A multicenter phase Ia study of AbGn-107, a novel antibody-drug conjugate, in patients with advanced gastrointestinal cancer.

AbGn-107 is an antibody-drug conjugate directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in a variety of gastrointestinal (GI) malignancies. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a GI cancer-specific Phase I trial. Standard 3 + 3 dose escalation was used evaluating intravenous doses ranging from 0.1 mg/kg every 4 weeks to 1.0 mg/kg every 2 weeks. Key eligibility included chemo-refractory locally advanced, recurrent, or metastatic gastric, colorectal, pancreatic, or biliary cancer, with ECOG PS 0-1; positive AG-7 expression was not required during dose escalation phase. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments every 8 weeks. Primary objectives included safety and determination of maximum tolerated dose; secondary objectives included efficacy defined by objective response rate. Thirty-nine patients were enrolled across seven dose levels during dose escalation phase. Based on safety profile and pharmacokinetic data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase, in which an additional seven patients were enrolled. Median number of lines of prior therapy was 3 (range 1-7). AbGn-107 was generally well-tolerated, with infections, cytopenias, hyponatremia, fatigue, abdominal pain, and diarrhea representing the most common grade 3 or higher treatment-emergent adverse events. One subject achieved a partial response, while 18 (46.2%) achieved a best response of stable disease. Disease control lasting > 6 months was observed in 6 subjects (13.0%), including 4 of 15 (26.7%) treated at the highest dose level. AbGn-107 showed a reasonable safety profile and modest clinical activity in this highly pretreated patient population. Further evaluation is required to assess the clinical validity of AG-7 as a suitable antigen for therapeutic targeting. Clinical Trial information: NCT02908451.

H2S- and Redox-State-Mediated PTP1B S-Sulfhydration in Insulin Signaling.

Because hydrogen sulfide (H2S) is classified as a gaseous signaling molecule, protein S-sulfhydration is known to be one of the mechanisms by which H2S signals are conducted. PTP1B, a negative regulator in insulin signaling, has been found to be S-sulfhydrated at Cys215-SH to form Cys215-SSH in response to endoplasmic reticulum (ER) stress. Therefore, we aimed to understand the change in PTP1B S-sulfhydration and cellular redox homeostasis in response to insulin stimulation. We demonstrated a feasible PEG-switch method to determine the levels of PTP1B S-sulfhydration. According to the results obtained from HEK293T and MDA-MB-231 cells, insulin induced a change in PTP1B S-sulfhydration that was similar to the change in Insulin receptor substrate 1 (IRS1) phosphorylation in both cell lines. However, insulin-induced PTP1B S-sulfhydration and IRS1 phosphorylation were only significantly affected by metformin in HEK293T cells. Insulin also induced an increase in reactive oxygen species (ROS) in both cell lines. However, the level of H2S, GSH, and GSSG was only significantly affected by insulin and metformin in HEK293T cells. HEK293T cells maintained high levels of H2S and cysteine, but low levels of GSSG and GSH in general compared to MDA-MB-231 cells. From these findings, we suggest that PTP1B activity is modulated by H2S and redox-regulated S-sulfhydration during insulin signaling.

Effect of Polarized Training on Cardiorespiratory Fitness of Untrained Healthy Young Adults: A Randomized Control Trial with Equal Training Impulse.

To explore the effects of 8-week polarized training (POL), high-intensity interval training (HIIT), and threshold training (THR) interventions on the cardiorespiratory fitness (CRF) of untrained healthy young adults. This study recruited 36 young adults and randomly assigned them to POL, HIIT, THR, or control (CG) groups to undergo an 8-week training intervention. The training impulse applied to all three intervention groups was identical. The training intensity was divided into Zone 1, 2, and 3 (Z1, Z2 and Z3) on the basis of the ventilatory thresholds (VT). The weekly training intensity distribution for POL was 75% of Z1 and 25% of Z3; HIIT was 100% of Z3 and THR was 50% of Z1 and 50% of Z2. Each group underwent Bruce protocol testing and supramaximal testing before, during, and after the intervention; relevant CRF parameters were assessed. 8 weeks of POL and HIIT significantly increased VT2 (p < 0.05); 8 weeks of POL, HIIT, THR and significantly increased VO2max and TTE (p < 0.05). The effect size of POL in relation to VO2max and TTE improvements was greater than that of HIIT and THR (g = 2.67 vs. 1.26 and 1.49; g = 2.75 vs. 2.05 and 1.60). Aerobic training models with different intensity distributions have different time effects on improving CRF. Relative to HIIT and THR, POL improved more variables of CRF. Therefore, POL is a feasible aerobic training method for improving CRF.

