bluuebunny/crossref_metadata_2025 huggingface dataset:
Silicone Substrate with Collagen and Carbon Nanotubes Exposed to Pulsed Current for MSC Osteodifferentiation
Authors: Jamal Daniyal , de Guzman Roche C.
Published: August 2017

Autologous human adipose tissue-derived mesenchymal stem cells (MSCs) have the potential for clinical translation through their induction into osteoblasts for regeneration. Bone healing can be driven by biophysical stimulation using electricity for activating quiescent adult stem cells. It is hypothesized that application of electric current will enhance their osteogenic differentiation, and addition of conductive carbon nanotubes (CNTs) to the cell substrate will provide increased efficiency in current transmission. Cultured MSCs were seeded and grown onto fabricated silicone-based composites containing collagen and CNT fibers. Chemical inducers, namely, glycerol phosphate, dexamethasone, and vitamin C, were then added to the medium, and pulsatile submilliampere electrical currents (about half mA for 5 cycles at 4 mHz, twice a week) were applied for two weeks. Calcium deposition indicative of MSC differentiation and osteoblastic activity was quantified through Alizarin Red S and spectroscopy. It was found that pulsed current significantly increased osteodifferentiation on silicone-collagen films without CNTs. Under no external current, the presence of 10% (m/m) CNTs led to a significant and almost triple upregulation of calcium deposition. Both CNTs and current parameters did not appear to be synergistic. These conditions of enhanced osteoblastic activities may further be explored ultimately towards future therapeutic use of MSCs.
Bimanual Microincision Cataract Surgery versus Coaxial Microincision Cataract Surgery: A Meta-Analysis of Randomized Controlled Trials and Cohort Studies
Authors: Fu Chenxi , Chu Naipin , Yu Xiaoning , Yao Ke
Published: August 2017

Purpose.This meta-analysis was conducted to compare the intraoperative and postoperative outcomes of bimanual microincision cataract surgery (B-MICS) and coaxial microincision cataract surgery (C-MICS).Methods.Three databases were searched for papers that compared B-MICS and C-MICS from inception to June 2016. The following intraoperative and postoperative outcomes were included in the final meta-analysis: ultrasound time (UST), effective phacoemulsification time (EPT), balanced salt solution use (BSS use), mean surgery time, best-corrected visual acuity (BCVA), central corneal thickness (CCT), and increased CCT.Results.There were no statistically significant differences in mean surgery time, UST, BSS use, BCVA, CCT, or increased CCT (one subgroup at postoperative day 7-8 and another subgroup at postoperative day 30). However, there was less EPT needed during surgery (p<0.01) and lower levels of increased CCT at postoperative day 1 (p=0.02) in the B-MICS group compared with the C-MICS group.Conclusions.The EPT was shorter and increased CCT was less at postoperative day 1 in the B-MICS group. There were no statistically significant differences in other intraoperative and postoperative outcomes between the B-MICS group and the C-MICS group. B-MICS is an efficient and safe cataract surgery procedure.
IL-25 Could Be Involved in the Development of Allergic Rhinitis Sensitized to House Dust Mite
Authors: Kim Dae Woo , Kim Dong-Kyu , Eun Kyoung Mi , Bae Jun-Sang , Chung Young-Jun , Xu Jun , Kim Yong Min , Mo Ji-Hun
Published: August 2017

Background and Purpose. When house dust mite (HDM), a common allergen, comes into the mucosal membrane, it may stimulate innate immunity. However, the precise role of interleukin- (IL-) 25 in the development of HDM-induced nasal allergic inflammation is still unclear. Therefore, we investigated the role of IL-25 in allergic rhinitis (AR) patients sensitized to HDM. Methods. To confirm the production of IL-25 in human nasal epithelial cells (HNECs), we stimulated HNECs. IL-25 expression in the nasal mucosa from control, non-AR (NAR) patients, and HDM-sensitized AR patients was assessed using immunohistochemistry, and quantitative reverse transcription PCR. Correlations between IL-25 and other inflammatory markers were explored. Results. An in vitro study showed significantly elevated concentrations of IL-25 in the HNEC samples with highest doses of HDM. Nasal tissues from AR patients sensitized to HDM showed significantly higher IL-25 expression, compared to those from the control or NAR patients. Moreover, the expression of IL-25 in nasal tissues from AR patients sensitized to HDM was positively associated with Th2 markers, such as ECP and GATA3. Conclusions. IL-25 expression increased with high-dose HDM stimulation and was related to Th2 markers. Therefore, IL-25 neutralization might offer a new strategy for treating patients with HDM-sensitized AR.
Odd Periodic Solutions of Fully Second-Order Ordinary Differential Equations with Superlinear Nonlinearities
Authors: Li Yongxiang , Guo Lanjun
Published: August 2017

