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Background: BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy. Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence. Methods: Maximum likelihood penetrance of breast/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1‐ABRAXAS1 interaction was assessed using a GFP‐fragment reassembly‐based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG/AMP classification rules specified for BRCA1/2. Results: Variant‐carriers displayed increased risk for ovarian cancer (HR = 33.0, 95% CI = 7.0–155.0; cumulative risk at age 70 = 27.6%, 95% CI = 12.6–40.0%) but not for breast cancer (HR = 0.7, 95% CI = 0.2–2.2). An increased risk of uterine cancer (HR = 8.0, 95% CI = 1.03–61.6) emerged, warranting further evaluation. Likelihood‐ratio in favor of pathogenicity was 98898642.82 under assumption of standard BRCA1 breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1‐ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG/AMP rule‐based model. Collectively, these findings allowed to classify the variant as pathogenic. Conclusion: Pathogenicity of BRCA1:c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most BRCA1 pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype. [ABSTRACT FROM AUTHOR]

Objective: We aimed to create a question bank about clinical factors for predicting the diagnoses of psoriatic arthritis in patients with psoriasis of various ancestries and skin tones, which can be completed entirely by patients. Methods: Utah Psoriasis Initiative participants without a psoriatic arthritis diagnosis at enrollment were observed for diagnosis during the study period. We inferred ancestry from exome sequencing data and performed Cox proportional hazards regression to identify clinical predictors of psoriatic arthritis in different ancestry groups. Based on results and literature review, we developed a question bank for assessing psoriatic arthritis risk among patients with psoriasis in various ancestries. Results: Patient‐reported untreated psoriasis induration and history of fingernail psoriasis were associated with psoriatic arthritis in participants of European and non‐European ancestry. We developed the Psoriatic Arthritis Prediction and Identification Question Bank for Diverse Ancestries (PAPRIKA) version 1.0, which included questions regarding psoriasis characteristics, arthritis symptoms, comorbidities, family history, and demographics. PAPRIKA is accessible at http://bjfenglab.org/. Conclusion: The clinical features (untreated psoriasis induration and history of fingernail psoriasis) that can predict psoriatic arthritis in European individuals also work for non‐European individuals. PAPRIKA can be used to gather psoriatic arthritis predictive data from patients with psoriasis without provider assistance and is relevant for patients across ancestries. [ABSTRACT FROM AUTHOR]

Herein, the spin‐polarized edge‐state transport properties in L‐shaped zigzag MoS2$\left(\text{MoS}\right)_{2}$ nanodevice (L-zMoS2ND$\left(\text{L�?zMoS}\right)_{2} \text{ND}$) are investigated based on tight‐binding model, Green's function method, and ballistic transport theory. The spin conductance and spin polarization are calculated by considering external exchange field and electric field. It is shown in the results that the spin conductance is closely related to the configuration of atomic non‐consistence on the edge of L-zMoS2ND$\left(\text{L�?zMoS}\right)_{2} \text{ND}$. Meanwhile, the spin conductance is determined by the spin channel opening on the edge, which can be modulated by external fields. The configuration characteristic and external fields give rise to effects of sublattice mismatch and spin mismatch on the edge channels, respectively. As a consequence, mismatch effects are actually employed to modulate the spin channel on the edge of L-zMoS2ND$\left(\text{L�?zMoS}\right)_{2} \text{ND}$, and 100% spin polarization is realized selectively. Moreover, the corresponding local density of states distributions are plotted to reveal the modulation of the spin‐resolved edge‐state and the spin‐filtering effects in the real space. These spin‐polarized edge‐state transport properties in L-zMoS2ND$\left(\text{L�?zMoS}\right)_{2} \text{ND}$ can have potential application in various kinds of spin valves and spin filters in nanocircuits. [ABSTRACT FROM AUTHOR]