Thermal physiology explains the elevational range for a lizard, Eutropis longicaudata, in Taiwan.

1: The decrease of temperatures along an elevation gradient imposes physiological constraints on reptiles that ultimately determine their distribution ranges. Forest patterns are likely to interact with this process, but very few studies have examined their contribution in determining distribution limits. 2: We examined the role played by thermal physiology and forest cover in determining the elevational ranges of a lizard, Eutropis longicaudata. We integrated this species' thermal traits in simulating its maximum activity time under different conditions of forest cover and elevation using a NicheMapR model. In addition, we evaluated the influence of winter temperatures on the range limit by examining the simulated soil temperatures at the occurrence sites. 3: Laboratory experiments showed that E. longicaudata has a high preferred body temperature and low cold tolerance. The model predicts that maximum activity time decreases with elevation and forest cover. Although unforested areas may provide longer active time in all simulated elevations, mountain areas in Taiwan are heavily forested and are predicted to allow only a very short period of activity above 1000 m elevation. 4: All sightings were indeed located in areas below 1000 m elevation, in which the predicted average soil temperature is above 10 °C in January in cold years. 5: Our results show that reptile physiological response does respond strongly to the change of microclimate induced by forest cover and elevation. Overall, this suggests that forest cover is a major determinant of some reptiles' elevational range.

Is the goal of 12,000 steps per day sufficient for improving body composition and metabolic syndrome? The necessity of combining exercise intensity: a randomized controlled trial.

BACKGROUND: To investigate the differences in body composition and metabolic syndrome (MS) under a daily 12,000-step strategy with or without moderate-intensity walking exercise in college students with obesity. METHODS: Thirty-two adults with obesity (mean (s.d.) age: 19.72 (0.80) years; height: 165.38 (3.99) cm; wt: 83.31 (4.66) kg; body mass index: 30.38 (0.83) kg m- 2) were recruited and randomly assigned to the walking step goal group (WSG; achieving 12,000 steps per day), walking exercise group (WEG; achieving 12,000 steps per day, including 3 days per week on which walking at a step rate of over 103 steps min- 1 was required), or control group (CG; maintaining a free-living life style). Each participant's accumulated daily steps from daily activities and walking exercises were monitored using a smartwatch for 8 weeks. The variables of body composition and MS were measured before and after intervention. RESULTS: Average daily steps over 8 weeks did not significantly differ between the WSG and WEG (11,677.67 (480.24) vs. 12,131.90 (527.14) steps per day, respectively, P > .05). Although the CG and WSG showed no improvement in body composition, the WEG exhibited significant improvements in terms of hip circumference and visceral fat area (VFA) (∆ - 2.28 (3.27) cm and ∆ - 13.11 (9.83) cm2, respectively, P < .05); high-density lipoprotein cholesterol (HDL-C), fasting glucose (FG), and triglycerides (TG) (∆ 16.36 (8.39), ∆ - 2.53 (3.73), and ∆ - 10.52 (36.26) mg dL- 1, respectively, P < .05). The WSG exhibited improvements only in HDL-C (∆ 14.24 (16.13) mg dL- 1, P < .05). CONCLUSION: The combination of walking exercise program and daily step goal is a more time efficient strategy in improving body composition and MS than simply establishing a daily step goal. Furthermore, this strategy may also include a potential reduction effect on the risk factors of cardiovascular diseases. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, number ACTR N12618001237279 (Retrospectively registered).

Association of Activation of Induced COX-2, iNOS and Cytokines with NF-kappa B Depression by Taiwan Wild Grape Ethanolic Extract in Mice.

