tbuckley/cabot-search huggingface dataset:
Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells
Authors: Kristen W. Cohen, Susanne L. Linderman, Zoe Moodie, Julie Czartoski, Lilin Lai, Grace Mantus, Carson Norwood, Lindsay E. Nyhoff, Venkata Viswanadh Edara, Katharine Floyd, Stephen C. De Rosa, Hasan Ahmed, Rachael Whaley, Shivan N. Patel, Brittany Prigmore, Maria P. Lemos, Carl W. Davis, Sarah Furth, James B. O’Keefe, Mohini P. Gharpure, Sivaram Gunisetty, Kathy Stephens, Rustom Antia, Veronika I. Zarnitsyna, David S. Stephens, Srilatha Edupuganti, Nadine Rouphael, Evan J. Anderson, Aneesh K. Mehta, Jens Wrammert, Mehul S. Suthar, Rafi Ahmed, M. Juliana McElrath
Journal: Cell Reports Medicine (2021)

Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.
Estimating recurrence free survivability of Non-Muscle Invasive Bladder Cancer (NMIBC) after intravesical therapy: A clinical-based recursive partition analysis
Authors: N. Corsi, A Sood, J. Keeley, D. Dalela, C. Bronkema, N. Rakic, M. Stricker, G. Novara, C. Rogers, F. Abdollah
Journal: European Urology (2021)
Be-RALP study: The effect of adjuvant treatment on quality of life, erectile function and continence
Authors: W. Devlies, G. Silversmit, G. De Coster, N. Van Damme, L. Van Eycken, T. Roumeguère, T. Quackels, B. Van Cleynenbreugel, P. Dekuyper, F. Ameye, W. Everaerts, S. Joniau
Journal: European Urology (2021)
TRIB3‒GSK-3β interaction promotes lung fibrosis and serves as a potential therapeutic target
Authors: Shanshan Liu, Xiaoxi Lv, Xupeng Wei, Chang Liu, Qiao Li, Jiali Min, Fang Hua, Xiaowei Zhang, Ke Li, Pingping Li, Yang Xiao, Zhuowei Hu, Bing Cui
Journal: Acta Pharmaceutica Sinica B (2021)

Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3β (GSK-3β) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) in alveolar macrophages (AMs), resulting in a profibrotic phenotype of AMs and promoting the development of PF. Here, we showed that chronic lung injury upregulated the stress response protein tribbles homolog 3 (TRIB3), which interacted with GSK-3β and stabilized GSK-3β from ubiquitination and degradation. Elevated GSK-3β expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBPβ and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBPβ, in turn, increased the transcription of TRIB3 and GSK-3β, thereby establishing a positive feedback loop in AMs. The knockdown of TRIB3 expression or the pharmacologic disruption of the TRIB3‒GSK-3β interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3‒GSK-3β‒A20‒C/EBPβ in AMs, which represents a target that may provide a promising treatment strategy for PF.
Abstract 1054: Patient derived organoids demonstrate synergistic antitumor effect of senogenic and senolytic drug combination of Aurora kinase inhibitor and BCL2/xL inhibitor
Authors: Vijaya Bharti, Vivian Weiss, Chengli Shen, Sheau Chiann Chen, Ashlyn Blevins, Rebecca L. Shattuck-Brandt, Ann Richmond, Anna E. Vilgelm
Journal: Cancer Research (2021)

