bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient and Reliable Error Detection Architectures of Hash-Counter-Hash Tweakable Enciphering Schemes
Authors: Mozaffari-Kermani Mehran , Azarderakhsh Reza , Sarker Ausmita , Jalali Amir
Published: January 2018

Through pseudorandom permutation, tweakable enciphering schemes (TES) constitute block cipher modes of operation which perform length-preserving computations. The state-of-the-art research has focused on different aspects of TES, including implementations on hardware [field-programmable gate array (FPGA)/ application-specific integrated circuit (ASIC)] and software (hard/soft-core microcontrollers) platforms, algorithmic security, and applicability to sensitive, security-constrained usage models. In this article, we propose efficient approaches for protecting such schemes against natural and malicious faults. Specifically, noting that intelligent attackers do not merely get confined to injecting multiple faults, one major benchmark for the proposed schemes is evaluation toward biased and burst fault models. We evaluate a variant of TES, i.e., the Hash-Counter-Hash scheme, which involves polynomial hashing as other variants are either similar or do not constitute finite field multiplication which, by far, is the most involved operation in TES. In addition, we benchmark the overhead and performance degradation on the ASIC platform. The results of our error injection simulations and ASIC implementations show the suitability of the proposed approaches for a wide range of applications including deeply embedded systems.
Rat models of 17β-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention
Authors: Shull James D. , Dennison Kirsten L. , Chack Aaron C. , Trentham-Dietz Amy
Published: January 2018

Numerous laboratory and epidemiologic studies strongly implicate endogenous and exogenous estrogens in the etiology of breast cancer. Data summarized herein suggest that the ACI rat model of 17β-estradiol (E2)-induced mammary cancer is unique among rodent models in the extent to which it faithfully reflects the etiology and biology of luminal types of breast cancer, which together constitute ~70% of all breast cancers. E2 drives cancer development in this model through mechanisms that are largely dependent upon estrogen receptors and require progesterone and its receptors. Moreover, mammary cancer development appears to be associated with generation of oxidative stress and can be modified by multiple dietary factors, several of which may attenuate the actions of reactive oxygen species. Studies of susceptible ACI rats and resistant COP or BN rats provide novel insights into the genetic bases of susceptibility and the biological processes regulated by genetic determinants of susceptibility. This review summarizes research progress resulting from use of these physiologically relevant rat models to advance understanding of breast cancer etiology and prevention.
Artificial intelligence, physiological genomics, and precision medicine
Authors: Williams Anna Marie , Liu Yong , Regner Kevin R. , Jotterand Fabrice , Liu Pengyuan , Liang Mingyu
Published: January 2018

Big data are a major driver in the development of precision medicine. Efficient analysis methods are needed to transform big data into clinically-actionable knowledge. To accomplish this, many researchers are turning toward machine learning (ML), an approach of artificial intelligence (AI) that utilizes modern algorithms to give computers the ability to learn. Much of the effort to advance ML for precision medicine has been focused on the development and implementation of algorithms and the generation of ever larger quantities of genomic sequence data and electronic health records. However, relevance and accuracy of the data are as important as quantity of data in the advancement of ML for precision medicine. For common diseases, physiological genomic readouts in disease-applicable tissues may be an effective surrogate to measure the effect of genetic and environmental factors and their interactions that underlie disease development and progression. Disease-applicable tissue may be difficult to obtain, but there are important exceptions such as kidney needle biopsy specimens. As AI continues to advance, new analytical approaches, including those that go beyond data correlation, need to be developed and ethical issues of AI need to be addressed. Physiological genomic readouts in disease-relevant tissues, combined with advanced AI, can be a powerful approach for precision medicine for common diseases.
RNF6 Promotes Colorectal Cancer by Activating the Wnt/β-Catenin Pathway via Ubiquitination of TLE3
Authors: Liu Lei , Zhang Yanquan , Wong Chi Chun , Zhang Jingwan , Dong Yujuan , Li Xiangchun , Kang Wei , Chan Francis K.L. , Sung Joseph J.Y. , Yu Jun
Published: January 2018

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the β-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of β-catenin to TCF4/LEF, triggering Wnt/β-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis.

Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/β-catenin pathway in colorectal carcinogenesis. Cancer Res; 78(8); 1958–71. ©2018 AACR.
Circulating Tumor Cells with Stem-Like Phenotypes for Diagnosis, Prognosis, and Therapeutic Response Evaluation in Hepatocellular Carcinoma
Authors: Guo Wei , Sun Yun-Fan , Shen Min-Na , Ma Xiao-Lu , Wu Jiong , Zhang Chun-Yan , Zhou Yan , Xu Yang , Hu Bo , Zhang Min , Wang Gang , Chen Wei-Qin , Guo Lin , Lu Ren-Quan , Zhou Chao-Hui , Zhang Xin , Shi Ying-Hong , Qiu Shuang-jian , Pan Bai-shen , Cao Ya , Zhou Jian , Yang Xin-Rong , Fan Jia
Published: January 2018

Background: In the present study, we assessed the clinical value of circulating tumor cells (CTC) with stem-like phenotypes for diagnosis, prognosis, and surveillance in hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC) by an optimized qPCR-based detection platform.

