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The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

The electron paramagnetic resonance (EPR) g factors for Cu2+ in [Cu(CH3NHCH2CH2NH2)2(BF4)2] are calculated using the high-order perturbation formulas of g factors for a 3d 9 ion in rhombically elongated octahedra. The calculated g factors show good agreement with the experimental data. The ligand orbital and spin-orbit coupling contributions are taken into account from the cluster approach in consideration of significant covalency due to the short and strongly covalent Cu2+–N3– bonds. The EPR behaviors and structural properties of [Cu(CH3NHCH2CH2NH2)2(BF4)2] are analyzed on the basis of the present perturbation calculations.

The spin Hamiltonian parameters (g factors g//, g⊥, hyperfine structure constants A//, A⊥ and superhyperfine parameters A z ′ , A x ′ and A y ′ ) and defect structures for Ag2+ in NaF and CsCdF3 crystals are theoretically studied using the improved perturbation formulas of these quantities for a 4d9 ion in a tetragonally elongated octahedron. The contributions from both the crystal-field and charge transfer mechanisms are taken into account, and the relevant model parameters are quantitatively obtained from the cluster approach in a consistent way. The impurity centers are found to undergo the relative tetragonal elongations of about 9.4% and 8.2% for Ag2+ in NaF and CsCdF3, respectively, along the C4 axis due to the Jahn–Teller effect. By employing the few adjustable parameters, the calculated spin Hamiltonian parameters based on the above uniform formulas and the local tetragonal elongation distortions agree well with the experimental data. Despite dominant ionicity of the hosts, the charge transfer contributions are actually important to the spin Hamiltonian parameters (e.g., about 20% for the g-shifts) due to strong covalency of impurity Ag2+.

The spin Hamiltonian parameters ( g factors and hyperfine structure constants) are theoretically studied for the two interstitial Cu 2+ centers I and II in the ZnO nanocrystals from the perturbation formulas of these parameters for a tetragonally elongated octahedral 3d 9 cluster. The ligand spin–orbit coupling and orbital contributions are involved from the cluster approach in view of moderate covalency. The two Cu 2+ centers demonstrate slight tetragonal elongation distortions (denoted by the relative elongation parameters ρ ≈ 3.4% and 3.2% for centers I and II, respectively) due to the Jahn–Teller effect. The calculated spin Hamiltonian parameters and three optical transition bands are in good agreement with the observed values. The differences in EPR and optical spectra for both centers can be ascribed to the weaker covalency (higher N ), stronger tetragonal elongation distortion (larger ρ ) and slightly larger core polarization constant κ as well as almost identical crystal-fields (nearly the same Dq ) for center I as compared to center II. The above delicate discrepancies in spectroscopic behaviors may be attributed to the tiny differences in local structures and electronic states for Cu 2+ at dissimilar parts of the ZnO nanocrystals.

4d1 (Mo5+) and 5d1 (W5+) impurities doped into nonlinear optical crystals KTiOPO4 (KTP) can occupy the inequivalent Ti1 and Ti2 sites and exhibit orthorhombically compressed octahedral nd1 (n = 4, 5) centres arising from the Jahn–Teller effect. Closely relevant to the electronic levels as well as optical and magnetic properties of these materials, the above local distortions can be suitably reflected by the anisotropic electron paramagnetic resonance (EPR) signals with the paramagnetic nd1 probes. This work stresses on the theoretical studies of the EPR parameters (g factors gx, gy, gz and hyperfine structure constants Ax, Ay, Az) and local distortions for the above nd1 impurity centres in a consistent way. The local distortions are characterised by the relative axial compression ratios ρ (≈0.040, 0.032 and 0.031) and the relative planar bond length variation ratios τ (≈0.030, 0.015 and 0.012) for Mo5+ centre I and W5+ centres II and III, respectively, which are larger than those of host Ti1 and Ti2 sites.

The aim of the present study was to investigate the usefulness of combined detection of liver stiffness (LS) and serum C-reactive protein (CRP) level in patients with hepatitis B virus (HBV)-related liver cirrhosis (LC). A total of 156 cases of previously untreated patients with HBV-related LC were classified into the LC group [LC without hepatocellular carcinoma (HCC)] and the HCC group (LC with HCC). Comparative analyses of LS and serum CRP level were conducted between these two groups. LS values and serum CRP levels were found to be significantly higher in the HCC group compared with those in the LC group (P