Abstract The management of metastatic melanoma continues to be challenging, despite of evolving treatments such as immune checkpoint blockade and inhibitors of mutated BRAF. New therapies that work via immune and BRAF-independent mechanisms are urgently required for tumors that are unresponsive to currently available treatments. Here we hypothesized that combination of Aurora Kinase inhibitor (AURKAi) alisertib (senescence inducer) with a drug that selectively kills senescent cells, such as BCL2/xL inhibitor (BCLi) navitoclax (senolytic), will induce apoptosis in melanoma cells. Patient derived organoids (PDOs) were used to test anti- tumor effect of AURKAi and BCLi combination treatment. H&amp;E staining of PDOs and their matched original tumors revealed similar histology. Fourteen out of ninety PDOs were highly sensitive to AURKAi and BCLi combination treatment exhibiting robust induction of cell death. NextGen DNA sequencing indicated that all sensitive PDOs retained wild type TP53, while resistant tumors had mutations in this gene. Knockout or knockdown of TP53 abrogated AURKAi and BCLi-induced cell death in melanoma cells, suggesting that transcription factor p53 encoded by TP53 is a key mediator of drug response. Addition of BCLi to AURKAi activated proapoptotic p53 targets BAX, NOXA and induced cleavage of PARP and Caspases 3, 7, and 8. Electron microscopy revealed morphological signs of apoptosis in combination-treated cells, including cell blebbing, apoptotic bodies, and nuclear fragmentation. This suggests that BCLi shifts cell fate decision in AURKAi-treated cells towards apoptosis. In conclusion, combination treatment with AURKAi and BCl2i induced p53-dependent apoptosis. Preclinical evaluation of this drug combination in PDO model demonstrated robust efficacy against melanomas with wild type p53. Since p53 mutations are relatively rare in melanoma, combination of AURKAi and BCLi presents promising therapeutic option for this deadly disease. Keywords: Apoptosis, melanoma, patient-derived organoids, aurora kinase, bcl-2 Citation Format: Vijaya Bharti, Vivian Weiss, Chengli Shen, Sheau Chiann Chen, Ashlyn Blevins, Rebecca L. Shattuck-Brandt, Ann Richmond, Anna E. Vilgelm. Patient derived organoids demonstrate synergistic antitumor effect of senogenic and senolytic drug combination of Aurora kinase inhibitor and BCL2/xL inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1054.
Abstract 1703: Development of NAV-005, a humoral immuno-suppressor antagonist for the treatment of CA125-expressing cancers
Authors: Nicholas C. Nicolaides, Brad Kline, Luigi Grasso
Journal: Cancer Research (2021)

Abstract Tumors employ a variety of mechanisms to avoid host cellular and humoral immune responses. Recent findings have found that the tumor-produced MUC16/CA125 protein elicits humoral immunosuppressive effects on antibody-mediated tumor cell killing. This effect is facilitated via direct binding to SIGLEC regulatory receptors on natural killer (NK) cells as well as through direct binding to therapeutic antibodies that blocks Fc-γ-receptor and C1q antibody engagement, leading to suppressed antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) activities, respectively. We have engineered a human IgG1 Fc fusion protein, called NAV-005, that binds to CA125 with high affinity and blocks its binding to SIGLEC receptors and affected antibodies, thus enabling efficient humoral immune mediated tumor cell killing. NAV-005 is being developed as a novel therapeutic agent to treat humoral immuno-suppressed CA125 expressing cancers. Citation Format: Nicholas C. Nicolaides, Brad Kline, Luigi Grasso. Development of NAV-005, a humoral immuno-suppressor antagonist for the treatment of CA125-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1703.
Abstract 106: Assessing the impact of staggered light exposure on breast cancer risk and metabolism
Authors: Lauren Palluth, Brittany Harlow, Bryan McCellan, Christopher Jolly, Molly Bray, Linda deGraffenried
Journal: Cancer Research (2021)