Methods: Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter patient study with independent validation (total n = 1,006), including healthy individuals and patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL), and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of the CTC panel in treatment response surveillance and its prognostic significance were further investigated.

Results: The AUC of the CTC panel was 0.88 in the training set [sensitivity = 72.5%, specificity = 95.0%, positive predictive value (PPV) = 92.4, negative predictive value (NPV) = 77.8] and 0.93 in the validation set (sensitivity = 82.1%, specificity = 94.2%, PPV = 89.9, NPV = 89.3). This panel performed equally well in detecting early-stage and α-fetoprotein–negative HCC, as well as differentiating HCC from CHB, LC, and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of the CTC panel in predicting tumor recurrence was further confirmed [training: HR = 2.692; 95% confidence interval (CI), 1.617–4.483; P < 0.001; and validation: HR = 3.127; 95% CI, 1.360–7.190; P = 0.007].

Conclusions: Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies. Clin Cancer Res; 24(9); 2203–13. ©2018 AACR.
Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study
Authors: George Daniel J. , Martini Jean-François , Staehler Michael , Motzer Robert J. , Magheli Ahmed , Escudier Bernard , Gerletti Paola , Li Sherry , Casey Michelle , Laguerre Brigitte , Pandha Hardev S. , Pantuck Allan J. , Patel Anup , Lechuga Maria J. , Ravaud Alain
Published: January 2018

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit.

Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan–Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated.

Results: Baseline characteristics were similar in patients with (n = 191) and without (n = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density ≥ versus < median [median (95% CI), not reached (6.83–not reached) versus 3.47 years (1.73–not reached); hazard ratio (HR) 0.40 (95% CI, 0.20–0.81); P = 0.009] treated with sunitinib (n = 101), but not with placebo (n = 90). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1+ versus PD-L1− tumors (HR 1.75; P = 0.103). Among all patients with PD-L1+ tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; P = 0.175).

Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. Clin Cancer Res; 24(7); 1554–61. ©2018 AACR.
Wide Expression and Significance of Alternative Immune Checkpoint Molecules, B7x and HHLA2, in PD-L1–Negative Human Lung Cancers
Authors: Cheng Haiying , Borczuk Alain , Janakiram Murali , Ren Xiaoxin , Lin Juan , Assal Amer , Halmos Balazs , Perez-Soler Roman , Zang Xingxing
Published: January 2018

Purpose: Immunotherapy targeting the PD-1/PD-L1 pathway has changed the treatment landscape of non–small cell lung carcinoma (NSCLC). We demonstrated that HHLA2, a newly identified immune inhibitory molecule, was widely expressed in NSCLC. We now compared the expression and function of PD-L1 with alternative immune checkpoints, B7x and HHLA2.

Experimental Design: Expression was examined in tissue microarrays consisting of 392 resected NSCLC tumors. Effects of PD-L1, B7x, and HHLA2 on human T-cell proliferation and cytokine production were investigated.

Results: PD-L1 expression was identified in 25% and 31% of tumors in the discovery and validation cohorts and was associated with higher stage and lymph node involvement. The multivariate analysis showed that stage, TIL status, and lymph node involvement were independently associated with PD-L1 expression. B7x was expressed in 69% and 68%, whereas HHLA2 was positive in 61% and 64% of tumors in the two sets. The coexpression of PD-L1 with B7x or HHLA2 was infrequent, 6% and 3%. The majority (78%) of PD-L1–negative cases expressed B7x, HHLA2, or both. The triple-positive group had more TIL infiltration than the triple-negative group. B7x-Ig and HHLA2-Ig inhibited TCR-mediated proliferation of CD4 and CD8 T cells more robustly than PD-L1-Ig. All three significantly suppressed cytokine productions by T cells.

Conclusions: The majority of PD-L1–negative lung cancers express alternative immune checkpoints. The roles of the B7x and HHLA2 pathway in mediating immune evasion in PD-L1–negative tumors deserve to be explored to provide the rationale for an effective immunotherapy strategy in these tumors. Clin Cancer Res; 24(8); 1954–64. ©2018 AACR.
Small-Cell Neuroendocrine Tumors: Cell State Trumps the Oncogenic Driver
Authors: Oser Matthew G. , Jänne Pasi A.
Published: January 2018

Small-cell neuroendocrine cancers often originate in the lung but can also arise in the bladder or prostate. Phenotypically, small-cell carcinoma of the bladder (SCCB) shares many similarities with small-cell lung cancer (SCLC). It is unknown whether SCCB and SCLC share common genetic driver mutations. Clin Cancer Res; 24(8); 1775–6. ©2018 AACR.

