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The chemosensory pathway HtChe2 from the marine bacterium Halomonas titanicae KHS3 controls the activity of a diguanylate cyclase. Constitutive activation of this pathway results in colony morphology alterations and an increased ability to form biofilm. Such characteristics resemble the behavior of the Wsp pathway of Pseudomonas. In this work, we investigate the specificity of Htc10, the only chemoreceptor coded within the HtChe2 gene cluster. The purine derivatives guanine and hypoxanthine were identified as ligands of the recombinantly produced Htc10 ligand‐binding domain, with dissociation constants in the micromolar range, and its structure was solved by X‐ray protein crystallography. The sensor domain of Htc10 adopts a double Cache folding, with ligands bound to the membrane‐distal pocket. A high‐resolution structure of the occupied guanine‐binding pocket allowed the identification of residues involved in ligand recognition. Such residues were validated by site‐directed mutagenesis and isothermal titration calorimetry analyses of the protein variants. Moreover, heterologous expression of Htc10 in a Pseudomonas putida mutant lacking the native Wsp chemoreceptor promoted biofilm formation, a phenotype that was further enhanced by Htc10‐specific ligands. To our knowledge, this is the first description of binding specificity of a chemoreceptor that controls the activity of an associated diguanylate cyclase, opening the way for dynamic studies of the signaling behavior of this kind of sensory complex. [ABSTRACT FROM AUTHOR]

Brain tumors are the leading cause of cancer‐related death in children. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of pediatric brain cancers are limited and hard to establish. We present a protocol that enables efficient generation, expansion, and biobanking of pediatric brain cancer organoids. Utilizing our protocol, we have established patient‐derived organoids (PDOs) from ependymomas, medulloblastomas, low‐grade glial tumors, and patient‐derived xenograft organoids (PDXOs) from medulloblastoma xenografts. PDOs and PDXOs recapitulate histological features, DNA methylation profiles, and intratumor heterogeneity of the tumors from which they were derived. We also showed that PDOs can be xenografted. Most interestingly, when subjected to the same routinely applied therapeutic regimens, PDOs respond similarly to the patients. Taken together, our study highlights the potential of PDOs and PDXOs for research and translational applications for personalized medicine. Synopsis: Patient‐derived organoids (PDOs) and patient‐derived xenograft organoids (PDXOs) have been established through direct in vitro culture of primary tumors and patient‐derived xenograft (PDX)‐derived tumors with the goal to better model pediatric tumors of the central nervous system. PDOs recapitulate cellular heterogeneity, histological features, mutational profiles (number of variants, microsatellite instability, tumor mutational burden) of the corresponding parental tumor even after 1 year of in vitro cultureZFTA‐RELA EPN‐ and G3 MB‐PDOs recapitulate patients' response to routinely applied therapeutic regimensSeveral PDOs and PDXOs were derived from human tumors for which there are currently very limited in vivo and in vitro models availablePDOs and PDXOs are available to the research community, and can be subjected to genetic manipulations, to drug screening, and translational applications for personalized medicine [ABSTRACT FROM AUTHOR]

Oxide–semiconductor interface quality has often a direct impact on the electrical properties of devices and on their performance. Traditionally, the properties are characterized through metal–oxide–semiconductor (MOS) structures by depositing a metal layer and measuring the capacitance–voltage (C–V) characteristics. However, metal deposition process itself may have an impact on the oxide and the oxide–semiconductor interface. The impact of magnetron sputtering, e‐beam evaporation, and thermal evaporation on an Al2O3/Si interface is studied, where atomic layer deposited (ALD) Al2O3 is used, by MOS C–V and corona oxide characterization of semiconductors (COCOS) measurements. The latter allows characterization of the interface also in its original state before metallization. The results show that sputtering induces significant damage at the underlying Al2O3/Si interface as the measured interface defect density Dit increases from 1011 to 1013 cm−2 eV. Interestingly, sputtering also generates a high density of positive charges Qtot at the interface as the charge changes from −2×1012 to +7×1012 cm−2. Thermal evaporation is found to be a softer method, with modest impact on Dit and Qtot. Finally, Alnealing heals the damage but has also a significant impact on the charge of the film recovering the characteristic negative charge of Al2O3 (∼−4 × 1012 cm−2). [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between Barthel Index (BI), which measures level of patients independence during daily living activities (ADL), and perioperative outcomes in a large cohort of consecutive bladder cancer (BCa) patients, who underwent radical cystectomy (RC) at a tertiary referral center. Methods: We retrospectively evaluated data from clinically nonmetastatic BCa patients treated with RC between 2015 and 2022. For each patient, BI was assessed preoperatively. According to BI score, patients were divided into three groups: ≤60 (total/severe dependency) vs. 65–90 (moderate dependency) vs. 95–100 (slight dependency/independency). Regression analyses tested the association between BI score and major postoperative complications (Clavien–Dindo >2), length of in‐hospital stay (LOHS), 90‐days readmission, and total costs. Results: Overall, 288 patients were included. According to BI score, the patient cohort was distributed as follows: 4% (n = 11) BI ≤60 vs. 15% (n = 42) BI 65–90 vs. 81% (n = 235) BI 95–100. Patients with BI ≤60 had more frequent ureterocutaneostomy performed, shorter operative time, higher rates of postoperative complications, longer LOHS, higher rates of readmission, and were associated with higher total costs, compared to patients with BI 65–90 and 95–100. In multivariable regression models, BI ≤60 remained an independent predictor of increased risk of major postoperative complications (odds ratio: 6.62, p = 0.006), longer LOHS (rate ratio: 1.25, p < 0.001), and higher costs (β: 2.617, p = 0.038). Conclusions: Total/severe dependency in ADL assessed by BI was associated with higher rates of major postoperative complications, longer hospitalization, and higher costs in BCa patients treated with RC. BI assessment should be considered during patients selection process and counseling before surgery. [ABSTRACT FROM AUTHOR]

