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Cu/La2Si2O7/TiO2 composite photothermal nanomaterials with broad spectral absorption modified were prepared by molten salt calcination using spherical SiO2@TiO2 and La/Cu-PDACP as precursors.

Purpose: To explore the role of TWEAK in tumor growth and antitumor immune response and the activity and mechanism of RG7212, an antagonistic anti-TWEAK antibody, in tumor models.Experimental Design: TWEAK-induced signaling and gene expression were explored in tumor cell lines and inhibition of these effects and antitumor efficacy with RG7212 treatment was assessed in human tumor xenograft-, patient-derived xenograft, and syngeneic tumor models and phase I patients. Genetic features correlated with antitumor activity were characterized.Results: In tumor cell lines, TWEAK induces proliferation, survival, and NF-κB signaling and gene expression that promote tumor growth and suppress antitumor immune responses. TWEAK-inducible CD274, CCL2, CXCL-10 and -11 modulate T-cell and monocyte recruitment, T-cell activation, and macrophage differentiation. These factors and TWEAK-induced signaling were decreased, and tumor, blood, and spleen immune cell composition was altered with RG7212 treatment in mice. RG7212 inhibits tumor growth in vivo in models with TWEAK receptor, Fn14, expression, and markers of pathway activation. In phase I testing, signs of tumor shrinkage and stable disease were observed without dose-limiting toxicity. In a patient with advanced, Fn14-positive, malignant melanoma with evidence of tumor regression, proliferation markers were dramatically reduced, tumor T-cell infiltration increased, and tumor macrophage content decreased. Antitumor activity, a lack of toxicity in humans and animals and no evidence of antagonism with standard of care or targeted agents in mice, suggests that RG7212 is a promising agent for use in combination therapies in patients with Fn14-positive tumors. Clin Cancer Res; 19(20); 5686–98. ©2013 AACR.

XLS file, 33K, Summary of RG7212 monotherapy and combination antitumor efficacy.

PDF file, 306K, RG7212 antitumor efficacy and characterization of tumor models used to assess RG7212 antitumor efficacy.

PDF file, 771K, TWEAK promotes proliferation and survival signaling with minimal effect on cell viability.

PDF file, 132K.

XLS file, 193K, Sorted Affymetrix gene array data.

PDF file, 29K, Lead antibodies have identical binding properties and neutralizing activities.

PDF file, 176K, Assessment of baseline gene expression in RG7212 responders and non-responders in qPCR array.

A girl, aged 11 years, was admitted due to recurrent rash on the whole body and mucosa for 10 years, and typical rash was erythema at the perioral region, hand-foot joints, vulva, and perianal region, with blisters, erosions, and ulcers on the erythema. The girl was improved after zinc supplementation. Her younger brother had similar rash and medical history. The histopathological examination showed epidermal parakeratosis with mild hyperkeratosis, severe spongiform edema of the stratum corneum, significant proliferation of acanthocytes, and vacuolation of keratinocytes. The genetic testing revealed that both the girl and her younger brother had a homozygous mutation of c.1456(exon9)delG in the SLC39A4 gene, and thus the girl was diagnosed with acrodermatitis enteropathica. It is concluded that for children with recurrent rash on the limbs and at the perioral region, genetic testing should be performed as early as possible to make a confirmed diagnosis, and a sufficient dose of zinc supplementation should be given, while the levels of trace elements such as blood zinc should be regularly monitored.

Cu-Modified La

Due to the strong reduction of the coating thickness and to the large stress gradient that may occur in coated structures, it is hard to guarantee the calculation accuracy in the design of coated structures by the commercial software. In this case, an accurate and efficient calculation method for researching the coated structure is valuable. It will contribute to the accurate design and quality promotion of coated structures. In this paper, the 3D solutions of elastic transversely isotropic coated structure under conical contact are derived based on the general solutions of the elastic transversely isotropic material. The solutions are derived in two cases including the normal contact load and the tangential contact load. The numerical results present that this method presents good convergence, high efficiency and stability. Based on this method, the optimal thickness of the coating and the interfacial stress can be obtained accurately. Because the interfacial stress can lead to the debonding failure of coated structures, a method for predicting interface security state with evaluation criterion for interfacial failure is proposed. The corresponding analysis will contribute to the strengthening design of the coated structure.