Introduction: A family history of psychiatric disorders is one of the strongest risk factors for schizophrenia. The characteristics of patients with a family history of psychiatric disorders have not been systematically evaluated. Methods: This multicenter study (26 centers, 2425 cases) was performed in a Chinese population to examine the sociodemographic and clinical characteristics of schizophrenia patients with a family history of psychotic disorders in comparison with those of patients with sporadic schizophrenia. Results: Nineteen percent of patients had a family history of mental disease. Multiple logistic regression analysis revealed that ≥4 hospitalizations (OR = 1.78, P =.004), tobacco dependence (OR = 1.48, P =.006), alcohol dependence (OR = 1.74, P =.013), and physical illness (OR = 1.89, P =.001) were independently and significantly associated with a family history of mental disease. Conclusion: Patients with a family history of mental disorders present different demographics and clinical features than patients without a family history of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Objectives: Acute lung injury (ALI) not only affects pulmonary function but also leads to intestinal dysfunction, which in turn contributes to ALI. Mesenchymal stem cell (MSC) transplantation can be a potential strategy in the treatment of ALI. However, the mechanisms of synergistic regulatory effects by MSCs on the lung and intestine in ALI need more in‐depth study. Materials and methods: We evaluated the therapeutic effects of MSCs on the murine model of lipopolysaccharide (LPS)‐induced ALI through survival rate, histopathology and bronchoalveolar lavage fluid. Metagenomic sequencing was performed to assess the gut microbiota. The levels of pulmonary and intestinal inflammation and immune response were assessed by analysing cytokine expression and flow cytometry. Results: Mesenchymal stem cells significantly improved the survival rate of mice with ALI, alleviated histopathological lung damage, improved intestinal barrier integrity, and reduced the levels of inflammatory cytokines in the lung and gut. Furthermore, MSCs inhibited the inflammatory response by decreasing the infiltration of CD8+ T cells in both small‐intestinal lymphocytes and Peyer's patches. The gut bacterial community diversity was significantly altered by MSC transplantation. Furthermore, depletion of intestinal bacterial communities with antibiotics resulted in more severe lung and gut damages and mortality, while MSCs significantly alleviated lung injury due to their immunosuppressive effect. Conclusions: The present research indicates that MSCs attenuate lung and gut injury partly via regulation of the immune response in the lungs and intestines and gut microbiota, providing new insights into the mechanisms underlying the therapeutic effects of MSC treatment for LPS‐induced ALI. [ABSTRACT FROM AUTHOR]

Background and Aims: Add‐on devices have been widely used in clinical practice. The aim of this meta‐analysis was to compare the adenoma detection rate between Endocuff‐assisted colonoscopy (EAC) and cap‐assisted colonoscopy (CAC). Methods: PubMed, EMBASE, SCOPUS, and Cochrane databases were searched. Outcomes included adenoma detection rate, cecal intubation rate, cecal intubation time, and withdrawal time. Dichotomous data were pooled to obtain the odds ratio or risk ratio. Continuous data were pooled using the mean difference. Results: Of the 240 articles reviewed, six randomized controlled trials were included, with a total of 1994 patients. In the meta‐analysis, no statistical difference in adenoma detection rate was detected between EAC and CAC (47.0% vs 45.1%; P = 0.33). EAC significantly improved detection rate of diminutive adenomas/polyps compared with CAC (P = 0.01). Cecal intubation was achieved in 96.5% in EAC group and 97.9% in CAC group (P = 0.04). Besides, no statistical difference was found in cecal intubation time (P = 0.86), withdrawal time (P = 0.88), small adenomas/polyps (P = 0.60), or large adenomas/polyps (P = 0.95). Conclusion: EAC and CAC have their respective merits. EAC significantly improve the detection of diminutive adenomas/polyps. CAC was better in cecal intubation rate. [ABSTRACT FROM AUTHOR]

The placenta and umbilical cord are pre‐eminent candidate sources of mesenchymal stem cells (MSCs). However, placenta‐derived MSCs (P‐MSCs) showed greater proliferation capacity than umbilical cord‐derived MSCs (UC‐MSCs) in our study. We investigated the drivers of this proliferation difference and elucidated the mechanisms of proliferation regulation. Proteomic profiling and Gene Ontology (GO) functional enrichment were conducted to identify candidate proteins that may influence proliferation. Using lentiviral or small interfering RNA infection, we established overexpression and knockdown models and observed changes in cell proliferation to examine whether a relationship exists between the candidate proteins and proliferation capacity. Real‐time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence assays were conducted to elucidate the mechanisms underlying proliferation. Six candidate proteins were selected based on the results of proteomic profiling and GO functional enrichment. Through further validation, yes‐associated protein 1 (YAP1) and β‐catenin were confirmed to affect MSCs proliferation rates. YAP1 and β‐catenin showed increased nuclear colocalization during cell expansion. YAP1 overexpression significantly enhanced proliferation capacity and upregulated the expression of both β‐catenin and the transcriptional targets of Wnt signaling, CCND1, and c‐MYC, whereas silencing β‐catenin attenuated this influence. We found that YAP1 directly interacts with β‐catenin in the nucleus to form a transcriptional YAP/β‐catenin/TCF4 complex. Our study revealed that YAP1 and β‐catenin caused the different proliferation capacities of P‐MSCs and UC‐MSCs. Mechanism analysis showed that YAP1 stabilized the nuclear β‐catenin protein, and also triggered the Wnt/β‐catenin pathway, promoting proliferation. [ABSTRACT FROM AUTHOR]

