tbuckley/cabot-search huggingface dataset:
Newly developed pseudogout arthritis after therapy with MAGE-A4 directed TCR T cells responded to treatment with tocilizumab
Authors: Sang T. Kim, Jean Tayar, Siqing Fu, Danxia Ke, Elliot Norry, Amy Sun, Juli Miller, David S. Hong
Journal: Journal for ImmunoTherapy of Cancer (2021)

With durable cancer responses, genetically modified cell therapies are being implemented in various cancers. However, these immune effector cell therapies can cause toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Pseudogout arthritis is an inflammatory arthritis induced by deposition of calcium pyrophosphate dihydrate crystals. Here, we report a case of pseudogout arthritis in a patient treated with MAGE-A4 directed T cell receptor T cells, for fallopian tube cancer. The patient developed CRS and ICANS 7 days after infusion of the T cells. Concurrently, the patient newly developed sudden onset of left knee arthritis. Synovial fluid analyses revealed the presence of calcium pyrophosphate dihydrate crystal. Notably, the pseudogout arthritis was resolved with tocilizumab, which was administered for the treatment of CRS and ICANS. Immunoprofiling of the synovial fluid showed that the proportion of inflammatory interleukin 17 (IL-17)-producing CD4 + T (Th17) cells and amount of IL-6 were notably increased, suggesting a potential role of Th17 cells in pseudogout arthritis after T-cell therapy. To the best of our knowledge, this is the first reported case of pseudogout arthritis after cell therapy. Clinicians, especially hematologists, oncologists and rheumatologists, should be aware that pseudogout arthritis can be associated with CRS/ICANS.
Abstract 380: WNT signal pathway activation correlates with innate resistant to immune checkpoint therapies in NSCLC
Authors: Dian Ren, Bo Zhang, Renwang Liu, Fuyu Gong, Yuezong Bai, Wenzhuan Xie, Huandong Huo, Hao Zhang, Zuoqing Song
Journal: Cancer Research (2021)

Abstract Background: Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with NSCLC. There are still lots of patients could not reach the clinical benefit, even though with the positive expression of the programmed cell death 1 ligand 1 (PD-L1). Here, we aimed to research the immune resistance mechanism in NSCLC. Methods: The genomic data and clinical data of the discovery cohort was obtained from The Cancer Genome Atlas (TCGA). The clinical data of validation cohort in NSCLC treated by immunotherapy was retrospective collected. And tissue from patients with NSCLC were performed to whole exome sequencing in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab. Results: Activation of WNT signaling was inferred that somatic mutations or somatic copy number alterations in WNT signaling elements including APC, WNT16, AXIN2, WNT4, AXIN1, CTNNB1, BCL9L and SMAD4. Two cohort have been enrolled in this study, the discovery cohort from TCGA, and the validation cohort from the Chinese patients with NSCLC. The frequency of WNT pathway alterations from the TCGA cohort was 16%, and which was represented mutually exclusive molecular subsets. In TCGA cohort, activating alteration WNT signaling were associated with shorter median PFS (18.8 vs 3.9 months, p=0.036, HR=0.24 (0.09-0.68)). Conclusions: Mutations predicted to activate the WNT pathway were associated with innate resistance to immune checkpoint blockade in NSCLC Citation Format: Dian Ren, Bo Zhang, Renwang Liu, Fuyu Gong, Yuezong Bai, Wenzhuan Xie, Huandong Huo, Hao Zhang, Zuoqing Song. WNT signal pathway activation correlates with innate resistant to immune checkpoint therapies in NSCLC [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 380.
Freedom of Speech
Authors: Leigh R. Hochberg, Sydney S. Cash
Journal: New England Journal of Medicine (2021)

Of the many functions delegated to the human nervous system, perhaps none is more essentially human than the ability to express one's thoughts. For persons with severe speech and motor impairments, restoration of the ability to communicate even simple needs is an important goal. Cognitively intact persons who are tetraplegic and anarthric know what they want to communicate — their brains prepare messages for delivery, but those messages are trapped. The goal in the design of brain–computer interfaces is to restore communication and mobility by harnessing voluntarily modulated brain signals to control useful external1-3 or implanted4 devices. Signals from the . . .
Abstract 3120: MMP-7 increases migration by decreasing intercellular cell junction complexes in prostate cancer microtumors formed by perlecan/HSPG2
Authors: Lissette A. Cruz, Tristen V. Tellman, Oleg Igoshin, Daniel Carson, Mary (Cindy) Farach-Carson
Journal: Cancer Research (2021)

