35 results on '"Aushev, Vasily N"'
Search Results
2. A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes
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Gruber, Joshua J., Afghahi, Anosheh, Timms, Kirsten, DeWees, Alyssa, Gross, Wyatt, Aushev, Vasily N., Wu, Hsin-Ta, Balcioglu, Mustafa, Sethi, Himanshu, Scott, Danika, Foran, Jessica, McMillan, Alex, Ford, James M., and Telli, Melinda L.
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- 2022
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3. A review and perspective paper: Ras oncogene gets modest, from kingpin to mere henchman.
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Camonis, Jacques H., Aushev, Vasily N., Zueva, Elina, and Zalcman, Gérard
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RAS proteins , *NUCLEAR proteins , *YAP signaling proteins , *SURVIVIN (Protein) , *CELL death , *RAS oncogenes - Abstract
The concomitant activation of both the YAP1 co-transcription factor and RAS GTPases is a hallmark of several aggressive cancers, though the intricacies of their relationship and implications for oncogenesis are still poorly understood. This review has presented a cooperative model where YAP1 and RAS are not independently acting oncogenes but rather interdependently acting ones, with each fulfilling an essential role within the oncogenic process. YAP1 is responsible for initiating the expression of key proteins that contribute to various cancer traits. However, these proteins must often be transported into the cytoplasm to exert their effects. We suggest that oncogenic RAS actually facilitates this transport, enabling the phosphorylation and subsequent activation of the nuclear transporter XPO1 (aka Exportin1). This mechanism is particularly crucial for anti-apoptotic proteins. Instead of being sequestered within the nucleus in an ineffective state, these proteins are rather shuttled into the cytoplasm. Within the cytoplasm, they can effectively inhibit apoptosis, undermining by these means the efficacy of chemotherapeutic agents designed to induce cell death in cancer cells. Therefore, a clearer understanding of the oncogenic partnership between RAS and YAP1 will likely provide new insights into the molecular underpinnings of cancer and highlight as well potential targets for therapeutic interventions designed to disrupt this pernicious interaction. I. YAP1 triggers expression of its target genes, some of which encode cargoes with a nuclear export signal. In response to physiological signals, some cargoes are shuttled into the cytoplasm. Exportin1 serves as the transfer vehicle from the nucleus into the cytoplasm (not shown). For functional nuclear proteins, this shuttling terminates their function, whereas for cytoplasmic proteins, it does initiate their function. In this drawing, the topology within the nucleus is not depicted. II. Oncogenic RAS leads to Exportin1 activation and subsequent unwarranted nuclear-cytoplasmic shuttling of cargoes [17, 35]. The cascade from RAS to Exportin1 is not depicted for the sake of clarity. Some of the cargoes are oncoproteins, cytoplasmic GTPases regulators, or antiapoptotic proteins (example shown: BIRC5 aka Survivin). These latter proteins are now empowered to hinder apoptosis, as expected upon anti-cancer therapies. Of course, the BIRC5 is not the only aberrantly shuttled protein. Another example is Beclin1 (BECN1), which is subjected to the same fate; once in the cytoplasm, it does initiate autophagy in the absence of any autophagic clue [35]. [ABSTRACT FROM AUTHOR]
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- 2024
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4. PAM50- and immunohistochemistry-based subtypes of breast cancer and their relationship with breast cancer mortality in a population-based study
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Wang, Lin, Li, Qian, Aushev, Vasily N., Neugut, Alfred I., Santella, Regina M., Teitelbaum, Susan, and Chen, Jia
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- 2021
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5. Impact of Circulating Tumor DNA–Based Detection of Molecular Residual Disease on the Conduct and Design of Clinical Trials for Solid Tumors
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Kasi, Pashtoon M., Fehringer, Gordon, Taniguchi, Hiroya, Starling, Naureen, Nakamura, Yoshiaki, Kotani, Daisuke, Powles, Thomas, Li, Bob T., Pusztai, Lajos, Aushev, Vasily N., Kalashnikova, Ekaterina, Sharma, Shruti, Malhotra, Meenakshi, Demko, Zachary P., Aleshin, Alexey, Rodriguez, Angel, Billings, Paul R., Grothey, Axel, Taieb, Julien, Cunningham, David, Yoshino, Takayuki, and Kopetz, Scott
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- 2022
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6. Gene expression profiles for low-dose exposure to diethyl phthalate in rodents and humans: a translational study with implications for breast carcinogenesis
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Gopalakrishnan, Kalpana, Aushev, Vasily N., Manservisi, Fabiana, Falcioni, Laura, Panzacchi, Simona, Belpoggi, Fiorella, Parada, Jr., Humberto, Garbowski, Gail, Hibshoosh, Hanina, Santella, Regina M., Gammon, Marilie D., Teitelbaum, Susan L., and Chen, Jia
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- 2020
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7. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): Interim analysis of BESPOKE CRC study.
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Kasi, Pashtoon Murtaza, Aushev, Vasily N., Ensor, Joe, Langer, Nathan, Wang, Christopher Gene, Cannon, Timothy Lewis, Berim, Lyudmyla Derby, Feinstein, Trevor, Grothey, Axel, McCollom, Joseph William, Kalmadi, Sujith R., Zakari, Ahmed, Dayyani, Farshid, Gravenor, Donald, Meyer, Janelle Marie, Sharif, Saima, Jurdi, Adham A, Liu, Minetta C., Aleshin, Alexey, and Kopetz, Scott
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- 2024
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8. Circulating tumor DNA (ctDNA) dynamics in patients with colorectal cancer (CRC) with molecular residual disease: Updated analysis from GALAXY study in the CIRCULATE-JAPAN.
