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The impact of sildenafil on pulmonary arterial hypertension (PAH) in Chinese patients has been less investigated. A prospective, open-label, uncontrolled and multicenter study, therefore, was carried out to address this issue. Ninety patients with multicause-induced PAH received oral sildenafil (75 mg/day) for 12 weeks. The 6-minute walk test (SMWT) and cardiac catheterization were performed at the beginning and the end of the 12 weeks. The primary endpoint was the changes in exercise capacity assessed by the SMWT; the secondary endpoint included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening. Drug safety and tolerability were also examined. The results showed that there was a significant improvement in SMWT distances (342 ± 93 m vs 403 ± 88 m, P < .0001), Borg dyspnea score (2.9 ± 2.6 vs 2.4 ± 2.0, P = .0046), World Health Organization functional class, and cardiopulmonary hemodynamics (mean pulmonary artery pressure, P < .0001; cardiac index, P < .0001; pulmonary vascular resistance, P < .0001) after 12 weeks of oral sidenafil therapy. Almost all enrolled patients did not experience significant clinical worsening. This study confirms and extends the findings of previous studies relating to effects of sildenafil on PAH, suggesting that oral sildenafil is safe and effective for the treatment of adult patients with PAH in the Chinese population. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: Globally, cervical cancer is the second most common cancer among women, and determining potential targets involved in tumor progression is necessary. This study investigated the clinic-pathological significance of twist homolog 2 (TWIST2), a basic helix–loop–helix transcription factor, and correlated TWIST2 and E-cadherin expression in cervical cancer. Methods: A series of 142 samples, including 14 cases of normal cervical tissues, 58 cases of cervical intraepithelial neoplasia (CIN) and 70 cases of squamous cell carcinoma (SCC), were examined TWIST2 and E-cadherin immunohistochemical staining and statistical analysis. Results: Increased cytoplasmic and nuclear expression levels of TWIST2 were associated with the malignant transformation of cervical epithelium and the histological progression of cervical cancer. A logistic test showed that TWIST2 was a relatively independent predictor of lymph node metastasis of SCC. Further, increased levels of TWIST2 were also associated with aberrant expression of E-cadherin, an important EMT indicator. Conclusions: The present data suggest that TWIST2 overexpression was significantly linked to cervical cancer progression, which makes it a promising marker for determining the metastatic potential of cervical cancer, and up-regulation of TWIST2, in combination with aberrant E-cadherin expression in primary cervical cancer tissues, may predict the malignant transformation and distal metastasis of carcinomas. [Copyright &y& Elsevier]

Pancreatic cancer is a lethal disease without effective treatments at present. It ranks as s as 4th and 5th in cancer-related mortality in the western countries and worldwide. Locally advanced pancreatic duct carcinoma (PDAC) and metastatic PDAC, usually found the metastases over liver, peritoneum, or lung, have been shown to be with dismal prognosis. Brain metastasis is a rare entity and most cases reported before were found post-mortem. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) has been deemed as a precursor of PDAC with very slow progression rate. Here we reported a case diagnosed with IPMN-derived PDAC with brain metastasis. After surgeries for PDAC and brain metastasis, subsequent chemotherapy and radiotherapy were also given. One and half year after surgery, this patient is still living with good performance status, which may warrant individualization of therapeutic strategy for PDAC with only brain metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Pulmonary embolism is a common disease associated with a high mortality rate. The risk assessment and appropriate treatment selection of patients with acute pulmonary embolism remains a challenge. Design and methods: This single center cohort study included a total of 150 patients (96 male, age=71±15years) with acute pulmonary embolism confirmed by spiral-computed tomography or magnetic resonance image. The prognostic performance of the clinical characteristics and laboratory values were investigated to predict the in-hospital hemodynamically instable events and 30-day all-cause mortality. Results: The rate of in-hospital hemodynamic instability and 30-day all-cause mortality was 21% and 12%, respectively. A multivariate Cox regression analysis demonstrated that a heart rate≥110bpm (odd ratio 4.26 [95% CI 1.42–12.77]), chronic pulmonary disease (6.47 [1.99–21.04]), WBC≥11,000mm3 (3.78 [1.32–10.82]), and D-dimer level≥4.0μg/mL (3.68 [1.01–13.43]) independently predicted the 30-day fatal outcome. A Kaplan–Meier survival analysis showed that the categorization based on the number of risk factors was significantly associated with the likelihood of 30-day all-cause mortality (P<0.0001). Conclusions: The initial presentation of tachycardia, presence of chronic pulmonary disease, elevated WBC and D-dimer on admission can be used to identify the risk for a short-term fatal outcome within 30days in patients with acute pulmonary embolism. [Copyright &y& Elsevier]

