bluuebunny/crossref_metadata_2025 huggingface dataset:
Fabrication of Bilayer Coating of Poly(3,4-ethylenedioxythiophene)-Halloysite/Chitosan and Mg2+/Sr2+-Doped HAP on Titanium Alloy for Biomedical Implant Applications: Physicochemical and In Vitro Biological Performances Studies
Authors: Chozhanathmisra Manickam , Govindaraj Dharman , Karthikeyan Palanisamy , Pandian Kannaiyan , Mitu Liviu , Rajavel Rangappan
Published: September 2018

The prime objective of the present work is to develop biocompatible overlayer-deposited titanium alloys to replace already available titanium alloy-based biomaterials for implantation applications. Here, we prefer to use a bilayer coating on titanium alloys instead of single coating. The adhesion and biocompatibility of titanium alloy is improved by coating with a bilayer, for example, PEDOT-HNT/CS-MHA composite using the electrochemical deposition method. Corrosion behavior of the PEDOT-HNT/CS-MHA bilayer composite coating was investigated in the PBS medium by polarization studies. The functional groups, phase purity, surface morphology, and wettability of the PEDOT-HNT/CS-MHA were characterized by various instrumental techniques like FTIR, XRD, SEM, and contact angle techniques. From the above studies, it is proved that PEDOT-HNT/CS-MHA-coated Ti alloy showing a better biocompatibility and corrosion resistance than the PEDOT-HNT-deposited Ti alloy. In addition, the in vitro bactericidal and cell viability studies were also carried out to further confirm the biocompatibility of the protective coating. Hence, the bilayer deposition has shown excellent stability and biocompatibility and can be used for the potential biomaterials for orthopedics applications.
Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
Authors: Stangl Stefan , Tei Lorenzo , De Rose Francesco , Reder Sybille , Martinelli Jonathan , Sievert Wolfgang , Shevtsov Maxim , Öllinger Rupert , Rad Roland , Schwaiger Markus , D'Alessandria Calogero , Multhoff Gabriele
Published: September 2018

High precision in vivo PET/CT imaging of solid tumors improves diagnostic credibility and clinical outcome of patients. An epitope of the oligomerization domain of Hsp70 is exclusively exposed on the membrane of a large variety of tumor types, but not on normal cells, and thus provides a universal tumor-specific target. Here we developed a novel PET tracer TPP-PEG24-DFO[89Zr] based on the tumor cell–penetrating peptide probe TPP, which specifically recognizes membrane Hsp70 (mHsp70) on tumor cells. The implemented PEG24 moiety supported tracer stability and improved biodistribution characteristics in vivo. The Kd of the tracer ranged in the low nanomolar range (18.9 ± 11.3 nmol/L). Fluorescein isothiocyanate (FITC)-labeled derivatives TPP-[FITC] and TPP-PEG24-[FITC] revealed comparable and specific binding to mHsp70-positive 4T1, 4T1+, a derivative of the 4T1 cell line sorted for high Hsp70 expression, and CT26 tumor cells, but not to mHsp70-negative normal fibroblasts. The rapid internalization kinetics of mHsp70 into the cytosol and the favorable biodistribution of the peptide-based tracer TPP-PEG24-DFO[89Zr] in vivo enabled a tumor-specific accumulation with a high tumor-to-background contrast and renal body clearance. The tumor-specific enrichment of the tracer in 4T1+ (6.2 ± 1.1%ID/g), 4T1 (4.3 ± 0.7%ID/g), and CT26 (2.6 ± 0.6%ID/g) mouse tumors with very high, high, and intermediate mHsp70 densities, respectively, reflected mHsp70 expression profiles of the different tumor types, whereas benign mHsp70-negative fibroblastic hyperplasia showed no tracer accumulation (0.2 ± 0.03%ID/g). The ability of our chemically optimized peptide-based tracer TPP-PEG24-DFO[89Zr] to detect mHsp70 in vivo suggests its broad applicability in targeting and imaging with high specificity for any tumor type that exhibits surface expression of Hsp70.

Significance: A novel peptide-based PET tracer against the oligomerization domain of Hsp70 has potential for universal tumor-specific imaging in vivo across many tumor type. Cancer Res; 78(21); 6268–81. ©2018 AACR.
Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women
Authors: Denholm Rachel , De Stavola Bianca L. , Hipwell John H. , Doran Simon J. , Holly Jeff M.P. , Folkerd Elizabeth , Dowsett Mitch , Leach Martin O. , Hawkes David J. , dos-Santos-Silva Isabel
Published: September 2018

Background:

Endogenous hormones are associated with breast cancer risk, but little is known about their role on breast tissue composition, a strong risk predictor. This study aims to investigate the relationship between growth and sex hormone levels and breast tissue composition in young nulliparous women.

Methods:

A cross-sectional study of 415 young (age ∼21.5 years) nulliparous women from an English prebirth cohort underwent a MRI examination of their breasts to estimate percent-water (a proxy for mammographic percent density) and provided a blood sample to measure plasma levels of growth factors (insulin-like growth factor-I, insulin-like growth factor-II, insulin growth factor-binding protein-3, growth hormone) and, if not on hormonal contraception (n = 117) sex hormones (dehydroepiandrosterone, androstenedione, testosterone, estrone, estadiol, sex hormone–binding globulin, prolactin). Testosterone (n = 330) and sex hormone–binding globulin (n = 318) were also measured at age 15.5 years. Regression models were used to estimate the relative difference (RD) in percent-water associated with one SD increment in hormone levels.

