bluuebunny/crossref_metadata_2025 huggingface dataset:
Image‐Based Concrete Crack Detection Using Convolutional Neural Network and Exhaustive Search Technique
Authors: Li Shengyuan , Zhao Xuefeng
Published: April 2019

Crack detection is important for the inspection and evaluation during the maintenance of concrete structures. However, conventional image‐based methods need extract crack features using complex image preprocessing techniques, so it can lead to challenges when concrete surface contains various types of noise due to extensively varying real‐world situations such as thin cracks, rough surface, shadows, etc. To overcome these challenges, this paper proposes an image‐based crack detection method using a deep convolutional neural network (CNN). A CNN is designed through modifying AlexNet and then trained and validated using a built database with 60000 images. Through comparing validation accuracy under different base learning rates, 0.01 was chosen as the best base learning rate with the highest validation accuracy of 99.06%, and its training result is used in the following testing process. The robustness and adaptability of the trained CNN are tested on 205 images with 3120 × 4160 pixel resolutions which were not used for training and validation. The trained CNN is integrated into a smartphone application to mobile more public to detect cracks in practice. The results confirm that the proposed method can indeed detect cracks in images from real concrete surfaces.
TRPV1 Induced Apoptosis of Colorectal Cancer Cells by Activating Calcineurin-NFAT2-p53 Signaling Pathway
Authors: Hou Nengyi , He Xuelai , Yang Yuhui , Fu Junwen , Zhang Wei , Guo Zhiyi , Hu Yang , Liang Liqin , Xie Wei , Xiong Haibo , Wang Kang , Pang Minghui
Published: April 2019

Background/Aims. TRPV1 is a nonselective Ca2+ channel which has recently been observed in many cancers, while its effect on cell proliferation, apoptosis, metabolism, and cancer development in colorectal cancer (CRC) is still unclear. In this study, we hypothesized that TRPV1 is a tumor suppressor in CRC development as well as the underlying mechanism. Methods. Immunohistochemistry assay was applied to detect the expression of TRPV1 protein in CRC tissues. HCT116 cell proliferation and apoptosis were measured by CCK-8 and flow cytometry, respectively. Cellular Ca2+ concentration was measured by Fluo-4/AM-based flow cytometer. Apoptosis-related proteins were measured by Western blotting. Results. In this study, we found that TRPV1 expression was significantly decreased in CRC tissues, compared with CRC-adjacent tissues and normal tissues, respectively. Then, we found that the TRVP1 agonist capsaicin treatment inhibited CRC growth and induced apoptosis by activating P53. Subsequent mechanistic study revealed that the TRPV1 induced cytosolic Ca2+ influx to regulate cell apoptosis and p53 activation through calcineurin. Conclusions. This study suggests that TRPV1 served as a tumor suppressor in CRC and contributed to the development of novel therapy of CRC.
May-Thurner Syndrome with Large Abdominal Varicosity, Treated Successfully Using Multiple Approaches
Authors: Jia Lori , Alexander Jason , Skeik Nedaa
Published: April 2019

May-Thurner syndrome (MTS) is a venous outflow obstruction disorder characterized by compression of the left common iliac vein by an overriding right common iliac artery. MTS primarily affects young to middle-aged women, although many patients remain entirely asymptomatic. Anatomic variations of MTS, while uncommon, have been described. Treatment usually involves endovascular management, including thrombolysis and/or thrombectomy with or without inferior vena cava filter placement, followed by angioplasty and stenting of the left common iliac vein. We report a unique case of a 31-year-old woman who presented with MTS-related deep vein thrombosis accompanied by symptomatic abdominal and pelvic varicosities. The varicosities were treated successfully using multiple procedures, resulting in complete resolution of all symptoms. Our case discusses a treatment approach for an unusual presentation of MTS-related postthrombotic syndrome, and provides a brief literature review of MTS complications and management.
Encapsulation of Gold Nanorods with Porphyrins for the Potential Treatment of Cancer and Bacterial Diseases: A Critical Review
Authors: Hlapisi Nthabeleng , Motaung Tshwafo E. , Linganiso Linda Z. , Oluwafemi Oluwatobi S. , Songca Sandile P.
Published: April 2019

Cancer and bacterial diseases have been the most incidental diseases to date. According to the World Health Report 2018, at least every family is affected by cancer around the world. In 2012, 14.1 million people were affected by cancer, and that figure is bound to increase to 21.6 million in 2030. Medicine therefore sorts out ways of treatment using conventional methods which have been proven to have many side effects. Researchers developed photothermal and photodynamic methods to treat both cancer and bacterial diseases. These methods pose fewer effects on the biological systems but still no perfect method has been synthesized. The review serves to explore porphyrin and gold nanorods to be used in the treatment of cancer and bacterial diseases: porphyrins as photosensitizers and gold nanorods as delivery agents. In addition, the review delves into ways of incorporating photothermal and photodynamic therapy aimed at producing a less toxic, more efficacious, and specific compound for the treatment.
Exposure to Messages on Risk Factors for Noncommunicable Diseases in a Rural Province of Vietnam
Authors: Pham Bich Diep , Kim Bao Giang , Nguyen Thi Thu Huyen , Hoang Van Minh
Published: April 2019

