tbuckley/cabot-search huggingface dataset:
Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation
Authors: Isha H. Jain, Luca Zazzeron, Olga Goldberger, Eizo Marutani, Gregory R. Wojtkiewicz, Tslil Ast, Hong Wang, Grigorij Schleifer, Anna Stepanova, Kathleen Brepoels, Luc Schoonjans, Peter Carmeliet, Alexander Galkin, Fumito Ichinose, Warren M. Zapol, Vamsi K. Mootha
Journal: Cell Metabolism (2019)
Calreticulin down-regulates E-cadherin gene expression via Slug in a Ca2+-dependent manner
Authors: Yasushi Hayashida, Yoshito Ihara, Yoshishige Urata, Yasuyoshi Miyata, Koichiro Nomata, Hiroshi Kanetake, Takahito Kondo
Journal: Cancer Research (2006)

2781  [Introduction] Calreticulin (CRT) is a multi-functional Ca2+-binding molecular chaperone in the endoplasmic reticulum. Recently, overexpression of CRT has been speculated to be associated with malignant potential in cancer cells. However, it is not well understood whether CRT is involved in the regulation of malignancy. On the other hand, human malignancies are mainly derived from epithelium and E-cadherin plays an important role in malignant aggressiveness of carcinomas. There are several mechanisms that regulate E-cadherin expression. However, it is not well understood whether CRT has a correlation with E-cadherin expression. In the present study, we clarified the functional relationship between CRT and E-cadherin in renal epithelial MDCK cells. [Methods] CRT-overexpressing renal epithelial cells were established by transfecting CRT-gene expression vector into MDCK cells. Protein and transcriptional expression of E-cadherin were examined by Immunoblot and Northern blot analysis, respectively. The regulatory mechanism of E-cadherin gene promoter was examined by luciferase-reporter and electrophoretic mobility shift assays. [Results] In CRT-overexpressing cells, E-cadherin expression was down-regulated both protein and transcriptional levels in Immunoblot and Northern blot analysis. Additional study including luciferase-reporter and electrophoretic mobility shift assays indicated that this downregulation was caused by one of E-cadherin transcriptional suppressor factors, Slug in a Ca2+-dependent manner. [Conclusion] These results indicate that CRT is involved in the regulation of E-cadherin gene expression through altering Ca2+ homeostasis in MDCK cells and suggest that CRT has the potential ability to regulate malignant aggressiveness in carcinoma..
Recurrent anal squamous carcinoma: Is HPV a risk factor?
Authors: Caroline Letendre, Francine Aubin, Jean-Pierre M. Ayoub, Richard Letourneau, Rasmy Lougnarath, Carole S. Richard, Guila Delouya, David Donath, Sophie Lavertu, Marie-Pierre Campeau, Isabelle Gorska, Genevieve Soucy, Bich Nguyen, Mustapha Ali Tehfe
Journal: Journal of Clinical Oncology (2013)

e15094 Background: Anal squamous carcinoma (ASC) is a rare cancer, representing only 1.5 to 2% of all gastrointestinal (GI) malignancies. Combined chemo-radiotherapy therapy (CRT) is the treatment of choice with a response rate of 80% and recurrence rate of 10 to 15%. HPV is a risk factor for anal cancer but its role in cancer recurrence is less clear. We conducted a retrospective study to analyze clinical outcome of ASC patients in function of their HPV status. Methods: Patients with non-metastatic ASC treated between 2005-2011 at the Centre Hospitalier de l’Université de Montréal were eligible. Patient characteristics, clinical outcomes, and tumoral HPV status were retrospectively identified. Results: Seventy patients (M:31; F:39) were included in the analysis. The median age of patients was 51 years. Patient and tumor characteristics are shown in the Table. CRT was done in 57 patients. Median follow-up was 37.6 months. Eleven patients had recurrence of whom 10 were HPV-positive. Median TTR was 13.2 months. The 3 deaths related to cancer occurred during the first year of diagnosis. The 3 year overall survival was 90.08%. In multivariate analysis neither the advanced stage of disease nor the HPV-positive status had a statistically significant impact on relapse. Conclusions: In this small cohort, we found a high prevalence of HPV positivity in ASC but HPV infection couldn’t be identified as a risk factor for ASC relapse. Inclusion of men in the HPV vaccination program may help in reducing HPV related ASC. [Table: see text]
CARMA3 deficiency abrogates G-protein-coupled receptor induced NF-κB activation
Authors: Brian Grabiner, Marzenna Blonska, Pei-Chun Lin, Yun You, Donghai Wang, Jiyuan Sun, Chen Dong, Xin Lin
Journal: Cancer Research (2007)