Abstract Background: Numerous epidemiological studies, including the Nurses' Health Study II, found that shift workers have a higher risk for breast cancer. These studies hypothesize that suppressed melatonin and disrupted clock gene expression likely lead to an immune compromised, proliferative phenotype. However, the majority of studies to date rely on correlative evidence. With the onset of the COVID-19 pandemic, shift work has become increasingly prevalent, making the need to understand the mechanisms promoting disease, including breast cancer, even more important. Objective: The objective of this study is to analyze the impact of staggered light exposure on the immune function and breast tissue gene expression in order to identify how breast cancer risk is mediated. Methods: An 18-week study with 10 C57BL/6 female mice was conducted whereby half of the mice were exposed to a staggered light/dark (LD) cycle, as would be experienced by shift workers, and half were exposed to a regular LD cycle. Body weight was monitored weekly and sera and mammary tissues were collected at termination. The sera from each group was pooled and cytokine levels assessed using an antibody-pair-based assay. Results: Intriguingly, although the mice from the two study groups did not significantly differ in average body weight, the staggered LD exposure group had higher levels of inflammatory cytokines indicative of chronic, low-grade inflammation. Notably, the staggered LD group had 75% higher IL-6 levels, 157% higher IL-10 levels, and 49% higher TNF-alpha levels compared to the control group. To determine the impact of staggered light exposure on localized breast tissue gene expression, qPCR arrays of breast cancer risk and inflammatory genes will be done comparing expression levels between the control and staggered LD groups. IHC techniques will be used to determine Ki67 and macrophage subtype infiltration in the breast tissue of the two groups. Conclusion: Our data show that staggered LD exposure induces chronic, low-grade inflammation independent from body mass, which can be indicative of increased breast cancer risk. These data help elucidate the metabolic and immune responses induced by staggered light exposure, helping to define the mechanisms promoting health risks imposed by shift work, with the ultimate goal to develop preventive measures to limit breast cancer development. Citation Format: Lauren Palluth, Brittany Harlow, Bryan McCellan, Christopher Jolly, Molly Bray, Linda deGraffenried. Assessing the impact of staggered light exposure on breast cancer risk and metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 106.
Abstract 735: hPG80 (circulating progastrin), a novel blood-based biomarker for detection of poorly differentiated neuroendocrine carcinoma and well differentiated neuroendocrine tumors
Authors: Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Thierry Cousin, Lea Payen, Younes Mahi, Madison Sanders, B. Mark Evers, Dominique Joubert, Lowell Anthony
Journal: Cancer Research (2021)

Abstract Background: Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. This is especially true for high-grade NENs (small and large cell neuroendocrine carcinomas). Human circulating progastrin (hPG80) is a novel biomarker for NENs and is easily measured in plasma using an ELISA test. This study is the first to explore hPG80 in NENs. Methods: Progastrin concentrations were quantified in plasma from 95 patients with stage IV NEN using DxPG80 technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in 50-80-year-old healthy donors (n=252) as well as a subgroup comprised of only the 18-25-year-olds (n=137). Results: The median hPG80 in NENs patients was 5.54 pM as compared to 1.5 pM for patients in the 50-80-year-old control group and 0.29 pM for patients in the 18-25-year-old cohort (p&amp;lt;0.0001, one-tailed Mann-Whitney U-test). A subgroup analysis of NENs revealed a median hPG80 of 3.54 pM in neuroendocrine carcinoma (NEC n=25) vs 5.8 pM in neuroendocrine tumor (NET n=70). Interestingly small cell lung cancer sub cohort (n=13) also showed significant elevation of hPG80 (9.09 pM). All the above-mentioned differences were statistically significant as compared to healthy controls. Conclusions: Plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood biomarker for both low- and high-grade NENs and further study is warranted. A prospective trial is ongoing in small cell lung cancer to evaluate its role in monitoring of disease (NCT03958045) and further prospective studies in low-grade neuroendocrine tumors are underway. Citation Format: Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Thierry Cousin, Lea Payen, Younes Mahi, Madison Sanders, B. Mark Evers, Dominique Joubert, Lowell Anthony. hPG80 (circulating progastrin), a novel blood-based biomarker for detection of poorly differentiated neuroendocrine carcinoma and well differentiated neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 735.
免疫抑制療法(IST)又は骨髄移植(BMT)での治療を受けた重篤な無形成性貧血(SAA)小児患者100名の長期的結果の比較
Authors: Kojima S, Yoshimi A, Inaba J, Horibe K, Kudo K, Maeda N, Kato K, Matsuyama T
Journal: Blood (1999)
Abstract 2472: Effective ER antagonists resist conformational restrictions imposed by somatic mutation but do not correlate with effects on receptor stability in live cells
Authors: David Hosfield, Nan-Sheng Li, Ross Han, Muriel Laine, Sandra Weber, Madaline Sauvage, Sylvie Madar, Geoffrey Greene, Sean Fanning
Journal: Cancer Research (2021)