See related article by Chang et al., p. 1965
Contextual and Individual Determinants of Root Caries in Older People
Authors: Souza João Gabriel S. , Costa Oliveira Bárbara E. , Sampaio Aline A. , Lages Vinicius A. , Romão Dayse A. , Martins Andrea M.E.B.L.
Published: January 2018

The aim of this study was to identify the association of the presence of root caries in older people with contextual and individual determinants using a multilevel model. Data from the National Survey of Oral Health collected in Brazil were used. A sample of older Brazilians (aged 65-74 years) was included and selected through multistage probability cluster sampling, using probability proportional to size. Contextual variables of municipalities and individual variables of older people were included. Descriptive, bivariate, and multilevel analyses were conducted. Of the 3,926 older people included in the study, 934 (21.8%) had at least 1 tooth with root caries. There seemed to be no pattern of involvement between the anterior and posterior teeth in the dental arches. Multilevel analysis showed a higher presence of root caries among older people resident in municipalities that were noncapital cities (OR = 1.50), who were over 70 years of age (odds ratio, OR = 1.22), had nonwhite skin color (OR 1.35), had coronal caries (OR = 5.58), were dissatisfied with their teeth and mouth (OR = 1.47), and had self-perceived dental treatment needs (OR = 1.33). Contextual and individual determinants were associated with the occurrence of root caries in older people. Lesion presence demonstrated a profile of social inequality.
Theoretical Effect of DBS on Axonal Fibers of Passage: Firing Rates, Entropy, and Information Content
Authors: Arle Jeffrey E. , Mei Longzhi Z. , Carlson Kristen W. , Shils Jay L.
Published: January 2018

Background: Deep brain stimulation (DBS) has effects on axons that originate and terminate outside the DBS target area. Objective: We hypothesized that DBS generates action potentials (APs) in both directions in “axons of passage,” altering their information content and that of all downstream cells and circuits, and sought to quantify the change in fiber information content. Methods: We incorporated DBS parameters (fiber firing frequency and refractory time, and AP initiation location along the fiber and propagation velocity) in a filtering function determining the AP frequency reaching the postsynaptic cell. Using neural circuitry simulation software, we investigated the ability of the filtering function to predict the firing frequency of APs reaching neurons targeted by axons of passage. We calculated their entropy with and without DBS, and with the electrode applied at various distances from the cell body. Results: The predictability of the filtering function exceeded 98%. Entropy calculations showed that the entropy ratio “without DBS” to “with DBS” was always >1.0, thus DBS reduces fiber entropy. Conclusions: (1) The results imply that DBS effects are due to entropy reduction within fibers, i.e., a reduction in their information. (2) Where fibers of passage do not terminate in target regions, DBS may have side effects on nontargeted circuitry.
Functional Outcomes after Behavioral Treatment of Paradoxical Vocal Fold Motion in Adults
Authors: Drake Karen , Palmer Andrew D. , Schindler Joshua S. , Tilles Stephen A.
Published: January 2018

Objective: Paradoxical vocal fold motion (PVFM) is responsive to behavioral therapy, often resulting in a remission of symptoms, but little is known about whether treatment is beneficial with regard to PVFM-associated psychological symptoms or functional limitations. The goal of the study was to identify patient perceptions of the impact of treatment for PVFM and characteristics associated with treatment outcomes. Methods: A survey was conducted of all adults who had received at least 1 session of treatment for PVFM in our outpatient clinic over a 2-year period. Results: The 39 participants ranged in age from 18 to 82 and had received a median of 3 treatment sessions. At a median follow-up of 10 months following treatment, respondents reported improvements in a wide range of areas, including sports and leisure, daily activities, and social participation. The majority reported improvements in feelings of anxiety, helplessness, and control. Poorer outcomes were associated with more severe voice symptoms, fewer treatment sessions, and needing oral steroids for asthma control. Conclusion: There was a reduction in a wide range of activity limitations after treatment. Feelings of control were strongly associated with positive outcomes. The therapy appeared to be equally effective for adults with exercise-induced and environmental variants of PVFM.
Fluid Overload and Inflammation Axis
Authors: Dekker Marijke J.E. , van der Sande Frank M. , van den Berghe Florence , Leunissen Karel M.L. , Kooman Jeroen P.
Published: January 2018

Extracellular fluid overload (FO), which is assessed using bioimpedance technologies, is an important predictor of outcome in dialysis patients and in patients with early stages of chronic kidney disease. While traditional cardiovascular abnormalities are assumed to mediate this risk, recently also, the importance of noncardiovascular factors, such as systemic inflammation and malnutrition has been shown. While both FO and inflammation are independent risk factors for mortality, recent studies have shown that their combined presence can lead to a cumulative risk profile. From a pathophysiologic viewpoint, FO and inflammation can also be mutually reinforcing. Inflammation could contribute to FO by hypoalbuminemia, capillary leakage, and a (unnoticed) decline in lean and/or fat tissue mass resulting in incorrect estimation of dry weight. Reciprocally, FO could lead to inflammation by the translocation of endotoxins through a congested bowel wall or by a proinflammatory effect of tissue sodium. The relative importance of these putative factors is, however, not clear yet and epidemiological studies have shown no clear temporal direction regarding the relationship between FO and inflammation. FO and inflammation appear to be part of (dynamic) clusters of risk factors, including malnutrition and hyponatremia. Technology-guided fluid management of the often vulnerable dialysis patient with FO and inflammation cannot yet be based on evidence from randomized controlled trials, in which these specific patients were in general not included. In the absence of those trials, treatment should be based on identifying actionable causes of inflammation and on the judicious removal of excess volume based on frequent clinical reassessment.
Sodium Intake and Blood Pressure in Patients with Chronic Kidney Disease: A Salty Relationship
Authors: Nerbass Fabiana B. , Calice-Silva Viviane , Pecoits-Filho Roberto
Published: January 2018

