bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy
Authors: Nishiyama Yayoi , Takahata Sho , Abe Shigeru 
Published: November 2016

ABSTRACT

The effects of ME1111, a novel antifungal agent, on the hyphal morphology and ultrastructure of
Trichophyton mentagrophytes
were investigated by using scanning and transmission electron microscopy. Structural changes, such as pit formation and/or depression of the cell surface, and degeneration of intracellular organelles and plasmolysis were observed after treatment with ME1111. Our results suggest that the inhibition of energy production by ME1111 affects the integrity and function of cellular membranes, leading to fungal cell death.
Acinetobacter baumannii Biofilm Formation in Human Serum and Disruption by Gallium
Authors: Runci Federica , Bonchi Carlo , Frangipani Emanuela , Visaggio Daniela , Visca Paolo 
Published: November 2016

ABSTRACT

Biofilm-associated infections caused by
Acinetobacter baumannii
are extremely recalcitrant to antibiotic treatment. We report that
A. baumannii
develops a mature biofilm when grown in complement-free human serum (HS). We demonstrate that 16 μM gallium nitrate (GaN) drastically reduces
A. baumannii
growth and biofilm formation in HS, whereas 64 μM GaN causes massive disruption of preformed
A. baumannii
biofilm. These findings pave the way to the repurposing of GaN as an antibiofilm agent for
A. baumannii
.
Screening and Characterization of a Non-
cyp51A
Mutation in an
Aspergillus fumigatus cox10
Strain Conferring Azole Resistance
Authors: Wei Xiaolei , Chen Peiying , Gao Rongsui , Li Yeqi , Zhang Anxue , Liu Feifei , Lu Ling 
Published: November 2016

ABSTRACT

The rapid and global emergence of azole resistance in the human pathogen
Aspergillus fumigatus
has drawn attention. Thus, a thorough understanding of its mechanisms of drug resistance requires extensive exploration. In this study, we found that the loss of the putative calcium-dependent protein-encoding gene
algA
causes an increased frequency of azole-resistant
A. fumigatus
isolates. In contrast to previously identified azole-resistant isolates related to
cyp51A
mutations, only one isolate carries a point mutation in
cyp51A
(F219L mutation) among 105 independent stable azole-resistant isolates. Through next-generation sequencing (NGS), we successfully identified a new mutation (R243Q substitution) conferring azole resistance in the putative
A. fumigatus
farnesyltransferase Cox10 (AfCox10) (AFUB_065450). High-performance liquid chromatography (HPLC) analysis verified that the decreased absorption of itraconazole in related
Afcox10
mutants is the primary reason for itraconazole resistance. Moreover, a complementation experiment by reengineering the mutation in a parental wild-type background strain demonstrated that both the F219L and R243Q mutations contribute to itraconazole resistance in an
algA
-independent manner. These data collectively suggest that the loss of
algA
results in an increased frequency of azole-resistant isolates with a non-
cyp51A
mutation. Our findings indicate that there are many unexplored non-
cyp51A
mutations conferring azole resistance in
A. fumigatus
and that
algA
defects make it possible to isolate drug-resistant alleles. In addition, our study suggests that genome-wide sequencing combined with alignment comparison analysis is an efficient approach to identify the contribution of single nucleotide polymorphism (SNP) diversity to drug resistance.
SecA—a New Twist in the Tale
Authors: Collinson Ian 
Published: November 2016

ABSTRACT

A paper published in this issue of the
Journal of Bacteriology
(D. Huber, M. Jamshad, R. Hanmer, D. Schibich, K. Döring, I. Marcomini, G. Kramer, and B. Bukau, J Bacteriol 199:e0622-16, 2017,
https://doi.org/10.1128/JB.00622-16
) provides us with a timely reminder that all is not as clear as we had previously thought in the general bacterial secretion system. The paper describes a new mode of secretion through the Sec system—“uncoupled cotranslocation”—for the passage of proteins across the bacterial inner membrane and suggests that we might rethink the nature and mechanism of the targeting and transport steps toward protein export.
Observational study of the safety of buprenorphine+naloxone in pregnancy in a rural and remote population
Authors: Jumah Naana Afua , Edwards Craig , Balfour-Boehm Jazmyn , Loewen Kassandra , Dooley Joseph , Gerber Finn Lianne , Kelly Len 
Published: November 2016

