tbuckley/cabot-search huggingface dataset:
Association of diversity and composition of the gut microbiome with differential responses to PD-1 based therapy in patients with metastatic melanoma.
Authors: Vancheswaran Gopalakrishnan, Christine Spencer, Alexandre Reuben, Tatiana Karpinets, Diane Hutchinson, Kristi Hoffman, Peter A. Prieto, Michael T. Tetzlaff, Alexander Lazar, Michael A. Davies, Jeffrey E. Gershenwald, Robert R. Jenq, Patrick Hwu, Padmanee Sharma, James Patrick Allison, Andrew Futreal, Nadim Ajami, Joseph Petrosino, Carrie Daniel-MacDougall, Jennifer A. Wargo
Journal: Journal of Clinical Oncology (2017)

2 Background: Tremendous advances have been made in cancer therapy through the use of immune checkpoint blockade, although responses are not always durable. There is a growing appreciation of the role of the microbiome in cancer-related outcomes and recent evidence in murine models suggests that modulation of the gut microbiome may enhance responses to immune checkpoint blockade in melanoma. However this has not been investigated in patients. Here, we demonstrate that differential bacterial “signatures” exist in the gut microbiome of responders (R) and non-responders (NR) to anti-PD1 therapy at baseline, and that insights gained could be used to derive actionable strategies to enhance responses. Methods: We collected oral (n = 222) and gut microbiome (n = 113) samples on a large cohort of patients with metastatic melanoma (n = 228), with a majority treated with anti-PD1 therapy (n = 110). Patients were classified as either R or NR based on RECIST criteria, and 16S rRNA gene sequencing was performed to characterize the diversity and composition of the microbiomes. Immune profiling (via 7-marker IHC panel of CD3, CD8, PD-1, PD-L1, Granzyme B, RORγT and FoxP3) was performed in available tumors at baseline. Results: In these studies, we observed significant differences in the diversity and composition of the gut microbiome in R versus NR to PD1 blockade at baseline, but no clear differences in oral microbiomes. Specifically, R had a significantly higher alpha diversity compared to NR (p = 0.017). Notable differences were also seen in the composition of the gut microbiome of R versus NR. Immune profiling demonstrated significantly increased immune infiltrates in baseline tumor samples of R, with a positive correlation between CD8, CD3, PD1 and FoxP3 T-cell density and abundance of specific bacteria enriched in R (e.g. Faecalibacterium). Conclusions: Differences exist in the diversity and composition of the gut microbiome in R vs NR to anti-PD1 therapy. These results have far-reaching implications and suggest that modifications to the gut microbiome could potentially enhance therapeutic responses to immune checkpoint blockade.
Analytical validation of an immune response assay for classifying solid tumors.
Authors: Jeff Conroy, Sean Glenn, Blake Burgher, Antonios Papanicolau-Sengos, Jonathan Andreas, Vincent Giamo, Kunle Odunsi, Marc S. Ernstoff, Kevin H. Eng, Ji He, Mark Gardner, Carl Morrison
Journal: Journal of Clinical Oncology (2017)

68 Background: An advanced diagnostic laboratory test (Immune Advance) was developed that analyzes multiple DNA and RNA biomarkers to predict the likelihood of response to checkpoint inhibitors in patients with solid tumors. Using RNA-seq and DNA-seq, the NGS test measures gene expression of immune response genes and overall mutational burden. The studies described here were designed to validate the analytical performance of the test on the Ion Torrent System in our CLIA lab. Methods: Studies were designed to characterize the analytical performance of an immune response NGS assay using total nucleic acids from &gt;100 FFPE tissues representing NSCLC, melanoma, renal cell carcinoma, and bladder cancer. Performance variables with respect to gene-specific amplicon specificity, linearity, and limits of detection were estimated with various sample dilutions and input nucleic acids. The effects of the tumor micro-environment (adjacent benign tissue, necrosis) was evaluated by including these potential interferents in the assay. Analytical precision including intra-assay, inter-assay, and inter-operator reproducibility was measured by testing replicate FFPE tissue sections. Accuracy was determined by comparing select transcript and DNA level variants with those from established IHC, RT-PCR, and NGS assays. Transcript stability in FFPE specimens was evaluated in serial sections from blocks with routine storage and compared to originating matched fresh frozen specimens. Results: RNA stability was demonstrated by high degree of correlation between matched frozen and FFPE samples. Analytic precision was demonstrated by high correlation between RNA-Seq and TaqMan results for genes evaluated. As compared to IHC the results for RNA-Seq were continuous rather than bimodal and allowed for a much more detailed analysis of the immune response. Immune signatures were maintained with variable RNA/DNA input amounts, altered tumor micro-environments, and potential interferents demonstrating tolerance to typical sample types tested. Reproducibility results show little variation between runs and operators. Conclusions: The analytical performance of the Immune Advance assay has been validated for clinical use using FFPE tumor specimens.
Whales, toxins, and a way of life
Authors: Ingrid Torjesen
Journal: BMJ (2018)