Abstract: We previously reported the discovery of 2-aryl-4-benzoyl-imidazoles (ABI-I) as potent antiproliferative agents for melanoma. To further understand the structural requirements for the potency of ABI analogs, gain insight in the structure–activity relationships (SAR), and investigate metabolic stability for these compounds, we report extensive SAR studies on the ABI-I scaffold. Compared with the previous set of ABI-I analogs, the newly synthesized ABI-II analogs have lower potency in general, but some of the new analogs have comparable potency to the most active compounds in the previous set when tested in two melanoma and four prostate cancer cell lines. These SAR studies indicated that the antiproliferative activity was very sensitive to subtle changes in the ligand. Tested compounds 3ab and 8a are equally active against highly paclitaxel resistant cancer cell lines and their parental cell lines, indicating that drugs developed based on ABI-I analogs may have therapeutic advantages over paclitaxel in treating resistant tumors. Metabolic stability studies of compound 3ab revealed that N-methyl imidazole failed to extend stability as literature reported because de-methylation was found as the major metabolic pathway in rat and mouse liver microsomes. However, this sheds light on the possibility for many modifications on imidazole ring for further lead optimization since the modification on imidazole, such as compound 3ab, did not impact the potency. [Copyright &y& Elsevier]

Ligustrum (privet) plants are used by Chinese physicians to prevent and cure hepatitis and chronic bronchitis. Three common Ligustrum plant spp., namely Ligustrum lucidum Ait. (LL), L. pricei Hayata (LP) and L. sinensis Lour. (LS) were collected to assess their analgesic/anti-inflammatory properties on chemical-induced nociception and carrageenan-induced inflammation in rodents. The methanol extracts from Ligustrum plants leaves effectively inhibited nociceptive responses induced by 1% acetic acid and 1% formalin. LP and LL reduced the edema induced by 1% carrageenan. LP exhibited the best potency of the Ligustrum plants. Furthermore, LP reduced the abdominal Evan's blue extravasations caused by lipopolysaccharide, lipoteichoic acid, autocrines and sodium nitroprusside. The triterpenoid content of the three Ligustrum spp. was measured by high performance liquid chromatography using a photodiode array detector. LP contained the highest content of amyrin, betulinic acid and lupeol. LL had the highest content of oleanolic acid and ursolic acid. The various degrees of analgesic/anti-inflammatory effects among three Ligustrum plants may be related to their different triterpenoid contents. LP is a potential analgesic and anti-inflammatory Ligustrum plant. The effects of LP are partially related to the inhibition of cyclooxygenase-2 activity and a decrease in microvascular permeability via the actions of autocrines and kinins. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative injury has been implicated in the etiology of Parkinson''s disease (PD). Gypenosides (GPs), the saponins extract derived from the Gynostemma pentaphyllum, has various bioactivities. In this study, GPs was investigated for its neuroprotective effects on the 1-methyl-4-phenylpyridinium ion (MPP+)-induced oxidative injury of dopaminergic neurons in primary nigral culture. It was found that GPs pretreatment, cotreatment or posttreatment significantly and dose-dependently attenuated MPP+-induced oxidative damage, reduction of dopamine uptake, loss of tyrosine hydrolase (TH)-immunopositive neurons and degeneration of TH-immunopositive neurites. However, the preventive effect of GPs was more potential than its therapeutical effect. Most importantly, the neuroprotective effect of GPs may be attributed to GPs-induced strengthened antioxidation as manifested by significantly increased glutathione content and enhanced activity of glutathione peroxidase, catalyze and superoxide dismutase in nigral culture. The neuroprotective effects of GPs are specific for dopaminergic neurons and it may have therapeutic potential in the treatment of PD. [Copyright &y& Elsevier]

