bluuebunny/crossref_metadata_2025_split huggingface dataset:
Personalizing Polymyxin B Dosing Using an Adaptive Feedback Control Algorithm
Authors: Lakota Elizabeth A. , Landersdorfer Cornelia B. , Nation Roger L. , Li Jian , Kaye Keith S. , Rao Gauri G. , Forrest Alan 
Published: May 2018

ABSTRACT

Polymyxin B is used as an antibiotic of last resort for patients with multidrug-resistant Gram-negative bacterial infections; however, it carries a significant risk of nephrotoxicity. Herein we present a polymyxin B therapeutic window based on target area under the concentration-time curve (AUC) values and an adaptive feedback control algorithm (algorithm) which allows for the personalization of polymyxin B dosing. The upper bound of this therapeutic window was determined through a pharmacometric meta-analysis of polymyxin B nephrotoxicity data, and the lower bound was derived from murine thigh infection pharmacokinetic (PK)/pharmacodynamic (PD) studies. A previously developed polymyxin B population pharmacokinetic model was used as the backbone for the algorithm. Monte Carlo simulations (MCS) were performed to evaluate the performance of the algorithm using different sparse PK sampling strategies. The results of the nephrotoxicity meta-analysis showed that nephrotoxicity rate was significantly correlated with polymyxin B exposure. Based on this analysis and previously reported murine PK/PD studies, the target AUC
0–24
(AUC from 0 to 24 h) window was determined to be 50 to 100 mg · h/liter. MCS showed that with standard polymyxin B dosing without adaptive feedback control, only 71% of simulated subjects achieved AUC values within this window. Using a single PK sample collected at 24 h and the algorithm, personalized dosing regimens could be computed, which resulted in >95% of simulated subjects achieving AUC
0–24
values within the target window. Target attainment further increased when more samples were used. Our algorithm increases the probability of target attainment by using as few as one pharmacokinetic sample and enables precise, personalized dosing in a vulnerable patient population.
Copper Acyl Salicylate Has Potential as an Anti-Cryptococcus Antifungal Agent
Authors: Ogundeji Adepemi O. , Porotloane Boitumelo F. , Pohl Carolina H. , Kendrekar Pravin S. , Sebolai Olihile M. 
Published: May 2018

ABSTRACT

The
in vitro
antifungal activity of aspirin against cryptococcal cells has been reported. However, the unwanted effects of aspirin may limit its clinical application. Conceivably, a derivative of aspirin could overcome this challenge. Toward this end, this study considered the usage of an aspirinate-metal complex, namely, copper acyl salicylate (CAS), as an anti-
Cryptococcus
antifungal agent. Additionally, the study examined the effects of this compound on macrophage function. The
in vitro
susceptibility results revealed that cryptococcal cells were vulnerable (in a dose-dependent manner) to CAS, which might have effected growth inhibition by damaging cryptococcal cell membranes. Interestingly, when CAS was used in combination with fluconazole or amphotericin B, synergism was observed. Furthermore, CAS did not negatively affect the growth or metabolic activity of macrophages; rather, it sensitized those immune cells to produce interferon gamma and interleukin 6, which, in turn, might have aided in the phagocytosis of cryptococcal cells. Compared to our aspirin data, CAS was noted to be more effective in killing cryptococcal cells (based on susceptibility results) and less toxic toward macrophages (based on growth inhibition results). Taking these findings together, it is reasonable to conclude that CAS may be a better anti-
Cryptococcus
drug that could deliver better therapeutic outcomes, compared to aspirin.
Occurrence of Traditional and Alternative Fecal Indicators in Tropical Urban Environments under Different Land Use Patterns
Authors: Saeidi Nazanin , Gu Xiaoqiong , Tran Ngoc Han , Goh Shin Giek , Kitajima Masaaki , Kushmaro Ariel , Schmitz Bradley William , Gin Karina Yew-Hoong 
Published: May 2018