Taiwan wild grape (Vitis thunbergii var. taiwaniana; VTT) is an important traditional herbal medicine used to treat muscle injuries and acute and chronic pain of the ligaments. Information on its bioactivity and the underlying mechanisms, which have not been elucidated thus far, is needed to demonstrate its value for pharmacological and clinical use. This study presents evidence to clarify the antinociceptive and anti-inflammatory activities of an ethanolic extract of VTT stem (VTTEtOH) and the possible molecular mechanisms involved in such biactivities. In the mice, VTTEtOH significantly reduced the acetic acid-induced writhing response (P < 0.01), formalin-induced licking time (P < 0.01), and edema paw volume at 4 and 5 h after λ-carrageenan injection. VTTEtOH obviously decreased the levels of tumor necrosis factor alpha (P < 0.01), interleukin (IL)-1ß (P < 0.05), interleukin (IL)-6 (P < 0.001), nuclear factor-kappa B (P < 0.001), iNOS (P < 0.001), cyclooxygenase-2 (P < 0.001) and Nitric oxide (P < 0.001) in edema-paw tissue. The molecular mechanisms underlying these effects might involve significant inhibition of the activity of cyclooxygenase-2 through suppression of nuclear factor-kappa B and inducible nitric oxide synthase expression and reduction of the levels of various inflammatory mediators, including tumor necrosis factor alpha, interleukin (IL)-1ß, IL-6, and nitric oxide. Our findings provided pharmacological and histopathological evidences that VTTEtOH alleviates inflammatory pain-related diseases.

Impact of postoperative daily image-guided intensity-modulated radiotherapy on overall and local progression-free survival in patients with oral cavity cancer.

BACKGROUND: We compared the outcome of patients who received non-image-guided intensity-modulated radiotherapy (IMRT) with those who received helical tomotherapy (HT), a daily image-guided radiotherapy (IGRT), after surgery for oral cavity cancer (OCC). METHODS: During the period November 2006 to December 2013, a total of 152 postoperative OCC patients underwent either IMRT (n = 79) or daily IGRT (n = 73) 4 to 6 weeks after surgery. Patients in the IMRT group received 6 MV photon beams to 7 fields and those in the IGRT group received daily fractions of 1.8 or 2 Gy on five consecutive days. RESULTS: Patients who received daily IGRT had higher 5-year overall survival than those who received IMRT (87% versus 48%, p = 0.015). The local progression-free survival rate was also higher in patients who received IGRT (85% versus 58%, p = 0.006). More patients in the IGRT group completed the package of overall treatment time in ≤ 13 weeks and completed their course of radiation therapy in ≤ 8 weeks than patients in the IMRT group (89% versus 68%, p = 0.002; 84% versus 58%, p = 0.001), respectively. The rate of local failure in the primary tumor area was 24.0 % in the IMRT group and 6.8% in the IGRT group. Among patients with primary local failure, the marginal failure rate was 52.6% in the IMRT group and 0 % in the IGRT group. CONCLUSIONS: For patients with locally advanced OCC, postoperative IGRT results in better overall survival, better local progression-free survival, less marginal failure and shorter overall treatment time than postoperative non-image-guided IMRT.

Target-specific identification and characterization of the putative gene cluster for brasilinolide biosynthesis revealing the mechanistic insights and combinatorial synthetic utility of 2-deoxy-l-fucose biosynthetic enzymes.