The local distortions and electron paramagnetic resonance (EPR) parameters for Cu2+in lithium sodium borate (LNB) glassesxLi2O·(30–x)·Na2O·69.5B2O3(5≤x≤25 mol%) are theoretically studied at various concentrationsxin a consistent way. Owing to the Jahn–Teller effect, the [CuO6]10−clusters are found to experience the significant tetragonal elongations of 16% along C4axis. Despite the nearly unchanging observedgfactors, measured d–d transition band (or cubic field parameterDq) shows remarkable linear increases with concentrationx, whose influences ong‖andg⊥are actually cancelled by the linearly increasing covalency factorNand relative elongation ratioηwithx. The almost unvarying hyperfine structure constants are attributed to the fact that the influences of the linearly increasingNand the linearly decreasing core polarisation constantκlargely cancel one another. The microscopic mechanisms of the above concentration dependences for these quantities are illustrated from mixed alkali effect (modification of B2O3network by transforming some BO3units into BO4ones with variations in modifier Li2O concentration).

The local structures and electron paramagnetic resonance (EPR) parameters as well as their composition (x) dependences for Cu 2 + in xMgO·(30 − x)·Na 2 O·69B 2 O 3 (5 ≤ x ≤ 17 mol%) glasses are theoretically studied by analyzing these parameters for tetragonally elongated 3d 9 complexes. The nonlinear variations of the EPR spectra with modifier MgO composition x can be ascribed to the approximately parabolic relationships between cubic field parameter Dq , orbital reduction factor k , local relative tetragonal elongation ratio ρ, core polarization constant κ and reduction factor H with x. The [CuO 6 ] 10 − complexes may experience the slight relative elongations of about 0.4% due to the Jahn–Teller effect. The theoretical d–d transition bands and EPR parameters for the various composition x are in good agreement with the observed results. The above composition dependences of the relevant quantities are illustrated as the modifications of the local crystal-fields and electronic states in the vicinity of the Cu 2 + dopants with x.

The alkylating agent melphalan is used in the treatment of hematological malignancies, especially multiple myeloma. In the past, the usefulness of melphalan has been solely attributed to its cytotoxicity on fast-growing cancerous cells. Although the immunomodulatory effects of melphalan were suggested many years ago, only recently has this aspect of melphalan’s activity begun to be elucidated at the molecular level. Emerging evidence indicates that melphalan can foster an immunogenic microenvironment by inducing immunogenic cell death (ICD) as characterized by membrane translocation of endoplasmic reticulum protein calreticulin (CRT) and by release of chromatin-binding protein high-mobility group box 1 (HMGB1). In addition, the lympho-depletive effect of melphalan can induce the release of pro-inflammatory cytokines and growth factors, deplete regulatory T cells, and create space to facilitate the expansion of infused tumor-reactive T cells. These features suggest that melphalan can be used as a preparative chemotherapy for adoptive T-cell therapy. This notion is supported by our recent work demonstrating that the combination of melphalan and adoptive transfer of tumor-reactive CD4+ T cells can mediate potent antitumor effects in animal models. This review summarizes the recent advances in understanding and utilizing the immunomodulatory effects of melphalan.

The electron paramagnetic resonance (EPR) parameters (g factors and hyperfine structure constants) for Cu2+ in [Cu(ipt)(dap)H2O] n •nH2O (ipt is isophthalic acid, dap–1,3-diaminopropane) are theoretically investigated from the high order perturbation formulas of these parameters for a 3d 9 ion in a rhombically elongated octahedron. The ligand orbital and spin-orbit coupling contributions are included from the cluster approach because of strong covalency of the system. The nearly axial anisotropies of the g factors and hyperfine structure constants are correlated to the significant elongation distortion of the five-fold coordinated Cu2+ (in a distorted square pyramidal [CuN2O3] group). Nevertheless, the perpendicular anisotropies arising from the nonequivalent planar ligands are largely concealed by the experimental uncertainties. The theoretical analysis of the EPR behaviours for [Cu(ipt)(dap)H2O] n •nH2O would be helpful to understand the local structures and properties of this and relevant systems.

The defect structures and spin Hamiltonian parameters (SHPs) for three Rh2+ centres (denoted C1 in KTiOAsO4 and C2 and C3 in KTiOPO4) are theoretically investigated by utilising the perturbation formulae for a 4d7 ion under orthorhombically (D2h) elongated octahedra. The defect structures are characterized by the axial elongation ratios of 4.91%, 4.93% and 4.90% along the Z axis and the planar bond length variation ratios of 0.05%, 0.01% and 0.04% for centres C1, C2 and C3, respectively, owing to the Jahn–Teller effect. The nearly identical moderate axial elongation ratios and the slightly different tiny planar bond length variation ratios may suitably account for the comparable moderate axial g anisotropies ∆g (≈0.6087, 0.6124 and 0.6067) and the slightly dissimilar tiny perpendicular g anisotropies δg (≈0.0649, 0.0097 and 0.0509) of the three centres, respectively. All centres demonstrate similar strong crystal-field interactions and moderate covalence arising from the comparable short impurity-ligand distances.