Abstract Background: Polarized epithelium is stabilized by lateral cell-cell interactions via cell adhesion molecules (CAMs) and by cell-matrix interactions with basement membrane including with perlecan/HSPG2 (pln). Prostate cancer (PCa) patients with bone metastases have circulating pln fragments, with inverse correlation between MMP-7 staining and loss of pln in cancer tissue. Cleavage of pln by MMP-7 increases cell-matrix interactions and dysregulates cell signaling, permitting migration. We earlier showed pln domain IV-3 (DmIV-3) drives cell-cell cohesion and, when digested with MMP-7, drives cell dyscohesion. Methods: To evaluate the impact of MMP-7 and pln fragments on microtumor dyscohesion and cell migration, uniformly sized PCa microtumors were pre-formed in a microwell system. Pre-formed microtumors were transferred to Dm IV-3 or full length perlecan (FL pln) coated wells for 16-24 hrs. Microtumors were treated with MMP-7 alone or MMP-7 plus predigested Dm IV-3 fragments or MMP-7 plus FL pln fragments. For live cell imaging, tracking of migratory cells leaving microtumors was performed with Imaris software. Co-location of cell adhesion complex components was assessed with Imaris Spots. Results: Pre-formed microtumors cultured with DmIV-3 cleaved by MMP-7 showed lower Pearson's correlation values at cell boundaries compared to microtumors treated with intact Dm IV-3. Line scan analysis revealed E-cadherin and F-actin fluorescent signals were enriched and co-aligned in microtumors treated with Dm IV-3; enrichment and co-alignment were reduced when DmIV-3 fragments and MMP-7 were present. Track number detected per cell cluster was highest in the presence of FL pln fragments plus MMP-7 along with a measurable change in distribution of track displacement lengths of cells toward high values. Conclusion: Boundary reorganization promotes a migratory cell phenotype in microtumors treated with MMP-7 and DmIV-3 fragments. DmIV-3 fragments generated by MMP-7 cleavage can enhance cell dyscohesion by disrupting interactions between CAMs. Ongoing work will identify DmIV-3 fragment(s) positively associated with tumor dyscohesion that play key roles in secondary metastasis formation. Following patterns of dyscohesion of pre-formed microtumors provides a good model to study dynamic changes in intercellular junction components and quantitate cell migration patterns that foster circulating tumor cell formation and metastasis. Citation Format: Lissette A. Cruz, Tristen V. Tellman, Oleg Igoshin, Daniel Carson, Mary (Cindy) Farach-Carson. MMP-7 increases migration by decreasing intercellular cell junction complexes in prostate cancer microtumors formed by perlecan/HSPG2 [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 3120.
Antifungal activity of nitroxoline against Candida auris isolates
Authors: Frieder Fuchs, Herbert Hof, Sandra Hofmann, Oliver Kurzai, Jacques F. Meis, Axel Hamprecht
Journal: Clinical Microbiology and Infection (2021)

To investigate the in vitro activity of nitroxoline against a molecularly characterized collection of clinical Candida auris isolates.Thirty-five clinical isolates of C. auris from diverse sources representing all five different C. auris clades were included in the study. Nitroxoline activity was assessed using broth microdilution. Additionally, susceptibility testing by disc diffusion was assessed on RPMI-1640 and Müller-Hinton agar plates. Minimal inhibitory concentrations of the antifungals fluconazole, voriconazole, amphotericin B and anidulafungin were determined.Nitroxoline MICs ranged from 0.125 to 1 mg/L (MIC50/90 0.25/0.5 mg/L). Compared with amphotericin B (MIC >1 mg/L in 4/35 isolates), anidulafungin (MIC >0.06 mg/L in 26/35 isolates) and fluconazole (MIC >4 mg/L in 31/35 isolates), in vitro activity of nitroxoline was high. Isolates belonging to clade I had marginally lower nitroxoline MICs (range 0.125-0.5 mg/L, mean MIC 0.375 mg/L) compared with clade III (range 0.5-1 mg/L, mean MIC 0.7 mg/L; p = 0.0094). The correlation of MIC and inhibition zones by disc diffusion was good when using RPMI-agar for disc diffusion, with a Pearson's correlation coefficient of -0.74 (95% CI -0.86 to -0.54).Nitroxoline has excellent in vitro activity against C. auris isolates, with MICs of 0.125-1 mg/L (for comparison, the EUCAST breakpoint for uncomplicated urinary tract infection with Escherichia coli is ≤ 16 mg/L). It is an approved, well-tolerated antimicrobial that achieves high urinary concentrations after oral administration and could be a useful treatment option in C. auris candiduria.
A novel vacuum-based tissue holding device for laparoscopic and robotic partial nephrectomy: The development process and in vitro evaluation in human cadaveric and porcine models
Authors: L. Hefermehl, V.M. Ramakrishnan, K. Lehmann, N. Brader, S. Pilz, C. Maake, M. Gabi
Journal: European Urology (2021)
The potential role of COVID-19 hygienic measures in reducing infective complications during hospitalization
Authors: D. Baiamonte, R. Biancolini, R. Aimar, P. Mannone, G. Di Gregorio, G. Tulone, S. Giannone, A. Abrate, M. Vella, V. Serretta, C. Pavone, R. Giaimo, E. Dalmasso, A. Simonato
Journal: European Urology (2021)
Abstract 2067: Genomic integration of circulating cell-free chromatin particles activates all known hallmarks of cancer and Immune checkpoint PDL-1
Authors: Indraneel Mittra, Shahid Chaudhary, Naveen Kumar Khare, Tannistha Saha, Dharana Satsangi, Jenevieve Dsouza, Shweta Johari, Harshada Wani, Ratnam Prasad, Soniya Shende, Kavita Pal
Journal: Cancer Research (2021)
Abstract 1499: Targeting Ras mutation with TCR therapy
Authors: Nan Mou, Yue Yu, Jijun Yuan
Journal: Cancer Research (2021)