This paper is concerned with the existence of periodic solutions for the fully second-order ordinary differential equation u′′(t)=ft,ut,u′t, t∈R, where the nonlinearity f:R3→R is continuous and f(t,x,y) is 2π-periodic in t. Under certain inequality conditions that f(t,x,y) may be superlinear growth on (x,y), an existence result of odd 2π-periodic solutions is obtained via Leray-Schauder fixed point theorem.
New Roles of the Primary Cilium in Autophagy
Authors: Ávalos Yenniffer , Peña-Oyarzun Daniel , Budini Mauricio , Morselli Eugenia , Criollo Alfredo
Published: August 2017

The primary cilium is a nonmotile organelle that emanates from the surface of multiple cell types and receives signals from the environment to regulate intracellular signaling pathways. The presence of cilia, as well as their length, is important for proper cell function; shortened, elongated, or absent cilia are associated with pathological conditions. Interestingly, it has recently been shown that the molecular machinery involved in autophagy, the process of recycling of intracellular material to maintain cellular and tissue homeostasis, participates in ciliogenesis. Cilium-dependent signaling is necessary for autophagosome formation and, conversely, autophagy regulates both ciliogenesis and cilium length by degrading specific ciliary proteins. Here, we will discuss the relationship that exists between the two processes at the cellular and molecular level, highlighting what is known about the effects of ciliary dysfunction in the control of energy homeostasis in some ciliopathies.
Effect of Weight Loss, Exercise, or Both on Undercarboxylated Osteocalcin and Insulin Secretion in Frail, Obese Older Adults
Authors: Colleluori Georgia , Napoli Nicola , Phadnis Uma , Armamento-Villareal Reina , Villareal Dennis T.
Published: August 2017

Background. Obesity exacerbates age‐related decline in glucometabolic control. Undercarboxylated osteocalcin (UcOC) regulates pancreatic insulin secretion. The long‐term effect of lifestyle interventions on UcOC and insulin secretion has not been investigated. Methods. One hundred seven frail, obese older adults were randomized into the control (N = 27), diet (N = 26), exercise (N = 26), and diet‐exercise (N = 28) groups for 1 year. Main outcomes included changes in UcOC and disposition index (DI). Results. UcOC increased in the diet group (36 ± 11.6%) but not in the other groups (P < 0.05 between groups). Although similar increases in DI occurred in the diet‐exercise and diet groups at 6 months, DI increased more in the diet‐exercise group (92.4 ± 11.4%) than in the diet group (61.9 ± 15.3%) at 12 months (P < 0.05). UcOC and body composition changes predicted DI variation in the diet group only (R2 = 0.712), while adipocytokines and physical function changes contributed to DI variation in both the diet (∆R2 = 0.140 and 0.107) and diet‐exercise (∆R2 = 0.427 and 0.243) groups (P < 0.05 for all). Conclusions. Diet, but not exercise or both, increases UcOC, whereas both diet and diet‐exercise increase DI. UcOC accounts for DI variation only during active weight loss, while adipocytokines and physical function contribute to diet‐exercise‐induced DI variation, highlighting different mechanisms for lifestyle‐induced improvements in insulin secretion. This trial was registered with ClinicalTrials.gov number NCT00146107.
Robust Output Synchronization of Arrays of Chaotic Sprott Circuits
Authors: Gonzalez Solis Ernesto V. , Rosas Almeida David I.
Published: August 2017

This article presents a technique for synchronizing arrays of a class of chaotic systems known as Sprott circuits. This technique can be applied to different topologies and is robust to parametric uncertainties caused by tolerances in the electronic components. The design of coupling signals is based on the definition of a set of functionals which depend on the errors between the outputs of the nodes and the errors between the output of a reference system and the outputs of the nodes. When there are no parametric uncertainties, we establish a criterion to design the coupling signals using only one state variable of each system. When the parametric uncertainties are present, we add a robust observer and a low pass filter to estimate the perturbation terms, which are subsequently compensated through the coupling signals, resulting in a robust closed loop system. The performance of the synchronization technique is illustrated by real-time simulations.
Towards a Biohybrid Lung: Endothelial Cells Promote Oxygen Transfer through Gas Permeable Membranes
Authors: Menzel Sarah , Finocchiaro Nicole , Donay Christine , Thiebes Anja Lena , Hesselmann Felix , Arens Jutta , Djeljadini Suzana , Wessling Matthias , Schmitz-Rode Thomas , Jockenhoevel Stefan , Cornelissen Christian Gabriel
Published: August 2017