Background. Providing messages on risk factors for noncommunicable diseases (NCDs) plays an important role in preventing disease. Objectives. This study investigated how often adults living in a rural area in northern Vietnam heard about risks factor for NCD and where they obtained that information. Methods. A cross-sectional survey was conducted using a multistage stratified cluster sampling to recruit 2970 participants. Data analyses were adjusted for all variables in a two-level multilevel Poisson regression model. Results. Overall, 77% of respondents had heard about NCDs, while 38.3 to 50% had been exposed to messages on risk factors of NCDs in the last month. Television, radio, and friends/neighbors were the most common sources of information. Most people exposed information no more than one or two sources. Factors associated with exposure to messages about risk were occupation, age group, education, and economic status. Conclusion. Intervention programs should focus on providing information primarily through television, considering influencing factors as well ensuring that messages reach target audiences.
Optimization and Standardization of Thermal Treatment as a Plasma Prefractionation Method for Proteomic Analysis
Authors: Chiangjong Wararat , Changtong Channarong , Panachan Jirawan , Weeraphan Churat , Srisomsap Chantragan , Hongeng Suradej , Svasti Jisnuson , Chutipongtanate Somchai
Published: April 2019

Prefractionation is a prerequisite step for deep plasma proteomics. Highly abundant proteins, particularly human serum albumin (HSA) and immunoglobulin G (IgG), typically interfere with investigation of proteins with lower abundance. A relatively simple preparation method based on high temperature can precipitate thermolabile proteins, providing a strategic window to access the thermostable plasma subproteome. This study aimed to optimize thermal treatment as a reliable prefractionation method and to compare it with two commercial kits, including HSA and IgG immunodepletion (IMDP) and combinatorial peptide ligand libraries (CPLL), using untreated plasma as a control condition. By varying the temperature and the incubation period, the optimal condition was found as treatment at 95°C for 20 min, which maintained about 1% recovery yield of soluble proteins. Consistency and reproducibility of thermal treatment-derived plasma subproteome were checked by two-dimensional electrophoresis. The coefficient of variation regarding protein spot numbers was less than 10% among three independent specimens. Highly abundant protein depletion of the thermal treatment was evaluated by immunoblotting against HSA and IgG as compared to the untreated plasma, IMDP, and CPLL. Multidimensional comparison based on 489 unique peptides derived from the label-free quantitative mass spectrometry revealed that the thermal treatment, IMDP, and CPLL provided distinct sets of plasma subproteome compared to untreated plasma, and these appeared to be complementary to each other. Comparing the characteristics of the three procedures suggested that thermal treatment was more cost-effective and less time-consuming than IMDP and CPLL. This study proposes the use of thermal treatment as a reliable and cost-effective method for plasma prefractionation which provides benefits to large-scale proteomic projects and biomarker studies.
Flexible, Front-Facing Luminescent Solar Concentrators Fabricated from Lumogen F Red 305 and Polydimethylsiloxane
Authors: Carbone Ian A. , Frawley Katelynn R. , McCann Melissa K.
Published: April 2019

Luminescent solar concentrators (LSCs) fabricated with transparent host materials and fluorescent organic dyes are cost effective and versatile tools for solar power production. In this study, the first flexible, front-facing LSCs utilizing Lumogen F Red 305 (LR305) and polydimethylsiloxane (PDMS) were demonstrated. Bulk-doped devices, fabricated with dye evenly distributed throughout the waveguide, were optimized for light gain with LR305 concentrations between 0.075 and 0.175 g/l. Thin-film devices, fabricated with a thin layer of luminescent material applied to the bottom side of the waveguide, were optimized between 0.5 and 0.75 g/l. The bulk-doped and thin-film devices produced light gains of 1.86 and 1.89, respectively, demonstrating that flexible designs can be developed without sacrificing power production. Bulk-doped devices proved to be less effective than thin-film devices at collecting direct light due to the placement of fluorescent dyes above the front-facing solar cell. Thin-film devices demonstrated less light collection than bulk-doped devices further from the device centers possibly due to quenching and self-absorption losses at higher dye concentrations. Light collection was minimally impacted by moderate bending in both LSC designs, suggesting that flexible, front-facing devices could be effectively deployed on curved and uneven surfaces. Finally, optical measurements of the LSC waveguides suggest that they could support plant growth underneath. Similar designs could be developed for applications in agricultural settings.
Concentrated Solar Power Plants with Molten Salt Storage: Economic Aspects and Perspectives in the European Union
Authors: Bielecki Andrzej , Ernst Sebastian , Skrodzka Wioletta , Wojnicki Igor
Published: April 2019

Concentrated solar power plants belong to the category of clean sources of renewable energy. The paper discusses the possibilities for the use of molten salts as storage in modern CSP plants. Besides increasing efficiency, it may also shift their area of application: thanks to increased controllability, they may now be used not only to cover baseload but also as more agile, dispatchable generators. Both technological and economic aspects are presented, with focus on the European energy sector and EU legislation. General characteristics for CSP plants, especially with molten salt storage, are discussed. Perspectives for their development, first of all in economic aspects, are considered.
New Insights on the Adjuvant Properties of theLeishmania infantumEukaryotic Initiation Factor
Authors: Koutsoni Olga S. , Barhoumi Mourad , Guizani Ikram , Dotsika Eleni
Published: April 2019