Through the experiment of Ciprofloxacin (CIP) adsorption by KMnO4modifiedDurio zibethinusMurr Shell (KDS), the best condition, adsorption kinetics and thermodynamic characteristics were studied. The isotherm parameters were estimated by linear regression analysis with Langmuir isotherm model, Temkin isotherm and Freundlich isotherm model. The equilibrium process was described well by the Freundlich isotherm model, which indicated that the adsorption thermodynamics of CIP on KDS is a multilayer adsorption process．The kinetics of the interactions showed better agreement with the pseudo-second-order model (R2=0.9999). This study demonstrated that KDS could be used for the removal of CIP in water treatment.

The perturbation formulas of the spin Hamiltonian parameters (zero-field splitting and g factor g// and g⊥) are established for a 3d8 ion in trigonally distorted tetrahedra for the first time. In the theoretical treatments, the contributions from the Jahn–Teller effect, the ligand orbital and spin–orbit coupling interactions and configuration interactions are taken into account from the cluster approach in a uniform way. The above formulas are applied to the studies of the spin Hamiltonian parameters for the three CoCl(PPh3)3 molecules, and the experimental electron paramagnetic resonance spectra of all the molecules are satisfactorily explained. The significant compressions of the ligand tetrahedra with mixed chlorine and PPh3 groups around Co+ are analysed for three distinct CoCl(PPh3)3 compounds, characterised by the Cl–Co–P bond angles θ larger than the tetrahedral angle of 109.47°. The local trigonal distortions are discussed in view of the Jahn–Teller effect.

CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.

The local angular distortions Δθ are theoretically studied for the various Ni

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

Polydopamine functionalized magnetic nanoparticles (PDA@Fe3O4) were prepared and characterized by transmission electron microscopy, scanning electron microscopy, zeta potential and vibrating sample magnetometry. They were found to enable highly efficient capture of genomic deoxyribonucleic acid (DNA). The adsorption capacity of PDA@Fe3O4 for genomic DNA can reach 161 mg g(-1). The extraction protocol used aqueous solutions for DNA binding to and releasing from the surface of the magnetic particles based on the pH inducing the charge switch of amino and phenolic hydroxyl groups on PDA@Fe3O4. The extracted DNA with high quality (A260/A280=1.80) can be directly used as templates for polymerase chain reaction (PCR) followed by capillary electrophoresis (CE) analysis. None of the toxic chemical reagents and PCR inhibitors was used throughout the whole procedure. PDA@Fe3O4 based magnetic solid phase extraction (MSPE) method was superior to those using commercial kit and traditional phenol-chloroform extraction methods in yield of DNA. The developed PDA@Fe3O4 based MSPE-PCR-CE method was applied for simultaneous and fast detection of Listeria monocytogenes and Escherichia coli O157:H7 in milk.

The local lattice distortions and the electron paramagnetic resonance (EPR) parameters (g factors, hyperfine structure constants and zero-field splittings) for Cu2+, Mn2+ and Fe3+ in ZnWO4 are theoretically studied based on the perturbation calculations for rhombically elongated octahedral 3d9 and 3d5 complexes. The impurity centres on Zn2+ sites undergo the local elongations of 0.01, 0.002 and 0.013 A along the C2 axis and the planar bond angle variations of 8.1°, 8.0° and 8.6° for Cu2+, Mn2+ and Fe3+, respectively, due to the Jahn–Teller effect and size and charge mismatch. In contrast to the host Zn2+ site with obvious axial elongation (∼0.31 A) and perpendicular (angular) rhombic distortion, all the impurity centres demonstrate more regular octahedral due to the above local lattice distortions. The copper centre exhibits significant Jahn–Teller reductions for the spin-orbit coupling and orbital angular momentum interactions, characterised by the Jahn–Teller reduction factor J (≈0.29 ≪ 1). The calculat...