Results:

Estradiol at age 21.5 and sex hormone–binding globulin at age 21.5 were positively associated with body mass index (BMI)-adjusted percent-water [RD (95% confidence interval (CI)): 3% (0%–7%) and 3% (1%–5%), respectively]. There was a positive nonlinear association between androstenedione at age 21.5 and percent-water. Insulin-like growth factor-I and growth hormone at age 21.5 were also positively associated with BMI-adjusted percent-water [RD (95% CI): 2% (0%–4%) and 4% (1%–7%), respectively].

Conclusions:

The findings suggest that endogenous hormones affect breast tissue composition in young nulliparous women.

Impact:

The well-established associations of childhood growth and development with breast cancer risk may be partly mediated by the role of endogenous hormones on breast tissue composition.
Prognostic Role of Circulating Exosomal miR-425-3p for the Response of NSCLC to Platinum-Based Chemotherapy
Authors: Yuwen Daolu , Ma Yuzhu , Wang Deqiang , Gao Jian , Li Xin , Xue Wenwen , Fan Minmin , Xu Qiang , Shen Yan , Shu Yongqian
Published: September 2018

Background:

Platinum-based doublets with a third-generation agent are the recommended option for many patients with non–small cell lung cancer (NSCLC) with no contraindications to platinum compounds. Unfortunately, the clinical effectiveness of such chemotherapy is limited by intrinsic or acquired resistance.

Methods:

Circulating exosomal miRNAs were isolated and used to perform HiSeq deep-sequencing analyses on serum pool samples from platinum-resistant or platinum-sensitive patients, and six exosomal miRNAs were further validated for their predictive utility by qRT-PCR in 170 serum samples of patients with advanced NSCLC. Gain- and loss-of-function experiments clarified the responsiveness regulating role of the clinically relevant miRNA. IHC analyses were performed to evaluate the association between basal autophagy in lung cancer tissues and responsiveness in 203 patients with NSCLC receiving platinum-based chemotherapy.

Results:

Six circulating exosomal miRNAs (miR-425-3p, miR-1273h, miR-4755-5p, miR-9-5p, miR-146a-5p, and miR-215-5p) were found to be differentially expressed with the largest fold change in platinum-resistant patients compared with platinum-sensitive patients. High miR-425-3p proved to be a potent predictive biomarker for low responsiveness and poor progression-free survival (PFS). Mechanistically, miR-425-3p upregulated the autophagic levels via targeting AKT1, leading to the decrease in therapeutic response. Concordantly, high levels of basal autophagy in lung cancer tissues correlate with low responsiveness in patients with NSCLC within the early and advanced disease stages.

Conclusions:

Our study highlights circulating exosomal miR-425-3p as a potential biomarker for improved predictions of the clinical response to platinum-based chemotherapy in patients with NSCLC.

Impact:

This study provides the first evidence that miR-425-3p in NSCLC patient–derived exosomes can be a marker for predicating the clinical response to platinum-based chemotherapy.
Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC
Authors: Le Xiuning , Puri Sonam , Negrao Marcelo V. , Nilsson Monique B. , Robichaux Jacqulyne , Boyle Theresa , Hicks J. Kevin , Lovinger Katherine L. , Roarty Emily , Rinsurongkawong Waree , Tang Ming , Sun Huiying , Elamin Yasir , Lacerda Lara C. , Lewis Jeff , Roth Jack A. , Swisher Stephen G. , Lee J. Jack , William William N. , Glisson Bonnie S. , Zhang Jianjun , Papadimitrakopoulou Vassiliki A. , Gray Jhanelle E. , Heymach John V.
Published: September 2018

Purpose:

Osimertinib was initially approved for T790M-positive non–small cell lung cancer (NSCLC) and, more recently, for first-line treatment of EGFR-mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described.

Experimental Design:

Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.

Results:

In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, P = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, P = 0.02).

Conclusions:

Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.

See related commentary by Devarakonda and Govindan, p. 6112.
Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin
Authors: Yang Dian , Denny Sarah K. , Greenside Peyton G. , Chaikovsky Andrea C. , Brady Jennifer J. , Ouadah Youcef , Granja Jeffrey M. , Jahchan Nadine S. , Lim Jing Shan , Kwok Shirley , Kong Christina S. , Berghoff Anna S. , Schmitt Anna , Reinhardt H. Christian , Park Kwon-Sik , Preusser Matthias , Kundaje Anshul , Greenleaf William J. , Sage Julien , Winslow Monte M.
Published: September 2018

The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms.

Significance: We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1316–31. ©2018 AACR.

See related commentary by Pozo et al., p. 1216.

