The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs

Summary

Objective

Older antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). However, evidence for newer AED is sparse. We quantified risks of SJS/TEN in association with use of all AEDs in the United Kingdom.

Methods

In a matched case-control study of 480 previously validated SJS/TEN cases (1995–2013) we used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs), and calculated absolute risks of SJS/TEN within separate cohorts of new users of 28 AEDs. We assessed causality between drugs and SJS/TEN in each exposed case, using an adapted version of the algorithm of drug causality for epidermal necrolysis (ALDEN) score.

Results

We observed a strong association between SJS/TEN and new use of carbamazepine (OR 92.57, 95% CI 19.89–∞), phenytoin (OR 49.96, 95% CI 10.13–∞), and lamotrigine (OR 26.90, 95% CI 4.88–∞), where causality, according to the ALDEN score, was very probable or probable for most exposed cases. Absolute risks for SJS/TEN were highest for phenytoin (45.86 cases/100,000 exposed), lamotrigine (44.17 cases/100,000 exposed), and carbamazepine (20.38 cases/100,000 exposed). Despite increased ORs for valproate (40,941 exposed), gabapentin (116,037 exposed), pregabalin (59,967 exposed), and clobazam (4,300 exposed), ALDEN suggested no causal association. There were no observed cases of SJS/TEN among new users of levetiracetam (n = 96,77), clonazepam (n = 18,075), or topiramate (n = 11,307).

Significance

The results of our study are consistent with those of previous studies of SJS/TEN, which found increased risks of SJS/TEN in new use of carbamazepine, phenytoin, and lamotrigine. Despite frequent use, no ALDEN-score confirmed cases were observed in new users of valproate, gabapentin, pregabalin, levetiracetam, topiramate, or clonazepam.

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Laparoscopic ventral hernia repair using only 5-mm ports

Background

The technique of laparoscopic ventral hernia repair has been evolving since it was first described over 20 years ago. We report a new technique where polyester mesh was back loaded through a 5-mm port site, coming into contact with the skin. This avoids the need for any 10–12-mm ports.

Methods

A prospective database of laparoscopic ventral hernia repairs was examined. A single surgeon performed 344 laparoscopic ventral hernia repairs using this technique over 60 months. Follow-up was conducted by both clinical and independent phone review. Surgical technique: Laparoscopic access was achieved via a 5-mm optical port, adding two, or occasionally three, 5-mm extra ports. Hernia contents were reduced and the extra-peritoneal fat excised; 5-mm tooth graspers were placed through the lateral port and then in a retrograde fashion through the uppermost port. The port was removed, and the mesh pulled back into the abdominal cavity and positioned with a minimum of 3-cm overlap. The mesh was fixed using absorbable tacks and sutures.

Results

Most patients had primary umbilical hernias. There was one case of mesh infection due to enteric organisms. This occurred in a patient undergoing repair of a stoma site hernia, resulting from a Hartmann's procedure for perforated diverticulitis. There was no other evidence of acute or chronic mesh infection despite cutaneous contact with the mesh. In this series, there was an overall hernia recurrence rate of 2.4%.

Conclusion

Laparoscopic ventral hernia repair using only 5-mm ports is a safe, effective technique with no extra risk of infection.

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On OX40 and PD-1 Combination: Why Should OX40 Be First in Sequence?

The larger fraction of patients treated with immune checkpoint inhibitors remain nonresponding eventually. Combination of checkpoint inhibitor and costimulatory antibodies is thought additive, but for such effect, they may require to be given in the right sequence. Clin Cancer Res; 23(20); 5999–6001. ©2017 AACR.

See related article by Messenheimer et al., p. 6165

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Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

Purpose: HSP90, a highly conserved molecular chaperone that regulates the function of several oncogenic client proteins, is altered in glioblastoma. However, HSP90 inhibitors currently in clinical trials are short-acting, have unacceptable toxicities, or are unable to cross the blood–brain barrier (BBB). We examined the efficacy of onalespib, a potent, long-acting novel HSP90 inhibitor as a single agent and in combination with temozolomide (TMZ) against gliomas in vitro and in vivo.

Experimental Design: The effect of onalespib on HSP90, its client proteins, and on the biology of glioma cell lines and patient-derived glioma-initiating cells (GSC) was determined. Brain and plasma pharmacokinetics of onalespib and its ability to inhibit HSP90 in vivo were assessed in non–tumor-bearing mice. Its efficacy as a single agent or in combination with TMZ was assessed in vitro and in vivo using zebrafish and patient-derived GSC xenograft mouse glioma models.

Results: Onalespib-mediated HSP90 inhibition depleted several survival-promoting client proteins such as EGFR, EGFRvIII, and AKT, disrupted their downstream signaling, and decreased the proliferation, migration, angiogenesis, and survival of glioma cell lines and GSCs. Onalespib effectively crossed the BBB to inhibit HSP90 in vivo and extended survival as a single agent in zebrafish xenografts and in combination with TMZ in both zebrafish and GSC mouse xenografts.

Conclusions: Our results demonstrate the long-acting effects of onalespib against gliomas in vitro and in vivo, which combined with its ability to cross the BBB support its development as a potential therapeutic agent in combination with TMZ against gliomas. Clin Cancer Res; 23(20); 6215–26. ©2017 AACR.

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T-cell Receptors for Clinical Therapy: In Vitro Assessment of Toxicity Risk

Adoptive therapy with T-cell receptor (TCR)–engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T-cell reactivity. Here, we propose a sequence of in vitro assays to improve selection of TCRs and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against cancer germline antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif toward its cognate peptide, and a TCR's cross-reactivity toward noncognate peptides. Clin Cancer Res; 23(20); 6012–20. ©2017 AACR.

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Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.

Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.

Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.

Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. Clin Cancer Res; 23(20); 6267–78. ©2017 AACR.

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The c.1085A>G Genetic Variant of CSF1R Gene Regulates Tumor Immunity by Altering the Proliferation, Polarization, and Function of Macrophages

Purpose: Targeting tumor-associated macrophages with colony-stimulating factor 1 receptor (CSF-1R) inhibition reveals a strategy for cancer therapy. Here, we studied the impact of CSF1R germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.

Experimental designs: CSF1R germline genetic variants were studied in 140 cancer patients. CSF-1R phosphorylation, endocytosis, and macrophage polarization were measured as the response to CSF-1 stimulation. Tumor-associated macrophages in surgical specimens and sensitivity to CSF-1R inhibitors were used to determine macrophage function.

Results: A CSF1R c.1085A>G genetic variant causing the change of histidine to arginine in the domain of receptor dimerization was identified as a high allele frequency in Eastern Asian population. Cancer patients with this variant allele had less M2-like tumor-associated macrophages accompanied by low VEGF expression in tumor tissues. Importantly, CSF1R genetic variant was significantly associated with disease-free survival in colorectal, endometrial, and ovarian cancer. In terms of differentiation, macrophages with CSF1R c.1085A>G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC₅₀ of 0.1 to 1 nmol/L range. On contrast, CSF-1 induced a prominent phosphorylation and rapid endocytosis of CSF-1R, leading to an M2-like dominant polarization in macrophages with CSF1R c.1085 genotype A_A, in which CSF-1R inhibitors of PLX3397, BLZ945, and GW2580 inhibited macrophage survival with IC₅₀ of 10 to 100 nmol/L range.

Conclusions: The CSF1R c.1085A>G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment. Clin Cancer Res; 23(20); 6021–30. ©2017 AACR.

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Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.

Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEX^mGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8⁺ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.

Results: Treatment with OncoVEX^mGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3⁺/CD8⁺) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8⁺ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEX^mGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEX^mGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8⁺ anti-AH1 T cells and systemic efficacy.

Conclusions: The data support a dual MOA for OncoVEX^mGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8⁺-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190–202. ©2017 AACR.

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Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.

Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.

Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.

Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044–53. ©2017 AACR.

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Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer

Purpose: Drugs targeting DNA repair and cell-cycle checkpoints have emerged as promising therapies for small-cell lung cancer (SCLC). Among these, the WEE1 inhibitor AZD1775 has shown clinical activity in a subset of SCLC patients, but resistance is common. Understanding primary and acquired resistance mechanisms will be critical for developing effective WEE1 inhibitor combinations.

Experimental Design: AZD1775 sensitivity in SCLC cell lines was correlated with baseline expression level of 200 total or phosphorylated proteins measured by reverse-phase protein array (RPPA) to identify predictive markers of primary resistance. We further established AZD1775 acquired resistance models to identify mechanism of acquired resistance. Combination regimens were tested to overcome primary and acquired resistance to AZD1775 in in vitro and in vivo SCLC models.

