bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Microbiota Contributes to CD8+T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis
Authors: Keselman Aleksander , Li Erqiu , Maloney Jenny , Singer Steven M. 
Published: July 2016

ABSTRACTGiardia duodenalisis a noninvasive luminal pathogen that impairs digestive function in its host in part by reducing intestinal disaccharidase activity. This enzyme deficiency has been shown in mice to require CD8+T cells. We recently showed that both host immune responses and parasite strain affected disaccharidase levels during murine giardiasis. However, high doses of antibiotics were used to facilitate infections in that study, and we therefore decided to systematically examine the effects of antibiotic use on pathogenesis and immune responses in the mouse model of giardiasis. We found that antibiotic treatment did not overtly increase the parasite burden but significantly limited the disaccharidase deficiency observed in infected mice. Moreover, while infected mice had more activated CD8+αβ T cells in the small intestinal lamina propria, this increase was absent in antibiotic-treated mice. Infection also led to increased numbers of CD4+αβ T cells in the lamina propria and activation of T cell receptor γδ-expressing intraepithelial lymphocytes (IEL), but these changes were not affected by antibiotics. Finally, we show that activated CD8+T cells express gamma interferon (IFN-γ) and granzymes but that granzymes are not required for sucrase deficiency. We conclude that CD8+T cells become activated in giardiasis through an antibiotic-sensitive process and contribute to reduced sucrase activity. These are the first data directly demonstrating activation of CD8+T cells and γδ T cells duringGiardiainfections. These data also demonstrate that disruption of the intestinal microbiota by antibiotic treatment prevents pathological CD8+T cell activation in giardiasis.
Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms
Authors: Chumbler Nicole M. , Farrow Melissa A. , Lapierre Lynne A. , Franklin Jeffrey L. , Lacy D. Borden 
Published: July 2016

ABSTRACT

As the major cause of antibiotic-associated diarrhea,
Clostridium difficile
is a serious problem in health care facilities worldwide.
C. difficile
produces two large toxins, TcdA and TcdB, which are the primary virulence factors in disease. The respective functions of these toxins have been difficult to discern, in part because the cytotoxicity profiles for these toxins differ with concentration and cell type. The goal of this study was to develop a cell culture model that would allow a side-by-side mechanistic comparison of the toxins. Conditionally immortalized, young adult mouse colonic (YAMC) epithelial cells demonstrate an exquisite sensitivity to both toxins with phenotypes that agree with observations in tissue explants. TcdA intoxication results in an apoptotic cell death that is dependent on the glucosyltransferase activity of the toxin. In contrast, TcdB has a bimodal mechanism; it induces apoptosis in a glucosyltransferase-dependent manner at lower concentrations and glucosyltransferase-independent necrotic death at higher concentrations. The direct comparison of the responses to TcdA and TcdB in cells and colonic explants provides the opportunity to unify a large body of observations made by many independent investigators.
Identification and Regulation of Genes for Cobalamin Transport in the Cyanobacterium Synechococcus sp. Strain PCC 7002
Authors: Pérez Adam A. , Rodionov Dmitry A. , Bryant Donald A. 
Published: July 2016