This article is highlighted in the In This Issue feature, p. 1195
Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer
Authors: O'Malley Grace , Treacy Oliver , Lynch Kevin , Naicker Serika D. , Leonard Niamh A. , Lohan Paul , Dunne Philip D. , Ritter Thomas , Egan Laurence J. , Ryan Aideen E.
Published: September 2018

Stromal cells of mesenchymal origin reside below the epithelial compartment and provide structural support in the intestine. These intestinal stromal cells interact with both the epithelial cell compartments, as well as infiltrating hematopoietic immune cells. The importance of these cells in regulating immune homeostasis during inflammation is well recognized. However, little is known about their function and phenotype in the inflammatory tumor microenvironment. Using a syngeneic, immunogenic model of colorectal cancer, we showed that TNFα-initiated inflammatory signaling in CT26 colorectal cancer cells selectively induced PD-L1 expression in stromal cells. Using CD274 shRNA and antibody-mediated approaches, we showed that stromal cell PD-L1 potentiated enhanced immunosuppression, characterized by inhibition of activated CD8+ granzyme B-secreting T cells in vitro, and the inhibition of CD8+ effector cells was associated with enhanced tumor progression. Stromal cell immunosuppressive and tumor-promoting effects could be reversed with administration of anti–PD-1 in vivo. We validated our findings of stromal cell CD274 expression in two cohorts of clinical samples and also observed PD-L1 induction on human stromal cells in response to exposure to the inflammatory secretome from human colon cancer cells, irrespective of microsatellite instability. Collectively, our data showed that tumor-associated stromal cells support T-cell suppression by PD-L1 induction, which is dependent on colon cancer inflammatory signaling. Our findings reveal a key role of mesenchymal stromal cells PD-L1 in suppression of CD8+ antitumor immune responses and potentiation of colorectal cancer progression. Cancer Immunol Res; 6(11); 1426–41. ©2018 AACR.
Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status
Authors: Hamada Tsuyoshi , Zhang Xuehong , Mima Kosuke , Bullman Susan , Sukawa Yasutaka , Nowak Jonathan A. , Kosumi Keisuke , Masugi Yohei , Twombly Tyler S. , Cao Yin , Song Mingyang , Liu Li , da Silva Annacarolina , Shi Yan , Gu Mancang , Li Wanwan , Koh Hideo , Nosho Katsuhiko , Inamura Kentaro , Keum NaNa , Wu Kana , Meyerhardt Jeffrey A. , Kostic Aleksandar D. , Huttenhower Curtis , Garrett Wendy S. , Meyerson Matthew , Giovannucci Edward L. , Chan Andrew T. , Fuchs Charles S. , Nishihara Reiko , Giannakis Marios , Ogino Shuji
Published: September 2018

The presence of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor–immune microenvironment between MSI-high and non–MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses’ Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (Pinteraction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22–0.92], but positively associated with TIL in non–MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12–3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect antitumor immune reactions. Cancer Immunol Res; 6(11); 1327–36. ©2018 AACR.

See related Spotlight on p. 1290.
Angiotensin-Converting Enzyme Inhibitor-Induced Gastrointestinal Angioedema: The First Danish Case Report
Authors: Rincic Antulov Marijana , Båtevik Runar B.
Published: September 2018

Angiotensin-converting enzyme inhibitors (ACEI) are widely used to treat hypertension and congestive heart failure. A rare side effect of ACEI therapy is angioedema, which in very rare cases may present as gastrointestinal angioedema (GA). A 45-year-old female presented with suddenly occurring diffuse abdominal pain. Imaging studies revealed small bowel wall edema. The patient had been on ACEI therapy for the last 6 months. The therapy was withdrawn, and the patient recovered quickly. There is no specific diagnostic test to confirm ACEI-induced GA, but symptoms usually regress completely after therapy discontinuation. An early diagnosis of ACEI-induced GA is important to avoid invasive diagnostic investigations and even laparotomy.
Tumour Expression of Histone Deacetylases in Uveal Melanoma
Authors: Levinzon Louis , Madigan Michele , Nguyen Vuong , Hasic Enisa , Conway Max , Cherepanoff Svetlana
Published: September 2018

Purpose: To determine the expression of histone deacetylase enzymes in uveal melanoma tumour cells. Procedures: This is an observational immunohistochemical study of 16 formalin-fixed, paraffin-embedded eyes enucleated for uveal melanoma between January 2001 and March 2002. Haematoxylin and eosin paraffin sections were reviewed for histopathological parameters according to the American Joint Committee on Cancer 7th edition. Sections were then immunohistochemically stained for histone deacetylases 1, 2, 3, 4 and 6 and sirtuin 2 using an automated Leica Bond II platform and Fast Red chromogen, then digitally scanned using Aperio software before assessment of staining. Results: Nuclear expression of histone deacetylases 1, 2, 3, 4 and 6 and of sirtuin 2 was confirmed in uveal melanoma tumour cells. In addition, the tumour cells showed cytoplasmic expression of histone deacetylases 4 and 6 and sirtuin 2. Nuclear and cytoplasmic immunostaining was also seen in intraocular tissues uninvolved by the tumour. Conclusion: Uveal melanoma tumour cells express histone deacetylases 1, 2, 3, 4 and 6 and sirtuin 2, confirming potential tissue targets for histone deacetylase inhibitors.
The Hospital and Patient Burden of Indwelling Pleural Catheters: A Retrospective Case Series of 210 Indwelling Pleural Catheter Insertions
Authors: Asciak Rachelle , Hallifax Robert John , Mercer Rachel Mary , Hassan Maged , Wigston Charlotte , Wrightson John M. , Psallidas Ioannis , Rahman Najib Mahboob
Published: September 2018