Results: High-throughput proteomic profiling demonstrate that SCLC models with primary resistance to AZD1775 express high levels of AXL and phosphorylated S6 and that WEE1/AXL or WEE1/mTOR inhibitor combinations overcome resistance in vitro and in vivo. Furthermore, AXL, independently and via mTOR, activates the ERK pathway, leading to recruitment and activation of another G2-checkpoint protein, CHK1. AZD1775 acquired resistance models demonstrated upregulation of AXL, pS6, and MET, and resistance was overcome with the addition of AXL (TP0903), dual-AXL/MET (cabozantinib), or mTOR (RAD001) inhibitors.

Conclusions: AXL promotes resistance to WEE1 inhibition via downstream mTOR signaling and resulting activation of a parallel DNA damage repair pathway, CHK1. These findings suggest rational combinations to enhance the clinical efficacy of AZD1775, which is currently in clinical trials for SCLC and other malignancies. Clin Cancer Res; 23(20); 6239–53. ©2017 AACR.

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PD-L1 Expression and Immune Escape in Melanoma Resistance to MAPK Inhibitors

Purpose: To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors.

Experimental Design: Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n = 12) or combination BRAF/MEK inhibitors (n = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, n = 17), early during treatment (EDT, n = 8), and progression (PROG, n = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC.

Results: Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-β-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.

Conclusions: PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor–treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. Clin Cancer Res; 23(20); 6054–61. ©2017 AACR.

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Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity

Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM.

Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry.

Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN^High and GLN^Low, mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN^High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN^High cultures are CD133^neg and display a mesenchymal signature in contrast to CD133^pos GLN^Low GBM cells.

Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292–304. ©2017 AACR.

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Pediatric Phase I Trial and Pharmacokinetic Study of Trebananib in Relapsed Solid Tumors, Including Primary Tumors of the Central Nervous System ADVL1115: A Children's Oncology Group Phase I Consortium Report

Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK).

Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI.

Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI.

Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.

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miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/{beta}-catenin Complex in Lung Adenocarcinoma

Purpose: This study was performed to identify the detailed mechanisms by which miR-296-3p functions as a tumor suppressor to prevent lung adenocarcinoma (LADC) cell growth, metastasis, and chemoresistance.

Experimental Design: The miR-296-3p expression was examined by real-time PCR and in situ hybridization. MTT, EdU incorporation, Transwell assays, and MTT cytotoxicity were respectively performed for cell proliferation, metastasis, and chemoresistance; Western blotting was performed to analyze the pathways by miR-296-3p and HDGF/DDX5 complex. The miRNA microarray and luciferase reporter assays were respectively used for the HDGF-mediated miRNAs and target genes of miR-296-3p. The ChIP, EMSA assays, and coimmunoprecipitation combined with mass spectrometry and GST pull-down were respectively designed to analyze the DNA–protein complex and HDGF/DDX5/β-catenin complex.

Results: We observed that miR-296-3p not only controls cell proliferation and metastasis, but also sensitizes LADC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that miR-296-3p directly targets PRKCA to suppress FAK–Ras-c–Myc signaling, thus stimulating its own expression in a feedback loop that blocks cell cycle and epithelial–mesenchymal transition (EMT) signal. Furthermore, we observed that suppression of HDGF–β-catenin–c-Myc signaling activates miR-296-3p, ultimately inhibiting the PRKCA–FAK–Ras pathway. Finally, we found that DDX5 directly interacts with HDGF and induces β-catenin–c-Myc, which suppresses miR-296-3p and further activates PRKCA–FAK–Ras, cell cycle, and EMT signaling. In clinical samples, reduced miR-296-3p is an unfavorable factor that inversely correlates with HDGF/DDX5, but not PRKCA.

Conclusions: Our study provides a novel mechanism that the miR-296-3p–PRKCA–FAK–Ras–c-Myc feedback loop modulated by HDGF/DDX5/β-catenin complex attenuates cell growth, metastasis, and chemoresistance in LADC. Clin Cancer Res; 23(20); 6336–50. ©2017 AACR.

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Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification

Purpose: Precise detection of copy number aberrations (CNA) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next-generation sequencing (NGS) is inexpensive, high throughput, and easily feasible, allowing single-nucleotide variant calls, but CNA estimation from this remains challenging.

Experimental Design: We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration-resistant prostate cancer biopsies and used capture-based whole-exome sequencing (WES), array comparative genomic hybridization (aCGH), and FISH to explore the viability of this approach.

Results: We showed that this method produced highly reproducible CNA results (r = 0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation. CNA estimates from targeted NGS were comparable with WES (r = 0.86) and aCGH (r = 0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN, and RB1), CNA estimation correlated well with WES (r = 0.91) and aCGH (r = 0.84) results. The frequency of CNAs in our population was comparable with that previously described (i.e., deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intratumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates.

Conclusions: Targeted NGS and CNVkit-based analyses provide a robust, precise, high-throughput, and cost-effective method for CNA estimation for the delivery of more precise patient care. Clin Cancer Res; 23(20); 6070–7. ©2017 AACR.

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Genomics of Immunotherapy-Associated Hyperprogressors--Response

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T2-FLAIR Mismatch, an Imaging Biomarker for IDH and 1p/19q Status in Lower-grade Gliomas: A TCGA/TCIA Project

Purpose: Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on IDH and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI features could distinguish between lower-grade glioma molecular subtypes.

Experimental Design: MRI scans from the TCGA/TCIA lower grade glioma database (n = 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2–FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate–substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular–radiographic associations. A separate institutional cohort (n = 82) was analyzed to validate the T2–FLAIR mismatch sign.

Results: Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity [ = 0.234 (0.111–0.358)], T2–FLAIR mismatch sign [ = 0.728 (0.538–0.918)], lesion margins [ = 0.292 (0.135–0.449)], and peritumoral edema [ = 0.173 (0.096–0.250)]. All 15 cases that were positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2–FLAIR mismatch sign [ = 0.747 (0.536–0.958)]; all 10 cases positive for the T2–FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (P < 0.00001; PPV = 100%, NPV = 76%).

Conclusions: Among lower-grade gliomas, T2–FLAIR mismatch sign represents a highly specific imaging biomarker for the IDH-mutant, 1p/19q non-codeleted molecular subtype. Clin Cancer Res; 23(20); 6078–85. ©2017 AACR.

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Phenytoin: its potential as neuroprotective and retinoprotective drug

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SID-1 Domains Important for dsRNA Import in Caenorhabditis elegans

In the nematode Caenorhabditis elegans, RNA interference (RNAi) triggered by double-stranded RNA (dsRNA) spreads systemically to cause gene silencing throughout the organism and its progeny. We confirm that Caenorhabditis nematode SID-1 orthologs have dsRNA transport activity and demonstrate that the SID-1 paralog CHUP-1 does not transport dsRNA. Sequence comparison of these similar proteins, in conjunction with analysis of loss-of-function missense alleles identifies several conserved 2-7 amino acid microdomains within the extracellular domain that are important for dsRNA transport. Among these missense alleles, we identify and characterize a sid-1 allele, qt95, which causes tissue-specific silencing defects most easily explained as a systemic RNAi export defect. However, we conclude from genetic and biochemical analyses that sid-1(qt95) disrupts only import and speculate that the apparent export defect is caused by the cumulative effect of sequentially impaired dsRNA import steps. Thus, consistent with previous studies, we fail to detect a requirement for sid-1 in dsRNA export, but demonstrate for the first time that SID-1 functions in the intestine to support environmental RNAi.

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A Predictive Model for Time-to-Flowering in the Common Bean Based on QTL and Environmental Variables

The common bean is a tropical facultative short day legume that is now grown in tropical and temperate zones. This observation underscores how domestication and modern breeding can change the adaptive phenology of a species. A key adaptive trait is the optimal timing of the transition from the vegetative to the reproductive stage. This trait is responsive to genetically controlled signal transduction pathways and local climatic cues. A comprehensive characterization of this trait can be started by assessing the quantitative contribution of the genetic and environmental factors, and their interactions. This study aimed to locate significant QTL (G) and environmental (E) factors controlling time-to-flower in the common bean, and to identify and measure G x E interactions. Phenotypic data were collected from a bi-parental [Andean x Mesoamerican] recombinant inbred population (F_11:14, 188 genotypes) grown at five environmentally distinct sites. QTL analysis using a dense linkage map revealed 12 QTL, five of which showed significant interactions with the environment. Dissection of G x E interactions using a linear mixed-effect model revealed that temperature, solar radiation, and photoperiod play major roles in controlling common bean flowering time directly, and indirectly by modifying the effect of certain QTLs. The model predicts flowering time across five sites with an adjusted r-square of 0.89 and root-mean square error of 2.52 days. The model provides the means to disentangle the environmental dependencies of complex traits, and presents an opportunity to identify in-silico QTL allele combinations that could yield desired phenotypes under different climatic conditions.