For sustainable biomethane production, energy crops should not compete for land against feed and food. In response to this requirement, a set of practices for an innovative way to produce food and biomethane was developed in Italy with the Biogasdoneright™ model, which introduces the double‐cropping system along with digestate fertilization and minimum tillage. Triticale is a promising feedstock as energy crop in such systems. Ninteen varieties of triticale harvested at milk and dough development stages were evaluated. Principal component analysis showed that cellulose content positively affects methane production whereas starch content has only a very weak relation with specific methane yield and methane formation rate. Despite these relations, triticale chemical composition did not influence the profitability of bioenergy production as much as the total biomass solids yields, the total solids concentration at harvest, and the timing of growth. Triticale can be considered a suitable energy crop for biomethane targeting at least 4600 Nm3 CH4 per hectare. © 2022 Society of Chemical Industry and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Lifespan is determined by complex and tangled mechanisms that are largely unknown. The early postnatal stage has been proposed to play a role in lifespan, but its contribution is still controversial. Here, we show that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no effect on lifespan, suggesting that a specific time window is involved in lifespan regulation. We also find that sulfotransferases are upregulated during early rapamycin treatment both in newborn mice and in Drosophila larvae, and transient dST1 overexpression in Drosophila larvae extends lifespan. Our findings unveil a novel link between early‐life treatments and long‐term effects on lifespan. Synopsis: This study reveals a link between early‐life treatments and long‐term effects on lifespan in Drosophila and mice. A short rapamycin treatment during early life prolongs lifespan in Mus musculus and Drosophila melanogaster while the same treatment at later time points has no effect on lifespan.Sulfotransferases are upregulated during early rapamycin treatment both in newborn mice and Drosophila larvae.Transient dST1 sulfotransferase overexpression in Drosophila larvae extends lifespan. [ABSTRACT FROM AUTHOR]

We report the case of a 13‐year‐old female who presented with punctate, erythematous macules coalescing into patches on the upper extremities and left thigh. A skin biopsy demonstrated dilated capillary‐sized blood vessels in the papillary dermis consistent with a diagnosis of cutaneous collagenous vasculopathy (CCV). To our knowledge, this is the youngest patient to present with CCV and will represent the third pediatric case in the literature. [ABSTRACT FROM AUTHOR]

Merkel cell carcinoma (MCC) is a rare, aggressive primary neuroendocrine carcinoma of the skin that can present in immunocompromised patients. Kaposi sarcoma (KS) is an indolent angioproliferative tumor associated with human herpesvirus 8 (HHV8). The concurrence of both MCC and KS is rare, and there have been limited cases reported in the literature. We present a rare case of concurrent MCC and KS in an immunocompromised patient. To our knowledge, this is the first report of MCC and KS described in the same histopathological specimen. A 37‐year‐old Black male with a history of recurrent AIDS‐related KS involving bilateral lower extremities was evaluated for a tender nodule on the left posterior leg. A punch biopsy was consistent with MCC. Magnetic resonance imaging brain and full‐body positron emission tomography/computed tomography (PET/CT) scan were without evidence of distant metastasis. The patient underwent wide local excision with negative margins and completed postoperative radiation therapy. However, he later developed cutaneous metastasis of MCC to the left medial thigh and excision revealed residual MCC with adjacent KS. Treatment is still ongoing with pembrolizumab for both KS and MCC. [ABSTRACT FROM AUTHOR]