Intrepid Cinema

The Faroese tradition of men taking to small boats to hunt pilot whales by hand, turning the sea red with blood, is a revolting spectacle to many outsiders. The hunts attract animal rights campaigners from across the globe, who turn up in expensive boats to protest against the slaughter.

Once landed, the whale meat is divided into portions and wheeled away by islanders, recalling a time when hunting was so important to these …
Abstract 24034: MFG-E8 Fragment Medin and Arterial Aging
Authors: yushi wang
Journal: Circulation (2017)

Background: Aging increases milk fat globule EGF-VIII (MFG-E8) expression in the rat, nonhuman primate and human aortic walls, facilitating the invasion, proliferation, and proinflammation of vascular smooth muscle cells (VSMCs). The MFG-E8 C-terminal fragment medin has been reported to be involved in the necrosis of VSMCs at the inflammatory sites of aortic dissection, however, its cleavage processes, aortic wall levels with aging and bio-role in VSMCs remains to be determined. Material and Methods: In this study, immunofluorescence, immunohistochemistry and western blot analysis demonstrate that MFG-E8 and its fragment medin ( Figure ), activated matrix metalloproteinase type II (MMP-2) and platelet derived growth factor receptor type-beta (PDGFR-β) protein levels were markedly increased in human grossly normal aortic walls from old (n=10, &gt;50 yrs) vs. younger donors (n=10, &lt;25 yrs). Importantly, exposure of medin peptide (20 to100nM) to primary cultured VSMCs isolated from young (8 mo) and old (30 mo) FXBN rat aortae significantly increased MMP-2 activation, PDGFR-β expression, and migratory capacity measured by a modified Boyden chamber in a dose-dependent manner in both also. Separate exposure of activated MMP-2 to recombinant human MFG-E8 protein and also to MFG-E8 enriched old human aortic protein markedly increased the cleavage product medin in both, which was substantially inhibited by an MMP inhibitor, GM6001. Exposure of medin to VSMCs did not significantly affect the expression of cell cycle related proteins. In addition, PDGF-BB treatment markedly activated MMP-2 in both young and old VSMCs, which was substantially reduced by a PDGFR-β inhibitor, RTK. Conclusion: Taken together, targeting MFG-E8 or its cleavage product medin is a novel approach to the prevention or treatment of large arterial aging or age-associated disease.
171P A phase I/II study of weekly nab-paclitaxel plus cisplatin in chemotherapy-naïve patients with advanced non-small cell lung cancer
Authors: Y. Kono, Y. Hattori, K. Nishino, R. Uozumi, S. Itoh, T. Inoue, T. Kumagai, S. Morita, F. Imamura, M. Satouchi
Journal: Journal of Thoracic Oncology (2018)
Avelumab in chemotherapy-refractory metastatic Merkel cell carcinoma: Subgroup analysis of efficacy.
Authors: Howard L. Kaufman, Jeffrey Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P. D'Angelo, Kent C. Shih, Celeste Lebbe, Gerald P Linette, Michele Milella, Isaac Brownell, Karl D. Lewis, Jochen H. Lorch, Anja von Heydebreck, Lisa Mahnke, Paul Nghiem
Journal: Journal of Clinical Oncology (2017)