Vaccination is the most effective tool against infectious diseases. Subunit vaccines are safer compared to live-attenuated vaccines but are less immunogenic and need to be delivered with an adjuvant. Adjuvants are essential for enhancing vaccine potency by improving humoral and cell-mediated immune responses. Only a limited number of adjuvants are licensed for human vaccines, and their mode of action is still not clear.Leishmaniaeukaryotic initiation factor (LeIF) has been described having a dual role, as a natural adjuvant and as an antigen that possesses advantageous immunomodulatory properties. In this study, we assessed the adjuvant properties of recombinantLeishmania infantumeukaryotic initiation factor (LieIF) throughin vitroandin vivoassays. LieIF was intraperitoneally administered in combination with the protein antigen ovalbumin (OVA), and the widely used alum was used as a reference adjuvant. Ourin vitrostudies using J774A.1 macrophages showed that LieIF induced stimulatory effects as demonstrated by the enhanced surface expression of CD80 and CD86 co-stimulatory molecules and the induced production of the immune mediators NO and MIP-1α. Additionally, LieIF co-administration with OVA in anin vivomurine model induced a proinflammatory environment as demonstrated by the elevated expression ofTNF-α,IL-1β, andNF-κB2genes in peritoneal exudate cells (PEC). Furthermore, PEC derived from OVA-LieIF-immunized mice exhibited elevated expression of CD80 molecule and production of NO and MIP-1αin culture supernatants. Moreover, LieIF administration in the peritoneum of mice resulted in the recruitment of neutrophils and monocytes at 24 h post-injection. Also, we showed that this immunopotentiating effect of LieIF did not depend on the induction of uric acid danger signal. These findings suggest the potential use of LieIF as adjuvant in new vaccine formulations against different infectious diseases.
The Laminin-α1 Chain-Derived Peptide, AG73, Binds to Syndecans on MDA-231 Breast Cancer Cells and Alters Filopodium Formation
Authors: Puchalapalli Madhavi , Mu Liang , Edwards Chevaunne , Kaplan-Singer Benjamin , Eni Pearl , Belani Kiran , Finkelstein David , Patel Arpan , Sayyad Megan , Koblinski Jennifer E.
Published: April 2019

Breast cancer is one of the most common forms of cancer affecting women in the United States, second only to skin cancers. Although treatments have been developed to combat primary breast cancer, metastasis remains a leading cause of death. An early step of metastasis is cancer cell invasion through the basement membrane. However, this process is not yet well understood. AG73, a synthetic laminin-α1 chain peptide, plays an important role in cell adhesion and has previously been linked to migration, invasion, and metastasis. Thus, we aimed to identify the binding partner of AG73 on breast cancer cells that could mediate cancer progression. We performed adhesion assays using MCF10A, T47D, SUM1315, and MDA-231 breast cell lines and found that AG73 binds to syndecans (Sdcs) 1, 2, and 4. This interaction was inhibited when we silenced Sdcs 1 and/or 4 in MDA-231 cells, indicating the importance of these receptors in this relationship. Through actin staining, we found that silencing of Sdc 1, 2, and 4 expression in MDA-231 cells exhibits a decrease in the length and number of filopodia bound to AG73. Expression of mouse Sdcs 1, 2, and 4 in MDA-231 cells provides rescue in filopodia, and overexpression of Sdcs 1 and 2 leads to increased filopodium length and number. Our findings demonstrate an intrinsic interaction between AG73 in the tumor environment and the Sdcs on breast cancer cells in supporting tumor cell adhesion and invasion through filopodia, an important step in cancer metastasis.
The Emerging Perspective of Morphine Tolerance: MicroRNAs
Authors: Zhang Teng J. , Qiu Yong , Hua Zhen
Published: April 2019

Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms underlying morphine tolerance remain disputed, which has prevented the development of therapies to maximize and sustain analgesic efficacy. Morphine tolerance is an adaptive process induced by chronic morphine that has been shown to result from complex alterations at the molecular level with μ opioid receptors (MORs), as well as at the synaptic, cellular, and circuit levels. MicroRNAs are noncoding RNAs that have been proposed to regulate gene expression and degradation at the posttranscriptional level, including the MOR, as well as synaptic plasticity and neuroplasticity, in both the peripheral and central nervous systems. This review covers some of the most striking microRNA functions involved in morphine tolerance and presents limitations on our knowledge of their physiological roles.
Octreotide Use in a Patient with MEN-1 Syndrome and Multifocal Pancreatic Neuroendocrine Tumors: A Case Report and Review of the Literature
Authors: Kemm Matthew H. , Manly Cory D. , Hoang Thanh D. , Mai Vinh Q. , Shakir Mohamed K. M.
Published: April 2019