Purpose: This study examined how optimal colour/illumination conditions and the efficacy of the iPad, LuxIQ and Smart Bulb varied as a function of print size in younger, older and visually impaired adults. Methods: Participants with visual impairments and simulated low vision (SLV) read the MNRead using the iPad, LuxIQ and Smart Bulb. Results: In the impairment condition at 1.20 logMAR, the iPad (M = 9.49, 95% CI [3.18, 19.42]) and LuxIQ (M = 15.95, 95% CI [9.54, 24.86]) improved the reading speeds. At 0.80 logMAR (SLV), all devices improved reading speeds of older adults (iPad (M = 28.70, 95% CI [14.65, 42.51]); LuxIQ (M = 49.63, 95% CI [30.04, 69.68]); Smart Bulb (M = 23.11, 95% CI [3.33, 42.11])), but in younger adults only the LuxIQ (M = 13.04, 95% CI [3.21, 21.27]) did so. In the impairment condition, the iPad (M = 5.54, 95% CI [0.31, 12.13]) and LuxIQ (M = 13.90, 95% CI [7.88, 23.49]) improved reading speeds. In the SLV condition, age was a significant predictor of reading speed at 1.20 logMAR (F3,164 = 10.74, p < 0.001, Adj. R2 = 0.16). At 0.80 logMAR, age and luminance, but not colour, were significant predictors (F3,164 = 52.52, p < 0.001, Adj. R2 = 0.49). In the impairment condition, both age and lux were significant predictors of reading speed at 1.20 (F3,85 = 7.14, p < 0.001, Adj. R2 = 0.20) and 0.80 logMAR (F3,85 = 7.97, p < 0.001, Adj. R2 = 0.22), but colour was not. Conclusions: Light source effectiveness and optimal colour/illumination vary as a function of print size. It appears that print size is the most important factor for improving reading speed. As print size decreases, luminance becomes crucial, and only at the smallest print sizes does the effect of colour become useful. [ABSTRACT FROM AUTHOR]

Molecular profiling of small extracellular vesicles (sEV) isolated from plasma of cancer patients emerges as promising strategy for biomarkers discovery. We investigated the proteomic profiles of sEV immunoselected using anti‐CSPG4 antibodies from 15 melanoma patients' plasma. The proteomes of sEV separated into melanoma cell‐derived (MTEX) and non‐malignant cell‐derived (NMTEX) were compared using high‐resolution mass spectrometry. Paired analysis identified the MTEX‐associated profile of 16 proteins that discriminated MTEX from NMETEX. We also identified the MTEX profile that discriminated between seven patients with no evidence of melanoma (NED) after therapy and eight with progressive disease (PD). Among 75 MTEX proteins overexpressed in PD patients, PDCD6IP (ALIX) had the highest discriminating value, while CNTN1 (contactin‐1) was upregulated only in MTEX of NED patients. This is the first report documenting that proteomes of tumour‐derived sEV in patients' plasma discriminate cancer from non‐cancer and identify proteins with potential to serve as prognostic biomarkers in melanoma. [ABSTRACT FROM AUTHOR]

To achieve sustainable energy crop production, energy crops should not compete for land against feed and food crops. One option for sustainable energy‐crop cultivation is the use of double cropping systems with minimum tillage use and digestate as natural fertilizer, where, in the same growing season, a second crop for biomethane production is planted after a first crop used for feed/food. Different sorghum phenotypes were evaluated in the present study as first and second crops in a double cropping system. A principal component analysis of the various sorghum phenotypes showed that starch content positively affected methane production. However, sorghum chemical composition did not influence the profitability of bioenergy production as much as the total solid biomass yields of the different sorghum phenotypes. The highest total solid biomass productive sorghum phenotype led to the highest methane hectare yield. © 2020 Society of Chemical Industry and John Wiley & Sons, Ltd [ABSTRACT FROM AUTHOR]

KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)‐specific monoclonal antibodies cetuximab and panitumumab‐based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS‐mutated cancer cell growth in vitro by natural killer (NK) cell‐mediated antibody‐dependent cellular cytotoxicity (ADCC), KRAS‐mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS‐mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fcγ‐CR constructs including CD16158F‐CR, CD16158V‐CR, CD32131H‐CR, and CD32131R‐CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32131H‐CR (83.5 ± 9.5) and CD32131R‐CR (77.7 ± 13.2) were significantly higher than those expressing with CD16158F‐CR (30.3 ± 10.2) and CD16158V‐CR (51.7 ± 13.7) (p < 0.003). CD32131R‐CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16158V‐CR T cells released high levels of interferon gamma (IFNγ = 1,145.5 pg/ml ±16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNFα = 614 pg/ml ± 21 pg/ml, p < 0.001) upon incubation with cetuximab‐opsonized HCT116 cells. Moreover, only CD16158V‐CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS‐mutated cells in vitro. CD16158V‐CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17‐SCID mice in vivo. Thus, CD16158V‐CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS‐mutated CRC immunotherapies. What's new? KRAS mutations downstream the epidermal growth factor receptor (EGFR) represent the major limitation in monoclonal antibody‐targeted therapy of EGFR+ colorectal cancers. To restore the sensitivity of KRAS‐mutated cancer cells to EGFR‐specific mAbs, here the authors explore different strategies based on the generation of extracellular CD16‐chimeric receptors linked to intracellular signalling and subsequent transduction into T cells. They demonstrate that T cells engineered with CD16158V‐chimeric receptor can be redirected by EGFR‐specific mAbs toward EGFR+ cancer cells, overcoming the limitation conferred by KRAS mutations in vitro and in vivo. This study might help develop innovative and effective treatments of EGFR+ KRAS‐mutated cancers. [ABSTRACT FROM AUTHOR]