Background Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. Methods Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. Results In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. Conclusions The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

A girl, aged 22 months, attended the hospital due to recurrent vulvar rashes for more than half a year. Skin biopsy showed Langerhans cell histiocytosis, and evaluation of systemic conditions showed no systemic involvement. Therefore, the girl was diagnosed with Langerhans cell histiocytosis (skin type). In conclusion, for rashes on the vulva alone, if there are no specific clinical manifestations, the possibility of Langerhans cell histiocytosis should be considered after molluscum contagiosum, sexually transmitted diseases, and Fordyce disease are excluded.

Crigler-Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine-diphosphate-glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1-modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first-in-human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First-in-human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.

Crigler‐Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine‐diphosphate‐glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1‐modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first‐in‐human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First‐in‐human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.

The objective of this study was to systemically and comprehensively evaluate the associations between smoking and disease outcomes in patients with ankylosing spondylitis (AS). Information on smoking, clinical features, and sociodemographic characteristics was collected by a questionnaire administered directly to the patient. Group differences were analyzed by t test or chi-square test. Logistic regression analysis was conducted with the Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), C-reactive protein, and erythrocyte sedimentation rate as the dependent variables and different stratification of smoking duration, smoking intensity, and cumulative smoking as independent variables. In order to compare our results with previous studies, meta-analysis was performed to calculate standardized mean difference (SMD) for relationship between outcomes and smoking status. A total of 1178 AS patients were analyzed. Compared with non-smokers, the risk of having active disease (BASDAI ≥ 4) was higher in patients who smoked at least 15 years, or 15 cigarettes per day, or 15 pack-years (OR = 1.70 [1.06, 2.73], 1.75 [1.08, 2.82], and 1.97 [1.06, 3.67], respectively); and smokers had increasing risk of BASDAI ≥ 4 with increasing years of smoking, or cigarettes per day, or pack-years (p-trend = 0.010, 0.008 and 0.006, respectively). The risk of having active disease was higher in patients who smoked at least 15 cigarettes per day or 15 pack-years (OR = 1.74 [1.06, 2.84] and 2.89 [1.56, 5.35], respectively), with increasing number of cigarettes per day and pack-years. Smokers had an increased risk of BASFI ≥ 4 (p-trend = 0.040 and 0.007, respectively). By meta-analysis, current, former and ever smokers had significantly higher BASDAI (SMD = 0.34 [0.18, 0.48], 0.10 [0.01, 0.19], and 0.27 [0.20, 0.34], respectively) and BASFI (SMD = 0.35 [0.16, 0.55], 0.30 [0.22, 0.39], and 0.35 [0.21, 0.50], respectively) compared to non-smokers. Smoking is a risk factor for greater disease activity and worse functioning in AS patients.

Using first-principles calculations, we investigate the geometric structures, stabilities, electronic structures, and magnetic properties of three kinds of AsP monolayers: blue-phosphorene-like AsP (blue AsP), black-phosphorene-like AsP (black AsP) and puckered AsP. Stability analysis implies a high possibility of fabricating AsP monolayers in experiments. The blue AsP monolayer possesses the most stable structure with an indirect band-gap of 2.52 eV. The blue AsP system is also a good candidate for visible light photocatalytic decomposition of water. The black one is a semiconductor with a direct band gap of 1.53 eV at the Γ point. The puckered AsP monolayer shows the lowest stability and narrowest indirect band gap of 1.38 eV. Both the intrinsic defects of P and As vacancies result in half-metallicity and magnetic semiconductor for blue and black AsP monolayers, respectively. Our results provide useful information to obtain new two dimensional materials for water splitting photocatalysts and spintronic devices.

Objective: To study the effect of Shenmai injection combined with irbesartan on the microinflammatory state and nutritional status of patients with peritoneal dialysis. Methods: A total of 108 patients with end-stage renal disease who received peritoneal dialysis in Guangyuan First People’s Hospital between May 2014 and November 2016 were selected and randomly divided into two groups, the combined group received Shenmai injection combined with irbesartan therapy, and the ARB group received irbesartan therapy. The renal function indicators, inflammatory response indicators and nutritional status indicators of the two groups were detected before treatment as well as 3 months and 6 months after treatment. Results: Scr, BUN and RRF of both groups 3 months and 6 months after treatment were not significantly different from those before treatment; serum SAA, CRP, PAPP-A, CHE, TNF-α, IL-6 and IL-8 contents of both groups 3 months and 6 months after treatment were significantly lower than those before treatment, and serum SAA, CRP, PAPP-A, CHE, TNF-α, IL-6 and IL-8 contents of combined group 3 months and 6 months after treatment were significantly lower than those of ARB group; serum Alb, PA and Tf contents as well as mid-arm muscle circumference and mid-arm circumference of combined group 3 months and 6 months after treatment were not significantly different from those before treatment while serum Alb, PA and Tf contents as well as mid-arm muscle circumference and mid-arm circumference of control group 3 months and 6 months after treatment were significantly lower than those before treatment. Conclusion: Shenmai injection combined with irbesartan for peritoneal dialysis can reduce the microinflammatory state and improve the nutritional status.