Background: Hypertension affects almost all chronic kidney disease patients and is related to poor outcomes. Sodium intake is closely related to blood pressure (BP) levels in this population and decreasing its intake consistently improves the BP control particularly in short-term controlled trials. However, most patients struggle in following a controlled diet on sodium according to the guidelines recommendation due to several factors and barriers discussed in this article. Summary: This review article summarizes the current knowledge related to the associations between sodium consumption, BP, and the risk of cardiovascular disease and chronic kidney disease (CKD); it also provides recommendations of how to achieve sodium intake lowering. Key Messages: Evidences support the benefits in decreasing sodium intake on markers of cardiovascular and renal outcomes in CKD. Trials had shorter follow-up and to maintain long-term sodium intake control is a major challenge. Larger studies with longer follow-up looking at hard endpoints will be important to drive future recommendations.
Pregnancy and End-Stage Renal Disease
Authors: Tangren Jessica , Nadel Molly , Hladunewich Michelle A.
Published: January 2018

Pregnancy is uncommon in women with end-stage renal disease (ESRD). Fertility rates are low in women on dialysis, and physicians still frequently counsel women with ESRD against pregnancy. Advancements in the delivery of dialysis and obstetric care have led to improved live birth rates in women on dialysis, so pregnancy for young women with ESRD is now more feasible and safer. However, these pregnancies remain high-risk for both maternal and fetal complications, necessitating experienced multidisciplinary care. In this article, we review fertility issues in women with ESRD, discuss pregnancy outcomes in women on dialysis, and provide an approach for management of pregnant women with ESRD.
Visions in a Crystal Ball: The Future of Peritoneal Dialysis
Authors: Bargman Joanne M. , Girsberger Michael
Published: January 2018

Background: Peritoneal dialysis (PD) is one of the corner stones of renal replacement therapy and should be strongly considered if preemptive kidney transplantation is not available. Summary: There are several initiatives that may help the growth in the use of PD around the world. First, PD is an underused and valuable option in patients with heart failure and the chronic cardiorenal syndrome, especially in those with frequent hospitalizations despite optimal medical therapy. To identify these patients, an interdisciplinary approach of nephrologists and cardiologists is needed. These patients and other CKD patients with significant residual kidney function may do well with a regimen employing fewer than the usual number of bag exchanges, referred to as “incremental” dialysis. Second, acute kidney injury (AKI) is a worldwide burden with high morbidity and mortality, especially in low income countries. To reach the goal of zero preventable deaths caused by AKI by 2025 endorsed by the International Society of Nephrology, PD is the therapy of choice for treatment in this setting. Third, although dextrose has served well as the osmotic agent in PD solutions, there has been a continuous search for alternative agents. Hyperbranched polyglycerol might be such an osmole. Finally, to obviate the need for production and delivery of bags of PD solution, the development of home-generated dialysate is of interest. Key Message: The future of PD lies not only in accruing experience from the past decades, but also in staying open to other uses.
Choosing Home Hemodialysis: A Critical Review of Patient Outcomes
Authors: Miller Brent W. , Himmele Rainer , Sawin Dixie-Ann , Kim Jeeseon , Kossmann Robert J.
Published: January 2018

Background/Aim: Home hemodialysis (HHD) has been associated with improved clinical outcomes vs. in-center HD (ICHD). The prevalence of HHD in the United States is still very low at 1.8%. This critical review compares HHD and ICHD outcomes for survival, hospitalization, cardiovascular (CV), nutrition, and quality of life (QoL). Methods: Of 545 publications identified, 44 were not selected after applying exclusion criteria. A systematic review of the identified publications was conducted to compare HHD to ICHD outcomes for survival, hospitalization, CV outcomes, nutrition, and QoL. Results: Regarding mortality, 10 of 13 trials reported 13–52% reduction; three trials found no differences. According to 6 studies, blood pressure and left ventricular size measurements were generally lower in HHD patients compared to similar measurements in ICHD patients. Regarding nutritional status, conflicting results were reported (8 studies); some found improved muscle mass, total protein, and body mass index in HHD vs. ICHD patients, while others found no significant differences. There were no significant differences in the rate of hospitalization between HHD and ICHD in the 6 articles reviewed. Seven studies on QoL demonstrated positive trends in HHD vs. ICHD populations. Conclusions: Despite limitations in the current data, 66% of the publications reviewed (29/44) demonstrated improved clinical outcomes in patients who chose HHD. These include improved survival, CV, nutritional, and QoL parameters. Even though HHD may not be preferred in all patients, a review of the literature suggests that HHD should be provided as a modality choice for substantially more than the current 1.8% of HHD patients in the United States.
Relationships between Neighborhood Walkability and Objectively Measured Physical Activity Levels in Hemodialysis Patients
Authors: Han Maggie , Ye Xiaoling , Preciado Priscila , Williams Schantel , Campos Israel , Bonner Marcee , Young Candace , Marsh Daniel , Larkin John W. , Usvyat Len A. , Maddux Franklin W. , Pecoits-Filho Roberto , Kotanko Peter
Published: January 2018