ABSTRACT

This study evaluated the geospatial distribution of fecal indicator bacteria (FIB) (i.e.,
Escherichia coli
,
Enterococcus
spp.) and the alternative fecal indicator pepper mild mottle virus (PMMoV) in tropical freshwater environments under different land use patterns. Results show that the occurrence and concentration of microbial fecal indicators were higher for urban than for parkland-dominated areas, consistent with land use weightage. Significant positive correlations with traditional FIB indicate that PMMoV is a suitable indicator of fecal contamination in tropical catchments waters (0.549 ≤ rho ≤ 0.612;
P
< 0.01). PMMoV exhibited a strong significant correlation with land use weightage (rho = 0.728;
P
< 0.01) compared to traditional FIB (rho = 0.583;
P
< 0.01). In addition, chemical tracers were also added to evaluate the potential relationships with microbial fecal indicators. The relationships between diverse variables (e.g., environmental parameters, land use coverage, and chemical tracers) and the occurrence of FIB and PMMoV were evaluated. By using stepwise multiple linear regression (MLR), the empirical experimental models substantiate the impact of land use patterns and anthropogenic activities on microbial water quality, and the output results of the empirical models may be able to predict the sources and transportation of human fecal pollution or sewage contamination. In addition, the high correlation between PMMoV data obtained from quantitative real-time PCR (qPCR) and viral metagenomics data supports the possibility of using viral metagenomics to relatively quantify specific microbial indicators for monitoring microbial water quality (0.588 ≤ rho ≤ 0.879;
P
< 0.05).

IMPORTANCE
The results of this study may support the hypothesis of using PMMoV as an alternative indicator of human fecal contamination in tropical surface waters from the perspective of land use patterns. The predictive result of the occurrence of human fecal indicators with high accuracy may reflect the source and transportation of human fecal pollution, which are directly related to the risk to human health, and thereafter, steps can be taken to mitigate these risks.
Cardiovascular phenotype and prognosis of patients with heart failure induced by cancer therapy
Authors: Nadruz Wilson , West Erin , Sengeløv Morten , Grove Gabriela L , Santos Mário , Groarke John D , Forman Daniel E , Claggett Brian , Skali Hicham , Nohria Anju , Shah Amil M 
Published: May 2018

ObjectiveThis study compared the clinical features, cardiac structure and function evaluated by echocardiography, cardiopulmonary response to exercise and long-term clinical outcomes between patients with heart failure (HF) induced by cancer therapy (CTHF) and heart failure not induced by cancer therapy (NCTHF).MethodsWe evaluated 75 patients with CTHF and 894 with NCTHF who underwent clinically indicated cardiopulmonary exercise testing, and followed these individuals for a median of 4.5 (3.0–5.8) years, during which 187 deaths and 256 composite events (death, heart transplantation and left ventricular (LV) assistant device implantation) occurred.ResultsCompared with NCTHF, patients with CTHF were younger, with lower prevalence of cardiovascular comorbidities, higher LV ejection fraction (LVEF), but similar global longitudinal strain. LV diastolic function (higher E/e′ ratio) and compliance (higher end-diastolic pressure/LV end-diastolic volume index ratio) were worse in CTHF and were both associated with adverse outcomes. Despite a favourable clinical profile, peak VO2 and VE/VCO2 slope were similarly impaired in CTHF and NCTHF. In multivariable Cox regression analysis including clinical characteristics, cardiopulmonary exercise testing variables and LVEF, CTHF was associated with a significantly higher risk of death (HR 2.64; 95% CI 1.53 to 4.55; p=0.001) and composite events (HR 1.79; 95% CI 1.10 to 2.91; p=0.019) compared with NCTHF.ConclusionsCTHF is characterised by a distinct clinical profile, better LVEF but worse LV diastolic properties, and similarly impaired global longitudinal strain, functional capacity and ventilatory efficiency. Accounting for differences in clinical characteristics, CTHF was associated with worse long-term prognosis than NCTHF.
High rates of variation in HLA-DQ2/DQ8 testing for coeliac disease: results from an RCPAQAP pilot program
Authors: Horan Martin Patrick , Chai Sze Yee , Munusamy Nalishia , Tay Kwang Hong , Wienholt Louise , Tye-Din Jason A , Daveson James , Varney Michael , Badrick Tony 
Published: May 2018

