tbuckley/cabot-search huggingface dataset:
Crosstalk between autophagy and metabolic regulation of cancer stem cells
Authors: Mouradi El Hout, Emma Cosialls, Maryam Mehrpour, Ahmed Hamaï
Journal: Molecular Cancer (2020)

Cancer is now considered as a heterogeneous ecosystem in which tumor cells collaborate with each other and with host cells in their microenvironment. As circumstances change, the ecosystem evolves to ensure the survival and growth of the cancer cells. In this ecosystem, metabolism is not only a key player but also drives stemness. In this review, we first summarize our current understanding of how autophagy influences cancer stem cell phenotype. We emphasize metabolic pathways in cancer stem cells and discuss how autophagy-mediated regulation metabolism is involved in their maintenance and proliferation. We then provide an update on the role of metabolic reprogramming and plasticity in cancer stem cells. Finally, we discuss how metabolic pathways in cancer stem cells could be therapeutically targeted.
Phase II study of avelumab plus intermittent axitinib in previously untreated patients with metastatic renal cell carcinoma (Tide-A study).
Authors: Roberto Iacovelli, Francesco Atzori, Umberto Basso, Melissa Bersanelli, Lucia Bonomi, Sergio Bracarda, Consuelo Buttigliero, Emanuela Fantinel, Fabio Calabro, Vincenzo Emanuele Chiuri, Giuseppe Di Lorenzo, Giuseppe Fornarini, Francesco Massari, Emanuele Naglieri, Cinzia Ortega, Giuseppe Procopio, Michele Milella, Matteo Santoni, Maria Giuseppa Vitale, Paolo Andrea Zucali
Journal: Journal of Clinical Oncology (2020)

TPS762 Background: The combination of avelumab plus axitinib has been recently reported to be superior than sunitinib alone for treatment of previously untreated mRCC patients (Motzer, NEJM 2019). The study reported a median PFS of 13.8 for the combination of avelumab plus axitinib compared to 8.4 months for sunitinib (p&lt;0.001) with an ORR of 48% vs 24%, respectively. To improve treatment efficacy and safety, TKI discontinuation has been considered in patients treated with sunitinib leading to a longer definitive progression free survival (22.4 months) and overall survival (34.8 months) with a better safety profile (Ornstein, JCO 2017). Despite a new tumor response at TKI reintroduction, many patients progressed after the first months of treatment discontinuation suggesting the necessity to maintain the previous response. This study aims to test if patients achieving a tumor response with the combination of avelumab plus axitinib, can discontinue the TKI in order to delay the resistance and decrease the toxicity related to the combination of therapies. Methods: The single arm, phase II TIDE-A trial, aims to evaluate the activity of avelumab as maintenance therapy in patients with mRCC who achieved a tumor response after the induction phase of therapy with the combination of avelumab and axitinib. Eligible patients have clear cell carcinoma, ECOG performance status 0 or 1, measurable, no bulky disease without tumor-related symptoms or hepatic metastases. Eligible patient will receive the combination of avelumab plus axitinib for 36 weeks. Patients achieving RECIST 1.1 partial response discontinue the axitinib and continue avelumab. At tumor progression, the axitinib will be restarted for at least six months. If a new tumor response is achieved, axitinib will be discontinued again until tumor progression. Patients with RECIST 1.1 stable disease continue the combination of avelumab and axitinib until progression of disease. The primary endpoint is to evaluate the rate of patients free of progression after 8 weeks from axitinib discontinuation. The study is currently ongoing in twenty centres in Italy.
A Novel Clinically Based Staging System for Gallbladder Cancer.
Authors: Siddhartha Yadav, Sri Harsha Tella, Anuhya Kommalapati, Kristin Mara, Kritika Prasai, Mohamed Hamdy Mady, Mohamed Hassan, Rory L. Smoot, Sean P. Cleary, Mark J. Truty, Lewis R. Roberts, Amit Mahipal
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background  Current staging systems for gallbladder cancer (GBC) are primarily based on surgical pathology and therefore are not relevant for unresectable patients and those undergoing neoadjuvant chemotherapy.  Methods  Patients with a confirmed diagnosis of GBC managed at a tertiary referral center (2000-2016) were included. Independent predictors of overall survival (OS) were identified using multivariable analysis (MVA). A combination of these variables was then assessed to identify a set of factors that provided maximal accuracy in predicting OS, and a nomogram and a new staging system were created based on these factors. Harrell's C-statistic was calculated to evaluate the predictive accuracy of the nomogram and staging system.  Results  A total of 528 patients were included in the final analysis. On MVA, factors predictive of poor OS were older age, ECOG performance status, hemoglobin level  200 U/L. A nomogram and a 4-tier staging system predictive of OS were created using age at diagnosis, ECOG status, tumor size, presence or absence of metastasis, and ALP level. The C-statistic for this novel staging system was 0.71 compared with 0.69 for the TNM staging system (P=.08). In patients who did not undergo surgery, the C-statistics of the novel and TNM staging systems were 0.60 and 0.51, respectively (P  Conclusions  We created a novel, clinically based staging system for GBC based on nonoperative information at the time of diagnosis that was superior to the TNM staging system in predicting OS in patients who did not undergo surgery, and that performed on par with TNM staging in surgical patients.
EBV+ diffuse large B-cell lymphoma associated with chronic inflammation expands the spectrum of breast implant-related lymphomas
Authors: Lénaïg Mescam, Vincent Camus, Jean-Marc Schiano, José Adélaïde, Jean-Michel Picquenot, Arnaud Guille, Marie Bannier, Philippe Ruminy, Pierre-Julien Viailly, Fabrice Jardin, Reda Bouabdallah, Isabelle Brenot Rossi, Elodie Bohers, Cyrielle Robe, Camille Laurent, Daniel Birnbaum, Andrew Wotherspoon, Philippe Gaulard, Luc Xerri
Journal: Blood (2020)
Targeted delivery of engineered auditory sensing protein for ultrasound neuromodulation in the brain
Authors: Chun-Yao Wu, Ching-Hsiang Fan, Nai-Hua Chiu, Yi-Ju Ho, Yu-Chun Lin, Chih-Kuang Yeh
Journal: Theranostics (2020)