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Yukami, Hiroki, Nakamura, Yoshiaki, Mishima, Saori, Ando, Koji, Bando, Hideaki, Watanabe, Jun, Hirata, Keiji, Akazawa, Naoya, Ikeda, Masataka, Yokota, Mitsuru, Kato, Kentaro, Laliotis, George, Aushev, Vasily N., Jurdi, Adham A, Liu, Minetta, Kotani, Daisuke, Oki, Eiji, Takemasa, Ichiro, Kato, Takeshi, and Yoshino, Takayuki
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- 2024
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9. Patient-reported outcomes from the BESPOKE CRC study.
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Kasi, Pashtoon Murtaza, Rivero, Samuel, Aushev, Vasily N., Langer, Nathan, Wang, Christopher Gene, Cannon, Timothy Lewis, Berim, Lyudmyla Derby, Feinstein, Trevor, Grothey, Axel, McCollom, Joseph William, Kalmadi, Sujith R., Zakari, Ahmed, Dayyani, Farshid, Gravenor, Donald, Meyer, Janelle Marie, Sharif, Saima, Jurdi, Adham A, Liu, Minetta C., Aleshin, Alexey, and Kopetz, Scott
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- 2024
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10. Prognostic value of circulating tumor DNA (ctDNA) testing in patients (pts) with rectal cancer after neoadjuvant therapy (NAT) and surgery.
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Chakrabarti, Sakti, Cohen, Stacey A., Tin, Antony, Dangl, Autumn, Aushev, Vasily N., Tejani, Mohamedtaki Abdulaziz, Chandana, Sreenivasa R, Malla, Midhun, Landmann, Ron G., Sharma, Vivek R., Botta, Gregory P., Nagarajan, Arun, Azzi, Georges, Cho, May Thet, Dayyani, Farshid, Hanna, Diana L., Jurdi, Adham A, Liu, Minetta C., Dasari, Arvind, and Kasi, Pashtoon Murtaza
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- 2024
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11. Comparison of colorectal cancer (CRC) characteristics across genetic ancestries: Implications for early cancer detection (ECD).
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Myer, Parvathi, Srinivasan, Preethi, Bristow, Sara L., Krinshpun, Shifra, Solari, Omid, Aushev, Vasily N., Jurdi, Adham A, Liu, Minetta C., Mitchell, Breeana L., Aleshin, Alexey, Reiter, Johannes G., Weitzel, Jeffrey N., Nakamura, Yoshiaki, Yoshino, Takayuki, Wall, Jeffrey, Ioannidis, Alexander, and Bustamante, Carlos
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- 2024
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12. Correlation between variant allele frequency and mean tumor molecules with tumor burden in patients with solid tumors.
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Kalashnikova, Ekaterina, Aushev, Vasily N., Malashevich, Allyson Koyen, Tin, Antony, Krinshpun, Shifra, Salari, Raheleh, Scalise, Carly Bess, Ram, Rosalyn, Malhotra, Meenakshi, Ravi, Harini, Sethi, Himanshu, Sanchez, Stephanie, Hagelstrom, Robert Tanner, Brevnov, Maxim, Rabinowitz, Matthew, Moshkevich, Solomon, Zimmermann, Bernhard G., Liu, Minetta C., and Aleshin, Alexey
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Several studies have demonstrated the prognostic value of circulating tumor DNA (ctDNA); however, the correlation of mean tumor molecules (MTM)/ml of plasma and mean variant allele frequency (mVAF; %) with clinical parameters is yet to be understood. In this study, we analyzed ctDNA data in a pan‐cancer cohort of 23 543 patients who had ctDNA testing performed using a personalized, tumor‐informed assay (Signatera™, mPCR‐NGS assay). For ctDNA‐positive patients, the correlation between MTM/ml and mVAF was examined. Two subanalyses were performed: (a) to establish the association of ctDNA with tumor volume and (b) to assess the correlation between ctDNA dynamics and patient outcomes. On a global cohort, a positive correlation between MTM/ml and mVAF was observed. Among 18 426 patients with longitudinal ctDNA measurements, 13.3% had discordant trajectories between MTM/ml and mVAF at subsequent time points. In metastatic patients receiving immunotherapy (N = 51), changes in ctDNA levels expressed both in MTM/ml and mVAF showed a statistically significant association with progression‐free survival; however, the correlation with MTM/ml was numerically stronger. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling-informed personalized monitoring assay.