Rhodopsin mutation and misfolding is a common cause of autosomal dominant retinitis pigmentosa (RP). Using a luciferase reporter assay, we undertook a small‐molecule high‐throughput screening (HTS) of 68, 979 compounds and identified nine compounds that selectively reduced the misfolded P23H rhodopsin without an effect on the wild type (WT) rhodopsin protein. Further, we found five of these compounds, including methotrexate (MTX), promoted P23H rhodopsin degradation that also cleared out other misfolded rhodopsin mutant proteins. We showed MTX increased P23H rhodopsin degradation via the lysosomal but not the proteasomal pathway. Importantly, one intravitreal injection (IVI) of 25 pmol MTX increased electroretinogram (ERG) response and rhodopsin level in the retinae of RhoP23H/+ knock‐in mice at 1 month of age. Additionally, four weekly IVIs increased the photoreceptor cell number in the retinae of RhoP23H/+ mice compared to vehicle control. Our study indicates a therapeutic potential of repurposing MTX for the treatment of rhodopsin‐associated RP. [ABSTRACT FROM AUTHOR]

Boron carbide and Tantalum boride composites were prepared by pressureless sintering of B4C with addition of TaC powder. The effect of TaC addition on the sinterability of boron carbide was studied. High densified ceramic with a relative density of 98.7% was obtained at sintering temperature of 2250°C. The composition and the microstructure of the dense composites are characterized by means of x‐ray diffraction (XRD), scanning electron microscopy (SEM), and energy‐dispersive x‐ray spectroscopy (EDX). The studies show that the composites contain boron carbide, TaB2, and carbon phases with a homogeneous structure. In addition, the correlation between the composition and the electrical conductivity was investigated. The electrical conductivity of the composite increased with increasing addition of TaC, and a change in conduction behavior from semiconducting to metallic was observed. High hardness value of 28.49 ± 1.33 GPa was obtained by the sample with 30 wt% TaC addition. [ABSTRACT FROM AUTHOR]

Combination cancer immunotherapy has shown promising potential for simultaneously eliciting antitumor immunity and modulating the immunosuppressive tumor microenvironment (ITM). However, combination immunotherapy with multiple regimens suffers from the varied chemo‐physical properties and inconsistent pharmacokinetic profiles of the different therapeutics. To achieve tumor‐specific codelivery of the immune modulators, an indocyanine green (ICG)‐templated self‐assembly strategy for preparing dual drug‐loaded two‐in‐one nanomedicine is reported. ICG‐templated self‐assembly of paclitaxel (PTX) nanoparticles (ISPN), and the application of ISPN for combination immunotherapy of the triple negative breast cancer (TNBC) are demonstrated. The ISPN show satisfied colloidal stability and high efficacy for tumor‐specific codelivery of ICG and PTX through the enhanced tumor permeability and retention effect. Upon laser irradiation, the ICG component of ISPN highly efficiently induces immunogenic cell death of the tumor cells via activating antitumor immune response through photodynamic therapy. Meanwhile, PTX delivered by ISPN suppresses the regulatory T lymphocytes (Tregs) to combat ITM. The combination treatment of TNBC with ISPN and αPD‐L1‐medaited immune checkpoint blockade therapy displays a synergistic effect on tumor regression, metastasis inhibition, and recurrence prevention. Overall, the ICG‐templated nanomedicine may represent a robust nanoplatform for combination immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: This meta‐analysis aimed to evaluate whether EndoCuff‐assisted colonoscopy (EAC) could improve adenoma detection rate (ADR) compared with standard colonoscopy (SC). Methods: PubMed, EMBASE, Scopus, Cochrane Library, and Google Scholar databases were searched for articles published up to March 2019. All pure randomized controlled trials comparing ADR between EAC and SC groups were included. Dichotomous data were pooled to obtain the odds ratio with a 95% confidence interval (CI), whereas continuous data were pooled using a mean difference with 95% CI. Review Manager Version 5.3 was used for data analysis. Results: Thirteen randomized controlled trials consisting of 9038 patients (EAC: 4574; SC: 4464) were included. The EAC group showed significant superiority over the SC group in ADR (odds ratio 1.37, 95% CI 1.15–1.62). However, there were no differences between the EAC and SC groups in adverse events, cecal intubation rate, and cecal intubation time. Conclusions: EAC could significantly improve ADR without increasing adverse events, especially for operators with low ADRs. In addition, no significant difference was observed in cecal intubation time and cecal intubation rate between EAC and SC. [ABSTRACT FROM AUTHOR]