Patients with surgically corrected aortic coarctation have increased proximal aortic stiffness that might contribute to the known worse cardiovascular outcomes. We examined the effect of stenting on the mid-term ascending aortic elastic properties and its relation to cardiac structure and function in adults with native coarctation of the aorta. A total of 20 consecutive patients (13 men, age at stenting 30 ± 8 years) were prospectively studied before and 14 ± 2 months after coarctation stenting. The aortic stiffness index was calculated using the ascending aortic diameters and right arm blood pressure values. The ventricular long-axis function was assessed using pulsed-wave tissue Doppler imaging at the septal site. The results were compared to those from 31 normal controls. Statistically significant improvement was found in aortic narrowing (catheter-derived gradient 32 ± 11 vs 10 ± 6 mm Hg), left ventricular mass index (132.8 ± 50.1 vs 114.7 ± 47.7 g/m2), long-axis function, and left atrial volume index (26.5 ± 5.3 vs 23.7 ± 5.6 mm3/m2). The patients continued to have a thicker left ventricle, reduced long-axis function, and larger left atrium after intervention than did the controls. They also had impaired proximal aortic function with respect to the controls that remained unchanged after stenting (aortic stiffness index 10.7 ± 4.5 to 10.1 ± 3.0). The poststenting aortic stiffness index correlated modestly with the left ventricular mass index and reduced long-axis velocity. In conclusion, aortic stenting resulted in partial mid-term improvement in cardiac structure and function in adults with coarctation of aorta but the ascending aortic elastic properties remained abnormal. Such a degree of impairment was related to residual left ventricular hypertrophy and dysfunction. Early identification of such patients and optimum management might avoid these irreversible ventriculoaortic disturbances and their known consequences. [Copyright &y& Elsevier]

Torreya grandis (Taxaceae) was studied for antinociceptive and anti-inflammatory effects. Leaves were extracted with 80% ethanol at 80°C for 3h and fractionated with petroleum ether, chloroform, ethylacetate and n-butanol. The aqueous ethanolic extract (aq.EE), ethylacetate fraction (EaF) and butanol fraction (BtF) at the doses of (100 and 200mg/kg, i.g.) body weight were used for study. Evaluation of antinociceptive activity was carried out by acetic acid-induced writhing response and formalin-induced paw licking time in the first and second phases of mice. The paw edema induced by formalin- and xylene-induced ear edema were used to assess anti-inflammatory activity. It was found that Torreya grandis extract and fractions at the doses of (100 and 200mg/kg, i.g.) were significantly attenuated the writhing responses induced by acetic acid and second phase of pain response induced by subplantar injection of formalin in mice. In addition, these extract and fractions inhibiting the formaldehyde-induced arthritis as well as xylene-induces edema prolifically. From acute oral toxicity studies no mortality was pragmatic even at highest dose (2500mg/kg, i.g.). Furthermore, our phytochemical studies indicated that the aq. ethanolic extract of leaves contains alkaloids, flavonoids, tannins, terpenoids and saponins. The results provide justification for the folkloric uses of Torreya grandis in the treatment of analgesic and inflammatory-based diseases across the China. [Copyright &y& Elsevier]

Abstract: A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure–activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60mg/kg. [Copyright &y& Elsevier]

Abstract: The objective of the present investigation was to develop and evaluate a drug-in-adhesive transdermal patch for S-amlodipine (S-AM) free base. Initial in vitro experiments were conducted to optimize the formulation parameters before transdermal delivery in rats. The effects of the type of adhesive and the content of permeation enhancers on S-AM free base transport across excised rat skin were evaluated. For in vivo studies, patches were administered transdermally to rats while orally administered S-AM in suspension and intravenously administered S-AM solution were used as controls. The plasma level of S-AM following transdermal application could be maintained for 72h. After transdermal administration to rats, the absolute bioavailability was 88.8% for S-AM free base. After dose normalization, the areas under the plasma concentration–time curve (AUC) and mean residence times (MRT) were evidently increased and extended, respectively. This suggests that the transdermal application of S-AM in a drug-in-adhesive transdermal patch may be used for the treatment for hypertension. [Copyright &y& Elsevier]