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Powles, Thomas, Young, Amanda, Nimeiri, Halla, Madison, Russell W., Fine, Alexander, Zollinger, Daniel R., Yanmei Huang, Chang Xu, Gjoerup, Ole V., Aushev, Vasily N., Hsin-Ta Wu, Aleshin, Alexey, Carter, Corey, Davarpanah, Nicole, Degaonkar, Viraj, Gupta, Pratyush, Mariathasan, Sanjeev, Schleifman, Erica, Assaf, Zoe June, and Oxnard, Geoffrey
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BLADDER cancer ,CANCER invasiveness ,TRANSITIONAL cell carcinoma ,CIRCULATING tumor DNA ,LEUCOCYTES ,UROTHELIUM ,CYSTOTOMY ,KIDNEY pelvis - Abstract
Introduction: Circulating tumor DNA (ctDNA) detection postoperatively may identify patients with urothelial cancer at a high risk of relapse. Pragmatic tools building off clinical tumor next-generation sequencing (NGS) platforms could have the potential to increase assay accessibility. Methods: We evaluated the widely available Foundation Medicine comprehensive genomic profiling (CGP) platform as a source of variants for tracking of ctDNA when analyzing residual samples from IMvigor010 (ClinicalTrials.gov identifier NCT02450331), a randomized adjuvant study comparing atezolizumab with observation after bladder cancer surgery. Current methods often involve germline sampling, which is not always feasible or practical. Rather than performing white blood cell sequencing to filter germline and clonal hematopoiesis (CH) variants, we applied a bioinformatic approach to select tumor (non-germline/CH) variants for molecular residual disease detection. Tissue-informed personalized multiplex polymerase chain reaction-NGS assay was used to detect ctDNA postsurgically (Natera). Results: Across 396 analyzed patients, prevalence of potentially actionable alterations was comparable with the expected prevalence in advanced disease (13% FGFR2/3, 20% PIK3CA, 13% ERBB2, and 37% with elevated tumor mutational burden =10 mutations/megabase). In the observation arm, 66 of the 184 (36%) ctDNA-positive patients had shorter disease-free survival [DFS; hazard ratio (HR) = 5.77; 95% confidence interval (CI), 3.84-8.67; P < 0.0001] and overall survival (OS; HR = 5.81; 95% CI, 3.41-9.91; P < 0.0001) compared with ctDNA-negative patients. ctDNA-positive patients had improved DFS and OS with atezolizumab compared with those in observation (DFS HR = 0.56; 95% CI, 0.38-0.83; P = 0.003; OS HR = 0.66; 95% CI, 0.42-1.05). Clinical sensitivity and specificity for detection of postsurgical recurrence were 58% (60/103) and 93% (75/81), respectively. Conclusion: We present a personalized ctDNA monitoring assay utilizing tissuebased FoundationOne® CDx CGP, which is a pragmatic and potentially clinically scalable method that can detect low levels of residual ctDNA in patients with resected, muscle-invasive bladder cancer without germline sampling. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Using Tumor-Informed Circulating Tumor DNA (ctDNA)-Based Testing for Patients with Anal Squamous Cell Carcinoma.
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Azzi, Georges, Tavallai, Mehrad, Aushev, Vasily N, Malashevich, Allyson Koyen, Botta, Gregory P, Tejani, Mohamedtaki A, Hanna, Diana, Krinshpun, Shifra, Malhotra, Meenakshi, Jurdi, Adham, Aleshin, Alexey, and Kasi, Pashtoon M
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EPITHELIAL cell tumors ,DISEASE progression ,SEQUENCE analysis ,GENETIC mutation ,CANCER relapse ,METASTASIS ,ANAL tumors ,GENES ,EXTRACELLULAR space ,TUMOR markers ,NUCLEIC acids - Abstract
Background Anal squamous cell carcinoma (SCCA) is an uncommon malignancy with a rising incidence that has a high cure rate in its early stages. There is an unmet need for a reliable method to monitor response to treatment and assist in surveillance. Circulating tumor DNA (ctDNA) testing has shown great promise in other solid tumors for monitoring disease progression and detecting relapse in real time. This study aimed to determine the feasibility and use of personalized and tumor-informed ctDNA testing in SCCA. Patients and Methods We analyzed real-world data from 251 patients (817 plasma samples) with stages I-IV SCCA, collected between 11/5/19 and 5/31/22. The tumor genomic landscape and feasibility of ctDNA testing was examined for all patients. The prognostic value of longitudinal ctDNA testing was assessed in patients with clinical follow-up (N = 37). Results Whole-exome sequencing analysis revealed PIK3CA as the most commonly mutated gene, and no associations between mutations and stage. Anytime ctDNA positivity and higher ctDNA levels (MTM/mL) were associated with metastatic disease (P =. 004). For 37 patients with clinical follow-up, median follow-up time was 21.0 months (range: 4.1-67.3) post-diagnosis. For patients with stages I-III disease, anytime ctDNA-positivity after definitive treatment was associated with reduced DFS (HR: 28.0; P =. 005). Conclusions Our study demonstrates the feasibility of personalized and tumor-informed ctDNA testing as an adjunctive tool in patients with SCCA as well as potential use for detection of molecular/minuteimal residual disease, and relapse during surveillance. Prospective studies are needed to better evaluate the use of ctDNA testing in this indication. [ABSTRACT FROM AUTHOR]
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- 2023
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15. OTUB1 triggers lung cancer development by inhibiting RAS monoubiquitination
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Baietti, Maria Francesca, Simicek, Michal, Asbagh, Layka Abbasi, Radaelli, Enrico, Lievens, Sam, Crowther, Jonathan, Steklov, Mikhail, Aushev, Vasily N, García, David Martínez, Tavernier, Jan, and Sablina, Anna A
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- 2016
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16. Analysis of Circulating Tumor DNA to Predict Risk of Recurrence in Patients With Esophageal and Gastric Cancers.
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Huffman, Brandon M., Aushev, Vasily N., Budde, Griffin L., Chao, Joseph, Dayyani, Farshid, Hanna, Diana, Botta, Gregory P., Catenacci, Daniel V.T., Maron, Steven B., Krinshpun, Shifra, Sharma, Shruti, George, Giby V., Malhotra, Meenakshi, Jurdi, Adham, Moshkevich, Solomon, Aleshin, Alexey, Kasi, Pashtoon M., and Klempner, Samuel J.