4158  G-protein-coupled receptors (GPCRs) represent the largest protein family in the human genome, and are involved in many cellular processes such as migration, proliferation, and invasion. GPCRs induce biological effects through the association of their cytoplasmic domains with trimeric G proteins that activate multiple signaling cascades, leading to the activation of various transcription factors including NF-κB. NF-κB is a family of transcription factors that play a pivotal role in regulating gene expression of many cytokines and survival factors. However, the molecular mechanism by which GPCRs induce NF-κB activation has not been fully characterized. Here we demonstrate that CARMA3 (Caspase recruitment domain and membrane associated guanylate kinase domain-containing protein 3), a scaffold molecule, is essential for GPCR-induced NF-κB activation. Using a gene-targeting approach, we generated CARMA3-deficient mice. We found that CARMA3-deficient mice exhibit a neural tube closure defect with incomplete penetrance, similar to that of a CARMA3-binding partner, Bcl10 (B-cell lymphoma protein 10). Using CARMA3-deficient cells, we show that the GPCR-ligands LPA (lysophosphatidic acid), ET-1 (endothelin-1), and 5-HT (serotonin) all signal through CARMA3 to activate NF-κB. Furthermore, 12-phorbol-myristate-13-acetate (PMA) and ionomycin (Iono.), two synthetic protein kinase C (PKC) agonists, also fail to activate NF-κB in CARMA3-deficient cells. Finally, our results indicate that this NF-κB activation defect is not due to an absence of phosphorylation of the inhibitor of NF-κB kinases (IKK) α and β. Instead, this defect is likely due deficient ubiquitination of the NF-κB-essential modulator (NEMO). Thus, we have provided the first genetic evidence that CARMA3 plays an essential role downstream of GPCRs and PKC to regulate NEMO ubiquitination, ultimately leading to NF-κB activation.
Extracellular vesicles expressing a single-chain variable fragment of an HIV-1 specific antibody selectively target Env<sup>+</sup> tissues
Authors: Xue Zou, Meng Yuan, Tongyu Zhang, Hongxia Wei, Shijie Xu, Na Jiang, Nan Zheng, Zhiwei Wu
Journal: Theranostics (2019)

Rationale: Antiretroviral therapy can effectively suppress HIV-1 replication in the peripheral blood to an undetectable level. However, elimination of the latent virus in reservoirs remains a challenge and is a major obstacle in the treatment of HIV-1-infected patients. Exosomes exhibit huge promise as an endogenous drug delivery nanosystem for delivering drugs to solid tissues given their unique properties, including low immunogenicity, innate stability, high delivery efficiency, and most importantly the ability to penetrate solid tissues due to their lipophilic properties. Methods: We engineered and expressed the scFv of a high affinity HIV-1-specific monoclonal antibody, 10E8, on the exosomal surface (10E8scFv-exos). Subsequently, the 10E8scFv-exos were loaded with curcumin (Cur), a chemical that kills HIV-1-infected cells, or miR-143, an apoptosis-inducing miRNA. We tested the ability of 10E8scFv-exos to deliver cargo to Env+ target cells and tissues, as well as their ability to suppress HIV-1 infection. Results: 10E8scFv-exos efficiently targeted CHO cells expressing a trimeric gp140 on their surface (Env+ cells) in vitro, as demonstrated by confocal imaging and flow cytometry. 10E8scFv-exos loaded with Cur or miR-143 showed specific killing of Env+ cells. In addition, 10E8scFv-exos loaded with Cur or miR-143 could suppress p24 expression in an HIV-1 latency cell line ACH2 and in PBMCs from an ART-treated HIV-1-infected patient. In an NCG mouse model grafted with tumorigenic Env+ CHO cells and which had developed solid tissue tumors, intravenously injected 10E8scFv-exos targeted the Env-expressing tissues and delivered Cur to induce a strong suppression of the Env+ tumor growth with low toxicity. Conclusion: In principle, engineered exosomes can deliver anti-HIV agents to solid tissues by specifically targeting cells expressing viral envelop proteins and inducing cell killing, suggesting that such an approach could be developed for eradicating virus-infected cells in tissue reservoirs.
Tumor suppressor gene Maspin and hypoxia inversely regulate lysyl oxidase-facilitated breast cancer motility.
Authors: Dawn A. Kirschmann, Stacey L. Payne, Elisabeth A. Seftor, Naira V. Margaryan, Mary J. C. Hendrix
Journal: Cancer Research (2005)