Abstract Ras oncogenes (K/N/HRAS) are frequently mutated in 20% of all human cancers. Globally, approximately 3.4 million new cancer cases are diagnosed annually carrying Ras mutations. There is a large unmet medical need for treating cancers carrying Ras mutations. KRAS mutations account for around 80% of total Ras mutations. Codon 12 and 13 are most frequently mutated in KRAS oncogene. RasG12V and RasG13D represent approximately 22-58% cases of KRAS mutations. RAS mutations are immunogenic and can be recognized by T cell receptors in HLA restricted manner (Steven A. Rosenberg, 2016). Here we report identification of two human TCRs specifically recognizing RasG12V and RasG13D mutations isolated from tumor infiltrating lymphocytes of colorectal cancer patients. Both TCRs show high avidity to RasG12V and RasG13D mutations presented by MHCII alleles widely distributed in human population. Engineered B13.14.1 TCR-T and B8.2.4 TCR-T recognize RASG12V and RASG13D presented on HLA matched tumor cell line and induce strong INFγ release. Furthermore, potent yet specific tumor cell lysis was observed in multiple RASG12V and RASG13D tumor cell lines. Our RasG12V and RasG13D targeted TCR-T therapy could hold great potential for treatment of oncogenic Ras mutation driven cancers. Citation Format: Nan Mou, Yue Yu, Jijun Yuan. Targeting Ras mutation with TCR therapy [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 1499.
Abstract 2029: The ER stress protein IRE1a regulates intracellular calcium, ROS, and the UV damage response through the IP3R inhibitor CIB1
Authors: Jeongin Son, Saie Mogre, Adam Glick
Journal: Cancer Research (2021)

Abstract UV induced DNA damage is the primary driver of human skin cancer. UV can also cause endoplasmic reticulum (ER) stress, but the role of unfolded protein response (UPR) in the cellular response to UV exposure is not clear. Inositol-requiring enzyme 1α (IRE1α) is one of the key regulators of the UPR but its function in the UV response has not been resolved. Here we show that IRE1α, is transiently dephosphorylated and its RNase activity downregulated by UVB resulting in reduced XBP1 splicing. Keratinocytes with either IRE1α knockout or knockdown have elevated cytosolic calcium and ROS resulting in increased apoptosis after UV. Pharmacological inhibition of the ER inositol triphosphate receptor (IP3R) or phospholipase C (PLC) restored normal cytosolic calcium and ROS levels to cells lacking IRE1α. While loss of IRE1α did not alter the frequency of cells with UV-induced cyclo-pyrimidine dimers (CPD), it significantly reduced the percent of γH2AX positive keratinocytes 6 hours after UVB irradiation. This percent of CPD positive cells and the level of γH2AX 6 hours after UV suggesting a defect in the DNA repair response. Pharmacological inhibition of IRE1α RNase or Xbp1 knockdown did not phenocopy IRE1α loss, but overexpression of IRE1α in IRE1α knockdown cells restored γH2AX expression and reduced keratinocyte apoptosis. IRE1α overexpression also enhanced the survival of keratinocytes deficient in p53 function after UV irradiation. Additionally, mice with an epidermal deletion of IRE1α showed more rapid loss of UV-induced CPD positive keratinocytes compared to wildtype mice, primarily through accelerated sloughing of UV damaged cells from the skin. Knockdown of Calcium and integrin binding protein 1 (CIB1), which binds and inhibits the IP3R, elevated cytosolic calcium in keratinocytes and suppressed UV-induced γH2AX. Knockdown of Apoptosis signal-regulating kinase 1 (ASK1), which can interact with IRE1α through TRAF2 as well as CIB1, restored normal levels of UV-induced γH2AX to IRE1α knockdown keratinocytes. Together these results show that IRE1α is essential for maintaining normal cellular calcium and ROS levels and the UV-induced repair response, and suggest a model where IRE1a activation state drives CIB1 binding either to the IP3R or ASK1 to regulate ER calcium efflux, ROS and DNA repair responses following UV. Citation Format: Jeongin Son, Saie Mogre, Adam Glick. The ER stress protein IRE1a regulates intracellular calcium, ROS, and the UV damage response through the IP3R inhibitor CIB1 [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 2029.
Abstract 2107: Transcription factor repertoire basis for epigenetic and consensus molecular subtypes of colorectal cancer
Authors: Yuba Bhandari, Rachael Powers, Sehej Parmar, Vinod Krishna, Kurtis E. Bachman, Steve Baylin, Hariharan Easwaran
Journal: Cancer Research (2021)