Background/PurposeLamivudine has been recommended as prophylaxis for the reactivation of hepatitis B virus (HBV) infection in patients undergoing chemotherapy. However, information on breast cancer patients in particular has been lacking. The purpose of this meta-analysis was to assess the overall efficacy of lamivudine prophylaxis compared to untreated patients with hepatitis B S-antigen (HBsAg) seropositive breast cancer who had undergone chemotherapy.MethodsStudies that compared the efficacy of treatment with lamivudine prophylaxis versus no prophylaxis in HBsAg seropositive breast cancer patients were identified through Medline, Cochrane, and Embase databases.ResultsSix studies involving 499 patients were analyzed. The rates of HBV reactivation in patients with lamivudine prophylaxis were significantly lower than those with no prophylaxis (risk ratio [RR] = 0.23, 95% confidence interval [CI]: 0.13–0.39, p

The spin Hamiltonian parameters ( g factors and hyperfine structure constants) and local structures are theoretically studied for the tetragonal Cu 2+ centers in the ZnX (X=O and S) nanocrystals from the perturbation formulas of these parameters for a 3d 9 ion in tetragonally distorted tetrahedra. The ligand orbital and spin–orbit coupling contributions are considered in view of strong covalency. Due to the Jahn–Teller effect, the local Cu 2+ ‒X 2− bond angles between the four equivalent impurity-ligand bonds and the four-fold axis are found to be about 2.47° and 1.68° larger than that (≈54.74°) for an ideal tetrahedron. This induces tetragonally compressed [CuX 4 ] 6− clusters on tetrahedral substitutional Zn 2+ sites, different from the assignments (i.e., Cu 2+ on tetragonally elongated octahedral and tetrahedral substitutional sites in the ZnO and ZnS nanocrystals, respectively) in the previous works. The calculated g factors for both systems and the parallel component of the hyperfine structure constants for the ZnS:Cu 2+ nanocrystals based on the above local angular distortions are in good agreement with the observed values. The validity of the present assignments for the local structures of the Cu 2+ centers is analyzed.

The spin Hamiltonian parameters (g factors and hyperfine structure constants) for Cu2+ in NaCl and AgCl are investigated theoretically for the case of the 3d 9 ion in tetragonally elongated octahedra using high-order perturbation formulas for these parameters. Due to the Jahn–Teller effect, the impurity Cu2+ centers are found to experience relative elongations along the four-fold axis of about 0.15 and 0.08 A in NaCl and AgCl, respectively. The calculated spin Hamiltonian parameters are in good agreement with the experimental data. The local structures and EPR spectra of the systems are discussed.

Purpose: The aim of this study was to demonstrate the surgical technique and clinical outcome of autologous neurosensory retinal patch transplantation for recurrent large macular hole (MH)-induced retinal detachment after failed surgery with internal limiting membrane (ILM) removal or transplantation. Methods: We reviewed 5 patients with recurrent MH-induced retinal detachment after failed surgeries with ILM removal or transplantation who underwent vitrectomy combined with autologous neurosensory retinal patch transplantations and were followed up over 6 months. In the autologous neurosensory retinal patch transplantation procedure, a small piece of neurosensory retina was removed and transplanted inside the MH. The anatomic outcomes of MH-induced retinal detachment were evaluated by fundus examinations and optical coherence tomography. The pre­operative and postoperative best-corrected visual acuities (BCVAs) were compared and the MH closure rates were measured as the main outcomes. Results: A total of 5 patients (3 men and 2 women; average age 35.4 ± 18.72 years) were included in our study. Complete MH sealing was achieved in 5 eyes after autologous neurosensory retinal patch transplantations, and no complications were observed. The mean BCVA was 2.38 ± 0.57 (range 1.6–3) before surgery, and 1.46 ± 0.51 (range 1–2) at 6 postoperative months. There was a significant difference in BCVA before versus after the surgery (p < 0.05, paired t test). Conclusions: Autologous neurosensory retinal patch transplantation is an effective addition to the surgical options for large MH-induced retinal detachment after failed surgery with ILM removal or transplantation.

// Michal P. Kuczma 1, 6 , Zhi-Chun Ding 1 , Tao Li 2 , Tsadik Habtetsion 1 , Tingting Chen 1 , Zhonglin Hao 1 , Locke Bryan 3 , Nagendra Singh 4 , James N. Kochenderfer 5 and Gang Zhou 1 1 Georgia Cancer Center, Augusta University, Augusta, Georgia, USA 2 Department of Oncology and Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, PR China 3 Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, Georgia, USA 4 Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia, USA 5 Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, Maryland, USA 6 Current/Present address: Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA Correspondence to: Gang Zhou, email: GZHOU@augusta.edu Keywords: antibiotics; intestinal microbiota; cyclophosphamide; chimeric antigen receptor; adoptive T-cell therapy Received: September 12, 2017 Accepted: November 26, 2017 Published: December 05, 2017 ABSTRACT In recent years the combined use of chemotherapy and immunotherapy, collectively termed chemoimmunotherapy, has emerged as a promising treatment option for patients with cancer. Antibiotics are commonly used to reduce infection-related complications in patients undergoing chemotherapy. Intriguingly, accumulating evidence has implicated gut microbiota as a critical determinant of host antitumor immune responses, raising the question as to whether the use of broad-spectrum antibiotics would invariably diminish tumor response to chemoimmunotherapies. We investigated the impact of antibiotics on the therapeutic outcomes of cyclophosphamide (CTX) chemotherapy and adoptive T-cell therapy (ACT) where CTX was used as the host-conditioning regimen in mice. We show that antibiotic prophylaxis dampened the endogenous T cell responses elicited by CTX, and reduced the efficacy of CTX against B-cell lymphoma. In the ACT setting, antibiotics administration impaired the therapeutic effects of adoptively transferred tumor-specific CD4+ T cells in mice with implanted colorectal tumors. In contrast, long-term antibiotic exposure did not affect the efficacy of ACT using CD19-targeting chimeric antigen receptor (CAR) T cells in mice with systemic B-cell lymphoma, although it correlated with prolonged CAR expression and sustained B-cell aplasia. Our study demonstrates that chemoimmunotherapies may have variable reliance on intestinal microbiota for T cell activation and function, and thus have different sensitivities to antibiotic prophylaxis. These findings may have implications for the judicial use of antibiotics in cancer patients receiving chemoimmunotherapies.