Brasilinolides exhibiting potent immunosuppressive and antifungal activities with remarkably low toxicity are structurally characterized by an unusual modified 2-deoxy-l-fucose (2dF) attached to a type I polyketide (PK-I) macrolactone. From the pathogenic producer Nocardia terpenica (Nocardia brasiliensis IFM-0406), a 210 kb genomic fragment was identified by target-specific degenerate primers and subsequently sequenced, revealing a giant nbr gene cluster harboring genes (nbrCDEF) required for TDP-2dF biosynthesis and those for PK-I biosynthesis, modification and regulation. The results showed that the genetic and domain arrangements of nbr PK-I synthases agreed colinearly with the PK-I structures of brasilinolides. Subsequent heterologous expression of nbrCDEF in Escherichia coli accomplished in vitro reconstitution of TDP-2dF biosynthesis. The catalytic functions and mechanisms of NbrCDEF enzymes were further characterized by systematic mix-and-match experiments. The enzymes were revealed to display remarkable substrate and partner promiscuity, leading to the establishment of in vitro hybrid deoxysugar biosynthetic pathways throughout an in situ one-pot (iSOP) method. This study represents the first demonstration of TDP-2dF biosynthesis at the enzyme and molecular levels, and provides new hope for expanding the structural diversity of brasilinolides by combinatorial biosynthesis.

Antitussive, anti-pyretic and toxicological evaluation of Ma-Xing-Gan-Shi-Tang in rodents.

BACKGROUND: Ma-Xing-Gan-Shi-Tang (abbreviated as MXGST), an important Chinese herbal prescribed for cough, bronchial inflammation and fever from pneumonia, consists of four medicinal herbs, including Ephedrae herb, Semen Pruni Armeniacae, licorice and Gypsum. These components, especially Ephedrae and Semen Pruni Armeniacae, possess antitussive activities, but they have severe adverse effects. METHODS: The pharmacological activities of MXGST extract in clinical use were investigated with citric acid-induced cough, acetylcholine/histamine-induced bronchial contraction and lipopolysaccharide (LPS)-induced fever in rodents. The subacute toxicology of MXGST extract was evaluated after a 28-day repeated oral administration in rats. RESULTS: Each gram of MXGST extract contained 60 ± 8 µg of ephedrine, 480 ± 40 µg of glycyrrhizic acid and 440 ± 8 µg of amygdalin according to high performance liquid chromatography and a photodiode array detector. MXGST extract produced pronounced, dose-dependent antitussive effects in guinea pigs and reduced hyperthermic syndrome induced by LPS in rats. MXGST extract blocked the bronchial contraction induced by acetylcholine/histamine. Oral administration of MXGST extract for 28 days did not cause any hematological, biochemical or histological changes in rats. CONCLUSIONS: MXGST extract is a safer, more effective Chinese prescription with antitussive and anti-pyretic effects. The antitussive mechanism of MXGST is related to partially relaxing the bronchial smooth muscle by blocking acetylcholinergic and histaminergic receptors.

Bilateral subthalamic stimulation for advanced Parkinson disease: early experience at an Eastern center.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can improve the life quality of patients with advanced Parkinson disease (PD). However, previous studies have stemmed mainly from Western centers. Present study analyzed the 6-month outcomes of bilateral STN-DBS therapy that were observed during a 9-year period at a Taiwanese institute. We retrospectively reviewed 72 consecutive patients, whose mean disease history was 8 years when they underwent surgery. The median "drug-off" Hoehn and Yahr stage was 3. The STN was targeted using T2-weighted magnetic resonance imaging and electrophysiological guidance. The over-time mean differences in the Unified PD Rating Scale (UPDRS) scores and daily levodopa-equivalent dose (LED) were assessed using the repeated measurements ANOVA at 3 and 6 months relative to those of presurgical drug-off baseline. At 6 months postsurgery, the mean UPDRS total, Part II and Part III subscores significantly decreased by 27, 30 and 25 %, respectively, with clinically high effect size. Tremors were markedly (66 %) ameliorated. Moreover, problems of akinesia, rigidity, and locomotion were significantly improved by 20 %. The mean daily LED needs decreased by 25 %; thus, drug-induced dyskinesia was markedly (80 %) diminished. STN-DBS therapy could provide similarly effective impacts to Eastern and Western PD patients. Preoperative optimal selection of patients and postoperative delicate programming ensure a better surgical improvement.

Anti-nociceptive, anti-inflammatory and toxicological evaluation of Fang-Ji-Huang-Qi-Tang in rodents.

