bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Nitric Oxide on Renal Proximal Tubular Na+Transport
Authors: Satoh Nobuhiko , Nakamura Motonobu , Suzuki Atsushi , Tsukada Hiroyuki , Horita Shoko , Suzuki Masashi , Moriya Kyoji , Seki George
Published: October 2017

Nitric oxide (NO) has a wide variety of physiological functions in the kidney. Besides the regulatory effects in intrarenal haemodynamics and glomerular microcirculation,in vivostudies reported the diuretic and natriuretic effects of NO. However, opposite results showing the stimulatory effect of NO on Na+reabsorption in the proximal tubule led to an intense debate on its physiological roles. Animal studies have showed the biphasic effect of angiotensin II (Ang II) and the overall inhibitory effect of NO on the activity of proximal tubular Na+transporters, the apical Na+/H+exchanger isoform 3, basolateral Na+/K+ATPase, and the Na+/HCO3-cotransporter. However, whether these effects could be reproduced in humans remained unclear. Notably, our recent functional analysis of isolated proximal tubules demonstrated that Ang II dose-dependently stimulated human proximal tubular Na+transport through the NO/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway, confirming the human-specific regulation of proximal tubular transport via NO and Ang II. Of particular importance for this newly identified pathway is its possibility of being a human-specific therapeutic target for hypertension. In this review, we focus on NO-mediated regulation of proximal tubular Na+transport, with emphasis on the interaction with individual Na+transporters and the crosstalk with Ang II signalling.
Basidiobolomycosis Simulating a Mycobacterium ulcerans Infection in a Togolese Rural Child
Authors: Saka Bayaki , Gnassingbe Waguena , Mahamadou Garba , Akakpo Sefako , Teclessou Julienne , Abilogun-Chokki Aurel , Mouhari-Toure Abas , Kombate Koussake , Pitché Palokinam
Published: October 2017

Background. Basidiobolomycosis is a deep mycosis which preferentially affects rural young people in tropical countries. We report an atypical case, with multiple ulcers, simulating a Buruli ulcer. Case Report. A 5-year-old boy, living in a rural area, was seen for ulcers on the buttocks and at the back and right flank that had been in progress for 4 months. On examination, we found an infiltrated plaque with sharp edges, little painful, located on the buttocks, back, and the right flank. On this plaque, there were multiple ulcers with polycyclic contours and fibrinous bottom. There were inguinal inflammatory lymph nodes. The patient had an altered general condition. Examination of other organs was normal. The diagnosis of Buruli ulcer was evoked first; the search for Mycobacterium ulcerans by polymerase chain reaction was negative. Histology test performed revealed hypodermic granulomatous inflammation with predominant macrophage and eosinophils. The mycological culture was not done. The child was treated successfully with ketoconazole (10 mg/kg/day) during eight weeks. Discussion. Our observation shows great clinical and epidemiological similarities between basidiobolomycosis and Buruli ulcer. It confirms the efficacy of ketoconazole in severe basidiobolomycosis infection with alteration of general condition. Histopathology is very important for differential diagnosis between these two diseases.
CO2 Induced Foaming Behavior of Polystyrene near the Glass Transition
Authors: Al-Enezi Salah
Published: October 2017

This paper examines the effect of high-pressure carbon dioxide on the foaming process in polystyrene near the glass transition temperature and the foaming was studied using cylindrical high-pressure view cell with two optical windows. This technique has potential applications in the shape foaming of polymers at lower temperatures, dye impregnation, and the foaming of polystyrene. Three sets of experiments were carried out at operating temperatures of 50, 70, and 100°C, each over a range of pressures from 24 to 120 bar. Foaming was not observed when the polymer was initially at conditions below Tg but was observed above Tg. The nucleation appeared to occur randomly leading to subsequent bubble growth from these sites, with maximum radius of 0.02–0.83 mm. Three models were applied on the foaming experimental data. Variable diffusivity and viscosity model (Model C) was applied to assess the experimental data with the WLF equation. The model shows very good agreement by using realistic parameter values. The expansion occurs by diffusion of a dissolved gas from the supersaturated polymer envelope into the bubble.
Influences of Waiting Time on Driver Behaviors While Implementing In-Vehicle Traffic Light for Priority-Controlled Unsignalized Intersections
Authors: Yang Bo , Zheng Rencheng , Kaizuka Tsutomu , Nakano Kimihiko
Published: October 2017