The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).

A sophisticated hierarchical neural network model for intelligent assessment of structural damage is constructed by the synergetic action of auto-associative neural networks (AANNs) and Levenberg-Marquardt neural networks (LMNNs). With the model, AANNs aided by the wavelet packet transform are firstly employed to extract damage features from measured dynamic responses and LMNNs are then utilized to undertake damage pattern recognition. The synergetic functions endow the model with a unique mechanism of intelligent damage identification in structures. The model is applied for the identification of damage in a three-span continuous bridge, with particular emphasis on noise interference. The results show that the AANNs can produce a low-dimensional space of damage features, from which LMNNs can recognize both the location and the severity of structural damage with great accuracy and strong robustness against noise. The proposed model holds promise for developing viable intelligent damage identification technology for actual engineering structures.

Nitrous oxide (N2O), a powerful greenhouse gas, is produced and consumed through denitrifying bacteria. However, the abundance, diversity and succession of denitrifying bacteria and their association with farming systems are largely unknown. Therefore, the objectives of the present study were: (1) to unravel the influence of long-term organic farming on diversity of nirK-, nirS- and nosZ-type denitrifying microorganisms; and (2) to analyze the association of diversity and abundance of these denitrifying microorganism with the emission of N2O from soil. The abundance and diversity of denitrifying bacteria with nirK, nirS and nosZ were compared among organic (ORG), integrated (INT), and conventional (CON) vegetable greenhouses located in northern China over four growing seasons using quantitative PCR and high-throughput DNA sequencing of PCR-amplified products. As compared to CON, the abundance of nosZ gene was significantly higher in the ORG, in which the N2O emission was 35% lower. In general, both abundance and diversity of nitrite reducing populations (nirK- and nirS-type) was influenced by growing seasons rather than farming systems. Additionally, dominant denitrifying populations displayed irregular, periodical, or persistent succession patterns. Co-occurrence network revealed that nirK-, nirS- and nosZ-type denitrifying bacteria formed microbial hubs associated with soil temperature, NO3−-N content, or pH. In summary, long-term organic farming enriched N2O reducing bacterial populations, while having little effect on nitrite reducing populations which mainly succeeded seasonally.

Local structure and g factors for (20-x)CaF2-10CaO-5Y2O3-10B2O3-55P2O5: xTiO2(x = 0.2, 0.4, 0.6, 0.8 and 1.0 mol%) glasses are theoretically studied by using the perturbation formulae for a tetragonally elongated octahedral 3d1 cluster. Six coordinated [TiO6]9‒ and five coordinated [TiO5]7‒ clusters are evaluated in view of the Jahn-Teller effect and the charge compensation of impurity Ti3+ for host Ti4+. d -d transition bands of E2 (2B2g→2A1g) and E3 (2B2g→2B1g) of the [TiO5]7‒ cluster is obtained with the piecewise linear fitting function of x. The microscopic mechanisms of the varying rules of relevant quantities g//, E2 and N with x are related with NBO. The role of various TiO2 concentrations in local structure and optical spectra is also comprehensively studied from the local optical basicity Λloc, which can represent the local environment and covalency of the Ti3+ center.