Abstract Colorectal cancer (CRC) is classified into distinct subtypes based on genetic, epigenetic and/or transcriptional subtypes. The underlying mechanisms that drive these subtypes are unknown. By integrating whole genome DNA methylation, gene expression, chromatin patterns, and enhancer elements in CRCs, we show that expression of large numbers of transcriptional factors (TFs) is deregulated in CRCs and these expression patterns drive epigenetic and transcriptional subtypes of CRCs. The first key result emerging is a new understanding of important DNA methylation patterns central to classifying CRCs. Of these, different degrees of cancer associated promoter methylation have been recognized that suppress expression, and/or inducibility of important tumor suppressor genes. Stratified by high to low degrees of hypermethylation, this pattern is termed CpG-island promoter DNA methylation phenotypes or CIMP. We now tightly link CIMP to a cancer-specific hypermethylation at enhancer regulatory elements we term, CpG- enhancer methylation phenotype (CEMP). CIMP and CEMP are driven by decreased expression of multiple TFs with binding sites in these regulatory elements, and the involved TFs are frequently identical between the two regions. In contrast, a different set of TF factors are downregulated in non-CIMP tumors, again in conjunction with methylation patterns linking promoter and enhancer target sites for the involved TFs. Further, enhancer regulatory elements that are hypomethylated in cancer relative to normal tissue are associated with increased expression of another distinct set of TFs with target sites in the corresponding enhancers. Importantly, the TF expression patterns, and the above CIMP, CEMP, and hypomethylation patterns, are established early in the pre-malignant adenomas. Importantly, pan-cancer analyses showed that the above CIMP and CEMP subtypes occur across important cancer types in addition to CRC, again in parallel with marked downregulation of TFs that have target sites in the methylated regulatory elements. All of the above newly defined patterns also provide a basis for the transcriptome-based consensus molecular subtypes (CMS) of CRC. Overall, our studies may provide key understanding of how cancers, and their initiation and progression, are diseases which at the end of the day depend on abnormal patterns of TF expression, and how these relate to methylation alterations at target enhancer and promoter regions. Citation Format: Yuba Bhandari, Rachael Powers, Sehej Parmar, Vinod Krishna, Kurtis E. Bachman, Steve Baylin, Hariharan Easwaran. Transcription factor repertoire basis for epigenetic and consensus molecular subtypes of colorectal 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 2107.
Abstract 3149: Investigation of the potential therapeutic value of CAF-derived milk fat globule-EGF factor 8 protein (MFG-E8) in esophageal squamous cell carcinoma
Authors: Beilei Liu
Journal: Cancer Research (2021)

