Coupling Mechanical and Electrical Properties in Spin Crossover Polymer Composites

Abstract

Spin crossover particles of formula [Fe{(Htrz)₂(trz)}_0.9(NH₂-trz)_0.3](BF₄)_1.1 and average size of 20 nm ± 8 nm are homogeneously dispersed in poly(vinylidene fluoride-co-trifluoro-ethylene), P(VDF-TrFE), and poly(vinylidene fluoride) (PVDF) matrices to form macroscopic (cm-scale), freestanding, and flexible nanocomposite materials. The composites exhibit concomitant thermal expansion and discharge current peaks on cycling around the spin transition temperatures, i.e., new "product properties" resulting from the synergy between the particles and the matrix. Poling the P(VDF-TrFE) (70–30 mol%) samples loaded with 25 wt% of particles in 18 MV m⁻¹ electric field results in a piezoelectric coefficient d₃₃ = −3.3 pC N⁻¹. The poled samples display substantially amplified discharges and altered spin transition properties. Analysis of mechanical and dielectric properties reveals that both strain (1%) and permittivity (40%) changes in the composite accompany the spin transition in the particles, giving direct evidence for strong electromechanical couplings between the components. These results provide a novel route for the deployment of molecular spin crossover materials as actuators in artificial muscles and generators in thermal energy harvesting devices.

P(VDFTrFE) and poly(vinylidene fluoride) (PVDF) composites of spin transition nanoparticles are synthesized to obtain flexible, freestanding, macroscopic objects displaying original electromechanical properties. The synergy between the components leads to concomitant thermal expansion and electrical discharge peaks at the spin transition providing scope for the deployment of spin crossover materials as actuators in artificial muscles and generators in thermal energy harvesting devices.

http://ift.tt/2CFNnSX

An Unusual Strong Visible-Light Absorption Band in Red Anatase TiO2 Photocatalyst Induced by Atomic Hydrogen-Occupied Oxygen Vacancies

Abstract

Increasing visible light absorption of classic wide-bandgap photocatalysts like TiO₂ has long been pursued in order to promote solar energy conversion. Modulating the composition and/or stoichiometry of these photocatalysts is essential to narrow their bandgap for a strong visible-light absorption band. However, the bands obtained so far normally suffer from a low absorbance and/or narrow range. Herein, in contrast to the common tail-like absorption band in hydrogen-free oxygen-deficient TiO₂, an unusual strong absorption band spanning the full spectrum of visible light is achieved in anatase TiO₂ by intentionally introducing atomic hydrogen-mediated oxygen vacancies. Combining experimental characterizations with theoretical calculations reveals the excitation of a new subvalence band associated with atomic hydrogen filled oxygen vacancies as the origin of such band, which subsequently leads to active photo-electrochemical water oxidation under visible light. These findings could provide a powerful way of tailoring wide-bandgap semiconductors to fully capture solar light.

In contrast to the common tail-like absorption band in hydrogen-free oxygen-deficient TiO₂, an unusual strong absorption band spanning the full spectrum of visible light is achieved in red anatase TiO₂ by intentionally introducing atomic hydrogen-mediated oxygen vacancies that subsequently lead to active photo-electrochemical water oxidation under visible light.

http://ift.tt/2D7ujy7

Citrate Improves Collagen Mineralization via Interface Wetting: A Physicochemical Understanding of Biomineralization Control

Abstract

Biological hard tissues such as bones always contain extremely high levels of citrate, which is believed to play an important role in bone formation as well as in osteoporosis treatments. However, its mechanism on biomineralization is not elucidated. Here, it is found that the adsorbed citrate molecules on collagen fibrils can significantly reduce the interfacial energy between the biological matrix and the amorphous calcium phosphate precursor to enhance their wetting effect at the early biomineralization stage, sequentially facilitating the intrafibrillar formation of hydroxyapatite to produce an inorganic–organic composite. It is demonstrated experimentally that only collagen fibrils containing ≈8.2 wt% of bound citrate (close to the level in biological bone) can reach the full mineralization as those in natural bones. The effect of citrate on the promotion of the collagen mineralization degree is also confirmed by in vitro dentin repair. This finding demonstrates the importance of interfacial controls in biomineralization and more generally, provides a physicochemical view about the regulation effect of small biomolecules on the biomineralization front.

The high level of citrate pretreated collagen fibrils can significantly reduce interfacial energy between the biological matrix and amorphous calcium phosphate precursors at the early mineralization stage, which sequentially facilitates intrafibrillar mineralization and produces an inorganic–organic composite using a wetting effect. This finding demonstrates the importance of interfacial controls in biomineralization.

http://ift.tt/2AEGwHx

Activatable Protein Nanoparticles for Targeted Delivery of Therapeutic Peptides

Abstract

Clinical translation of therapeutic peptides, particularly those that require penetration of the cell membrane or are cytolytic, is a major challenge. A novel approach based on a complementary mechanism, which has been widely used for guided synthesis of DNA or RNA nanoparticles, for de novo design of activatable protein nanoparticles (APNPs) for targeted delivery of therapeutic peptides is described. APNPs are formed through self-assembly of three independent polypeptides based on pairwise coiled-coil dimerization. They are capable of long circulation in the blood and can be engineered to target diseases. Peptides to be delivered are incorporated into APNPs and released into the disease microenvironment by locally enriched proteases. It is demonstrated that APNPs mediate efficient delivery of NR2B9c, a neuroprotective peptide that functions after cell penetration, and melittin, a cytolytic peptide that perturbs the lipid bilayer, for effective treatment of stroke and cancer, respectively. Due to their robust properties, simple design, and economic costs, APNPs have great potential to serve as a versatile platform for controlled delivery of therapeutic peptides.