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Interview about the GIFT Trial, Pharmacogenetics, and Warfarin

Pharmacogenomics, Ahead of Print.


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Platinum or nonplatinum in recurrent ovarian cancer: that is the question

Future Oncology, Ahead of Print.


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Trabectedin mechanism of action and platinum resistance: molecular rationale

Future Oncology, Ahead of Print.


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Managing relapsed ovarian cancer in a rapidly evolving landscape

Future Oncology, Ahead of Print.


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Update on relapsed ovarian cancer treatment: from new consensus to daily clinical practice

Future Oncology, Ahead of Print.


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Monocytes and granulocytes reduce CD38 expression levels on myeloma cells in patients treated with daratumumab

Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma (MM) cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction. Experimental design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of MM cells and non-tumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed. Results: In both trials daratumumab reduced CD38 expression on MM cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on non-tumor immune cells, including NK-, T- B-cells and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of MM cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38high MM cells can contribute to CD38 reduction. In addition, we discovered that daratumumab-CD38 complexes and accompanying cell membrane were actively transferred from MM cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins including CD49d, CD56, and CD138. Conclusion: Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance.

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CAR T therapy targeting ICAM-1 eliminates advanced human thyroid tumors

Purpose: Poorly-differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors including papillary thyroid cancer (PTC) and ATC are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1-targeting agents for the treatment of aggressive cancer. We developed a third-generation CAR targeting ICAM-1 to leverage adoptive T cell therapy as a new treatment modality. Experimental Design: ICAM-1 CAR T cells were applied on multiple malignant and non-malignant target cells to investigate specific target cell death and 'off-tumor' toxicity in vitro. In vivo therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases. Results: ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR-T cells mediated profound tumor killing that resulted in long term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells in vitro and in animal models. Conclusions: Our findings are the first demonstration of CAR T therapy for metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies.

http://ift.tt/2wRt0iy

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer [Research Articles]

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell surface HLA class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knock-out of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

http://ift.tt/2gfow2z

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells [Research Articles]

Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19⁺ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.

SIGNIFICANCE: We provide a detailed clinical, radiologic, and pathologic characterization of neuro-toxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1–16. ©2017 AACR.

http://ift.tt/2yjYqBQ

Hydrophobic Effect from Conjugated Chemicals or Drugs on In Vivo Biodistribution of RNA Nanoparticles

Human Gene Therapy , Vol. 0, No. 0.


http://ift.tt/2zjvRCw

PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival

Abstract

Aim

Our aim was to evaluate overall survival and parameters prognosticating longer survival in a large and homogeneous group of patients treated with ¹⁷⁷Lu-PSMA-617 radioligand therapy with heavily pretreated advanced metastatic castration resistant prostate cancer.

Methods

A total of 104 patients were treated with 351 cycles of ¹⁷⁷Lu-PSMA-617. Prostate specific antigen (PSA) changes after the first cycle of therapy were documented prior to a second cycle. Patients were followed-up for overall survival (OS). Any PSA decline, PSA decline ≥50%, initial PSA, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), visceral metastases and cumulative injected activity were analyzed and evaluated according to OS. Multivariable analysis with parameters with a p-value ≤0.05 in univariate analysis was performed, additionally adjusting for age and presence of visceral metastases.

Results

A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases. All patients were treated with at least one line of chemotherapy. Either abiraterone or enzalutamide had been given in 100% of the patients. Any PSA decline occurred in 70 (67%) and a PSA decline ≥50% in 34 (33%) of patients after the first cycle. The median OS was 56.0 weeks (95%CI: 50.5–61.5). Initial PSA decline ≥50%, initial LDH, visceral metastases, second line chemotherapy or prior radium-223 did not have an effect on survival, whereas any initial PSA decline, initial ALP <220 U/L and cumulative injected activity ≥18.8 GBq were associated with a longer survival. A step-by-step analysis revealed a PSA decline ≥20.87% as the most noticeable cut-off prognosticating longer survival, which remained an independent prognosticator of improved OS in the multivariate analysis.

Conclusion

¹⁷⁷Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced mCRPC pretreated with chemotherapy, abiraterone and/or enzalutamide.

http://ift.tt/2wRTel8

miR-449a: a potential therapeutic agent for cancer.

MicroRNAs (miRNAs) have been reported to be associated with cancer progression and carcinogenesis. They are small, highly conserved, noncoding RNA molecules consisting of 19-25 nucleotides. By binding to complementary binding sites within the 3'-untranslated region of target mRNAs, miRNAs inhibit the translation of mRNAs or promote their degradation. miRNAs play critical roles in cancer initiation and development by functioning either as oncogenes or as tumor suppressors. Similarly, several studies have shown that miRNAs are involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, signal transduction, and carcinogenesis. Among miRNAs, one that may be of particular interest in cancer biology is miR-449a, which has been reported to inhibit tumor growth, invasion, and metastasis, and to promote apoptosis and differentiation through the transforming growth factor-[beta] activated kinase 1, NOTCH, nuclear factor-[kappa]B/P65/vascular endothelial growth factor, retinoblastoma-E2F, mitogen-activated protein kinase signaling pathways, WNT-[beta]-catenin signaling, tumor protein P53, and androgen receptor signaling pathways. The miR-449 cluster is located in the second intron of CDC20B on chromosome 5q11.2, a region that has been identified as a susceptibility locus in cancer, and the abnormal expression of miR-449a may be related to the occurrence and development of tumors. As one example, miR-449a has been reported to be involved in the development of carcinoma and may be a potential prognostic indicator. On the basis of the putative pathogenetic relationships between cancer and miR-449a, we consider that miR-449a has the potential to serve as a therapeutic agent for the treatment of some types of cancer. In this review, the role of miR-449a in tumorigenesis and its mechanism of action are explored. Furthermore, its potential as a therapeutic agent in cancer treatment is considered. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2z3CxUF

Anticancer effect of acid ceramidase inhibitor ceranib-2 in human breast cancer cell lines MCF-7, MDA MB-231 by the activation of SAPK/JNK, p38 MAPK apoptotic pathways, inhibition of the Akt pathway, downregulation of ER[alpha].

Acid ceramidase is the key enzyme of the ceramide metabolic pathway, which plays a vital role in regulating ceramide - sphingosine-1-phosphate rheostat. Ceramide acts as a proapoptotic molecule, but its metabolite sphingosine-1-phosphate, in contrast, signals for cell proliferation, cell survival, and angiogenesis. Acid ceramidase is highly upregulated in breast tumors and treatment with an acid ceramidase inhibitor, ceranib-2, significantly induced apoptosis in human breast cancer cell lines. However, the mechanisms underlying the induction of apoptosis remain ambiguous to date. Hence, in the present study, we have explored ceranib-2-mediated apoptotic signaling pathways in human breast cancer cell lines. MCF-7 and MDA MB-231 cells were treated with IC50 doses of ceranib-2 and tamoxifen. Nuclear changes showed the apoptotic effect of ceranib-2 in both the cell lines. Loss in the mitochondrial membrane potential was observed only in ceranib-2-treated MCF-7 cells. Ceranib-2 activated intrinsic and extrinsic apoptotic pathways in MCF-7 cells, but only the extrinsic apoptotic pathway was activated in MDA MB-231 cells. Further, ceranib-2 induced apoptosis by activating SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase), p38 MAPK (mitogen-activated protein kinase) apoptotic pathways and by inhibiting the Akt (antiapoptotic) pathway in both the cell lines. Most importantly, ER[alpha] (estrogen receptor-[alpha]) expression was highly downregulated after ceranib-2 treatment and a docking study predicted the highest binding affinity of ceranib-2 than tamoxifen with ER[alpha] in MCF-7 cells. Hence, ceranib-2 may have potential as a chemotherapeutic drug of breast cancer. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2zjmPW8

Co-occurrence of genes for aerobic and anaerobic biodegradation of dichloroethane in organochlorine-contaminated groundwater

Abstract

1,2-dichloroethane (DCA) is a problematic groundwater pollutant. Factors influencing the distribution and activities of DCA-degrading bacteria are not well-understood, which has hampered their application for bioremediation. Here, we used quantitative PCR (qPCR) to investigate the distribution of putative DCA-dehalogenating bacteria at a DCA-impacted site in Sydney (Australia). The dehalogenase genes dhlA, tceA and bvcA were detected in all groundwater samples (n = 15), while vcrA was found in 11/15 samples. The 16S rRNA gene sequences specific to the dehalogenating genera Dehalobacter, Desulfitobacterium and Dehalogenimonas were detected in 15/15, 13/15, and 13/15 samples, respectively, while Dehalococcoides sequences were found in 9/15 samples. The tceA, bvcA and vcrA genes occurred in the same samples as Dehalococcoides and Dehalobacter. Microcosm experiments confirmed the presence of bacteria capable of dechlorination under anoxic conditions. The abundance of the dhlA gene, which is found in hydrolytic DCA degraders, was positively correlated to the DCA concentration, and was unexpectedly most abundant in samples with low oxygen conditions. A dhlA-containing bacterium isolated from the site (Xanthobacter EL8) was capable of anaerobic growth on DCA under denitrifying conditions. The presence of diverse DCA-dehalogenating bacteria at this site indicates that natural attenuation or biostimulation could be valid approaches for site cleanup.

http://ift.tt/2xBllcW

Conflicting Data on the Incidence of Leukopenia and Neutropenia After Heated Intraperitoneal Chemotherapy with Mitomycin C

Abstract

Background

During heated intraperitoneal chemotherapy (HIPEC), neutropenia rates of 20 to 40% have been reported when mitomycin C (MMC) is dosed by weight or body surface area (BSA). This study investigated the authors' HIPEC experience using a fixed 40-mg dose of MMC, per consensus guidelines, and analyzed predictors for severe leukopenia and neutropenia.

