (BL 23),mainly distributed in the Bladder Meridian,Conception Vessel,Governor Vessel,Stomach Meridian,and extra points;syndrome differentiation,symptomatic analysis,and empiric selection were predominant in the point-selection rules.Acupuncture-moxibustion at the above points can effectively improve pulmonary function indexes and attenuate asthma symptoms,thus worth promoting in clinic.

Novel GM-CSF-based vaccines: One small step in GM-CSF gene optimization, one giant leap for human vaccines.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a potent immunomodulatory cytokine that is known to facilitate vaccine efficacy by promoting the development and prolongation of both humoral and cellular immunity. In the past years we have generated a novel codon-optimized GM-CSF gene as an adjuvant. The codon-optimized GM-CSF gene significantly increased protein expression levels in all cells tested and helped in generating a strong immune responses against HIV-1 Gag and HPV-associated cancer. Here, we review the literature dealing with the adjuvant activity of GM-CSF both in animal models and clinical trials. We anticipate that the codon-optimized GM-CSF gene offers a practical molecular strategy for potentiating immune responses to tumor cell-based vaccinations as well as other immunotherapeutic strategies.

Active Tumor Permeation and Uptake of Surface Charge-Switchable Theranostic Nanoparticles for Imaging-Guided Photothermal/Chemo Combinatorial Therapy.

To significantly promote tumor uptake and penetration of therapeutics, a nanovehicle system comprising poly(lactic-co-glycolic acid) (PLGA) as the hydrophobic cores coated with pH-responsive N-acetyl histidine modified D-α-tocopheryl polyethylene glycol succinate (NAcHis-TPGS) is developed in this work. The nanocarriers with switchable surface charges in response to tumor extracellular acidity (pHe) were capable of selectively co-delivering indocyanine green (ICG), a photothermal agent, and doxorubicin (DOX), a chemotherapy drug, to tumor sites. The in vitro cellular uptake of ICG/DOX-loaded nanoparticles by cancer cells and macrophages was significantly promoted in weak acidic environments due to the increased protonation of the NAcHis moieties. The results of in vivo and ex vivo biodistribution studies demonstrated that upon intravenous injection the theranostic nanoparticles were substantially accumulated in TRAMP-C1 solid tumor of tumor-bearing mice. Immunohistochemical examination of tumor sections confirmed the active permeation of the nanoparticles into deep tumor hypoxia due to their small size, pHe-induced near neutral surface, and the additional hitchhiking transport via tumor-associated macrophages. The prominent imaging-guided photothermal therapy of ICG/DOX-loaded nanoparticles after tumor accumulation induced extensive tumor tissue/vessel ablation, which further promoted their extravasation and DOX tumor permeation, thus effectively suppressing tumor growth.

Indocyanine Green-Encapsulated Hybrid Polymeric Nanomicelles for Photothermal Cancer Therapy.

Indocyanine green (ICG), an FDA approved medical near-infrared (NIR) imaging agent, has been extensively used in cancer theranosis. However, the limited aqueous photostability, rapid body clearance, and poor cellular uptake severely restrict its practical applications. For these problems to be overcome, ICG-encapsulated hybrid polymeric nanomicelles (PNMs) were developed in this work through coassociation of the amphiphilic diblock copolymer poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and hydrophobic electrostatic complexes composed of ICG molecules and branched poly(ethylenimine) (PEI). The ICG-encapsulated hybrid PNMs featured a hydrophobic PLGA/ICG/PEI core stabilized by hydrophilic PEG shells. The encapsulation of electrostatic ICG/PEI complexes into the compact PLGA-rich core not only facilitated the ICG loading but also promoted its aqueous optical stability. The effects of the chain length of PEI in combination with ICG on the physiochemical properties of PNMs and their drug leakage were also investigated. PEI(10k) (10 kDa) could form highly robust and dense complexes with ICG, and thus prominently reduced ICG outflow from the PNMs. The results of in vitro cellular uptake and cytotoxicity studies revealed that the ICG/PEI(10k)-loaded PNMs significantly promoted cellular uptake of ICG by HeLa cells due to their near-neutral surface, and thereby augmented the NIR-triggered hyperthermia effect in destroying cancer cells. These findings strongly indicate that the ICG/PEI10k-loaded PNMs have significant potential for attaining effective cancer imaging and photothermal therapy.