Abstract: Aim of the study: To investigate the effects of the ethanol extract from Portulaca oleracea (EEPO) on hypoxia models mice and to find the possible mechanism of its anti-hypoxic actions so as to elucidate the anti-hypoxia activity and provide scientific basis for the clinical use of Portulaca oleracea. Materials and methods: EEPO was evaluated on anti-hypoxic activity in several hypoxia mice models, including closed normobaric hypoxia and sodium nitrite or potassium cyanide toxicosis. To verify the possible mechanism(s), we detected the activities of pyruvate kinase (PK), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and the level of adenosine triphosphate (ATP) in mice cortices. Results: Given orally, the EEPO at doses of 100, 200, 400mg/kg could dose-dependently enhance the survival time of mice in both of the normobaric and chemical hypoxia models. The activity of the glycolysis enzymes and the level of ATP were higher than those of the control. In the pentobarbital sodium-induced sleeping time test and the open-field test, EEPO neither significantly enhanced the pentobarbital sodium-induced sleeping time nor impaired the motor performance, indicating that the observed anti-hypoxic activity was unlikely due to sedation or motor abnormality. Conclusions: These results demonstrated that the EEPO possessed notable anti-hypoxic activity, which might be related to promoting the activity of the key enzymes in glycolysis and improving the level of ATP in hypoxic mice. [Copyright &y& Elsevier]

Abstract: A novel dengue vaccine candidate comprised of a consensus dengue virus envelope protein domain III (cED III) was developed to fight against dengue virus infection. The amino acid sequence of this novel cED III was obtained by alignment of amino acid sequences from different isolates of the four serotypes of dengue viruses. A proof-of-concept study demonstrated that BALB/c mice immunized with the recombinant cED III developed neutralizing antibodies against all serotypes of dengue virus. Moreover, formulation of recombinant cED III with aluminum phosphate could induce long-lasting antibody responses and anamnestic neutralizing antibody responses following challenge with dengue virus at week 28 after priming. These results demonstrate the possibility of developing a single tetravalent vaccine against dengue viral infections. [Copyright &y& Elsevier]

Purpose To evaluate the prophylactic effect of krypton yellow laser for the treatment of macular holes in high myopic eyes in order to reduce the risk of retinal detachment. Methods Twenty-seven eyes of 27 patients with high myopia and macular holes were randomly assigned to two groups. Fifteen patients (group A, 15 eyes) were subject to laser photocoagulation around the hole margin along with an oral placebo (vitamin B1), while 12 patients (group B, 12 eyes) were only given the oral placebo (vitamin B1). The incident rate of retinal detachment due to macular hole and the mean best-corrected visual acuity of the two groups before and after treatment were measured. The data were statistically tested by X2 test and Student's t test. Results The incident rates of retina1 detachment in group A and group B were 20%(3/15) and 58.3%(7/12), respectively (X2=4.201, P<0.05). The mean best-corrected visual acuity (BCVA) of group A on the initial examination was 20/200, while the mean BCVA at the final follow-up was 24/200 (P>0.05). The mean BCVA of group B on the initial examination was 24/200, while the mean BCVA at the final follow-up was 30/200 (P>0.05). No significant difference in initial visual acuity (P>0.05) or final visual acuity (P>0.05) was found between the two groups. Conclusion Krypton yellow laser photocoagulation could reduce the incidence of retinal detachment due to a macular hole in high myopia with acceptable functional results in this study. [ABSTRACT FROM AUTHOR]