ABSTRACT

The cyanobacterium
Synechococcus
sp. strain PCC 7002 is a cobalamin auxotroph and utilizes this coenzyme solely for the synthesis of
l
-methionine by methionine synthase (MetH).
Synechococcus
sp. strain PCC 7002 is unable to synthesize cobalamin
de novo
, and because of the large size of this tetrapyrrole, an active-transport system must exist for cobalamin uptake. Surprisingly, no cobalamin transport system was identified in the initial annotation of the genome of this organism. With more sophisticated
in silico
prediction tools, a
btuB
-
cpdA
-
btuC
-
btuF
operon encoding components putatively required for a B
12
uptake (
btu
) system was identified. The expression of these genes was predicted to be controlled by a cobalamin riboswitch. Global transcriptional profiling by high-throughput RNA sequencing of a cobalamin-independent form of
Synechococcus
sp. strain PCC 7002 grown in the absence or presence of cobalamin confirmed regulation of the
btu
operon by cobalamin. Pérez et al. (A. A. Pérez, Z. Liu, D. A. Rodionov, Z. Li, and D. A. Bryant, J Bacteriol 198:2743–2752, 2016,
http://dx.doi.org/10.1128/JB.00475-16
) developed a cobalamin-dependent yellow fluorescent protein reporter system in a
Synechococcus
sp. strain PCC 7002 variant that had been genetically modified to allow cobalamin-independent growth. This reporter system was exploited to validate components of the
btu
uptake system by assessing the ability of targeted mutants to transport cobalamin. The
btuB
promoter and a variant counterpart mutated in an essential element of the predicted cobalamin riboswitch were fused to a
yfp
reporter. The combined data indicate that the
btuB
-
cpdA
-
btuF
-
btuC
operon in this cyanobacterium is transcriptionally regulated by a cobalamin riboswitch.

IMPORTANCE
With a cobalamin-regulated reporter system for expression of yellow fluorescent protein, genes previously misidentified as encoding subunits of a siderophore transporter were shown to encode components of cobalamin uptake in the cyanobacterium
Synechococcus
sp. strain PCC 7002. This study demonstrates the importance of experimental validation of
in silico
predictions and provides a general scheme for
in vivo
verification of similar cobalamin transport systems. A putative cobalamin riboswitch was identified in
Synechococcus
sp. strain PCC 7002. This riboswitch acts as a potential transcriptional attenuator of the
btu
operon that encodes the components of the cobalamin active-transport system.
Impact of physical function impairment and multimorbidity on mortality among community-living older persons with sarcopaenia: results from theilSIRENTEprospective cohort study
Authors: Landi Francesco , Calvani Riccardo , Tosato Matteo , Martone Anna Maria , Bernabei Roberto , Onder Graziano , Marzetti Emanuele 
Published: July 2016

ObjectiveSarcopaenia and physical function impairment may have a greater effect on survival than other clinical characteristics, including multimorbidity. In this study, we evaluated the impact of sarcopaenia on all-cause mortality and the interaction among muscle loss, physical function impairment and multimorbidity on mortality risk over 10 years in older community-dwellers.DesignProspective cohort study.SettingPopulation-based study.ParticipantsAll persons aged 80+ years living in the community in the Sirente geographic area (L'Aquila, Italy) (n=364). Participants were categorised in the sarcopaenic or non-sarcopaenic group based on the European Working Group on Sarcopenia in Older People criteria.Primary and secondary outcome measures(1) All-cause mortality over 10 years according to the presence of sarcopaenia and (2) impact of physical function impairment, assessed using the Short Physical Performance Battery (SPPB), and multimorbidity on 10-year mortality risk in persons with sarcopaenia.ResultsSarcopaenia was identified in 103 participants (29.1%). A total of 253 deaths were recorded over 10 years: 90 among sarcopaenic participants (87.4%) and 162 among non-sarcopaenic persons (65.1%; p<0.001). Participants with sarcopaenia had a higher risk of death than those without sarcopaenia (HR=2.15; 95% CI 1.02 to 4.54). When examining the effect of sarcopaenia and physical function impairment on mortality, participants with low physical performance levels showed greater mortality. Conversely, the mortality risk was unaffected by multimorbidity.ConclusionsOur findings show that physical function impairment, but not multimorbidity, is predictive of mortality in older community-dwellers with sarcopaenia. Hence, in sarcopaenic older persons, interventions against functional decline may be more effective at preventing or postponing negative health outcomes than those targeting multimorbidity.
Official government statistics of road traffic deaths in India under-represent pedestrians and motorised two wheeler riders
Authors: Bhalla Kavi , Khurana Nidhi , Bose Dipan , Navaratne Kumari Vinodhani , Tiwari Geetam , Mohan Dinesh 
Published: July 2016