In patients with respiratory failure, extracorporeal lung support can ensure the vital gas exchange via gas permeable membranes but its application is restricted by limited long-term stability and hemocompatibility of the gas permeable membranes, which are in contact with the blood. Endothelial cells lining these membranes promise physiological hemocompatibility and should enable prolonged application. However, the endothelial cells increase the diffusion barrier of the blood-gas interface and thus affect gas transfer. In this study, we evaluated how the endothelial cells affect the gas exchange to optimize performance while maintaining an integral cell layer. Human umbilical vein endothelial cells were seeded on gas permeable cell culture membranes and cultivated in a custom-made bioreactor. Oxygen transfer rates of blank and endothelialized membranes in endothelial culture medium were determined. Cell morphology was assessed by microscopy and immunohistochemistry. Both setups provided oxygenation of the test fluid featuring small standard deviations of the measurements. Throughout the measuring range, the endothelial cells seem to promote gas transfer to a certain extent exceeding the blank membranes gas transfer performance by up to 120%. Although the underlying principles hereof still need to be clarified, the results represent a significant step towards the development of a biohybrid lung.
On 2‐Absorbing Primary Fuzzy Ideals of Commutative Rings
Authors: Sönmez Deniz , Yeşilot Gürsel , Onar Serkan , Ersoy Bayram Ali , Davvaz Bijan
Published: August 2017

In this work, we give a characterization of generalizations of prime and primary fuzzy ideals by introducing 2‐absorbing fuzzy ideals and 2‐absorbing primary fuzzy ideals and establish relations between 2‐absorbing (primary) fuzzy ideals and 2‐absorbing (primary) ideals. Furthermore, we give some fundamental results concerning these notions.
Evaluation of Mechanical Properties and Marginal Fit of Crowns Fabricated Using Commercially Pure Titanium and FUS-Invest
Authors: Wu Jinshuang , Wang Xianli , Xing Helin , Guo Tianwen , Dong Chaofang , Yang Sefei
Published: August 2017

This study investigated the mechanical properties and single crown accuracy of the tailor-made Fourth University Stomatology investment (FUS-invest) for casting titanium. Background. Current investment for casting titanium is not optimal for obtaining high-quality castings, and the commercially available titanium investment is costly. Methods. Titanium specimens were cast using the tailor-made FUS-invest. The mechanical properties were tested using a universal testing machine. Fractured castings were characterized by energy-dispersive spectroscopy. 19 titanium crowns were produced using FUS-invest and another 19 by Symbion. The accuracy of crowns was evaluated. Results. The mechanical properties of the titanium cast by FUS-invest were elastic modulus 125.6 ± 8.8 GPa, yield strength 567.5 ± 11.1 MPa, tensile strength 671.2 ± 15.6 MPa, and elongation 4.6 ± 0.2%. For marginal fit, no significant difference (P>0.05) was found at four marker points of each group. For internal fit, no significant difference (P>0.05) was found between two groups, whereas significant difference (P<0.01) was found at different mark point of each group. Conclusions. The mechanical properties of titanium casted using FUS-invest fulfilled the ISO 9693 criteria. The marginal and internal fit of the titanium crowns using either the FUS-invest or Symbion were similar.
In Situ SEM Torsion Test of Metallic Glass Microwires Based on Micro Robotic Manipulation
Authors: Jiang Chenchen , Lu Haojian , Cao Ke , Wan Wenfeng , Shen Yajing , Lu Yang
Published: August 2017

Microwires, such as metallic, semiconductor, and polymer microwires and carbon fibers, have stimulated great interest due to their importance in various structural and functional applications. Particularly, metallic glass (MG) microwires, because of their amorphous atoms arrangement, have some unique mechanical properties compared with traditional metals. Despite the fact that substantial research efforts have been made on the mechanical characterizations of metallic glass microwires under tension or flexural bending, the mechanical properties of microwires under torsional loading have not been well studied, mainly due to the experimental difficulties, such as the detection of torsion angle, quantitative measurement of the torsional load, and the alignment between the specimen and torque meter. In this work, we implemented the in situ SEM torsion tests of individual La50Al30Ni20 metallic glass (MG) microwires successfully based on a self-developed micro robotic mechanical testing system. Unprecedented details, such as the revolving vein-pattern along the torsion direction on MG microwires fracture surface, were revealed. Our platform could provide critical insights into understanding the deformation mechanisms of other microwires under torsional loading and can even be further used for robotic micromanufacturing.
Expression Profiling of Cellular MicroRNA in Asymptomatic HBsAg Carriers and Chronic Hepatitis B Patients
Authors: Hou Xianliang , Liang Yan , Chen Jianing , Wei Yingfeng , Zeng Ping , Wang Lin , Lu Chong , Diao Hongyan
Published: August 2017