BACKGROUND: Fang-Ji-Huang-Qi-Tang (abbreviated as FJHQT), composed by six medicinal herbs including Radix Stephania Tetrandra, Radix Astragali, Rhizoma Atractylodis Macrocephalae, Radix Glycyrrhizae, Rhizoma Zingiberis and Fructus Ziziphi Jujubae, is a frequently Chinese prescription for treating painful and inflammatory disorders such as rheumatoid arthritis. When Radix Stephania Tetrandra was misused with Aristolochia species, acute or chronic nephropathy caused by aristolochic acid was happened. Thus, the present study was aimed to identify Radix Stephania Tetrandra and performed the pharmacological and toxicological evaluation of FJHQT extract in rodents. METHODS: Radix Stephania Tetrandra was identified by macroscopic and microscopic observation, and the content of tetrandrine in FJHQT extract was measured by high performance liquid chromatography. Then, the pharmacological activities of FJHQT extract with respect to clinical use was investigated with acetic acid-induced writhing response, formalin-induced licking response and carrageenan-induced paw edema. Finally, we evaluated the subacute toxicology of FJHQT extract after 28-day repeated oral administration in rats. RESULTS: Radix Stephania Tetrandra was correctly used in FJHQT extract, and the content of tetrandrine in FJHQT extract was 2.5 mg/g. FJHQT extract produced a pronounced and dose-dependent antinociceptive and anti-inflammatory effects in three above models. FJHQT extract after 28-day repeated administration did not caused any hematological, biochemical and histological change in rats. CONCLUSIONS: We suggest that FJHQT extract is a high safety index Chinese medicine for antinociceptive and anti-inflammatory application when Radix Stephania Tetrandra was correctly used in FJHQT. Its antinociceptive and anti-inflammatory mechanism might be related to peripheral nociceptive pathway such as prostaglandins.

Do low skeletal muscle bulk and disturbed body fat mass impact tumor recurrence in stage I/II HCC undergoing surgery? An observational cohort study.

INTRODUCTION: The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed. METHODS: From 2012 to 2021, stage I and II HCC patients who underwent liver resection at our institute were retrospectively reviewed. Their preoperative body composition including skeletal muscle mass and body fat volume was measured by computed tomography (CT). The recurrence outcome was recorded and analyzed. The preoperative serum was collected and subjected to metabolomic analysis. RESULTS: A total of 450 stage I and II HCC patients were included in the current study. Among them, 76% were male and around 60% had HBV infection. After stratified by normal cutoff values obtained from a healthy cohort, 6.4% of stage I/II HCC patients were found to have a low psoas muscle index (PMI), 17.8% a high subcutaneous adipose tissue (SAT) index, and 27.8% a high visceral adipose tissue (VAT) index. Cox regression multivariate analysis further demonstrated that low PMI and high SAT index were independent prognostic factors for time-to-recurrence (TTR) after surgery. Metabolomic analysis discovered that free fatty acid ß-oxidation was enhanced in with low PMI or high SAT index. CONCLUSION: The current study demonstrated that reduced psoas muscle mass may impair while elevated SAT may prolong the TTR of stage I/II HCC patients undergoing liver resections. VAT, on the other hand, was not associated with recurrence outcome after surgery. Further studies are warranted to validate our findings.

Risk factors for second primary neoplasia of esophagus in newly diagnosed head and neck cancer patients: a case-control study.

BACKGROUND: The prevalence of esophageal neoplasia in head and neck (H&N) cancer patients is not low; however, routine esophageal surveillance is not included in staging of newly-diagnosed H&N cancers. We aimed to investigate the risk factors for synchronous esophageal neoplasia and the impact of endoscopy on management of H&N cancer patients. METHODS: A total of 129 newly diagnosed H&N cancer patients who underwent endoscopy with white-light imaging, narrow-band imaging (NBI) with magnifying endoscopy (ME), and chromoendoscopy with 1.5% Lugol's solution, before definite treatment were enrolled prospectively. RESULTS: 60 esophageal lesions were biopsied from 53 (41.1%) patients, including 11 low-grade, 14 high-grade intraepithelial neoplasia and 12 invasive carcinoma in 30 (23.3%) patients. Alcohol consumption [odds ratio (OR) 5.90, 95% confidence interval (CI) 1.23-26.44], advanced stage (stage III and IV) of index H&N cancers (OR 2.98, 95% CI 1.11-7.99), and lower body mass index (BMI) (every 1-kg/m2 increment with OR 0.87, 95% CI 0.76-0.99) were independent risk factors for synchronous esophageal neoplasia. NBI with ME was the ideal screening tool (sensitivity, specificity, and accuracy of 97.3%, 94.1%, and 96.3%, respectively, for detection of dysplastic and cancerous esophageal lesions). The treatment strategy was modified after endoscopy in 20 (15.5%) patients. The number needed to screen was 6.45 (95% CI 4.60-10.90). CONCLUSIONS: NBI-ME surveillance of esophagus should be done in newly-diagnosed H&N cancer patients, especially those with alcohol drinking, lower BMI, and advanced stage of primary tumor.