In-vehicle traffic lights that assist drivers in crossing intersections are in development; however, the availability of the in-vehicle traffic light will be limited if the waiting time of a vehicle is not considered in actual traffic conditions, especially at priority-controlled unsignalized intersections that normally consist of one major and two minor roads. The present study therefore investigated the effects of the waiting time on driver behaviors to improve the in-vehicle traffic light for the priority-controlled unsignalized intersections. Gap acceptance theory that considers the waiting time was adopted in the implementation of the in-vehicle traffic light, to assist minor-road drivers in passing through the intersections by selecting appropriate major-road gaps. A driving simulator experiment involving 12 participants was performed for the minor and major roads, by applying the in-vehicle traffic light with and without the consideration of waiting time. Results demonstrate that the maximum acceleration strokes of minor-road vehicles were significantly reduced, indicating a lower possibility of aggressive driving when the in-vehicle traffic light was applied while considering the waiting time. Meanwhile, an improved steering stability was observed from the driver behaviors at the intersections, as the maximum lateral acceleration of minor-road vehicles significantly decreased when the waiting time was considered.
Therapeutic Management of a Substantial Pelvic Aneurysmatic Bone Cyst Including the Off-Label Use of Denosumab in a 35-Year-Old Female Patient
Authors: Ntalos D. , Priemel M. , Schlickewei C. , Thiesen D. M. , Rueger J. M. , Spiro A. S.
Published: October 2017

Aneurysmal bone cysts (ABC) are benign bone tumors, which are highly vascularized. The main course of treatment is curettage followed by bone grafting or cement insertion. Still recurrence remains a main problem for patients. Denosumab is a monoclonal antibody, which acts as an inhibitor of the RANK/RANKL pathway, diminishing bone turnover. Recent case reports have shown that Denosumab can be a promising therapeutic agent for people suffering from therapy-resistant ABC. We report the case of a 35-year-old female patient presenting with a pronounced ABC of the pelvis. Since the tumor was inoperable, Denosumab was administered, leading to a significant shrinkage of the lesion, which allowed surgical intervention. Upon recurrence, Denosumab was restarted putting the patient once more into remission. Follow-up was four years overall with a clinical and radiological stable disease for fifteen months after final discontinuation of the monoclonal antibody. Therefore, our case further underlines the potential of Denosumab in the treatment of ABC.
Coevolution of Interorganizational Psychological Contract and Interorganizational Relationship: A Case Study of Manufacturing Company in China
Authors: He Wei
Published: October 2017

As the belief of the beholder in an exchange about the obligations that another party should have, interorganizational psychological contract (IPC) from a micro perspective provides a new angle to study interorganizational relationship (IOR). This paper studies the interrelation and coevolution of IORs and IPCs by building a system dynamics (SD) model. Firstly based on the structural analysis of the interrelations of IPC and IOR, this paper builds the qualitative causal loop diagram of the interrelations. Based on investigation of 55 manufacturing enterprises in China we further draw the stock and flow diagram. Then we apply the data of Jiangxi Motors Co., Ltd., to simulate the model. The results reveal the development and evolution of IORs and IPCs and their interrelations. Furthermore, the sensitivity analysis is conducted and the influences of trust on IORs and IPCs are discussed. Finally managerial implications and some recommendations are provided for the decision-making of developing IORs.
The Anti-Inflammatory Activity of Toonaciliatin K against Adjuvant Arthritis
Authors: Gou HaiXing , Ye Jie , Wang YiRu , Xu XiaoLi , Shen QiXing , Xue JingWei , Zhao Jie , Lu XinGang
Published: October 2017

Toonaciliatin K is a natural limonoid purified from the Toona ciliata Roem. var. ciliata (Meliaceae). This study is to reveal the inflammatory suppression effect of toonaciliatin K and further the intrinsic mechanism. Firstly, anti-inflammatory effect of toonaciliatin K was evaluated in lipopolysaccharide- (LPS-) induced RAW264.7 cells. RT-PCR results indicated that the mRNA expressions of TNF-α, IL-6, and IL-1β were downregulated by toonaciliatin K. The toonaciliatin K inhibited TNF-α, IL-6, and IL-1β levels stimulated by LPS. Furthermore, LPS elicited the excess iNOS and COX-2 mRNA and protein production and toonaciliatin K attenuated the excess production. Western blot assay demonstrated that MAPK and NF-κB signaling pathways play critical roles in the toonaciliatin K’s anti-inflammatory activity. Secondly, toonaciliatin K inhibited carrageenan-induced paw edema in rats. Thirdly, toonaciliatin K alleviated the paw swelling and improved arthritis clinical scores in the adjuvant arthritis rats. Toonaciliatin K decreased the proinflammatory cytokines levels and Mankin scores in adjuvant arthritis rats. The HE staining, safranin O-fast green, and toluidine blue staining results demonstrated that toonaciliatin K alleviated the histological changes of paw, for example, pannus formation, focal loss of cartilage, bone erosion, and presence of extra-articular inflammation. Hence, toonaciliatin K is a promising agent for treatment of arthritis.
Toll-Like Receptor Ligand-Induced Liver Injury in D-Galactosamine-Sensitized Mice: Differences between TLR7/8 and TLR9 Ligands, Cytokine Patterns, and Cross-Tolerance Induction by TLR2 Ligand Pretreatment
Authors: Seki Reiko
Published: October 2017