Sonogenetics is a promising approach for in vivo neuromodulation using ultrasound (US) to non-invasively stimulate cells in deep tissue. However, sonogenetics requires accurate transduction of US-responsive proteins into target cells. Here, we introduce a non-invasive and non-viral approach for intracerebral gene delivery. This approach utilizes temporary ultrasonic disruption of the blood-brain barrier (BBB) to transfect neurons at specific sites in the brain via DNA that encodes engineered US-responsive protein (murine Prestin (N7T, N308S))-loaded microbubbles (pPrestin-MBs). Prestin is a transmembrane protein that exists in the mammalian auditory system and functions as an electromechanical transducer. We further improved the US sensitivity of Prestin by introducing specific amino acid substitutions that frequently occur in sonar species into the mouse Prestin protein. We demonstrated this concept in mice using US with pPrestin-MBs to non-invasively modify and activate neurons within the brain for spatiotemporal neuromodulation. Method: MBs composed of cationic phospholipid and C3F8 loaded with mouse Prestin plasmid (pPrestin) via electrostatic interactions. The mean concentration and size of the pPrestin-MBs were (16.0 ± 0.2) × 109 MBs/mL and 1.1 ± 0.2 μm, respectively. SH-SY5Y neuron-like cells and C57BL mice were used in this study. We evaluated the gene transfection efficiency and BBB-opening region resulting from pPrestin-MBs with 1-MHz US (pressure = 0.1-0.5 MPa, cycle = 50-10000, pulse repetition frequency (PRF): 0.5-5 Hz, sonication time = 60 s) using green fluorescence protein (Venus) and Evans blue staining. Results: The maximum pPrestin expression with the highest cell viability occurred at a pressure of 0.5 MPa, cycle number of 5000, and PRF of 1 Hz. The cellular transfection rate with pPrestin-MBs and US was 20.2 ± 2.5%, which was 1.5-fold higher than that of commercial transfection agents (LT-1). In vivo data suggested that the most profound expression of pPrestin occurred at 2 days after performing pPrestin-MBs with US (0.5 MPa, 240 s sonication time). In addition, no server erythrocyte extravasations and apoptosis cells were observed at US-sonicated region. We further found that with 0.5-MHz US stimulation, cells with Prestin expression were 6-fold more likely to exhibit c-Fos staining than cells without Prestin expression. Conclusion: Successful activation of Prestin-expressing neurons suggests that this technology provides non-invasive and spatially precise selective modulation of one or multiple specific brain regions.
Progression-free survival (PFS) and overall survival (OS) across ethnicities for patients with metastatic renal cell carcinoma (mRCC) receiving targeted therapies (TT) as first-line (1L) treatment.
Authors: Nicholas Salgia, Nazli Dizman, Paulo Gustavo Bergerot, Cristiane Decat Bergerot, Joann Hsu, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2020)