Background/Aims: Neighborhood walkability is associated with indicators of health in the general population. We explored the association between neighborhood walkability and daily steps in hemodialysis (HD) patients. Methods: We measured daily steps over 5 weeks using Fitbit Flex (Fitbit, San Francisco, CA, USA) and retrieved Walk Score® (WS) data by patient’s home ZIP code (www.walkscore.com; 0 = poorest walkability; 100 = greatest walkability). Results: HD patients took a mean of 6,393 ± 3,550 steps/day (n = 46). Median WS of the neighborhood where they resided was 28. Patients in an above-median WS (n = 27) neighborhood took significantly more daily steps compared to those (n = 19) in a below-median WS neighborhood (7,514 ± 3,900 vs. 4,800 ± 2,228 steps/day; p < 0.001, t test). Daily steps and WS were directly correlated (R = 0.425; p = 0.0032, parametric test; R = 0.359, p = 0.0143, non-parametric test). Conclusion: This is the first study conducted among HD patients to indicate a direct relationship between neighborhood walkability and the actual steps taken. These results should be considered when designing initiatives to increase and improvise exercise routines in HD populations.
Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation
Authors: Cooper David K.C. , Iwase H. , Wang L. , Yamamoto T. , Li Qi , Li J. , Zhou H. , Hara H.
Published: January 2018

Background: There is a continuing critical shortage of organs from deceased human donors for transplantation, particularly for patients awaiting kidney transplantation. Efforts are being made to resolve the donor kidney shortage by the transplantation of kidneys from genetically-engineered pigs. Summary: This review outlines the pathobiological barriers to pig organ xenotransplantation in primates, which include (i) antibody-dependent complement-mediated rejection, (ii) a T cell-mediated elicited antibody and cellular response, (iii) coagulation dysregulation between pigs and primates, and (iv) a persistent inflammatory response. As a result of increasing genetic manipulation of the pig and the introduction of novel immunosuppressive agents, pig kidney graft survival has increased from minutes to months, and even to >1 year in some cases. Aspects of the selection of the patients for a first clinical trial are discussed. Although there would appear to be some cross-reactivity between anti-human leukocyte antigen (HLA) antibodies and swine leukocyte antigens expressed in pigs, some HLA-sensitized patients will be at no disadvantage if they receive a pig kidney. Furthermore, the current limited evidence is that, even if the patient becomes sensitized to pig antigens (after a pig organ transplant), this would not be detrimental to a subsequent allotransplant. The potential risk of infection with a pig microorganism, and the function of a pig kidney in a primate are also discussed. Key Message: The recent encouraging results of pig kidney transplantation in nonhuman primates suggest the likelihood of a successful (and safe) initial clinical trial, with graft survival for months or possibly years.
Treatment of Rapidly Progressive Glomerulonephritis in the Elderly
Authors: Appel Gerald B. , Lau Wai L.
Published: January 2018

As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease.
Standardized Protocol for Hemodialysis Vascular Access Assessment: The Role of Ultrasound and ColorDoppler
Authors: Nalesso Federico , Garzotto Francesco , Petrucci Ilaria , Samoni Sara , Virzì Grazia Maria , Gregori Dario , Meola Mario , Ronco Claudio
Published: January 2018

Introduction: Ultrasound and colorDoppler technique, which is relatively inexpensive, rapid, non-invasive and repeatable is a powerful tool used for early diagnosis of vascular access (VA) complications in hemodialysis patients. To date a standard and widely comprehensible echocolorDoppler (ECD) protocol is not available. Materials and Methods: A simple step-by-step protocol based on anatomical and hemodynamic parameters of VA has been developed during a 3-years VA ECD follow-up. It consists of an ECD study scheme. The algorithm created involves the calculation of brachial artery flow, description of artero-venous and/or graft-vascular anastomosis and efferent vessel and/or graft. Results: The algorithm allows to formulate a medical report that takes into account both anatomic and hemodynamic parameters of the VA. Reduction of complications and the prevention of chronic complications as well as the early detection of acute problems were achieved. Discussion and Conclusion: The creation of a step-by-step protocol may simplify the multidisciplinary management of VA, its monitoring and the early diagnosis of its complications.
Predicting Acute Kidney Injury in Intensive Care Unit Patients: The Role of Tissue Inhibitor of Metalloproteinases-2 and Insulin-Like Growth Factor-Binding Protein-7 Biomarkers
Authors: Di Leo Laura , Nalesso Federico , Garzotto Francesco , Xie Yun , Yang Bo , Virzì Grazia Maria , Passannante Alberto , Bonato Raffaele , Carta Mariarosa , Giavarina Davide , Gregori Dario , Brendolan Alessandra , Ferrari Fiorenza , Ronco Claudio
Published: January 2018