Background Atopic dermatitis (AD) is a chronic inflammatory skin disease. The 5q22.1 region was found to have an association with AD in our previous genome-wide association study (GWAS). Objective To identify the AD susceptibility gene in 5q22.1 and observe its expression in AD tissues. Methods Suggestive indels from the GWAS data were genotyped in 3013 AD patients and 5075 controls from the Chinese Han population with the SequenomMassArray system. Association, Bayesian and bioinformatics analyses were used to identify possible causal indels and genes in the 5q22.1 region. Immunohistochemistry (IHC) was performed to observe protein expression in the tissues. PLINK 1.07 software was used for all statistical analyses. Results The genotyping and association analysis showed that six deletions and four SNPs were associated with AD (P Conclusions The study indicates that TMEM232 in the 5q22.1 region is the causal gene for AD in the Chinese Han population.

The study aimed to determine whether unique clinical patterns of AS may exist in China, specifically to explore the different clinical manifestations caused by gender, HLA-B27 status, and age at disease onset. The multicenter cross-sectional survey was conducted and 1251 patients were enrolled across China, representing a broad spectrum of Chinese AS patients. The mean age at onset and diagnosis were 29.2 (11.4) and 33.5 (12.6) years, respectively. The male/female ratio was 2.7:1. Acute anterior uveitis (AAU) was experienced in 10.3% of AS patients and 9.1% patients had juvenile-onset AS (JoAS). Men were significantly younger at onset and diagnosis and showed a higher frequency of HLA-B27 positivity, JoAS, and AAU than women. HLA-B27-positive patients had a younger age of onset than HLA-B27-negative patients. HLA-B27-positive patients were nearly three times as likely to develop AAU than negative patients (P = 0.04). JoAS patients had a family history of AS more often than adult-onset AS (AoAS) patients, and 4.9% of JoAS patients underwent surgical treatments, a rate more than six times that of AoAS patients (P = 0.01). Men had higher levels of C-reactive protein than women, as did HLA-B27 positives compared to negative patients, and JoAS compared to AoAS (all P

Mesenchymal stem cells (MSCs) serve immuno-regulatory functions and offer a promising novel treatment for certain autoimmune diseases. The present study investigated the therapeutic effect of mice bone marrow (BM)-MSCs on mice with relatively late stage of Sjögren-like disease and the impact of BM-MSCs on the microRNA (miRNA) expression profiles of splenic CD4+ T cells. Female NOD/Ltj mice were randomized into two groups: The disease group (n=8) and the MSC-treated group (n=8). Female ICR mice served as the healthy control group (n=8). The MSC-treated group received an injection of MSCs when they were 26 weeks old. Water intake, blood glucose and salivary flow rate were measured and submandibular glands were resected and stained with hematoxylin and eosin to calculate the focus score. The concentrations of interleukin (IL)-2, IL-6, hepatocyte growth factor, interferon γ, IL-10, prostaglandin E2, transforming growth factor β1 and tumor necrosis factor-α in serum were measured using ELISA. The expression of miRNAs in splenic CD4+ T cells were measured using deep sequencing. The results demonstrated that treatment with BM-MSCs prevented a decline in the salivary flow rate and lymphocyte infiltration in the salivary glands of NOD mice, indicating that MSC-treatment had a therapeutic effect on NOD mice with relatively late stage of Sjögren-like disease. ELISA and deep sequencing results showed that the three groups of mice had different serum concentrations of cytokines/growth factors and different miRNA expression profiles of splenic CD4+ T cells. This implies that the alteration in serum levels of cytokines/growth factors and miRNA expression profiles of splenic CD4+ T cells may explain the therapeutic effect MSCs have on Sjögren's syndrome.

A girl, aged 15 months, attended the hospital due to recurrent skin erythema, blisters, and desquamation for more than 7 months. Giemsa staining and immunohistochemical staining showed mast cell infiltration and degranulation. Hematoxylin staining showed spinous layer edema and blister formation under the epidermis, with a large amount of serous fluid and a small number of inflammatory cells in the blister. Marked edema was observed in the dermis, with diffused mononuclear cell infiltration. The girl was diagnosed with mastocytosis. Mastocytosis should be considered for children with recurrent skin erythema and blisters.