645 Background: Recent efforts have sought to characterize differences in clinical and pathological characteristics across ethnicities in mRCC (Batai et al CGUC 2018), however, the relationship between ethnicity and treatment outcomes has yet to be explored. We sought to compare survival outcomes across ethnic groups for patients receiving 1L TT for treatment of mRCC. Methods: Patients receiving 1L systemic treatment for mRCC were retrospectively identified from a single institution database from 2009 to present. Patient ethnicity data were collected from electronic health records. Due to the demographics of the patient population, ethnicity was categorized as Non-Hispanic Caucasian American (CA), Hispanic American (HA), or Asian American (AsA). Patients prescribed tyrosine kinase and/or mTOR inhibitors as 1L therapy were included for analysis. PFS and OS were analyzed across ethnic groups and comparisons were performed using the Kaplan Meier Survival Function in SPSS. Results: Of 294 (77:217 F:M) patients with documented survival data, 183 (62%) were CA, 82 (28%) HA, and 29 (10%) AsA. The most frequently used TTs were sunitinib (63%), temsirolimus (10%), pazopanib (7%), sorafenib (5%), and cabozantinib (4%). Median PFS for CA was 5.6 months (95% Confidence Interval [CI]: 4.1-7.1) vs. 4.7 months (95% CI: 3.1-6.2) for HA vs. 4.7 months (95% CI: 2.1-7.3) for AsA. Median OS was 32.0 months (95% CI: 26.2-37.8) for CA vs. 31.7 months (95% CI: 21.1-42.4) for HA vs. 51.7 months (95% CI: 31.6-71.8) for AsA. No significant difference in PFS or OS was calculated across the three ethnic groups (p=0.652 and p=0.435, respectively). Conclusions: The lack of a statistically significant difference in both PFS and OS across ethnic groups is a promising assessment for the current landscape of health disparities in mRCC. As these data are distinct from recent findings identifying disparities in other malignancies (e.g., prostate cancer), multicenter collaborations should be encouraged to validate these findings.
The use of DNA promoter methylation testing for prostate cancer diagnosis in the Department of Veterans Affairs.
Authors: Kyung Min Lee, Jeffrey A. Jones, Olga Efimova, Scott L. DuVall, Julie Ann Lynch
Journal: Journal of Clinical Oncology (2020)

394 Background: It is essential to study real-world evidence of novel molecular diagnostic tests to measure their impact on clinical decision-making and health outcomes. Studying test utilization within the Department of Veterans Affairs (VA) informs about clinical validity in a racially diverse population. This study analyzed the impact of DNA promoter methylation (ConfirmDx), on the diagnostic workup of Veterans. Methods: The VA Corporate Data Warehouse (CDW) was used to identify all incident prostate biopsies and cancers from 1/2014-10/2019. We captured patient clinical characteristics, including number and date of biopsies, date of cancer diagnosis, dates and values of PSA tests, comorbidities, demographics, whether the patient underwent DNA promoter methylation testing, and the results of that test. Results: Each year an average of 25,299 biopsies are conducted in the VA. Between 2014 and 2019, 151,794 biopsies were performed. 98,155 (70%) Veterans underwent first-time biopsies and 54,447 (55%) were positive for carcinoma. 8,062 (8.2%) underwent multiple biopsies, among whom 3,589 (44%) were subsequently diagnosed with cancer. 34 Veterans underwent 5 or more biopsies before being diagnosed. 33,878 (35%) did not undergo another biopsy in the study period. 328 (0.3%) of the 98,155 Veterans underwent the DNA promoter methylation test. 55 (17%) of these Veterans were eligible for Medicare coverage of the test. Of the 328 tested for DNA methylation, 217 (66%) were minorities. 132/328 (40%) tested positive for carcinoma and 168/328 (51%) were negative. Conclusions: Most Veterans referred for prostate biopsy have detectable cancer, and a large number are minorities with potential increased prostate cancer risk. DNA promoter methylation may improve care by reducing the need for multiple biopsies, limiting exposure to infection, and reducing time to diagnosis and treatment.
TD-8236, a lung-selective inhaled pan-JAK inhibitor, inhibits gene expression related to severe asthma and exhaled nitric oxide (FeNO), in 3-D airway epithelium liquid interface (ALI) cultures derived from asthmatic donors
Authors: Elad Kaufman, Melanie Kleinschek, Edmund Moran, Jacky Woo, Reuben Sana, Emma Gordon, Wanju Lee, Glenn Crater, Thomas Southworth, Thomas Scott, Dave Singh, Nathan Pfeiffer
Journal: Journal of Allergy and Clinical Immunology (2020)
2ME2 inhibits HIF-1 mRNA translation and its association with microtubules: Loss of microtubule-dependent HIF regulation in renal carcinoma cells
Authors: Aurora O’Brate, Erik Kline, Yue Feng, Mikhail V. Blagosklonny, Paraskevi Giannakakou
Journal: Cancer Research (2005)