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CIRCULATING tumor DNA , *STOMACH cancer , *DISEASE relapse , *ESOPHAGEAL cancer , *NUCLEOTIDE sequencing , *COLON cancer - Abstract
PURPOSE: Circulating tumor DNA (ctDNA) analyses allow for postoperative risk stratification in patients with curatively treated colon and breast cancers. Use of ctDNA in esophagogastric cancers (EGC) is less characterized and could identify high-risk patients who have been treated with curative intent. METHODS: In this retrospective analysis of real-world data, ctDNA levels were analyzed in the preoperative, postoperative, and surveillance settings in patients with EGC using a personalized multiplex polymerase chain reaction–based next-generation sequencing assay. Plasma samples (n = 943) from 295 patients at > 70 institutions were collected before surgery, postoperatively, and/or serially during routine clinical follow-up from September 19, 2019, to February 21, 2022. ctDNA detection was annotated to clinicopathologic features and recurrence-free survival. RESULTS: A total of 295 patients with EGC were analyzed, and 212 patients with stages I-III disease were further explored. Pretreatment ctDNA was detected in 96% (23/24) of patients with preoperative time points. Postoperative ctDNA was detected in 23.5% (16/68) of patients with stage I-III EGC within 16 weeks (molecular residual disease window) after surgery without receiving systemic therapy. ctDNA detection at any time point after surgery (hazard ratio [HR], 23.6; 95% CI, 10.2 to 66.0; P <.0001), within the molecular residual disease window (HR, 10.7; 95% CI, 4.3 to 29.3; P <.0001), and during the surveillance period (HR, 17.7; 95% CI, 7.3 to 50.7; P <.0001) was associated with shorter recurrence-free survival. In multivariable analysis, ctDNA status and clinical stage of disease were independently associated with outcomes. CONCLUSION: Using real-world data, we demonstrate that postoperative tumor-informed ctDNA detection in EGC is feasible and allows for enhanced patient risk stratification and prognostication during curative-intent therapy. Postsurgical tumor-informed #ctDNA in esophagogastric cancer is associated with ↑ recurrence risk. #GICSM [ABSTRACT FROM AUTHOR]
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- 2022
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17. Sa1175 COMPARISON OF COLORECTAL CANCER (CRC) CHARACTERISTICS ACROSS GENETIC ANCESTRIES: IMPLICATIONS FOR EARLY CANCER DETECTION.
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Myer, Parvathi A., Srinivasan, Preethi, Bristow, Sara L., Krinshpun, Shifra, Solari, Omid Shams, Aushev, Vasily N., Jurdi, Adham, Liu, Minetta C., Mitchell, Breeana L., Aleshin, Alexey, Reiter, Johannes G., Weitzel, Jeffrey N., Nakamura, Yoshiaki, Yoshino, Takayuki, Wall, Jeffrey, Ioannidis, Alexander, and Bustamante, Carlos
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- 2024
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18. Placental gene network modules are associated with maternal stress during pregnancy and infant temperament.
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Aushev, Vasily N., Li, Qian, Deyssenroth, Maya, Zhang, Wei, Finik, Jackie, Hurd, Yasmin L., Nomura, Yoko, and Chen, Jia
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Maternal psychosocial stress during pregnancy (MPSP) is a known contributor to maladaptive neurobehavioral development of the offspring; however, the underlying molecular mechanisms linking MPSP with childhood outcome remain largely unknown. Transcriptome‐wide gene expression data were generated using RNA‐seq from placenta samples collected in a multi‐ethnic urban birth cohort in New York City (n = 129). Weighted gene co‐expression network analysis (WGCNA) was used to characterize placental co‐expression modules, which were then evaluated for their associations with MPSP and infant temperament. WGCNA revealed 16 gene coexpression modules. One module, enriched for regulation of chromosome organization/gene expression, was positively associated with MPSP and negatively associated with Regulatory Capacity (REG), a component of infant temperament. Two other modules, enriched for cotranslational protein targeting and cell cycle regulation, respectively, displayed negative associations with MPSP and positive associations with REG. A module enriched with oxidative phosphorylation/mitochondrial translation was positively associated with REG. These findings support the notion that the placenta provides a functional in utero link between MPSP and infant temperament, possibly through transcriptional regulation of placental gene expression. [ABSTRACT FROM AUTHOR]
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- 2021
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19. Different metastasis promotive potency of small G-proteins RalA and RalB in in vivo hamster tumor model
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Trukhanova Lyubov S, Aushev Vasily N, Komelkov Andrei V, Knizhnik Anna V, Rybko Vera A, and Tchevkina Elena M
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metastasis ,Ral proteins ,invasion ,Ral effector mutants ,tumor growth ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background Previously we have shown that oncogenic Ha-Ras stimulated in vivo metastasis through RalGEF-Ral signaling. RalA and RalB are highly homologous small G proteins belonging to Ras superfamily. They can be activated by Ras-RalGEF signaling pathway and influence cellular growth and survival, motility, vesicular transport and tumor progression in humans and in animal models. Here we first time compared the influence of RalA and RalB on tumorigenic, invasive and metastatic properties of RSV transformed hamster fibroblasts. Methods Retroviral vectors encoding activated forms or effector mutants of RalA or RalB proteins were introduced into the low metastatic HET-SR cell line. Tumor growth and spontaneous metastatic activity (SMA) were evaluated on immunocompetent hamsters after subcutaneous injection of cells. The biological properties of cells, including proliferation, clonogenicity, migration and invasion were determined using MTT, wound healing, colony formation and Boyden chamber assays respectively. Protein expression and phosphorylation was detected by Westen blot analysis. Extracellular proteinases activity was assessed by substrate-specific zymography. Results We have showed that although both Ral proteins stimulated SMA, RalB was more effective in metastasis stimulation in vivo as well as in potentiating of directed movement and invasion in vitro. Simultaneous expression of active RalA and RalB didn't give synergetic effect on metastasis formation. RalB activity decreased expression of Caveolin-1, while active RalA stimulated MMP-1 and uPA proteolytic activity, as well as CD24 expression. Both Ral proteins were capable of Cyclin D1 upregulation, JNK1 kinase activation, and stimulation of colony growth and motility. Among three main RalB effectors (RalBP1, exocyst complex and PLD1), PLD1 was essential for RalB-dependent metastasis stimulation. Conclusions Presented results are the first data on direct comparison of RalA and RalB impact as well as of RalA/RalB simultaneous expression influence on in vivo cell metastatic activity. We showed that RalB activation significantly more than RalA stimulates SMA. This property correlates with the ability of RalB to stimulate in vitro invasion and serum directed cell movement. We also found that RalB-PLD1 interaction is necessary for the acquisition of RalB-dependent high metastatic cell phenotype. These findings contribute to the identification of molecular mechanisms of metastasis and tumor progression.