Background: Indwelling pleural catheters (IPC) offer an alternative to talc pleurodesis in recurrent effusion, especially in patients wishing to avoid hospitalization. Two randomized trials have demonstrated reduced time in hospital using IPCs versus talc pleurodesis in malignant pleural effusion (MPE). However, the impact of IPCs on hospital services and patients has not been well studied. Objectives: To analyze long-term outcomes of IPCs and understand the hospital burden in terms of requirement for hospital visits and contacts with healthcare, while the IPC was in situ. Methods: IPC insertions in a tertiary pleural center were analyzed retrospectively. Reviews of patients with IPCs in situ considered “additional” to routine clinical follow-up were defined pre-hoc. Results: A total of 202 cases were analyzed: 89.6% MPE group (n = 181) and 10.4% non-MPE group (n = 21). There were a median 3.0 (interquartile range [IQR] 3) and 2.0 (IQR 2) ipsilateral pleural procedures prior to each IPC insertion in non-MPE and MPE groups, respectively (p = 0.26), and a mean 1.3 (SD 1.7) planned IPC-related outpatient follow-up visits per patient. There were 2 (9.5%) and 14 (7.7%) IPC-related infections in non-MPE and MPE groups, respectively. Four (19.0%) and 44 (24.3%) patients required additional IPC-related reviews in non-MPE and MPE groups, respectively (p = 0.6), and these occurred within 250 days post IPC insertion. Conclusions: Although IPCs decrease initial length of hospital stay compared to talc pleurodesis via chest drain, IPCs are associated with significant hospital-visit burden, in addition to planned visits and regular home IPC drainages. IPC-using services need to be prepared for this additional work to run an IPC service effectively.
Geographic Hematology: Some Observations in Mexico
Authors: Colunga-Pedraza Perla R. , Gomez-Cruz Gisela B. , Colunga-Pedraza Julia E. , Ruiz-Argüelles Guillermo J.
Published: September 2018

In 1963 Jean Bernard introduced the concept of “geographic hematology” and distinguished 2 branches, i.e., “ethnic hematology,” which deals with differences between populations, and “environmental hematology,” which considers factors such as food habits, infections, and others. Both of these branches have implications in the distribution of hematological diseases worldwide. In comparison with Caucasian populations, in Mexico a significantly higher prevalence of acute lymphoblastic, acute promyelocytic, and acute megakaryoblastic leukemias has been described. The rate of chronic myeloid leukemia seems to be as high as that reported in Caucasian populations, while other myeloproliferative neoplasias are significantly less frequent in Mexico. Significantly lower prevalences of hairy cell leukemia, chronic lymphocytic leukemia, multiple myeloma, and Waldenström’s macroglobulinemia have been reported from Mexico. Regrettably, the influence of drug companies interested in selling their new and expensive drugs has resulted in both overdiagnosis of some diseases and overidentification of the refractory forms of some of these conditions to justify the use of unnecessary drugs.
Survival after Endoscopic Valve Therapy in Patients with Severe Emphysema
Authors: Gompelmann Daniela , Benjamin Nicola , Bischoff Elena , Kontogianni Konstantina , Schuhmann Maren , Hoffmann Hans , Heussel Claus Peter , Herth Felix J.F. , Eberhardt Ralf
Published: September 2018

Background: Endoscopic valve therapy leads to an improvement of lung function, exercise tolerance, and quality of life in a selected cohort of patients with advanced emphysema. So far, only few data exist on the long-term outcome. Objectives: This analysis evaluated the impact of valve therapy on the survival of emphysema patients. Methods: Survival rates of emphysema patients who underwent valve therapy were assessed according to their radiological outcome following valve placement. Results: From 2005 to 2013, 449 emphysema patients (mean age 64 ± 7 years) underwent valve therapy and were followed for a mean time of 37.3 ± 21.3 months. A total of 128 patients (29%) developed complete lobar atelectasis, 34 out of these also experienced a pneumothorax; 50 patients (11%) developed pneumothorax without lobar atelectasis, and 261 patients (58%) target lobe volume reduction or no volume change. Patients with atelectasis showed significantly better baseline forced expiratory volume in 1 second (%), residual volume (L), total lung capacity (L), and transfer factor for carbon monoxide (%; all p < 0.05), but there was no significant difference in the BODE score (p = 0.195). Patients with valve-induced lobar atelectasis had a significant survival benefit compared to patients without atelectasis (p = 0.009; 5-year survival rate 65.3 vs. 43.9%). The advent of pneumothorax in 84 patients did not influence survival (p = 0.52). Conclusions: Lobar atelectasis following endoscopic valve therapy is associated with a survival benefit.
Early Hospital Readmission in Older and Younger Kidney Transplant Recipients
Authors: Haugen Christine E. , King Elizabeth A. , Bae Sunjae , Bowring Mary Grace , Holscher Courtenay M. , Garonzik-Wang Jacqueline , McAdams-DeMarco Mara , Segev Dorry L.
Published: September 2018