BackgroundReliable data on traffic deaths are important for planning road safety programmes and evaluating progress. Although pedestrians comprise approximately 40% of traffic deaths in low-income and middle-income countries, official government statistics in India suggest that pedestrians comprise less than 10% of deaths.ObjectiveTo assess the accuracy of official tabulations of traffic deaths among various road users in India.MethodWe reviewed police first information reports (FIRs) of traffic deaths in one district (Belgaum) in 2013 and 2014 and extracted information about crash victims. We validated the FIRs by linking with case files from four police stations in the district. Finally, we compared the information on types of road users killed based on FIRs with the district's official tabulations.ResultsWe found that the distribution of deaths by types of road users reported in official tabulations differed substantially from the underlying police reports. While official tabulations reported that only 9% of deaths in 2013 were pedestrians and 37% were riders of motorised two wheelers, FIRs showed that these groups accounted for 21% and 49% of deaths, respectively.DiscussionOfficial tabulations of traffic deaths in India do not correctly represent the types of roads users killed. Until the Indian National Crime Records Bureau has corrected the process of generating statistical tabulations from police reports, data on the types of road users killed in India should not be used for research and policy. In the interim, researchers and policy makers who need such information should extract it from police case files.
Implications of the Bystander and Abscopal Effects of Radiation Therapy
Authors: Verma Vivek , Lin Steven H. 
Published: July 2016

Abstract
Siva and colleagues have demonstrated that localized thoracic radiation resulted in DNA damage at out-of-field sites. Although these interesting findings require validation, we discuss the important clinical implications of these data, especially in the era of immune therapies. Clin Cancer Res; 22(19); 4763–5. ©2016 AACR.
See related article by Siva et al., p. 4817
Abstract 1003: Targeting liver-tumor initiating cells via hampering the lipogenesis pathways through stearoyl - CoA desaturase
Authors: Ma Kin Fai , Lo Jessica , Lau Eunice Yuen-Ting , Copland John A. , Ng Irene Oi-Lin , Lee Terence Kin-Wah 
Published: July 2016

Abstract
Hepatocellular carcinoma is one of the most lethal cancers in the world. Most of the patients are diagnosed at advanced stage, and they receive sorafenib as their treatment modality. However, sorafenib can only extend patients’ survival to a median of 3-4 months. Hence, there is an urgent need to identify a new therapeutic target for treatment of this disease. Increasing evidence showed that tumor-initiating cells (T-ICs) are intrinsically resistant to conventional treatments. Identification of the signalling pathways that maintain the functions of T-ICs provides potential targets for treatment of HCC. For this purpose, we cultured serial passages of hepatospheres combined with chemotherapeutic regimens as a strategy to enrich liver T-IC population. Using cDNA microarray, we found upregulation of several key enzymes in lipogenesis in enriched T-IC population, among which Stearoyl CoA desaturase-1 (SCD1), the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was the most significant. In HCC clinical samples, 62% (36/58) was found to be overexpressed (&gt; 2-fold) when compared with non-tumor counterparts and patients with SCD1 overexpression had shorter disease free survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of T-ICs, including tumorigenicity, self-renewal, drug resistance and expression of liver T-IC markers. SCD1 was found critical in survival of T-ICs, as enriched T-IC population are more sensitive to the inhibition of SCD1 compared to adherent lineages. Interestingly, SCD1 was found to be upregulated in sorafenib-resistant HCC cells. Pharmacological inhibition of SCD1 by A939572 not only suppressed self-renewal ability but also consistently enhanced the sensitivity towards sorafenib. Using a patient-derived xenograft model, we found that a new inhibitor against SCD1 demonstrated significant growth suppressive effect. By comparing the genetic profiles between SCD1 knockdown cells and control cells by RNA sequencing analysis, we found that upregulation of ER stress signature genes may be the potential downstream targets of SCD1 to maintain the properties of T-ICs. In conclusion, we demonstrated the crucial role of SCD1 in maintenance of liver T-ICs, and targeting SCD1 in combination with sorafenib might be a novel therapeutic regimen against HCC.
Citation Format: Kin Fai Ma, Jessica Lo, Eunice Yuen-Ting Lau, John A. Copland, Irene Oi-Lin Ng, Terence Kin-Wah Lee. Targeting liver-tumor initiating cells via hampering the lipogenesis pathways through stearoyl - CoA desaturase. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1003.
Abstract 1053: Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy
Authors: li zhenfei , Alyamani Mohammad , Sharifi Nima 
Published: July 2016