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- 2011
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20. Exosomal miRNAs in urine associated with children's cardiorenal parameters: a cross-sectional study.
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Levin-Schwartz, Yuri, Curtin, Paul, Flores, Daniel, Aushev, Vasily N, Tamayo-Ortiz, Marcela, Svensson, Katherine, Pantic, Ivan, Estrada-Gutierrez, Guadalupe, Pizano-Zárate, María L, Gennings, Chris, Satlin, Lisa M, Baccarelli, Andrea A, Tellez-Rojo, Martha M, Wright, Robert O, and Sanders, Alison P
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- 2021
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21. The STK38–XPO1 axis, a new actor in physiology and cancer.
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Martin, Alexandre PJ., Aushev, Vasily N., Zalcman, Gérard, and Camonis, Jacques H.
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PHYSIOLOGY , *CELLULAR signal transduction , *CELL death , *CELL proliferation - Abstract
The Hippo signal transduction pathway is an essential regulator of organ size during developmental growth by controlling multiple cellular processes such as cell proliferation, cell death, differentiation, and stemness. Dysfunctional Hippo signaling pathway leads to dramatic tissue overgrowth. Here, we will briefly introduce the Hippo tumor suppressor pathway before focusing on one of its members and the unexpected twists that followed our quest of its functions in its multifarious actions beside the Hippo pathway: the STK38 kinase. In this review, we will precisely discuss the newly identified role of STK38 on regulating the nuclear export machinery by phosphorylating and activating, the major nuclear export receptor XPO1. Finally, we will phrase STK38′s role on regulating the subcellular distribution of crucial cellular regulators such as Beclin1 and YAP1 with its implication in cancer. [ABSTRACT FROM AUTHOR]
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- 2021
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22. Tumor expression of environmental chemical-responsive genes and breast cancer mortality.
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Aushev, Vasily N., Gopalakrishnan, Kalpana, Teitelbaum, Susan L., Parada Jr, Humberto, Santella, Regina M., Gammon, Marilie D., and Chen, Jia
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BRCA genes , *CANCER-related mortality , *PERSONAL care product ingredients , *METASTATIC breast cancer , *DIETHYL phthalate , *MORTALITY - Abstract
Environmental phenols and phthalates are common ingredients in personal care products and some have been implicated in breast cancer progression. We have previously identified genes differentially expressed in response to low-dose exposure to diethyl phthalate (DEP) and methyl paraben (MPB) in a rat model. Herein we explore if these genes are associated with breast cancer mortality in humans. We profiled MPB- and DEP-responsive genes in tumors by NanoString® from a population-based cohort of 606 women with first primary breast cancer among whom 119 breast can cer-specific deaths occurred within 15+ years of follow-up. For each gene, Cox prop ortional hazards models were used to estimate hazard ratios (HRs) and 95% confidence int ervals (CIs). Results were validated in two publicly available datasets. The following results were obtained. From 107 DEP- and 77 MPB-responsive genes profiled, 44 and 30 ge nes, respectively, were significantly associated with breast cancer-specific mortality. Some top DEPresponsive genes are novel for breast cancer mortality, such as ABHD14B (for high-vs-low expression, HR 0.36, 95% CI: 0.2-0.5) and TMC4 (HR 0.37, 95% CI: 0.3-0.5); top hits for MPB (SLC40A1 (HR 0.37, 95% CI: 0.3-0.5) and NTN4 (HR 0.39, 95% CI: 0.3-0.6)) are wellknown predictors of breast cancer survival. PLEKHA6 was another novel survival predictor, sensitive to hormonal receptor status (HR 0.5, 95% CI 0.3-0.9 f or hormonal receptorpositive and HR 3.2, 95% CI 1.7-6.2 for -negative group). In co nclusion, tumor expression of DEP- and MPB-responsive genes is associated with breast cancer mortality, supporting that exposure to these chemicals may influence the progression of breast cancer. [ABSTRACT FROM AUTHOR]
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- 2019
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23. Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with surgically resected stage II/III melanoma.
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Kollipara, Revathi, Budde, Griffin, Aushev, Vasily N., Brunsgaard, Elise Kornreich, Kuzel, Timothy, O'Donoghue, Cristina, Riddell, Timothy, Palsuledesai, Charuta C., Krainock, Michael, Liu, Minetta C., and Tan, Alan
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- 2023
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24. Circulating tumor DNA as a marker of recurrence risk in locoregional esophagogastric cancers with pathologic complete response.
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Lander, Eric Michael, Huffman, Brandon, Klempner, Samuel J, Aushev, Vasily N., Ferguson, Jenifer, Sharma, Shruti, Jurdi, Adham A, Liu, Minetta C., Eng, Cathy, and Gibson, Michael K.
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- 2023
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25. Evaluation of genomic alterations in early-onset versus late-onset colorectal cancer.
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Lander, Eric Michael, Rivero-Hinojosa, Samuel, Aushev, Vasily N., Jurdi, Adham A, Liu, Minetta C., and Eng, Cathy
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- 2023
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26. A new method to study the change of miRNA-mRNA interactions due to environmental exposures.