Methods

Patients who underwent MMC-HIPEC from 2007 to 2016 at a single tertiary care center were retrospectively reviewed.

Results

Among 314 MMC-HIPEC cases, 72 patients in the early era of the authors' program received routine prophylactic postoperative granulocyte-colony-stimulating factor (GCSF). This early cohort had five severe leukopenic reactions and one neutropenic reaction. In the subsequent 242 cases without GCSF prophylaxis, severe leukopenia developed in 16 patients (7%), with neutropenia occurring in 11 (4.5%) of these cases. A history of prior systemic chemotherapy was noted in 9 (56%) of the 16 leukopenic patients compared with 112 (46%) of the patients who had no leukopenia (nonsignificant difference). The median nadir of leukopenia was 5 days (range 1–11 days). Of the 11 neutropenic patients, 6 received therapeutic GCSF, and 5 recovered without intervention. The 30-day postoperative mortality of the patients with leukopenia was 0%.

Conclusion

In this study, the incidence of neutropenia after HIPEC with 40 mg of MMC was markedly lower than reported in the literature for doses adjusted by BSA or weight. The authors report that GCSF is not necessary for routine prophylaxis of all MMC-HIPEC patients. The findings suggest that a fixed 40-mg dose of MMC allows HIPEC to be performed with less risk of immunosuppression.

http://ift.tt/2hDZk2h

Recurrence of Optimally Treated Malignant Peritoneal Mesothelioma with Cytoreduction and Heated Intraperitoneal Chemotherapy

Abstract

Background

The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improved with cytoreductive surgery and intraperitoneal chemotherapy. Little is known about disease recurrence after treatment. We analyzed the time to and predictors of recurrence in a large cohort of optimally treated patients.

Methods

We examined 113 patients completing a two-stage cytoreduction and intraperitoneal chemotherapy protocol. All patients achieved optimal surgical resection with completeness of cytoreduction (CC) score ≤ 1 and were divided into two groups based on absence (Group A) or presence (Group B) of gross disease at the outset of the second operation. Predictors of disease recurrence and recurrence-free survival (RFS) were determined using Cox proportional hazard regression modeling, and estimates were obtained by using the Kaplan–Meier method.

Results

Forty-six percent of patients had no gross evidence of disease at the second operation; the remaining 54% were cytoreduced to CC ≤ 1 (Group B). Forty-two percent of patients developed disease recurrence with a median recurrence-free survival of 38.5 months for the cohort; 79% of these received a form of iterative treatment. There was no statistically significant difference in recurrence-free survival between Group A (median RFS: 44.6 months) and B (median RFS: 35.5 months) (log-rank test, p = 0.06). Additionally, the only variable significantly associated with RFS was male gender (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.16–3.38).

Conclusions

Absence of gross disease at the second operation was not statistically protective against recurrence compared with presence of quantifiable residual disease (Group B) that was effectively cytoreduced. Long-term disease surveillance is recommended, because recurrence continues years after treatment. Where a question of recurrence arises on surveillance, males may benefit from a higher degree of suspicion.

http://ift.tt/2yHPBmf

In the Next Issue

No abstract available

http://ift.tt/2i3CTY7

Bioengineering a Human Face Graft: The Matrix of Identity

Objective: During the last decade, face allotransplantation has been shown to be a revolutionary reconstructive procedure for severe disfigurements. However, offer to patients remains limited due to lifelong immunosuppression. To move forward in the field, a new pathway in tissue engineering is proposed. Background: Our previously reported technique of matrix production of a porcine auricular subunit graft has been translated to a human face model. Methods: 5 partial and 1 total face grafts were procured from human fresh cadavers. After arterial cannulation, the specimens were perfused using a combined detergent/polar solvent decellularization protocol. Preservation of vascular patency was assessed by imaging, cell and antigen removal by DNA quantification and histology. The main extracellular matrix proteins and associated cytokines were evaluated. Lip scaffolds were cultivated with dermal, muscle progenitor and endothelial cells, either on discs or in a bioreactor. Results: Decellularization was successful in all facial grafts within 12 days revealing acellular scaffolds with full preservation of innate morphology. Imaging demonstrated a preservation of the entire vascular tree patency. Removal of cells and antigens was confirmed by reduction of DNA and antigen markers negativation. Microscopic evaluation revealed preservation of tissue structures as well as of major proteins. Seeded cells were viable and well distributed within all scaffolds. Conclusions: Complex acellular facial scaffolds were obtained, preserving simultaneously a cell-friendly extracellular matrix and a perfusable vascular tree. This step will enable further engineering of postmortem facial grafts, thereby offering new perspectives in composite tissue allotransplantation.

http://ift.tt/2i4zMz0

Validation of an in vitro system for studies of pathogenicity mechanisms in Xanthomonas campestris

Abstract

Several minimal media capable of inducing pathogenicity genes have been used to study plant-pathogen interactions. An in planta assay to study a closer interaction between the bacteria and the host was also developed and has been employed by our group. In order to determine whether growth medium could be improved to better approximate in planta conditions beyond that offered by the defined minimal medium XVM1, we compared the expression of twenty Xanthomonas campestris pv. campestris (Xcc) genes by qRT-PCR under in vivo (bacteria recovered from the plant) and in vitro (rich medium NYG, minimal medium XVM1 and XVM1 + leaf extract) growth systems. The results showed a higher expression level of the genes in the in planta system when compared to growth in culture media. In planta growth is closest to a real interaction condition and captures the complexity of the plant cell environment; however, this system has some limitations. The main finding of our work is that the addition of plant extract to XVM1 medium results in a gene expression profile that better matches the in planta profile, when compared with the XVM1 medium alone, giving support to the use of plant extract to study pathogenicity mechanisms in Xanthomonas.

http://ift.tt/2kI96Fj

Quantitative Whole-mount Immunofluorescence Analysis of Cardiac Progenitor Populations in Mouse Embryos

Here, we describe a protocol for whole mount immunofluorescence and image-based quantitative volumetric analysis of early stage mouse embryos. We present this technique as a powerful approach to qualitatively and quantitatively assess cardiac structures during development, and propose that it may be widely adaptable to other organ systems.

http://ift.tt/2ziH2eJ

The effects of subclinical neck pain on sensorimotor integration following a complex motor pursuit task

Abstract

Recurrent subclinical neck pain (SCNP) may be associated with neural plastic changes in sensory processing and sensorimotor integration (SMI); however, its impact on motor learning has not been investigated. The aim of this study was to investigate whether SCNP alters neural markers of SMI during a complex motor acquisition task as compared to a healthy control group. Peripheral N9, spinal N13, brainstem N18, and cortical N20, P25, N24 and N30 early somatosensory evoked potentials (SEPs) were recorded following median nerve stimulation for 24 participants (12 control and 12 SCNP) before and after a 10-min tracing motor task intervention. Retention was assessed 24–48 h later. Significant amplitude differences were observed for both N18 and N24 SEP waveforms between groups, indicating there may be a difference in SMI due to altered afferent input as a result of SCNP. Accuracy increased significantly for both groups post-motor training; however, at retention only the control group showed an additional increase in accuracy. Both N18 and N24 SEP peaks are linked with cerebellar pathways, suggesting that SCNP impacts these connections. Significant correlations between these peaks and performance data were also seen. The differential changes in neurophysiological markers of SMI seen in SCNP suggest that SEPs have the potential to be used as an early screening tool for those at risk of having maladaptive neural plastic changes in response to motor training as a result of SCNP.

http://ift.tt/2kJak2Z

Controlling the Release of Small, Bioactive Proteins via Dual Mechanisms with Therapeutic Potential

Abstract

Injectable delivery systems that respond to biologically relevant stimuli present an attractive strategy for tailorable drug release. Here, the design and synthesis of unique polymers are reported for the creation of hydrogels that are formed in situ and degrade in response to clinically relevant endogenous and exogenous stimuli, specifically reducing microenvironments and externally applied light. Hydrogels are formed with polyethylene glycol and heparin-based polymers using a Michael-type addition reaction. The resulting hydrogels are investigated for the local controlled release of low molecular weight proteins (e.g., growth factors and cytokines), which are of interest for regulating various cellular functions and fates in vivo yet remain difficult to deliver. Incorporation of reduction-sensitive linkages and light-degradable linkages affords significant changes in the release profiles of fibroblast growth factor-2 (FGF-2) in the presence of the reducing agent glutathione or light, respectively. The bioactivity of the released FGF-2 is comparable to pristine FGF-2, indicating the ability of these hydrogels to retain the bioactivity of cargo molecules during encapsulation and release. Further, in vivo studies demonstrate degradation-mediated release of FGF-2. Overall, our studies demonstrate the potential of these unique stimuli-responsive chemistries for controlling the local release of low molecular weight proteins in response to clinically relevant stimuli.