Moderating roles of grit and locus of control on rumination and suicidality.

Cognitive factors constitute an important risk factor to the development of suicidal thoughts and behaviors (STBs). Engaging in depressive and anger rumination are uniquely associated with elevated vulnerabilities to STBs. Variations in attentional focus and control may further modify the impacts of rumination. For one, grit resembles the inflexible thinking patterns inherent in rumination, potentially contributing to one's capability of persisting in carrying out suicidal behaviors despite fears of pain or death. In the context of rumination, locus of control may alter the perspectives to which individuals attribute negative experiences. The current study examines the moderating roles of grit and locus of control on the impact of depressive and anger rumination on suicidality. Participants (N = 322) completed a battery of self-report questionnaires measuring depressive rumination, anger rumination, grit, locus of control, and suicidal history (a history of suicidal ideation, history of suicidal attempts, or neither). Using hierarchical multinomial logistic regression in R, results revealed that, as opposed to working together, the proposed variables are more independently informative in distinguishing those with a history of suicidal ideation, suicidal attempts, or neither. Findings provide unique contribution to the suicide literature pertaining to how individuals may perceive of their own internal locus of control and grit following suicidal thoughts and beliefs. Clinical implications and future directions are provided as recommendations in line with current findings.

Targeting androgen receptor and the variants by an orally bioavailable Proteolysis Targeting Chimeras compound in castration resistant prostate cancer.

BACKGROUND: Despite the advent of improved therapeutic options for advanced prostate cancer, the durability of clinical benefits is limited due to inevitable development of resistance. By constitutively sustaining androgen receptor (AR) signaling, expression of ligand-binding domain truncated AR variants (AR-V(ΔLBD)) accounts for the major mechanism underlying the resistance to anti-androgen drugs. Strategies to target AR and its LBD truncated variants are needed to prevent the emergence or overcome drug resistance. METHODS: We utilize Proteolysis Targeting Chimeras (PROTAC) technology to achieve induced degradation of both full-length AR (AR-FL) and AR-V(ΔLBD) proteins. In the ITRI-PROTAC design, an AR N-terminal domain (NTD) binding moiety is appended to von-Hippel-Lindau (VHL) or Cereblon (CRBN) E3 ligase binding ligand with linker. FINDINGS: In vitro studies demonstrate that ITRI-PROTAC compounds mechanistically degrade AR-FL and AR-V(ΔLBD) proteins via ubiquitin-proteasome system, leading to impaired AR transactivation on target gene expression, and inhibited cell proliferation accompanied by apoptosis activation. The compounds also significantly inhibit enzalutamide-resistant growth of castration resistant prostate cancer (CRPC) cells. In castration-, enzalutamide-resistant CWR22Rv1 xenograft model without hormone ablation, ITRI-90 displays a pharmacokinetic profile with decent oral bioavailability and strong antitumor efficacy. INTERPRETATION: AR NTD that governs the transcriptional activities of all active variants has been considered attractive therapeutic target to block AR signaling in prostate cancer cells. We demonstrated that utilizing PROTAC for induced AR protein degradation via NTD represents an efficient alternative therapeutic strategy for CRPC to overcome anti-androgen resistance. FUNDING: The funding detail can be found in the Acknowledgements section.

