tbuckley/cabot-search huggingface dataset:
Abstract 2410: Supraphysiological androgens induce ferroptotic cell death in prostate cancer cells
Authors: Rajendra Kumar, Kavya Boyapati, Naiju Thomas, Deven Topiwala, Suthicha Kanacharoen, Olutosin Owoyemi, Max Coffey, Michael Carducci, Mark C. Markowski, Emmanuel S. Antonarakis, Drew Pardoll, Samuel Denmeade, Sushant K. Kachhap
Journal: Cancer Research (2020)

Abstract Castration resistant prostate cancer (CRPC) first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of a functioning androgen receptor (AR) axis. This observation led to the development of “second-line” therapies aimed at further blocking androgen/AR signaling. Unfortunately, resistance to these agents can also develop quickly. Paradoxically, several studies have suggested that the growth of AR-positive human CRPC cell lines may be inhibited by supraphysiologic levels of testosterone (SupT). These studies suggested that the adaptive reliance on AR signaling by CRPC cells becomes a therapeutic liability that can be exploited through the administration of SupT, which we termed as bipolar androgen therapy (BAT). Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses. Our data indicates that SupT induces autophagy mediated degradation of ferritin in prostate cancer (PCa) cells. Degradation of ferritin results in increase in labile iron pool increasing lipid peroxidation. Our data further indicates that SupT distinctly induces ferroptosis, a nonapoptotic regulated form of cell death induced by the accumulation of labile iron. Ferroptosis is thought to have tumor suppressing capabilities by clearing tumor cells via immune system activation. BAT has been discussed as a potential therapy for prostate cancer, but further research is needed to understand its full potential. Future combination of BAT with existing immunotherapeutics including immune checkpoint blockade may prove beneficial for treatment of CRPC. Citation Format: Rajendra Kumar, Kavya Boyapati, Naiju Thomas, Deven Topiwala, Suthicha Kanacharoen, Olutosin Owoyemi, Max Coffey, Michael Carducci, Mark C. Markowski, Emmanuel S. Antonarakis, Drew Pardoll, Samuel Denmeade, Sushant K. Kachhap. Supraphysiological androgens induce ferroptotic cell death in prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2410.
Community-wide HIV testing, linkage case management, and defaulter tracing in Bukoba, Tanzania: pre-intervention and post-intervention, population-based survey evaluation
Authors: Claire Steiner, Duncan MacKellar, Haddi Jatou Cham, Oscar Ernest Rwabiyago, Haruka Maruyama, Omari Msumi, Sherri Pals, Rachel Weber, Gerald Kundi, Johnita Byrd, Kokuhumbya Kazaura, Caitlin Madevu-Matson, Fernando Morales, Jessica Justman, Thomas Rutachunzibwa, Anath Rwebembera
Journal: The Lancet HIV (2020)
Fractured guidewire fragment on the peripheral side of a malignant biliary obstruction: successful removal using a biliary balloon dilation catheter
Authors: Yuki Tanisaka, Shomei Ryozawa, Masafumi Mizuide, Akashi Fujita, Tomoya Ogawa, Tatsuya Noguch, Tomoaki Tashima
Journal: Endoscopy (2020)

Fractured guidewire fragments in the bile duct need to be removed because they may lead to infected liver hematoma or cholangitis [1] [2] [3] [4]. We report the successful endoscopic removal of a fractured guidewire fragment on the peripheral side of a malignant biliary obstruction using a biliary balloon dilation catheter.
Abstract A63: Whole-genome CRISPR/CAS9 screen using patient samples reveals JunB as a unique genetic liability
Authors: Nobuhiro Takahashi, Heather Keys, Raghav Mohan, Lihua Zhang, Yi Li, Hatice D. Saatcioglu, Nicholas Nagykery, Patricia K. Donahoe, David Sabatini, David Pépin
Journal: Clinical Cancer Research (2020)