We report a patient with multiple endocrine neoplasia type 1 with pancreatic polypeptide (PP) secreting subcentimeter pancreatic neuroendocrine tumors (pNETs) treated with octreotide and review the current literature that pertains to the management of these patients. Clinical data, laboratory results, and imaging were reviewed. A literature search was performed in PUBMED using combinations of the terms “multiple endocrine neoplasia type 1,” “somatostatin,” octreotide,” “pancreatic polypeptide,” and “pancreatic tumor.” Relevant references were selected and reviewed. A 43-year-old male with a history of MEN1 and multiple subcentimeter neuroendocrine tumors with elevation of PP was treated with octreotide therapy leading to a reduction and normalization of PP levels. The patient tolerated octreotide therapy but self-discontinued octreotide after 24 months with a rise in PP levels off therapy. Tumors remained stable in size through 40 months of imaging follow-up. In patients with MEN1 and subcentimeter pNETs, octreotide therapy is well tolerated and can lead to a significant drop in PP levels with no change in lesion size. There is insufficient data to suggest long-term benefit with octreotide therapy but it may be considered versus standard conservative management.
Massive Subchorionic Thrombohematoma (Breus’ Mole) Associated with Fetal Growth Restriction, Oligohydramnios, and Intrauterine Fetal Death
Authors: Miyagi Miyuki , Kinjo Tadatsugu , Mekaru Keiko , Nitta Hayase , Masamoto Hitoshi , Aoki Yoichi
Published: April 2019

Massive subchorionic thrombohematoma (MST), termed Breus’ mole, is a rare condition in which a large maternal blood clot separates the chorionic plate from the villous chorion. Common complications of MST include fetal growth restriction, preeclampsia, and intrauterine fetal death. Here, we present a case of a 17-year-old Japanese woman referred to our institution at 21 weeks of gestation. Ultrasound examination revealed a large placental mass with mixed high and low echogenicity measuring approximately 7.6 cm in thickness. Doppler examination showed absence of end-diastolic velocity of the umbilical artery. At 22 weeks of gestation, the patient had a stillbirth weighing 138g. The placenta weighed 502 g and was 8 cm thick, and the total blood loss was 270 g. Macroscopic examination revealed that a subchorionic blood clot measuring 12 cm × 5 cm covered a large portion of the placenta with well-defined margins on the fetal surface. Microscopic examination revealed an intervillous hematoma and fibrinous deposits directly beneath the chorionic plate with adjacent compressive effects. Based on these findings, MST was diagnosed. Because MST is rare, it must be considered in the differential diagnosis of parental conditions. Magnetic resonance imaging can be optimal for diagnosing MST when ultrasound diagnosis is difficult.
Thermal Response and Degressive Reaction Study of Oxo-Biodegradable Plastic Products Exposed to Various Degradation Media
Authors: Al-Salem S. M. , Al-Nasser A. Y. , Behbehani M. H. , Sultan H. H. , Karam H. J. , Al-Wadi M. H. , Al-Dhafeeri A. T. , Rasheed Z. , Al-Foudaree M.
Published: April 2019

In this work, three plastic film products commonly used as commodity thermoplastic articles were analysed with the aim of characterizing their thermal behaviour and stability. The test specimens were subjected to a series of analytical tests to confirm their biodegradable nature. The specimens ranged between 30 and 70 μm in thickness and showed high concentrations of regulated metals, namely, lead (Pb), postchemical analysis which can lead to its migration to natural sinks. The specimens were also exposed to degressive media, namely, accelerated (UV induced) weathering and soil burial field testing. The weight loss measured exceeded 58% after soil burial indicating deterioration under natural environmental stressors. In addition, the thermal characterization campaign executed with the aim of determining the product’s thermal response followed internationally recognised experimental protocols for the determination of thermal stability. The methodology used followed the International Confederation for Thermal Analysis and Calorimetry (ICTAC) recommendation for thermal stability and the computation of kinetic parameters. The degradation reaction kinetics were also determined postexposure to degressive media. Thermogravimetric analysis coupled with differential scanning calorimetry heat flow analysis and Fourier infrared spectroscopy results was also used in studying the degradation behaviour of the specimens. Analytical kinetic estimation methods relying on model free solutions enabled the determination of the apparent activation energy (Ea) of the specimens postexposure to degradation media. A shift in the degradation mechanism was also detected after studying the kinetic parameters which showed a range of Ea between 86.64 and 226.90 kJ mol-1 depending on the type of specimens and exposure media. It can be concluded that the oxo-biodegradable films are well suited for thermal treatment in the future as discarded plastic solid waste (PSW) articles. This work also paves the way for developing national standards and future plans for societies burdened with PSW accumulation.
Prevalence of Metabolic Syndrome and Its Components in Bamboutos Division’s Adults, West Region of Cameroon
Authors: Marbou Wiliane J. T. , Kuete Victor
Published: April 2019

The prevalence of metabolic syndrome (MetS) and its associated risks remain unappreciated in Bamboutos Division, west region of Cameroon. This study aimed to evaluate the prevalence of MetS, its individual components, and associated risk factors among Bamboutos Division’s adults population using a Joint Interim Statement of the International Diabetes Federation (IDF) Task Force on Epidemiology and Prevention definitions parameters. A cross-sectional study was conducted from May 2016 to May 2018 in Mbouda ADLUCEM Hospital and Mbouda District Hospital, two reference hospitals in Bamboutos Division, west region of Cameroon. Interview, physical and clinical examinations, and lipid and fasting blood glucose measurements were conducted for 604 adults. The definition of MetS proposed by IDF was used. The prevalence of MetS was 32.45% with highly significant female predominance (46.11% for females and 14.01 % for males). In the entire participants, the most common abnormalities were low-HDL (82.78%) and hypertriglyceridemia (53.97%) [p<0.001]. Participants with obesity (OR: 16.34; 95% CI: 9.21-28.96), overweight (OR: 7.45; 95% CI: 4.17-13.30), and highest hs-CRP (hs-CRP >11 mg/l) had a higher risk of developing MetS. The most common MetS component was abdominal obesity (OR: 353.13; 95% CI: 136.16-915.81). MetS is prevalent among Bamboutos Division’s adults in west region of Cameroon and abdominal obesity is the most common MetS component. This study highlights the need for evidence-based prevention, diagnosis, and management of MetS and its associated factors among Bamboutos Division’s adults in Cameroon.
Quality of Life in Yoga Experienced and Yoga Naïve Asian Indian Adults with Obesity
Authors: Telles Shirley , Sharma Sachin Kumar , Singh Alok , Kala Niranjan , Upadhyay Vikas , Arya Jaideep , Balkrishna Acharya
Published: April 2019