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody‐dependent‐cellular‐cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low‐affinity CD32A131R‐chimeric receptor (CR), and those engineered with the low‐affinity CD16158F‐CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T‐cell transduction, the percentage of CD32A131R‐CR T cells was 74 ± 10%, whereas the percentage of CD16158F‐CR T cells was 46 ± 15%. Only CD32A131R‐CR T cells bound panitumumab. CD32A131R‐CR T cells combined with the mAb 8.26 (anti‐CD32) and CD16158F‐CR T cells combined with the mAb 3g8 (anti‐CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A131R‐CR on T cells by cetuximab or panitumumab and CD16158F‐CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA‐MB‐468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ‐CR T antitumor activity against Kirsten rat sarcoma (KRAS)‐mutated HCT116, nonsmall‐cell‐lung‐cancer, A549 and TNBC, MDA‐MB‐231 cells. The ADCC of Fcγ‐CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A131R‐CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR. What's new? The role of antibody‐dependent cellular cytotoxicity in the antitumor activity of tumor antigen‐specific monoclonal antibodies has stimulated interest in genetically engineering T cells with the CD16 chimeric receptor (CD16‐CR). Here, the authors expand the application of this methodology to triple negative breast cancer (TNBC) overexpressing EGFR by utilizing a novel CD32A131R‐CR in combination with anti‐EGFR mAbs. The study supports the use of CD32A131R‐CR T cells combined with either panitumumab or cetuximab—an IgG2 and IgG1 monoclonal antibody, respectively—for targeting TNBC cells overexpressing EGFR. The results may be utilized as a platform for designing therapies targeting TNBC overexpressing EGFR. [ABSTRACT FROM AUTHOR]

Carex elata All. is a well‐known species widely distributed in western Eurasia. The name C. elata All. is the oldest name applied to the species of concern, but it was abandoned for C. stricta Gooden soon after publication. At the end of the 19th century and the beginning of the 20th century, different authors dismissed C. stricta Gooden. as a later homonym of C. stricta Lam. and simultaneously resurrected C. elata All. We discuss usage of the name C. elata and propose a neotype to fix its current application. [ABSTRACT FROM AUTHOR]

Background: Gnathodiaphyseal dysplasia (GDD) is a rare skeletal disorder that has not been well studied. Methods: Sanger sequencing, whole‐genome sequencing (WGS), and bioinformatics and structural modeling analyses were performed. Results: A family with patients with fibro‐osseous lesions of the jawbones were initially diagnosed with cherubism. Sequencing of SH3BP2, which is the causal gene of cherubism, revealed no pathogenic mutation. Through WGS, we identified a novel mutation c.1067G>T (p.C356F) in ANO5, and bioinformatics analyses and structural modeling showed that the mutation was deleterious. Because ANO5 is the gene responsible for GDD, we reappraised the clinical data of the patients, and the diagnosis was corrected to atypical GDD. A review of the literature showed that 67% of GDD cases confirmed by molecular testing were initially misdiagnosed. Conclusions: The novel mutation c.1067G>T (p.C356F) in ANO5 is responsible for the atypical GDD observed in our patients. GDD should be included in the differential diagnosis for patients with fibro‐osseous lesions. [ABSTRACT FROM AUTHOR]

Primary cutaneous small/medium-sized T-cell lymphoma ( PCSM-TCL), which was included in the World Health Organization - European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas as a provisional entity in 2008, has recently been reclassified as primary cutaneous small/medium-sized T-cell lymphoproliferative disorder ( PCSM-TCLPD) because of its indolent behavior and uncertain malignant potential. Treatment with local therapies is usually curative, although there have been reports of aggressive, systemic disease. This spectrum of disease behavior evokes the consideration that this entity may actually be multiple diseases with a shared clinicopathologic features rather than a singular disease process with a variety of behaviors. PCSM-TCLPD retained its designation as a provisional entity under the updated WHO-EORTC guidelines; however, additional cases of PCSM-TCLPD are needed to shed more light on this rare disorder. [ABSTRACT FROM AUTHOR]

We report on a three-layer organic light-emitting transistor (3LOLET) comprising a novel set of semiconductors as transport layers, 2,7-Dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) and 2,5-bis[4-(heptadecafluorooctyl)phenyl]thieno[3,2-b]thiophene (N-F2-6). These materials, combined with an emissive layer of a 4,4'-Bis(N-carbazolyl)-1,1'-biphenyl (CBP) derivative, 4,4'-bis(3,6-dineopentyl-9H-carbazole-9-yl)-1,'-biphenyl (NP4-CBP) and a new dye (BLUE1), have been used to obtain blue electroluminescent device. [ABSTRACT FROM AUTHOR]

The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B-Raf kinase (BRAF inhibitors, BRAFi). We generated drug-resistant cell variants in vitro from human BRAF-mutant melanoma cell lines MEL-HO, COLO-38, SK-MEL-37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug-resistant cell variants remained susceptible to lysis by IL-2-activated NK cells; and two BRAFi-resistant lines (BRAFi-R) became significantly more susceptible to NK-cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD-L1 upregulation on the drug-resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi-R and parental cells to NK-cell-mediated lysis, antibody-mediated inhibition of PD1-PD-L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi-R melanoma variants thus appears to play a major role in their susceptibility to NK-cell cytotoxicity. These findings suggest that NK-cell-based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors. [ABSTRACT FROM AUTHOR]