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Petralia, Francesca, Aushev, Vasily N., Gopalakrishnan, Kalpana, Kappil, Maya, Khin, Nyan W., Jia Chen, Teitelbaum, Susan L., and Pei Wang
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MESSENGER RNA , *MICRORNA , *BIOMOLECULES , *PHENOTYPES , *MAMMARY glands - Abstract
Motivation: Integrative approaches characterizing the interactions among different types of biological molecules have been demonstrated to be useful for revealing informative biological mechanisms. One such example is the interaction between microRNA (miRNA) and messenger RNA (mRNA), whose deregulation may be sensitive to environmental insult leading to altered phenotypes. The goal of this work is to develop an effective data integration method to characterize deregulation between miRNA and mRNA due to environmental toxicant exposures. We will use data from an animal experiment designed to investigate the effect of low-dose environmental chemical exposure on normal mammary gland development in rats to motivate and evaluate the proposed method. Results: We propose a new network approach--integrative Joint Random Forest (iJRF), which characterizes the regulatory system between miRNAs and mRNAs using a network model. iJRF is designed to work under the high-dimension low-sample-size regime, and can borrow information across different treatment conditions to achieve more accurate network inference. It also effectively takes into account prior information of miRNA-mRNA regulatory relationships from existing databases. When iJRF is applied to the data from the environmental chemical exposure study, we detected a few important miRNAs that regulated a large number of mRNAs in the control group but not in the exposed groups, suggesting the disruption of miRNA activity due to chemical exposure. Effects of chemical exposure on two affected miRNAs were further validated using breast cancer human cell lines. [ABSTRACT FROM AUTHOR]
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- 2017
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27. Kinetics of postoperative circulating cell-free DNA and impact on minimal residual disease detection rates in patients with resected stage I-III colorectal cancer.
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Cohen, Stacey A., Kasi, Pashtoon Murtaza, Aushev, Vasily N., Hanna, Diana L., Botta, Gregory P., Sharif, Saima, Laliotis MD, PhD, Georgios I., Sharma, Vivek R., Alqahtani, Ali, Chandana, Sreenivasa R, Kang, Sandra, Chakrabarti, Sakti, Somer, Bradley G., Kasi, Anup, Dayyani, Farshid, Malla, Midhun, Jurdi, Adham A, Liu, Minetta C., Aleshin, Alexey, and Kopetz, Scott
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- 2023
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28. Circulating tumor DNA (ctDNA) informs clinical practice in patients with recurrent/metastatic gastroesophageal cancers.
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Mehta, Rutika, Rivero-Hinojosa, Samuel, Dayyani, Farshid, Chao, Joseph, Izaguirre Carbonell, Jesus, Ferguson, Jenifer, Shariff, Bushra, Aushev, Vasily N., Budde, Griffin, Sharma, Shruti, Malhotra, Meenakshi, Jurdi, Adham A, Liu, Minetta C., Klempner, Samuel J, and Huffman, Brandon
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- 2023
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29. Complex Selection on Human Polyadenylation Signals Revealed by Polymorphism and Divergence Data.
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Kainov, Yaroslav A., Aushev, Vasily N., Naumenko, Sergey A., Tchevkina, Elena M., and Bazykin, Georgii A.
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MESSENGER RNA , *NUCLEOTIDES , *NUCLEIC acids , *GENETICS , *GENETIC polymorphisms - Abstract
Polyadenylation is a step of mRNA processing which is crucial for its expression and stability. Themajor polyadenylation signal (PAS) represents a nucleotide hexamer that adheres to the AATAAA consensus sequence. Over a half of human genes have multiple cleavage and polyadenylation sites, resulting in a great diversity of transcripts differing in function, stability, and translational activity. Here,weuse availablewhole-genomehumanpolymorphismdata together withdataoninterspeciesdivergence tostudy thepatterns of selectionactingonPAShexamers.CommonvariantsofPAShexamers aredepletedof single nucleotidepolymorphisms (SNPs),and SNPs within PAS hexamers have a reduced derived allele frequency (DAF) and increased conservation, indicating prevalent negative selection; at the same time, the SNPs that "improve" the PAS (i.e., those leading to higher cleavage efficiency) have increased DAF, compared to those that "impair" it. SNPs are rarer at PAS of "unique" polyadenylation sites (one site per gene); among alternative polyadenylation sites, at the distal PAS and at exonic PAS. Similar trends were observed in DAFs and divergence between species of placental mammals. Thus, selection permits PAS mutations mainly at redundant and/or weakly functional PAS. Nevertheless, a fractionof the SNPs at PAShexamers likely affect gene functions; in particular, someof the observed SNPs are associatedwithdisease. [ABSTRACT FROM AUTHOR]
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- 2016
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30. The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response.
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Simicek, Michal, Lievens, Sam, Laga, Mathias, Guzenko, Dmytro, Aushev, Vasily N., Kalev, Peter, Baietti, Maria Francesca, Strelkov, Sergei V., Gevaert, Kris, Tavernier, Jan, and Sablina, Anna A.
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GUANOSINE triphosphatase ,VIRUS diseases ,AUTOPHAGY ,UBIQUITINATION ,DOUBLE-stranded RNA ,IMMUNE response - Abstract
The RAS-like GTPase RALB mediates cellular responses to nutrient availability or viral infection by respectively engaging two components of the exocyst complex, EXO84 and SEC5. RALB employs SEC5 to trigger innate immunity signalling, whereas RALB-EXO84 interaction induces autophagocytosis. How this differential interaction is achieved molecularly by the RAL GTPase remains unknown. We found that whereas GTP binding turns on RALB activity, ubiquitylation of RALB at Lys 47 tunes its activity towards a particular effector. Specifically, ubiquitylation at Lys 47 sterically inhibits RALB binding to EXO84, while facilitating its interaction with SEC5. Double-stranded RNA promotes RALB ubiquitylation and SEC5-TBK1 complex formation. In contrast, nutrient starvation induces RALB deubiquitylation by accumulation and relocalization of the deubiquitylase USP33 to RALB-positive vesicles. Deubiquitylated RALB promotes the assembly of the RALB-EXO84-beclin-1 complexes driving autophagosome formation. Thus, ubiquitylation within the effector-binding domain provides the switch for the dual functions of RALB in autophagy and innate immune responses. [ABSTRACT FROM AUTHOR]
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- 2013
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31. RalA and RalB Proteins Are Ubiquitinated GTPases, and Ubiquitinated RalA Increases Lipid Raft Exposure at the Plasma Membrane.