Abstract
Prostate cancer is the most diagnosed cancer in men and Abiraterone is used for castration resistant prostate cancer therapy by suppressing androgen production. In patients, abiraterone is converted to D4A, a novel metabolite with more potent anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is further metabolized by the related steroidogenic enzymes to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial with patients taking abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted by dutasteride, while D4A concentrations rise, effectively blocking production of a tumor promoting metabolite and permitting D4A accumulation. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine tuning abiraterone metabolism to optimize therapy.
Citation Format: zhenfei li, Mohammad Alyamani, Nima Sharifi. Redirecting abiraterone metabolism to biochemically fine tune prostate cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1053.
Abstract 1068: The promise of miR-205 in HER2+ breast cancer: predicting response to Trastuzumab and overcoming resistance
Authors: Piovan Claudia , D’Ippolito Elvira , Plantamura Ilaria , Casalini Patrizia , Tagliabue Elda , Iorio Marilena V. 
Published: July 2016

Abstract
HER2, member of HER family, is overexpressed in up to 30% of breast cancers and often associated to a more aggressive phenotype, resistance to chemotherapeutic agents and increased risk of metastasis. Anti-HER2 targeted therapies significantly increased the overall survival of HER2 breast cancer patients, however tumor cells frequently develop alternative resistance mechanisms and the molecular bases of this phenomenon are still far to be fully elucidated. A crucial issue is then represented by the urgent need of biomarkers able to predict the response to treatment, and certainly of new therapeutic tools to counteract the resistance mechanisms. The oncosuppressive role of miR-205 in the pathogenesis of breast cancer has been demonstrated, as well as a possible cross-regulation between miR-205 and HER signaling. MiR-205 is in fact negatively regulated by HER2 and is involved in the regulation of HER2-mediated proliferation by directly targeting HER3, preferential partner of HER2. We have investigated miR-205 role on trastuzumab resistance by using human HER2 overexpressing breast cancer cell lines and patient-derived xenograft (PDX) models. Here we show that HER3 silencing, either mediated by miR-205 or by a siRNA specific against HER3, is able to improve the responsiveness to Trastuzumab, reducing tumor cell growth and colony formation capability. This effect is mediated by impairment of Akt-mediated pathway.Combination of Trastuzumab treatment and in vivo delivery of miR-205-conjugated lipid nanoparticles in PDX models is currently on going. Finally, expression analysis of miR-205 in breast cancer patients treated in adjuvant with trastuzumab has provided new insights about its possible role as predictive biomarker of response. In summary, here we show that miR-205 improves the responsiveness to Trastuzumab treatment at least partially though HER3 silencing, and associated to outcome of patients treated in adjuvant setting, thus representing a potential adjuvant tool and predictive biomarker.
Citation Format: Claudia Piovan, Elvira D’Ippolito, Ilaria Plantamura, Patrizia Casalini, Elda Tagliabue, Marilena V. Iorio. The promise of miR-205 in HER2+ breast cancer: predicting response to Trastuzumab and overcoming resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1068.
Abstract 1087: Circulating microRNAs as metastasis biomarkers in oral cavity and oropharyngeal squamous cell carcinomas
Authors: Andreghetto Flavia Maziero , de Souza Mariana Barbosa , Moyses Raquel Ajub , Toporcov Tatiana Natasha , Nunes Fabio Daumas , de Carvalho Marcos Brasilino , Severino Patricia 
Published: July 2016