245  We have previously demonstrated an up-regulation of lysyl oxidase (LOX) gene expression in invasive/metastatic breast cancer cell lines, compared to their poorly invasive/non-metastatic counterparts. In addition, inactivation of enzymatic LOX activity (treatment with βAPN; an irreversible inhibitor of LOX) or knock down of gene expression (LOX-specific antisense oligonucleotides) in invasive/metastatic breast cancer cells inhibited their ability to invade a collagen IV/laminin/gelatin matrix in vitro. Here we further demonstrate that LOX specifically facilitates breast cancer cell motility/migration. Invasive/metastatic breast cancer cell lines treated with βAPN had significantly reduced random migration through a 10 μM pore polycarbonate filter, as well as haptokinetic motility on a collagen or fibronectin matrix. Furthermore, an increase in LOX expression, and a corresponding increase in cellular invasiveness, was induced in poorly invasive/non-metastatic breast cancer cell lines under hypoxic culture conditions. Conversely, a decrease in LOX expression, and a corresponding decrease in cellular motility, was observed in highly invasive/metastatic breast cancer cells with the introduction of the tumor suppressor gene maspin. These results demonstrate that LOX facilitates breast cancer cell motility and that LOX expression and cellular motility are regulated by exogenous and endogenous stimuli, hypoxia and maspin, respectively. Supported in part by DAMD17-99-1-9225 and Eisenberg Scholar Research Award (DAK), and NIH/NCI CA59702 and Order of the Eastern Star Breast Cancer Research Fund (MJCH).
Characterization of a Fhit protein complex suggests a novel pathway to apoptosis of cancer cells
Authors: Flavia Pichiorri, Francesco Trapasso, Marco Gaspari, Tiziana Palumbo, Eugenio Gaudio, Hiroshi Okumura, Di Leva Giampiero, Muller Fabbri, Rodolfo Iuliano, Salvatore Venuta, Luigi Giusto Spagnoli, Kay Huebner, Carlo Maria Croce
Journal: Cancer Research (2007)

451  The fragile histidine triad (FHIT) gene, spanning FRA3B at 3p14.2, the most active human common fragile site, shows abnormal transcripts, promoter hypermethylation and/or allelic loss in a large fraction of human cancers of various organs. Furthermore, FHIT restoration in a number of malignant cell lines triggers apoptosis in vitro and in preclinical models. However, though more than 600 publications document involvement of FHIT alterations in cancers, the mechanisms through which Fhit protein signals tumor suppression have not been defined, partially because interacting proteins have been difficult to identify. We have now used protein-protein cross-linking followed by identification of cross-llinked proteins by proteomics methods to identify a Fhit protein complex responsible for triggering apoptosis in Fhit virally-transduced lung cancer cells. Our experimental results demonstrate that Fhit localizes in both cytosol (where it interacts with Hsp60 and Hsp10) and mitochondria where it interacts with main mitochondria chain respiratory proteins. Interestingly, Fhit restoration significantly increases the production of reactive oxygen species (ROS) in lung and colon cancer-derived cells in response to stressful treatments.  Delineation of direct downstream effectors of the Fhit suppressor pathway will lead to intensification of mechanistic studies of Fhit function that may influence future preventive and therapeutic strategies to activate the Fhit pathway.  The finding that ROS generation is crucial for Fhit-mediated apoptosis emphasizes the importance of Fhit loss as a negative prognostic factor in various clinical settings; for example, assessment of Fhit status in preneoplastic or neoplastic conditions may be predictive of responses to antioxidant treatments.
The impact of methylthioadenosine phosphorylase (MTAP) mediated purine salvage on pemetrexed activity
Authors: Shrikanta Chattopadhyay, Eugenia Tsai, Vern Schramm, I. David Goldman
Journal: Cancer Research (2006)