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Neyraud, Vincent, Aushev, Vasily N., Hatzoglou, Anastassia, Meunier, Brigitte, Cascone, Ilaria, and Camonis, Jacques
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LIPID rafts , *GUANOSINE triphosphatase , *GENETIC translation , *CELL membranes , *ENDOCYTOSIS , *CARCINOGENESIS - Abstract
Ras GTPases signal by orchestrating a balance among several effector pathways, of which those driven by the GTPases RalA and RalB are essential to Ras oncogenic functions. RalA and RalB share the same effectors but support different aspects of oncogenesis. One example is the importance of active RalA in anchorage-independent growth and membrane raft trafficking. This study has shown a new post-translational modification of Ral GTPases: nondegradative ubiquitination. RalA (but not RalB) ubiquitination increases in anchorage-independent conditions in a caveolin-dependent manner and when lipid rafts are endocytosed. Forcing RalA mono-ubiquitination (by expressing a protein fusion consisting of ubiquitin fused N-terminally to RalA) leads to RalA enrichment at the plasma membrane and increases raft exposure. This study suggests the existence of an ubiquitination/de-ubiquitination cycle superimposed on the GDP/GTP cycle of RalA, involved in the regulation of RalA activity as well as in membrane raft trafficking. [ABSTRACT FROM AUTHOR]
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- 2012
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32. Different metastasis promotive potency of small G-proteins RalA and RalB in in vivo hamster tumor model.
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Rybko, Vera A., Knizhnik, Anna V., Komelkov, Andrei V., Aushev, Vasily N., Trukhanova, Lyubov S., and Tchevkina, Elena M.
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CANCER invasiveness ,CANCER research ,METASTASIS ,WOUND healing ,MEMBRANE proteins - Abstract
Background: Previously we have shown that oncogenic Ha-Ras stimulated in vivo metastasis through RalGEF-Ral signaling. RalA and RalB are highly homologous small G proteins belonging to Ras superfamily. They can be activated by Ras-RalGEF signaling pathway and influence cellular growth and survival, motility, vesicular transport and tumor progression in humans and in animal models. Here we first time compared the influence of RalA and RalB on tumorigenic, invasive and metastatic properties of RSV transformed hamster fibroblasts. Methods: Retroviral vectors encoding activated forms or effector mutants of RalA or RalB proteins were introduced into the low metastatic HET-SR cell line. Tumor growth and spontaneous metastatic activity (SMA) were evaluated on immunocompetent hamsters after subcutaneous injection of cells. The biological properties of cells, including proliferation, clonogenicity, migration and invasion were determined using MTT, wound healing, colony formation and Boyden chamber assays respectively. Protein expression and phosphorylation was detected by Westen blot analysis. Extracellular proteinases activity was assessed by substrate-specific zymography. Results: We have showed that although both Ral proteins stimulated SMA, RalB was more effective in metastasis stimulation in vivo as well as in potentiating of directed movement and invasion in vitro. Simultaneous expression of active RalA and RalB didn't give synergetic effect on metastasis formation. RalB activity decreased expression of Caveolin-1, while active RalA stimulated MMP-1 and uPA proteolytic activity, as well as CD24 expression. Both Ral proteins were capable of Cyclin D1 upregulation, JNK1 kinase activation, and stimulation of colony growth and motility. Among three main RalB effectors (RalBP1, exocyst complex and PLD1), PLD1 was essential for RalBdependent metastasis stimulation. Conclusions: Presented results are the first data on direct comparison of RalA and RalB impact as well as of RalA/RalB simultaneous expression influence on in vivo cell metastatic activity. We showed that RalB activation significantly more than RalA stimulates SMA. This property correlates with the ability of RalB to stimulate in vitro invasion and serum directed cell movement. We also found that RalB-PLD1 interaction is necessary for the acquisition of RalB-dependent high metastatic cell phenotype. These findings contribute to the identification of molecular mechanisms of metastasis and tumor progression. [ABSTRACT FROM AUTHOR]
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- 2011
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33. STK38 kinase acts as XPO1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes.