Abstract: Background: IV epinephrine is widely used in the treatment of shock to increase blood pressure (BP). However, whether it may also induce hypotension remains unknown. Objective: The aim of this randomized, open-label, controlled pilot study was to observe hemodynamic changes after an IV bolus of epinephrine in healthy rats. Methods: Healthy male Sprague-Dawley rats were randomized to 1 of 5 groups to receive IV epinephrine in doses of 0.5 μg/kg (group 1); 1 μg/kg (group 2); 2 μg/kg (group 3); 4 μg/kg (group 4); or 8 μg/kg (group 5). A sixth group received placebo (0.3 mL of normal saline) and served as the control. BP was monitored continuously. Mean arterial pressure (MAP) and heart rate (HR) were recorded at 0, 5, 15, and 30 seconds and 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, and 20 minutes after administration. The highest mean (SD) systolic BP (SBP) and the lowest mean (SD) diastolic BP (DBP) during this period were also recorded. Hypertension and hypotension were defined as BP increased or decreased > 10% from baseline. Results: Forty-two Sprague-Dawley rats were included in the study. The initial hypertension occurred at ~18 seconds in all epinephrine-treated groups (all, P < 0.01), and the subsequent hypotension occurred at mean (SD) 1.3 (0.5), 2.2 (0.4), 3.0 (0.6), and 3.4 (1.1) minutes in groups 2, 3, 4, and 5, respectively (all, P < 0.01). The highest mean (SD) SBP and the lowest mean (SD) DBP in groups 1, 2, 3, 4, 5, and the control group were 184 (12)/78 (11), 208 (14)/78 (10), 219 (18)/69 (14), 232 (17)/55 (11), 243 (16)/56 (15), and 148 (12)/91 (7) mm Hg, respectively, compared with baseline. HR decreased significantly at 15 seconds in groups 2 and 3, and at 5, 15, and 30 seconds in groups 4 and 5 (all, P < 0.01). One rat in group 4 and 1 rat in group 5 died due to treatment-related cerebral hemorrhage. The control group had no significant hemodynamic changes from baseline. Compared with the control group, MAP increased significantly at 5, 15, and 30 seconds and 1 minute in the epinephrine-treated groups and decreased significantly at 2, 3, and 4 minutes in group 3 and at 2, 3, 4, and 6 minutes in groups 4 and 5 (all, P < 0.05). Conclusions: An IV bolus of epinephrine > 1 μg/kg was associated with biphasic changes in BP, including initial hypertension and subsequent hypotension, in these healthy rats. Future blinded and larger studies using lower doses are needed. [Copyright &y& Elsevier]

Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-β1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-β1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses fibrosis and mediators of the TGF-β1 pathway in the bleomycin (BLM) model of fibrosis. Fibrosis was induced into the skin of female C57BL/6 mice by repeated injections of BLM (50 μg/100 μL) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)2pD using 5, 15, or 30 μg/kg for 21 days. The injected skin was biopsied; analyzed histologically; examined for total collagen by Sircol; and examined for mRNA expression of MMP-13, BMP-7, MCP-1, Gli1, and Gli2 by TR-PCR. Spleen was analyzed for lymphocytes using flow cytometry. Serum was analyzed for cytokines using a multiplexed ELISA. Results showed that all three doses of 17,20S(OH)2pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)2pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-α, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)2pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)2pD offers new therapeutic approaches for fibrotic disorders. [ABSTRACT FROM AUTHOR]

Abstract: We report here the investigation on the effects of Achyranthes bidentata polysaccharides (ABPS) against Lewis lung cancer (LLC) in C57BL/6 mice. Depending on its doses administered in vivo, ABPS was shown to have inhibitory as well as stimulative effects on tumor growth in LLC-bearing C57BL/6 mice. ABPS at low dose could significantly inhibit LLC growth, while high dose treatment of ABPS stimulated, rather than inhibited, LLC growth in C57BL/6 mice. Tumor cell cycle analysis revealed that more tumor cells arrested at G2/M phase after daily low dose intraperitoneal injection of ABPS for consecutive 15 days. The spleen weight increased markedly in LLC-bearing C57BL/6 mice treated with high dose of ABPS. However, the spleen cytotoxicity activity was significantly despaired in mice of high dose treatment of ABPS. Furthermore, we demonstrated that the expressions of IL-6 mRNA and TNF-α mRNA were markedly up-regulated in spleens from mice treated with a high dose of ABPS by RT-PCR reactions, suggesting that the low dose of ABPS inhibits tumor growth via its effect on tumor cell cycle distribution, rather than activation of NK activity as previously suggested. We postulate that the stimulation of tumor growth by high dose of ABPS is associated with dysfunction of NK cell and up-regulation of IL-6 mRNA and TNF-α mRNA expression in murine spleen. [Copyright &y& Elsevier]

We report a case with dextrocardia, corrected transposition of the great arteries. He also had an atrial septum defect (ASD) with patch repair. Activation map showed a centrifugal activation from a focal origin on the systemic lower left atrial ASD patch. Ablation of the origin can terminate the atrial tachycardia. (PACE 2012; 35:e306-e308) [ABSTRACT FROM AUTHOR]