ObjectivesTo describe the effect of in utero exposure to the buprenorphine+naloxone combination product in a rural and remote population.SettingA district hospital that services rural and remote, fly-in communities in Northwestern Ontario, Canada.ParticipantsA retrospective cohort study was conducted of 855 mother infant dyads between 1 July 2013 and 30 June 2015. Cases included all women who had exposure to buprenorphine+naloxone during pregnancy (n=62). 2 control groups were identified; the first included women with no opioid exposure in pregnancy (n=618) and the second included women with opioid exposure other than buprenorphine+naloxone (n=159). Women were excluded if they had multiple pregnancy or if they were part of a methadone programme (n=16). The majority of women came from Indigenous communities.OutcomesThe primary outcomes were birth weight, preterm delivery, congenital anomalies and stillbirth. Secondary neonatal outcomes included gestational age at delivery, Apgar scores at 1 and 5 min, NAS Score >7 and treatment for neonatal abstinence syndrome (NAS). Secondary maternal outcomes included the number of caesarean sections, postpartum haemorrhages, out of hospital deliveries and transfer of care to tertiary centres.ResultsNo difference was found in the primary outcomes or in the Apgar score and caesarean section rate between in utero buprenorphine+naloxone exposure versus no opioid exposure in pregnancy. Compared to women taking other opioids, women taking buprenorphine+naloxone had higher birthweight babies (p=0.001) and less exposure to marijuana (p<0.001) during pregnancy.ConclusionsRetrospective data suggest that there likely is no harm from taking buprenorphine+naloxone opioid agonist treatment in pregnancy. Larger, prospective studies are needed to further assess safety.
Individual surgeon mortality rates: can outliers be detected? A national utility analysis
Authors: Harrison Ewen M , Drake Thomas M , O'Neill Stephen , Shaw Catherine A , Garden O James , Wigmore Stephen J 
Published: November 2016

ObjectivesThere is controversy on the proposed benefits of publishing mortality rates for individual surgeons. In some procedures, analysis at the level of an individual surgeon may lack statistical power. The aim was to determine the likelihood that variation in surgeon performance will be detected using published outcome data.DesignA national analysis surgeon-level mortality rates to calculate the level of power for the reported mortality rate across multiple surgical procedures.SettingThe UK from 2010 to 2014.ParticipantsSurgeons who performed colon cancer resection, oesophagectomy or gastrectomy, elective aortic aneurysm repair, hip replacement, bariatric surgery or thyroidectomy.OutcomesThe likelihood of detecting an individual with a 30-day, 90-day or in-patient mortality rate of up to 5 times the national mean or median (as available). This was represented using a novel heat-map approach.ResultsOverall mortality rates for the procedures ranged from 0.07% to 4.5% and mean/median surgeon volume was between 23 and 75 cases. The national median case volume for colorectal (n=55) and upper gastrointestinal (n=23) cancer resections provides around 20% power to detect a mortality rate of 3 times the national median, while, for hip replacement, this is a rate 5 times the national average. At the mortality rates reported for thyroid (0.08%) and bariatric (0.07%) procedures, it is unlikely a surgeon would perform a sufficient number of procedures in his/her entire career to stand a good chance of detecting a mortality rate 5 times the national average.ConclusionsAt present, surgeons with increased mortality rates are unlikely to be detected. Performance within an expected mortality rate range cannot be considered reliable evidence of acceptable performance. Alternative approaches should focus on commonly occurring meaningful outcome measures, with infrequent events analysed predominately at the hospital level.
Trametinib Drives T-cell–Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis
Authors: Allegrezza Michael J. , Rutkowski Melanie R. , Stephen Tom L. , Svoronos Nikolaos , Perales-Puchalt Alfredo , Nguyen Jenny M. , Payne Kyle K. , Singhal Sunil , Eruslanov Evgeniy B. , Tchou Julia , Conejo-Garcia Jose R. 
Published: November 2016