Administration of Toll-like receptor ligands (TLRLs) is known to cause liver injury in D-galN-sensitized mice. In the present study, we aimed to complement preceding reports on the TLRL/D-galN system by analyzing comparisons among TLRLs, mouse strain dependence, effects on serum levels of cytokines, and effects of sequential administrations of different TLRLs. In a preliminary set of analyses, we first confirmed that liver failure can be induced by diverse TLRLs, including LTA and R848 in combination with D-galN. Analysis using TLR4-deficient mice excluded potential confounding effects of endogenous TLR4Ls that include those referred to as DAMPs in CpG DNA/D-galN hepatotoxicity. Subsequently, we showed that LTA pretreatment could prevent mortality in both CpG DNA/D-galN- and R848/D-galN-treated mice compared to without pretreatment. Incidentally, we observed that without the LTA pretreatment, CpG DNA/D-galN showed relatively higher liver-specific toxicity whereas R848/D-galN showed more symptoms of multiple organ failure. These findings suggest that, in D-galN-sensitized mice, different TLRLs not only show similarity in the ability to induce hepatic injury but also exhibit distinctive abilities in inducing systemic inflammation and multiple organ failure. These findings also suggest the potential usefulness of cross-tolerance induction using LTA in the prevention of organ failure in TLRL-mediated acute inflammation.
An Akt3 Splice Variant Lacking the Serine 472 Phosphorylation Site Promotes Apoptosis and Suppresses Mammary Tumorigenesis
Authors: Suyama Kimita , Yao Jiahong , Liang Huizhi , Benard Outhiriaradjou , Loudig Olivier D. , Amgalan Dulguun , McKimpson Wendy M. , Phillips Greg R. , Segall Jeffrey , Wang Yihong , Fineberg Susan , Norton Larry , Kitsis Richard N. , Hazan Rachel B.
Published: October 2017

The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/−S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple-negative breast cancer cells, specific ablation of Akt3/−S472 enhanced, whereas overexpression, suppressed mammary tumor growth, consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to striking induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by marked endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting, as opposed to suppressing, apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.

Significance: These results illuminate an unexpected function for an endogenously expressed Akt isoform in promoting apoptosis, underscoring the likelihood that different Akt isoforms exert distinct functions in human cancer. Cancer Res; 78(1); 103–14. ©2017 AACR.
Administering xCT Inhibitors Based on Circadian Clock Improves Antitumor Effects
Authors: Okazaki Fumiyasu , Matsunaga Naoya , Hamamura Kengo , Suzuki Kayoko , Nakao Takaharu , Okazaki Hiroyuki , Kutsukake Masahiko , Fukumori Shiro , Tsuji Yasuhiro , To Hideto
Published: October 2017

Clock genes encoding transcription factors that regulate circadian rhythms may inform chronomodulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here, we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chronomodulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies. Cancer Res; 77(23); 6603–13. ©2017 AACR.
Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression
Authors: Kim Sungjin , Alsaidan Omar Awad , Goodwin Octavia , Li Qianjin , Sulejmani Essilvo , Han Zhen , Bai Aiping , Albers Thomas , Beharry Zanna , Zheng Y. George , Norris James S. , Szulc Zdzislaw M. , Bielawska Alicja , Lebedyeva Iryna , Pegan Scott D. , Cai Houjian
Published: October 2017

Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects in vivo. Structural optimization based on structure–activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. Cancer Res; 77(24); 6950–62. ©2017 AACR.
Tissue Force Programs Cell Fate and Tumor Aggression
Authors: Northey Jason J. , Przybyla Laralynne , Weaver Valerie M.
Published: October 2017

Biomechanical and biochemical cues within a tissue collaborate across length scales to direct cell fate during development and are critical for the maintenance of tissue homeostasis. Loss of tensional homeostasis in a tissue not only accompanies malignancy but may also contribute to oncogenic transformation. High mechanical stress in solid tumors can impede drug delivery and may additionally drive tumor progression and promote metastasis. Mechanistically, biomechanical forces can drive tumor aggression by inducing a mesenchymal-like switch in transformed cells so that they attain tumor-initiating or stem-like cell properties. Given that cancer stem cells have been linked to metastasis and treatment resistance, this raises the intriguing possibility that the elevated tissue mechanics in tumors could promote their aggression by programming their phenotype toward that exhibited by a stem-like cell.