Background. Obesity adversely affects quality of life which then acts as a barrier to weight loss and weight loss maintenance. Hence, those interventions which positively influence the quality of life along with weight reduction are considered useful for sustained weight loss in persons with obesity. An earlier study showed better quality of life in obese adults who had experience of yoga compared to yoga naïve obese adults. However, the main limitation of the study was the small sample size (n=20 in each group). Objective. The present study aimed to determine whether with larger sample sizes the quality of life would differ in yoga experienced compared to yoga naïve adults with obesity. Methods. There were 596 Asian Indian obese adults (age range 20 to 59 years; group mean age ± SD; 43.9 ± 9.9 years): of whom (i) 298 were yoga experienced (154 females; group mean age ± SD; 44.0 ± 9.8 years) with a minimum of 1 month of experience in yoga practice and (ii) 298 were yoga naïve (154 females; group mean age ± SD; 43.8 ± 10.0 years). All the participants were assessed for quality of life using the Moorehead–Ardelt quality of life questionnaire II. Data were drawn from a larger nationwide trial which assessed the effects of yoga compared to nutritional advice on obesity over a one-year follow-up period (CTRI/2018/05/014077). Results. There were higher participant-reported outcomes for four out of six aspects of quality of life in the yoga experienced compared to the yoga naïve (p<0.008, based on t values of the least squares linear regression analyses, Bonferroni adjusted, and adjusted for age, gender, and BMI as covariates). These were enjoyment in physical activities, ability to work, self-esteem, and social satisfaction. Conclusion. Obese adults with yoga experience appear to have better quality of life in specific aspects, compared to yoga naïve persons with a comparable degree of obesity.
Genome-Wide Association Studies of Endometrial Cancer: Latest Developments and Future Directions
Authors: O'Mara Tracy A. , Glubb Dylan M. , Kho Pik Fang , Thompson Deborah J. , Spurdle Amanda B.
Published: April 2019

Endometrial cancer, the most commonly diagnosed cancer of the female reproductive tract in developed countries, has a heritable component. To date, 16 genetic risk regions have been robustly discovered by genome-wide association studies (GWAS) of endometrial cancer. Post-GWAS analyses including expression quantitative trait loci analysis and laboratory-based functional studies have been successful in identifying genes and pathways involved in endometrial carcinogenesis. Mendelian randomization analysis studies have confirmed factors causal for endometrial cancer risk, including increased body mass index and early onset of menarche. In this review, we summarize findings from GWAS and post-GWAS analyses of endometrial cancer. We discuss clinical implications of these findings, current knowledge gaps, and future directions for the study of endometrial cancer genetics.
The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear β-Catenin
Authors: Shukla Samriddhi , Milewski David , Pradhan Arun , Rama Nihar , Rice Kathryn , Le Tien , Flick Matthew J. , Vaz Sara , Zhao Xueheng , Setchell Kenneth D. , Logarinho Elsa , Kalinichenko Vladimir V. , Kalin Tanya V.
Published: April 2019

The oncogenic transcription factor FOXM1 has been previously shown to play a critical role in carcinogenesis by inducing cellular proliferation in multiple cancer types. A small-molecule compound, Robert Costa Memorial drug-1 (RCM-1), has been recently identified from high-throughput screen as an inhibitor of FOXM1 in vitro and in mouse model of allergen-mediated lung inflammation. In the present study, we examined antitumor activities of RCM-1 using tumor models. Treatment with RCM-1 inhibited tumor cell proliferation as evidenced by increased cell-cycle duration. Confocal imaging of RCM-1–treated tumor cells indicated that delay in cellular proliferation was concordant with inhibition of FOXM1 nuclear localization in these cells. RCM-1 reduced the formation and growth of tumor cell colonies in the colony formation assay. In animal models, RCM-1 treatment inhibited growth of mouse rhabdomyosarcoma Rd76-9, melanoma B16-F10, and human H2122 lung adenocarcinoma. RCM-1 decreased FOXM1 protein in the tumors, reduced tumor cell proliferation, and increased tumor cell apoptosis. RCM-1 decreased protein levels and nuclear localization of β-catenin, and inhibited protein–protein interaction between β-catenin and FOXM1 in cultured tumor cells and in vivo. Altogether, our study provides important evidence of antitumor potential of the small-molecule compound RCM-1, suggesting that RCM-1 can be a promising candidate for anticancer therapy.
IL15-Based Trifunctional Antibody-Fusion Proteins with Costimulatory TNF-Superfamily Ligands in the Single-Chain Format for Cancer Immunotherapy
Authors: Beha Nadine , Harder Markus , Ring Sarah , Kontermann Roland E. , Müller Dafne
Published: April 2019