Background. MicroRNAs (miRNAs) may serve as potential molecular markers to predict liver injury resulting from chronic hepatitis B (CHB). In the present study, we want to study the expression profile and clinical significance of miRNAs at different stages of CHB virus infection. Methods. Using miRNA microarray, we investigated the global expression profiles of cellular miRNA in asymptomatic hepatitis B antigen carriers (ASCs) and CHB patients, compared with healthy controls (HCs). Results. We identified 79 and 203 differentially expressed miRNAs in the peripheral blood mononuclear cells of ASCs and CHB patients compared to HCs, respectively. Some of these miRNAs were common to ASCs and CHB patients, but another set of miRNAs that showed differential expression between ASCs and CHB patients was also identified. Gene ontology and pathway enrichment analysis showed that the target genes of the identified miRNAs played a role in important biological functions, such as learning or memory, cell-cell adherens junction, ion channel inhibitor activity, TGF-beta signaling pathway, and p53 signaling pathway. Conclusion. We identified some significant differentially expressed miRNA in different phases of HBV infection, which might serve as biomarkers or therapeutic targets in the future.
Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid-Loaded Nanoparticles
Authors: Machado-Pereira Marta , Santos Tiago , Ferreira Lino , Bernardino Liliana , Ferreira Raquel
Published: August 2017

Inflammatory mechanisms triggered by microglial cells are involved in the pathophysiology of several brain disorders, hindering repair. Herein, we propose the use of retinoic acid-loaded polymeric nanoparticles (RA-NP) as a means to modulate microglia response towards an anti-inflammatory and neuroprotective phenotype (M2). RA-NP were first confirmed to be internalized by N9 microglial cells; nanoparticles did not affect cell survival at concentrations below 100 μg/mL. Then, immunocytochemical studies were performed to assess the expression of pro- and anti-inflammatory mediators. Our results show that RA-NP inhibited LPS-induced release of nitric oxide and the expression of inducible nitric oxide synthase and promoted arginase-1 and interleukin-4 production. Additionally, RA-NP induced a ramified microglia morphology (indicative of M2 state), promoting tissue viability, particularly neuronal survival, and restored the expression of postsynaptic protein-95 in organotypic hippocampal slice cultures exposed to an inflammatory challenge. RA-NP also proved to be more efficient than the free equivalent RA concentration. Altogether, our data indicate that RA-NP may be envisioned as a promising therapeutic agent for brain inflammatory diseases.
Physiotherapy and Rehabilitation in a Child with Joubert Syndrome
Authors: İpek Özge , Akyolcu Özge , Bayar Banu
Published: August 2017

Objective. Joubert syndrome (JS) is a rare autosomal recessive genetic disorder characterized by brain malformation, hypotonia, breathing abnormalities, ataxia, oculomotor apraxia, and developmental delay. The purpose of this study was to report the efficiency of the physiotherapy and rehabilitation program in a child with JS.Materials and Methods.Our case is a 19-month-old female child with mild clinical signs of JS. The pretreatment and posttreatment motor functioning level of the case was evaluated through the Gross Motor Function Measure (GMFM), whereas the independence level was evaluated through the Pediatric Functional Independence Measure (WeeFIM). The case was included in the rehabilitation program by the physiotherapist for one hour for five days a week throughout the period of 13 months in accordance with the neurodevelopmental treatment principles.Results.The case was able to turn around from the supine position to the reverse direction by oneself, and she was able to rise on her forearms facedown and was able to sit, crawl, and walk independently. The GMFM score was 210, whereas WeeFIM score was 65.Discussion. In the direction of those findings, in Joubert Syndrome, physiotherapy and rehabilitation can be effective in coping with the symptoms causing developmental delay.
Sporotrichoid-Like Spread of Cutaneous Mycobacterium chelonae in an Immunocompromised Patient
Authors: Kemp Daria Marley , Govind Anusha G. , Kang Jun , Brugger Caroline C. , Kauh Young C.
Published: August 2017

Mycobacterium chelonae is a rapidly growing mycobacterium found in water and soil that can cause local cutaneous infections in immunocompetent hosts but more frequently affects immunocompromised patients. Typically, patients will present with painful subcutaneous nodules of the joints or soft tissues from traumatic inoculation. However, exhibiting a sporotrichoid-like pattern of these nodules is uncommon. Herein, we report a case of sporotrichoid-like distribution of cutaneous Mycobacterium chelonae in a patient with systemic lupus erythematosus on significant immunosuppressive medications. Clinicians treating immunocompromised patients should be cognizant of their propensity to develop unusual infections and atypical presentations.
Triple Synchronous Primary Neoplasms of the Cervix, Endometrium, and Ovary: A Rare Case Report and Summary of All the English PubMed-Indexed Literature
Authors: Abu-Zaid Ahmed , Alsabban Mohannad , Abuzaid Mohammed , Alomar Osama , Salem Hany , Al-Badawi Ismail A.
Published: August 2017