Significance: Recent findings argue that mechanical stress and elevated mechanosignaling foster malignant transformation and metastasis. Prolonged corruption of tissue tension may drive tumor aggression by altering cell fate specification. Thus, strategies that could reduce tumor mechanics might comprise effective approaches to prevent the emergence of treatment-resilient metastatic cancers. Cancer Discov; 7(11); 1224–37. ©2017 AACR.
A Blueprint to Advance Colorectal Cancer Immunotherapies
Authors: Le Dung T. , Hubbard-Lucey Vanessa M. , Morse Michael A. , Heery Christopher R. , Dwyer Andrea , Marsilje Thomas H. , Brodsky Arthur N. , Chan Emily , Deming Dustin A. , Diaz Luis A. , Fridman Wolf H. , Goldberg Richard M. , Hamilton Stanley R. , Housseau Franck , Jaffee Elizabeth M. , Kang S. Peter , Krishnamurthi Smitha S. , Lieu Christopher H. , Messersmith Wells , Sears Cynthia L. , Segal Neil H. , Yang Arvin , Moss Rebecca A. , Cha Edward , O'Donnell-Tormey Jill , Roach Nancy , Davis Anjelica Q. , McAbee Keavy , Worrall Sharyn , Benson Al B.
Published: October 2017

Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability–high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942–9. ©2017 AACR.
Diagnosing Psychopathy through Emotional Regulation Tasks: Heart Rate Variability versus Implicit Association Test
Authors: Flórez Gerardo , Vila Xosé A. , Lado María J. , Cuesta Pedro , Ferrer Ventura , García Luis S. , Crespo María R. , Pérez Manuel
Published: October 2017

Background: Nowadays, the assessment of psychopathy relies on semistructured interviews plus file reviews. In order to improve the predictive validity of psychopathy at the individual level, tools that are not based on the rating of signs and symptoms are in great need. Sampling and Methods: The present study was conducted in a representative sample of 204 Spanish sentenced inmates. These inmates have served at least 6 months of their sentence at the Pereiro de Aguiar (Ourense, Spain) penitentiary. Psychopathy signs and symptoms were scored through interview and file review. The Implicit Association Test (IAT) and heart rate variability (HRV) experiments were also conducted. The Iowa Gambling Task (IGT) was performed as a control measure. Results: Spectral HRV indices were able to detect psychopathic inmates at a significant level, while IAT experiments and the IGT could not discriminate them. HRV indices showed a more significant difference when assessing the affective-interpersonal dimensions of psychopathy. Conclusions: An HRV experiment is better than IAT in order to detect psychopathy in a representative sample of Spanish inmates.
Abdominal Ultrasound Findings of Tumor-Forming Hepatic Malignant Lymphoma
Authors: Kitahata Shogo , Hiraoka Atsushi , Kudo Masatoshi , Murakami Taisei , Ochi Marie , Izumoto Hirofumi , Ueki Hidetaro , Kaneto Miho , Aibiki Toshihiko , Okudaira Tomonari , Yamago Hiroka , Miyamoto Yuji , Iwasaki Ryuichiro , Tomida Hideomi , Mori Kenichiro , Kishida Masato , Miyata Hideki , Tsubouchi Eiji , Hirooka Masashi , Koizumi Yohei , Ninomiya Tomoyuki , Hiasa Yoichi , Michitaka Kojiro
Published: October 2017

Aim/Background: Evaluations of abdominal ultrasonography (US) findings of primary and secondary tumor-forming hepatic malignant lymphoma (HML) have not been adequately reported. In this study, we elucidated US and contrast-enhanced US (CEUS) findings in patients with HML. Materials/Methods: From January 2006 to March 2017, 25 patients with HML were enrolled (primary 7, secondary 18), each of whom was diagnosed pathologically. They were divided into 2 groups based on tumor diameter (cutoff, 30 mm). US imaging findings were retrospectively analyzed. Results: All tumors in patients with a small HML (<30 mm in diameter, small group, n = 14) were revealed as homogeneous hypo-echoic type (100%), with penetrating sign observed in only 1 patient. Tumors in 11 patients in the small group, examined with CEUS, showed homogeneous enhancement in the early vascular phase (91%) and a washout pattern in the portal phase (100%), and they were revealed as defective in the post-vascular phase (100%). In the large group (≥30 mm; n = 11), tumors were revealed as a heterogeneous hypo-echoic lesion in 10 (91%) and penetrating sign was observed in 8 (73%). Dilatation of the distal intrahepatic bile duct by the tumor was observed in 4 patients in the large group. In 7 large group patients examined with CEUS, imaging findings in the early vascular phase varied, with 5 (71%) showing a washout pattern in the portal phase and 5 (71%) revealed as defective in the post-vascular phase. Conclusion: We found that US imaging features of HML differ depending on the tumor diameter.
Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients
Authors: Kobayashi Natsuko , Kumada Takashi , Toyoda Hidenori , Tada Toshifumi , Ito Takanori , Kage Masayoshi , Okanoue Takeshi , Kudo Masatoshi
Published: October 2017