IL15 and costimulatory receptors of the tumor necrosis superfamily (TNFRSF) have shown great potential to support and drive an antitumor immune response. However, their efficacy as monotherapy is limited. Here, we present the development of a novel format for a trifunctional antibody-fusion protein that combines and focuses the activity of IL15/TNFSF-ligand in a targeting-mediated manner to the tumor site. The previously reported format consisted of a tumor-directed antibody (scFv), IL15 linked to an IL15Rα-fragment (RD), and the extracellular domain of 4-1BBL, where noncovalent trimerization of 4-1BBL into its functional unit led to a homotrimeric molecule with 3 antibody and 3 IL15-RD units. To reduce the size and complexity of the molecule, we have now designed a second format, where 4-1BBL is introduced as single-chain (sc), that is 3 consecutively linked 4-1BBL ectodomains. Thus, a monomeric trifunctional fusion protein presenting only 1 functional unit of each component was generated. Interestingly, the in vitro activity on T-cell stimulation was conserved or even enhanced for the soluble and target-bound molecule, respectively. Also, in a lung tumor mouse model, comparable antitumor effects were observed. Furthermore, corroborating the concept, OX40L and GITRL were also successfully incorporated into the novel single-chain format and the advantage of target-bound trifunctional versus corresponding combined bifunctional fusion proteins demonstrated by measuring T-cell proliferation and cytotoxic potential in vitro and antitumor effects of RD_IL15_scFv_scGITRL in a lung tumor mouse model in vivo. Thus, the trifunctional antibody-fusion protein single-chain format constitutes a promising innovative platform for further therapeutic developments.
Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents
Authors: Lossos Chen , Liu Yunpeng , Kolb Kellie E. , Christie Amanda L. , Van Scoyk Alexandria , Prakadan Sanjay M. , Shigemori Kay , Stevenson Kristen E. , Morrow Sara , Plana Olivia D. , Fraser Cameron , Jones Kristen L. , Liu Huiyun , Pallasch Christian P. , Modiste Rebecca , Nguyen Quang-De , Craig Jeffrey W. , Morgan Elizabeth A. , Vega Francisco , Aster Jon C. , Sarosiek Kristopher A. , Shalek Alex K. , Hemann Michael T. , Weinstock David M.
Published: April 2019

The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fide human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells in vivo that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infiltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identified a “super-phagocytic” subset that expressed CD36/FCGR4. Together, these findings define a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance.

Significance:

mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specific antibody resistance and define an ER stress–dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types.

See related commentary by Duval and De Palma, p. 834.

This article is highlighted in the In This Issue feature, p. 813
Reconsideration on Clinical Benefit of Pelvic Lymph Node Dissection during Radical Prostatectomy for Clinically Localized Prostate Cancer
Authors: Fujimoto Naohiro , Shiota Masaki , Tomisaki Ikko , Minato Akinori , Yahara Katsuya
Published: April 2019

We conducted a review of the literature to identify the clinical benefits of pelvic lymph node dissection (PLND) during radical prostatectomy for clinically localized prostate cancer. The most recent guidelines recommend PLND, particularly extended PLND, during radical prostatectomy for localized prostate cancer. PLND is undoubtedly the most accurate method for nodal staging, and most patients, particularly those with high-risk cancer, are likely to undergo PLND during radical prostatectomy. Although many retrospective studies have assessed oncologic outcomes after PLND, its therapeutic benefit remains controversial. Patients with positive node(s) often have other more common unfavorable prognostic factors, such as seminal vesicle invasion, extra-prostatic extension, and positive surgical margins. Oncologic outcomes in patients who have not undergone PLND and those who have undergone PLND are almost identical. If an effective standard adjuvant therapy after prostatectomy is defined, the nodal status may be important and valuable. However, adjuvant treatment strategies for patients with a positive node have not been identified thus far. Therefore, determining the nodal status at surgery may not provide therapeutic benefit. PLND requires additional surgical time and is associated with several complications. Therefore, the indication for PLND should be considered carefully until well-designed prospective randomized trials establish high-quality clinical evidence.
Transforming Growth Factor-β in the Acute Kidney Injury to Chronic Kidney Disease Transition
Authors: Gewin Leslie S.
Published: April 2019

Transforming growth factor-β (TGF-β) is a key profibrotic growth factor that is activated in acute kidney injury (AKI) and associated with cellular responses that lead to the development of chronic kidney disease (CKD). The persistently injured, de-differentiated tubular epithelial cell is an important mediator of the transition from AKI to CKD. TGF-β signaling may perpetuate proximal tubule injury through de-differentiation, cell cycle arrest, and increased susceptibility to apoptosis. In addition, TGF-β signaling promotes macrophage chemotaxis, endothelial injury, and myofibroblast differentiation after AKI. Future studies that block TGF-β signaling after cessation of AKI are needed to better define its role in the progression of acute to chronic renal injury.
Risk Factors for New-Onset Diabetes Mellitus after Heart Transplantation in Chinese Patients: A Single Center Experience
Authors: Zhang Min , Han Yong , Yuan Yonghua , Cai Jie , Zhang Jing , Wang Yirong , Xiang Hongping , Zhou Hong
Published: April 2019