Background: Up to 31% of kidney transplant (KT) recipients experience early hospital readmission (EHR). We hypothesized that EHR among older KT recipients is higher than younger recipients due to increased comorbidities and higher prevalence of frailty. Methods: We identified 22,458 older (age ≥65) and 86,372 younger (18 to < 65) first-time KT recipients (December 1, 1999 – December 31, 2014) using United States Renal Data System data. We estimated the association between patient-level characteristics and EHR (30 days post-KT discharge) with modified Poisson regression among older and younger KT recipients, separately. We estimated the association between graft loss and mortality and EHR using Cox proportional hazards. Results: EHR was more common in older KT recipients (30.1 vs. 27.6%; p < 0.001). Risk factors for EHR that differed by recipient age included female sex, African American race, diabetes, smoking, dialysis vintage, donor age, and length of stay. Risk of graft loss associated with EHR was greater among older KT recipients (adjusted hazard ratio [aHR] 1.64, 95% CI 1.51–1.77, p < 0.001) than younger KT recipients (aHR 1.43, 95% CI 1.38–1.48, p < 0.001; interaction p < 0.01). However, the risk of mortality associated with EHR was greater among younger recipients (aHR 1.52, 95% CI 1.47–1.57, p < 0.001) than that in older ­recipients (aHR 1.40, 95% CI 1.34–1.47, p < 0.001; interaction p < 0.01). Conclusions: Older KT recipients are more likely to experience EHR and are at a higher risk of graft loss after EHR than younger recipients. Targeted interventions to prevent EHR and subsequent graft loss in this population should be identified.
MPT0B169 and MPT0B002, New Tubulin Inhibitors, Induce Growth Inhibition, G2/M Cell Cycle Arrest, and Apoptosis in Human Colorectal Cancer Cells
Authors: Lee Chih-Hsin , Lin Yuan-Feng , Chen Yen-Chou , Wong Shuit-Mun , Juan Shu-Hui , Huang Huei-Mei 
Published: September 2018

We previously synthesized new tubulin inhibitors, MPT0B169 and MPT0B002, which induced growth inhibition and apoptosis in leukemia cells. However, their effects on solid tumor cells have not been determined. In this study, we investigated the effects of MPT0B169 and MPT0B002 on glioblastoma, breast, lung, and colorectal cancer (CRC) cell lines. A cell viability analysis showed that MPT0B169 and MPT0B002 were more effective in inhibiting the proliferation of COLO205 and HT29 CRC cells than U87MG and GBM8401 glioblastoma, MCF-7 and MDA-MB-231 breast cancer, and A549 lung cancer cells. MPT0B169 and MPT0B002 inhibited growth of COLO205 and HT29 cells in dose- and time-dependent manners. A colony-formation assay confirmed the growth inhibitory effects of MPT0B169 and MPT0B002 on COLO205 and HT29 cells. MPT0B169 and MPT0B002 disrupted tubulin polymerization and arrested the cell cycle at the G2/M phase, with a concomitant increase of the cyclin B1 level. MPT0B169 and MPT0B002 induced apoptosis, accompanied by induction of the intrinsic apoptotic pathway, as shown by a reduction in the caspase-9 level and increases in cleaved caspase-3 and cleaved PARP. These results suggest that MPT0B169 and MPT0B002, new tubulin inhibitors, induced growth inhibition, G2/M arrest, and apoptosis in COLO205 and HT29 cells, and they could potentially be anticancer agents for CRC cells.
Dental Caries in European Adults and Senior Citizens 1996–2016: ORCA Saturday Afternoon Symposium in Greifswald, Germany – Part II
Authors: Carvalho Joana Christina , Schiffner Ulrich
Published: September 2018

This review assesses the development of oral health habits and status in European adults (35–44 years old) and senior citizens (65–74 years old) over the period of 1996–2016. There seem to be good opportunities for improving oral health habits by brushing twice daily with fluoride toothpaste among adults, as only 33–85% reported doing so. Caries experience was extensive among adults (≥92%). In adults of 23 countries, the mean DMFT score ranged from 6.6 to 17.6 (median 12.1). In senior citizens of 21 countries, the mean DMFT score varied from 14.7 to 25.5 (median 22.0). Repeated cross-sectional studies on caries trends in adults revealed a reduction of the DMFT value by 20%, referring to country-wide data. Among senior citizens, the corresponding reduction was 13%, with a shift in the DMFT components, i.e., with lower MT and higher FT scores. Edentulousness in the age group of 35- to 44-year-olds started disappearing in Europe from the year 2000, and had been markedly reduced in some countries during the last decade. However, the eradication of edentulousness among 65- to 74-year-olds has not yet been reported. Further epidemiological surveys should apply caries diagnostic criteria that, besides representing our contemporary understanding of oral health care, allow comparisons with previous surveys using the WHO criteria. In conclusion, in the last two decades, a decline in caries was observed among European adults, and to a lesser extent among senior citizens. It is expected that the decline in caries will contribute to better oral health of individuals.
Endovascular Thrombectomy in Acute-Onset Ischemic Stroke – beyond the Standard Time Windows: A Case Report and a Review of the Literature
Authors: So Conan  , Chaudhry Naveed , Gandhi Dheeraj , Cole John W. , Motta Melissa
Published: September 2018