This review discusses the potential use of intracellular tumor antigens as targets of antibody-based immunotherapy for the treatment of solid tumors. In addition, it describes the characteristics of the intracellular tumor antigens targeted with antibodies which have been described in the literature and have been identified in the authors' laboratory. Finally, the mechanism underlying the trafficking of the intracellular tumor antigens to the plasma membrane of tumor cells are reviewed. [ABSTRACT FROM AUTHOR]

Poly (ADP-Ribose) polymerase-1 (PARP-1) is involved in the DNA repairing system by sensing and signaling the presence of DNA damage. Inhibition of PARP-1 is tested in combination with DNA damaging agents such as topoisomerase I inhibitors or ionizing radiations (RT) for the treatment of glioblastoma (GBM). Disruption of p53, widely prevalent in GBMs, plays a major role in DNA repairing system. The current study investigates whether p53 activity has an effect on the sensitivity of human GBM cells to PARP-1 inhibitors in combination with topoisomerase I inhibitor topotecan (TPT) and/or RT. Human GBM cell lines carrying a different functional status of p53 were treated with PARP-1 inhibitor NU1025, in combination with TPT and/or RT. Cytotoxic effects were examined by analyzing the antiproliferative activity, the cell cycle perturbations, and the DNA damage induced by combined treatments. PARP inhibition enhanced the antiproliferative activity, the cell cycle perturbations and the DNA damage induced by both TPT or RT in GBM cells. These effects were influenced by the p53 activity: cells carrying an active p53 were more sensitive to the combination of PARP inhibitor and RT, while cells carrying an inactive p53 displayed a higher sensitivity to the combination of PARP inhibitor and TPT. Our study suggests that p53 activity influences the differential sensitivity of GBM cells to combined treatments of TPT, RT, and PARP inhibitors. © 2014 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

Background: Neural tube defects (NTD) have a strong genetic component, with up to 70% of variance in human prevalence determined by heritable factors. Although the identification of causal DNA variants by sequencing candidate genes from functionally relevant pathways and model organisms has provided some success, alternative approaches are demanded. Methods: Next generation sequencing platforms are facilitating the production of massive amounts of sequencing data, primarily from the protein coding regions of the genome, at a faster rate and cheaper cost than has previously been possible. These platforms are permitting the identification of variants (de novo, rare, and common) that are drivers of NYTD etiology, and the cost of the approach allows for the screening of increased numbers of affected and unaffected individuals from NTD families and in simplex cases. Conclusion: The next generation sequencing platforms represent a powerful tool in the armory of the genetics researcher to identify the causal genetic basis of NTDs. Birth Defects Research (Part A) 100:642-646, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease-relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10−3) and 22 (LOD = 3.45, p = 6 × 10−5) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies. [ABSTRACT FROM AUTHOR]

Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 ( p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype ( p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes. [ABSTRACT FROM AUTHOR]

Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from ICD. Docetaxel treatment of tumor cells did not induce ATP or high-mobility group box 1 (HMGB1) secretion, or cell death. However, calreticulin (CRT) exposure was observed in all cell lines examined after chemotherapy treatment. Killing by carcinoembryonic antigen (CEA), MUC-1, or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by CRT membrane translocation, as determined by functional knockdown of CRT, PERK, or CRT-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+, CD133+) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of 'immunogenic modulation,' where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to ICD and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy. [ABSTRACT FROM AUTHOR]

BACKGROUND The prognosis of metastatic melanomas to the brain (MBM) is variable with prolonged survival in a subset. It is unclear whether MBM differ from extracranial metastases (EcM) and primary melanomas (PrM). METHODS To study the biology of MBM, histopathologic analysis of tumor blocks from patients' craniotomy samples and whole-genome expression profiling (WGEP) with confirmatory immunohistochemistry were performed. RESULTS High mononuclear infiltrate and low intratumoral hemorrhage were associated with prolonged overall survival (OS). Pathway analysis of WGEP data from 29 such craniotomy tumor blocks demonstrated that several immune-related BioCarta gene sets were associated with prolonged OS. WGEP analysis of MBM in comparison with same-patient EcM and PrM showed that MBM and EcM were similar, but both differ significantly from PrM. Immunohistochemical analysis revealed that peritumoral CD3+ and CD8+ cells were associated with prolonged OS. CONCLUSIONS MBMs are more similar to EcM compared with PrM. Immune infiltrate is a favorable prognostic factor for MBM. Cancer 2013;119:2737-2746. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy. CA Cancer J Clin 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