AbstractTargeted therapies elicit seemingly paradoxical and poorly understood effects on tumor immunity. Here, we show that the MEK inhibitor trametinib abrogates cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) from human or mouse myeloid progenitors. MEK inhibition also reduced the production of the mMDSC chemotactic factor osteopontin by tumor cells. Together, these effects reduced mMDSC accumulation in tumor-bearing hosts, limiting the outgrowth of KRas–driven breast tumors, even though trametinib largely failed to directly inhibit tumor cell proliferation. Accordingly, trametinib impeded tumor progression in vivo through a mechanism requiring CD8+ T cells, which was paradoxical given the drug's reported ability to inhibit effector lymphocytes. Confirming our observations, adoptive transfer of tumor-derived mMDSC reversed the ability of trametinib to control tumor growth. Overall, our work showed how the effects of trametinib on immune cells could partly explain its effectiveness, distinct from its activity on tumor cells themselves. More broadly, by providing a more incisive view into how MEK inhibitors may act against tumors, our findings expand their potential uses to generally block mMDSC expansion, which occurs widely in cancers to drive their growth and progression. Cancer Res; 76(21); 6253–65. ©2016 AACR.
Structure and Function of a Prostate Cancer Dissemination–Permissive Extracellular Matrix
Authors: Penet Marie-France , Kakkad Samata , Pathak Arvind P. , Krishnamachary Balaji , Mironchik Yelena , Raman Venu , Solaiyappan Meiyappan , Bhujwalla Zaver M. 
Published: November 2016

Abstract
Purpose: The poor prognosis of metastatic prostate cancer continues to present a major challenge in prostate cancer treatment. The tumor extracellular matrix (ECM) plays an important role in facilitating metastasis. Here, we investigated the structure and function of an ECM that facilitates prostate cancer metastasis by comparing orthotopic tumors that frequently metastasize to poorly metastatic subcutaneous tumors.
Experimental Design: Both tumors were derived from a human prostate cancer PC3 cell line engineered to fluoresce under hypoxia. Second harmonic generation (SHG) microscopy was used to characterize collagen 1 (Col1) fiber patterns in the xenografts as well as in human samples. MRI was used to determine albumin-Gd-diethylenetriaminepenta-acetate (alb-GdDTPA) transport through the ECM using a saturation recovery MR method combined with fast T1 SNAPSHOT-FLASH imaging. Cancer-associated fibroblasts (CAF) were also quantified in these tumors.
Results: Significant structural and functional differences were identified in the prometastatic orthotopic tumor ECM compared to the less metastatic subcutaneous tumor ECM. The significantly higher number of CAFs in orthotopic tumors may explain the higher Col1 fiber volumes in these tumors. In vivo, alb-GdDTPA pooling was significantly elevated in metastatic orthotopic tumors, consistent with the increased Col1 fibers.
Conclusions: Developing noninvasive MRI indices of macromolecular transport, together with characterization of Col1 fiber patterns and CAFs can assist in stratifying prostate cancers for aggressive treatments or active surveillance. These results highlight the role of CAFs in supporting or creating aggressive cancers, and the importance of depleting CAFs to prevent metastatic dissemination in prostate cancer. Clin Cancer Res; 23(9); 2245–54. ©2016 AACR.
Abstract A007: Intratumoral delivery of inactivated vaccinia virus is more efficacious than live oncolytic vaccinia virus in murine bilateral tumor implantation models
Authors: Wang Weiyi , Dai Peihong , Yang Ning , Shuman Stewart , Merghoub Taha , Wolchok Jedd D. , Deng Liang 
Published: November 2016