Background: New-onset diabetes after transplantation ­(NODAT) is a frequent complication after heart transplantation (HT) and is associated with graft loss and patient survival. Objectives: The aim of this study was to identify the incidence and associated factors contributing to NODAT in Chinese heart transplant recipients. Methods: Adult patients without diabetes mellitus before HT were enrolled in this study. NODAT was diagnosed according to the criteria recommended by the American Diabetes Association. The cumulative incidence was determined at 3, 6, and 12 months, respectively. The risk factors of NODAT were estimated by logistic regression analysis. Results: A total of 154 adults who first received HT were included. Among them, 50 (32.5%) recipients were diagnosed with NODAT after a median follow-up time of 611 days. The cumulative incidence of NODAT was 27.3% at 3 months, 29.9% at 6 months, and 30.5% at 12 months, respectively. Independent risk factors for NODAT included age ≥45 years (OR 3.82, 95% CI 1.57–9.31; p = 0.003), hypertension (OR 3.28, 95% CI 1.17–9.20; p= 0.024), and transient hyperglycemia (OR 12.13, 95% CI 3.35–43.92; p < 0.001). Moreover, recipients treated with both acarbose and insulin for transient hyperglycemia had a significantly higher prevalence of NODAT than those without any anti-diabetic agents (OR 5.35, 95% CI 1.21–23.64; p = 0.027). Conclusions: Age ≥45 years, hypertension, transient hyperglycemia, and associated treatment strategies are imperative to identify recipients at high risk of developing ­NODAT.
Lack of Ability to Present Antigens on Major Histocompatibility Complex Class II Molecules Aggravates Atherosclerosis in ApoE
−/−
Mice
Authors: Wigren Maria , Rattik Sara , Yao Mattisson Ingrid , Tomas Lukas , Grönberg Caitriona , Söderberg Ingrid , Alm Ragnar , Sundius Lena , Ljungcrantz Irena , Björkbacka Harry , Fredrikson Gunilla Nordin , Nilsson Jan
Published: April 2019

Background:

Hypercholesterolemic mice lacking factors required for activation of CD4
+
T cells are characterized by reduced development of atherosclerosis. Consequently, it has been assumed that atherosclerosis involves loss of tolerance against modified self-antigens generated in response to hypercholesterolemia and that presentation of such antigens on major histocompatibility complex class II (MHCII) leads to activation of proatherogenic Th1 cells. In this study, we wanted to determine the role of antigen presentation on MHCII in atherosclerosis development.

Methods:

Apolipoprotein E (ApoE
−/−
) mice deficient for MHCII (ApoE
−/−
MHCII
−/−
) were used to study the role of MHCII in atherosclerosis development.

Results:

Compared with ApoE
−/−
mice, ApoE
−/−
MHCII
−/−
mice had reduced levels of CD4
+
T cells, immunoglobulin G and M levels, and Th1 and Th2 cytokines in plasma. CD8
+
T cells were increased and regulatory T cells were reduced both in spleen and in lesions of ApoE
−/−
MHCII
−/−
mice. Decreased plasma levels of inflammatory cytokines in ApoE
−/−
MHCII
−/−
mice indicated reduced systemic inflammation. Despite this, ApoE
−/−
MHCII
−/−
mice had significantly more atherosclerosis as assessed by en face Oil Red O staining of the aorta (4.7±2.9% versus 1.9±1.3%;
P
<0.01) and cross-sectional area of subvalvular lesions (7.7±2.2×10
5
µm
2
versus 4.6±2.8×10
5
µm
2
;
P
<0.05). Cell transfer and blocking antibody studies suggested that loss of regulatory T cells is the most important cause of aggravated atherosclerosis in ApoE
−/−
MHCII
−/−
mice.

Conclusions:

Our observations demonstrate that antigen presentation on MHCII has important protective functions in atherosclerosis and that this is primarily the result of activation of regulatory T cells. These findings have implications for understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease.
Validation of Wall Enhancement as a New Imaging Biomarker of Unruptured Cerebral Aneurysm
Authors: Quan Kai , Song Jianping , Yang Zixiao , Wang Dongdong , An Qingzhu , Huang Lei , Liu Peixi , Li Peiliang , Tian Yanlong , Zhou Liangfu , Zhu Wei
Published: April 2019

Background and Purpose—

High-resolution vessel wall magnetic resonance imaging is a promising technique for assessing wall structures of unruptured intracranial aneurysms (UIAs). However, the relationship between aneurysmal high-resolution vessel wall magnetic resonance imaging features and their histopathologic mechanism remains poorly understood.

Methods—

From February 2016 to February 2018, a total of 19 men and 28 women with 54 UIAs treated surgically were prospectively enrolled. The intraoperative observed gross pathology of the aneurysmal wall was compared with the enhancement features on high-resolution vessel wall magnetic resonance imaging. Specimens of the UIAs were harvested for histopathologic and immunohistochemistry analysis.

Results—

An irregular shape and large size was significantly related to UIA wall enhancement. Both uniform and focal wall enhancement may demonstrate the inflammation processes of UIA walls, although the latter may indicate more atherosclerotic plaque formation.