Abstract Background: Epithelial ovarian cancers are the fifth leading cause of cancer-related deaths in American women, with a five-year overall survival rate for patients diagnosed at advanced stages of less than 30%. High-grade serous ovarian cancers (HGSOCs), the most common histologic subtype, often initially responds to platinum-based chemotherapy. However, over 80% of patients experience chemoresistant recurrence in advanced-stage disease. Methods: We have established over 40 patient-derived HGSOC cell lines from ascites of patients with recurrences and hypothesized that these refractory HGSOC cell lines may each possess genetic liabilities and be dependent on unique pathways for survival that can be identified using an unbiased screening approach for the development of personalized therapies. In one such example, we identified candidate genes that are uniquely essential to a single HGSOC patient (ptD), as proof of concept, using a genome-wide lentiviral sgRNA library, containing 187,536 sgRNAs targeting 18,543 protein-coding human genes and 1,504 nontargeting control sgRNAs in a Cas9-containing vector. Results: The unbiased CRISPR screen identified BRAF (p=2E-6) as a specific susceptibility of ptD, confirming the known oncogene addiction of this primary cell line carrying a V600E mutation, as well as a significant sensitivity to JUNB deletion (p=6E-6). Knockout of the JUNB gene, using lentiviruses expressing guide RNAs and Cas9 protein targeted to JUNB, repressed cell proliferation in vitro in ptD cells but not other primary cell lines. Moreover, in a xenograft mouse model, JUNB KO ptD cells displayed slower tumor growth than control JUNB WT cells. Conclusion: We have confirmed in a single patient cell line our ability to identify and validate unique genetic liabilities, suggesting the approach can be scaled to rapidly screen primary HGSOC samples for personalized therapy. Citation Format: Nobuhiro Takahashi, Heather Keys, Raghav Mohan, Lihua Zhang, Yi Li, Hatice D. Saatcioglu, Nicholas Nagykery, Patricia K. Donahoe, David Sabatini, David Pépin. Whole-genome CRISPR/CAS9 screen using patient samples reveals JunB as a unique genetic liability [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A63.
A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity
Authors: Vincent Legros, Solène Denolly, Manon Vogrig, Bertrand Boson, Eglantine Siret, Josselin Rigaill, Sylvie Pillet, Florence Grattard, Sylvie Gonzalo, Paul Verhoeven, Omran Allatif, Philippe Berthelot, Carole Pélissier, Guillaume Thiery, Elisabeth Botelho-Nevers, Guillaume Millet, Jérôme Morel, Stéphane Paul, Thierry Walzer, François-Loïc Cosset, Thomas Bourlet, Bruno Pozzetto
Journal: Cellular and Molecular Immunology (2021)

Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and, thus, for public health policy and vaccine development for COVID-19. In this study, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections, including patients with mild symptoms and also more severe forms, including those that required intensive care. We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers; conversely, patients with milder disease symptoms had heterogeneous nAb titers, and asymptomatic or exclusive outpatient-care patients had no or low nAbs. We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses. Moreover, we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2. Finally, we found that the D614G mutation in the spike protein, which has recently been identified as the current major variant in Europe, does not allow neutralization escape. Altogether, our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease, and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.
Abstract PR07: Reprogramming the tumor microenvironment with losartan to enhance immunotherapy of ovarian cancer
Authors: Yao Sun, Wenjianlong Zhao, David R. Spriggs, Rakesh K. Jain, Lei Xu
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint blockers (ICBs) and chimeric antigen receptor (CAR)-T cells—which have revolutionized the treatment of multiple malignancies—have had limited efficacy in OvCa patients. This lack of efficacy is partly due to abnormal extracellular matrix (ECM) deposition leading to a buildup of compressive forces that induce vessel collapse, hypoperfusion, poor delivery of nutrients and drugs, and compromised trafficking of cytotoxic T cells to these tumors. The resulting tumor microenvironment (TME) is also hypoxic, acidic, and immunosuppressive. Our overarching hypothesis is that losartan, an FDA-approved antihypertensive drug that blocks angiotensin signaling, can overcome these challenges by normalizing the TME to enhance the delivery and efficacy of therapies in OvCa. Retrospective study showed that treatment with angiotensin blockers is associated with a 30-month overall survival benefit in OvCa patients. In our OvCa models, losartan reduced matrix content and reopened compressed vessels. As a result, blood perfusion increased, leading to enhanced drug delivery and improved chemotherapy efficacy. Losartan also relieved lymphatic vessel collapse in the diaphragm, which increased the drainage of peritoneal fluid and reduced ascites. Using unbiased RNASeq analysis, we found that in addition to normalizing the tumor matrix and vasculature, losartan treatment also activates immune response pathways. Furthermore, losartan increases the infiltration and function of immune effector cells and improves the outcome of immunotherapy using ICBs. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and immunotherapy in ovarian cancer patients. This abstract is also being presented as Poster B75. Citation Format: Yao Sun, Wenjianlong Zhao, David R. Spriggs, Rakesh K. Jain, Lei Xu. Reprogramming the tumor microenvironment with losartan to enhance immunotherapy of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR07.
The relationships of vitamin D, vitamin D receptor gene polymorphisms, and vitamin D supplementation with Parkinson’s disease
Authors: Lingling Lv, Xuling Tan, Xinke Peng, Rongrong Bai, Qile Xiao, Ting Zou, Jieqiong Tan, Hainan Zhang, Chunyu Wang
Journal: Translational Neurodegeneration (2020)

Abstract In recent years, many studies have investigated the correlations between Parkinson’s disease (PD) and vitamin D status, but the conclusion remains elusive. The present review focuses on the associations between PD and serum vitamin D levels by reviewing studies on the associations of PD with serum vitamin D levels and vitamin D receptor (VDR) gene polymorphisms from PubMed, Web of Science, Cochrane Library, and Embase databases. We found that PD patients have lower vitamin D levels than healthy controls and that the vitamin D concentrations are negatively correlated with PD risk and severity. Furthermore, higher vitamin D concentrations are linked to better cognitive function and mood in PD patients. Findings on the relationship between VDR gene polymorphisms and the risk of PD are inconsistent, but the FokI (C/T) polymorphism is significantly linked with PD. The occurrence of FokI (C/T) gene polymorphism may influence the risk, severity, and cognitive ability of PD patients, while also possibly influencing the effect of Vitamin D 3 supplementation in PD patients. In view of the neuroprotective effects of vitamin D and the close association between vitamin D and dopaminergic neurotransmission, interventional prospective studies on vitamin D supplementation in PD patients should be conducted in the future.
Roles of METTL3 in cancer: mechanisms and therapeutic targeting
Authors: Chengwu Zeng, Wanxu Huang, Yangqiu Li, Hengyou Weng
Journal: Journal of Hematology & Oncology (2020)

N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Accumulating evidence in recent years reveals that METTL3 plays key roles in a variety of cancer types, either dependent or independent on its m6A RNA methyltransferase activity. While the roles of m6A modifications in cancer have been extensively reviewed elsewhere, the critical functions of METTL3 in various types of cancer, as well as the potential targeting of METTL3 as cancer treatment, have not yet been highlighted. Here we summarize our current understanding both on the oncogenic and tumor-suppressive functions of METTL3, as well as the underlying molecular mechanisms. The well-documented protein structure of the METTL3/METTL14 heterodimer provides the basis for potential therapeutic targeting, which is also discussed in this review.
Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure
Authors: Natalie A. Mordi, Ify R. Mordi, Jagdeep S. Singh, Rory J. McCrimmon, Allan D. Struthers, Chim C. Lang
Journal: Circulation (2020)