Background: Acute kidney injury (AKI) diagnosis is based on a rise in serum creatinine and/or fall in urine output. It has been shown that there are patients that fulfill AKI definition but do not have AKI, and there are also patients with evidence of renal injury who do not meet any criteria for AKI. Recently the innovative and emerging proteomic technology has enabled the identification of novel biomarkers that allow improved risk stratification. Methods: Tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7) were measured to a cohort of 719 consecutive patients admitted to Intensive Care Unit (ICU). The primary endpoint was the evaluation of clinical performances of the biomarkers focusing on the probability do develop AKI in the first 7 days. Results: The Kaplan-Meier analysis considering the first 7 days of ICU stay suggested a lower risk of developing AKI (p < 0.0001) for patients with a negative (<0.3; TIMP-2*IGFBP7) test. Conclusion: (TIMP-2*IGFBP7) at ICU admission has a good performance in predicting AKI, especially in the first 4 days in ICU.
Fistula Cannulation with a Novel Fistula Cannula: A Review of Cannulation Devices and Procedures
Authors: Nalesso Federico , Garzotto Francesco , Muraro Eva , Brendolan Alessandra , Ronco Claudio
Published: January 2018

Arteriovenous fistula cannulation for dialysis treatments in Europe has traditionally been done by metal needles. In ­Japan, plastic cannulas have been available for many years and are used in the majority of the dialysis patients. The mechanical structure and the cannulation procedure of the plastic cannulas differ from those of the metal needles. These differences are particularly beneficial for patients with delicate fistulas, tortuous vessels, metal allergies, oligophrenic patients, and also for the safety of the medical staff. In this paper, we present the main features of a novel fistula plastic cannula and the innovations introduced by it compared to the traditional metal needles.
Vascular Endothelial Growth Factor-A165b Restores Normal Glomerular Water Permeability in a Diphtheria-Toxin Mouse Model of Glomerular Injury
Authors: Stevens Megan , Neal Christopher R. , Salmon Andrew H.J. , Bates David O. , Harper Steven J. , Oltean Sebastian
Published: January 2018

Background/Aims: Genetic cell ablation using the human diphtheria toxin receptor (hDTR) is a new strategy used for analysing cellular function. Diphtheria toxin (DT) is a cytotoxic protein that leaves mouse cells relatively unaffected, but upon binding to hDTR it ultimately leads to cell death. We used a podocyte-specific hDTR expressing (Pod-DTR) mouse to assess the anti-permeability and cyto-protective effects of the splice isoform vascular endothelial growth factor (VEGF-A165b). Methods: The Pod-DTR mouse was crossed with a mouse that over-expressed VEGF-A165b specifically in the podocytes (Neph-VEGF-A165b). Wild type (WT), Pod-DTR, Neph-VEGF-A165b and Pod-DTR X Neph-VEGF-A165b mice were treated with several doses of DT (1, 5, 100, and 1,000 ng/g bodyweight). Urine was collected and the glomerular water permeability (LpA/Vi) was measured ex vivo after 14 days. Structural analysis and podocyte marker expression were also assessed. Results: Pod-DTR mice developed an increased glomerular LpA/Vi 14 days after administration of DT (all doses), which was prevented when the mice over-expressed VEGF-A165b. No major structural abnormalities, podocyte ablation or albuminuria was observed in Pod-DTR mice, indicating this to be a mild model of podocyte disease. However, a change in expression and localisation of nephrin within the podocytes was observed, indicating disruption of the slit diaphragm in the Pod-DTR mice. This was prevented in the Pod-DTR X Neph-VEGF-A165b mice. Conclusion: Although only a mild model of podocyte injury, over-expression of the anti-permeability VEGF-A165b isoform in the podocytes of Pod-DTR mice had a protective effect. Therefore, this study further highlights the therapeutic potential of VEGF-A165b in glomerular disease.
Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice
Authors: Ito Yoko , Schaefer Niccolette , Sanchez Amelia , Francisco David , Alam Rafeul , Martin Richard J. , Ledford Julie G. , Stevenson Connor , Jiang Di , Li Liwu , Kraft Monica , Chu Hong Wei
Published: January 2018