Abstract The physiological state of the tumor microenvironment (TME) is closely linked with tumorigenesis. RNA sequencing data from our lab showed a broad range of dysregulated genes between ESCC isolated CAFs and paired peripheral blood isolated Fbcs. Among the 2347 up-regulated genes, we found the GO analysis is many focused in extracellular matrix and the top 4 GO terms enriched in cell development and adhesion. Due to this, enriched CAF-secreted extarcellular proteins attracts our attention. MFG-E8 is highly expressed secreted protein in CAFs but low expressed in tumor cells. TCGA database revealed high expression of MFG-E8 is associated with poor overall survival and disease-free survival. In addition, ESCC cell line k410 and K180 with MFG-E8 protein showed a strong ability in cell migration, cell invasion and apoptosis inhibition compared with the PBS group. The further western blot demonstrated MFG-E8 promoted ESCC cell migration and invasion by triggering EMT, and activated an altered akt/stat3 signaling pathway. Moreover, Anti-MFG-E8 antibody effectively reduced tumor size, especially combined with cisplatin. Therefore, MFG-E8 may act as a potential target effective therapeutic strategies. Citation Format: Beilei Liu. Investigation of the potential therapeutic value of CAF-derived milk fat globule-EGF factor 8 protein (MFG-E8) in esophageal squamous cell carcinoma [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 3149.
Abstract 16398: Oxidative Stress Regulates the Phenotype of Vascular Smooth Muscle Cells via Promoting Drp1-Mediated Mitochondrial Fission
Authors: Zifang Song, Wei Li, Xiaowei Tang, Qihong Yu
Journal: Circulation (2019)

Introduction: Vascular smooth muscle cell (VSMC) phenotypic modulation, the switch from a contractile state to a synthetic phenotype, is a central event in the development of neointimal formation t...
Ureteral stenting does not increase the risk of metachronous upper tract urothelial carcinoma in patients with bladder cancer presenting with hydronephrosis in comparison with percutaneous nephrostomy: A multicenter analysis
Authors: L. Afferi, C. Lonati, F. Montorsi, A. Briganti, A. Mari, W. Krajewski, G. Simone, G.B. Schulz, P. Black, M.C. Mir, M. Roumiguié, J.Y. Teoh, F. Soria, M. Roupret, M.J. Ribal, E. Xylinas, S. Zamboni, A. Antonelli, A. Tafuri, S. Albisinni, A. Mattei, M. Alvarez-Maestro, S.F. Shariat, M. Moschini
Journal: European Urology (2021)
Perturbation in B Cell-Subsets Can Explain the Observed Suppression of Uninvolved Immunoglobulins and Their Impact on T Tell-Subsets As Well As Patients Outcome in Myeloma
Authors: Rao Prabhala, Shree Acharya, Megan Stekla, Srikanth Talluri, Raphael Szalat, Puru Nanjappa, Michael A Lopez, Kenneth Wen, Chaitanya Yenumula, Alexander Heubeck, Yu-Tzu Tai, Ansh Mehta, Mariateresa Fulciniti, Suzan Lazo-Kallanian, John Daley, Paul G Richardson, Kenneth C Anderson, Nikhil Munshi
Journal: Blood (2017)
Abstract 1201: Amentoflavone inhibits cell growth and metastasis in colorectal cancer was associated with the suppression of KIAA1199
Authors: Hsiang-Ju Ku, Zhao-Lin Tan, I-Tsang Chiang, Yuan Chang, Fei-Ting Hsu
Journal: Cancer Research (2021)

Abstract Amentoflavone (AF), a kind of diflavonoid compound, which was used as a traditional folk medicine thousands years ago. AF had been proven to prevent cells degeneration, aging, and could also induce cell cycle arrest and apoptosis in various human cancer cells to achieve anti-tumor effects. Cell migration-induced hyaluronic acid binding protein (CEMIP, KIAA1199), an oncogene protein, has been confirmed to be associated with the abnormal expression of epithelial-mesenchymal transition (EMT) markers. Several studies also reported that the inhibition of KIAA1199 can suppress the proliferation of colorectal cancer (CRC). At present, there is no study identify whether AF can inhibit the growth of colorectal cancer by regulating KIAA1199. The aim of this study was to investigate the anticancer effect and mechanism of AF in colorectal in vitro and in vivo. First, we indicated that the cytotoxic effect was induced by AF in human and mouse CRC (CT26 &amp; HT29) cells. The fewest colony formation was found in AF treated group, which represent the suppression of proliferation. Cell cycle was arrest at G1 by AF treatment which was evaluated by flow cytometry. Then, the migration and invasion suppression was also found in amentoflavone treatment group by wound healing and invasion/migration transwell assay. Furthermore, real-time polymerase chain reaction detection and Western blotting results indicated that KIAA1199 related genes, such as E-cadherin, N-cadherin, Vimentin and Fibronectin were all downregulated by amentoflavone. In animal experiments, the CRC tumors volume were reduced in AF treatment groups. In summary, AF can achieve therapeutic effects in colorectal cancer by inhibiting cell proliferation, migration/invasion ability and EMT potential via suppression of KIAA1199. Citation Format: Hsiang-Ju Ku, Zhao-Lin Tan, I-Tsang Chiang, Yuan Chang, Fei-Ting Hsu. Amentoflavone inhibits cell growth and metastasis in colorectal cancer was associated with the suppression of KIAA1199 [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 1201.