Clinical translation of therapeutic peptides, particularly those that require penetration of the cell membrane or are cytolytic, is a major challenge. A novel approach for de novo design of "activatable" protein nanoparticles (APNPs) for targeted delivery of peptides is described. It is demonstrated that APNPs safely deliver therapeutic peptides regardless of their toxicity for effective disease treatment.

http://ift.tt/2COILxQ

Broadband MoS2 Field-Effect Phototransistors: Ultrasensitive Visible-Light Photoresponse and Negative Infrared Photoresponse

Abstract

Inverse photoresponse is discovered from phototransistors based on molybdenum disulfide (MoS₂). The devices are capable of detecting photons with energy below the bandgap of MoS₂. Under the illumination of near-infrared (NIR) light at 980 and 1550 nm, negative photoresponses with short response time (50 ms) are observed for the first time. Upon visible-light illumination, the phototransistors exhibit positive photoresponse with ultrahigh responsivity on the order of 10⁴–10⁵ A W⁻¹ owing to the photogating effect and charge trapping mechanism. Besides, the phototransistors can detect a weak visible-light signal with effective optical power as low as 17 picowatts (pW). A thermally induced photoresponse mechanism, the bolometric effect, is proposed as the cause of the negative photocurrent in the NIR regime. The thermal energy of the NIR radiation is transferred to the MoS₂ crystal lattice, inducing lattice heating and resistance increase. This model is experimentally confirmed by low-temperature electrical measurements. The bolometric coefficient calculated from the measured transport current change with temperature is −33 nA K⁻¹. These findings offer a new approach to develop sub-bandgap photodetectors and other novel optoelectronic devices based on 2D layered materials.

Broadband phototransistors based on molybdenum disulfide (MoS₂) with inverse photoresponse are reported. At 454 nm, the phototransistors exhibit ultrahigh photoresponsivity on the order of 10⁴–10⁵ A W⁻¹. While upon near-infrared light illumination, negative photoresponses with fast response time (50 ms) are observed for the first time. This work offers a new approach to developing sub-bandgap photodetectors and other novel optoelectronic devices.

http://ift.tt/2ADMgkO

Defining the phenotypic spectrum of SLC6A1 mutations

Summary

Objective

Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.

Methods

We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects.

Results

Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg).

Significance

Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

http://ift.tt/2mbZMYK

Cytotoxic edema at onset in West syndrome of unknown etiology: A longitudinal diffusion tensor imaging study

Summary

Objective

To clarify longitudinal changes in white matter microstructures from the onset of disease in patients with West syndrome (WS) of unknown etiology.

Methods

Diffusion tensor imaging (DTI) was prospectively performed at onset and at 12 and 24 months old in 17 children with WS of unknown etiology. DTI was analyzed using tract-based spatial statistics (TBSS) and tract-specific analysis (TSA) of 13 fiber tracts, and fractional anisotropy (FA) and mean diffusivity (MD) were compared with those of 42 age-matched controls. Correlations of FA and MD with developmental quotient (DQ) at age 24 months were analyzed. Multiple comparisons were adjusted for using the false discovery rate (q-value).

Results

TBSS analysis at onset showed higher FA and lower MD in the corpus callosum and brainstem in patients. TSA showed lower MD in bilateral uncinate fasciculi (UF) (right: q < 0.001; left: q = 0.03) at onset in patients. TBSS showed a negative correlation between FA at onset and DQ in the right frontal lobe, whereas FA at 24 months old exhibited a positive correlation with DQ in the diffuse white matter. MD for bilateral UF at 24 months old on TSA correlated positively with DQ (q = 0.04, both).

Significance

These findings may indicate the existence of cytotoxic edema in the immature white matter and dorsal brainstem at onset, and subsequent alterations in the diffuse white matter in WS of unknown etiology. Microstructural development in the UF might play important roles in cognitive development in WS.

http://ift.tt/2Fcn606

Lateral bone augmentation in narrow posterior mandibles, description of a novel approach, and analysis of results

Abstract

Background

Combination of particulate grafts and collagen membranes is widely used for augmentation of bony defects for implant placement. Fixation of the barrier membrane may avoid complications due to unfavorable mechanical properties and poor stability leading to collapse of the augmented area.

Purpose

To evaluate a new simplified method for resorbable collagen membrane fixation in lateral bone augmentation procedures in narrow posterior mandibles.