Toll-interacting protein (Tollip) is a key negative regulator of innate immunity by preventing excessive proinflammatory responses. Tollip genetic variation has been associated with airflow limitation in asthma subjects and Tollip expression. Whether Tollip regulates lung inflammation in a type 2 cytokine milieu (e.g., IL-13) is unclear. Our goal was to determine the in vivo role of Tollip in IL-13-mediated lung eosinophilic inflammation and the underlying mechanisms. Tollip-knockout (KO) and wild-type (WT) mice were inoculated intranasally with recombinant mouse IL-13 protein to examine lung inflammation. To determine how Tollip regulates inflammation, alveolar macrophages and bone marrow-derived macrophages from Tollip KO and WT mice were cultured with or without IL-13 and/or IL-33. IL-13-treated Tollip KO mice significantly increased lung eosinophilic inflammation and eotaxin-2 (CCL24) levels compared with the WT mice. IL-13- treated Tollip KO (vs. WT) macrophages, in the absence and particularly in the presence of IL-33, increased expression of the IL-33 receptor ST2L and CCL24, which was in part dependent on enhanced activation of interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) and signal transducer and activator of transcription 6 (STAT6). Our results suggest that Tollip downregulates IL-13-mediated pulmonary eosinophilia in part through inhibiting the activity of the ST2L/IL-33/IRAK1 axis and STAT6.
Activation of Bombesin Receptor Subtype-3 Promotes Antigen-Presenting Action in Human Bronchial Epithelial Cells
Authors: Liu Huijun , Peng Lihua , Liu Chi , Tan Yurong , Xiang Yang , Qu Xiangping , Weber H. Christian , Dai Minhui , Qin Xiaoqun
Published: January 2018

Background: Bombesin receptor subtype-3 (BRS-3) is a member of the bombesin-like peptide receptor family. Our previous studies demonstrated that activation of the human BRS-3 plays a protective role in oxidation-injured human bronchial epithelial cells (HBEC). The present study was designed to determine the role of BRS-3 activation in the antigen-presenting action of HBEC and the corresponding proliferation and differentiation of T cells. Materials and Methods: In vivo, an asthma animal model was established and the expression and distribution of BRS-3 were analyzed by immunocytochemistry. In vitro, 2 kinds of B7 costimulatory molecules, i.e., B7H1 and B7DC, on HBEC were analyzed by flow cytometry. The antigen uptake by HBEC was examined by confocal microscopy and flow cytometry. The antigen-presenting-action-induced proliferation of T cells was determined by MTT assays. IFN-γ and IL-4 levels were measured by ELISA. All studies were performed in the absence or presence of the synthetic peptide P3513. Results: BRS-3 expression was induced in asthma animal models and mainly distributed in bronchial epithelial cells. HBEC express the costimulatory molecules B7H1 and B7DC. BRS-3 activation increased B7H1 expression but decreased B7DC expression on HBEC. BRS-3 activation also increased the antigen uptake by HBEC and the subsequent T cell proliferation. In addition, BRS-3 activation promoted the releases of IFN-γ, but not IL-4, in the supernatant of cocultured HBEC and T cells. Conclusion: These data suggest that HBEC can present antigen to T cells and BRS-3 activation promotes the process of antigen presentation and subsequent T cell proliferation and Th1 differentiation.
Downregulated Expression of TRPV2 in Peripheral Blood Cells following Acute Myocardial Infarction Is Inversely Correlated with Serum Levels of CRP and Troponin I
Authors: Rozenbaum Zach , Cohen Lena , Bigelman Einat , Shacham Yacov , Keren Gad , Entin-Meer Michal
Published: January 2018

Objectives: We have recently shown that the transient receptor potential vanilloid 2 (TRPV2) channel is exclusively upregulated in rat/murine peri-infarct monocytes/macrophages following an acute myocardial infarction (AMI), and that this overexpression might be detrimental for cardiac recovery. We aimed to characterize the expression levels of TRPV2 in peripheral blood mononuclear cells (PBMCs) of AMI patients relative to individuals with normal coronaries, and to analyze potential associations with inflammatory and cardiac ischemic markers. Methods: Patients who underwent coronary angiography due to AMI or chest pain were prospectively included. PBMCs were isolated from whole blood by Ficoll gradient centrifugation. TRPV2 expression was analyzed by real-time PCR. C-reactive protein (CRP) and troponin I (TpI) levels were determined at the central chemistry laboratory; interleukin 6 and insulin-like growth factor (IGF)-1 levels were tested by ELISA. Results: Following AMI, the number of TRPV2-expressing PBMCs was reduced when compared to in patients with normal coronaries. An inverse correlation was documented between the numbers of circulating macrophages and TRPV2 expression. Additionally, TRPV2 expression was inversely correlated with CRP and TpI and directly correlated with serum IGF-1. Conclusions: We assume that peripheral TRPV2 downregulation occurs concomitantly with the accumulation of TRPV2-white blood cells in the peri-infarct zone. TRPV2 may thus represent a novel target for treatment in the acute phase after MI.
Isoliquiritigenin Ameliorates Indomethacin-Induced Small Intestinal Damage by Inhibiting NOD-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation
Authors: Nakamura Shiro , Watanabe Toshio , Tanigawa Tetsuya , Shimada Sunao , Nadatani Yuji , Miyazaki Takako , Iimuro Masaki , Fujiwara Yasuhiro
Published: January 2018