There is a serious need for fast-acting drugs to treat post-traumatic stress disorder (PTSD). Our previous studies revealed that YL-IPA08, a novel small-molecule TSPO agonist, exerted significant anti-PTSD effects in various animal models. However, the onset time of YL-IPA08 and its underlying mechanisms remain unclear. In the present study, we first investigated the time course of YL-IPA08 compared to selective serotonin reuptake inhibitors (SSRIs) in the well-known time-dependent sensitization model of PTSD. YL-IPA08 required only 2-4 days of treatment to take effect in behavioural models of PTSD, whereas sertraline required 7-8 days. Furthermore, the mechanism study revealed that YL-IPA08 elicited anti-PTSD-like effects associated with increased GABA levels and allopregnanolone efflux in the hippocampus and prefrontal cortex and increased corticosterone levels in the serum after only 5 days of treatment, whereas sertraline required 9 days. Our results demonstrate that YL-IPA08 can exert fast-onset anti-PTSD-like effects, and its mechanisms may be related to the increased GABA levels, allopregnanolone efflux and the hypothalamic-pituitary-adrenal (HPA) axis function.

In this study, an organophosphonate scale inhibitor, ethylenediamine tetra(methylenephosphonic acid) sodium salt (EDTMPA-Na) draw solution, was adopted for alleviating the membrane fouling in the forward osmosis (FO) application of produced water treatment. Compared with the typical NaCl draw solution, the employment of EDTMPA-Na draw solution can alleviate the membrane fouling effectively and therefore achieve a higher water recovery rate (60.6%) after a continuous 48-h test. And the mechanism of membrane fouling control with EDTMPA-Na draw solution has been systemically explored by varying the feed or draw solution compositions. The results turn out that the leakage of EDTMPA-Na draw solute to the feed solution can alleviate the formation of gypsum scales on the membrane surface effectively, ascribed to its excellent scale inhibition ability and the unique diffusion route of the draw solute (resulting in a relative higher concentration of EDTMPA-Na near the membrane surface) in FO process. And the alleviation of membrane scaling can further mitigate the accumulation of organic foulant on the FO membrane. This study may provide an efficient strategy for alleviating the membrane fouling in the FO application of produced water treatment.

Objective: The objective of this study was to observe the effect of Yangxinshi tablets on the phenotype and function of peripheral blood monocytes in patients with unstable angina of coronary heart disease (CHD) and to explore the possible mechanism of Yangxinshi tablets in the treatment of CHD. Methods: A total of 100 patients with unstable angina of CHD were randomly divided into two groups: Group A – treatment group and Group B – control group. The phenotypic and functional changes in blood monocytes and the changes in serum inflammatory factors before and after treatment were compared in the two groups. Results: The expression of CD14+CD163+ interleukin (IL)-10+ was significantly higher in the control group than in the patients with unstable angina of CHD, whereas the expression of CD14+CD163−IL-12+ was lower. The concentration of IL-10 was higher in the control group than in the patients with unstable angina, whereas the concentration of tumor necrosis factor-α (TNF-α) and IL-12 was significantly lower. In Group A, the expression of CD14+CD163+, CD14+CD206+, and CD14+CD163+CD206+ in peripheral blood monocytes increased after treatment than before treatment, whereas the expression of CD14+CD163−CD206− decreased. The expression of CD14+CD163−IL-12+ decreased after treatment than before, whereas CD14+CD163+IL-10+ expression increased. The serum concentration of IL-10 in Group A was higher after treatment than before, whereas that of IL-12 and TNF-α was lower. In Group B, the phenotype and function of the peripheral blood monocytes remained unchanged. Conclusion: Yangxinshi tablet therapy can change the phenotype of the peripheral blood monocytes in patients with unstable angina of CHD. Yangxinshi tablet therapy changes the inflammatory state in patients with an increase in the expression of anti-inflammatory factors and a decrease in the expression of inflammatory factors.

The improved perturbation formulas of the spin Hamiltonian parameters (zero-field splitting D and g factors) for a 3d5 ion in trigonally distorted tetrahedra are constructed from the cluster approach by including both the crystal-field and charge-transfer contributions. These formulas are applied to the studies of the local structures and the electron paramagnetic resonance (EPR) spectra for Fe3+ in CdX (X = S, Se, Te). The impurity Fe3+ is found not to occupy exactly the host Cd2+ sites but to experience the small outward shifts 0.014 and 0.006 A away from the ligand triangles along the C3 axis in CdS and CdSe, respectively. The charge-transfer contributions to the spin Hamiltonian parameters are important and increase significantly with increasing atomic number of the ligand (i.e., S2− < Se2− < Te2−) arising from the decreases of charge-transfer energy levels and the increases of ligand spin–orbit coupling coefficients. The results are discussed.