Abstract Approximately 50% of luminal breast cancer patients become resistant to first-line endocrine therapies after an average of 5 years. Acquired activating mutations to the ESR1 ligand binding domain enable hormone therapy resistance in approximately 25-40% of these patients. Competitive estrogen antagonists function by maintaining the receptor in a transcriptionally inactive state by forcing estrogen receptor alpha ligand binding domain (ERα LBD) helix 12 into the AF-2 cleft to prevent the docking of LXXLL-containing transcriptional coactivators. Multiple next-generation ERα antagonists that function as molecular degraders of the receptor have been described and shown activity in breast cancers harboring the activating ESR1 mutations. To understand whether ERα antagonism correlates with receptor stability, we examined a comprehensive panel of structurally diverse antagonists in live breast cancer cell assays using WT, Y537S, and D538G-mutant receptors. We found that potent antagonists are able to both stabilize and degrade the receptor and further demonstrate that the D538G mutation reduces turnover with ICI due to specific defects in receptor ubiquitination and SUMOylation. High resolution x-ray crystal structures of WT and Y537S ERα LBD in complex with stabilizing and degrading antiestrogens suggest that modulators that enforce the classical antagonist-like helix 12 conformation in the mutant receptor achieve the greatest activity in transcriptional assays, regardless of their effects on receptor stability Citation Format: David Hosfield, Nan-Sheng Li, Ross Han, Muriel Laine, Sandra Weber, Madaline Sauvage, Sylvie Madar, Geoffrey Greene, Sean Fanning. Effective ER antagonists resist conformational restrictions imposed by somatic mutation but do not correlate with effects on receptor stability in live cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2472.
Abstract 1999: DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas
Authors: Gamze Bildik, Joshua P. Gray, Weiqun Mao, Robert C. Bast, Zhen Lu
Journal: Cancer Research (2021)

Abstract Mutant KRAS drives human cancers from several sites, including pancreatic ductal adenocarcinoma (PDAC) and low-grade serous ovarian cancer (LGSOC). Despite the prevalence of RAS mutations in many different cancers, effective RAS-targeted treatment remains a challenge. More than 90% of PDACs are driven by mutant KRAS. Genetic suppression of KRAS or pharmacological inhibition of its effectors, ERK/MAPK, enhances the reliance of PDAC on autophagy that can provide a target for treatment. DIRAS3 (ARHI) is an imprinted tumor suppressor gene that is downregulated in pancreatic and ovarian cancers. When re-expressed, DIRAS3 blocks cancer cell proliferation, inhibits motility, and induces autophagy by multiple mechanisms. DIRAS3 inhibits RAS signaling by heterodimerizing directly with KRAS, inhibiting homodimerization of KRAS and disrupting KRAS nanoclustering. In this study, we tested whether inhibiting RAS signaling by re-expressing DIRAS3 would sensitize RAS-driven cancers to autophagy inhibition. Re-expression of DIRAS3 decreased phosphorylation of Erk1/2 (pThr202/Tyr204), inhibiting the RAF-MEK-ERK signaling pathway. Re-expression of DIRAS3 induced autophagic flux indicated by an increased LC3-mCherry/eGFP ratio. DIRAS3 re-expression decreased LKB1 (pS428) and increased AMPK (pT172) and ULK1 (pS555), suggesting that induction of autophagic flux may be partly mediated by the activation of the energy-sensing LKB1-AMPK1-ULK1 axis following suppression of upstream RAF-MEK-ERK signaling. In addition, we confirmed that DIRAS3-induced autophagy enhanced the sensitivity of cancer cells to autophagy inhibition as evidenced by decreasing the IC50 of both chloroquine (CQ) and di-chloroquine (DC661) in human KRAS-driven PDAC and LGSOC. The greater potency of DC661, blocking autophagy with an IC50 in the low nanomolar range, should prove more effective for combinatorial therapies in vivo. Citation Format: Gamze Bildik, Joshua P. Gray, Weiqun Mao, Robert C. Bast, Zhen Lu. DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1999.
Assessing the relationship between micro-ultrasound results and pathology at radical prostatectomy
Authors: P.P. Avolio, D. Maffei, M. Paciotti, N. Frego, P. Diana, V. Fasulo, A. Uleri, R. Contieri, P. Casale, R. Hurle, M. Lazzeri, N.M. Buffi, A. Saita, G. Lughezzani
Journal: European Urology (2021)
Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in COVID-19
Authors: Duco Steven Koenis, Issa Beegun, Charlotte Camille Jouvene, Gabriel Amador Aguirre, Patricia Regina Souza, Maria Gonzalez-Nunez, Lucy Ly, Kimberly Pistorius, Hemant M. Kocher, William Ricketts, Gavin Thomas, Mauro Perretti, Ghassan Alusi, Paul Pfeffer, Jesmond Dalli
Journal: Circulation Research (2021)