SGLT2 (sodium-glucose cotransporter-2) inhibitors improve heart failure-associated outcomes in patients with type 2 diabetes. In patients with heart failure, SGLT2 inhibitors will likely be coprescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics.The RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) was a randomized, double-blind, placebo-controlled, crossover trial of patients with type 2 diabetes and heart failure with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline to week 6.Twenty-three participants (mean age, 69.8 years; 73.9% male; mean furosemide dose, 49.6±31.3 mg/d; mean HbA1c, 7.9±3.8%) were recruited. Compared with placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference, 535 mL [95% CI, 133-936]; P=0.005) and week 6 (mean difference, 545 mL [95% CI, 136-954]; P=0.005) after adjustment for treatment order, baseline 24-hour urine volume, and percentage change in loop diuretic dose. At 6 weeks, empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference, -7.85 mmol/L [95% CI, -2.43 to 6.73]; P=0.57). Empagliflozin caused a nonsignificant increase in fractional excretion of sodium at day 3, which was absent at week 6 (mean difference day 3, 0.30% [95% CI, -0.03 to 0.63]; P=0.09; week 6, 0.11% [95% CI, -0.22 to 0.44]; P>0.99), and a significant increase in electrolyte-free water clearance at week 6 (mean difference, 312 mL [95% CI, 26-598]; P=0.026) compared with placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6.Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03226457.
Abstract 1115: Patient-derived explant cultures (PDECs) as a model system for immuno-oncology studies
Authors: Rita Turpin, Pauliina Munne, Ilida Suleymanova, Satu Mustjoki, Jeroen Pouwels, Juha Klefström
Journal: Cancer Research (2020)

Abstract Despite the great promise of immunotherapy, only relatively few patients show long-term complete remission. In addition, immunotherapy is not effective against every cancer type. Cancer types with low mutational burden such as breast cancer (BCa), for example, are thought to not elicit an immune reaction and are therefore considered non-immunogenic. A major hurdle in the advancement of immunotherapy is the lack of preclinical models that faithfully preserve the tumor microenvironment and recapitulate human disease. We have developed a method to grow 3D cultures of intact fragments of patient-derived tissue (Patient-Derived Explant Cultures; PDECs), which has been used to assess the efficacy of novel treatment regimens on real human tumors (Haikala et al., Nature Comm. 2019; Tervonen et al., Oncogene 2016). PDECs offer many advantages over other cancer model systems; PDECs preserve the human tumor microenvironment, reflect inter- and intra-patient tumor heterogeneity and results are obtained within one week. Up to 16 experimental samples can be obtained from one clinical sample, allowing the same ‘patient' to be experimentally treated with different drug regimens and/or measurement of more than one endpoint.To assess whether PDECs are also a suitable model for IO studies we performed immunoprofiling experiments using FACS, RT-PCR, cytokine profiling and immunofluorescence, showing that the immune-contexture, i.e. the number and activation status of different immune cell types, is similar in PDECs than in the primary tumor they were derived from. Subsequently, we addressed whether the resident immune cells in PDECs were functional. Preliminary data showed that direct T cell activation in PDECs led to apoptosis of cancer cells and invoked a complex immune response, as assessed using cytokine profiling and FACS. Treatment with the immune checkpoint inhibitor anti-PD-1 had more moderate effects. These data reflect the clinical reality where very few BCa patients respond to immune checkpoint monotherapy, but also show that T cells in BCa can be activated to kill the cancer cells, suggesting that with the right treatment strategies, BCa can be targeted with immunotherapy. All in all, our data show that the tumor's immunocontexture is conserved in PDECs and that resident immune cells in PDECs can be activated to attack cancer cells, and thus support the use of PDECs as an ex vivo model system to study immuno-oncology in real human cancers for the development of the immunotherapies of tomorrow. Citation Format: Rita Turpin, Pauliina Munne, Ilida Suleymanova, Satu Mustjoki, Jeroen Pouwels, Juha Klefström. Patient-derived explant cultures (PDECs) as a model system for immuno-oncology studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1115.
Biochemical reprogramming of tumors for active modulation of receptor-mediated nanomaterial delivery
Authors: Seungbeom Ko, Jinwon Park, Yeon Lee, Da Woon Lee, Robert B. Macgregor, Yu-Kyoung Oh
Journal: Biomaterials (2020)