Bacterial biocontrol strains used as an alternative to chemical fungicides may influence bacterial communities in the rhizosphere and effects might differ depending on the soil type. Here we present baseline data on the effects of Pseudomonas jessenii RU47 on the bacterial community composition in the rhizosphere of lettuce grown in diluvial sand, alluvial loam and loess loam at the same field site. 16S rRNA gene fragments amplified from total community DNA were analyzed by denaturing gradient gel electrophoresis (DGGE) and pyrosequencing. DGGE fingerprints revealed that in three consecutive years (2010-2012) RU47 had a slight but statistically significant effect on the bacterial community composition in one (2010), two (2011) or all the three soils (2012). However, these effects were much less pronounced compared with the influence of soil types. Additional pyrosequence analysis of samples from 2011 showed that significant changes in bacterial community compositions in response to RU47 inoculation occurred only in alluvial loam. Different taxonomic groups responded to the RU47 application depending on the soil type. Most remarkable was the increased relative abundance of OTUs belonging to the genera Bacillus and Paenibacillus in alluvial loam. Pyrosequencing allowed side-effects of the application of bacterial inoculants into the rhizosphere to be identified.

By establishing the perturbation formulas of the spin Hamiltonian parameters (anisotropic g factors and hyperfine structure constants) for a rhombically compressed 4d 7 cluster, the EPR spectra and local structure are theoretically investigated for Rh 2+ :ZnWO 4 . Due to the Jahn–Teller effect, the impurity center shows slight axial compression of about 0.002 nm along the Z -axis and the perpendicular angular variation of about 6° for the planar impurity–ligand bonds. These lattice deformations transform the significant elongation (by about 0.031 nm) of host Zn 2+ site into slight compression in the impurity center. The local distortion of the Jahn–Teller nature is discussed.

The anisotropic g factors and local structure for the rhombic Fe+ center in NaF are theoretically studied using the perturbation formulas of the g factors for a rhombically distorted octahedral 3d7 cluster. The impurity Fe+ is found not to occupy exactly the host Na+ site in NaF but to experience the off-center displacement of about 0.28 A along [1 1 0] axis due to size mismatch substitution. The calculated g factors based on the above impurity displacement show reasonable agreement with the experimental data. The local structure of the Fe+ center is discussed.

Objective To investigate the clinical efficacy of acupuncture combined with tuina in treating patients with cervical vertigo.

To analyze effects of quay environment on the AUV radiated acoustic field test, the PNAH (PNAH: planar near-field acoustical holography) was used to simulate acoustic field. By simulating the free and non-free acoustic field and comparing amplitudes and angles of complex sound pressure, Analyze effects of quay wall and seabed reflection on the AUV radiated acoustic field test to determine the standard of quay wall and seabed environment which meets testing. The work would provide a certain reference for the AUV radiated acoustic field test.

Background/Aims: The invasion of trophoblast cells into the maternal uterine decidua is critical for normal placentation, establishment of pregnancy and maintenance of fetal growth in humans. Several growth factors and cytokines have been implicated in trophoblast invasion, but the underlying regulatory mechanisms of invasion are not fully understood. Our earlier studies have found that caudal-related homeobox transcription factor 2 (CDX2) is hypomethylated in human pre-eclampsia placental tissues. However, whether CDX2 is involved in trophoblast invasion was unclear. Methods and Results: In this study, we investigated CDX2 function using a human HTR-8/SVneo cell line that overexpressed CDX2. Cell invasion assays demonstrated that CDX2 enhanced trophoblast cell invasiveness. Meanwhile, MTT assays revealed that CDX2 did not affect cell proliferation. Western blot analysis and quantitative real-time PCR demonstrated that the expression level of matrix metalloproteinase-9 (MMP-9) was significantly increased, whereas the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) was markedly suppressed in the CDX2-overexpressing trophoblast cells. The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is involved in proliferation, migration, metastasis and invasion. Our study showed that inhibition of PI3K/Akt signaling led to decreased expression of CDX2. Conclusion: We concluded that CDX2 is likely regulated by the PI3K/Akt signaling pathway during trophoblast cell invasion. Our findings may reveal new insights into the regulatory mechanisms of trophoblast cell invasion and may be an important contributor to the pathogenesis of pregnancy-related diseases.

To localize and identify the noise sources of the AUV, the cylindrical NAH method was proposed. The feasibility was verified by the acoustic field simulation, the influence of the array test distance, holographic planar array position errors and the reconstruction phase errors on the accuracy of the sound field reconstruction was analyzed, which would provide some references for the engineering applications.