Fat mass and obesity-associated protein (FTO), an RNA N 6-methyladenosine (m6A) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy. • Development of two potent FTO inhibitors with IC 50 values in the low nanomolar range • KD of FTO or pharmacological inhibition of FTO suppresses LSC/LIC self-renewal • Targeting FTO suppresses immune checkpoint gene expression and immune evasion • Targeting FTO by potent inhibitors holds therapeutic promise against various cancers Su et al. develop two potent small-molecule inhibitors against an RNA N6-methyladenosine demethylase called FTO. FTO inhibition shows anti-tumor effects in several types of cancers in mouse models by restricting self-renewal of cancer stem cells and suppressing immune evasion. [ABSTRACT FROM AUTHOR]

Keywords: drug delivery; endosomal escape; microfluidics; pH-responsive; polymer nanoparticles In article number 1905352, Shiqi Wang, Hélder A. Santos, Wei Li, and co-workers report a virus-mimicking polymeric nanoparticle with endosomolytic activity and pH-responsive drug release properties. Drug delivery, endosomal escape, microfluidics, pH-responsive, polymer nanoparticles. [Extracted from the article]

Achieving cellular internalization and endosomal escape remains a major challenge for many antitumor therapeutics, especially macromolecular drugs. Viral drug carriers are reported for efficient intracellular delivery, but with limited choices of payloads. In this study, a novel polymeric nanoparticle (ADMAP) is developed, resembling the structure and functional features of a virus. ADMAP is synthesized by grafting endosomolytic poly(lauryl methacrylate‐co‐methacrylic acid) on acetalated dextran. The endosomolytic polymer mimics the capsid protein for endosomal escape, and acetalated dextran resembles the viral core for accommodating payloads. After polymer synthesis, the subsequent controlled nanoprecipitation on a microfluidic device yields uniform nanoparticles with high encapsulation efficiency. At late endosomal pH (5.0), the ADMAP particles successfully destabilize endosomal membranes and release the drug payloads synergistically, resulting in a greater therapeutic efficacy compared with that of free anticancer drugs. Further conjugation of a tumor‐penetrating peptide enhances the antitumor efficacy toward 3D spheroids and finally leads to spheroid disintegration. The unique structure along with the synergistic endosomal escape and drug release make ADMAP nanoparticles favorable for intracellular delivery of antitumor therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of the study is to evaluate the efficacy and safety of buprenorphine/naloxone sublingual tablets for the treatment of opioid dependence in Chinese adults. Methods: This multicenter, double‐blind, placebo‐controlled study included four periods: induction (3‐5 days), stabilization (7‐21 days), randomization/treatment (6 weeks), and postmedication follow‐up (1 week). A total of 442 participants with opioid dependence were enrolled; 260 were randomized to buprenorphine/naloxone or placebo. The primary outcome was retention in treatment, defined as the time from randomization to treatment completion or treatment failure. Secondary outcomes included maximum consecutive days of abstinence from opioids, self‐reported craving and opioid withdrawal symptoms, and urine drug screen results. Safety assessments included adverse event reporting, electrocardiograms, clinical laboratory tests, vital signs, and prior/concomitant medications. Results: The median treatment retention time (95% confidence internal) with buprenorphine/naloxone was 32 days (26‐38) versus 6 days (5‐8) for placebo, with a Cox hazard ratio of 0.28 (95% confidence interval, 0.21‐0.38; P < 0.0001). The median maximum consecutive days of abstinence (95% confidence interval) was: buprenorphine/naloxone, 21 days (26‐38); placebo, 5 days (5‐8) with a Cox hazard ratio of 0.38 (95% confidence interval, 0.25‐0.60; P < 0.0001). Withdrawal and craving symptoms were significantly milder with buprenorphine/naloxone versus placebo (P < 0.001). Urine drug screen results indicated significantly lower opioid usage in the buprenorphine/naloxone group compared with placebo (P < 0.001). The most commonly reported adverse events in the buprenorphine/naloxone group during treatment were aspartate aminotransferase increased and nasopharyngitis. Discussion: Efficacy and safety results from this clinical trial support a positive benefit‐risk ratio for buprenorphine/naloxone sublingual tablet use in the treatment of an opioid‐dependent Chinese population. [ABSTRACT FROM AUTHOR]