Here we report that reactive oxygen species (ROS) can reprogram cancer cells to increase the expression of specific receptors and modulate the delivery of nanomaterials. Gold and γ-polyglutamic acid (γ-PGA) hybrid nanoparticles (PGANP) were prepared via a facile single-step process. Gold nanoclusters in PGANP were dispersed within the tangled γ-PGA matrix of the nanoparticles. The condensed assembly of gold nanoclusters in γ-PGA matrix enabled the interparticle plasmon coupling effect, which lacks in single gold nanoparticles. Compared with gold nanoparticles of the similar sizes, PGANP showed significantly higher absorbance at near infrared (NIR) wavelength and light-to-heat converting ratios, resulting in greater temperature increase upon NIR light irradiation. Pretreatment of HeLa cancer cells with methylene blue (MB) generated reactive oxygen species. The ROS reprogrammed the cancer cells to express higher cell membrane levels of gamma glutamyl transferase (GGT), which is known to bind to γ-PGA of PGANP. MB pretreatment significantly enhanced delivery of PGANP to cancer cells. Cancer cells internalized PGANP to a greater extent and, were highly susceptible to irradiation with NIR light, which reduced cell viability to near zero. In vivo, MB pretreatment of HeLa xenograft mice increased the expression of GGT in tumor tissues. In mice pretreated with MB and exposed to NIR irradiation, PGANP treatment resulted in complete tumor ablation. The strategy of actively reprogramming tumor membrane levels of target receptors could be widely applied to overcome the heterogeneity of cancer cells. Although we used interparticle plasmon coupling effect-based PGANP for proving the concept of receptor-modulated delivery, this strategy could be broadly applicable to the active modulation of the receptor-mediated delivery of anticancer nanomaterials.
High-Flow Aerosol-Dispersing versus Aerosol-Generating Procedures
Authors: Jie Li, Stephan Ehrmann
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Here, the authors examine the effect of high-flow aerosol-dispersing versus aerosol-generating procedures  Hypoxemia is the main symptom and primary reason for hospital admission among patients with coronavirus disease (COVID-19), and oxygen therapy is the mainstay therapy to treat hypoxemia  Among 10,054 patients with COVID-19 admitted to ICUs in the United Kingdom during the pandemic, more than 70% required advanced respiratory support, including high-flow nasal cannula (HFNC) oxygen therapy, noninvasive (NIV) and invasive ventilation, and extracorporeal membrane oxygenation  HFNC and NIV have been categorized as aerosol-generating procedures, based on the hypothesis that high-velocity gas flows may promote aerosolization of patients' secretions containing viable virus, which may then be dispersed in the environment and be inhaled by healthcare workers  Indeed, retrospective studies assessing risk factors of nosocomial transmission of the severe acute respiratory syndrome (SARS) observed that healthcare workers caring for patients with SARS treated by NIV had a twofold higher risk of infection transmission than those who did not  Furthermore, Gaeckle and colleagues provide evidence that the difference of the aerosol particle concentrations generated by various oxygenation devices is clinically insignificant and probably negligible, compared with the intersubject variability of patient-generated bioaerosols
Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer
Authors: Johann Gout, Lukas Perkhofer, Mareen Morawe, Frank Arnold, Michaela Ihle, Stephanie Biber, Sebastian Lange, Elodie Roger, Johann M Kraus, Katja Stifter, Stephan A Hahn, Andrea Zamperone, Thomas Engleitner, Martin Müller, Karolin Walter, Eva Rodriguez-Aznar, Bruno Sainz Jr, Patrick C Hermann, Elisabeth Hessmann, Sebastian Müller, Ninel Azoitei, André Lechel, Stefan Liebau, Martin Wagner, Diane M Simeone, Hans A Kestler, Thomas Seufferlein, Lisa Wiesmüller, Roland Rad, Pierre-Olivier Frappart, Alexander Kleger
Journal: Gut (2020)

(ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).