The present Review opens with an overview of metal oxides and the description of their material properties. The first part mainly deals with various preparation techniques and growth mechanisms, which have been largely developed in the last few decades to fabricate different types of metal oxide nanostructures. The second part, on the other hand, will provide the Reader with an up-to-date summary of different applications in which metal oxides nanostructures have been successfully implemented and/or suggested. In particular, great attention will be dedicated to the implementation of metal oxide nanostructures for gas sensing as well as light emission applications, for which both working principles and integration, as well as the latest reported cutting edge results are herein reported. Finally, we emphasize on the current potentials of metal oxide nanostructured materials and future challenges that this field in continuous expansion is currently facing. [ABSTRACT FROM AUTHOR]

Summary Chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane proteoglycan originally identified as a highly immunogenic tumor antigen on the surface of melanoma cells, is associated with melanoma tumor formation and poor prognosis in certain melanomas and several other tumor types. The complex mechanisms by which CSPG4 affects melanoma progression have started to be defined, in particular the association with other cell surface proteins and receptor tyrosine kinases (RTKs) and its central role in modulating the function of these proteins. CSPG4 is essential to the growth of melanoma tumors through its modulation of integrin function and enhanced growth factor receptor-regulated pathways including sustained activation of ERK 1,2. This activation of integrin, RTK, and ERK1,2 function by CSPG4 modulates numerous aspects of tumor progression. CSPG4 expression has further been correlated to resistance of melanoma to conventional chemotherapeutics. This review outlines recent advances in our understanding of CSPG4-associated cell signaling, describing the central role it plays in melanoma tumor cell growth, motility, and survival, and explores how modifying CSPG4 function and protein-protein interactions may provide us with novel combinatorial therapies for the treatment of advanced melanoma. [ABSTRACT FROM AUTHOR]

Summary Renal failure occurs in 5-18% of sickle cell disease (SCD) patients and is associated with early mortality. At-risk SCD patients cannot be identified prior to the appearance of proteinuria and the pathobiology is not well understood. The myosin, heavy chain 9, non-muscle ( MYH9) and apolipoprotein L1 ( APOL1) genes have been associated with risk for focal segmental glomerulosclerosis and end-stage renal disease in African Americans. We genotyped 26 single nucleotide polymorphisms (SNPs) in MYH9 and 2 SNPs in APOL1 (representing the G1 and G2 tags) in 521 unrelated adult (18-83 years) SCD patients screened for proteinuria. Using logistic regression, SNPs were evaluated for association with proteinuria. Seven SNPs in MYH9 and one in APOL1 remained significantly associated with proteinuria after multiple testing correction ( P < 0·0025). An MYH9 risk haplotype ( P = 0·001) and the APOL1 G1/G2 recessive model ( P < 0·0001) were strongly associated with proteinuria, even when accounting for the other. Glomerular filtration rate was negatively correlated with proteinuria ( P < 0·0001), and was significantly predicted by an interaction between MYH9 and APOL1 in age-adjusted analyses. Our data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 and APOL1 are both associated with risk. [ABSTRACT FROM AUTHOR]

The article presents research on the role of tumor infiltration in the survival of patients with colorectal carcinoma (CRC). The significance of macrophage and natural killer (NK) cell infiltration in CRC is said to be still unclear. An investigation of the CRC innate inflammatory infiltrate was conducted and the survival time was assessed using the Kaplan-Meier method. It concludes that CD16+ cell infiltration showed favorable prognostic factor in CRC.

Background. CD44 was found as a surface marker in cancer stem cell (CSC) of squamous cell carcinoma of the head and neck (SCCHN); however, the immunologic properties of such CSCs have not yet been elucidated. Methods. The immunologic properties of CD44+ cancer stem-like cells were compared with those of CD44+ cells using flow cytometry and enzyme-linked immunosorbent assay. Results. CD44+ cells exhibited weak HLA-A2 and class II expression. Interestingly, downregulation of transporter antigen processing (TAP)2 was found in CD44+ cells. The CD44+ cell population produced significantly higher levels of interleukin (IL)-8, granulocyte colony-stimulating factor (G-CSF), and transforming growth factor (TGF)-β than the CD44+ cell population. Moreover, CD44+ cells have been shown to not only more strongly inhibit T-cell proliferation, but also to more efficiently inhibit regulatory T cells (Treg cells) and myeloidderived suppressor cells (MDSC) as compared with CD44+ cells. Additionally, CD44+ cells suppressed Th1 responses and enhanced regulatory T cell responses. Conclusion. CSCs might have higher malignant potential with numerous escape strategies from immune attack. [ABSTRACT FROM AUTHOR]