80 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. In a phase 2 trial in previously treated metastatic MCC (mMCC; JAVELIN Merkel 200, NCT02155647), avelumab, a fully human IgG1 anti–PD-L1 antibody, showed durable responses and a manageable safety profile, including confirmed objective response rate (ORR) of 31.8% (95.9% CI 21.9-43.1), 6-mo duration of response (DOR) rate estimate of 92%, and 6-mo progression-free survival (PFS) rate of 40% (95% CI 29-50). We report post-hoc subgroup analyses from this trial. Methods: Pts with mMCC and prior disease progression on chemotherapy received avelumab 10 mg/kg (1h IV) Q2W. Tumors were assessed every 6 wks (RECIST v1.1) by independent review. Kaplan-Meier method was used to estimate 6-mo DOR and PFS rate. Results: 88 pts were treated with avelumab and followed for ≥ 6 mos (data cutoff Mar 3, 2016). Responses occurred in all subgroups analyzed (Table). Trends of higher ORR and 6-mo PFS rates were seen in pts with fewer prior lines, lower disease burden (sum of target lesion diameters), or PD-L1+ tumors. 6-mo response durability was similar across evaluable subgroups. Conclusions: In post-hoc analyses, avelumab showed durable efficacy across subgroups. This trial is enrolling treatment-naive pts with mMCC to receive 1L avelumab. Clinical trial information: NCT02155647. [Table: see text]
146P The clinical impact of comprehensive cfDNA genomic testing in lung cancer
Authors: S. Geva, A. Belilovski Rozenblum, R. Grinberg, A. Dvir, L. Soussan-Gutman, L.C. Roisman, E. Dudnik, A. Zer, O. Rotem, N. Peled
Journal: Journal of Thoracic Oncology (2018)
Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses
Authors: Chenguang Wang, Yukun Guan, Mengze Lv, Rui Zhang, Zhaoying Guo, Xiaoming Wei, Xiaoxia Du, Jing Yang, Tong Li, Yi Wan, Xiaodong Su, Xiaojun Huang, Zhengfan Jiang
Journal: Immunity (2018)
Investigating the interplay between substrate stiffness and ligand chemistry in directing mesenchymal stem cell differentiation within 3D macro-porous substrates
Authors: Matthew G. Haugh, Ted J. Vaughan, Christopher M. Madl, Rosanne M. Raftery, Laoise M. McNamara, Fergal J. O'Brien, Sarah C. Heilshorn
Journal: Biomaterials (2018)
Induction of tumor cell-based ADCC resistance to create new tumor cell survival and therapy resistance mechanisms.
Authors: Dalal S. Aldeghaither, Joseph C. Murray, Sarah Martinez Roth, Elana J. Fertig, Shaojun Tang, Sandra A Jablonski, Louis M. Weiner
Journal: Journal of Clinical Oncology (2017)

130 Background: EGFR overexpression &amp; amplification is seen in many types of cancer. Cetuximab is an EGFR targeting monoclonal antibody that acts by signal perturbation, complement activation &amp; inducing antibody dependent cellular cytotoxicity(ADCC) by recruiting effector cells. Cetuximab resistance has been extensively investigated, but it has proven difficult to study the molecular mechanisms underlying ADCC resistance because such models are not readily available. Methods: We established an EGFR-targeted ADCC resistance model system using NK92-CD16V effector cells, Cetuximab, and the A431 EGFR-expressing squamous cell carcinoma cell line. Continuous ADCC challenge of A431 (26+ passages) yielded an ADCC-resistant phenotype (ADCCr) that exhibits a stable phenotype in the absence of continued ADCC selection. To further understand the evolution of resistance to ADCC, we explored the ADCCr cell surface signature, gene expression profile &amp; ability to activate NK cells. Results: We find that ADCCr cells(when compared to its ADCC-sensitive(ADCCs) counterpart) have a modest reduction of EGFR expression, a distinctive transcriptional profile highlighted by overexpression of histone &amp; interferon related genes, altered cell surface expression of important cell adhesion molecules, reduced in vitro proliferation and in vivo growth &amp; resistance that is specific to the formation and function of immune synapses. ADCCr can be partially reversed by the exposure to an inhibitor of the histone acetyl transferase p300 subunit. Interestingly, the ADCCr cell line has reduced sensitivity (compared with ADCCs) to antimetabolite, DNA-intercalating and ABC transporter-regulated cytotoxic agents.The PD-L1 immune checkpoint does not modulate ADCC in this model system. Conclusions: These findings suggest that the induction of resistance to EGFR-targeted immune attack in this model system creates broadly useful survival and potential therapy resistance mechanisms.
The impact of checkpoint blockade prior to adoptive cell therapy using tumor-infiltrating lymphocytes for metastatic melanoma: An update from MD Anderson Cancer Center.
Authors: Marie-Andree Forget, Cara L. Haymaker, Kenneth R. Hess, Jason Roszik, Scott Eric Woodman, Orenthial J. Fulbright, Arely Wahl, Esteban Flores, Shawne T. Thorsen, Rene J. Tavera, Renjith Ramachandran, Rodabe Navroze Amaria, Patrick Hwu, Chantale Bernatchez
Journal: Journal of Clinical Oncology (2017)