Objective: Artificial ulcers after endoscopic submucosal dissection (ESD) are usually treated by proton pump inhibitors (PPIs) in clinical setting. Vonoprazan, a newly developed potassium‐competitive acid blocker, has recently been used to treat post‐ESD ulcers. We aimed to evaluate the efficacy and safety of vonoprazan on the healing of post‐ESD artificial ulcers compared with those of proton pump inhibitors (PPIs) using a meta‐analysis. Methods: EMBASE, MEDLINE, Scopus and Cochrane Library databases were searched for all studies comparing the efficacy and safety of vonoprazan with those of PPIs in the treatment of post‐ESD ulcers. Results: Fourteen articles with 1328 patients were included in this meta‐analysis. When comparing ulcer shrinkage rate, vonoprazan showed a better efficacy than PPIs (mean difference 0.56, 95% confidence interval [CI] 0.18‐0.93). Vonoprazan also led to a higher scar formation rate (odds ratio [OR] 1.58, 95% CI 1.00‐2.47) and showed a potential superiority on reducing the risk of post‐ESD bleeding compared with PPIs, with a pooled OR of 0.69, although there was no statistically significant difference. Conclusions: Compared with PPIs, vonoprazan showed a better efficacy in ulcer shrinkage rate and achieved more complete healing in the treatment of post‐ESD ulcers. Vonoprazan did not induce any incremental risk of post‐ESD bleeding as well. It may be an appropriate choice in the management of artificial ulcers after ESD. [ABSTRACT FROM AUTHOR]

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. However, the pathogenesis of psoriasis is multifactorial and is not fully understood. MicroRNAs (miRNAs) represent a promising class of small, noncoding RNA molecules that have a large impact on cellular functions by regulating gene expression. Here we reported that microRNA‐187 (miR‐187), which is one of the most dynamic microRNAs identified in the deep screening miRNAs profile, is downregulated in inflammatory cytokines‐stimulated keratinocytes and psoriatic skins. By luciferase activity assay and gain‐of‐function studies, we showed that miR‐187 inhibits keratinocytes hyperproliferation by targeting CD276. Moreover, overexpression of miR‐187 decreases acanthosis and reduces the disease severity in psoriasis mouse models. Taken together, the results of our study implies miR‐187 as a critical factor in psoriasis pathogenesis, which could be a potent target for psoriasis treatment. MicroRNA‐187, which is declined in the inflammatory cytokines‐stimulated keratinocytes and psoriatic skins, can contribute to keratinocytes hyperproliferation by promoting CD276‐STAT3 signaling. [ABSTRACT FROM AUTHOR]

SAPO‐11 catalysts are prepared by both solvent‐free and hydrothermal methods. SAPO‐11 samples prepared by the solvent‐free method have a higher density of acid sites compared with the samples obtained by the hydrothermal method. We performed 29Si NMR spectroscopy to determine the acid properties of the samples, and most Si species exist in the SAPO region. The SAPO‐11 materials were loaded with the noble metal Pt at a content of approximately 0.5 wt.‐%, and the bifunctional catalysts were applied in the hydroisomerization of n‐hexadecane. Remarkably, a higher catalytic activity and isomer yield were obtained for the catalyst synthesized by the solvent‐free method. In particular, the higher yield of multibranched isomers, including dibranched and tribranched isomers, can be ascribed to the lower nPt/nA ratio (an expression of the balance between metal and acid sites) accompanied by the longer residence of carbenium ions at the acid sites. The solvent‐free samples can produce isomer products with lower pour points and enhanced low‐temperature mobility. [ABSTRACT FROM AUTHOR]