Abstract
Poxviruses are large cytoplasmic DNA viruses that have potentials as vaccine vectors and oncolytic agents. Although almost all of the oncolytic vaccinia viruses that are being investigated in clinical trials are replication competent, it is still unclear how these viruses exert antitumor immunologic effects, and whether viral replication is even necessary to achieve systemic antitumor efficacy. In this study, we compared therapeutic efficacy of the intratumoral delivery of the live, attenuated, replication competent oncolytic vaccinia virus expressing mGM-CSF (VC-TK−-mGM-CSF)vs. its heat-inactivated counterpart (iVC-TK−-mGM-CSF) in two bilateral tumor implantation models- B16-F10 murine melanoma and MC38 colon adenocarcinoma. We found that intratumoral injection of inactivated virus exerted stronger systemic antitumor effects than the live virus. FACS analyses of tumor infiltrating immune cells revealed that intratumoral injection of iVC-TK−-mGM-CSF lead to increased percentages and numbers of activating effector CD8+ and CD4+ T cells and reduced percentages and numbers of CD4+Foxp3+ regulatory T cells in the non-injected tumors compared with intratumoral delivery of the live virus. Infection of bone marrow-derived dendritic cells (DCs) with iVC-TK−-mGM-CSF induced type I IFN and proinflammatory cytokine and chemokine production and DC maturation, whereas the live virus did not. Taken together, our results demonstrate that intratumoral delivery of inactivated vaccina virus is safer and more efficacious than live oncolytic vaccinia virus expressing mGM-CSF in two murine bilateral tumor implantation models. Our findings have important implications for the design of poxviral-based immunotherapeutics for patients with metastatic cancers.
Note: This abstract was not presented at the conference.
Citation Format: Weiyi Wang, Peihong Dai, Ning Yang, Stewart Shuman, Taha Merghoub, Jedd D. Wolchok, Liang Deng. Intratumoral delivery of inactivated vaccinia virus is more efficacious than live oncolytic vaccinia virus in murine bilateral tumor implantation models [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A007.
Abstract A010: A novel DNA vaccine targeting fibroblast activation protein (FAP) breaks tolerance and synergizes with anticancer immune therapy in mice
Authors: Duperret Elizabeth , Ammons Dylan , Wise Megan C. , Yan Jian , Humeau Laurent M. , Weiner David B. 
Published: November 2016

Abstract
Fibroblast activation protein (FAP) is a membrane-bound enzyme with gelatinase and peptidase activity that is up-regulated in cancer-associated fibroblasts in over 90% of human carcinomas. Previous studies have shown that ablation of FAP-expressing cells from transgenic mice attenuates tumor growth and synergizes with other immune therapies such as immune checkpoint blockade. Groups have additionally shown that T cells expressing chimeric antigen receptors targeting FAP slow tumor progression; however, in some mouse strains these CARs cause lethal toxicity. There is therefore a need to develop safer therapies targeting FAP. In this study we designed a novel consensus-based FAP DNA vaccine to help break tolerance. We hypothesized that this FAP vaccine could break tolerance and synergize with other immunotherapies to induce anti-tumor immunity without causing overt toxicity. Upon delivery of our FAP DNA vaccine intramuscularly followed by electroporation (EP), we detected IFN-γ and TNF-α CD8 T cell responses (p&lt;0.05), and TNF-α CD4 responses (p&lt;0.05) against native mouse FAP peptides, indicating that our vaccine is capable of breaking tolerance. Furthermore, we detected cytotoxic CD107a/IFNγ/T-bet triple-positive CD8 T cells that are reactive to native FAP peptides (p&lt;0.05). In a prostate cancer model, vaccination with FAP alone or the prostate cancer antigen PSMA alone did not significantly alter tumor growth. However, vaccination with a combination of FAP and PSMA significantly attenuated tumor growth (p&lt;0.0005), with final tumor volumes that were approximately 9 times smaller than tumors in naïve mice. Thus, our results support the use of FAP vaccines to target the tumor microenvironment in combination with immune therapies targeting the tumor cells themselves. We are investigating additional combination therapies with our FAP vaccine to modulate tumor infiltrating lymphocytes and to broaden responses to additional tumor antigens.
Citation Format: Elizabeth Duperret, Dylan Ammons, Megan C. Wise, Jian Yan, Laurent M. Humeau, David B. Weiner. A novel DNA vaccine targeting fibroblast activation protein (FAP) breaks tolerance and synergizes with anticancer immune therapy in mice [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A010.
Abstract A024: Predicting cancer survival with neo-epitope burden
Authors: Akers Nicholas K. , Schadt Eric , Losic Bojan 
Published: November 2016