Background: Several laboratory markers used in lieu of liver biopsy are reportedly useful in the diagnosis of nonalcoholic steatohepatitis (NASH). In the present study, we investigated the diagnostic impact of various non-invasive markers for predicting NASH. Methods: A total of 229 nonalcoholic fatty liver disease (NAFLD) patients who underwent liver biopsy were enrolled for the study. The diagnostic ability of various markers to diagnose NASH from NAFLD was investigated. Results: A total of 140 patients were histologically diagnosed with NASH. Of these, 104 had degree 0-2 fibrosis (F0-2), and 36 had degree 3-4 fibrosis (F3-4). Multiple logistic regression analysis identified hyaluronic acid (HA) (OR 1.014; 95% CI 1.002-1.026; p = 0.024), FIB-4 index (OR 2.097; 95% CI 1.177-3.735; p = 0.012), and cytokeratin-18 fragments (CK-18F) (OR 1.002; 95% CI 1.001-1.002; p < 0.001) as factors independently associated with the diagnosis of NASH. The areas under the receiver operating characteristic curves (AUROCs) of HA, FIB-4 index, and CK-18F for the diagnosis of NASH were 0.77, 0.76, and 0.72, respectively. In addition, FIB-4 index (OR 1.907; 95% CI 1.063-3.419; p = 0.03) and CK-18F (OR 1.002; 95% CI 1.001-1.002; p < 0.001) could differentiate between NASH and NAFL, even when NASH patients with advanced fibrosis (F3-4) were excluded. AUROCs of FIB-4 index and CK-18F for the diagnosis of NASH with mild fibrosis (F0-2) from NAFLD were 0.70 and 0.70, respectively. Conclusions: FIB-4 index and CK-18F have good diagnostic abilities not only for NASH overall, but also for NASH with mild fibrosis.
Impact of Tumor Factors on Survival in Patients with Hepatocellular Carcinoma Classified Based on Kinki Criteria Stage B2
Authors: Arizumi Tadaaki , Minami Tomohiro , Chishina Hirokazu , Kono Masashi , Takita Masahiro , Yada Norihisa , Hagiwara Satoru , Minami Yasunori , Ida Hiroshi , Ueshima Kazuomi , Kamata Ken , Minaga Kosuke , Komeda Yoriaki , Takenaka Mamoru , Sakurai Toshiharu , Watanabe Tomohiro , Nishida Naoshi , Kudo Masatoshi
Published: October 2017

Background: Tumors classified based on the Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are heterogeneous in nature. Previously, the Kinki criterion was proposed for a more precise subclassification of tumors in BCLC-stage B. However, tumors in sub-stage B2 include various size and number of HCCs even with the Kinki criteria, which could lead to heterogeneity for overall survival (OS). In this study, we assessed how the size and number of tumors affect the OS and time to progression (TTP) in patients with Kinki criteria stage B2 tumors and treated with transarterial chemoembolization (TACE). Methods: Of 906 HCC patients treated with TACE at Kindai University Hospital, 236 patients with HCC considered as Kinki criteria stage B2 were examined. They were classified into the following 4 groups according to the maximum tumor diameter and number of tumors: B2a group, tumor size ≤6 cm and total number of tumors ≤6; B2b group, size ≤6 cm and number >6; B2c group, size >6 cm and number ≤6; and B2d group, size >6 cm and number >6. The OS and TTP of patients in each group were compared. Results: There were 131 patients (55.5%) in the B2a group, 58 (24.6%) in the B2b group, 41 (17.4%) in the B2c group, and 6 (0.03%) in the B2d group. Comparison of the survivals revealed that the median OS was 2.8 years (95% CI 2.0-3.5) in the B2a group, 2.8 years (95% CI 2.0-3.3) in the B2b group, 1.9 years (95% CI 0.8-4.0) in the B2c group, and 2.3 years (95% CI 1.2-ND [no data]) in the B2d group, respectively (p = 0.896). The median TTP in B2a, B2b, B2c, and B2d sub-substage HCC were13.2, 12.1, 13.8, and 11.5 months, respectively (p = 0.047). The median TTP in B2a + B2c sub-substage patients was longer than that in B2b + B2d sub-substage HCC patients (14.0 months and 10.4 months; p = 0.002). Conclusion: No significant differences were observed in the OS among HCC patients subclassified based on the maximum tumor diameter and tumor number in Kinki criteria stage B2. Consequently, Kinki criteria stage B2 HCC is a homogeneous subgroup in terms of OS prediction. However, shorter TTP in B2b+B2c sub-substage HCC patients than that in B2a + B2c sub-substage HCC patients suggests that different treatment strategy, such as systemic therapy with targeted agents instead of TACE, may be suitable to preserve the liver function.
Immune Checkpoint Inhibitor-Associated Type 1 Diabetes Mellitus: Case Series, Review of the Literature, and Optimal Management
Authors: Kapke Jonathan , Shaheen Zachary , Kilari Deepak , Knudson Paul , Wong Stuart
Published: October 2017