Background: Malignant insulinoma is extremely rare and accounts for only 10% of total insulinoma cases. The goal of this study is to retrospectively analyze clinical data from 15 patients with malignant insulinoma treated at Peking Union Medical College Hospital (PUMCH) from 1984 to April 2017. Methods: "Malignant insulinoma" was used as the keywords in the PUMCH medical record retrieval system to search and obtain patients' clinical information. We identified subjects diagnosed with malignant insulinoma based on clinical or surgical pathological signs and subsequently analyzed their clinical data. Results: Eight males and seven females with a median age at diagnosis of 40 years (38–54 years) were included. Eight patients (53%) had developed metastases at diagnosis, while the others (46.67%) developed metastases during the follow-up visits. The major sites of metastasis were the liver (86.7%), local tissues and blood vessels (33%) and abdominal lymph nodes (13%). All patients displayed neuroglycopenic (100%) and/or autonomic (60%) symptoms, mostly during fasting periods (73.3%), with an average blood glucose level of 1.66 ± 0.51 mmol/L. A total of 93% of the patients had one primary pancreatic lesion, 53% had a lesion in the head of the pancreas, and 47% had a lesion in the tail of the pancreas, with diameters ranging between 0.9 and 6.0 cm. Most liver metastases were multiple lesions. Selective celiac arteriography yielded 100% sensitivity for both primary pancreatic lesions and liver metastases. Most patients received synthetical treatments, including surgery, chemoembolization, and octreotide. Conclusions: Malignant insulinomas have a similar diagnostic process to that of benign insulinomas but require far more comprehensive therapies to alleviate hypoglycemic symptoms and extend patients' survival. [ABSTRACT FROM AUTHOR]

Objective Chordoid meningioma (CM) and clear-cell meningioma (CCM) are rare World Health Organization grade II meningioma subtypes. This study aimed to evaluate favorable factors and appropriate therapeutic strategies for these lesions. Methods We retrospectively reviewed clinical data from 111 cases of grade II meningiomas, including 55 cases of CM and 56 cases of CCM, between January 2011 and December 2015. Results The mean follow-up time of the rare World Health Organization grade II meningiomas ( n = 111) was 45.3 months. In the CM group, 8 patients (14.5%) experienced recurrence, and 2 patients (3.6%) died. In the CCM group, 22 patients (39.3%) experienced recurrence, and 9 patients (16.1%) died. Significant differences were observed between the CM and CCM groups in tumor size ( P = 0.019), history of surgery ( P = 0.038), and peritumoral edema ( P = 0.004). In the CM group, gross total resection was associated with favorable progression-free survival (hazard ratio, 0.144; 95% confidence interval, 0.029–0.714; P = 0.018). In the CCM group, univariate analyses showed that preoperative Karnofsky Performance Status <80 ( P < 0.001), tumor size ≥5 cm ( P = 0.015), tumor size (per-centimeter increase) ( P = 0.022), bone invasion ( P = 0.004), a history of surgery ( P < 0.001), and subtotal resection ( P = 0.009) were associated with worse progression-free survival. Male gender ( P = 0.039), tumor size (per-centimeter increase) ( P = 0.043), bone invasion ( P = 0.030), and a history of surgery ( P = 0.007) were associated with poor overall survival. Conclusions This study showed that gross total resection should be achieved in grade II meningiomas. Patients with larger tumors and/or surgical histories had worse outcomes. [ABSTRACT FROM AUTHOR]