549  Pemetrexed (PMX) antitumor activity is a consequence of primary inhibition of thymidylate synthase (TS) with much weaker inhibition of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine, a byproduct of the polyamine synthetic pathway, and therefore has the potential for antagonizing the antipurine effect of PMX. It has been suggested that the deletion of the MTAP gene from the majority of mesothelioma tumors enhances the activity of PMX. To investigate the role of MTAP in PMX activity, the impact of a highly potent transition-state inhibitor of this enzyme (MT-DADMe-Immucillin A (ImmA) - Ki = 86 pM) was assessed in two human mesothelioma cell lines: NCI-H28 which is MTAP+ and NCI-H2052 which is MTAP-. The relative inhibition of TS and GARFT was determined by the use of nucleoside protection. TS was found to be the primary target in both cell-lines (IC50s for H28 and H2052 were ∼100 nM and ∼40 nM respectively; there was no protection with addition of hypoxanthine alone). In the presence of thymidine, the IC50s for H28 and H2052 increased to ∼3 μM and ∼0.9 μM respectively. Full protection from PMX cytotoxicity at and beyond these concentrations required both thymidine and hypoxanthine. Hence, the antipurine effect mediated by GARFT inhibition occurred at 20-30 fold higher PMX concentrations than suppression of TS. ImmA did not alter the IC50 for PMX in the absence of thymidine. However, in the presence of thymidine, ImmA decreased the PMX IC50 by 3-4 fold in MTAP+ H28 cells without an effect in MTAP- H2052 cells. In a separate experiment in MTAP+ Hela cells, Imm A resulted in a 2-fold decrease in PMX IC50 in the presence of thymidine, but there was no effect in the absence of thymidine. Transfection of MTAP into H2052 MTAP- cells increased the PMX IC50 in the presence of thymidine with at least partial reversal with ImmA. However, there was essentially no difference noted in the absence of thymidine. These data suggest that purine salvage mediated by MTAP has no effect on PMX activity in the absence of thymidine, consistent with the primary role of TS in the action of PMX. Even under conditions in which purine inhibition is the primary site of action, suppression of MTAP has only a small effect on PMX activity. Hence, MTAP deletion in mesothelioma is unlikely to play an important role in the clinical activity of PMX in this disease.
Usefulness of serial measurement of serum N-telopeptides of type I collogen (NTx) in patients with lung cancer who developed bone metastasis: A prospective study.
Authors: Motohiro Tamiya, Hideaki Okada, Masashi Kobayashi, Hidekazu Suzuki, Norio Okamoto, Shinji Sasada, Naoko Morishita, Yuka Matsuura, Haruko Daga, Shinya Tokunaga, Koichi Taira, Michiyo Hattori, Natsuko Miyamoto, Koji Takeda, Tomonori Hirashima
Journal: Journal of Clinical Oncology (2012)

e18036 Background: The bone resorption biomarkers urinary NTx (uNTx) and serum NTx (sNTx) have been shown to aid in the diagnosis of bone metastasis in patients with lung cancer. Patients with metastatic bone disease from lung cancer (MBDLC) are often treated with zoledronic acid. Zoledronic acid reduces the levels of bone resorption biomarkers and also the risk of skeletal adverse events in patients with MBDLC. We studied the effects of treatments including zoledronic acid on levels of sNTx during disease progression. Methods: Patients with MBDLC at the initial diagnosis were entered to this study. sNTx was measured once a month using the sNTx assay OSTEOMARK serum NTx (Alere Medical). MBDLC was characterized by monthly physical examination and by bone scintigraphy every 3 months for 12 months. All patients were required to provide written informed consent. Results: Twenty patients were enrolled between June and December 2010. The mean +/- 1 SD of the sNTx concentrations was 19.8 +/- 5.8 nM BCE/L at baseline. In the 16 patients receiving zoledronic acid, the levels of sNTx showed a significant decrease in the first month of treatment (baseline: 21.3 +/- 5.5 nM BCE/L; one month later: 13.6 +/- 2.7 nM BCE/L; p&lt;0.01). During follow-up period, 12 of the patients treated with zoledronic acid experienced worsening MBDLC or had died from lung cancer, and there were statistically significant differences in the levels of sNTx at baseline (19.7 +/- 4.47 nM BCE/L), at the lowest levels after the administration of zoledronic acid (11.5 +/- 2.73 nM BCE/L) and at the point of measurable disease progression or death (13.0 +/- 2.07 nM BCE/L). Conclusions: Serial measurements of sNTx in patients with MBDLC treated with zoledronic acid might predict disease progression of bone metastasis. Administration of zoledronic acid significantly decreased the level of sNTx from baseline within one month and maintained the level of sNTx lower than baseline during study periods.
Analysis of microRNA expression in glioblastoma invasion
Authors: Jakub Godlewski, Michal Nowicki, Herbert Newton, E Chiocca, Sean Lawler
Journal: Cancer Research (2007)