Injectable depots that sequester small bioactive proteins and respond to clinically relevant internal and external stimuli enable local controlled release of therapeutics in the body. Degradation of these depots in response to reducing microenvironments, such as found in tumors, and externally applied light allows tailored release of therapeutic proteins, including basic fibroblast growth factor, with relevance for a variety of biomedical applications.

http://ift.tt/2kJK6NR

2D Organic Materials for Optoelectronic Applications

Abstract

The remarkable merits of 2D materials with atomically thin structures and optoelectronic attributes have inspired great interest in integrating 2D materials into electronics and optoelectronics. Moreover, as an emerging field in the 2D-materials family, assembly of organic nanostructures into 2D forms offers the advantages of molecular diversity, intrinsic flexibility, ease of processing, light weight, and so on, providing an exciting prospect for optoelectronic applications. Herein, the applications of organic 2D materials for optoelectronic devices are a main focus. Material examples include 2D, organic, crystalline, small molecules, polymers, self-assembly monolayers, and covalent organic frameworks. The protocols for 2D-organic-crystal-fabrication and -patterning techniques are briefly discussed, then applications in optoelectronic devices are introduced in detail. Overall, an introduction to what is known and suggestions for the potential of many exciting developments are presented.

Assembling organic nanostructures into 2D form offers the advantages of molecular diversity, flexibility, and unique physical properties, providing exciting future prospects for optoelectronic applications. This review focuses on the applications of organic 2D materials for optoelectronic devices. After a brief discussion on the protocols for 2D crystal fabrication and patterning techniques, their applications in optoelectronic devices are introduced and an outlook is provided.

http://ift.tt/2gzHnCj

The Electrical and Optical Properties of Organometal Halide Perovskites Relevant to Optoelectronic Performance

Abstract

Organometal halide perovskites are under intense study for use in optoelectronics. Methylammonium and formamidinium lead iodide show impressive performance as photovoltaic materials; a premise that has spurred investigations into light-emitting devices and photodetectors. Herein, the optical and electrical material properties of organometal halide perovskites are reviewed. An overview is given on how the material composition and morphology are tied to these properties, and how these properties ultimately affect device performance. Material attributes and techniques used to estimate them are analyzed for different perovskite materials, with a particular focus on the bandgap, mobility, diffusion length, carrier lifetime, and trap-state density.

Organometal halide perovskites offer promise as high-performance solution-processed optoelectronic materials. Herein, the optical and electrical properties of these materials are reviewed, as well as how these relate to material aspects and their influence on device performance.

http://ift.tt/2yk4wSr

Electronic-Reconstruction-Enhancedis-Tunneling Conductance at Terrace Edges of Ultrathin Oxide Films

Abstract

Quantum mechanical tunneling of electrons across ultrathin insulating oxide barriers has been studied extensively for decades due to its great potential in electronic-device applications. In the few-nanometers-thick epitaxial oxide films, atomic-scale structural imperfections, such as the ubiquitously existed one-unit-cell-high terrace edges, can dramatically affect the tunneling probability and device performance. However, the underlying physics has not been investigated adequately. Here, taking ultrathin BaTiO₃ films as a model system, an intrinsic tunneling-conductance enhancement is reported near the terrace edges. Scanning-probe-microscopy results demonstrate the existence of highly conductive regions (tens of nanometers wide) near the terrace edges. First-principles calculations suggest that the terrace-edge geometry can trigger an electronic reconstruction, which reduces the effective tunneling barrier width locally. Furthermore, such tunneling-conductance enhancement can be discovered in other transition metal oxides and controlled by surface-termination engineering. The controllable electronic reconstruction can facilitate the implementation of oxide electronic devices and discovery of exotic low-dimensional quantum phases.

Intrinsic tunneling-conductance enhancement is discovered near the terrace edges of ultrathin BaTiO₃ films. The terrace-edge geometry can trigger an electronic reconstruction, which reduces the effective-tunneling-barrier width locally. Such tunneling-conductance enhancement can be found in other transition metal oxides and is controlled by surface termination engineering.

http://ift.tt/2xBIHKx

Metal-Halide Perovskite Transistors for Printed Electronics: Challenges and Opportunities

Abstract

Following the unprecedented rise in photovoltaic power conversion efficiencies during the past five years, metal-halide perovskites (MHPs) have emerged as a new and highly promising class of solar-energy materials. Their extraordinary electrical and optical properties combined with the abundance of the raw materials, the simplicity of synthetic routes, and processing versatility make MHPs ideal for cost-efficient, large-volume manufacturing of a plethora of optoelectronic devices that span far beyond photovoltaics. Herein looks beyond current applications in the field of energy, to the area of large-area electronics using MHPs as the semiconductor material. A comprehensive overview of the relevant fundamental material properties of MHPs, including crystal structure, electronic states, and charge transport, is provided first. Thereafter, recent demonstrations of MHP-based thin-film transistors and their application in logic circuits, as well as bi-functional devices such as light-sensing and light-emitting transistors, are discussed. Finally, the challenges and opportunities in the area of MHPs-based electronics, with particular emphasis on manufacturing, stability, and health and environmental concerns, are highlighted.

Their extraordinary electrical and optical properties combined with the abundance of their raw materials, have driven metal-halide perovskites (MHPs) to the forefront of functional electronic materials research, with envisioned applications spanning across several technology sectors. Herein, the recent advances in the use of MHPs in the area of transistors and transistor-related applications are summarized.

http://ift.tt/2yk3Ix1

3D Porous Hydrogel/Conducting Polymer Heterogeneous Membranes with Electro-/pH-Modulated Ionic Rectification

Abstract

Heterogeneous membranes composed of asymmetric structures or compositions have enormous potential in sensors, molecular sieves, and energy devices due to their unique ion transport properties such as ionic current rectification and ion selectivity. So far, heterogeneous membranes with 1D nanopores have been extensively studied. However, asymmetric structures with 3D micro-/nanoscale pore networks have never been investigated. Here, a simple and versatile approach to low-costly fabricate hydrogel/conducting polymer asymmetric heterogeneous membranes with electro-/pH-responsive 3D micro-/nanoscale ion channels is introduced. Due to the asymmetric heterojunctions between positively charged nanoporous polypyrrole (PPy) and negatively charged microscale porous hydrogel poly (acrylamide-co-acrylic acid) (P(AAm-co-AA)), the membrane can rectify ion transmembrane transport in response to both electro- and pH-stimuli. Numerical simulations based on coupled Poisson and Nernst–Plank equations are carried out to explain the ionic rectification mechanisms for the membranes. The membranes are not dependent on elaborately fabricated 1D ion channel substrates and hence can be facilely prepared in a low-cost and large-area way. The hybridization of hydrogel and conducting polymer offers a novel strategy for constructing low-cost, large-area and multifunctional membranes, expanding the tunable ionic rectification properties into macroscopic membranes with micro-/nanoscale pores, which would stimulate practical applications of the membranes.