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Martin, Alexandre PJ, Jacquemyn, Maarten, Lipecka, Joanna, Chhuon, Cerina, Aushev, Vasily N, Meunier, Brigitte, Singh, Manish K, Carpi, Nicolas, Piel, Matthieu, Codogno, Patrice, Hergovich, Alexander, Parrini, Maria Carla, Zalcman, Gerard, Guerrera, Ida Chiara, Daelemans, Dirk, and Camonis, Jacques H
- Abstract
STK38 (also known as NDR1) is a Hippo pathway serine/threonine protein kinase with multifarious functions in normal and cancer cells. Using a context‐dependent proximity‐labeling assay, we identify more than 250 partners of STK38 and find that STK38 modulates its partnership depending on the cellular context by increasing its association with cytoplasmic proteins upon nutrient starvation‐induced autophagy and with nuclear ones during ECM detachment. We show that STK38 shuttles between the nucleus and the cytoplasm and that its nuclear exit depends on both XPO1 (aka exportin‐1, CRM1) and STK38 kinase activity. We further uncover that STK38 modulates XPO1 export activity by phosphorylating XPO1 on serine 1055, thus regulating its own nuclear exit. We expand our model to other cellular contexts by discovering that XPO1 phosphorylation by STK38 regulates also the nuclear exit of Beclin1 and YAP1, key regulator of autophagy and transcriptional effector, respectively. Collectively, our results reveal STK38 as an activator of XPO1, behaving as a gatekeeper of nuclear export. These observations establish a novel mechanism of XPO1‐dependent cargo export regulation by phosphorylation of XPO1's C‐terminal auto‐inhibitory domain. Synopsis: Cytoplasmic accumulation of STK38 kinase is essential for starvation‐induced autophagy. STK38 phosphorylates and activates the nuclear export factor XPO1, thereby supporting the shuttling of the autophagy regulator Beclin1 and other XPO1 cargoes to the cytoplasm. XPO1 is a substrate for the STK38 kinase.XPO1 is activated by this phosphorylation event on Ser1055.STK38 behaves as a regulator of XPO1 activity, which is inactive in absence of phosphorylation of its Ser1055. [ABSTRACT FROM AUTHOR]
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- 2019
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34. Comparisons of microRNA Patterns in Plasma before and after Tumor Removal Reveal New Biomarkers of Lung Squamous Cell Carcinoma.
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Aushev, Vasily N., Zborovskaya, Irina B., Laktionov, Konstantin K., Girard, Nicolas, Cros, Marie-Pierre, Herceg, Zdenko, and Krutovskikh, Vladimir
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MICRORNA , *BLOOD plasma , *BIOMARKERS , *LUNG cancer , *SQUAMOUS cell carcinoma , *GENETIC code - Abstract
Lung cancer is the major human malignancy, accounting for 30% of all cancer-related deaths worldwide. Poor survival of lung cancer patients, together with late diagnosis and resistance to classic chemotherapy, highlights the need for identification of new biomarkers for early detection. Among different cancer biomarkers, small non-coding RNAs called microRNAs (miRNAs) are considered the most promising, owing to their remarkable stability, their cancer-type specificity, and their presence in body fluids. However, results of multiple previous attempts to identify circulating miRNAs specific for lung cancer are inconsistent, likely due to two main reasons: prominent variability in blood miRNA content among individuals and difficulties in distinguishing tumor-relevant miRNAs in the blood from their non-tumor counterparts. To overcome these impediments, we compared circulating miRNA profiles in patients with lung squamous cell carcinoma (SCC) before and after tumor removal, assuming that the levels of all tumor-relevant miRNAs would drop after the surgery. Our results revealed a specific panel of the miRNAs (miR-205, -19a, -19b, -30b, and -20a) whose levels decreased strikingly in the blood of patients after lung SCC surgery. Interestingly, miRNA profiling of plasma fractions of lung SCC patients revealed high levels of these miRNA species in tumor-specific exosomes; additionally, some of these miRNAs were also found to be selectively secreted to the medium by cultivated lung cancer cells. These results strengthen the notion that tumor cells secrete miRNA-containing exosomes into circulation, and that miRNA profiling of the exosomal plasma fraction may reveal powerful cancer biomarkers. [ABSTRACT FROM AUTHOR]
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- 2013
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35. Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer.
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Hou, June Y., Chapman, Jocelyn S., Kalashnikova, Ekaterina, Pierson, William, Smith-McCune, Karen, Pineda, Geovanni, Vattakalam, Reena Marie, Ross, Alexandra, Mills, Meredith, Suarez, Carlos J., Davis, Tracy, Edwards, Robert, Boisen, Michelle, Sawyer, Sarah, Wu, Hsin-Ta, Dashner, Scott, Aushev, Vasily N., George, Giby V., Malhotra, Meenakshi, and Zimmermann, Bernhard
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CIRCULATING tumor DNA , *OVARIAN epithelial cancer , *OVARIAN cancer , *ADJUVANT chemotherapy , *LEAD time (Supply chain management) - Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. We examined the utility of circulating tumor DNA (ctDNA) as a prognostic biomarker for EOC by assessing its relationship with patient outcome and CA-125, pre-surgically and during post-treatment surveillance. Plasma samples were collected from patients with stage I-IV EOC. Cohort A included patients with pre-surgical samples (N = 44, median follow-up: 2.7 years), cohort B and C included: patients with serially collected post-surgically (N = 12) and, during surveillance (N = 13), respectively (median follow-up: 2 years). Plasma samples were analyzed using a tumor-informed, personalized multiplex-PCR NGS assay; ctDNA status and CA-125 levels were correlated with clinical features and outcomes. Genomic profiling was performed on the entire cohort and was consistent with that seen in TCGA. In cohort A, ctDNA-positivity was observed in 73% (32/44) of presurgical samples and was higher in high nuclear grade disease. In cohort B and C, ctDNA was only detected in patients who relapsed (100% sensitivity and specificity) and preceded radiological findings by an average of 10 months. The presence of ctDNA at a single timepoint after completion of surgery +/− adjuvant chemotherapy and serially during surveillance was a strong predictor of relapse (HR:17.6, p = 0.001 and p < 0.0001, respectively), while CA-125 positivity was not (p = 0.113 and p = 0.056). The presence of ctDNA post-surgically is highly prognostic of reduced recurrence-free survival. CtDNA outperformed CA-125 in identifying patients at highest risk of recurrence. These results suggest that monitoring ctDNA could be beneficial in clinical decision-making for EOC patients. • Post-surgical ctDNA detection is prognostic of reduced recurrence-free survival. • Post-surgically, ctDNA detected relapse with 100% sensitivity and specificity. • ctDNA detection preceded radiological findings by an average lead time of 10 months. • The presence of ctDNA and not CA-125 was a strong predictor of relapse. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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