AimCoeliac disease(CD) is a highly prevalent, gluten-dependent, autoimmune enteropathy. While the diagnosis is based on serological and histological criteria, genotyping of the human leucocyte antigens (HLA) DQ2 and DQ8 has been shown to have substantial clinical utility, especially in excluding the diagnosis in patients who do not carry either antigen. As a result, HLA genotyping is now being performed by more laboratories and has recently become one of the most frequently requested genetic tests in Australia. To date, there has been little scrutiny on the accuracy and reporting of results by laboratories new to HLA typing. In response to clinician feedback that identified potentially clinically significant discrepancies in HLA typing results, the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) undertook a pilot study to assess laboratory performance in the detection of HLA-DQ2/DQ8 and their associatedHLA-DQA1andHLA-DQB1alleles.MethodsDNA was extracted from 5 patients and sent to 10 laboratories for external quality assurance (EQA) testing. Laboratories were assessed for reporting in genotyping, interpretation and methodology.ResultsOur findings showed that at least 80% of laboratories underperform with respect to recommended guidelines for HLA typing and reporting for CD, with 40% of laboratories failing to provide any clinical interpretation or full genotyping data. This suboptimal level of reporting may lead to ambiguities for downstream clinical interpretation that may compromise patient management.ConclusionsThese findings highlight the importance of adherence to standardised guidelines for optimal performance and reporting of HLA results and substantiate the need for EQA and proficiency testing for laboratories providing this service.
Examining perceptions about IQOS heated tobacco product: consumer studies in Japan and Switzerland
Authors: Hair Elizabeth C , Bennett Morgane , Sheen Emily , Cantrell Jennifer , Briggs Jodie , Fenn Zoe , Willett Jeffrey G , Vallone Donna 
Published: May 2018

ObjectiveTo examine consumer perceptions, attitudes and behaviours regarding the heated tobacco product, IQOS, as well as to document the product’s marketing strategies to determine its potential for appealing to youth and young adults.MethodTruth Initiative, in collaboration with Flamingo, collected qualitative data via: (1) expert interviews, (2) semiotic analysis of IQOS packing and marketing materials, and (3) 12 focus groups with adults in Switzerland (ages 19–44 years; June 6–9, 2016) and Japan (ages 20–39 years; June 22–24, 2016) (n=68 for both groups).ResultsExpert interviews and IQOS packing and marketing analyses revealed the product is being marketed as a clean, chic and pure product, which resonated very well in Japan given the strong cultural values of order, cleanliness, quality and respect for others. Focus groups results indicated Japanese IQOS users used the product for socialising with non-smokers. Focus group participants in both Japan and Switzerland reported lower levels of satisfaction with the product relative to combustible cigarettes, although many found the product packaging to be appealing. While participants identified several benefits and barriers related to IQOS, few reported any potential health benefits of use compared with combustible tobacco products.ConclusionIQOS was marketed as a sophisticated, high tech and aspirational product. Because youth and young adults are more interested in such product positioning, this approach raises some concern about youth appeal. This research shows cultural factors appeared to affect the appeal of this messaging, indicating that prevalence and uptake data will likely not be similar from country to country.
Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity
Authors: Ventura Alessandra , Vassall Aaron , Robinson Eve , Filler Renata , Hanlon Douglas , Meeth Katrina , Ezaldein Harib , Girardi Michael , Sobolev Olga , Bosenberg Marcus W. , Edelson Richard L. 
Published: May 2018

Abstract
Extracorporeal photochemotherapy (ECP) is a cancer immunotherapy for cutaneous T-cell lymphoma (CTCL) operative in more than 350 centers worldwide. Although its efficacy and favorable safety profile have driven its widespread use, elucidation of its underlying mechanism has been difficult. In this study, we identify the principal contributors to the anticancer immunotherapeutic effects of ECP, with the goal of enhancing potency and broadening applicability to additional malignancies. First, we scaled down the clinical ECP leukocyte-processing device to mouse size. Second, we used that miniaturized device to produce a cellular vaccine that regularly initiated therapeutic antimelanoma immunity. Third, we individually subtracted key factors from either the immunizing inoculum or the treated animal to ascertain their contribution to the in vivo antimelanoma response. Platelet-signaled monocyte-to-dendritic cell (DC) differentiation followed by sorting/processing/presentation of tumor antigens derived from internalized apoptotic tumor cells were absolute requirements. As in clinical ECP, immunogenic cell death of tumor cells was finely titrated by DNA cross-linkage mediated by photoactivated 8-methoxypsoralen (8-MOPA). ECP-induced tumor-loaded DC were effective immunotherapeutic agents only if they were spared exposure to 8-MOPA, indicating that healthy DC are required for ECP. Infusion of responder T cells into naïve tumor-challenged mice established the protective role of stimulated T-cell antitumor immunity. Collectively, these results reveal that selective antitumor effects of ECP are initiated by tumor antigen–loaded, ECP-induced DC, which promote potent collaboration between CD4 and CD8 tumor-specific T cells. These mechanistic insights suggest potential therapeutic applicability of ECP to solid tumors in addition to CTCL.
Significance: These findings identify principal cellular contributors to the anticancer immunotherapeutic impact of ECP and suggest this treatment may be applicable to a broad spectrum of immunogenic malignancies. Cancer Res; 78(14); 4045–58. ©2018 AACR.
Abstract A17: Novel patient-derived xenograft (PDX) models from peritoneal metastasis of colorectal carcinoma for drug testing and biomarker analysis
Authors: Walther Wolfgang , Pachmayr Eva , Brzezicha Bernadette , Büttner Britta , Rau Beate , Stein Ulrike 
Published: May 2018