Rationale: Resolution mechanisms are central in both the maintenance of homeostasis and the return to catabasis following tissue injury and infections. Among the proresolving mediators, the essential fatty acid-derived specialized proresolving lipid mediators (SPM) govern immune responses to limit disease severity. Notably, little is known about the relationship between the expression and activity of SPM pathways, circulating phagocyte function and disease severity in patients infected with the novel severe acute respiratory syndrome coronavirus 2 leading to coronavirus disease 2019 (COVID-19). Objective: Herein, we investigated the link between circulating SPM concentrations and phagocyte activation status and function in patients with COVID-19 (n=39) compared with healthy (n=12) and post-COVID-19 (n=8) volunteers. Methods and Results: Lipid mediator profiling demonstrated that plasma SPM concentrations were upregulated in patients with mild COVID-19 and are downregulated in those with severe disease. SPM concentrations were correlated with both circulating phagocyte activation status and function. Perturbations in plasma SPM concentrations and phagocyte activation were retained after the resolution of COVID-19 clinical symptoms. Treatment of patients with dexamethasone upregulated both the expression of SPM biosynthetic enzymes in circulating phagocytes and plasma concentration of these mediators. Notably, incubation of phagocytes from patients with COVID-19 with SPM rectified their phenotype and function. This included a downregulation in the expression of activation markers, a decrease in the tissue factor and inflammatory cytokine expression, and an upregulation of bacterial phagocytosis. Conclusions: The present findings suggest that downregulation of systemic SPM concentrations is linked with both increased disease severity and dysregulated phagocyte function. They also identify the upregulation of these mediators by dexamethasone as a potential host protective mechanism elicited by this drug in patients with COVID-19. Taken together, our findings elucidate a role for altered resolution mechanisms in the disruption of phagocyte responses and the propagation of systemic inflammation in COVID-19.
Abstract 1323: Novel autophagy inhibitor to treat pancreatic cancer
Authors: Mythili Ramachandran, Zhao Ma, Yuanpei Li
Journal: Cancer Research (2021)

Abstract In this study, we develop a novel autophagy inhibitor targeting one of the most aggressive cell populations present in pancreatic tumors, the pancreatic cancer stem cell (CSC). Targeting this population which has the malignant properties of tumorigenesis/tumor recurrence, the ability to differentiate into a heterogenous tumor cell types and can self-renew is a new strategy to alleviate the current dismal 10% five-year survival rate of pancreatic cancer. Here we characterize an autophagy inhibitor which is a first-in-class nanoparticle comprised of a chloroquine-derived small molecule drug that can self-assemble into a micelle. Due to its favorable pharmacokinetic properties and the CSC reliance on autophagy, our compound is able to selectively target this cell population both in vitro and in vivo. Additionally, the compound has shown synergy with the current standard of care chemotherapeutic, gemcitabine, with an 88.9% reduction in tumor volume in the combination of the two drugs compared to gemcitabine treated alone (p&amp;lt;0.0001) in two separate treatment regimens using a pancreatic PDX mouse model. We further illustrate that the stem cell population is targeted by inhibiting tumorsphere formation in established pancreatic cancer cell lines MIA-PaCa2 and PANC-1 and in pancreatic PDX-derived CSCs in vitro. The drug treatment also promotes a decrease in pluripotency markers, particularly in Sox2 levels. Finally, the drug is well-tolerated with a maximum tolerated dose above 100 mg/kg in mice and is orally bioavailable. Citation Format: Mythili Ramachandran, Zhao Ma, Yuanpei Li. Novel autophagy inhibitor to treat pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1323.