Materials and Methods

This retrospective study analyzed 16 procedures performed in 15 patients who followed lateral ridge augmentation procedures before implant placement in the posterior mandible. A particulate mineralized bone allograft was covered with a cross-linked resorbable collagen barrier membrane, which was fixated with a single, nonresorbable pin. Complications were registered and results analyzed on pre and post op measurements on computerized tomographic scans. Descriptive statistical analysis and ANOVA with repeated measures were performed.

Results

No complications were recorded. Average bone gain was 3.3 mm at implant platform level and 4.29 mm at 3 mm apically, both, statistically significant. All sites had sufficient bone width allowing implant placement. Thirty-three implants placed in the augmented areas, integrated and survived for over a 2-year follow-up.

Conclusion

The simplified membrane fixation procedure enables large horizontal bone gain with minimal complications while allowing adequate implant placement.

http://ift.tt/2EkhO1z

Issue Information

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Prenatal exposure to Chernobyl fallout in Norway: neurological and developmental outcomes in a 25-year follow-up

Abstract

Ionizing radiation at high doses early in life may cause neurodevelopmental problems. Possible effects of lower doses are, however, controversial. We use carefully collected exposure data for Norway following the Chernobyl accident in April 1986 combined with population-based registries to assess long-term effects of fetal exposure on neurodevelopmental outcomes. Radiation doses were estimated for each Norwegian municipality for each calendar month from May 1986 to April 1989. We established a cohort of all Norwegian pregnancies during the three-year period of radiation measurement and compared them with appropriate unexposed groups. All cohorts were followed into adulthood. Risks of cerebral palsy, mental retardation, schizophrenia, epilepsy, vision or hearing problems, school dropout, and low income were estimated. We also conducted an analysis of mathematics and language grades using siblings born after the exposure period as comparison. There was little evidence of associations between radiation exposure and cerebral palsy, mental retardation, schizophrenia, epilepsy, or hearing or vision problems associated with radiation exposure. (p-values for trend with exposure dose were 0.27, 0.14, 0.83, 0.35 and 0.42.) Slightly more of the exposed failed to complete high school (p = 0.05), but there was no increase in the proportion with low income (p = 0.38). The natural advantage of older siblings over younger siblings in mathematics grades was diminished with exposure of older siblings (p = 0.003), but there was no association of exposure with Norwegian language grades (p = 0.37). There is scant evidence that the low-dose fallout from Chernobyl in Norway increased the risk for serious neurodevelopmental problems. We cannot exclude the possibility of lower mathematics grades with exposure, similar to a report from Sweden.

http://ift.tt/2ADN7C9

APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution

Abstract

The APOBEC mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer.

http://ift.tt/2CMTc4n

PD-1 blockade with nivolumab in endemic Kaposi sarcoma

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Outcome in colorectal cancer – tumour, stroma and so much more

colorectal cancerprognosisinflammationtumour microenvironment

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The T-cell Receptor {beta}-Chain Is an Immunotherapy Target for Lymphomas [Lymphoma]

Targeting the TRBC gene expressed by T-cell malignancies mitigates severe immunosuppression.

http://ift.tt/2COwQ2d

Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression [Research Briefs]

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.

Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59–73. ©2017 AACR.

See related commentary by Carugo and Draetta, p. 17.

This article is highlighted in the In This Issue feature, p. 1

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First-Line Osimertinib Beneficial in Advanced NSCLC [News in Brief]

Osimertinib is more effective as first-line therapy than other EGFR inhibitors for patients with advanced EGFR-mutated non–small cell lung cancer—notably Asians, who have a higher incidence of the disease compared with Western populations. The conclusion is based on data from a subgroup analysis of the phase III FLAURA trial.

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The DNA Transposase PGBD5 Sensitizes Tumors to Inhibition of DNA Repair [Pediatric Cancers]

PGBD5 expression in pediatric solid tumors confers sensitivity to inhibitors of DNA damage signaling.

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Dasatinib Approved for Pediatric CML [News in Brief]

The FDA approved dasatinib to treat pediatric chronic myeloid leukemia. This drug is the second tyrosine kinase inhibitor, alongside imatinib, approved for this indication and represents an important new option for first- and second-line treatment.

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PMN-MDSC Infiltration Blocks the Antitumor Effects of CSF1R Inhibition [Immunology]

CSF1R inhibition both reduces protumorigenic TAMs and recruits protumorigenic PMN-MDSCs.

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Blocking IDO1 Helps Shrink Bladder, Cervical Tumors [News in Brief]

Findings from a phase I/IIa study indicate that combining the investigational indoleamine 2,3-dioxygenase 1 inhibitor BMS-986205 with nivolumab is safe and boosts response rates among patients with bladder and cervical cancers.

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PD-1 Functions as a Tumor Suppressor in T-cell Lymphoma [Lymphoma]

Oncogenic T-cell signaling upregulates PD-1, which increases PTEN expression to suppress oncogenesis.

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People [News in Brief]

Josep Tabernero, MD, PhD, and Alexis A. Thompson, MD, MPH, are featured.