Abstract
MicroRNAs are small non-coding RNA molecules with roles in gene expression regulation and implications in cancer initiation and progression. Cell-free microRNAs detected in body fluids, and in particular in plasma, are of clinical interest due to their possible use as biomarkers. Despite the fact that their reliable quantification depends on several technical parameters, there is great clinical interest in this approach due to its simplicity and low risk to the patient. Squamous cell carcinoma of the head and neck is one of the most common cancer types worldwide, with survival rates of about 50% in 5 years. Tobacco and alcohol consumption are the most important risk factors and, currently, the presence of cervical lymph node metastases remain the strongest prognostic factor for this cancer type. In this study we identified plasma microRNAs associated with squamous cell carcinomas of the oral cavity and oropharynx as well as with the presence of cervical lymph node metastases. We evaluated the expression of 179 microRNAs in plasma from 45 patients (28 presenting cervical lymph node metastases at diagnosis and 17 with no lymph node metastasis) and 15 healthy controls. Samples were matched according to age, sex, drinking and smoking habits. Among microRNAs mostly expressed in tumor samples, some had been already detected in oral squamous cell carcinoma tissues, such as miR-210, while others, such as miR-573, are still poorly studied. Comparisons between oral and oropharyngeal carcinomas yielded several differences, in accordance with molecular distinctions between these cancer types. MicroRNAs possibly involved in the metastatic process were identified when comparing plasma samples from individuals presenting lymph node metastasis at diagnosis and plasma from patients who were metastasis-free. Among these molecules, miR-192 and miR-574 were identified as more expressed in plasma from individuals with metastatic oropharyngeal cancer. We conclude that plasma microRNAs associated with specific clinical conditions or cancer sub-sites may help in the diagnosis and prognosis assessment of head and neck squamous cell carcinomas.
Citation Format: Flavia Maziero Andreghetto, Mariana Barbosa de Souza, Raquel Ajub Moyses, Tatiana Natasha Toporcov, Fabio Daumas Nunes, Marcos Brasilino de Carvalho, Patricia Severino. Circulating microRNAs as metastasis biomarkers in oral cavity and oropharyngeal squamous cell carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1087.
Abstract 1165: TRPM8 is avidly targeted for degradation in prostate cancer
Authors: Asuthkar Swapna , Zakharian Eleonora 
Published: July 2016

Abstract
Transient receptor potential melastatin 8 (TRPM8) is a cold-sensing receptor and a hallmark Ca2+ channel of the prostate epithelium. The TRPM8 mRNA is overexpressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Thus, androgens, which are at the crossroads of several signaling pathways, appear to be associated with TRPM8-mediated Ca2+ signaling. Although, TRPM8 mRNA levels are upregulated during prostate cancer progression, this upregulation is not adequately translated to the TRPM8 protein levels. We identified that the lower TRPM8 protein abundance and activation in LNCaP cells is associated with increased ubiquitination and loss of TRPM8 from the plasma membrane (PM). The mass-spectrometry analysis of TRPM8, immunoprecipitated from LNCaP cells identified ubiquitin-like modifier-activating enzyme 1 (UBA1). PYR-41, a potent inhibitor of the initial enzyme in the ubiquitination cascade, UBA1, increased TRPM8 activity on the PM of LNCaP cells. Our data indicate that PMTRPM8 plays a protective role in prostate cancer progression accompanied by enhanced activation of p53 and Caspase-9. In addition, we found that the promoter region of trpm8 possesses putative binding sites for p53 and that the overexpression of p53 increased the TRPM8 mRNA levels. Our findings support previous studies that suggest the fine balance between AR and p53 expression that regulates androgen-dependent growth of prostate cancer. Thus, we hypothesize that TRPM8 activity significantly contributes to anti-tumor defense mechanism and may serve as a novel therapeutic target in prostate cancer.
Citation Format: Swapna Asuthkar, Eleonora Zakharian. TRPM8 is avidly targeted for degradation in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1165.