Effectiveness of theta-burst repetitive transcranial magnetic stimulation for treating chronic tinnitus.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS), a noninvasive method for altering cortical excitability, is becoming a therapeutic strategy in auditory research institutions worldwide. Application of inhibiting rTMS on these overactive cortical regions can result in effective tinnitus suppression. The aim of this study is to investigate the efficacy of theta-burst rTMS in patients with chronic tinnitus. STUDY DESIGN: Parallel randomized control study. SETTING: Tertiary referral center. PATIENTS: We enrolled 2 female and 20 male patients in this study. The evaluative tools included tinnitus frequency- and loudness-matching, tinnitus questionnaires (TQ), and the Tinnitus Handicap Inventory (THI). METHODS: The orthogonal projection of the auditory cortex on the scalp was focalized. A figure-eight coil was placed on the surface of the skull over the targeted region with the intensity setting at 80% of the resting motor threshold. We delivered 900 pulses of theta-burst rTMS daily for 10 business days. MAIN OUTCOME MEASURES: Nine of twelve patients (75%) in the active-stimulation group reported tinnitus suppression following treatment with rTMS. The treatment led to reductions of 8.58 and 8.33 in the mean TQ global and THI scores, respectively. Tinnitus loudness also decreased significantly after delivering rTMS. RESULTS: Descriptive analysis of the TQs revealed that patients experienced significant improvements in emotional distress levels and somatic symptoms. CONCLUSIONS: Our preliminary results demonstrate that theta-burst rTMS treatments offer a method of modulating tinnitus. Patients could benefit from emotional improvements, even more than auditory perceptive relief. Further studies are needed to establish a standard protocol and to clarify nervous propagation along the auditory and psychological projection following treatment with rTMS.

Microstructures and magnetic anisotropy of single-layered Fe-Pt alloy films by in-situ annealing.

The single-layered Fe-Pt films with thickness of 30 nm are in-situ deposited directly on Si substrate at various substrate temperatures (Ts) of 350 to 590 degrees C. As the Fe-Pt film is sputtered at substrate temperature is 350 degrees C, it shows (111) preferred orientation and tends to in-plane magnetic anisotropy. The L1(0) Fe-Pt film with (001) texture is obtained and exhibited perpendicular magnetic anisotropy as the substrate temperature is increased to 470 degrees C. The perpendicular coercivity (Hc perpendicular), saturation magnetization (Ms) and perpendicular squareness (S perpendicular) of this film are 6.9 kOe, 674 emu/cm3 and 0.89, respectively, which reveal its significant potential as perpendicular magnetic recording media.

Analgesic and Anti-Inflammatory Activities of Methanol Extract of Cissus repens in Mice.

The aim of this study was to investigate possible analgesic and anti-inflammatory mechanisms of the CR(MeOH). Analgesic effect was evaluated in two models including acetic acid-induced writhing response and formalin-induced paw licking. The anti-inflammatory effect was evaluated by λ-carrageenan-induced mouse paw edema and histopathologic analyses. The results showed that CR(MeOH) (500 mg/kg) decreased writhing response in the acetic acid assay and licking time in the formalin test. CR(MeOH) (100 and 500 mg/kg) significantly decreased edema paw volume at 4th to 5th hours after λ-carrageenan had been injected. Histopathologically, CR(MeOH) abated the level of tissue destruction and swelling of the edema paws. These results were indicated that anti-inflammatory mechanism of CR(MeOH) may be due to declined levels of NO and MDA in the edema paw through increasing the activities of SOD, GPx, and GRd in the liver. Additionally, CR(MeOH) also decreased IL-1ß, IL-6, NFκB, TNF-α, COX-2, and iNOS levels. The contents of two active ingredients, ursolic acid and lupeol, were quantitatively determined. This paper demonstrated possible mechanisms for the analgesic and anti-inflammatory effects of CR(MeOH) and provided evidence for the classical treatment of Cissus repens in inflammatory diseases.

Antidepressant-Like Activity of the Ethanolic Extract from Uncaria lanosa Wallich var. appendiculata Ridsd in the Forced Swimming Test and in the Tail Suspension Test in Mice.