Background Cumulative evidence implicates the epidermal growth factor receptor (EGFR) as an important therapeutic target in head and neck squamous cell carcinoma (HNSCC). The basis for the lack of correlation between EGFR expression in the HNSCC tumor and clinical responses to EGFR inhibitors is incompletely understood. Although a variety of mechanisms likely contribute to the effectiveness of EGFR blockade, this review focuses on the biologic implications of known EGFR variations and the role of the immune system in mediating clinical responses to EGFR inhibitors. Methods A Medline review of articles published in the last 10 years (1999-present) on EGFR in HNSCC was performed in combination with preliminary data from our laboratories. Results Studies published to date suggest no association between the expression of EGFR on HNSCC tumors and clinical responses to EGFR inhibitors. Several mechanisms have been proposed to mediate clinical response to EGFR inhibitors in HNSCC. Cumulative results from our laboratories support the role of several mechanisms, including cellular immune activation and mutated EGFR variants, in contributing to the discrepancy between level of EGFR expression and clinical response to EGFR inhibitors. Conclusion The efficacy of EGFR targeted therapies may be mediated, at least in part, by the immune system and the presence of the truncated EGFR variant, EGFRvIII, among other factors. Criteria to identify the subset of patients likely to be responsive to EGFR targeted therapies are needed. © 2010 Wiley Periodicals, Inc. Head Neck, 2010 [ABSTRACT FROM AUTHOR]

Baccarani U, Isola M, Adani GL, Avellini C, Lorenzin D, Rossetto A, Currò G, Comuzzi C, Toniutto P, Risaliti A, Soldano F, Bresadola V, De Anna D, Bresadola F. Steatosis of the hepatic graft as a risk factor for post-transplant biliary complications. Clin Transplant 2009 DOI: 10.1111/j.1399-0012.2009.01128.x. © 2009 John Wiley & Sons A/S. Despite recent advances in organ preservation, immunosuppression, and surgical techniques, the biliary tree is still considered the Achilles' heel of liver transplantation. The aim of this study is to retrospectively analyze the incidence of biliary complications and identify risk factors that might predispose to the development of biliary problems. Methods: From January 2004 to December 2007, 117 consecutive liver transplantations were retrospectively analyzed for the development of biliary complications by the review of medical records. Patients were divided into group 1 with biliary complications (n = 43) and group 2 without biliary complications (n = 74). Results: The overall biliary complication rate was 36.8% (leakage 6% and stricture 30.8%). Univariate analysis indicated that significant predictors of biliary complications were the time interval between portal and arterial reperfusion (p = 0.037) and macrovacuolar steatosis of the graft > 25% (p = 0.004). Stepwise logistic regression model demonstrated that a macrosteatosis of the graft > 25% (OR = 5.21 CI 95% [1.79-15.15], p = 0.002) was the only independent risk factor predicting biliary complications after liver transplantation. No differences in patient's and graft's survival were noted between the two groups. Conclusion: According to our experience, transplanting a liver with > 25% of steatosis is a risk factor for the development of biliary complication. [ABSTRACT FROM AUTHOR]

To investigate the effects of 17beta-estradiol (E2) on extracellular matrix (ECM) protein synthesis (collagen type I, fibronectin, and laminin) using cultures of normal and scleroderma (SSc) skin fibroblasts. Primary fibroblasts cultures, obtained from skin biopsies of six female voluntary subjects and three female SSc patients, were treated for 24 h with E2 (10−10M) alone or in combination with tamoxifene (TAM, 10−7M) as an estrogen receptor (ER) antagonist. ECM protein synthesis was analyzed by immunocytochemistry and Western blotting. E2 induced a significant increase of fibronectin, collagen type I, and laminin synthesis both in normal ( P < 0.01, P < 0.05, P < 0.01, respectively) and SSc fibroblasts ( P < 0.001, P < 0.05, P < 0.001, respectively) when compared to untreated fibroblasts. TAM induced a significant decrease of ECM protein synthesis when compared to E2-treated TAM-untreated fibroblasts. This study seems to support important modulatory effects of E2 in the fibrotic progression of the SSc process via ER interactions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) prevalence is greater in females than in males, supporting estrogens as modulators of immune response. Leflunomide (LEF) is employed in the RA treatment. We studied the combinatory effects of LEF active metabolite A77 1726 (LEF-M) and 17beta-estradiol (E2) on inflammatory cytokine production by cultured macrophages obtained from activated human monocytes (THP-1 cells). Macrophages were cultured with LEF-M alone and in combination with E2. IL-6, TNF-α, and TGF-β were evaluated by immunocytochemistry (ICC), Western blot (WB), and reverse transcriptase-polymerase chain reaction (RT-PCR). ICC, as well as WB and RT-PCR, showed that LEF-M, in respect to untreated cells, significantly downregulated the cytokine production (IL-6 P < 0.01, TNF-α P < 0.001, TGF-β P < 0.01). On the contrary, E2 increased the cytokine production, a result that was significantly reversed when LEF-M was subsequently added (IL-6, TNF-α, TGF-β P < 0.001 vs. E2). E2 seems to contrast the LEF-M activity. These results might support a more efficient therapeutical effect of LEF in male with respect to female RA patients. [ABSTRACT FROM AUTHOR]

The effects of low dose prednisone (PD) alone or in combination with leflunomide (LEF) were tested on inflammatory gene expression in early rheumatoid arthritis (RA). Ten RA patients were assigned as group A (untreated)and group B (pretreated with PD 5 mg/day for 3 months -T0). Therefore, both groups were treated with LFN (20mg/day). Expression ratio of 34 inflammatory genes was detected by microarray analysis in early RA patients and CNT (5), before (T0), and after 3 months (T1) of combined therapy (PN+LFN). At T0, 17 genes linked with arthritis were found altered in early RA, (A and B groups), compared to CNT. At T1 in the group A, 41% of genes were found unchanged, 12% upregulated, and 47% downregulated, whereas in the group B, 65% of genes were found unchanged, 6% upregulated, and 29% downregulated. The results suggest that the combination of PN and LEF seems to play a synergistic effect by modulating some inflammatory genes in early RA. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about the use of high molecular weight antigen as a biomarker for desmoplastic melanoma (DM).