Abstract
For many common cancers, survival and efficacy of state-of-the-art therapies are strongly predicted by the number of non-synonymous mutations. It is widely hypothesized that this association between mutations and survival is a result of mutations leading to neo-epitopes which in turn induce a robust anti-tumor immune response. It follows that accurately quantifying the number of neo-epitopes within a patient should better predict survival than that of non-synonymous mutations, however that has generally not been the case. Indeed, mutations and predicted neo-epitopes explain roughly the same survival variance, likely due to the difficulty of accurately predicting and prioritizing immunogenic neo-epitopes from mutations. We hypothesized that by integrating several data types and using state-of-the-art techniques for major histocompatibility complex (MHC) class I and II allele calling and epitope binding prediction, we could predict survival of cancer patients better than with mutation calls alone. We have developed a pipeline to characterize the potential immunogenicity of neo-epitopes. The pipeline uses copy-number variants and reads from whole-exome sequencing to assess the clonality of a given neo-epitope. MHC class I and class II allelotyping is performed, and expression of MHC alleles and mutations is determined using RNA-Seq. Similarity of epitopes to self-peptides is assessed by measuring similarity to predicted self-ligands, as well as by measuring the MHC affinity of wild-type versions of mutated epitopes. With this pipeline we were able to rapidly process the cancer genome atlas (TCGA) breast cancer (BRCA), non-small cell lung cancer (NSCLC), melanoma (SKCM), and pancreatic cancer (PAAD) datasets to infer neo-epitopes burden with high resolution. A linear model of survival as a function of mutations and their putative immunogenicity was constructed using these datasets via elastic net regularization, while modeling variance was controlled with k-fold cross validation. Our results confirm that the putatively immunogenic mutational burden is a highly significant term is such models. Finally, we quantify epitope response in these models by incorporating TCR sequence entropy as a proxy for clonal tumor infiltrating lymphocyte expansion.
Citation Format: Nicholas K. Akers, Eric Schadt, Bojan Losic. Predicting cancer survival with neo-epitope burden [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A024.
Abstract A028: Pre-clinical development of a first-in-class fully synthetic heat shock protein-based personalized cancer vaccine
Authors: Khattar Mithun , Tanne Antoine , Morin Benjamin , Wilson Nicholas , Uduman Mohamed , Zelin Justin , Stein Robert , Exley Mark , Castle John , Levey Daniel L. 
Published: November 2016

Abstract
Tumors accumulate spontaneous somatic mutations which can give rise to neo-epitopes (neoantigens) recognizable as non-self by T-cells. Advances in next-generation sequencing and bioinformatics make it possible to analyze individual patients' tumor genomes and predict immunogenic mutations, which can be synthesized as short peptides, RNA or DNA for use in personalized cancer vaccines. However, these approaches need optimization for safe and effective induction of anti-tumor T-cell responses. We addressed this challenge by complexing synthetic long peptides comprising predicted tumor neo-epitopes to recombinant Hsc70, creating personalized vaccine candidates, AutoSynVax™ (ASV™), administered with QS-21 Stimulon® adjuvant. The same platform comprising Hsc70 plus synthetic long viral peptides was previously validated in a Phase-2 clinical trial, demonstrating effective T-cell responses and reduced viral load in HSV-2+ subjects. ASV immunization is intended to facilitate antigen processing and presentation of neo-epitopes to T-cells, resulting in robust immune responses. The innate immune modulating properties of the Hsc70 protein as well as that of QS-21 Stimulon adjuvant are also under investigation at the vaccine injection site, in draining lymph node, and in cultures of antigen presenting cell populations exposed to the two agents. Finally, ASV is being explored in combination with various agonistic and antagonistic immune modulating monoclonal antibodies with the aim of increasing the duration of immunological memory and durability of tumor control. With an acceptable safety profile associated with Hsc70 and QS-21 Stimulon exposure in humans and demonstrated preclinical anti-tumor activity of ASV, we are poised to begin a first-in-human clinical trial by the first half of 2017.
Citation Format: Mithun Khattar, Antoine Tanne, Benjamin Morin, Nicholas Wilson, Mohamed Uduman, Justin Zelin, Robert Stein, Mark Exley, John Castle, Daniel L. Levey. Pre-clinical development of a first-in-class fully synthetic heat shock protein-based personalized cancer vaccine [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A028.