3D porous hydrogel/conducting polymer heterogeneous membranes with electro-/pH-modulated ionic rectification have been fabricated by electrochemically depositing nanoporous conducting polymer polypyrrole onto a hydrogel polyacrylamide-polyacrylic acid substrate. The facilely prepared heterogenous membranes with 3D interconnected channels would find numerous applications in sensors, biomolecular sieves, and energy conversion devices.

http://ift.tt/2xC2B7X

An All-Integrated Anode via Interlinked Chemical Bonding between Double-Shelled–Yolk-Structured Silicon and Binder for Lithium-Ion Batteries

Abstract

The concept of an all-integrated design with multifunctionalization is widely employed in optoelectronic devices, sensors, resonator systems, and microfluidic devices, resulting in benefits for many ongoing research projects. Here, maintaining structural/electrode stability against large volume change by means of an all-integrated design is realized for silicon anodes. An all-integrated silicon anode is achieved via multicomponent interlinking among carbon@void@silica@silicon (CVSS) nanospheres and cross-linked carboxymethyl cellulose and citric acid polymer binder (c-CMC-CA). Due to the additional protection from the silica layer, CVSS is superior to the carbon@void@silicon (CVS) electrode in terms of long-term cyclability. The as-prepared all-integrated CVSS electrode exhibits high mechanical strength, which can be ascribed to the high adhesivity and ductility of c-CMC-CA binder and the strong binding energy between CVSS and c-CMC-CA, as calculated based on density functional theory (DFT). This electrode exhibits a high reversible capacity of 1640 mA h g⁻¹ after 100 cycles at a current density of 1 A g⁻¹, high rate performance, and long-term cycling stability with 84.6% capacity retention after 1000 cycles at 5 A g⁻¹.

An all-integrated anode design via multicomponent chemical interlinking among carbon@void@silica@silicon (CVSS) nanospheres and cross-linked carboxymethyl cellulose and citric acid polymer binder (c-CMC-CA) is developed for achieving electrode/structural stability of a silicon anode during lithiation/delithiation. The obtained excellent electrochemical performance can be ascribed to the collaboration of the double-shelled–yolk-structured silicon and the covalent-interlinked high-strength binder system.

http://ift.tt/2yk4xFZ

Bioinspired Dynamic Wetting on Multiple Fibers

Abstract

Natural fibers have versatile strategies for interacting with water media and better adapting to the local environment, and these strategies offer inspiration for the development of artificial functional fibers with diverse applications. Wetting on fibers is a dynamic liquid-moving process on/in fibrous systems with various patterns, and the process is normally driven by the structural gradient, chemical gradient, elasticity of a single fiber, or the synergistic effect of these factors in multiple fibers in an integrated system in which the spatial geometry of the fibers is involved. Compared with the directional liquid movement on a single fiber, wetting on multiple fibers in both the micro- and macroscales is particularly fascinating, with various performances, including directional liquid transport, controllable liquid transfer, efficient liquid encapsulation, and capillary-induced fibrous coalescence. Based on these properties, fibrous materials offer an alternative open system for liquid manipulation that is applicable to various functional liquid materials. Here, recent achievements in bioinspired dynamic wetting on multiple fibers are highlighted, and perspectives on future directions are presented.

Recent research progress in bioinspired dynamic wetting on multiple fibers is summarized, and the distinctive wetting behaviors of five types of natural fibrous systems, including water strider legs, a shorebird beak, a Chinese brush, dandelion pappi, and wet hairs, are presented, along with related bioinspired systems. Meanwhile, perspectives on the research trends in the wetting of multiple fibers are discussed.

http://ift.tt/2xBDUbN

Superlyophilic Interfaces and Their Applications

Abstract

Superlyophilic interfaces denote interfaces displaying strong affinity to diverse liquids, including superhydrophilic, superoleophilic, and superamphiphilic interfaces. When coming in contact with these interfaces, water or oil droplets tend to spread completely with contact angles close to 0°, presenting versatile applications including self-cleaning, antifogging, controllable liquid transport, liquid separation, and so forth. Inspired by nature, scientists have developed various kinds of artificial superlyophilic (SLPL) interfaces in the past decades. In terms of dimensional characteristics, the artificial SLPL interfaces can be divided into four categories: i) 0D particles, whose dispersibility or catalytic performance can be notably enhanced by superlyophilicity; ii) 1D micro-/nanofibers or nanotubes/channels, which can efficiently transfer liquids with SLPL interfaces; iii) 2D flat SLPL interfaces, on which different functional molecules can be deposited uniformly, forming ultrathin and smooth films; and iv) 3D structures, which can be obtained by either constructing 0D, 1D, or 2D SLPL materials separately or directly fabricating random SLPL frameworks, and can always be used as functional coatings or bulk materials. Here, natural and artificial SLPL interfaces are briefly introduced, followed by a short discussion of the limit between lyophilicity and lyophobicity, and then a snapshot of methods to generate SLPL interfaces is given. Specific focus is placed on recent achievements of constructing SLPL interfaces from zero to three dimensions. Following that, broad applications of SLPL interfaces in commercial areas will be introduced. Finally, a short summary and outlook for future challenges in this field is presented.

Recent progress regarding superlyophilic interfaces with different dimensions is reviewed, including 0D particles, 1D fibers or tubes, 2D flat interfaces, and 3D materials. Moreover, the broad applications of superlyophilic interfaces are described, spanning from conductivity enhancement and self-cleaning, liquid transport, and antifogging, to printing and liquid separation, heat transfer, and film fabrication.

http://ift.tt/2yjLaN3

4D Biofabrication Using Shape-Morphing Hydrogels

Abstract

Despite the tremendous potential of bioprinting techniques toward the fabrication of highly complex biological structures and the flourishing progress in 3D bioprinting, the most critical challenge of the current approaches is the printing of hollow tubular structures. In this work, an advanced 4D biofabrication approach, based on printing of shape-morphing biopolymer hydrogels, is developed for the fabrication of hollow self-folding tubes with unprecedented control over their diameters and architectures at high resolution. The versatility of the approach is demonstrated by employing two different biopolymers (alginate and hyaluronic acid) and mouse bone marrow stromal cells. Harnessing the printing and postprinting parameters allows attaining average internal tube diameters as low as 20 µm, which is not yet achievable by other existing bioprinting/biofabrication approaches and is comparable to the diameters of the smallest blood vessels. The proposed 4D biofabrication process does not pose any negative effect on the viability of the printed cells, and the self-folded hydrogel-based tubes support cell survival for at least 7 d without any decrease in cell viability. Consequently, the presented 4D biofabrication strategy allows the production of dynamically reconfigurable architectures with tunable functionality and responsiveness, governed by the selection of suitable materials and cells.

An advanced 4D biofabrication approach, based on shape-morphing biopolymer hydrogels, is presented for the fabrication of hollow self-folding tubes with unprecedented control over their diameters and architectures at high resolution. The approach paves new avenues for the creation of tailored cell-laden shape-morphing architectures for tissue engineering and regenerative medicine applications.

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Structurally Deformed MoS2 for Electrochemically Stable, Thermally Resistant, and Highly Efficient Hydrogen Evolution Reaction

Abstract

The emerging molybdenum disulfide (MoS₂) offers intriguing possibilities for realizing a transformative new catalyst for driving the hydrogen evolution reaction (HER). However, the trade-off between catalytic activity and long-term stability represents a formidable challenge and has not been extensively addressed. This study reports that metastable and temperature-sensitive chemically exfoliated MoS₂ (ce-MoS₂) can be made into electrochemically stable (5000 cycles), and thermally robust (300 °C) while maintaining synthetic scalability and excellent catalytic activity through physical-transformation into 3D structurally deformed nanostructures. The dimensional transition enabled by a high throughput electrohydrodynamic process provides highly accessible, and electrochemically active surface area and facilitates efficient transport across various interfaces. Meanwhile, the hierarchically strained morphology is found to improve electronic coupling between active sites and current collecting substrates without the need for selective engineering the electronically heterogeneous interfaces. Specifically, the synergistic combination of high strain load stemmed from capillarity-induced-self-crumpling and sulfur (S) vacancies intrinsic to chemical exfoliation enables simultaneous modulation of active site density and intrinsic HER activity regardless of continuous operation or elevated temperature. These results provide new insights into how catalytic activity, electrochemical-, and thermal stability can be concurrently enhanced through the physical transformation that is reminiscent of nature, in which properties of biological materials emerge from evolved dimensional transitions.

Bioinspired dimensional transition of MoS₂ enables the modulation of catalytic property and drastically improves the long-term operational stability while preserving the synthetic scalability. The experimental demonstration provides elegant insights into how physical transformation can be leveraged to direct energetics of electrochemical processes.

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Hollow Co3O4 Nanosphere Embedded in Carbon Arrays for Stable and Flexible Solid-State Zinc–Air Batteries

Abstract

Highly active and durable air cathodes to catalyze both the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) are urgently required for rechargeable metal–air batteries. In this work, an efficient bifunctional oxygen catalyst comprising hollow Co₃O₄ nanospheres embedded in nitrogen-doped carbon nanowall arrays on flexible carbon cloth (NC-Co₃O₄/CC) is reported. The hierarchical structure is facilely derived from a metal–organic framework precursor. A carbon onion coating constrains the Kirkendall effect to promote the conversion of the Co nanoparticles into irregular hollow oxide nanospheres with a fine scale nanograin structure, which enables promising catalytic properties toward both OER and ORR. The integrated NC-Co₃O₄/CC can be used as an additive-free air cathode for flexible all-solid-state zinc–air batteries, which present high open circuit potential (1.44 V), high capacity (387.2 mAh g⁻¹, based on the total mass of Zn and catalysts), excellent cycling stability and mechanical flexibility, significantly outperforming Pt- and Ir-based zinc–air batteries.