Iron is essential for most living organisms. The iron‐regulated transporter1 (IRT1) plays a major role in iron uptake in roots, and its trafficking from endoplasmic reticulum (ER) to plasma membrane (PM) is tightly coordinated with changes in iron environment. However, studies on the IRT1 response are limited. Here, we report that Malus xiaojinesis IRT1 (MxIRT1) associates with detergent‐resistant membranes (DRMs, a biochemical counterpart of PM microdomains), whereas the PM microdomains are known platforms for signal transduction in the PM. Depending on the shift of MxIRT1 from microdomains to homogeneous regions in PM, MxIRT1‐mediated iron absorption is activated by the cholesterol recognition/interaction amino acid consensus (CRAC) motif of MxIRT1. MxIRT1 initially associates with DRMs in ER via its transmembrane domain 1 (TMD1), and thus begins DRMs‐dependent intracellular trafficking. Subsequently, MxIRT1 is sequestered in COPII vesicles via the ER export signal sequence in MxIRT1. These studies suggest that iron homeostasis is influenced by the CRAC motif and TMD1 domain due to their determination of MxIRT1‐DRMs association. [ABSTRACT FROM AUTHOR]

A reactive oxygen species (ROS)-activatable doxorubicin (Dox) prodrug vesicle (RADV) is presented for image-guided ultrafast drug release and local-regional therapy of the metastatic triple-negative breast cancer (TNBC). RADV is prepared by integrating a ROS-activatable Dox prodrug, a poly(ethylene glycol) (PEG)-modified photosensitizer pyropheophorbide-a, an unsaturated phospholipid 1,2-dioleoyl- sn-glycero-3-phosphocholine, and cholesterol into one single nanoplatform. RADV is of extremely high drug loading ratio (27.5 wt%) by self-assembly of the phospholipid-mimic Dox prodrug into the liposomal bilayer membrane. RADV displays good colloidal stability to prevent premature drug leakage during the blood circulation and inert photochemotoxicity to avoid nonspecific side effect. RADV passively accumulates at tumor site through the enhanced permeability and retention effect when administrated systemically. Once deposited at the tumor site, RADV generates fluorescent and photoacoustic signals to guide near-infrared (NIR) laser irradiation, which can induce localized ROS generation, not only to trigger prodrug activation and ultrafast drug release but also conduct photodynamic therapy in a spatiotemporally controlled manner. In combination with NIR laser irradiation, RADV efficiently inhibits the tumor growth and distant metastasis of TNBC. Local-regional tumor therapy using intelligent theranostic nanomedicine might provide an alternative option for highly efficient treatment of the metastatic TNBC. [ABSTRACT FROM AUTHOR]

Nanomedicine is a promising approach for combination chemotherapy of triple-negative breast cancer (TNBC). However, the therapeutic efficacy of nanoparticulate drugs is suppressed by a series of biological barriers. The authors herein present a programmed stimuli-responsive liposomal vesicle to overcome the sequential barriers for enhanced TNBC therapy. The intelligent vesicles are engineered by integrating an enzyme-cleavable polyethylene glycol (PEG) corona, a light-responsive photosensitizer pheophorbide a (PPa), and a temperature-sensitive liposome (TSL) into a single nanoplatform. The resultant enzyme, light, and temperature multisensitive liposome (ELTSL) is sequentially coloaded with a lipophilic oxaliplatin prodrug of hexadecyl-oxaliplatin carboxylic acid (HOC) and hydrophilic doxorubicin hydrochloride (DOX). Dual drug-loaded ELTSL displays enhanced tumor penetration and increased cellular uptake upon matrix metalloproteinase 2 mediated cleavage of the PEG corona. Under NIR laser irradiation, PPa induces mild hyperthermia effect to trigger ultrafast drug release in the tumor cells. In combination with PPa-mediated photodynamic therapy, HOC and DOX coloaded ELTSL show significantly improved antitumor efficacy than monotherapy. Given the clinically translatable potential of the liposomal vesicles, ELTSL might represent a promising nanoplatform for combination TNBC therapy. [ABSTRACT FROM AUTHOR]