7525 Background: TG-1701 is a selective, covalent BTK inhibitor administered once daily (QD). Both the “U2” combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ε inhibitor umbralisib) and BTK inhibition are highly active in treatment-naïve (TN) and relapsed/refractory (R/R) CLL, each having previously demonstrated superiority over standard chemoimmunotherapy. Here we report the results of the dose escalation of TG-1701 monotherapy and TG-1701+U2. Methods: Pts with R/R CLL and lymphoma were enrolled in a Ph 1 study initially evaluating dose escalation (DE) of oral TG-1701 QD continuously administered in 28-day cycles (100, 200, 300, and 400 mg). After characterizing the safety profile of TG-1701 monotherapy, we implemented a parallel DE arm of TG-1701+U2. Select dose levels of TG-1701 monotherapy were expanded in CLL, MCL and Waldenström's (WM). All pts were treated until disease progression. The primary objectives are to characterize the safety profile and define the recommended Ph 2 doses for the drugs alone and in combination. Results: As of 03 February 2021, 123 pts were treated with TG-1701: 25 in the monotherapy DE arm, 61 in the 200 mg disease-specific cohorts (20 CLL [5 TN], 21 MCL [4 TN], 20 WM [8 TN]), 20 in the 300 mg CLL cohort (4 TN), and 17 in the 1701+U2 DE arm. The median # of prior therapies was 1 (range, 1 - 10). All pts were BTKi-naïve. All 123 pts were evaluable for safety. TG-1701 was well tolerated and the maximum tolerated dose (MTD) for monotherapy was not reached at 400 mg (demonstrating near 100% saturation of the BTK at all dose levels studied). Treatment emergent adverse events (TEAE) of clinical interest included atrial fibrillation (AF 4.0% of pts, G ≥3 in 1 case), G ≥3 hypertension (2.4%), and bleeding events (18.7%, all G1-2). No cases of ventricular tachyarrhythmia were reported. TEAEs leading to TG-1701 dose reduction occurred in 6.5% of pts. TEAEs leading to treatment discontinuation occurred in 1.6% of pts (AF, COVID-19). At the data cut-off, 119 pts were evaluable for response, including 40 in DE (Table). The median duration of response has not been reached among responders overall. The median follow-up (mFU range) was 15.9 mos (1.3 - 28.6+) in DE and 8.5 mos (1.4 -15.6+) in disease-specific cohorts. Conclusions: TG-1701 exhibits an encouraging safety and efficacy profile. The combination of 1701+U2 has been well tolerated and dose escalation continues. The combination shows enhanced depth of response over TG-1701 monotherapy. Recruitment to this study continues. Response per investigator review by treatment group. Clinical trial information: NCT03671590. [Table: see text]

// Santasree Banerjee 1,* , Dongzhu Lei 2,* Shengran Liang 1,* , Li Yang 3,* , Saijun Liu 1 , Zhu Wei 4 and Jian Ping Tang 4,* 1 BGI-Shenzhen, Shenzhen, China 2 Center of Prenatal Diagnosis, ChenZhou No.1 peoples hospital, Hunan, China 3 Biological therapy center, The Third Affiliated Hospital, Sun-Yet-San University, Guangzhou, China 4 Department of dermatology, Hunan Children’s Hospital, Hunan, China * These authors have contributed equally to the manuscript Correspondence to: Jian Ping Tang, email: // Keywords : neurofibromatosis type 1, next generation sequencing, novel mutation, NF1 gene, mutational screening Received : July 10, 2016 Accepted : December 06, 2016 Published : December 14, 2016 Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe´-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple cafe-au-lait spots throughout her whole body. In family 2, the proband is a 6 months old girl with several cafe-au-lait spots mostly in her trunk and in lower limbs. In family 3, the proband is a 4 months old boy with several cafe-au-lait spots, tibial pseudarthrosis, and chronic iron deficiency anemia. In family 4, the proband is a 14 years old boy with multiple cafe-au-lait spots of variable sizes. Targeted exome capture based next generation sequencing and Sanger sequencing identified a novel mutation and three previously reported mutations in these four probands. These four mutations in NF1 gene were causing disease phenotypes in these four probands and was absent in unaffected family members and in healthy controls. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), these four mutations, are classified as “likely pathogenic”. Our result expands the mutational spectrum of the NF1 gene associated with neurofibromatosis type1.

Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism. Loss of alanine glyoxylate aminotransferase (AGT) function to convert intermediate metabolite glyoxylate to glycine causes the accumulation and reduction of glyoxylate to glycolate, which eventually is oxidized to oxalate. Excess oxalate in PH1 patients leads to the formation and deposition of calcium oxalate crystals in the kidney and urinary tract. Oxalate crystal deposition causes a decline in renal function, systemic oxalosis, and eventually end-stage renal disease and premature death. mRNA-based therapies are a new class of drugs that work by replacing the missing enzyme. mRNA encoding AGT has the potential to restore normal glyoxylate to glycine metabolism, thus preventing the buildup of calcium oxalate in various organs. Panels of codon-optimized AGT mRNA constructs were screened in vitro and in wild-type mice for the production of a functional AGT enzyme. Two human constructs, wild-type and engineered AGT (RHEAM), were tested in Agxt-/- mice. Repeat dosing in Agxt-/- mice resulted in a 40% reduction in urinary oxalate, suggesting therapeutic benefit. These studies suggest that mRNA encoding AGT led to increased expression and activity of the AGT enzyme in liver that translated into decrease in urinary oxalate levels. Taken together, our data indicate that AGT mRNA may have the potential to be developed into a therapeutic for PH1.

The thermal load performance optimization and control is an important means for performance analysis, control research and operation optimization of steam turbine. It has great significance for operator training, parameter adjustment and decision support. In saturated steam turbine, the rapid expansion of steam will lead to non-equilibrium two-phase condensation flow, and the model establishment is more complicated. In order to study the thermal characteristics of saturated steam turbine during load changing process, the non-equilibrium box model of two phase flow was used to simulate the process of vapor-liquid two phase flow in the saturated steam turbine cascade, analysed the energy and mass exchange process in cascade passage of saturated steam turbine, on the basis of these theories, a segemented lumped parameter model that could reflect parameter distribution between cascade passage of saturated steam turbine was established.

Based on ab initio density functional theory calculations within the generalized gradient approximation, the electronic structure and magnetic properties of the one- and two-C-doped CdS monolayer are investigated. The results show that the C-doped CdS system exhibits half-metallic behaviors with a total magnetic moment of 2.0μB/C, which is in good accord with the results obtained from the HSE06 functional. The magnetic moment mainly comes from the spin-polarized C-2p states in the band gap. The long-range ferromagnetic order with a Curie temperature of about 280 K is attributed to the p–d and p–p hybridizations via the C–Cd–S coupling chains.

