tbuckley/cabot-search huggingface dataset:
In vivo screens using a selective CRISPR antigen removal lentiviral vector system reveal immune dependencies in renal cell carcinoma
Authors: Juan Dubrot, Sarah Kate Lane-Reticker, Emily A. Kessler, Austin Ayer, Gargi Mishra, Clara H. Wolfe, Margaret D. Zimmer, Peter P. Du, Animesh Mahapatra, Kyle M. Ockerman, Thomas G.R. Davis, Ian C. Kohnle, Hans W. Pope, Peter M. Allen, Kira E. Olander, Arvin Iracheta-Vellve, John G. Doench, W. Nicholas Haining, Kathleen B. Yates, Robert T. Manguso
Journal: Immunity (2021)
A clinical score (CS) for patients with well-differentiated neuroendocrine tumors (WD NETs) under consideration for peptide receptor radionuclide therapy (PRRT) with Lu 177-dotatate.
Authors: Satya Das, Liping Du, Aimee Schad, Shikha Jain, Aaron Jessop, Chirayu Shah, David Eisner, Dana Backlund Cardin, Kristen Keon Ciombor, Laura Williams Goff, Marques Bradshaw, Dominique Delbeke, Martin P. Sandler, Jordan Berlin
Journal: Journal of Clinical Oncology (2021)

363 Background: Despite the benefit of PRRT for patients with WD NETs, questions remain regarding sequencing and optimal patient selection for the treatment. We developed a CS at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with WD NETs receiving PRRT. Methods: Patients with progressive WD NETs (N = 146) under consideration for PRRT with Lu 177-dotatate between 3/1/2016-3/17/2020 at VICC (N = 122) and Rush Medical Center (RMC) (N = 24) were scored. The CS included 5 categories: available non-PRRT treatments for tumor type, prior systemic treatments, patient symptoms, tumor burden in critical organs and peritoneal carcinomatosis presence. All categories were scored from 0-2 except the peritoneal carcinomatosis category which was scored from 0-1; scoring criteria were determined by the VICC NET tumor board. All patients at VICC were prospectively scored, while patients from RMC were scored retrospectively with the investigator blinded to patient outcomes. The primary outcome, progression-free survival (PFS) was estimated by the Kaplan‐Meier method; a Cox proportional‐hazards model adjusting primary tumor site, tumor grade and number of PRRT doses administered (none, 1-2 doses or 3-4 doses) was used to analyze effect of CS. Results: Median patient age was 62.7 while median CS was 5 (range 1-8); the most common primary tumor sites were small intestinal (N = 81) and pancreatic (N = 37). A total of 101 patients and 31 patients received 3-4 doses and no doses of PRRT, respectively. On multivariable analysis, in patients treated with 3-4 doses of PRRT, for each 2-point increase in CS, the estimated hazard ratio (HR) for PFS was 3.26 (95% confidence interval (CI) 2.05-5.19). On multivariable analysis, in patients who received no doses of PRRT, for each 2-point increase in CS, the estimated HR for PFS was 1.37 (95% CI .78-2.41). Conclusions: Among patients treated with 3-4 doses PRRT, those with lower CS had better PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive PRRT, suggesting the predictive utility of the CS for patients with WD NETs receiving PRRT with Lu 177-dotatate. Though the CS needs to be validated, it is the first of its kind reported.
Impact of<i> KRAS</i> alterations in localized pancreatic cancer (PC).