2166  Gliomas are therapeutically challenging because tumor cells infiltrate normal brain tissue, thereby evading surgical resection. There are currently no therapies available to block glioma invasion, although a large number of genes are known to play a role in the process. MicroRNAs are a recently identified group of non-protein coding genes that modulate expression of protein coding genes. Aberrant expression of microRNAs plays an important role in tumorigenesis by affecting the expression of oncogenes and tumor suppressor genes. However, little is known about the role of microRNAs in glioblastoma multiforme. We therefore used a microarray to examine the global expression of microRNAs in patient tumor samples, and also in glioma cells from an in vitro invasion assay. Several major changes in microRNA expression were observed in this study, and validated by RT-PCR. These changes included substantial alterations in mir-21 and mir-128 levels. The functional significance of these alterations is currently being explored. This will provide the basis for future studies in which microRNAs may be used as diagnostic or therapeutic agents, and also provides a novel approach to invasion that may provide significant mechanistic insights.
Changing the narrative: responsibility for youth engagement is a two-way street
Authors: Arush Lal, Barbara Bulc, Marlene Joannie Bewa, Muhammed Yaeesh Cassim, Shakira Choonara, Enes Efendioglu, Stefan Germann, Hira Hafeez, Katja Iversen, Sania Nishtar, Charlotte O'Leary, Petra Orlic, Johanna Ralston, Rohit Ramchandani, Sarah Walji
Journal: The Lancet Child & Adolescent Health (2019)
Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease
Authors: Xiaokang Li, Jian Lu, Yixiang Xu, Jiaying Wang, Xiaoxia Qiu, Lei Fan, Baoli Li, Wenwen Liu, Fei Mao, Jin Zhu, Xu Shen, Jian Li
Journal: Acta Pharmaceutica Sinica B (2019)

Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.
Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma
Authors: Minjie Gao, Hua Bai, Yogesh Jethava, Yujie Wu, Yuqi Zhu, Ye Yang, Jiliang Xia, Huojun Cao, Reinaldo Franqui-Machin, Kalyan Nadiminti, Gregory S Thomas, Mohamed E Salama, Peter Altevogt, Gail Bishop, Michael Tomasson, Siegfried Janz, Jumei Shi, Lijuan Chen, Ivana Frech, Guido Tricot, Fenghuang Zhan
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant. Methods Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group. Results CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P &amp;lt; .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo. Conclusion Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.
CMIP is a negative regulator of T cell signaling
Authors: Julie Oniszczuk, Kelhia Sendeyo, Cerina Chhuon, Berkan Savas, Etienne Cogné, Pauline Vachin, Carole Henique, Ida Chiara Guerrera, Giuseppe Astarita, Vincent Frontera, Andre Pawlak, Vincent Audard, Dil Sahali, Mario Ollero
Journal: Cellular and Molecular Immunology (2019)
Endoscopic ultrasonography-guided fine-needle biopsy from ascending colon using a novel curved linear echoendoscope
Authors: Hiroshi Kawakami, Tesshin Ban, Yoshimasa Kubota, Takaho Noda, Kazusato Oshikawa
Journal: Endoscopy (2019)

Use of colonic endoscopic ultrasonography-guided fine-needle aspiration/biopsy (EUS-FNA/B) remains limited owing to the maneuverability of the conventional curved linear echoendoscope, particularly for right-sided colonic lesions [1].