The incidence rate of triple or more synchronous primary neoplasms of the female genital system is exceedingly uncommon. To the best of our knowledge, only 13 such cases have been reported in the PubMed-indexed English literature. Herein, we report a single case of triple synchronous primary neoplasms of the cervix, endometrium, and left ovary with three distinct histological patterns that were not reported previously. Moreover, we briefly present a summary table of all the English PubMed-indexed cases of triple or more synchronous primary neoplasms of the female genital system (n=13).
Vasectomy and Risk of Prostate Cancer in a Screening Trial
Authors: Shoag Jonathan , Savenkov Oleksander , Christos Paul J. , Mittal Sameer , Halpern Joshua A. , Askin Gulce , Shoag Daniel , Golan Ron , Lee Daniel J. , O'Malley Padraic , Najari Bobby , Eisner Brian , Hu Jim C. , Scherr Douglas , Schlegel Peter , Barbieri Christopher E.
Published: August 2017

Background: Vasectomy has been implicated as a risk factor for prostate cancer in multiple epidemiologic studies over the past 25 years. Whether this relationship is causal remains unclear. This study examines the association between vasectomy and prostate cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which randomized men to usual care or annual prostate cancer screening.

Methods: We performed a retrospective analysis of 13-year screening and outcomes data from the PLCO trial. Multivariable Cox proportional hazards regression stratified by study arm and age at vasectomy was performed.

Results: There was an increased risk of prostate cancer in men who had undergone a vasectomy and were randomized to the usual care arm of the study (adjusted HR, 1.11; 95% confidence interval, 1.03–1.20; P = 0.008). There was no association between vasectomy and diagnosis of prostate cancer in men randomized to the prostate cancer screening arm. Only men undergoing vasectomy at an older age in the usual care arm of the study, but not the prostate cancer screening arm, were at increased risk of being diagnosed with prostate cancer.

Conclusions: Vasectomy was not associated with prostate cancer risk among men who were screened for prostate cancer as part of a clinical trial, but was associated with prostate cancer detection in men receiving usual care.

Impact: The positive association between vasectomy and prostate cancer is likely related to increased detection of prostate cancer based on patterns of care rather than a biological effect of vasectomy on prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(11); 1653–9. ©2017 AACR.
Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations
Authors: Cook Michael B. , Stanczyk Frank Z. , Wood Shannon N. , Pfeiffer Ruth M. , Hafi Muhannad , Veneroso Carmela C. , Lynch Barlow , Falk Roni T. , Zhou Cindy Ke , Niwa Shelley , Emanuel Eric , Gao Yu-Tang , Hemstreet George P. , Zolfghari Ladan , Carroll Peter R. , Manyak Michael J. , Sesterhann Isabell A. , Levine Paul H. , Hsing Ann W.
Published: August 2017

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.

Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.

Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.

Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.

Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.
Cell-Free Circulating DNA Integrity Based on Peripheral Blood as a Biomarker for Diagnosis of Cancer: A Systematic Review
Authors: Cheng Jie , Tang Qiuqiong , Cao Xue , Burwinkel Barbara
Published: August 2017

Background: Cell-free DNA integrity (cfDI) has been identified as a potential diagnostic biomarker for different types of cancer, suggesting the importance of liquid biopsy.

Methods: This systematic review aims to assess the diagnostic performance of cfDI in cancer. After an extensive search of literature published through February 28, 2017, 25 articles that included 40 studies were identified. The descriptions of all the studies were analyzed. The sensitivity, specificity, positive and negative likelihood ratios, diagnostic ORs, weighted symmetric summary receiver operating characteristic curve, and the area under the curve (AUC) of cfDI in these studies were calculated.

Results: Aberrant results of cfDI were observed. Some studies observed an increased cfDI in cancer patients, while some studies confirmed a decreased cfDI compared with healthy or benign controls.

Conclusions: This review suggests that cfDI is controversial as a blood-based biomarker of cancers, although the sensitivity and AUC were relatively high.

Impact: cfDI shows heterogeneity between different studies; more perspective studies are needed to further assess its diagnostic performance, especially with other markers in combination. Cancer Epidemiol Biomarkers Prev; 26(11); 1595–602. ©2017 AACR.
Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy
Authors: Kong Yan , Sheng Xinan , Wu Xiaowen , Yan Junya , Ma Meng , Yu Jiayi , Si Lu , Chi Zhihong , Cui Chuanliang , Dai Jie , Li Yiqian , Yu Huan , Xu Tianxiao , Tang Huan , Tang Bixia , Mao Lili , Lian Bin , Wang Xuan , Yan Xieqiao , Li Siming , Guo Jun
Published: August 2017

Purpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma.

Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated.

Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss.

Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946–57. ©2017 AACR.
HPMA–Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer
Authors: Zimel Melissa N. , Horowitz Chloe B. , Rajasekhar Vinagolu K. , Christ Alexander B. , Wei Xin , Wu Jianbo , Wojnarowicz Paulina M. , Wang Dong , Goldring Steven R. , Purdue P. Edward , Healey John H.
Published: August 2017

Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701–10. ©2017 AACR.
Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance
Authors: Emdal Kristina B. , Dittmann Antje , Reddy Raven J. , Lescarbeau Rebecca S. , Moores Sheri L. , Laquerre Sylvie , White Forest M.
Published: August 2017

Approximately 10% of non–small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry–based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy-resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third-generation EGFR-inhibitor, osimertinib, or the novel dual-targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine-phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase (SFK) substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as SFK signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro. This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages. Mol Cancer Ther; 16(11); 2572–85. ©2017 AACR.
Itolizumab – A New Biologic for Management of Psoriasis and Psoriatic Arthritis
Authors: Pai Ganesh , Pai Anusha H.
Published: August 2017

Psoriasis is a chronic, relapsing, inflammatory, immune-mediated systemic disease with mainly skin and joint manifestations. The available treatment options to cure psoriasis include topical therapy, phototherapy, and biological therapy. Biological therapy has become a promising option due to the rapid action and less adverse effects associated with its use. The newly developed biologic itolizumab is a humanized recombinant anti-CD6 monoclonal antibody of IgG1 isotype that binds to domain 1 of CD6, thereby immunomodulating human lymphocytes without interfering with the binding of CD6 to the activated leukocyte-cell adhesion molecule. In this case series, a total of 5 patients with chronic plaque psoriasis were treated with itolizumab. They exhibited a rapid PASI 75 response after 4 doses of itolizumab infusion. The patients were poor responders to methotrexate and/or cyclosporine therapy for a long time. All infusions were well tolerated by all patients with no adverse reactions or infections during the treatment period. Itolizumab can be a good option for management of psoriasis and psoriatic arthritis.
Preoperative Diagnosis of Intestinal Endometriosis by Magnifying Colonoscopy and Target Biopsy
Authors: Tomiguchi Jun , Miyamoto Hideaki , Ozono Kazutaka , Gushima Ryosuke , Shono Takashi , Naoe Hideaki , Tanaka Motohiko , Baba Hideo , Katabuchi Hidetaka , Sasaki Yutaka
Published: August 2017

Endometriosis can affect any portion of the gastrointestinal tract. A preoperative definitive diagnosis of intestinal endometriosis is difficult, because there is no characteristic endoscopic finding and the endoscopic biopsies usually sample insufficient endometrial tissue for pathologic diagnosis. To our knowledge, the magnifying endoscopic features of intestinal mucosal endometriosis have not been well documented. In this study, we report a case of intestinal endometriosis diagnosed preoperatively by magnifying image-enhanced colonoscopy and target biopsy. A 45-year-old woman was referred to our hospital with abdominal pain in the left lower quadrant. Colonoscopy showed a submucosal tumor-like lesion of approximately 30 mm in diameter exhibiting surface reddening and granular changes in the sigmoid colon. Magnifying endoscopy revealed sparsely distributed round pits in the granules. The mucosal biopsy specimen from the granule provided the diagnosis of intestinal endometriosis. Segmental sigmoidectomy was performed, and pathological examination revealed that the surface colonic mucosa was partially replaced by endometrial tissue, which accounted for the granular change detected in the colonoscopy. It can be speculated that the round pit might reflect the endometrial glands surrounded by endometrial stroma. This case illustrated the characteristic finding and utility of magnifying endoscopy for mucosal intestinal endometriosis.
Extrascleral Tumor Extension Associated with Localized Scleral Melt following Plaque Brachytherapy for Uveal Melanoma: Clinical and Histologic Findings
Authors: Pham Chau M. , Couch Steven M. , Harocopos George J.
Published: August 2017