3265  We have previously shown that the microtubule destabilizing drug 2ME2 down-regulates the HIF-1 α protein (HIF-1α) and inhibits its transcriptional activity at concentrations that disrupt interphase microtubules. We have further shown that 2ME2 inhibits the de novo synthesis of HIF-1α by at least 10-fold, based on immunoprecipitation of newly synthesized HIF-1 α. To investigate the molecular mechanism by which 2ME2 inhibits HIF-1 α synthesis, we examined the polyribosome association profile of the HIF-1 mRNA by linear sucrose gradient fractionation (LSGF). Using LSGF followed by Northern blotting, we showed that the HIF-1 α mRNA was associated with the translationally active components in untreated cells, while upon 2ME2 treatment there was a complete shift towards translation-inactive fractions. This effect was specific for HIF-1α as no shift in the actin and HIF-1β translation was observed. To test the hypothesis that the HIF-1α mRNA requires association with microtubules for efficient translation, we used fluorescent molecular beacons (MB) complimentary to the HIF-1 α mRNA. Transfection of HIF-1α MBs into MCF-7 cells followed by confocal microscopy revealed colocalization between the HIF-1α mRNA and microtubules in untreated cells. Upon 2ME2 treatment extensive microtubule depolymerization was observed leading to lack of colocalization between HIF-1α mRNA and microtubules. These preliminary results support our hypothesis that 2ME2 inhibits HIF-1α translation by affecting the localization of the HIF-1α mRNA complexes with the microtubule cytoskeleton, thus impairing efficient HIF-1α translation. We next investigated whether cells with constitutively high levels of HIF-1 protein due to lack of its degradation (VHL−/− cells) would retain sensitivity to 2ME2. Surprisingly we found that 2ME2 destabilized microtubules but nevertheless had no effect on HIF-1α in renal carcinoma cells lacking VHL and therefore expressing constitutively high HIF-1. In these RCC cells the HIF-1α half life was 4 hr, which is much longer than wt VHL harboring cancer cells (10 min), but nevertheless shorter than the time of exposure to 2ME2 (20 hr). This indicates that RCC cells have lost microtubule control of HIF-1α translation. Next we used the isogenic RCC2/VHL and RCC4/VHLcells, in which wild-type VHL has been stably re-introduced. Despite restoration of VHL, 2ME2 failed to downregulate HIF-1α under hypoxia. Under hypoxia, the half-life of HIF-1α was 4 hr so this could not be responsible for the lack of downregulation of HIF-1 during the 20 hr treatment with 2ME2. We conclude that, in addition to stabilization of HIF-1α due to loss of VHL, RCC cells also acquire microtubule-independent regulation of HIF-1α expression that could not be restored by VHL. We hypothesize that in RCC cells HIF-1α translation is independent of microtubules and contributes to HIF-1 dyregulation.
Changes in Opioid Use After Florida’s Restriction Law for Acute Pain Prescriptions
Authors: Juan M. Hincapie-Castillo, Amie Goodin, Marie-Christin Possinger, Silken A. Usmani, Scott Martin Vouri
Journal: JAMA Network Open (2020)

This quality improvement study assesses the number of new opioid users and the number of units dispensed per prescription before and after implementation of Florida's 2018 restriction law on opioid prescribing.
18-year prostate cancer-specific mortality after prostatectomy, brachytherapy, external beam radiation therapy, hormonal therapy, or monitoring for localized prostate cancer.
Authors: Annika Herlemann, Janet E. Cowan, Samuel L. Washington, Anthony C. Wong, Jenny M. Broering, Peter R. Carroll, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2020)