The spin Hamiltonian parameters (zero-field splitting D, g factors and hyperfine structure constants) are theoretically studied for Mn2+ in the ZnS nanocrystals and bulks from the perturbation formulae of these quantities for trigonal and cubic tetrahedral 3d5 clusters, respectively. The trigonal Mn2+ centre in the ZnS nanocrystals is attributed to the impurity–ligand bond angle related to the C3 axis about 0.39° larger than that (≈109.47°) of an ideal tetrahedron. Almost the same g factors and hyperfine structure constants for the nanocrystals and bulks can be ascribed to similar crystal-field environments (i.e. comparable cubic field parameters Dq), nearly the same covalency (i.e. the equal covalency factors N) and the Mn2+ 3d–3s orbital admixture (i.e. the identical core polarisation constants κ) in both systems. The ligand orbital and spin–orbit coupling contributions are found to be important and should be included in the electron paramagnetic resonance analysis in view of significant covalency.

In this paper, coaxial inside-beam powder feeding technique was used. According to theoretical analysis and the single layer cladding experiments, the initial parameters and experimental scheme of width-changing layer cladding based on the coaxial inside-beam powder feeding were confirmed. The theory model of piecewise transition was established. The real-time control of scanning speed and the defocus amount to carry out the experiments were used while the laser power and powder feed rate were not changed. Finally, the layers with uniformly width changing and stable layer height were achieved. Performance analysis showed that the formed layer had smooth surface and a high rigidity without powder paste outside the surface, and the size was basically as same as the design value. Its microstructure was small and dense and good metallurgical combination was formed between part and substrate.

The local lattice distortions and the electron paramagnetic resonance (EPR) parameters (anisotropic g factors and the hyperfine structure constants) for the two Pt3+ centers in ZnWO4 are theoretically investigated by utilizing the perturbation formulas of these parameters for a 5d 7 ion under rhombically elongated and compressed octahedra. The elongated (and compressed) centers are ascribed to the [PtO6]9− clusters on Zn2+ site suffering the axial elongation of 0.01 A (and compression of 0.02 A) along Z axis and the planar bond angle variations of 7.4° (and 7.8°), respectively, due to the Jahn–Teller effect. The above local lattice deformations may considerably cancel the original large axial elongation (~0.31 A) and perpendicular rhombic angular distortion of the host [ZnO6]10− cluster and yield more regular [PtO6]9− clusters in the impurity centers. The calculated EPR parameters based on the above lattice deformations show good agreement with the experimental data, and the local structures of the impurity centers are discussed.

Excessive nitrogen application has caused serious environmental problems in the vegetable field. Based on a 12-year greenhouse trial of organic (ORG), low-input (LOW) and conventional (CON) vegetable production in northern China, a two-year study on nitrogen (N) budget was conducted to evaluate N management and its environmental impact. The main results were as follows: 1) total N contents in the 0-20 cm soil layer were significantly higher in ORG; 2) ORG statistically increased vegetable yield and decreased yield-scaled nitrous oxide emissions; 3) N leaching was the primary N loss pathway in three systems and ORG significantly reduced N leaching intensities (the ratio of cumulative N leaching to N inputs) and cumulative N leaching as compared to CON; and 4) ORG significantly increased relative N budgets and had the potential to accumulate organic N. These results indicated that under the condition of similar N inputs, long-term organic vegetable cultivation could reduce N leaching and increase soil organic N stock, thus may be a feasible strategy to improve greenhouse vegetable production in northern China.

Cancer cells face increased oxidative stress driven by oncogene activation, tumor suppressor gene mutation and increased metabolism. Even though cancer cells can resist this redox imbalance by activating various antioxidant defense mechanisms, they are more susceptible to further redox disruption by pro-oxidants. Our previous study indicated that adoptive T-cell therapy (ACT) leads to heightened oxidative stress in tumor cells reflected by depletion of cellular antioxidant glutathione (GSH), accumulation of reactive oxygen species (ROS), and presence of oxidative DNA damages. Based on this observation, we propose that intensifying oxidative stress in tumor with pro-oxidants can sensitize cancer cells to ACT and lead to improved therapeutic outcomes. In this study, we used clinically relevant ACT models to screen a panel of pro-oxidant agents for their ability to potentiate the antitumor effects of ACT. We identified several clinically applicable pro-oxidants, including some commonly used non-steroidal anti-inflammatory drugs (NSAIDs), that can benefit the infusion of tumor-specific CD4+ T cells or CD19-targeting CAR T cells. Our data provide a rationale for combining selected pro-oxidants with ACT to achieve synergistic antitumor effect. Citation Format: Nada Aboelella, Gang Zhou, Kateryna Fesenkova, Zhi-chun Ding. Adding fuel to the fire: Augmenting the efficacy of adoptive T-cell therapy with pro-oxidants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4095.

Metal organic frameworks (MOFs) have been well-known and extensively researched due to the high storage /good selectivity for gas molecules. Herein, the structures and electron paramagnetic resonan...