Endovascular thrombectomy following an acute ischemic stroke can lead to improved functional outcome when performed early. Current guidelines suggest treatment within 6 h after symptom onset. Recent studies including the DEFUSE-3 and DAWN trials demonstrate that some patients may benefit from thrombectomy up to 16 and 24 h after symptom onset, respectively. We present a case of delayed thrombectomy in a 43-year-old man with acute dysarthria, left-sided weakness, and visual neglect. Initial MRI/A demonstrated a small completed stroke and a thrombus in the right middle cerebral artery. Thirty-seven hours after symptom onset, his weakness acutely worsened. A repeat MRI revealed an unchanged core infarct volume and a cerebral angiogram suggested an abrupt occlusion of the right distal M1. Thrombectomy was performed with complete reperfusion and the patient’s strength recovered following the procedure. We compared our clinical reasoning with the DEFUSE-3 and DAWN study criteria, and conclude that there is a subset of patients that may safely benefit from thrombectomy in later time windows beyond the trial criteria, especially in the setting of clinical examination of imaging mismatch.
Asymptomatic Lupus Cystitis with Bilateral Hydronephrosis
Authors: Aziza Bawazier Lucky
Published: September 2018

Lupus cystitis is a rare complication of systemic lupus erythematosus (SLE). It is characterized by an increase in bladder wall thickness and may be associated with hydroureteronephrosis. Reports, mostly from East Asian countries, indicate that lupus cystitis usually presents with gastrointestinal tract symptoms such as diarrhea, nausea, or abdominal pain. Lower urinarytract symptoms such as dysuria, nocturia, polyuria, and suprapubic pain are also common presenting symptoms. We report a 22-year-old female patient who presented at Cipto Mangunkusumo Teaching Hospital in Indonesia, with profuse and prolonged vaginal bleeding without any other accompanying symptoms. She had a history of polyarthralgias, fever, bleeding gums, anemia, and thrombocytopenia 3 months earlier. Abdominal ultrasound examination revealed bilateral hydronephrosis and a thickened bladder wall; the other organs were normal. Laboratory examination confirmed the diagnosis of SLE complicated by lupus nephritis and lupus cystitis. The patient responded well to the treatment with methylprednisolone. The vaginal bleeding stopped within 2 days, and the laboratory parameters improved. She was discharged on oral methylprednisolone and is scheduled for detailed workup after 1 month.
Clinical and Pathological Challenges in the Diagnosis of Gastric-Type Differentiated Adenocarcinoma in the Stomach: A Study of Endoscopic Submucosal Dissection Cases
Authors: Kitaichi Tomoko , Dohi Osamu , Fujita Yasuko , Majima Atsushi , Horii Yusuke , Yasuda-Onozawa Yuriko , Suzuki Kentaro , Tomie Akira , Okayama Tetsuya , Yoshida Naohisa , Kamada Kazuhiro , Uchiyama Kazuhiko , Ishikawa Takeshi , Handa Osamu , Konishi Hideyuki , Kishimoto Mitsuo , Yagi Nobuaki , Naito Yuji , Yanagisawa Akio , Itoh Yoshito
Published: September 2018

Background/Aims: Gastric-type differentiated adenocarcinoma (GDA) of the stomach is a rare variant of gastric cancer that is highly infiltrating and exhibits early metastasis. However, the endoscopic and pathological features of “early-stage” GDA remain unknown. The aim of this study is to characterize early-stage GDA. Methods: We retrospectively enrolled 479 differentiated-type early gastric cancer cases who underwent endoscopic submucosal dissection (ESD). GDA cases were selected based on morphology and immunohistochemistry. Clinicopathological data were compared between gastric- and intestinal-type differentiated adenocarcinomas (IDAs). Results: Thirteen lesions were classified as GDAs. GDAs as well as IDAs showed irregular microvascular and microsurface patterns with clear demarcation line on magnifying endoscopy with narrow band imaging (M-NBI). The rate of pathological misdiagnosis of GDAs in biopsy specimens was higher than that of IDAs (p = 0.016). GDA was significantly associated with positive lymphovascular invasion (p = 0.016). There was one intramucosal lesion with lymphatic invasion in GDA. Conclusions: Although M-NBI is useful to detect GDA, the pathological diagnosis of GDAs in biopsy specimens often remains challenging. When suspicious lesions are not diagnosed as GDA, they should be followed up intensively, or diagnostic ESD has to be performed. ESD specimens should be carefully evaluated because of a higher incidence of lymphovascular invasion.
Transurethral Enucleation of Bladder Leiomyoma: A Series of Six Cases and Review of the Literature
Authors: Li Axing , Zhang Pu , Zhang Mengzhao , Yang Tao , Yue Yang , Chen Guanqiu , Li Wei , Fan Jinhai
Published: September 2018