300 Background: The optimal treatment of localized prostate cancer (PCa) remains controversial. We compared long-term survival among men who underwent radical prostatectomy (RP), brachytherapy (BT), external beam radiation therapy (EBRT), primary androgen deprivation therapy (PADT), or monitoring (AS/WW) for localized PCa. Methods: Within the CaPSURE registry, we analyzed 12,062 men with localized PCa. PCa risk was assessed using the Stephenson preoperative nomogram and the Cancer of the Prostate Risk Assessment (CAPRA) score. Multivariable analyses were performed to compare prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) by primary treatment, adjusting for age and case-mix. An inverse probability weighted regression adjustment was used to reflect propensity for treatment assignment and any imbalances in censoring. Results: 6,357 men (53%) underwent RP, 1,351 (11%) BT, 1,716 (14%) EBRT, 1,605 (13%) PADT, and 1,033 (9%) AS/WW. During the 18-year follow-up period, 514 men died from PCa. Adjusting for clinical CAPRA score, the hazard ratios for PCSM relative to RP were 1.46 (95% CI, 1.00-2.12, p=0.050) for BT, 1.81 (95% CI, 1.43-2.30, p&lt;0.001) for EBRT, 2.77 (95% CI, 2.18-3.51, p&lt;0.001) for PADT, and 1.81 (95% CI, 1.23-2.66, p=0.003) for AS/WW. The greatest difference in PCSM between treatment modalities was observed for high-risk patients. Adjusting for age, comorbidity, and clinical CAPRA score, the hazard ratios for ACM were 1.46 (95% CI, 1.28-1.67) for BT, 1.38 (95% CI, 1.24-1.54) for EBRT, 1.89 (95% CI, 1.67-2.13) for PADT, and 1.60 (95% CI, 1.39-1.84) for AS/WW compared to RP (all p&lt;0.001). Additional analyses using 100-Stephenson score or Fine-Gray competing risks analysis demonstrated similar results. Conclusions: In a large, prospective cohort of men with localized PCa, after adjustment for age and comorbidity, risk of PCSM and ACM was lowest after RP. Mortality was significantly higher after EBRT and AS/WW, and highest after PADT. RP should be offered as part of the management paradigm for high-risk disease, AS/WW should be preferred for most low-risk PCa.
The role of microRNAs in ovarian function and the transition toward novel therapeutic strategies in fertility preservation: from bench to future clinical application
Authors: C Alexandri, A Daniel, G Bruylants, I Demeestere
Journal: Human Reproduction Update (2019)

New therapeutic approaches in oncology have converted cancer from a certain death sentence to a chronic disease. However, there are still challenges to be overcome regarding the off-target toxicity of many of these treatments. Oncological therapies can lead to future infertility in women. Given this negative impact on long-term quality of life, fertility preservation is highly recommended. While gamete and ovarian tissue cryopreservation are the usual methods offered, new pharmacological-based options aiming to reduce ovarian damage during oncological treatment are very attractive. In this vein, advances in the field of transcriptomics and epigenomics have brought small noncoding RNAs, called microRNAs (miRNAs), into the spotlight in oncology. MicroRNAs also play a key role in follicle development as regulators of follicular growth, atresia and steroidogenesis. They are also involved in DNA damage repair responses and they can themselves be modulated during chemotherapy. For these reasons, miRNAs may be an interesting target to develop new protective therapies during oncological treatment. This review summarizes the physiological role of miRNAs in reproduction. Considering recently developed strategies based on miRNA therapy in oncology, we highlight their potential interest as a target in fertility preservation and propose future strategies to make the transition from bench to clinic.How can miRNA therapeutic approaches be used to develop new adjuvant protective therapies to reduce the ovarian damage caused by cytotoxic oncological treatments?A systematic search of English language literature using PubMed and Google Scholar databases was performed through to 2019 describing the role of miRNAs in the ovary and their use for diagnosis and targeted therapy in oncology. Personal data illustrate miRNA therapeutic strategies to target the gonads and reduce chemotherapy-induced follicular damage.This review outlines the importance of miRNAs as gene regulators and emphasizes the fact that insights in oncology can inspire new adjuvant strategies in the field of onco-fertility. Recent improvements in nanotechnology offer the opportunity for drug development using next-generation miRNA-nanocarriers.Although there are still some barriers regarding the immunogenicity and toxicity of these treatments and there is still room for improvement concerning the specific delivery of miRNAs into the ovaries, we believe that, in the future, miRNAs can be developed as powerful and non-invasive tools for fertility preservation.