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BLU-285 Targets KIT/PDGFRA Conformation and Activating Loop Mutations [Targeted Therapy]

The small-molecule inhibitor BLU-285 inhibits clinically relevant KIT and PDGFRA mutations.

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Basket Study Yields Approval for Rare Cancer [News in Brief]

The FDA, in a regulatory first, approved a targeted therapy based on a basket study. The move, which expanded the indications for the BRAF inhibitor vemurafenib to include Erdheim–Chester disease, points to a new approval pathway for drugs that treat rare cancers.

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In This Issue [In This Issue]

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JCAR015 in ALL: A Root-Cause Investigation [News in Brief]

After conducting an internal probe of the five deaths that halted JCAR015's development for acute lymphoblastic leukemia, Juno Therapeutics has concluded that multiple factors were at play. A surge in inflammatory cytokine levels from rapid, early T-cell proliferation may have provoked the blood–brain barrier disruption seen in these patients, inducing fatal cerebral edema.

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NFS1 Expression Protects Lung Tumor Cells from Ferroptosis [Lung Cancer]

NFS1 activity is essential for maintenance of iron–sulfur cluster biosynthesis in response to oxidative stress.

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Poziotinib Shows Promise for Rare Lung Cancer [News in Brief]

Poziotinib, an EGFR inhibitor that was previously shelved as ineffective against non–small cell lung cancer, is showing promising activity in a subset of patients with EGFR exon 20 insertions. According to preliminary data from a phase II trial, the drug led to a 73% overall response rate in patients with this disease subtype, which is typically highly resistant to standard therapy.

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Osteoblasts Promote Release of Tumor-Promoting SiglecFhi Neutrophils [Lung Cancer]

Lung tumors activate OCN⁺ osteoblasts in distant bone stroma to supply tumor-infiltrating neutrophils.

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FDA Approves Second CAR T-cell Therapy [News in Brief]

The FDA approved the chimeric antigen receptor T-cell therapy axicabtagene ciloleucel, making it the second such treatment for blood cancers in the United States. The therapy is indicated for adults with certain non-Hodgkin lymphomas who have tried at least two other treatments.

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Pancreatitis-Induced p62 Accumulation Promotes Pancreatic Cancer [Pancreatic Cancer]

Defective autophagy and stress in acinar cells drives the progression of PanIN1 lesions to PDAC.

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Rare Tumors in Kids May Respond to Tazemetostat [News in Brief]

In a phase I trial of the EZH2 inhibitor tazemetostat, children with INI1-deficient tumors—including relapsed or refractory malignant rhabdoid tumors, atypical teratoid rhabdoid tumors, epithelioid sarcomas, and poorly differentiated chordomas—responded well to treatment, with some experiencing durable responses.

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NTZ Increases {beta}-catenin Citrullination to Suppress WNT Signaling [Signaling]

The antiparasitic drug NTZ inhibits WNT signaling and APC-mutant colorectal cancer cell growth.

http://ift.tt/2m5cis0

Health care disparities among octogenarians and nonagenarians with stage III lung cancer

BACKGROUND

To the authors' knowledge, the practice patterns for patients aged more than 80 years with stage III non-small cell lung cancer (NSCLC) is not well known. The purpose of the current study was to investigate factors predictive of and the impact on overall survival (OS) after concurrent chemoradiation (CRT) among patients aged ≥80 years with American Joint Committee on Cancer stage III NSCLC in the National Cancer Data Base (NCDB).

METHODS

In the NCDB, patients aged ≥80 years who were diagnosed with stage III NSCLC from 2004 to 2013 with complete treatment records were identified. Multivariable logistic regression and Cox proportional hazard models were generated and propensity score-matched analysis was used.

RESULTS

A total of 12,641 patients met the entry criteria: 6018 (47.6%) had stage IIIA disease and 6623 (52.4%) had stage IIIB disease. The median age at the time of diagnosis was 83.0 years (range, 80-91 years). A total of 7921 patients (62.7%) received no therapy. Black race (odds ratio [OR], 1.23; 95% confidence interval [95% CI], 1.06-1.43) and living in a lower educated census tract of residence (OR, 1.20; 95% CI, 1.03-1.40) were found to be associated with not receiving care, whereas treatment at an academic center (OR, 0.80; 95% CI, 0.70-0.92) was associated with receiving cancer-directed therapy. Receipt of no treatment (hazard ratio [HR], 2.69; 95% CI, 2.57-2.82) or definitive radiation alone (HR, 1.15; 95% CI, 1.07-1.24) compared with CRT was associated with worse OS. On propensity score matching, not receiving CRT was found to be associated with worse OS (HR, 1.58; 95% CI, 1.44-1.72).

CONCLUSIONS

In this NCDB analysis, approximately 62.7% of patients aged ≥80 years with stage III NSCLC received no cancer-directed care. Black race and living in a lower educated census tract were associated with not receiving cancer-directed care. OS was found to be improved in patients receiving CRT. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2m8IE5l

Rabdocoestin B exhibits antitumor activity by inducing G2/M phase arrest and apoptosis in esophageal squamous cell carcinoma

Abstract

Purpose

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive squamous cell carcinomas and is generally resistant to chemotherapy. In the present study, the cytotoxic activity of Rabdocoestin B (Rabd-B) against ESCC and the underlying mechanisms were investigated.