Abstract
Peritoneal metastasis (PM) represents a terminal tumor stage with limited therapy options for patients with colorectal cancer (CRC). To improve therapeutic efficacy and overall survival, availability of appropriate in vivo models of PM could improve the evaluation of chemosensitivity as well as identification of novel biomarkers and therapeutic targets to improve the therapeutic outcome of PM patients. In this context, we generated the first patient-derived xenograft (PDX) models of PM from CRC as platform to test chemotherapy response and to potentially analyze biomarkers.
For the PDX establishment colorectal surgical specimens were subcutaneously (s.c.) transplanted onto immunocompromised NOG mice. The engrafted tumors were transferred to NMRI nu/nu mice for further passaging. They were characterized by histopathology, immunohistochemistry, and gene expression analyses using real-time RT-PCR. Chemosensitivity of PDX models was evaluated in vivo by application of a panel of conventional chemotherapeutic and of targeted drugs.
For PDX establishment 68 CRC surgical specimens (taken from peritoneum and omentum) were transplanted, from which 22 PDX have engrafted. From those, 13 models of 10 patients have been analyzed. Their tumor doubling times ranged between 4 to 28 days. The histopathologic evaluation revealed maintenance of the original CRC histology in the PDX. The chemosensitivity testing of conventional and of targeted drugs in the 13 PM PDX models revealed the individual, diverging response of the PDX, such as for 5-FU, irinotecan, oxaliplatin, cetuximab, and erlotinib. More interestingly, different responses were observed in PDX of the omentum vs. peritoneum, which were derived from the same patient.
Our results demonstrate that this novel panel of PDX maintains the morphology of the patient tumor in early passages, reflect heterogeneous response rates, and can be used as a preclinical in vivo platform for translational studies of potential clinical use. In conclusion, this PDX panel of PM of the CRC can be used for further studies to evaluate new biomarkers and to test novel therapies or combinations for PM of CRC.
Citation Format: Wolfgang Walther, Eva Pachmayr, Bernadette Brzezicha, Britta Büttner, Beate Rau, Ulrike Stein. Novel patient-derived xenograft (PDX) models from peritoneal metastasis of colorectal carcinoma for drug testing and biomarker analysis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A17.
Abstract A32: Sall2 transcription factor: A novel regulator of G1-S cyclins
Authors: Hermosilla Viviana E. , Escobar David E. , Hepp Matias I. , Riffo Elizabeth N. , Salgado Ginessa , Morin Violeta , Galindo Mario , Castro Ariel F. , Pincheira Roxana , Pincheira Roxana 
Published: May 2018