Authors: Aditya Varnam Shreenivas, Kaitlin Annunzio, Mandana Kamgar, Sakti Chakrabarti, James P. Thomas, Srivats Madhavan, Kulwinder Dua, Abdul H. Khan, William Adrian Hall, Beth Erickson, Kathleen K. Christians, Callisia Clarke, Douglas B. Evans, Susan Tsai, Aniko Szabo, Raul Urrutia, Michael T Zimmermann, Honey V Reddi, Ben George
Journal: Journal of Clinical Oncology (2021)

431 Background: Patients (pts) with localized PC do not routinely undergo comprehensive genomic profiling (CGP) unless they develop recurrent or metastatic disease. KRAS is the most frequently mutated gene in PC, however, the impact of different KRAS mutations in localized PC has not been well characterized. We interrogated our genomic database to analyze the KRAS status in PC pts who presented with localized disease at diagnosis (Dx). Methods: We identified PC pts at our institution who underwent CGP utilizing the Foundation One CDx assay and had localized disease at initial Dx; these pts were categorized into resectable/borderline resectable PC (LPC) and locally advanced PC (LAPC). All pts with LPC and LAPC underwent neoadjuvant chemotherapy and chemoradiation prior to possible surgery (all intended therapy - AIT). Tissue from metastatic sites was used for CGP in pts who developed recurrent/metastatic disease before or after completion of AIT. The primary tumor was used for CGP in pts who completed AIT without subsequent relapse or in the absence of adequate metastatic tissue. Effect of each gene on response and survival outcomes was estimated using proportional odds and Cox regression analysis, respectively, adjusting for stage. Results: 75 pts were identified, median age at Dx was 65 years, 59% were male, 65% had a primary tumor in the pancreatic head. 38 (86%) pts with LPC completed AIT compared to 21 (68%) pts with LAPC (p&lt;0.001). KRAS mutation was detected in 95% (71/75) of pts– 94% (67/71) in codon 12 and 6% (4/71) in codon 61. The various KRAS mutations and their association with completion of AIT is summarized in the table. The likelihood of completing AIT did not differ based on KRAS wildtype (WT) vs mutated status (p =1.00), the mutated codon (codon 12 vs. codon 61; p =1.00) or the individual KRAS point mutations (p = 0.7); however, all patients with G12A (N= 1), G12C (N=1), G12L (N=1) and G12R (N=11) mutations completed AIT. KRAS status (mutated vs. WT) and the individual KRAS mutations were not associated with overall survival (OS) after adjusting for stage (p= 0.13 and p = 0.26 respectively). Median OS for patients with LPC and LAPC, was 39 months (mos) and 29 mos respectively. Conclusions: KRAS status and individual KRAS mutations did not have an impact on completing AIT or mOS; however, these findings need to be interpreted with caution due to the inherent biases involved in such analyses. The clinical significance and functional relevance of KRAS G12A, G12C, G12L and G12R mutations, though relatively rare, needs further characterization as well as mechanistic elucidation. [Table: see text]
Dissecting novel mechanisms of hepatitis B virus-related hepatocellular carcinoma using meta-analysis of public data.
Authors: Jihad Aljabban, Michael Rohr, Saad A Syed, Eli Cohen, Naima Hashi, Sharjeel Syed, Kamal Khorfan, Emmanuel Boateng, Mary Nemer, Maryam Panahiazar, Dexter Hadley, Sajid Jalil, Khalid Mumtaz, Hisham Aljabban
Journal: Journal of Clinical Oncology (2021)

333 Background: Hepatitis B is a cause of hepatocellular carcinoma (HCC) globally, irrespective of viral loads. Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation, and has implications in early diagnosis and treatment. Methods: We employed our Search, Tag, Analyze, Resource (STARGEO) platform to conduct a meta-analysis of public data from NCBI's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples. We present the results from the meta-analysis in Ingenuity Pathway Analysis. Results:Our analysis revealed LXR/RXR activation, LPS-IL-1 mediation inhibition of RXR, and FXR/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene RABL6. The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. Additionally, HOXA10 was a top upstream regulator and was strongly upregulated in our analysis. While described in other cancer, HOXA10 has not been well documented in HBV-related HCC and our causal analysis suggests it mediates pathogenesis through downregulation of tumor suppressors and its protective effect from oxidative stress. Conclusions: This meta-analysis describes possible role of viral regulatory proteins such as RABL6 and HOXA10 in the pathogenesis of HBV -related HCC. Further prospective studies are needed to confirm our findings.
Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment
Authors: Hui Qin Wang, Iain J. Mulford, Fiona Sharp, Jinsheng Liang, Sema Kurtulus, Gina Trabucco, David S. Quinn, Tyler A. Longmire, Nidhi Patel, Roshani Patil, Matthew D. Shirley, Yan Chen, Hao Wang, David A. Ruddy, Claire Fabre, Juliet A. Williams, Peter S. Hammerman, Jennifer Mataraza, Barbara Platzer, Ensar Halilovic
Journal: Cancer Research (2021)

Abstract p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell-cycle arrest or induction of apoptosis. However, the effects of p53 in antitumor immunity are poorly understood. To investigate the role of p53 in controlling tumor-immune cell cross-talk, we studied murine syngeneic models treated with HDM201, a potent and selective second-generation MDM2 inhibitor. In response to HDM201 treatment, the percentage of dendritic cells increased, including the CD103+ antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet+Eomes+ CD8+ T cells and the CD8+/Treg ratio within the tumor. These immunophenotypic changes were eliminated with the knockout of p53 in tumor cells. Enhanced expression of CD80 on tumor cells was observed in vitro and in vivo, which coincided with T-cell–mediated tumor cell killing. Combining HDM201 with PD-1 or PD-L1 blockade increased the number of complete tumor regressions. Responding mice developed durable, antigen-specific memory T cells and rejected subsequent tumor implantation. Importantly, antitumor activity of HDM201 in combination with PD-1/PD-L1 blockade was abrogated in p53-mutated and knockout syngeneic tumor models, indicating the effect of HDM201 on the tumor is required for triggering antitumor immunity. Taken together, these results demonstrate that MDM2 inhibition triggers adaptive immunity, which is further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in patients with wild-type p53 tumors. Significance: This study provides a mechanistic rationale for combining checkpoint blockade immunotherapy with MDM2 inhibitors in patients with wild-type p53 tumors.
Economic Evaluation of Pharmaco- and Behavioral Therapies for Smoking Cessation: A Critical and Systematic Review of Empirical Research
Authors: Jennifer Prah Ruger, Christina M. Lazar
Journal: Annual Review of Public Health (2012)

Economic evaluations are an important tool to improve our understanding of the costs and effects of health care services and to create sustainable health care systems. This article critically assesses empirical evidence from economic evaluations of pharmaco- and behavioral therapies for smoking cessation. A comprehensive literature review of PubMed and the British National Health Service Economic Evaluation Database was conducted. The search identified 15 articles on nicotine-based pharmacotherapies, 12 articles on nonnicotine based pharmacotherapies, no articles on selegiline, and 10 articles on brief counseling for smoking cessation treatment. Results show that both pharmaco- and behavioral therapies for smoking cessation are cost-effective or even cost-saving. The review highlights several shortcomings in methodology and a lack of standardization of current economic evaluations. Efforts to improve methodology will help make future studies more comparable and increase the evidence base so that such evaluations can be more useful to public health practitioners and policy makers.
AB0046 Prevalence of tuberculosis infection in rheumatoid arthritis patients treated by corticosteroid pulse therapy
Authors: C Di Girolamo, MG Ferrucci, N Pappone, C Crisci
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Several pathogens have been previously reported in rheumatoid arthritis (RA) patients treated by corticosteroid pulse therapy (CPT)<sup>1–3</sup> and we recently described a case of upper lobe cavitary tuberculosis in a patient with RA under CPT associated to methotrexate.<sup>4</sup> <h3>Objectives</h3> In order to establish the prevalence of tuberculosis infection in RA patients undergoing CPT, we analysed medical charts of consecutive patients affected by these disease who underwent this regimen. <h3>Methods</h3> All the records were from patients attending the clinic for at least 2 years since the CPT administration and were analysed in order to detect a clinical diagnosis of tuberculosis. Routine blood analysis and a Chest x-ray film was available for all the patients in the period established for the follow-up, even if asymptomatic. At present, 11 females (mean age 57.54 years, range 40–74) have been identified, who took 1 gr of Methyilprednisolone i.v. daily in a 3-day course of CPT. One of them was taking