138 Background: Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can produce long lasting treatment responses in patients (pts) with metastatic melanoma. In our initial report of 31 treated pts, we demonstrated overall response rate (ORR) of 48%. Due to the evolution of treatment options for metastatic melanoma with heavy reliance on immunomodulatory therapies, we sought to re-evaluate responses in the era of checkpoint blockade. Methods: Pts receive treatment consisting of 7 days of lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. High dose interleukin-2 (720,000 IU/kg IV q 8 hrs up to 15 doses) was infused after TIL infusion. Responses were assessed by imaging per irRC. Results: A total of 74 pts have been treated in our initial TIL study with an updated ORR assessment of 43%. Stratification of pts according to their checkpoint blockade immune-modulator therapy prior to TIL ACT, demonstrated that prior Ipilimumab (Ipi) decreased ORR to 33% compared to 51% in checkpoint naïve pts and decreased overall survival (OS) post-TIL therapy (median 7.7 vs 24.6 months respectively). There were too few pts to assess the impact of anti-PD1 as a single agent. A multiparametric analysis revealed that LDH levels at the time of therapy mainly influences OS and ORR to TIL but still could not invalidate the impact of Ipi prior to TIL ACT. The durability of the response was also found to be different between the 2 groups (30% for Ipi prior and 50% No Ipi prior). This new reality also impacted previously reported parameters that correlated with ORR to TIL ACT such as the expression of B-and-T lymphocyte attenuator (BTLA) on CD8 + TIL. Interestingly, assessment of mutation load (ML) of the tumors prior to TIL ACT showed that the check point naïve group display a high ML ( &gt; 100) within their tumor whereas some patients who had Ipi prior to TIL have a low ML ( &lt; 100). Conclusions: Our preliminary analysis shows that pre-treatment with Ipi decreases ORR to TIL ACT. Understanding how prior ipi modifies TIL, the tumor and microenvironment will help to define the full extent of the impact and how to best treat Ipi refractory pts with TIL. Clinical trial information: NCT00338377.
Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone
Authors: James P. Dugan, Bradley M. Haverkos, Lynda Villagomez, Ludmila K. Martin, Mark Lustberg, John Patton, Marisa Martin, Ying Huang, Gerard Nuovo, Fengting Yan, Robert Cavaliere, Joyce Fingeroth, Shannon C. Kenney, Richard F. Ambinder, Gerard Lozanski, Pierluigi Porcu, Michael A. Caligiuri, Robert A. Baiocchi
Journal: Clinical Cancer Research (2018)

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273-81. ©2018 AACR.
A phase II study of weekly nanoparticle albumin-bound paclitaxel combined with cisplatin in patients with metastatic breast cancer.
Authors: Biyun Wang, Xi-Chun Hu, Si Sun, Jian Zhang, Lichen Tang, Zhong Hua Wang, Lei Ping Wang, Fangfang Lv, Qunling Zhang, Chunlei Zheng, Zhen Jia, Yunhua Lu
Journal: Journal of Clinical Oncology (2012)