Background/Aims: Our study aims to better characterize the clinical and histopathologic features of eyes with extrascleral uveal melanoma associated with scleral melt following brachytherapy. Methods: A retrospective review was performed on patients who had undergone 125I (iodine-125) brachytherapy for uveal melanoma at our institution between 1992 and 2015. Patients with postradiation scleral necrosis who required enucleation were identified, and an analysis including a review of histopathology results was performed on those cases. Results: A total of 301 patients underwent plaque brachytherapy for uveal melanoma, of whom 31 required eventual enucleation. The histologic analysis showed extraocular extension through full-thickness scleral discontinuities in 6 cases. All but 1 (5 of 6) of these eyes exhibited either mitotic figures or Ki-67 positivity. Mitotic figures were noted in 4 specimens, including 3 eyes exhibiting mitoses within or adjacent to the extrascleral portion of the tumor. Two eyes exhibiting mitoses, as well as the case with Ki-67 positivity, also had clinical evidence of tumor regrowth. Conclusion: We found evidence of mitotic activity at the area of scleral discontinuity in some eyes with and in some without clinical evidence of tumor regrowth. Protruding pigmented material in areas of scleral necrosis after plaque brachytherapy may represent actively proliferating tumors even without internal evidence of tumor regrowth.
Multimodal Therapy for Non-Superacute Vertebral Basilar Artery Occlusion
Authors: He Xiongjun , Zhang Liang , Yang Juan , Zheng Hui , Li Kaifeng , Liu Yajie
Published: August 2017

Objective: The aim of this study was to evaluate the feasibility and safety of multimodal therapy for patients with non-superacute vertebral basilar artery occlusion. Method: We performed a retrospective analysis of multimodal therapy for patients with vertebral basilar artery occlusion. All patients who were beyond the time window to receive intravenous thrombolysis and who had deterioration of symptoms after drug treatment received small-balloon dilatation of the occlusive artery to estimate vascular occlusion aetiology. Thrombectomy with a Solitaire AB system was applied to the thrombus, and angioplasty with intracranial stents was used to treat stenosis. During the 3-month follow-up, National Institute of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) scores were recorded regularly. Results: We included 12 patients with a mean age of 60.4 (SD: 12.9) years. The average score on the NIHSS was 16.6 (SD: 11.6), and the average time from onset to admission was 95 h (SD: 121). The arteries were recanalized for all patients, but the degree of residual stenosis in the parent artery was 17.5% (SD: 20.1). During the follow-up period, one patient died of pulmonary haemorrhage and infection, and another patient died from haemorrhage related to high perfusion. After 3 months of follow-up, the 10 surviving patients showed an average NIHSS score of 7.9 (SD: 8.7) and an average mRS score below 2 (1.3 ± 1.4). Conclusion: For patients with posterior circulation stroke due to basilar artery or vertebral artery occlusion who present to the hospital 6 h after symptom onset and who exhibit deterioration of symptoms after drug treatment, multimodal recanalization of the occluded artery may be a feasible and safe therapy.
Acute-on-Chronic Liver Failure: A Portuguese Single-Center Reference Review
Authors: Verdelho Miguel , Perdigoto Rui , Machado João , Mateus Élia , Marcelino Paulo , Pereira Rui , Fortuna Philip , Bagulho Luís , Bento Luís , Ribeiro Francisco , Nolasco Fernando , Martins Américo , Barroso Eduardo
Published: August 2017

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by an acute deterioration of a patient with cirrhosis, frequently associated with multi-organ failure and a high short-term mortality rate. We present a retrospective study that aims to characterize the presentation, evolution, and outcome of patients diagnosed with ACLF at our center over the last 3 years, with a comparative analysis between the group of patients that had ACLF precipitated by infectious insults of bacterial origin and the group of those with ACLF triggered by a nonbacterial infectious insult; the incidence of acute kidney injury and its impact on the prognosis of ACLF was also analyzed. Twenty-nine patients were enrolled, the majority of them being male (89.6%), and the mean age was 53 years. Fourteen patients (48.3%) developed ACLF due to a bacterial infectious event, and 9 of them died (64.2%, overall mortality rate 31%); however, no statistical significance was found (p < 0.7). Of the remaining 15 patients (51.7%) with noninfectious triggers, 11 died (73.3%, overall mortality rate 37.9%); again there was no statistical significance (p < 0.7). Twenty-four patients (83%) developed acute kidney injury (overall mortality rate 65.5%; p < 0.022) at the 28-day and 90-day follow-up. Twelve patients had acute kidney injury requiring renal replacement therapy (41.37%; overall mortality rate 37.9%; p < 0.043). Hepatic transplant was performed in 3 patients, with a 100% survival at the 28-day and 90-day follow-up (p < 0.023). Higher grades of ACLF were associated with increased mortality (p < 0.02; overall mortality 69%). Conclusions: ACLF is a heterogeneous syndrome with a variety of precipitant factors and different grades of extrahepatic involvement. Most cases will have some degree of renal dysfunction, with an increased risk of mortality. Hepatic transplant is an efficient form of therapy for this syndrome.
Dermoscopic Features of Subungual Squamous Cell Carcinoma: A Study of 44 Cases
Authors: Teysseire Sandra , Dalle Stephane , Duru Gerard , Phan Alice , Debarbieux Sebastien , Poulhalon Nicolas , Thomas Luc
Published: August 2017