methotrexate, 3 cyclosporin and 4 the combination of cyclosporin and methotrexate; 3 patients was under no DMARD. CPT was already administered in 3 patients no more than once in the previous year. <h3>Results</h3> Two patients revealed a tuberculosis infection, characterised by cavitary lung involvement and meningitis respectively; diagnosis was confirmed by standard methods for tuberculosis in both the patients. One patient affected by tuberculosis belonged to the treatment group CPT + methotrexate, while the other suspended methotrexate less than one year before the administration of CPT. <h3>Conclusion</h3> This finding underlines the necessity of close monitoring for severe opportunistic infections in rheumatoid patients during treatment with CPT and MTX, but seem to suggest a more prominent role played by CPT with respect to other DMARDs. <h3>References</h3> Weusten BLAM, Jacobs JWG, Bijlsma JWJ. Corticosteroid pulse therapy in active rheumatoid arthritis. Semin Arthritis 1993;23:183–92 Van Der Veen MJ, Bijlsma JWJ. The effect of methylprednisolone pulse therapy on methotrexate treatment of rheumatoid arthritis. Clin Rheumatol. 1993;12:500–5 Boerbooms AMT, Kerstens PJSM, van Loenhout JWA, Mulder J, van de Putte LBA. Infections during low-dose methotrexate treatment in Rheumatoid arthritis. Semin Arthritis Rheum. 1995;24:411–21 di Girolamo C, Pappone N, Melillo E, Rengo C, Giuliano F, Melillo G. Cavitary lung tuberculosis in a rheumatoid arthritis patient treated with low-dose methotrexate and steroid pulse therapy. Br J Rheumatol. 1998;37:1136–7
68Ga-FAPI-04 PET-CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-associated interstitial lung disease: a single-centre, pilot study
Authors: Christina Bergmann, Jörg H W Distler, Christoph Treutlein, Koray Tascilar, Anna-Theresa Müller, Armin Atzinger, Alexandru-Emil Matei, Johannes Knitza, Andrea-Hermina Györfi, Anja Lück, Clara Dees, Alina Soare, Andreas Ramming, Verena Schönau, Oliver Distler, Olaf Prante, Philipp Ritt, Theresa Ida Götz, Markus Köhner, Michael Cordes, Tobias Bäuerle, Torsten Kuwert, Georg Schett, Christian Schmidkonz
Journal: The Lancet Rheumatology (2021)
OP0023 Adeno-associated virus encoding for il-4 inhibits collagen-induced arthritis
Authors: N Bessis, V Cottard, D Mulleman, MC Boissier
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Gene therapy is a promising strategy for rheumatoid arthritis. Adeno-associated virus (AAV) are recently developed vectors with unique set of characteristics like their ability to infect host cells at any time of their division cycle, and their possible weak immunogenicity in mammals. IL-4 is a Th-2 anti-inflammatory cytokine that is efficient if delivered by continuous administration in collagen-induced arthritis (CIA) in mice. <h3>Objectives</h3> The present study was undertaken to investigate the possibility to use AAV vectors in CIA. <h3>Methods</h3> AAV vectors, expressing lacZ (AAV-lacZ) or IL-4 (AAV-IL-4) cDNA under CMV promotor control, were produced and purified by Généthon (Evry, France). DBA/1 mice were used for all studies. After i.m. injection of 2.5 109 AAV-lacZ particles, lacZ expression was examined on tissue cryosection by X-gal staining. IL-4 transgene expression was evaluated <i>in vivo</i> different times after i.m. injection of AAV-IL-4 by an IL-4 ELISA on muscles lysates. LacZ quantitative expression was evaluated after i.m. injections of AAV-lacZ by X-gal colorimetric assay on muscle lysates. AAV antibodies levels were measured by a neutalizing assay. CIA was induced by immunisation with bovine type II collagen. For treatment, 1.3 1010 AAV-IL-4 were administered i.m. to mice 11 days prior to induction of CIA. <h3>Results</h3> Peri-articular injection of AAV-lacZ showed an expression of the transgene localised in the deep muscles cells near the bone. IL-4 <i>in vivo</i> expression was detected at least 120 days after AAV-IL-4 injection i.m. Anti-AAV neutralising antibodies were detected in the serum after AAV-lacZ administration <i>in vivo</i>, but they didn't altered the transgene expression after readministration of AAV-lacZ. CIA mice treated with AAV-IL-4 were significantly improved in comparisation to control, in terms of prevalence of the disease, arthritis scores, and histological evaluation. Locally, a slight inflammation at the point of vector injection was noted. <h3>Conclusion</h3> AAV is a powerful vector for gene therapy in CIA. AAV IL-4 prevent the development of CIA. In addition, our data are consistent with a long term persistance of the transgene and the possibility of a readministration.