e11568 Background: This prospective phase II study was to investigate the efficacy and toxicity of weekly albumin-bound paclitaxel (nab-paclitaxel) and cisplatin combination in patients with metastatic breast cancer. Methods: Females with unresectable, recurrent or metastatic breast cancer were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m 2 on d1, 8, 15, followed by cisplatin 75 mg/m 2 on d1, repeated every 28 days with a maximum of 6 cycles. The primary objective was overall response rate (ORR) and the second objectives were progression free survival (PFS), safety, and overall survival (OS). Results: Seventy-three women were enrolled into this study. A total of 384 chemotherapy cycles were administered with a median of 6 cycles. A high overall response rate (67.1%) was achieved in the whole population. The highest response rate was observed in the first line patients (80.6%) and in patients who had not received taxane previously (80%). After a median follow-up of 12.8 months, the median PFS was 10.5 months. For the patients receiving first-, second- and third-line or more,median PFS was 12.3, 9.0 and 7.7 months, respectively (P=0.006). Subgroup analysis showed that the highest response rate was obtained in Her-2 positive patients, followed by patients with triple negative and luminal subtypes, yielding a response rate of 77.8%, 68.8% and 63.9%, respectively (P=0.584). The corresponding median PFS was 13.6, 12.7 and 10.0 months, respectively (P=0.83). While grade 4 neutropenia occurred in 46 patients (63.0%), febrile neutropenia occurred only in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%), 13 of whom had to stop chemotherapy due to no recovery to grade 2 or less within 2 weeks. Other common toxicities included alopecia, nausea, vomiting and rash. Conclusions: The results of this trial add to the clinical evidence that doublet of nab-paclitaxel and cisplatin has high efficacy and a good safety profile in treatment of patients with metastatic breast cancer. Further evaluation of this regimen in metastatic breast cancer, especially triple negative subtype, is justified.
Population pharmacokinetics and pharmacodynamics of fosfomycin in non–critically ill patients with bacteremic urinary infection caused by multidrug-resistant Escherichia coli
Authors: V. Merino-Bohórquez, F. Docobo-Pérez, J. Sojo, I. Morales, C. Lupión, D. Martín, M. Cameán, W. Hope, Á. Pascual, J. Rodríguez-Baño
Journal: Clinical Microbiology and Infection (2018)
Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy
Authors: Romina Fiorotto, Mariangela Amenduni, Valeria Mariotti, Luca Fabris, Carlo Spirli, Mario Strazzabosco
Journal: Hepatology (2017)

Cystic fibrosis transmembrane conductance regulator (CFTR), the channel mutated in cystic fibrosis (CF), is expressed by the biliary epithelium (i.e., cholangiocytes) of the liver. Progressive clinical liver disease (CF‐associated liver disease; CFLD) occurs in around 10% of CF patients and represents the third leading cause of death. Impaired secretion and inflammation contribute to CFLD; however, the lack of human‐derived experimental models has hampered the understanding of CFLD pathophysiology and the search for a cure. We have investigated the cellular mechanisms altered in human CF cholangiocytes using induced pluripotent stem cells (iPSCs) derived from healthy controls and a ΔF508 CFTR patient. We have devised a novel protocol for the differentiation of human iPSC into polarized monolayers of cholangiocytes. Our results show that iPSC‐cholangiocytes reproduced the polarity and the secretory function of the biliary epithelium. Protein kinase A/cAMP‐mediated fluid secretion was impaired in ΔF508 cholangiocytes and negligibly improved by VX‐770 and VX‐809, two small molecule drugs used to correct and potentiate ΔF508 CFTR. Moreover, ΔF508 cholangiocytes showed increased phosphorylation of Src kinase and Toll‐like receptor 4 and proinflammatory changes, including increased nuclear factor kappa‐light‐chain‐enhancer of activated B cells activation, secretion of proinflammatory chemokines (i.e., monocyte chemotactic protein 1 and interleukin‐8), as well as alterations of the F‐actin cytoskeleton. Treatment with Src inhibitor (4‐amino‐5‐(4‐chlorophenyl)‐7‐(t‐butyl)pyrazolo[3,4‐d]pyramidine) decreased the inflammatory changes and improved cytoskeletal defects. Inhibition of Src, along with administration of VX‐770 and VX‐809, successfully restored fluid secretion to normal levels. Conclusion: Our findings have strong translational potential and indicate that targeting Src kinase and decreasing inflammation may increase the efficacy of pharmacological therapies aimed at correcting the basic ΔF508 defect in CF liver patients. These studies also demonstrate the promise of applying iPSC technology in modeling human cholangiopathies. (H epatology 2018;67:972–988)