Introduction Agents targeting BTK have demonstrated activity in a variety of B-cell malignancies, however not all patients respond to therapy, and amongst those that do respond, complete remissions are rare. BTK-based combination regimens have the potential to increase depth of response and permit time-limited therapy, however innovative approaches to accelerate the development of combination regimens are needed. TG-1701 is a novel, orally available and covalently-bound BTK inhibitor that exhibits superior selectivity for BTK compared with ibrutinib in in vitro whole kinome screening (Abstr 3973, EHA 2018). Herein we report the first results of a unique Phase 1 parallel dose-escalation study of TG-1701 monotherapy and TG-1701 in combination with umbralisib, a novel PI3K-δ and casein kinase-1ε inhibitor, and ublituximab, a glycoengineered anti-CD20 mAb (1701 + U2). Methods The primary objectives of the study are to characterize the safety profile and to determine the recommended Phase 2 dose of TG-1701 as a single agent and in combination with U2. Other objectives include assessment of pharmacokinetics (PK), preliminary antitumor activity, and pharmacodynamics (PD [BTK occupancy]). Eligible patients must have B-cell malignancy relapsed or refractory (R/R) to one or more prior standard therapy. Treatment consists of escalating doses of oral TG-1701 once daily (QD), continuously administered in 28-day (D) cycles (C). Patients in the 1701 + U2 combination arm receive escalating TG-1701 oral QD + umbralisib 800 mg oral QD + ublituximab 900 mg IV on D1, 8, 15 of C1, and D1 of C2-6. All patients are treated until disease progression, unacceptable toxicity, or investigator/patient decision to withdraw study consent. Results As of July 15, 2019, 19 patients (WM = 6, CLL = 4, FL = 4, MZL = 2, DLBCL = 2, MCL = 1) have been treated with TG-1701: 3 patients at 100 mg QD, 9 patients at 200 mg QD (expansion before opening combination), 3 patients at 300 mg QD single agent arm, and 4 patients at 100 mg QD combination arm. Patients had a median of 2 prior systemic therapies (range, 1 - 5), and all of them received previous anti-CD20 therapy. Four patients were refractory to their last prior therapy, 8 had extranodal disease, and 8 had bulky disease. To date, patients have received a median of 4 (range, 2 - 10) cycles of TG-1701. No dose-limiting toxicity (DLT) have been observed to date. The most common treatment-related adverse events (TRAE) are: neutropenia (21%), diarrhea (16%), nausea (16%), bruising (16%), infection (16%), ALT/AST elevation (11%), rash (11%), abdominal pain (11%), and fatigue (11%). Grade 3 TRAE are: asymptomatic and isolated lipase elevation (N=1), nausea (N=1), rash (N=1), and acute respiratory tract infection (N=1). There have been no grade 4 TRAE nor treatment discontinuations due to adverse events. Linear kinetics are apparent, evidenced by approximately dose proportional increase in AUC on C1D1 and C1D8. High systemic clearance (CL) has been observed with a mean CL/F of 55.4 L/hr and half-life of 2.24 hours. Tmax is observed between 1 to 4 hours post dose. PK-PD (BTK occupancy) relationship at 200 mg on C1D1 is presented in Figure 1. Decrease from baseline in tumor burden is presented in Figure 2. Two patients at the lowest dose (100 mg QD) have achieved a partial response (PR): MCL = ↓78% and WM = ↓88%. All 3 evaluable patients treated with 100 mg 1701 + U2 have achieved a response at the first response assessment: 1 CR (FL) and 2 PR (FL ↓88%, and MZL ↓65%). All patients remain on study treatment, except for both patients with DLBCL that discontinued due to disease progression. All patients with CLL have shown lymphocytosis during the first 2 cycles of therapy. Near complete BTK occupancy has been achieved in all patients at all dose levels (Figure 1). Conclusions TG-1701, a once daily BTK inhibitor has an encouraging preliminary safety profile, with clinical and pharmacodynamic activity at all dose levels evaluated. This study (NCT03671590) continues enrollment in TG-1701 single-agent and 1701 + U2 combination arms. Disclosures Cheah: Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Roche, Abbvie: Research Funding; Roche: Other: Travel expenses. Wickham:Roche: Honoraria; Celgene: Other: Travel/Meeting Expenses . Turpuseema:TG Therapeutics Inc.: Employment, Equity Ownership. Miskin:TG therapeutics Inc.: Employment, Equity Ownership. Tang:TG Therapeutics Inc., Roche, Alexion: Equity Ownership; TG Therapeutics Inc.: Employment. Normant:TG Therapeutics Inc.: Employment, Equity Ownership. Ricart:TG Therapeutics, Pfizer, Merck: Equity Ownership; TG therapeutics Inc.: Employment. Tam:Abbvie, Janssen, Beigene, Roche, Novartis: Honoraria; Abbvie, Janssen: Research Funding.

Purpose: To explore the role of TWEAK in tumor growth and antitumor immune response and the activity and mechanism of RG7212, an antagonistic anti-TWEAK antibody, in tumor models. Experimental Design: TWEAK-induced signaling and gene expression were explored in tumor cell lines and inhibition of these effects and antitumor efficacy with RG7212 treatment was assessed in human tumor xenograft-, patient-derived xenograft, and syngeneic tumor models and phase I patients. Genetic features correlated with antitumor activity were characterized. Results: In tumor cell lines, TWEAK induces proliferation, survival, and NF-κB signaling and gene expression that promote tumor growth and suppress antitumor immune responses. TWEAK-inducible CD274, CCL2, CXCL-10 and -11 modulate T-cell and monocyte recruitment, T-cell activation, and macrophage differentiation. These factors and TWEAK-induced signaling were decreased, and tumor, blood, and spleen immune cell composition was altered with RG7212 treatment in mice. RG7212 inhibits tumor growth in vivo in models with TWEAK receptor, Fn14, expression, and markers of pathway activation. In phase I testing, signs of tumor shrinkage and stable disease were observed without dose-limiting toxicity. In a patient with advanced, Fn14-positive, malignant melanoma with evidence of tumor regression, proliferation markers were dramatically reduced, tumor T-cell infiltration increased, and tumor macrophage content decreased. Antitumor activity, a lack of toxicity in humans and animals and no evidence of antagonism with standard of care or targeted agents in mice, suggests that RG7212 is a promising agent for use in combination therapies in patients with Fn14-positive tumors. Clin Cancer Res; 19(20); 5686–98. ©2013 AACR.