Nanoscale dielectric films made of alumina grown by atomic layer deposition (ALD) have been implemented as high-k dielectric material in organic light emitting transistors (OLETs). This leads to the reduction of both the threshold and operating bias regime of the devices while obtaining comparable light emission, when compared to our standard polymer-based dielectric platform. [ABSTRACT FROM AUTHOR]

We present 17 penile traumatic neuromas. The mean patient age at presentation was 38 years (range 23–59 years). The most common site involved was the penile shaft. The lesions ranged from 1 to 7 mm in greatest dimension. The clinical diagnosis in all cases included condyloma acuminatum. In all cases, a history of trauma because of prior biopsy and/or circumcision was found. Histologically, all lesions showed similar features consisting of an increased number of dermal nerve bundles embedded within a fibrous stroma. Often, single or multiple Meissner corpuscle-like structures were noted in the papillary dermis. Our study suggests that circumcision or other forms of trauma to the skin of the penis likely plays an important role in the pathogenesis and clinical presentation of this peculiar neural neoplasm. We call attention to this entity because it is often clinically misdiagnosed as condyloma acuminatum. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the long-term activity and toxicity profile of rituximab in adult patients with idiopathic immune thrombocytopenic purpura (ITP). Patients and methods: Twenty-six patients with active and symptomatic ITP relapsed or refractory received weekly infusions of rituximab 375 mg/m2 for 4 wk. Median time from diagnosis to rituximab was 34.5 months . The following parameters of efficacy and toxicity were considered: complete response (CR) and partial response (PR), relapse rate, relapse-free survival (RFS), therapy-free survival (TFS), short- and long-term toxicity. Results: CR and PR were 14/26 (54%) and 4/26 (15%), respectively. Median time of observation was 56.5 months (range 39–77). Nine of the 18 responding patients relapsed after a median of 21 months (range 8–66); 9/26 patients (35%) maintained the response, with a median follow-up of 57 months (range 39–69), and 11/26 (42%) did not necessitate further therapy; estimated 5 yr RFS and TFS were 61% and 72%, respectively. Younger age and shorter interval from diagnosis to rituximab appeared indicators of better outcome. Rituximab administration was associated with two episodes of short-term toxicity, with one case of serum sickness syndrome; no infectious or other significant long-term complications were documented. Conclusion: Rituximab therapy may achieve long-lasting remission in nearly one-third of patients with relapsed or refractory ITP, with a good safety profile. [ABSTRACT FROM AUTHOR]

Purpose To investigate the relevance of increasing b-values in evaluating liver fibrosis through the agreement of two diffusion-weighted (DW) sequences. Materials and Methods A total of 29 cirrhotic patients and 29 healthy volunteers were studied on a 1.5T system. Two single-shot spin-echo echo-planar sequences were acquired using sets of increasing b-values: 0, 150, 250, and 400 seconds/mm2 (first sequence: DW1a) and 0, 150, 250, 400, 600, and 800 seconds/mm2 (second sequence: DW2a). Apparent diffusion coefficients (ADCs) of the hepatic parenchyma were calculated on ADC maps. Noise-scaled single-point ADCs were calculated for each sequence from b = 400 seconds/mm2. Results ADCs resulted significantly lower in cirrhotic patients compared to controls using both DW1a (mean 1.14 ± 0.20 × 10−3mm2/second vs. 1.54 ± 0.12 × 10−3mm2/second; P < 0.0001) and DW2a (mean 0.91 ± 0.18 × 10−3mm2/second vs. 1.04 ± 0.18 × 10−3mm2/second; P = 0.0089). DW1 and DW2, respectively significantly differed in diagnostic performance at receiver operating characteristic (ROC) curve analysis ( P = 0.003), showing AUCs of 0.93 (sensitivity 89.7%, specificity 100%) and 0.73 (sensitivity 62.1%, specificity 79.3%), respectively. Noise-scaled single-point ADCs showed a progressive convergence to similar values in cirrhotic and healthy livers at b = 800 seconds/mm2 (1.12 ± 0.27 × 10−3mm2/second vs. 1.13 ± 0.17 × 10−3mm2/second). Conclusion A DW sequence is accurate in assessing liver fibrosis using intermediate (400 seconds/mm2) rather than high (800 seconds/mm2) maximum b-values, but after proper recalculation of ADCs the effects of perfusion rather than diffusion should be considered responsible for the higher accuracy at lower b-values. J. Magn. Reson. Imaging 2008;28:411-419. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]