Objectives: To investigate the feasibility and initial surgical outcomes of transurethral enucleation for 6 patients with bladder leiomyoma. Materials: Six patients (mean age 50.2, range [34–67]) with bladder leiomyoma underwent transurethral enucleation. In each case, the resectoscope was inserted into the bladder. A resecting loop was used to incise the urothelium along the surgical margin of the bladder tumor, and a push was given through the resecting loop to further separate the tumor until it was shelled off the bladder wall. The intact mass was then cut into pieces and flushed out. After the operation, irrigation therapy was given. Results: Surgery was performed successfully in all 6 patients. The mean size of the tumor was 3.9 cm (1.8–6.7 cm). The mean operation time was 60 min (30–100 min). The mean follow-up period was 14.8 months (2–30 months), and no evidence of recurrence was found in all cases. Conclusion: Transurethral enucleation is a safe, reliable, and effective surgical technique for selected patients with well-encapsulated tumors and is well suited for further pathological diagnosis and radical treatment.
Medical Expulsive Therapy for Symptomatic Distal Ureter Stones: Is the Combination of Bromelain and Tamsulosin More Effective than Tamsulosin Alone? Preliminary Results of a Single-Center Study
Authors: Palmisano Franco , Spinelli Matteo Giulio , Luzzago Stefano , Boeri Luca , De Lorenzis Elisa , Albo Giancarlo , Gadda Franco , Gelosa Marco , Longo Fabrizio , Dell’Orto Paolo Guido , Montanari Emanuele
Published: September 2018

Objectives: To assess the safety and efficacy of bromelain plus tamsulosin versus tamsulosin alone as medical expulsive therapy (MET) for promoting spontaneous stone passage (SSP) of symptomatic distal ureter stones. Patients and Methods: One-hundred-fourteen patients with a 4–10 mm distal ureteral stone were enrolled (Group A). Patients self-administered daily bromelain with tamsulosin for 30 days or until SSP or intervention was mandatory. Patients were compared to those from a control group taking tamsulosin as MET (Group B) and matched for the following factors: sex, age ±10%, stone diameter. A logistic regression model evaluated bromelain and the ureteral stone diameter as explanatory variables. Results: SSP rates were 87.7 vs. 75.4% for group A vs. group B respectively (p = 0.016); with no difference observed for the time to self-reported stone expulsion (11.68 vs. 11.57 days; p = 0.91). Considering larger stones (> 5 mm), the SSP rate was 83.3% in group A and 61% in group B (p < 0.01). With each millimeter increment of stone diameter, the probability of SSP decreased by 59.1% (p < 0.0001), while it increased of 3.3 when bromelain was present. Only 3 cases of tamsulosin-related adverse events were recorded. Conclusion: The association of bromelain and tamsulosin as MET increases the probability of SSP of symptomatic distal ureteral stones, with no bromelain-related side effects recorded.
Expanding the Boundaries of Combined Renal Replacement Therapy for Non-Renal Indications
Authors: Kamboj Mayanka , Kazory Amir
Published: September 2018

Over the last decades, there have been major advancements in the field of renal replacement therapy (RRT) with utilization of newer technologies and advent of various modalities. Once exclusively used for treatment of renal failure and its metabolic consequences, the science of RRT has expanded to include non-renal indications such as treatment of fluid overload in patients with refractory heart failure. Hepatic encephalopathy due to sudden rise in serum ammonia level in the setting of acute liver failure represents an underexplored area in which RRT can potentially be helpful. While the key role of hyperammonemia in the pathogenesis of hepatic encephalopathy in patients with liver failure is well established, emerging data points to distinct pathophysiologic mechanisms underlying chronic alterations in neural metabolic functions and acute changes in cerebral perfusion. In the acute setting, ammonia can cross the blood–brain barrier at high levels leading to sudden formation of strong osmolytes, significant transcellular shift of water, and cerebral edema. Herein, we provide a brief overview of the role of RRT in management of acute hyperammonemia in the setting of acute liver failure and discuss the practical aspects of the available therapeutic modalities. Larger studies are needed to shed light on a number of clinical aspects such as the impact on the outcomes, criteria for selection of the patients that would benefit most from this therapeutic approach, optimal timing of initiation of RRT, and the most appropriate modality.
Ecdysone Elicits Chronic Renal Impairment via Mineralocorticoid-Like Pathogenic Activities
Authors: Lu Minglei , Wang Pei , Zhou Sijie , Flickinger Bryce , Malhotra Deepak , Ge Yan , Tatar Marc , Dworkin Lance , Liu Zhangsuo , Gong Rujun
Published: September 2018