Methods

The inhibitory effect of Rabd-B on KYSE30 and KYSE450 was evaluated by Cell Counting Kit-8 (CCK8) and colony formation assays in vitro. The cell cycle distribution and apoptosis of cells treated with Rabd-B were determined by flow cytometry. The mechanisms underlying the effects of Rabd-B were systematically examined by Western blot. The in vivo anti-tumor ability of Rabd-B was measured in mouse xenograft models and cisplatin (DDP) was used as positive control.

Results

Rabd-B efficiently induced G2/M phase arrest in ESCC cells by upregulating the Chk1/Chk2-Cdc25C axis to inhibit the G2→M transition facilitated by Cdc2/Cyclin B1. Furthermore, Rabd-B suppressed ATM/ATR phosphorylation, thereby inhibiting BRCA1-mediated DNA repair, which resulted in mitotic catastrophe and induced cell apoptosis. Rabd-B also decreased the activity of the Akt and NF-κB survival signaling pathways and ultimately initiated the caspase-9-dependent intrinsic apoptotic pathway in ESCC cells. The apoptosis induced by Rabd-B could be partially reversed by a caspase-9-specific inhibitor (Z-LEHD-FMK) and a pan-caspase inhibitor (Z-VAD-FMK). Moreover, Rabd-B effectively suppressed tumor growth in mouse xenografts which was comparable to that of DDP without significant injuries to the mice.

Conclusion

Taken together, these findings indicate that Rabd-B is a promising precursor compound that may be useful as a treatment for ESCC and thus warrants further investigation.

http://ift.tt/2CRxaON

Evaluation of sex hormones and sperm parameters in male epileptic patients

Objectives

The aim of this study was to investigate the effect of carbamazepine (CBZ) and sodium valproate (VPA) monotherapy on sexual functions, sex hormones, and semen analysis and quality in male patients with epilepsy.

Methods

A total of 59 male patients with epilepsy, of which 30 were on VPA monotherapy and 29 were on CBZ monotherapy, were included in the study between January 2015 and March 2016. A control group was established with 30 healthy males. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), free testosterone (fT), estradiol (E2), sex hormone-binding globulin (SHBG) levels and bioactive testosterone (BAT)/bioactive estradiol (BAE), and BAT/LH ratio were studied in groups. All groups received semen analysis and International Index of Erectile Function Scale (IIEF-5) test for erectile dysfunction.

Results

E2 and DHEAS levels were higher in VPA and CBZ groups compared to control group (P < .001, P = .014). The decrease in fT levels in the VPA group was statistically significant (P = .038). No significant difference was detected in levels of SHBG, LH, and FSH (P > .05). BAT/BAE ratios were low both in VPA and CBZ groups (P < .001; P < .001), while BAT/LH ratios were low only in CBZ group (P = .033). In semen analysis, semen volume and number of normal sperms were found to be significantly lower in patients receiving antiepileptic drugs compared to control group (P < .05). There were no differences between the groups in rates of abnormal sperm morphology. IIEF-5 scores were found to be significantly lower in VPA and CBZ groups (P < .001).

Conclusion

VPA or CBZ therapy may lead to dysregulation of sex hormones, sexual dysfunction, and alterations in semen analysis in male patients with epilepsy. This must be considered for the selection of antiepileptic drugs in young male patients.

http://ift.tt/2CPYqwW

Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis

Background

Cystatin C (CysC) is associated with many neurodegenerative disorders and autoimmune diseases, but its relationship with anti-N-Methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown.

Methods

Serum levels of CysC were determined in 66 patients with anti-NMDAR encephalitis and 115 healthy controls. Of the 66 patients, 30 had a follow-up evaluation at 3 months after admission. Association of CysC with anti-NMDAR encephalitis and its clinical parameters were evaluated in the patients.

Results

The serum levels of CysC were significantly lower in patients with anti-NMDAR encephalitis than in controls (0.70 ± 0.13 vs 0.83 ± 0.17 mg/mL, P < .001). Disease severity and disease duration were significantly associated with CysC levels. Furthermore, a follow-up evaluation revealed that after treatment anti-NMDAR encephalitis patients had significantly increased serum CysC levels (P < .001) and significantly decreased modified Rankin Scale (mRS) scores (P < .001) compared with before treatment. In addition, a significant negative correlation was observed between the change in CysC levels and the change in mRS scores (r = −.700, P < .001).

Conclusion

Our results show that the serum levels of CysC are associated with anti-NMDAR encephalitis and its clinical parameters and that the changes in CysC levels correlate with therapeutic effect. Therefore, our findings provide new insights into the association between serum CysC and anti-NMDAR encephalitis.

http://ift.tt/2AEjzUI

Pretherapeutic functional neuroimaging predicts tremor arrest after thalamotomy

Objective

Essential tremor (ET) represents the most common movement disorder. Drug-resistant ET can benefit from standard stereotactic procedures (deep brain stimulation or radiofrequency thalamotomy) or alternatively minimally invasive high-focused ultrasound or radiosurgery. All aim at same target, thalamic ventro-intermediate nucleus (Vim).