Integration of chemotherapy with photodynamic therapy (PDT) has been emerging as a novel strategy for treatment of triple negative breast cancer (TNBC). However, the clinical translation of this approach is hindered by the unwanted dark toxicity due to the 'always-on' model and low tumor specificity of currently approved photosensitizer (PS). Here, the design of a multifunctional prodrug nanoparticle (NP) is described for precise imaging and organelle-specific combination cancer therapy. The prodrug NP is composed of a newly synthesized oxaliplatin prodrug, hexadecyl-oxaliplatin-trimethyleneamine (HOT), an acid-activatable PS, derivative of Chlorin e6 (AC), and functionalized with a targeting ligand iRGD for tumor homing and penetration. HOT displays much higher antitumor efficiency than oxaliplatin by simultaneously inducing mitochondria depolarizing and DNA cross-linking. AC is specifically activated in the orthotopic or metastatic TNBC tumor for fluorescence imaging and PDT, while it remains inert in blood circulation to minimize the dark toxicity. Under the guide of acid-activatable fluorescence imaging, PDT and chemotherapy can be synergistically performed for highly efficient regression of TNBC. Taken together, this versatile prodrug nanoplatform could achieve tumor-specific imaging and organelle-specific combination therapy, which can provide an alternative option for cancer theranostic. [ABSTRACT FROM AUTHOR]

The acquisition of multidrug resistance (MDR) is a major hurdle for the successful chemotherapy of tumors. Herein, a novel hybrid micelle with pH and near-infrared (NIR) light dual-responsive property is reported for reversing doxorubicin (DOX) resistance in breast cancer. The hybrid micelles are designed to integrate the pH- and NIR light-responsive property of an amphiphilic diblock polymer and the high DOX loading capacity of a polymeric prodrug into one single nanocomposite. At physiological condition (i.e., pH 7.4), the micelles form compact nanostructure with particle size around 30 nm to facilitate blood circulation and passive tumor targeting. Meanwhile, the micelles are quickly dissociated in weakly acidic environment (i.e., pH ≤ 6.2) to release DOX prodrug. When exposed to NIR laser irradiation, the hybrid micelles can trigger notable tumor penetration and cytosol release of DOX payload by inducing tunable hyperthermia effect. In combination with localized NIR laser irradiation, the hybrid micelles significantly inhibit the growth of DOX-resistant MCF-7/ADR breast cancer in an orthotopic tumor bearing mouse model. Taken together, this pH and NIR light-responsive micelles with hyperthermia-triggered tumor penetration and cytoplasm drug release can be an effective nanoplatform to combat cancer MDR. [ABSTRACT FROM AUTHOR]

The synthesis and production of thermoelectrical active ceramic materials, the concepts of the module design by simulation, the assembly of modules by laser joining, and the investigations concerning the operation modes are described in this paper. Investigations of the material structure, the phase composition, and the thermoelectrical properties illustrate the material development. The newly developed technological route is described. The simulated results of thermoelectric modules for operational cases are compared with gained experimental data. [ABSTRACT FROM AUTHOR]

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by autoantibodies against presynaptic voltage-gated calcium channels that impair neuromuscular transmission. Malignancies, especially small cell lung cancer (SCLC), have been associated with LEMS and account for approximately 60% of cases, making malignancy management a central step in LEMS therapy. In addition, immunosuppressive therapy is also recommended for symptomatic control. Interestingly, both pathological and epidemiological data suggest that the autoimmune response can inhibit progression of tumors in malignancy-associated LEMS. Thus, conventional broad-spectrum immunosuppressants may not be effective agents for treatment of LEMS, especially in those with malignancy-associated LEMS. Recent preclinical and clinical studies have indicated that proteasome inhibitors can eliminate antibody-producing cells efficiently, block dendritic cell maturation, and have anti-tumor activity. We hypothesize that proteasome inhibitors may be promising agents for treatment of malignancy-related LEMS. Muscle Nerve 49:325-328, 2014 [ABSTRACT FROM AUTHOR]