Background: Subungual squamous cell carcinoma (SSCC) is the most frequent tumor of the nail apparatus. Its diagnosis is often missed or delayed because the clinical presentation is atypical and can mimic other conditions. Accurate diagnosis can only be made by performing an appropriate surgical biopsy, but biopsy is painful and often leaves definitive dystrophic scars. The use of dermoscopy, a noninvasive technique, has been described to be useful for the preoperative evaluation of nail diseases. Objectives: To define the different clinical and dermoscopic presentations of SSCC and to compare them with onychomatricoma-associated clinical and dermoscopic features published in our previous study. Methods: A retrospective review of 44 cases of SSCC seen in our institution over an 8-year period. Six observers scored 19 clinical criteria and 14 dermoscopic criteria as present or absent. Then, we compared those data to a previously published study about the preoperative diagnosis of onychomatricoma. Results: Only 1 dermoscopic criterion was significantly associated with SSCC compared to onychomatricoma: localized hyperkeratosis (odds ratio, OR = 6.25, p = 0.012, 95% confidence interval CI = 1.50-26.01). In contrast, parallel edges (OR = 0.03, p < 0,001, 95% CI = 0.003-0.20) and sharp demarcation of the lesion (OR = 0.24, p = 0.004, 95% CI = 0.09-0.63) can statistically significantly be considered as in favor of onychomatricoma. By contrast, we believe that the presence of unparalleled lateral edges of the nail lesion or of fuzzy edges are more in favor of SSCC. Conclusions: Dermoscopy of the nail plate and of the nail free edge in SSCC provides useful information in order to better select cases to be submitted to biopsy.
Clinical Utility of Endometrial Cell Block Cytology in Postmenopausal Women
Authors: Nishida Naoyo , Murakami Fumihiro , Kuroda Aki , Sakamoto Yoshitaka , Tasaki Kazuto , Tasaki Shingo , Shimomura Takuya
Published: August 2017

Objective: To investigate the diagnostic utility of endometrial (EM) cell block (CB) cytology for the detection of intrauterine malignancy in postmenopausal women. Methods: We reviewed the medical records of 104 postmenopausal women between January 2012 and November 2014. We reviewed symptoms upon admission, body mass index, parity, transvaginal ultrasonographic findings, and histopathological results based on CB and conventional cytology. Results: The mean age was 62.6 (range 48-95) years. The mean menopausal age was 50.8 years and the mean duration of menopause was 12.0 years. The sensitivity of CB and conventional cytology was 82.3% (29/35) and 85.7% (30/35) and the specificity was 98.6% (68/69) and 94.2% (65/69), respectively. The sensitivity and specificity of CB cytology combined with conventional cytology were 82.3% (29/35) and 94.2% (65/69), respectively. The predictive values for EM hyperplasia and type-II carcinoma were 100 and 85.7%, respectively. Conclusion: CB cytology provides specimens for examination in a single outpatient session. Additionally, immunohistochemical staining can provide useful information for histological diagnosis. A combination of CB and conventional cytology can improve the diagnostic accuracy of EM lesions and may be a valid method for screening in postmenopausal women.
Screening for Sex Chromosome Aneuploidy by Cell-Free DNA Testing: Patient Choice and Performance
Authors: Bevilacqua Elisa , Ordóñez Elena , Hurtado Ivan , Rueda Laura , Mazzone Eléonora , Cirigliano Vincenzo , Jani Jacques C.
Published: August 2017

Objective: To study patient choice regarding testing for sex chromosome aneuploidy (SCA) and the performance of cell-free DNA (cfDNA) screening for SCA. Methods: Patient choice regarding screening for SCA and factors influencing this choice were evaluated in a single center. In a subsequent two-center study, cases that screened positive for SCA were analyzed to determine the positive predictive value (PPV) for each SCA. Results: In all, 1,957 (61.9%) of the 3,162 patients undergoing cfDNA testing opted for SCA screening. Regression analysis demonstrated that independent predictors of a patient's decision for SCA were earlier gestational age, spontaneous conception, and cfDNA chosen as a primary method of screening. A total of 161 cases screened positive for SCA and follow-up data were available for 118 (73.3%). Forty-six of the 61 cases of 45,X were false-positive results and 15 were concordant with the fetal karyotype (PPV = 24.6%). Seventeen of the 22 cases of 47,XXX were false positive and 5 concordant (PPV = 22.7%). Eleven of the 30 cases of 47,XXY were false positive and 19 concordant (PPV = 63.3%). All 5 cases of 47,XYY were correctly identified, thus yielding a PPV of 100%. Conclusion: More than half of the patients undergoing cfDNA aneuploidy screening also opted for SCA testing, but they were less likely to do so in the presence of an increased risk of trisomy. SCAs involving the X chromosome had a lower PPV than those involving the Y chromosome.