Conclusions—

Different high-resolution vessel wall magnetic resonance imaging enhancement features may represent variable inflammation status of a UIA wall, which may provide new insights into assessing the UIA wall structure and optimizing treatment.
Baseline Carotid Intima-Media Thickness and Stroke Recurrence During Secondary Prevention With Pravastatin
Authors: Wada Shinichi , Koga Masatoshi , Minematsu Kazuo , Toyoda Kazunori , Suzuki Rieko , Kagimura Tatsuo , Nagai Yoji , Aoki Shiro , Nezu Tomohisa , Hosomi Naohisa , Origasa Hideki , Ohtsuki Toshiho , Maruyama Hirofumi , Yasaka Masahiro , Kitagawa Kazuo , Uchiyama Shinichiro , Matsumoto Masayasu ,   on behalf of the Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study Collaborators
Published: April 2019

Background and Purpose—

As a prespecified post hoc analysis of the J-STARS (Japan Statin Treatment Against Recurrent Stroke) Echo Study, the 5-year stroke recurrence rate according to the baseline mean carotid intima-media thickness (IMT) with and without pravastatin treatment was investigated.

Methods—

Patients were randomly assigned to receive pravastatin 10 mg/day (pravastatin group) or control group (nonstatin treatment; 1:1) for 5 years. Baseline mean IMT of the common carotid artery was measured by ultrasonography. Cox proportional hazards models were used to investigate whether the stroke (any ischemic stroke, atherothrombotic brain infarction, or lacunar infarction) recurrence rate was different according to tertiles of baseline mean IMT.

Results—

A total of 793 patients, including 388 in the pravastatin group and 405 in the control group, were investigated. In the control group, Cox proportional hazards models showed that participants in the highest tertile IMT group (≥0.931 mm) had a higher rate of atherothrombotic brain infarction than those in the lowest tertile IMT group (<0.812 mm; [hazard ratio, 9.08; 95% CI, 1.15–71.43]). Patients in the pravastatin group had a lower risk of atherothrombotic brain infarction than those in the control group only in the highest tertile IMT group by the log-rank test (
P
value=0.045).

Conclusions—

Long-term pravastatin administration may prevent the occurrence of atherothrombotic brain infarction in noncardioembolic infarction patients with the highest tertile IMT.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00361530.
A new species of the deep-sea squat lobster genus Eumunida Smith, 1883 (Decapoda: Anomura: Eumunididae) from the Arabian Sea off southwestern India
Authors: KOMAI TOMOYUKI , CHAKRABORTY REKHA DEVI , PARAMASIVAM PURUSHOTHAMAN , GIDDA MAHESWARUDU
Published: April 2019

A new species of the squat lobster genus Eumunida Smith, 1883 (Chirostyloidea: Eumunididae), E. multispina, is described and illustrated primarily on the basis of two male specimens from the Arabian Sea off the Kerala State, southwestern India, at depths of 250–400 m. One specimen from Lakshadweep, previously identified with E. funambulus Gordon, 1930, is also referred to the new species. The new species is morphologically most similar to E. funambulus among the 29 known congeners, but the presence of four epigastric spines and more numerous lateral spines on the carapace (four on the anterolateral and seven to 10 on the branchial margins) immediately distinguish the new species from E. funambulus. Genetic analysis using the mitochondrial COI and 16S rRNA markers also indicates that the new species is distinct from congenerics for which the sequence data are available.
Theorica valuliae Pinkaew, new species (Lepidoptera: Tortricidae: Olethreutinae), the first record of the genus in Thailand
Authors: PINKAEW NANTASAK , MUADSUB SOPITA
Published: April 2019

The genus Theorica Diakonoff, 1966 includes two previously described species that occur in Vietnam (i.e., T. secunda Kuznetsov, 1997) and New Guinea (i.e., T. lamyra (Meyrick, 1911)). We report the first occurrence of this genus in Thailand, represented by a new species: Theorica valuliae Pinkaew, n. sp. In addition to illustrations of the adult and genitalia, we also present photographs of living specimens in their natural resting posture.
Descriptions of two new species of Fibuloides Kuznetsov, 1997 (Lepidoptera: Tortricidae: Eucosmini) from Thailand
Authors: SIRAPHATTARATHAMRONG PAPHATPRON , MUADSUB SOPITA , PINKAEW NANTASAK
Published: April 2019

Two new species of genus Fibuloides, F. bacriora Siraphattarathamrong and Pinkaew, n. sp., and F. falcatus Siraphattarathamrong and Pinkaew, n. sp., are described from Thailand. Adults and genitalia are illustrated. The two new taxa increase the number of described Fibuloides species in Thailand to 17.
Incorporating User Values into Climate Services
Authors: Parker Wendy S. , Lusk Greg
Published: April 2019

Increasingly there are calls for climate services to be “co-produced” with users, taking into account not only the basic information needs of users but also their value systems and decision contexts. What does this mean in practice? One way that user values can be incorporated into climate services is in the management of inductive risk. This involves understanding which errors in climate service products would have particularly negative consequences from the users’ perspective (e.g., underestimating rather than overestimating the change in an impact variable) and then prioritizing the avoidance of those errors. This essay shows how inductive risk could be managed in climate services in ways that serve user values and argues that there are both ethical and practical reasons in favor of doing so.