Abstract
Spalt-like proteins are Zinc finger transcription factors present from C. elegans to vertebrates, with critical roles in development. In vertebrates, four paralogues have been identified (Sall1-4), with Sall2 being the most dissimilar member of the family. Sall2 has shown to be important for brain and eye development and–unlike its vertebrate paralogues–it has also been proposed as a tumor suppressor. Sall2 activity promotes cell cycle arrest and cell death and its expression is downregulated in several types of cancer. Despite this, very few Sall2 transcriptional targets have been identified until date.
In agreement with previous reports, characterization of primary and immortalized mouse embryonic fibroblasts (MEFs) showed a proliferative advantage of isogenic Sall2-/- vs Sall2+/+ cells. In order to identify the molecular mechanisms underlying Sall2 function during cell cycle, iMEFs were synchronized at G2/M phase with nocodazole. Flow cytometry, Western blot, and qRT-PCR analyses were performed after nocodazole release. In accordance with the role of Sall2 in promoting cell cycle arrest, a more rapid progression from G2/M to G1/S was noticed in Sall2-deficient cells, which correlates with an increased expression of Cyclin D1 (Ccnd1) and Cyclin E1 (Ccne1). Similar results were obtained in HEK293 and SKOV3 human cell lines, suggesting that Sall2 controls cell cycle progression by downregulating G1-S cyclins. Sall2-mediated repression of CCND1 and CCNE1 was confirmed by luciferase reporter assays. In addition, bioinformatic analysis led to the identification of several putative Sall2 binding sites within CCND1 and CCNE1 promoters. Sall2 binding to CCND1 and CCNE1 promoters was demonstrated by chromatin immunoprecipitation. Analysis of tissues from Sall2+/+ and Sall2-/- mice confirmed the inverse correlation between expression of SALL2 and G1-S cyclins.
Importantly, the same correlation was found in different types of tumor by analyzing publicly available databases, suggesting that Sall2-Cyclin D1-Cyclin E1 axis could be downregulated in cancer. Thus, we have identified two novel Sall2 transcriptional targets at G1-S transition.
Altogether, our findings support the role of Sall2 as a tumor suppressor, by acting as a transcriptional repressor during cell cycle.
Citation Format: Viviana E. Hermosilla, David E. Escobar, Matias I. Hepp, Elizabeth N. Riffo, Ginessa Salgado, Violeta Morin, Mario Galindo, Ariel F. Castro, Roxana Pincheira, Roxana Pincheira. Sall2 transcription factor: A novel regulator of G1-S cyclins [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A32.
Abstract A33: Loss of Id4 initiates PIN-like lesions by maintaining stemness in mice prostate
Authors: Bostanthirige Dhanushka Hewa , Joshi Jugal , Kumar Shravan , Patel Divya , Chaudhary Jaideep 
Published: May 2018

Abstract
Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators, has emerged as a tumor suppressor in prostate cancer (PCa). Recent studies have shown that Id4 is highly expressed in the normal prostate and decreases in prostate cancer (PCa) due to epigenetic silencing. Id4 knockdown in androgen-sensitive LNCaP cells has been shown to lead to castration-resistant prostate cancer (CRPC) in vitro and in vivo. Id4-/- mice leads to underdeveloped prostate without the loss of androgen receptor (AR) expression. In this study we demonstrate that prostates from the Id4 knockout (Id4-/-) mice show PIN-like lesions, suggesting that loss of Id4 plays a major role in initiation of prostate PCa. Histology of Id4 -/- mice prostate shows more PIN lesions at 3 months and 6 months without showing clear evidence of prostate cancer. Immunohistochemical analysis demonstrated increased expression of Amacr, which is a biomarker for PIN and PCa, only in Id4-/- 3-month- and 6-month-old prostate tissue. The expression of Nkx3.1 and Pten tumor suppressor genes in Id4-/-mouse prostate was undetectable, suggesting that loss of Id4 has potential to initiate or progress to PCa. Although PTEN protein was not present in Id4-/- mice, the presence of the corresponding PTEN mRNA suggested intact transcriptional program. These results suggested that Id4 plays a role in regulating the translation of the PTEN mRNA. We are currently investigating the ID4-regulated mechanisms involved in the translational control of PTEN. The results suggested that id4-/- results in PIN lesions that are in part due to a block in Pten translation.
Sca-1 is a member of the Ly6 family of glycosyl phostidylinositol (GPI)-anchored cell surface proteins used as stem cell marker in murine prostate. According to cancer stem cell theory, stem cells in basal layer of the prostate tubules give rise to transient amplifying cells and differentiate into terminally differentiated secretory luminal epithelial cells. From the same pathway it gives rise to the tumor-promoting cells, which ultimately form prostate cancer. Sca-1 is expressed in Id4-/- mice 3-month- and 6-month-old prostate glands.
These data suggest that loss of Id4 can initiate PIN like lesions by maintaining stemness through regulating transcriptional, translational mechanism via altering the expression of PTEN, NKX3.1, C-MYC and other regulatory molecules. Currently we are investigating that regulatory mechanism, mainly focusing on mRNA interference mechanisms.
Citation Format: Dhanushka Hewa Bostanthirige, Jugal Joshi, Shravan Kumar, Divya Patel, Jaideep Chaudhary. Loss of Id4 initiates PIN-like lesions by maintaining stemness in mice prostate [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A33.