With the introduction of immune checkpoint inhibitors into clinical practice, various autoimmune toxicities have been described. Antibodies targeting the receptor:ligand pairing of programmed death receptor-1 (PD-1) and its cognate ligand programmed death-ligand 1 (PD-L1) in rare reports have been associated with autoimmune diabetes mellitus. We report 2 cases of rapid-onset, insulin-dependent, type 1 diabetes mellitus in the setting of administration of nivolumab, a fully human monoclonal antibody to PD-1, and atezolizumab, a humanized monoclonal antibody to PD-L1. This appears to be the first report of autoimmune diabetes mellitus associated with atezolizumab. In addition, we provide a brief review of similar cases reported in the literature and a discussion of potential mechanisms for this phenomenon and propose a diagnostic and treatment algorithm.
Sulforaphane and Epigallocatechin Gallate Restore Estrogen Receptor Expression by Modulating Epigenetic Events in the Breast Cancer Cell Line MDA-MB-231: A Systematic Review and Meta-Analysis
Authors: Gianfredi Vincenza , Vannini Samuele , Moretti Massimo , Villarini Milena , Bragazzi Nicola Luigi , Izzotti Alberto , Nucci Daniele
Published: October 2017

Background/Aims: Epigenetics refers to modifications in gene activity and expression without alteration at the DNA sequence. Environment and diet could influence gene expression. Diet modifications may be meaningful in preventing and treating chronic diseases, cancer included. Dietary bioactive compounds, such as polyphenols (e.g., curcumin, resveratrol, or epigallocatechin gallate [EGCG]) or isothiocyanate (e.g., sulforaphane [SFN]), can regulate histone acetylation. The aim of this systematic review and meta-analysis was to evaluate the effect of SFN and EGCG on breast cancer (BC) cells cultured in vitro. Methods: Due to the enormous variability observed in study protocols and the innumerable genes involved, only studies analyzing the number of apoptotic cells in the MDA-MB-231 cell line were evaluated. The effect size (ES) was computed as the ratio of means. Results: We identified 7 studies, 4 regarding the effect of 10 µM SFN on MDA-MB-231 cells (ES = 4.59, 95% confidence interval 4.05-5.20) and 3 focusing on the impact of 20 µM EGCG (ES = 2.84, 95% confidence interval 2.60-3.10). Conclusion: The findings suggest beneficial effects of dietary bioactive compounds such as SFN and EGCG and their effect on BC cells by restoring estrogen receptor gene expression, modulating epigenetic changes and events, and interfering with tumor growth rate. Publication bias limits the generalizability of the conclusions. High-quality studies are needed.
Wilms' Tumor Gene 1 (WT1) Peptide Vaccine Therapy for Hematological Malignancies: From CTL Epitope Identification to Recent Progress in Clinical Studies Including a Cure-Oriented Strategy
Authors: Oka Yoshihiro , Tsuboi Akihiro , Nakata Jun , Nishida Sumiyuki , Hosen Naoki , Kumanogoh Atsushi , Oji Yusuke , Sugiyama Haruo
Published: October 2017

The identification of human Wilms' tumor gene 1 (WT1) protein-derived cytotoxic T lymphocyte (CTL) epitopes and the in vivo efficacy of WT1 peptide-based immunotherapy in a mouse model were reported in 2000. This successful basic research led to clinical studies of a WT1 peptide vaccine, and a positive impact on clinical response was first demonstrated in 2003 in the form of a reduction in blast cells of vaccine-treated patients with myelodysplastic syndromes (MDS). Since then, data on WT1 peptide vaccine-treated patients with immunological and/or clinical response have been accumulated. MDS and acute myeloid leukemia were the major target diseases to provide proof of concept for the therapeutic potential of the WT1 peptide vaccine. WT1 vaccination-induced clinical responses or usefulness were also shown for chronic myeloid leukemia, multiple myeloma, and acute lymphoblastic leukemia, as well as various types of solid cancers. Non-Hodgkin's lymphoma and myeloproliferative neoplasms may also be target diseases because of their WT1 expression. Of note, recent clinical studies have demonstrated that patients with hematological malignancies who have minimal residual disease after chemotherapy or allogeneic hematopoietic stem cell transplantation may be cured by WT1 peptide vaccination. Further enhancement of the efficacy and usefulness of the WT1 peptide vaccine is expected.
Genetic Variations of Oxidative Stress Related Genes ALOX5, ALOX5AP and MPO Modulate Ischemic Stroke Susceptibility Through Main Effects and Epistatic Interactions in a Chinese Population
Authors: Liu Ding , Liu Lei , Song Zhi , Hu Zhongyang , Liu Jia , Hou Deren
Published: October 2017