Background/Aims: Ecdysteroids are steroidal insect molting hormones that also exist in herbs. Ecdysteroid-containing adaptogens have been popularly used to improve well-being and by bodybuilders for muscle growth. However, the use of ecdysone in mammals is also associated with kidney growth and enlargement, indications of disturbed kidney homeostasis. The underlying pathogenic mechanism remains to be clarified. Methods: Virtual screening tools were employed to identify compounds that are homologous to ecdysone and to predict putative ecdysone-interacting proteins. The kidney effect of ecdysone was examined in vitro and in vivo and compared with that of aldosterone. Cellular apoptosis was estimated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Cell motility was assessed by scratch-wound cell migration assay. Blood urea nitrogen was measured to evaluate renal function. Western immunblot analysis was employed to determine the expression profile of interested proteins. Results: Computational molecular structure analysis revealed that ecdysone is highly homologous to aldosterone. Moreover, virtual screening based on compound-protein interaction profiles identified the Mineralocorticoid Receptor (MR) to potentially interact with ecdysone. Accordingly, to assess potential biological functions of ecdysone in mammals, ecdysone was applied to mineralocorticoid-sensitive inner medullar collecting duct cells. Ecdysone induced mesenchymal accumulation of extracellular matrix and epithelial dedifferentiation characterized by de novo expression of α-smooth muscle actin. In addition, ecdysone elicited cellular apoptosis and retarded cell motility, akin to the effect of aldosterone. In vivo, daily treatment of mice with ecdysone increased cell apoptosis in the kidney, impaired renal function and elicited early signs of renal fibrogenesis, marked by deposition of collagen and fibronectin in tubulointerstitium, reminiscent of the action of aldosterone. The MR signaling pathway is likely responsible for the cellular and pathobiological effects of ecdysone, as evidenced by strong ecdysone-induced MR nuclear translocation in renal tubular cells both in vitro and in vivo, while blockade of MR by concomitant spironolactone treatment largely abolished the detrimental effects of ecdysone. Conclusion: Our findings suggest that ecdysone induces mineralocorticoid-dependent activities that impair renal function and elicit renal injury.
Expression of Toll-Like Receptors in Human Atherosclerotic Lesions
Authors: Edfeldt Kristina , Swedenborg Jesper , Hansson Göran K. , Yan Zhong-qun
Published: September 2018

Background

—

Innate immune reactions against bacteria and viruses have been implicated in the pathogenesis of atherosclerosis. To explore the molecular mechanism by which microbe recognition occurs in the artery wall, we characterized the expression of toll-like receptors (TLRs), a family of pathogen pattern recognition receptors, in atherosclerotic lesions.

Methods and Results

—

Semiquantitative polymerase chain reaction and immunohistochemical analysis demonstrated that of 9 TLRs, the expression of TLR1, TLR2, and TLR4 was markedly enhanced in human atherosclerotic plaques. A considerable proportion of TLR-expressing cells were also activated, as shown by the nuclear translocation of nuclear factor-κB.

Conclusion

—

Our findings illustrate a repertoire of TLRs associated with inflammatory activation in human atherosclerotic lesions, and they encourage further exploration of innate immunity in the pathogenesis of atherosclerosis.
Skeletal Muscle Abnormalities and Iron Deficiency in Chronic Heart Failure
Authors: Melenovsky Vojtech , Hlavata Katerina , Sedivy Petr , Dezortova Monika , Borlaug Barry A. , Petrak Jiri , Kautzner Josef , Hajek Milan
Published: September 2018

Background:

Heart failure (HF) is often associated with iron deficiency (ID). Skeletal muscle abnormalities are common in HF, but the potential role of ID in this phenomenon is unclear. In addition to hemopoiesis, iron is essential for muscle bioenergetics. We examined whether energetic abnormalities in skeletal muscle in HF are affected by ID and if they are responsive to intravenous iron.

Methods and Results:

Forty-four chronic HF subjects and 25 similar healthy volunteers underwent
31
P magnetic resonance spectroscopy of calf muscle at rest and during exercise (plantar flexions). Results were compared between HF subjects with or without ID. In 13 ID-HF subjects, examinations were repeated 1 month after intravenous ferric carboxymaltose administration (1000 mg). As compared with controls, HF subjects displayed lower resting high-energy phosphate content, lower exercise pH, and slower postexercise PCr recovery. Compared with non-ID HF, ID-HF subjects had lower muscle strength, larger PCr depletion, and more profound intracellular acidosis with exercise, consistent with an earlier metabolic shift to anaerobic glycolysis. The exercise-induced PCr drop strongly correlated with pH change in HF group (
r
=−0.71,
P
<0.001) but not in controls (
r
=0.13,
P
=0.61, interaction:
P
<0.0001). Short-term iron administration corrected the iron deficit but had no effect on muscle bioenergetics assessed 1 month later.

Conclusions:

HF patients display skeletal muscle myopathy that is more severe in those with iron deficiency. The presence of ID is associated with greater acidosis with exercise, which may explain early muscle fatigue. Further study is warranted to identify the strategy to restore iron content in skeletal muscle.
The Language Resource Switchboard
Authors: Zinn Claus
Published: September 2018

The CLARIN research infrastructure gives users access to an increasingly rich and diverse set of language-related resources and tools. Whereas there is ample support for searching resources using metadata-based search, or full-text search, or for aggregating resources into virtual collections, there is little support for users to help them process resources in one way or another. In spite of the large number of tools that process texts in many different languages, there is no single point of access where users can find tools to fit their needs and the resources they have. In this squib, we present the Language Resource Switchboard (LRS), which helps users to discover tools that can process their resources. For this, the LRS identifies all applicable tools for a given resource, lists the tasks the tools can achieve, and invokes the selected tool in such a way so that processing can start immediately with little or no prior tool parameterization.