BACKGROUND: MicroRNAs (miRNAs) have been identified as important posttranscriptional regulators involved in various biological and pathological processes of cells, but their association with tumor chemoresistance has not been fully understood. METHODS: We detected miRNA-200b (miR-200b) expression in different lung adenocarcinoma cell lines and then focused on its roles in regulation of docetaxel chemoresistance. We also identified E2F3 as a novel target of miR-200b. RESULTS: Based on miRNA microarray data, miR-200b was identified as the most down-regulated miRNA in docetaxel-resistant SPC-A1/DTX cells compared with parental SPC-A1 cells. Ectopic miR-200b expression reversed docetaxel chemoresistance of lung adenocarcinoma cells through cell proliferation inhibition, apoptosis enhancement, and G2/M cell cycle arrest. In a nude mouse xenograft model, up-regulation of miR-200b significantly enhanced response of SPC-A1/DTX cells to docetaxel. Luciferase reporters containing the 3′ untranslated region sequence of E2F3 messenger RNA were used to demonstrate that miR-200b could directly target E2F3. Small interfering RNA-mediated E2F3 knockdown revealed similar effects as that of ectopic miR-200b expression. Decreased miR-200b expression was also detected in tumor tissues sampled from lung adenocarcinoma patients treated with docetaxel-based chemotherapy and was proved to be correlated with high expression of E2F3, decreased sensitivity to docetaxel, and poor prognosis. CONCLUSIONS: Our results suggest that down-regulation of miR-200b could lead to E2F3 overexpression and in turn contribute to chemoresistance of lung adenocarcinoma cells to docetaxel. Cancer 2011. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

The ubiquitin-proteasome pathway (UPP) has been indicated to contribute to dysfunction of endothelial cells (ECs). Nevertheless, the relationship between UPP and vascular complications of uraemia remains unknown. We aimed to determine whether the UPP is activated in vascular ECs when cultured with uraemic serum, and to examine the role of the UPP on dysfunction of ECs in uraemia. Rabbit aortic endothelial cells (RAECs) were cultured with normal serum or different concentrations of uraemic serum. The expression of the ubiquitin-activating enzyme (E1), an indicator of the UPP, was detected by real-time RT-PCR and Western blot; proteasome activity was determined by fluorescence spectrophotometry; and nuclear factor-κB (NF-κB) activity and expression, as well as tumour necrosis factor-α (TNF-α) expression, were also detected. We found that the expression of E1 and the activities of three kinds of proteasomes were increased significantly in RAECs after incubation with uraemic serum. Proliferation of RAECs was increased significantly by incubation with 3-15% uraemic serum but decreased markedly when incubated with uraemic serum above 15% (increased apoptosis). Incubation of RAECs with uraemic serum induced increased NF-κB DNA-binding activity and nuclear translocation of NF-κB, decreased nitric oxide production and increased expression of TNF-α, which is the final effector of inflammatory activation of cells. All of these responses in RAECs were suppressed by the specific proteasome inhibitor, MG132. The inhibition of inflammatory responses by MG132 was further supported by a parallel experiment with pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB. These findings suggest that the UPP was activated in RAECs by administration of uraemic serum, and played a pivotal role in the dysfunction of vascular ECs, such as inflammatory activation. [ABSTRACT FROM AUTHOR]