Background/Aims: To investigate the roles of the oxidative stress related-genes ALOX5, ALOX5AP and MPO in ischemic stroke susceptibility in the Han Chinese population. Methods: A total of 351 ischemic stroke patients and 417 controls were recruited. The ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 gene polymorphisms were genotyped. Results: We identified that rs2107545 of MPO gene was significantly associated with ischemic stroke susceptibility after adjusting for covariates. Furthermore, we also considered the likely complexity of oxidative stress and inflammatory process in stroke by assessing the combined effects of multiple genes. Generalized multifactor dimensionality reduction (GMDR) analysis revealed that the combination of ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 was significantly associated with increased risk of ischemic stroke (P=0.0040, OR (95% CI) =1.991 (1.241 to 3.195)). Additionally, the MPO rs2107545 genotype was significantly associated with clinical outcomes at 6 months after discharge from the hospital. Conclusion: Our study revealed that epistatic interaction among the ALOX5, ALOX5AP and MPO genes played a significant role in vulnerability to ischemic stroke. Furthermore, these results also suggest that the rs2107545 of MPO gene can be used as a biomarker for the susceptibility and prognosis of ischemic stroke patients.
Neutrophils Kill Reactive Oxygen Species-Resistant Pseudomonas aeruginosa by Sphingosine
Authors: Becker Katrin Anne , Li Xiang , Seitz Aaron , Steinmann Joerg , Koch Anne , Schuchman Edward , Kamler Markus , Edwards Michael J. ,  Caldwell Charles C. , Gulbins Erich
Published: October 2017

Background/Aims: Cystic fibrosis (CF) is dominated by chronic inflammation and infection of the lung resulting in lung destruction and early death of patients. The lungs of CF patients are characterized by a massive accumulation of neutrophils. It requires definition why these massive numbers of neutrophils fail to eliminate typical CF pathogens like Staphylococcus aureus and Pseudomonas aeruginosa (P. aeruginosa) in CF lungs. Methods: We determined ceramide, sphingosine and reactive oxygen species (ROS) in neutrophils from wildtype and CF mice and determined the effect of sphingosine and ROS alone or in combination on killing of different P. aeruginosa strains. Results: We demonstrate that wildtype neutrophils are able to kill non-mucoid and mucoid clinical P. aeruginosa strains, while neutrophils from CF mice are insufficient to kill these P. aeruginosa strains, although both types of neutrophils infected with P. aeruginosa produce comparable levels of superoxide. All three analyzed P. aeruginosa strains are resistant to reactive oxygen species. The inability of CF neutrophils to kill P. aeruginosa is caused by a marked decrease of surface sphingosine levels in CF neutrophils. Wildtype neutrophils contain much higher concentrations of surface sphingosine than CF neutrophils. Further, wildtype neutrophils, but not CF neutrophils, release sphingosine, most likely as microparticles, upon infection. Sphingosine kills P. aeruginosa in vitro at low micromolar concentrations. Reconstitution of sphingosine in CF neutrophils restores their ability to kill these pathogens, demonstrating the significance of sphingosine for bacterial killing. Conclusion: The data provide evidence for a new paradigm explaining how neutrophils kill ROS-resistant P. aeruginosa, i.e. by sphingosine that kills P. aeruginosa at low concentrations. This mechanism is defective in CF neutrophils.
Gene Microarray Integrated with High-Throughput Proteomics for the Discovery of Transthyretin in Rhabdomyolysis-Induced Acute Kidney Injury
Authors: Li Ou , Geng Xiaodong , Ma Qian , Wang Weiwei , Liu Ran , Yin Zhong , Wang Siyang , Cai Guangyan , Chen Xiangmei , Hong Quan
Published: October 2017

Background/Aims: Rhabdomyolysis, one of the leading causes of acute kidney injury (AKI), develops after trauma, drug toxicity, infections, burns, and physical exertion. The aim of this study was to investigate differences in gene and protein expression to elucidate the pathogenesis of rhabdomyolysis (RM)-induced AKI. Methods: In this study, we used glycerol induced renal injury as a model of RM-induced AKI. Affymetrix U133 plus 2.0 microarrays were used to perform gene microarray analysis. Isobaric tagging with related and absolute quantitation (iTRAQ) labeling mass spectrometry (MS) was applied to screen and identify differentially expressed proteins between RM-induced AKI and normal murine renal tissue. Verification experiments included immunohistochemistry (IHC), real-time PCR, Western blotting, and the measurement of ATP and ROS production. HK-2 cells were incubated in vitro with ferrous myoglobin and pcDNA-TTR, followed by assays to detect cell proliferation, ROS and apoptosis. Results: According to gene microarray and iTRAQ-MS analysis, we screened 17 common elements. After multiple analyses, we selected transthyretin (TTR) as our focus and investigated TTR in the kidney. Verification experiments with IHC confirmed differential expression levels of TTR proteins. Furthermore, Western blotting showed a stepwise decrease in TTR in AKI renal tissues. Cell-based experiments showed that overexpression of TTR could improve HK-2 cell viability and inhibit apoptosis. TTR reduced apoptosis by decreasing the accumulation of reactive oxygen species (ROS). Conclusion: This study reports a possible mechanism for RM-induced AKI and suggests that reductions in TTR could increase the generation of ROS and induce apoptosis. TTR may be a potentially valuable target for RM-induced AKI.
Precision Medicine for Cardiac Resynchronization
Authors: Nassif Michael E. , Tang Yuanyuan , Cleland John G. , Abraham William T. , Linde Cecilia , Gold Michael R. , Young James B. , Daubert J. Claude , Sherfesee Lou , Schaber Dan , Tang Anthony S.L. , Jones Philip G. , Arnold Suzanne V. , Spertus John A.
Published: October 2017

Background:

Clinical trials have established the average benefit of cardiac resynchronization therapy (CRT), but estimating benefit for individual patients remains difficult because of the heterogeneity in treatment response. Accordingly, we created a multivariable model to predict changes in quality of life (QoL) with and without CRT.