Methods

The study included a cohort of 17 consecutive patients, with ET, treated only with left unilateral stereotactic radiosurgical thalamotomy (SRS-T) between September 2014 and August 2015. The mean time to tremor improvement was 3.32 months (SD 2.7, 0.5-10). Neuroimaging data were collected at baseline (n = 17). Standard tremor scores, including activities of daily living (ADL) and tremor score on treated hand (TSTH), were completed pretherapeutically and 1 year later. We further correlate these scores with baseline inter-connectivity in twenty major large-scale brain networks.

Results

We report as predictive three networks, with the interconnected statistically significant clusters: primary motor cortex interconnected with inferior olivary nucleus, bilateral thalamus interconnected with motor cerebellum lobule V² (ADL), and anterior default-mode network interconnected with Brodmann area 10³ (TSTH). For all, more positive pretherapeutic interconnectivity correlated with higher drop in points on the respective scores. Age, disease duration, or time-to-response after SRS-T were not statistically correlated with pretherapeutic brain connectivity measures (P > .05). The same applied to pretherapeutic tremor scores, after using the same methodology described above.

Conclusions

Our findings have clinical implications for predicting clinical response after SRS-T. Here, using pretherapeutic magnetic resonance imaging and data processing without prior hypothesis, we show that pretherapeutic network(s) interconnectivity strength predicts tremor arrest in drug-naïve ET, following stereotactic radiosurgical thalamotomy.

http://ift.tt/2CQIvyh

No excess of autoimmune diseases in multiple sclerosis families from the Netherlands

Objectives

Autoimmune diseases (AIDs) cluster in families; however, to what extent AIDs co-occur in MS multiplex families with two or more affected individuals is still controversial. The study aimed to evaluate coexisting AIDs in this type of families from the Netherlands.

Materials and methods

A total of 155 MS multiplex families (155 MS probands, 959 first-degree relatives and 212 spouses) were characterized for a history of 11 AIDs by means of a self-administered questionnaire.

Results

In 43.2% of MS multiplex families, at least one AID was present in the first-degree relatives. Overall, the frequency of AIDs was not significantly different between patients with MS (11%), their first-degree family members (11%) and controls (5.2%). After correction for age at inclusion and gender, the odds ratios (OR) for AIDs were not significant for patients with MS (OR = 1.8 [0.77-4.34], P = .17) and first-degree family members (OR = 2.0 [0.98-4.10], P = .06) when both compared to spouses. The frequency of AIDs in mothers did not differ from that in fathers after correction for sex bias (19% vs 8%, P = .51). A presence of AID was more often reported in maternal than paternal second-degree relatives (23% vs 10%, P = .0020).

Conclusion

Although nearly half of the Dutch MS multiplex families reported an AID, no excess of AIDs was present in patients with MS from multiplex families or their first-degree family members compared to the spouses.

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Erratum

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WEO Newsletter

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Cover Image

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Issue Information

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The 95th Congress of the Japan Gastroenterological Endoscopy Society

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Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells

Zanthoxylum ailanthoides (ZA) has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG) biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M) could reduce oleic acid- (OA-) induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions. As a result, treatment of ZA-M blocked de novo TG biosynthesis and subsequently mitigated intracellular neutral lipid accumulation in HepG2 cells. ZA-M also inhibited OA-induced production of reactive oxygen species (ROS) and TNF-α, suggesting that ZA-M possess the anti-inflammatory feature in fatty acid over accumulated condition. Taken together, these results suggest that ZA-M attenuates OA-induced lipid accumulation and inflammation through the activation of LKB1/AMPK signaling pathway in HepG2 cells.

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Locally Advanced Uterine Cancer: A Multimodality Model or Muddle?

A 54-year-old gravida 3 para 3 postmenopausal woman female has a 1-year history of intermittent vaginal bleeding. Pelvic examination reveals a bulky 6-cm mass at the cervical os obliterating the vaginal fornices. Computed tomography of the abdomen and pelvis shows a heterogeneously enhancing mass in the cervix extending into the lower uterine cavity and vagina, with extensive retroperitoneal lymphadenopathy involving periaortic and aortocaval lymph nodes. The mass is biopsied, and pathology reveals a high-grade carcinoma.

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In reply to Royce

To the Editor: We would like to thank those who have responded (1) to our analysis (2) of the current radiation oncology job market and offer our thoughts on their comments. We appreciate their interest expressed in this topic, and in particular our publication.

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Radiation Is the Place to Start

Surgery is the mainstay of treatment for most patients with endometrial cancer, but for patients with bulky disease centered on the cervix, radiation may be a better choice. In general, cervical cancers are considered more radiation sensitive than endometrial cancer and thus more amenable to definitive radiation therapy. However, the efficacy of radiation in cervical cancer may be more a function of the favorable anatomy of cervical cancers that makes it possible to create highly conformal dose distributions with brachytherapy.