Docetaxel has been used as first-line chemotherapy in advanced non-small cell lung carcinoma (NSCLC), but further extensive and effective application is prevented by drug resistance. MicroRNAs (miRNAs) have recently been identified as important posttranscriptional regulators, which are involved in various biological processes. The aim of this study was to identify microRNA expression profiles involved in the development of docetaxel resistance in NSCLC. Here, microarray chip technology was employed to identify miRNA expression profiles in docetaxel-resistant human NSCLC cell line (SPC-A1/docetaxel). Then, the changes of miRNAs expression (>2-fold compared with control SPC-A1 cell line) were testified by quantitative real-time RT-PCR (qRT-PCR) assay. Furthermore, the potential target genes regulated by selected miRNAs were analysed by various target prediction tools. The expression of a total of 52 miRNAs showed significant difference between SPC-A1/docetaxel cells and control SPC-A1 cells ( P < 0.01). Six miRNAs (miR-192, 200b, 194, 424, 98 and 212) exhibited more than 2-fold changes in their expression levels, which were validated by qRT-PCR. The expression of three miRNAs (miR-200b, 194 and 212) was significantly down-regulated in SPC-A1/docetaxel cells, while the expression of other three miRNAs (miR-192, 424 and 98) was significantly up-regulated in SPC-A1/docetaxel cells ( P < 0.01). Potential target genes controlled by six selected miRNAs were divided into four groups according to various functions: apoptosis and proliferation (71 genes), cell cycle (68 genes), DNA damage (26 genes) and DNA repair (59 genes). The expression of a few target genes in SPC-A1/docetaxel and SPC-A1 cells were further confirmed by qRT-PCR and Western blot. Taken together, the identification of microRNA expression profiles in docetaxel-resistant NSCLC cells could provide a better understanding of mechanisms involved in drug sensitivity or resistance, which would be helpful to develop novel strategies for targeted therapies in chemorefractive NSCLC patients. [ABSTRACT FROM AUTHOR]

GLO:8DU/01jun20:cge13757-toc-0001.jpg PHOTO (COLOR): . gl Two previous studies link heterozygous germline variants in ribosomal protein S20 ( I RPS20 i , [OMIM: 603682]) to colorectal cancer (CRC). One I RPS20 i frameshift variant (c.147dupA) was reported to segregate with CRC in a large Finnish family.[1] Another I RPS20 i frameshift variant (c.181 182delTT) was identified in a single CRC case during whole exome sequencing of 863 CRC cases of European decent, and a predicted deleterious missense variant in I RPS20 i (c.160G>C, p.Val54Leu) was identified in a different CRC case from the same study.[2] Here we report a novel germline variant in the canonical splice donor dinucleotide of I RPS20 i intron 3 (c.177+1G>A). Predicted loss-of-function variants in I RPS20 i are rare, with only 11 instances observed in 134 187 subjects from the gnomAD v2.1 non-cancer database.[3] RT-PCR targeted to I RPS20 i c.177+1 confirms that the G>A variant interferes with splicing. [Extracted from the article]

Exosomes are small membrane vesicles 50‐150 nm in diameter released by a variety of cells, which contain miRNAs, mRNAs and proteins with the potential to regulate signalling pathways in recipient cells. Exosomes deliver nucleic acids and proteins to participate in orchestrating cell‐cell communication and microenvironment modulation. In this review, we summarize recent progress in our understanding of the role of exosomes in hepatocellular carcinoma (HCC). This review focuses on recent studies on HCC exosomes, considering biogenesis, cargo and their effects on the development and progression of HCC, including chemoresistance, epithelial‐mesenchymal transition, angiogenesis, metastasis and immune response. Finally, we discuss the clinical application of exosomes as a therapeutic agent for HCC. [ABSTRACT FROM AUTHOR]

In article 1703674, Siling Wang, Haijun Yu, Yaping Li, and co‐workers report a caged doxorubicin prodrug vesicle (RADV) for imaging‐guided cancer therapy. Near‐infrared light illumination generates reactive oxygen species that trigger prodrug activation and ultrafast drug release exactly at the tumor site, thus improving therapeutic efficacy while avoiding the side effects of chemotherapeutics. RADV might provide a novel theranostic nanoplatform for local‐regional management of cancer. [ABSTRACT FROM AUTHOR]

In article number 1606530, Haijun Yu, Yaping Li, and co‐workers present a clinically translatable multi‐responsive vesicle to overcome the sequential biological barriers for improved therapy of triple‐negative breast cancer (TNBC). The liposomal vesicles display multi‐stimuli sensitivity toward enzymes, light, and temperature, and can encapsulate both a hydrophobic drug and a hydrophilic drug, thereby presenting a novel nanoplatform for TNBC combination therapy. [ABSTRACT FROM AUTHOR]

On page 2489 H. Yu, Y. Li, and co‐workers report a pH and near‐infrared light responsive micelle for combating cancer multidrug resistance (MDR). The micelles induce moderate hyperthermia effect upon NIR laser illumination to facilitate their tumor penetration and lysosome escape, thus improving the therapeutic efficacy of doxorubicin. This study implies a novel strategy for treatment of MDR cancer. [ABSTRACT FROM AUTHOR]