Methods and Results:

Patient-level data from 5 randomized trials comparing CRT with no CRT were used to create a prediction model of change in QoL at 3 months using a partial proportional odds model for no change, small, moderate, and large improvement, or deterioration of any magnitude. The C statistics for not worsening or obtaining at least a small, moderate, and large improvement were calculated. Among the 3614 patients, regardless of assigned treatment, 33.3% had a deterioration in QoL, 9.2% had no change, 9.2% had a small improvement, 13.5% had a moderate improvement, and the remaining 34.9% had a large improvement. Patients undergoing CRT were less likely to have a decrement in their QoL (28.2% versus 38.9%;
P
<0.001) and more likely to have a large QoL improvement (38.7% versus 30.6%;
P
<0.001). A partial proportional odds model identified baseline QoL, age, and an interaction of CRT with QRS duration as predictors of QoL benefits 3 months after randomization. C statistics of 0.65 for not worsening, 0.68 for at least a small improvement, 0.69 for at least a moderate improvement, and 0.73 for predicting a large improvement were observed.

Conclusions:

There is marked heterogeneity of treatment benefit of CRT that can be predicted based on baseline QoL, age, and QRS duration.
Effect of Elective Percutaneous Coronary Intervention on Hyperemic Absolute Coronary Blood Flow Volume and Microvascular Resistance
Authors: Kanaji Yoshihisa , Murai Tadashi , Yonetsu Taishi , Usui Eisuke , Araki Makoto , Matsuda Junji , Hoshino Masahiro , Yamaguchi Masao , Niida Takayuki , Hada Masahiro , Ichijyo Sadamitsu , Hamaya Rikuta , Kanno Yoshinori , Isobe Mitsuaki , Kakuta Tsunekazu
Published: October 2017

Background—

The hemodynamics involved in the relationship between absolute coronary blood flow (ABF) volume and myocardial resistance (MR) are complex, and the effect of percutaneous coronary intervention (PCI) on their changes remains unclear. The aim of this study was to investigate the differences in hyperemic ABF and MR before and after elective PCI using a thermodilution method.

Methods and Results—

We investigated 28 vessels (right coronary artery, 9; left anterior descending coronary artery, 18; left circumflex coronary artery, 1) from 28 patients with stable angina pectoris undergoing elective PCI. ABF was measured pre- and post-PCI using a pressure–temperature sensor-equipped wire, based on a thermodilution method with a continuous saline infusion of 20 mL/min through a proximally located microcatheter with an end-hole in the target vessel. MR equals distal coronary perfusion pressure divided by ABF at maximal hyperemia. Conventional fractional flow reserve was also measured pre- and post-PCI. Fractional flow reserve increased significantly after PCI (from 0.70 [0.65–0.75] to 0.88 [0.85–0.95]) in all examined territories. ABF also increased significantly (from 137.8 mL/min [86.3–180.8 mL/min] to 173.3 mL/min [137.9–234.3 mL/min] ; increase: 52.8 mL/min [9.7–80.8 mL/min]) while MR decreased in 11 vessels and increased in 17. No significant relationship was detected between these increases in fractional flow reserve and ABF. Both pre- and post-PCI MR distributed in a wide range, and there was a significant relationship between pre-PCI MR and the increase in ABF (
r
=0.44;
P
=0.02) although no significant change in MR was observed between pre- and post-PCI (
P
=0.37).

Conclusions—

Direct measurement of ABF and MR using thermodilution method offers a feasible approach that could shed a light on previously unclear aspects of coronary hemodynamics.
Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts
Authors: Magnussen Christina , Niiranen Teemu J. , Ojeda Francisco M. , Gianfagna Francesco , Blankenberg Stefan , Njølstad Inger , Vartiainen Erkki , Sans Susana , Pasterkamp Gerard , Hughes Maria , Costanzo Simona , Donati Maria Benedetta , Jousilahti Pekka , Linneberg Allan , Palosaari Tarja , de Gaetano Giovanni , Bobak Martin , den Ruijter Hester M. , Mathiesen Ellisiv , Jørgensen Torben , Söderberg Stefan , Kuulasmaa Kari , Zeller Tanja , Iacoviello Licia , Salomaa Veikko , Schnabel Renate B.
Published: October 2017

Background:

Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood.

Methods:

In N=79 793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1–97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years.

Results:

Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12–1.23 in women versus 1.31; 95% CI 1.25–1.38 in men; interaction
P
value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81–0.90 versus 0.92; 95% CI, 0.88–0.97 in men; interaction
P
value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index.

Conclusions:

Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.