Cancer of Unknown Primary in the Molecular Era
Authors: Shumei Kato, Ahmed Alsafar, Vighnesh Walavalkar, John Hainsworth, Razelle Kurzrock
Journal: Trends in cancer (2021)

Cancer of unknown primary (CUP) is a rare malignancy that presents with metastatic disease and no identifiable site of origin. Most patients have unfavorable features and attempts to treat based on tissue-of-origin identification have not yielded a survival advantage compared with empiric chemotherapy. Next-generation sequencing has revealed genomic alterations that can be targeted in selected cases, suggesting that CUP represents a unique malignancy in which the genomic aberrations may be integral to the diagnosis. Recent trials focusing on tailored combination therapy matched to the genomic alterations in each cancer are providing new avenues of clinical investigation. Here, we discuss recent findings on molecular aberrations in CUP and how the genomic and immune landscape can be leveraged to optimize therapy.
SAT0134 Patient perceived benefits and side effects of therapeutic interventions in fibromyalgia
Authors: PH Dessein, AE Stanwix, Z Moomal
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The efficacy of treatment programs in fibromyalgia (FM) as currently used in practice is unsatisfactory and more innovative and effective therapies need to be developed. <h3>Objectives</h3> The present study comprises part of an audit of a rheumatology clinic in which central sensitisation and neuroendocrine deficiencies were considered in the evaluation and management of FM. <h3>Methods</h3> Forty two consecutive female FM (22 primary; 20 sary) patients, who had been followed up for at least 2 months, were enrolled. Their mean (SD, range) age was 42 (12, 15–78), disease duration 8 (11, 0.3–45) and follow up duration 2.9 (2.2, 0.28–8.6) years, respectively. Patients completed Fibromyalgia Impact Questionnaires (FIQ) and reported on the benefits and side effects of each intervention. Results were expressed as mean (SD) where appropriate. <h3>Results</h3> The total FIQ improved from 74.1 (11.9) to 21.6 (13.2) (p &lt; 0.001). N users and% patients of users benefiting, experiencing side effects and discontinuing treatment for the different interventions were: (1) dehydroepiandrosterone: 33, 97, 6, 6; (2) IM methylprednisolone (120 mg): 33, 91, 9, 21 (duration of benefit: 2.4 (2.6), range 0–13 months); (3) exercise: 30, 100, 3, 0; (4) diet: 30, 100, 0, 0; (5) NSAID: 26, 69, 31, 50; (6) hydrocortisone: 26, 73, 35, 31; (7) clonazepam: 19, 89, 11, 21; (8) clonidine: 18, 90, 0, 22; (9) tri/tetracyclics: 18, 89, 44, 39; (10) trazodone: 16, 87, 25, 13; (11) subcutaneous sterile water: 16, 87, 0, N/A (duration of benefit: 2.5 (3.1), range 0–12 months); (12) pemoline: 14, 64, 21, 71; (13) fludrocortisone: 13, 85, 8, 38; (14) chloroquine (in secondary fibromyalgia only): 12, 100, 0, 8. More detailed results will be presented. Each FIQ score improved more in secondary as compared to primary FM and these differences reached significance for tiredness and morning tiredness (p &lt; 0.04). After controlling for the use of chloroquine, the respective differences disappeared. <h3>Conclusion</h3> Although none of our patients were involved in disability claims and only 4 (10%) were not working because of their disease, our results suggest that an individualised and multimodal management approach is associated with a marked improvement in health status in FM. Also, the potential role of chloroquine in primary FM deserves evaluation. <h3>References</h3> Wolfe F, <i>et al</i>. Arthritis Rheum. 1997;40:1571–9 Dessein PH, <i>et al</i>. Pain 2000;86:213–15
Residual symptoms and lower lung function in patients recovering from SARS-CoV-2 infection
Authors: Frederik Trinkmann, Michael Müller, Alexandra Reif, Nicolas Kahn, Michael Kreuter, Franziska Trudzinski, Monika Eichinger, Claus-Peter Heussel, Felix J.F. Herth
Journal: European Respiratory Journal (2021)

<b>About half of the patients recovering from SARS-CoV-2 have persistent symptoms and lower lung function as long as 2 months after infection. This is common even in younger SARS-CoV-2 convalescents with few comorbidities.</b>https://bit.ly/38dyCYB