To investigate the correlation between carbapenem consumption and rates of antimicrobial resistance in Acinetobacter baumannii, carbapenem consumption was expressed as defined daily dose based on the World Health Organization (WHO) anatomical therapeutic chemical classification index. Clinical isolates from 2001-2009 were collected and analyzed using WHONET 5.4 software. Results show that the consumption of imipenem/cilastatin, meropenem, and total carbapenem is significantly correlated with imipenem resistance in A baumannii (r = 0.818, P = .007; r = 0.817, P = .007; r = 0.827, P = .006). Furthermore, total carbapenem consumption is significantly correlated with meropenem resistance in A baumannii (r = 0.900, P = .037). In addition, consumption of imipenem/cilastatin, meropenem, and total carbapenem is associated with A baumannii resistance to piperacillin-tazobactam, ceftazidime, cefepime, amikacin, and levofloxacin. These drugs are mainly β-lactams, aminoglycosides, and fluoroquinolones. The imipenem and meropenem resistance rates are significantly correlated with resistance rates to numerous antimicrobial drugs (eg, β-lactams, aminoglycosides, and fluoroquinolones) in A baumannii. Therefore, increased consumption of carbapenem may contribute to the development of resistance in A baumannii to imipenem, meropenem, and other antimicrobial drugs. Cross-resistance possibly occurs among imipenem/cilastatin and meropenem, as well as with β-lactams, aminoglycosides, and fluoroquinolones.

A two-month-old boy visited the hospital due to unexpected cutaneous purpura and thrombocytopenia for 2 days. The physical examination revealed a purple mass on the back. The soft tissue color Doppler ultrasound showed rich blood signals in the tissue, and the results of bone marrow puncture indicated an increased number of megakaryocytes. After the treatment with hormone and gamma globulin, the platelet count rapidly increased and maintained at a normal level. Meanwhile, the boy was given oral administration of propranolol. He was followed up for 4 months and the volume of the mass on the back was reduced significantly. He had a definite diagnosis of hemangioma and immune thrombocytopenia. As for the patients with hemangioma complicated by thrombocytopenia, knowledge of Kasabach-Merritt syndrome should be enhanced and there should be a clarification of the association between thrombocytopenia and hemangioma. There should also be an alertness for thrombocytopenia of other causes.

Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.

Microwave assisted-semi bionic extraction (MASBE) process for lignans from Fructus Forsythiae was studied. The influences of solvent pH value, microwave power, dosage of solvent and irradiation time were investigated. Optimum extracting parameters were determined by orthogonal experiments as follows: pH value of solvent at first extraction is 5.5–6.0, that at the second extraction is 7–8; microwave power is 700 W; mass ratio of Fructus Forsythiae to water is 1:12; irradiation time is 10 min, and extracting times is two. Under these optimal conditions, the yield of lignans reaches 0.364%. Compared with the conventional extraction methods, the MASBE process has the advantages of high extraction rate, high extraction selectivity.

R411 is a dual alpha4beta1-alpha4beta7 integrin antagonist under development for the treatment of chronic asthma. The objective of this study was to investigate the pharmacokinetics and safety of R411 and its active metabolite, RO0270608, in humans. A 3-part phase I trial was conducted in 132 healthy volunteers: (1) 12 subjects received 200 mg R411 as a single oral dose or 100 mg RO0270608 as an intravenous infusion in a 1-sequence crossover design; (2) 7 groups of 10 subjects received 1 of 7 single oral doses of R411 (10-1200 mg) in a parallel, placebo-controlled, ascending adaptive dose design; and (3) 5 groups of 10 subjects each received repeated oral qd doses of R411 (50-900 mg) for up to 3 weeks in a parallel, placebo-controlled, ascending adaptive dose design. The absolute bioavailability of RO0270608 (mean +/- standard deviation) after oral administration of R411 was 27% +/- 4%, and the terminal half-life was 7.33 +/- 2.29 hours. After IV infusion of RO0270608, total clearance (mean +/- standard deviation) was 19.4 +/- 7.1 L/h, and the volume of distribution was 93.1 +/- 36.1 L. After single ascending oral doses of R411, area under the concentration-time curve from 0 to infinity of active metabolite RO0270608 increased proportionally from 150 to 1200 mg (P > .05). Following repeated administration, the oral clearance was independent of time. No drug accumulation was observed, and no safety concerns were revealed up to a dose of 900 mg after up to 3 weeks of treatment.