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Meetings

February 8-10, 2018

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In Reply to Tallet et al

To the Editor: We would like to thank Dr Tallet and colleagues for their letter regarding our article on the clinical outcomes of RapidArc versus tomotherapy for patients with head and neck cancer (1). We showed that patients in the group treated with tomotherapy had better local control and cancer-specific survival, but no difference was found on overall and progression-free survival. We agree with the authors that variability in delineation and patient positioning might have contributed to the differences we showed in our analysis of the prospective trial ART-ORL (Advanced Radiotherapy Oto-Rhino-Laryngologie) (2).

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Rescuing Spanish Radiation Therapy: The Role of Leadership and Opportunity

Radiation therapy is a major cornerstone in cancer treatment. Organ preservation in early tumors, treatment of locally advanced cancers, and the curative or palliative treatment of metastatic disease is possible thanks to the efforts of radiation oncologists in caring for their patients and to the tremendous technological advances available in recent decades. Unfortunately, much of this good news is unknown and unnoticed by either the general population, the media, or by politicians. Furthermore, globally there is a wide variation in resources and access to radiation therapy by countries, regions, and even within cities (1).

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In Regard to Chowdhary et al

To the Editor: In the September 2017 issue of the International Journal of Radiation Oncology, Biology, Physics, Chowdhary et al published a clever geographic distribution analysis of the US radiation oncology (RO) job market by using the publically available job postings on the American Society for Radiation Oncology (ASTRO) Career Center website (1). They found a disproportionately small number of jobs relative to the number of graduates in certain regions of the country (ie, the Northeast). Their findings help inform graduating residents on the current state of a sometimes-challenging market (2).

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Chemo-radiation, Then on to Surgery

Preoperative radiation was quite common before the ascendancy of total hysterectomy as the initial approach to uterine cancer, and it continues to have a role in situations in which the standard surgical approach is likely to result in incomplete clearance of gross disease, such as parametrial involvement (1, 2).

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Modeling of Normal Tissue Complications Using Imaging and Biomarkers After Radiation Therapy for Hepatocellular Carcinoma

To develop normal tissue complications (NTCP) models for hepatocellular cancer (HCC) patients who undergo liver radiation therapy (RT) and to evaluate the potential role of functional imaging and measurement of blood-based circulating biological markers before and during RT to improve the performance of these models.

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Cardiac Morbidity and Radiation Therapy for Breast Cancer

The relationship between radiation treatment for breast cancer and subsequent risk of cardiac morbidity and mortality has been known for decades (1, 2), but risks in the modern era are less clear and seem to be significantly lower than in prior eras (3-5). There have been significant improvements in technology and awareness, allowing more nuanced dosimetric analysis and attention to cardiac exposure in patients treated with modern computed tomography (CT)–based planning, but long-term follow-up with more modern techniques is limited.

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Chemo First, Then Radiation, and Perhaps Surgery

This lady has a clinical stage IIIB endometrial cancer (involvement of vaginal wall) and image evidence highly suspicious for International Federation of Gynecology and Obstetrics stage IIIC2 disease (para-aortic adenopathy) (1). In addition, magnetic resonance imaging also suggests parametrial spread of disease. Staging and/debulking surgery is the standard initial therapy for endometrial cancer. In high-grade histology such as this case, an optimal outcome requires that staging surgery is comprehensive, and where extrauterine disease is grossly apparent, all visible disease resected to R0 (no residual disease) (2).

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Issue Highlights

Lara et al

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In Regard to Bibault et al

To the Editor: We thank Bibault et al for their valuable contribution to the knowledge regarding the meaningful clinical impact of dosimetric differences among different arc therapy techniques. Their recent work obviously calls for a prospective evaluation, because we noticed some caveats susceptible to modifying their results.

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Erratum to: Wang SY, Kelly G, Gross C, et al. Information needs of older women with early-stage breast cancer when making radiation therapy decisions. Int J Radiat Oncol Biol Phys 2017;98:733-740.

In the above-referenced article,1 the last 2 sentences of the Participants section should be: "Overall, 25 participants did not receive RT. Among them, 23 participants (92.0%) had radiation oncologist visits." We regret the errors.

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Erratum to: Hafeez S, McDonald F, Lalondrelle S, et al. Clinical outcomes of image guided adaptive hypofractionated weekly radiation therapy for bladder cancer in patients unsuitable for radical treatment. Int J Radiat Oncol Biol Phys 2017;98:115-122.

The authors wish to bring to the readers' attention typographical error identified in Supplementary Table 2 with the online version of the article showing the dose constraints guidance used for 3D conformal planning for total prescription dose of 36Gy in 6 fractions (1). The content of the columns for other bowel were inadvertently moved in formatting. This was not recognized by the authors at the time of manuscript review. The corrected Supplementary Table 2 is as below. We apologize for any inconvenience.