An efficient bifunctional oxygen catalyst comprising hollow Co₃O₄ nanospheres embedded in N-doped carbon nanowall arrays (NC-Co₃O₄) is facilely fabricated from a metal–organic framework. The additive-free NC-Co₃O₄ electrode can be directly utilized as an efficient air cathode for a flexible solid-state Zn–air battery, which demonstrates much improved cycling stability and mechanical flexibility than Pt- and Ir-based zinc–air batteries.

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Chemical Patterning of High-Mobility Semiconducting 2D Bi2O2Se Crystals for Integrated Optoelectronic Devices

Abstract

Patterning of high-mobility 2D semiconducting materials with unique layered structures and superb electronic properties offers great potential for batch fabrication and integration of next-generation electronic and optoelectronic devices. Here, a facile approach is used to achieve accurate patterning of 2D high-mobility semiconducting Bi₂O₂Se crystals using dilute H₂O₂ and protonic mixture acid as efficient etchants. The 2D Bi₂O₂Se crystal after chemical etching maintains a high Hall mobility of over 200 cm² V⁻¹ s⁻¹ at room temperature. Centimeter-scale well-ordered arrays of 2D Bi₂O₂Se with tailorable configurations are readily obtained. Furthermore, integrated photodetectors based on 2D Bi₂O₂Se arrays are fabricated, exhibiting excellent air stability and high photoresponsivity of ≈2000 A W⁻¹ at 532 nm. These results are one step towards the practical application of ultrathin 2D integrated digital and optoelectronic circuits.

Controlled patterning of high-mobility semiconducting two-dimensional Bi₂O₂Se crystals was achieved by a facile wet-chemical etching approach using diluted H₂O₂/protonic acid etchants. Centimeter-scale well-ordered two-dimensional Bi₂O₂Se arrays exhibit a high Hall mobility of over 200 cm² V⁻¹ s⁻¹ at room temperature, and are integrated into air-stable photodetectors with an ultrahigh photoresponsivity of ≈2000 A W⁻¹ at 532 nm.

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TSPO PET using 18 F-GE-180: a new perspective in neurooncology?

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Whole-cell Currents Induced by Puff Application of GABA in Brain Slices

We describe the puff technique, by which pharmacological reagents can be administered during whole-cell patch-clamp recording, and highlight various aspects of the features that are crucial for its success.

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Predicting the cancer burden in Catalonia between 2015 and 2025: the challenge of cancer management in the elderly

Abstract

Background

Developing effective cancer control programmes requires information on the future cancer burden in an ageing population. In our study we predicted the burden of cancer in Catalonia from 2015 to 2025.

Methods

Bayesian age–period–cohort models were used to predict the burden of cancer from 2015 to 2025 using incidence data from the Girona and Tarragona cancer registries and cancer mortality data from the Catalan mortality registry. Using the Bashir–Estève method, we divided the net change in the number of cases between 2015 and 2025 into changes due to population size (S), cancer risk (R) and age (A) distribution.

Results

By 2025, there will be 21,743 new cancer cases in men (40% aged > 74 years) and 17,268 in women (37% aged > 74 years). More than 40% of the new cases will be diagnosed among population aged 74 and older in prostate, colorectal, lung, bladder, pancreatic and stomach cancers in men, and in colorectal, pancreatic and bladder cancers and leukaemia in women. During 2015–2025, the number of new diagnoses will increase by 5.5% in men (A + R + S = 18.1% − 13.3% + 0.7% = 5.5%) and 11.9% in women (A + R + S = 12.4% − 1.1% + 0.6% = 11.9%). Overall cancer mortality rates will continue to decrease during 2015–2025. Lung cancer will be the most lethal cancer among men (N = 2705) and women (N = 1174).

Conclusions

The increase in the number of cancer cases in Catalonia from 2015 to 2025 will mostly affect the elderly, prompting the need for increased collaboration between geriatricians and oncologists.

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A rat model of FOLFOX-induced neuropathy: effects of oral dimiracetam in comparison with duloxetine and pregabalin

Abstract

Background and aim

The FOLFOX family of chemotherapy regimens are hampered by the development of a painful neuropathy. Current clinical treatments are inadequate, and furthermore, the research of innovative drugs is strongly disadvantaged by the absence of a preclinical model based on the complete mixture of FOLFOX components. The aim of this study was to set up a rat model of FOLFOX-induced neuropathy in rats, validate its predictability by reference drugs, and evaluate the effectiveness of the new anti-neuropathic compound dimiracetam.

Methods

Male Sprague–Dawley rats were treated intraperitoneally with the FOLFOX components (6 mg kg⁻¹ oxaliplatin, 50 mg kg⁻¹ 5-FU, 90 mg kg⁻¹ leucovorin calcium salt) or oxaliplatin alone (6 mg kg⁻¹) on days 0, 7, 14, and 21, whereas a separate group received one more injection of FOLFOX on day 28. Pain behavioural measurements (paw pressure, cold plate, and electronic Von Frey tests) and motor coordination (Rota-rod test) were assessed before and after treatments. Behavioural, motor, neurological, and autonomic parameters (open field and Irwin tests) were evaluated.

Results

FOLFOX reduced the pain threshold in response to mechanical noxious and thermal (cold) non-noxious stimuli beginning from day 14 up to day 42 comparably to oxaliplatin alone. A fifth FOLFOX injection enhanced the severity but not the duration of painful alterations. Spontaneous activity, behavioural, autonomic, and neurological functions were also affected, whereas the motor coordination was not altered. On day 22, duloxetine (15 mg kg⁻¹, per os), morphine (10 mg kg⁻¹, subcutaneously), or pregabalin (20 mg kg⁻¹, per os), acutely administered, reduced the FOLFOX-dependent hypersensitivity. Repeated treatments with dimiracetam (150 mg kg⁻¹, per os, twice daily, from day 22) significantly protected rats from FOLFOX-induced alterations of pain threshold as well as from autonomic and neurological impairments taking effect after 7 days treatment. Pregabalin repeatedly administered (20 mg kg⁻¹, per os, twice daily, from day 22) was less effective in reducing mechanical hypersensitivity.

Conclusion

A clinically consistent model of FOLFOX-induced neurotoxicity has been developed in rats. Dimiracetam fully reduced hypersensitivity and neurological alterations showing a relevant profile as anti-neuropathic resource.

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Pembrolizumab Secures FDA Approval in Stomach Cancer

The FDA has granted accelerated approval to the immunotherapy drug pembrolizumab (Keytruda®) for use in patients with advanced gastric (stomach) cancer that is PD-L1 positive.

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Cell-free Biochemical Fluorometric Enzymatic Assay for High-throughput Measurement of Lipid Peroxidation in High Density Lipoprotein

We describe here a fluorometric cell-free biochemical assay for determination of HDL-lipid peroxidation. This rapid and reproducible assay can be used to determine HDL function in large scale studies and can contribute to our understanding of HDL function in human disease.

http://ift.tt/2yfPZ8E

Imaging Patterns of Rhino-Orbital-Cerebral Mucormycosis in Immunocompromised Patients

Abstract

Purpose

The aim of this study was to describe radiological imaging findings of a complicated sinusitis, which should raise the suspicion of rhino-orbital-cerebral mucormycosis as being the underlying cause.

Methods

In this retrospective analysis, we describe the cases and imaging findings of 8 patients with proven mucormycosis. These patients presented mostly with new facial or orbital swelling and were referred for imaging to our institution. Magnetic resonance imaging and computed tomography images were classified as abnormal or normal with respect to orbital, paranasal and cerebral signal results. Special emphasis was placed on the distribution of the signal abnormalities regarding involvement of the skull base and the cavernous sinus.

Results

Out of a pool of 43 patients with colonization or proven Mucorales infection at different sites of the body, we identified 8 patients with infiltration of the midface and skull base. Unexpectedly seven out of the eight patients with abnormal findings of the paranasal sinuses and the adjacent tissues showed no bony sinus wall destruction. Of the eight patients seven showed inflammatory changes involving the infratemporal fossa and facial/periorbital tissues, three of the eight patients suffered from fungal invasion of the cavernous sinus and the carotid artery and one of the eight patients had a local infection of the hard palate only.

Conclusion

Imaging findings of inflammatory tissue infiltration adjacent to the paranasal sinuses with possible extension into the pterygopalatine fossa, infratemporal fossa and orbit or the cavernous sinus should raise the suspicion of a mucormycosis, especially in immunocompromised patients.