The electronic structures and magnetic properties in zinc-blende structure ZnS doped with non- magnetic noble metal palladium have been investigated by means of density functional theory (DFT) calculations employing the generalised gradient approximation (GGA) and the GGA plus Hubbard U (GGA+ U). Both the GGA and GGA+ U methods demonstrate half-metallicity in Pd-doped ZnS with total magnetic moments of about 2.0μB per supercell. The half-metallic ferromagnetism stems from the hy- bridisation between Pd-4d and S-3p states and could be attributed to a double-exchange mechanism. These results suggest a recipe for obtaining a promising dilute magnetic semiconductor by doping nonmagnetic 4d elements in ZnS matrix.

Purpose. The purpose of this investigation was to examine the effect of aging on the blood-brain barrier (BBB) transport of tryptophan.

To investigate the correlation between carbapenem consumption and rates of antimicrobial resistance in Acinetobacter baumannii, carbapenem consumption was expressed as defined daily dose based on the World Health Organization (WHO) anatomical therapeutic chemical classification index. Clinical isolates from 2001-2009 were collected and analyzed using WHONET 5.4 software. Results show that the consumption of imipenem/cilastatin, meropenem, and total carbapenem is significantly correlated with imipenem resistance in A baumannii (r = 0.818, P = .007; r = 0.817, P = .007; r = 0.827, P = .006). Furthermore, total carbapenem consumption is significantly correlated with meropenem resistance in A baumannii (r = 0.900, P = .037). In addition, consumption of imipenem/cilastatin, meropenem, and total carbapenem is associated with A baumannii resistance to piperacillin-tazobactam, ceftazidime, cefepime, amikacin, and levofloxacin. These drugs are mainly β-lactams, aminoglycosides, and fluoroquinolones. The imipenem and meropenem resistance rates are significantly correlated with resistance rates to numerous antimicrobial drugs (eg, β-lactams, aminoglycosides, and fluoroquinolones) in A baumannii. Therefore, increased consumption of carbapenem may contribute to the development of resistance in A baumannii to imipenem, meropenem, and other antimicrobial drugs. Cross-resistance possibly occurs among imipenem/cilastatin and meropenem, as well as with β-lactams, aminoglycosides, and fluoroquinolones.

To investigate the allergens of various allergic diseases in children.Serum levels of Fx5E, Phadiatop and specific IgE were measured by the UniCAP100 System in 3 504 children with allergic diseases.The positive rate of aeroallergens was obviously higher than that of food allergens in children with allergic rhinitis, allergic conjunctivitis, asthma and papular urticaria. In contrast, the positive rate of food allergens was obviously higher than that of aeroallergens in children with Henoch-Schonlein purpura and digestive diseases. The serum specific IgE level of aeroallergens was higher than that of food allergens. The dust and mite specific IgE levels reached to grade 6, while the food allergen specific IgE levels were lower than grade 3.Aaeroallergens or food allergens vary remarkably in different allergic diseases in children. The level of specific IgE of aeroallergens is higher than that of food allergens.

Very little information is available on the permeability of the blood-brain barrier (BBB) to small polar drugs in chronic hypertension. The blood and cerebrospinal fluid (CSF) pharmacokinetics of libenzapril (LZP), a potent angiotensin converting enzyme inhibitor, were investigated in hypertensive (SH) and normotensive (SD) rats. Following intravenous bolus administration of this hydrophilic drug, the terminal rate constant for elimination (beta), steady-state volume of distribution (Vdss), and systemic clearance (CL) were similar in these two animal groups. Other pharmacokinetic parameters (Cpo, alpha, k12, and k21) were significantly (P less than 0.05) greater in the hypertensive group, except for the volume of the central compartment (Vc) and ratio of Vc to Vdss, which were smaller in SH rats. The ratio of area under the concentration-time curve (AUC) in CSF to blood was about twofold higher in SH rats compared to normotensive rats, showing increased BBB permeability in hypertensive rats. An acute brain uptake study was also performed in SH, SD, and WK rats by intracarotid administration of 14C-LZP along with 3H2O as a reference marker. Both LZP and water transport was found to be significantly higher (about two- to five-fold) in six of the seven different brain regions in SH rats as compared to the normotensive (SD and WK) controls. Because of this simultaneous increase in concentrations of both the drug and the reference marker, BUI values were not affected. Regional brain concentrations in SH rats were also linearly correlated with the mean arterial pressure (MAP) values, providing further evidence of the systemic pressure related increase in BBB permeability.