Activation of the NOD-Like Receptor Family, Pyrin Domain-Containing 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, triggers pro-caspase-1 cleavage promoting the processing of pro-interleukin (IL)-1β into mature IL-1β, which is critical for the development of non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy. We investigated the effects of isoliquiritigenin, a flavonoid derived from the roots of Glycyrrhiza species, on NSAID-induced small intestinal damage and the inflammasome activation. To induce enteropathy, mice were administered indomethacin by gavage with or without isoliquiritigenin pretreatment. Some mice received an intraperitoneal injection of recombinant murine IL-1β in addition to isoliquiritigenin and indomethacin. Indomethacin induced small intestinal damage and increased protein levels of cleaved caspase-1 and mature IL-1β in the small intestine. Treatment with 7.5 and 75 mg/kg isoliquiritigenin inhibited indomethacin-induced small intestinal damage by 40 and 56%, respectively. Isoliquiritigenin also inhibited the indomethacin-induced increase in cleaved caspase-1 and mature IL-1β protein levels, whereas it did not affect the mRNA expression of NLRP3, ASC, caspase-1, and IL-1β. Protection against intestinal damage in isoliquiritigenin-treated mice was completely abolished with exogenous IL-1β. NLRP3–/– and caspase-1–/– mice exhibited resistance to intestinal damage, and isoliquiritigenin treatment failed to inhibit the damage in NLRP3–/– and caspase-1–/– mice. Isoliquiritigenin prevents NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation.
BDNF VAL66MET Polymorphism Elevates the Risk of Bladder Cancer via MiRNA-146b in Micro-Vehicles
Authors: Li Cong , Zeng Xing , Liu Zheng , Li Fan , Wang Kun , Wu Baisen
Published: January 2018

Background/Aims: Emerging studies on brain-derived neurotrophic factor (BDNF) have shown that might be novel biomarkers and therapeutic targets for cancer. We explore the role of BDNF in the tumorigenesis of bladder cancer and the underlying molecular mechanism. Methods: 368 patients with diagnosed bladder cancer and 352 healthy controls were enrolled to evaluate the association of BDNF and the miR-146b. Bioinformatics algorithm analysis and luciferase assay were performed to identify the target genes of miR-146b. Real-time PCR and western-blot were carried out to validate the relationship between miR-146b and CRK. MTT assay and FACS were used to evaluated the proliferation and apoptosis of cancer cells. MVs were isolated and transfect into the culture cells to confirm the above observation. Results: The clinical study shows that BDNF Met/Met was significantly associated with the risk of bladder cancer. In addition, comparing with Val/Val and Val/Met, Met/Met has lower miR-146b level. Luciferase assay shows that BDNF Val/Val is apparently enhanced miR-146b promoter-luciferase, but not BDNF Met/Met. Based on luciferase assay, CRK is a direct target gene of miR-146b. MiR-146b mimics significantly inhibited the expression of CRK and activation of AKT level. The expression of CRK and the activation of AKT (p-AKT) were significantly inhibited by MV-BDNF Val/Val-miR-146b or MV-BDNF Val/Met-miR-146b, but not MV-BDNF Met/Met-miR-146b. MV-BDNF Val/Val-miR-146b or Val/Met-miR-146b obviously inhibited cell proliferation, which eliminated by CRK. Meanwhile, with MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not affect the proliferation. MV-BDNF Val/Val-miR-146b or Val/Met-miR-146b enhanced cell apoptosis, which could be eliminated by CRK. Meanwhile, MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not promote apoptosis. Conclusion: BDNF VAL66MET polymorphism is associated with miR-146b and its target gene CRK. MiR-146b and CRK mediated BDNF VAL66MET polymorphism associated proliferation and apoptosis via activation of AKT. Thus, BDNF Val66Met is associated with the risk of bladder cancer, and the BDNF variant could be used a biomarker for the diagnosis of bladder cancer.
Angiotensin II Silencing Alleviates Erectile Dysfunction Through Down-Regulating the Rhoa/Rho Kinase Signaling Pathway in Rats with Diabetes Mellitus
Authors: Zhang Ying , Jia Linpei , Zhang Ying , Ji Wei , Li Hai
Published: January 2018

Background/Aims: We aim to explore the role of angiotensin (Ang)II and the RhoA/Rho kinase signaling pathway in the pathogenesis of erectile dysfunction in diabetes mellitus (DM). Methods: Male Sprague-Dawley (SD) rats were used for experiments and short hairpin RNA (shRNA) was used to silence the AngII gene. The erectile function of rats was observed and intracavernous pressure and mean arterial pressure (ICP/MAP) were measured after electrical stimulation. Relaxation and contraction of smooth muscle in the corpus cavernosum were tested. Western blotting and quantitative RT-PCR were applied to measure the expressions of RhoA, Rho-associated kinase (ROCK)1 and ROCK2. Radioimmunoassay was applied to detect the levels of AngII. Results: Rats in the control group had the most erectile times, followed by AngII-silenced rats with DMED and rats with DMED. Rats with DMED had worse ICP and MAP than AngII-silenced rats. The contraction ability was markedly improved and relaxation ability was decreased in AngII-silenced rats with DMED as compared with rats with DMED. The levels of AngII were significantly increased in DMED rats while significantly decreased after AngII silencing. The mRNA and proteins of RhoA and ROCK2 were expressed in a similar way. Conclusion: AngII silencing improves erectile dysfunction via down-regulating the RhoA/Rho kinase signaling pathway.