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Assessing Urinary Tract Junction Obstruction Defects by Methylene Blue Dye Injection

Methylene blue dye injection into the renal pelvis facilitates the assessment of urinary tract junction obstruction defects during mouse embryonic urinary tract development. Here, a protocol for methylene blue dye injection into the renal pelvis is described.

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Impact of Surveillance for Hepatocellular Carcinoma on Survival in Patients with Compensated Cirrhosis

Abstract

Surveillance for hepatocellular carcinoma (HCC) has been recommended in patients with cirrhosis. In this work, we examine the extent to which the competing risk of hepatic decompensation influences the benefit of HCC surveillance, by investigating the impact of availability of liver transplantation (LTx) and rate of progression of hepatic decompensation on survival gain from HCC surveillance. A multistate Markov model was constructed simulating a cohort of 50-year old patients with compensated cirrhosis. The primary outcome of interest was all-cause and HCC-specific mortality. The main input data included incidence of HCC, sensitivity of screening test, and mortality from hepatic decompensation. Treatment modalities modeled included LTx, resection, and radiofrequency ablation. In the base case scenario, LTx would be available to rescue a proportion of patient from deaths. In the absence of surveillance, 68.2% of the cohort members died by 15 years, which was from HCC in 25.1% and from hepatic decompensation in 43.6% of decedents. With surveillance, the median survival improved from 10.4 years to 11.2 years. The number needed to be under surveillance to reduce one all- cause and HCC-specific death over 15 years was 28 and 18, respectively. In sensitivity analyses, incidence of HCC and progression of cirrhosis had the strongest effect on the benefit of surveillance, whereas LTx availability had negligible impact.

CONCLUSIONS: HCC surveillance decreases all-cause and tumor-specific mortality in patients with compensated cirrhosis regardless of LTx availability. In addition, incidence of HCC and sensitivity of surveillance test also had a substantial impact on the benefits of surveillance. This article is protected by copyright. All rights reserved.

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Myeloid Notch1 Deficiency Activates RhoA/ROCK Pathway and Aggravates Hepatocellular Damage In Mouse Ischemic Livers

Abstract

Notch signaling plays an emerging role in the regulation of immune cell development and function during inflammatory response. Activation of the ras homolog gene family, member A (RhoA)/Rho-associated protein kinase (ROCK) pathway promotes leukocyte accumulation in tissue injury. However, it remains unknown whether Notch signaling regulates RhoA/ROCK-mediated immune responses in liver ischemia and reperfusion injury (IRI). This study investigated intracellular signaling pathways regulated by Notch receptors in the IR-stressed liver and in vitro. In a mouse model of IR-induced liver inflammatory injury, we found that mice with myeloid specific Notch1 knockout (Notch1^M-KO) showed aggravated hepatocellular damage, with increased serum ALT levels, hepatocellular apoptosis, macrophage/neutrophil trafficking, and pro-inflammatory mediators compared to the Notch1-proficient (Notch1^FL/FL) controls. Unlike in the Notch1^FL/FL controls, myeloid Notch1 ablation diminished hairy and enhancer of split-1 (Hes1) and augmented c-Jun N-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), JNK, ROCK1, and PTEN activation in ischemic livers. Disruption of JSAP1 in Notch1^M-KO livers improved hepatocellular function and reduced JNK, ROCK1, PTEN, and TLR4 activation. Moreover, ROCK1 knockdown inhibited PTEN and promoted Akt, leading to depressed TLR4. In parallel in vitro studies, transfection of lentivirus-expressing Notch1 intracellular domain (NICD) promoted Hes1 and inhibited JSAP1 in LPS-stimulated bone marrow-derived macrophages (BMMs). Hes1 deletion enhanced JSAP1/JNK activation whereas CRISPR/Cas9-mediated JSAP1 knockout diminished ROCK1/PTEN and TLR4 signaling. Conclusions: Myeloid Notch1 deficiency activates the RhoA/ROCK pathway and exacerbates hepatocellular injury by inhibiting transcriptional repressor Hes1 and inducing scaffold protein JSAP1 in IR-triggered liver inflammation. Our findings underscore the crucial role of the Notch-Hes1 axis as a novel regulator of innate immunity-mediated inflammation and imply the therapeutic potential for the management of organ IRI in transplant recipients. This article is protected by copyright. All rights reserved.

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Erratum: Reassessing the Safety Concerns of Utilizing Blood Donations from Patients with Hemochromatosis

After publication of our manuscript, it came to our attention that the Australian Red Cross does indeed accept blood donations from patient with hemochromatosis (HH). Additionally, rates of transfusion-transmittable infections in donations destined for component manufacture have been found to be significantly lower in therapeutic donations compared to voluntary donations, while bacterial contamination were similar in both cohorts, further emphasizing the safety of blood from HH donors.(1)

Table 1 should be corrected to reflect that the Australian Red Cross does accept donations from therapeutic phlebotomy of HH patients.

The conclusions of this manuscript are not affected by this error.

We regret the oversight in omitting this citation.

1. Hoad V, Bentley P, Bell B, Pathak P, Chan HT, Keller A. The infectious disease blood safety risk of Australian hemochromatosis donations. Transfusion 2016;56:2934-2940. This article is protected by copyright. All rights reserved.

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Is mIndy a mediator of energy metabolism reprogramming in hepatocellular carcinoma induced by IL-6/STAT3 signaling?

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Radioembolization for hepatocellular carcinoma – the time has come

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Is mIndy a mediator of energy metabolism reprogramming in hepatocellular carcinoma induced by IL-6/STAT3 signaling?

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Melanocyte Stem Cell Activation and Translocation Initiate Cutaneous Melanoma in Response to UV Exposure

White and colleagues define the critical early steps of melanoma development from adult melanocyte stem cells. Although stem cell quiescence can work as a tumor suppressor in cutaneous melanoma formation, UV radiation can initiate melanoma formation from these quiescent melanocyte stem cells via an immune-dependent process.

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The Primate-Specific Gene TMEM14B Marks Outer Radial Glia Cells and Promotes Cortical Expansion and Folding

Wang and colleagues show that the primate-specific gene TMEM14B marks a subset of human neural progenitors and induces cortical folding, providing insights into human brain evolution. Expressing TMEM14B in the fetal mouse brain increases proliferation of progenitor subsets and cortical thickening through nuclear shuttling of IQGAP1, which promotes G1/S transitions.

http://ift.tt/2wR3ni2

Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes

The precise cellular origin of cutaneous melanoma has been a topic of intense debate. Using a refined mouse model that faithfully recapitulates key histopathological features of early stages of human melanomagenesis, Köhler et al. report that melanoma can arise from mature, pigment-producing melanocytes located within the interfollicular epidermis.

http://ift.tt/2yf7J47

To Everything There Is a Season: Summer-to-Winter Food Webs and the Functional Traits of Keystone Species

Abstract

From a trophic perspective, a seasonal increase in air temperature and photoperiod propagates as bottom-up pulse of primary production by plants, secondary production by herbivores, and tertiary production by carnivores. However, food web seasonality reflects not only abiotic variation in temperature and photoperiod, but also the composition of the biotic community and their functional responses to this variation. Some plants and animals—here referred to as seasonal specialists—decouple from food webs in winter through migration or various forms of metabolic arrest (e.g., senescence, diapause, and hibernation), whereas some plants and resident animals—here referred to as seasonal generalists—remain present and trophically coupled in winter. The co-occurrence of species with divergent responses to winter introduces seasonal variation in interaction strengths, resulting in summer-to-winter differences in trophic organization. Autumn cooling and shortening day length arrests primary productivity and cues seasonal herbivores to decouple, leaving generalist carnivores to concentrate their predation on the few generalist herbivores that remain resident, active, and vulnerable to predation in winter, which themselves feed on the few generalist plant structures available in winter. Thus, what was a bottom-up pulse, spread among many species in summer, including highly productive seasonal specialists, reverses into strong top-down regulation in winter that is top-heavy, and concentrated among a small number of generalist herbivores and their winter foods. Intermediate-sized, generalist herbivores that remain active and vulnerable to predation in winter are likely to be keystone species in seasonal food webs because they provide the essential ecosystem service of turning summer primary productivity into winter food for carnivores. Empirical examination of terrestrial mammals and their seasonal trophic status in the boreal forest and across an arctic-to-tropics seasonality gradient indicates seasonal specialization is more common among herbivores, small body sizes, and in regions with intermediate seasonality, than among carnivores, large body size, and regions where summers are very short or very long. Better understanding of food webs in seasonal environments, including their vulnerability and resilience to climate change, requires a multi-season perspective.

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Delirium in Hospitalized Older Adults

Foreword. This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations. Stage. A 75-year-old…

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