This study investigated the antidepressant activity of ethanolic extract of U. lanosa Wallich var. appendiculata Ridsd (UL(EtOH)) for two-weeks administrations by using FST and TST on mice. In order to understand the probable mechanism of antidepressant-like activity of UL(EtOH) in FST and TST, the researchers measured the levels of monoamines and monoamine oxidase activities in mice brain, and combined the antidepressant drugs (fluoxetine, imipramine, maprotiline, clorgyline, bupropion and ketanserin). Lastly, the researchers analyzed the content of RHY in the UL(EtOH). The results showed that UL(EtOH) exhibited antidepressant-like activity in FST and TST in mice. UL(EtOH) increased the levels of 5-HT and 5-HIAA in cortex, striatum, hippocampus, and hypothalamus, the levels of NE and MHPG in cortex and hippocampus, the level of NE in striatum, and the level of DOPAC in striatum. Two-week injection of IMI, CLO, FLU and KET enhanced the antidepressant-like activity of UL(EtOH). UL(EtOH) inhibited the activity of MAO-A. The amount of RHY in UL(EtOH) was 17.12 mg/g extract. Our findings support the view that UL(EtOH) exerts antidepressant-like activity. The antidepressant-like mechanism of UL(EtOH) may be related to the increase in monoamines levels in the hippocampus, cortex, striatum, and hypothalamus of mice.

Attenuation of in vitro and in vivo melanin synthesis using a Chinese herbal medicine through the inhibition of tyrosinase activity.

BACKGROUND: In traditional Chinese medicine, the skin reflects the health of body organs. A skin whitening agent, named seven whitening creams (also called Chi-Bai-San), has been used since ancient times in China. Chi-Bai-San reduces melanin and helps to reduce wrinkles. PURPOSE: We aimed to determine the skin-whitening ability and safe dose of the seven compounds in Chi-Bai-San. STUDY DESIGN: A common use for Chinese medicine is decocted in water. To mimic the function of Chi-Bai-San apply in clinical, we boiled all seven compound in water, respectively. These single recipe extractions and a mixture of these seven items were used in zebrafish embryo and B16F10 melanoma cell to identify the anti-melanogenesis function. METHODS: Chi-Bai-San comprises Bai-Lian (Ampelopsis japonica), Bai-Ji (Bletilla striata), Bai-Zhi (Angelica dahurica), Bai-Zhu (Atractylodes macrocephala), Bai-Shau (Paeonia lactiflora), Fu-Ling (Wolfiporia cocos), and Jen-Ju-Fen (Pearl powder). All components were extracted by heating in distilled water. The supernatant was collected after centrifugation. The extracted components were introduced into zebrafish embryos at different doses to determine the safe dose. B16F10 melanoma cells were treated with the final dose of each component and the component mixture. Melanin content and tyrosinase activity were assessed in zebrafish and B16F10 cells. Chi-Bai-San and its components were exposed to α MSH-induced B16F10 cells, and detected for mechanism of anti-melanogenesis pathway. RESULTS: Most compounds were not toxic at a low dose (0.1 mg/ml), except A. macrocephala, which resulted in a survival rate of only 30% at 72 hpf. The final dose of A. dahurica, P. lactiflora, W. cocos, and pearl was 1 mg/ml; that of A. japonica was 0.5 mg/ml; and that of A. macrocephala and B. striata was 0.1 mg/ml. Chi-Bai-San markedly decreased melanin content 37.47% in zebrafish embryos. Further, Chi-Bai-San abolished tyrosinase activity and MITF-mediated tyrosinase expression by down regulating the upstream transcription factors ZEB2, ß-catenin, and CREB2 in α MSH-induced B16F10 cells. Additionally, Chi-Bai-San might reduce melanosome secretion from melanocytes. CONCLUSION: Our findings indicate that safety and efficacy of heat-extracted Chi-Bai-San, which can reduce αMSH-induced melanin production by inhibiting the key role of melogenic-related transcription factor and promote the synergic effect of seven types of traditional Chinese herbal medicines.