Marine microorganisms are prolific resources of novel antitumor compounds. Inducing cancer cell apoptosis has become a new possibility for tumor treatment. Reactive oxygen species (ROS) are important mediators in apoptosis induced by various antitumor agents. Trichodimerol, a secondary metabolite compound isolated from the marine fungus Trichothecium sp., has been proven to exhibit strong cytotoxic activity on several cancer cell lines. In this study, the anti-proliferative and pro-apoptotic effects of trichodimerol on A375-S2 human melanoma cells were investigated, and related mechanisms also examined. It was found that trichodimerol significantly decreased cell viability in a dose- and time-dependent manner in the MTT assay. Furthermore, trichodimerol increased the percentage of apoptotic cells in DAPI staining assays, the levels of activated caspase-3/7, and sub-G1 fraction in the cell cycle as assessed by flow cytometry, which indicates that trichodimerol has a potent pro-apoptotic effect in A375-S2 cells. Trichodimerol induced ROS levels also showed dose-dependent increases as measured by DCFH-DA, while trichodimerol induced apoptosis was effectively blocked by the ROS inhibitor N-Acetyl-L-cysteine (NAC). Western blot results showed that trichodimerol could increase phosphorylated p38 level and decrease extracellular signal-regulated kinase (ERK) and phosphorylated ERK level. In conclusion, our findings reveal that the anti-proliferative and pro-apoptotic effects of trichodimerol were mediated by ROS, while activation of p38 and inhibition of ERK may also be involved in these effects. The results suggest that trichodimerol may function as a potential therapeutic agent for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer's disease ( AD) treatment as an inhibitor of PS1/ BACE1 interaction. 3- α-Akebonoic acid, which emanated from a high throughput screening ( HTS), was discovered to interfere with PS1/ BACE1 interaction and reduce amyloid β-protein (Aβ) production. In view of the limited source, we instead used naturally rich betulinic acid (compound 2) as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship ( SAR) of triterpenoid-type inhibitor of PS1/ BACE1 interaction. Compound 22 was finally chosen as the most potent PS1/ BACE1 interaction inhibitor, which reduced Aβ generation effectively. [ABSTRACT FROM AUTHOR]

Two major challenges facing cancer immunotherapy are the relatively low therapeutic efficacy and the potential side effects. New drug delivery system and efficient drug combination are required to overcome these challenges. We utilize an alginate hydrogel system to locally deliver 2 FDA-approved drugs, celecoxib and programmed death 1 (PD-1) monoclonal antibody (mAb), to treat tumor-bearing mice. In two cancer models, B16-F10 melanoma and 4T1 metastatic breast cancer, the alginate hydrogel delivery system significantly improves the antitumor activities of celecoxib (CXB), PD-1 mAb, or both combined. These effects are associated with the sustained high concentrations of the drugs in peripheral circulation and within tumor regions. Strikingly, the simultaneous dual local delivery of celecoxib and PD-1 from this hydrogel system synergistically enhanced the presence of CD4+inteferon (IFN)-γ+and CD8+IFN-γ+T cells within the tumor as well as in the immune system. These effects are accompanied with reduced CD4+FoxP3+regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the tumor, reflecting a weakened immuosuppressive response. Furthermore, this combinatorial therapy increases the expression of two anti-angiogenic chemokines C-X-C motif ligand (CXCL) 9 and CXCL10, and suppresses the intratumoral production of interleukin (IL)-1, IL-6, and cycloxygenase-2 (COX2), suggesting a dampened pro-tumor angiogenic and inflammatory microenvironment. This alginate-hydrogel-mediated, combinatorial therapy of celecoxib and PD-1 mAb provides a potential valuable regimen for treating human cancer. [ABSTRACT FROM AUTHOR]

Excess mesangial extracellular matrix (ECM) and mesangial cell proliferation is the major pathologic feature of diabetic nephropathy (DN). Fenofibrate, a PPARα agonist, has been shown to attenuate extracellular matrix formation in diabetic nephropathy. However, the mechanisms underlying this effect remain to be elucidated. In this study, the effect of fenofibrate on high-glucose induced cell proliferation and extracellular matrix exertion and its mechanisms were investigated in cultured rat mesangial cells by the methylthiazoletetrazolium (MTT) assay, flow cytometry and western blot. The results showed that treatment of mesangial cells (MCs) with fenofibrate repressed high-glucose induced up-regulation of extracellular matrix Collagen-IV, and inhibited entry of cell cycle into the S phase. This G1 arrest and ECM inhibition was caused by the reduction of phosphorylation and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT. On the contrary, PPARα siRNA accelerated high glucose-induced cell cycle progression by ERK1/2 and AKT activation. Taken together, fenofibrate ameliorated glucose-induced mesangial cell proliferation and matrix production via its inhibition of PI3K/AKT and ERK1/2 signaling pathways. Such mechanisms may contribute to the favorable effects of treatment using fenofibrate in diabetic nephropathy. [ABSTRACT FROM AUTHOR]