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Corrigendum to “All-Atom Four-Body Knowledge-Based Statistical Potentials to Distinguish Native Protein Structures from Nonnative Folds”

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Mechanism and dynamics of INPP5E transport into and inside the ciliary compartment

Journal Name: Biological Chemistry
Issue: Ahead of print


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Contact heat evoked potentials: reliable acquisition from lower extremities

Contact heat evoked potentials (CHEPs) reflect cortical responses of Aδ-nociceptors activated by noxious heat stimuli (Greffrath et al. 2007; Baumgartner et al. 2012). In addition to Aδ-fibers, C-fibers are also known to be involved in the perception of contact heat. The reliable recording of C-fiber volley is, however, extremely challenging (Magerl et al. 1999).

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Prognostic significance of S100A16 sub-cellular localization in lung adenocarcinoma

To discover novel tumor markers for lung adenocarcinoma (AC), we performed proteomics analysis and reported a correlation between S100A16 membranous expression in AC tissues and a poor prognosis. However, some patients with a good prognosis also showed S100A16 membranous staining. We re-evaluated immunohistochemically stained tissues, and found membrane-positive and nucleus- negative expressions to be significantly higher in the presence of the following: male, smoker, positive nodal metastasis, higher p-TNM stage, larger tumor, poorer differentiation, positive for lymphatic invasion, positive for vascular invasion, and positive for pleural invasion (all factors P < 0.05).

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Downregulated SASH1 Expression Indicates Poor Clinical Prognosis in Gastric Cancer

SASH1 (SAM- and SH3-domain containing 1), a novel candidate tumor suppressor, has attracted attention due to its role in intracellular signal transduction and its tumor prognostic value in diverse cancers. Reports have demonstrated that reduced SASH1 expression correlates with tumor proliferation, invasion, and metastasis. However, the expression and prognostic significance of SASH1 in gastric cancer (GC) remain unclear. In this study, 8 paired fresh-frozen GC tissues and corresponding gastric mucosal tissues were examined by Western blot to analyze the protein expression of SASH1.

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Uterine Rhabdomyosarcoma in Adults

Rhabdomyosarcoma (RMS) is an aggressive mesenchymal tumor most commonly diagnosed in the pediatric population, and when occurring in adults, tends to develop in the deep soft tissue of the limbs. Primary uterine RMS comprises an even more restricted subset, with little known or reported when compared to most other gynecologic sarcomas. Our goal with this study was to retrospectively evaluate cases from two academic institutions and describe the main histopathologic findings of this rare gynecologic malignancy.

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Characteristics of cribriform morular variant of papillary thyroid carcinoma in post-Chernobyl affected region

The aim is to study the characteristics of cribriform morular variant of papillary thyroid carcinoma (CMV-PTC) in patients living in radiation-affected area of Belarus. The clinical and pathological features of 35 patients with CMV-PTC from Belarus were studied and compared with those of conventional papillary thyroid carcinoma diagnosed in the same period. The patients with CMV-PTC were all females and were younger at presentation (mean age = 24) than those with conventional papillary thyroid carcinoma.

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Atypical multivacuolated lipoblasts and atypical mitoses are not compatible with the diagnosis of spindle cell/pleomorphic lipoma—reply

We thank Dr Creytens et al for their comments on our articles [1,2]. We would like to make some additional comments in response to their letter.

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The Many Faces of Intestinal Tract Gastric Heterotopia; A Series of Four Cases Highlighting Clinical and Pathological Heterogeneity

Gastric heterotopia of the intestinal tract can have a diverse clinicopathologic presentation, resulting in a diagnostic dilemma. We present a series of four cases, two male and two female patients with age range of 31-82 year, found in the duodenum, jejunum, and transverse colon. The most common and rather unusual clinical presentation was iron deficiency anemia, seen in three cases, while one patient presented with abdominal pain. Endoscopically two cases were visualized as pedunculated polyps and two as sessile/plaques like lesions.

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The value of detection of S100A8 and ASAH1 in predicting the chemotherapy response for breast cancer patients

Chemotherapy plays an important role in the treatment of breast cancer. However, chemoresistance remains the main obstacle for effective treatment, leading to poor prognosis. This study aims to investigate the value of detection of S100A8 and ASAH1 in predicting the chemotherapy response. Miller and Payne grades were used to assess the chemotherapy response in breast cancers. The expression of S100A8 and ASAH1, as well as ER, PR, HER-2 and Ki-67 were assessed by immunohistochemical staining in 120 cases of non-special type invasive ductal carcinoma (IDC-NOS).

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A Rat Model of Mild Intrauterine Hypoperfusion with Microcoil Stenosis

Mild intrauterine hypoperfusion was produced by artery stenosis with metal microcoils wrapped around the uterine and ovarian arteries in rats at embryonic day 17. This procedure produced prenatal hypoperfusion and intrauterine growth restriction.

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Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT)

The current article describes the generation and metabolic characterization of high-fat diet-fed mice as a model of diet-induced insulin resistance and obesity. It further features detailed protocols to perform the oral glucose tolerance test and the insulin tolerance test, monitoring whole-body alterations of glucose metabolism in vivo.

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iSepsis – The Lactate Myths

Lactate the Myths. Lactate is good for the patient and not bad.

EMCrit Project by Paul Marik.

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