Publications by authors named "George Miller"

263 Publications

Fungi, host immune response, and tumorigenesis.

Am J Physiol Gastrointest Liver Physiol 2021 08 7;321(2):G213-G222. Epub 2021 Jul 7.

Biology Department, Brooklyn College, City University of New York, New York, New York.

Advances in -omics analyses have tremendously enhanced our understanding of the role of the microbiome in human health and disease. Most research is focused on the bacteriome, but scientists have now realized the significance of the virome and microbial dysbiosis as well, particularly in noninfectious diseases such as cancer. In this review, we summarize the role of mycobiome in tumorigenesis, with a dismal prognosis, and attention to pancreatic ductal adenocarcinoma (PDAC). We also discuss bacterial and mycobial interactions to the host's immune response that is prevalently responsible for resistance to cancer therapy, including immunotherapy. We reported that the species associated with scalp and skin infections, colonize in human PDAC tumors and accelerate tumorigenesis via activating the C3 complement-mannose-binding lectin (MBL) pathway. PDAC tumors thrive in an immunosuppressive microenvironment with desmoplastic stroma and a dysbiotic microbiome. Host-microbiome interactions in the tumor milieu pose a significant threat in driving the indolent immune behavior of the tumor. Microbial intervention in multimodal cancer therapy is a promising novel approach to modify an immunotolerant ("cold") tumor microenvironment to an immunocompetent ("hot") milieu that is effective in eliminating tumorigenesis.
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http://dx.doi.org/10.1152/ajpgi.00025.2021DOI Listing
August 2021

Third-Generation Minimally Invasive Chevron and Akin Osteotomies (MICA) in Hallux Valgus Surgery: Two-Year Follow-up of 292 Cases.

J Bone Joint Surg Am 2021 Jul;103(13):1203-1211

The London Clinic, London, United Kingdom.

Background: There is interest in hallux valgus deformity correction using internal fixation with the minimally invasive chevron and Akin osteotomies (MICA) technique. The objective of this study was to assess the correction measured on postoperative radiographs and clinical outcomes, using validated outcome measures, at 2 years following third-generation MICA.

Methods: This is a prospective single-surgeon case series of 333 consecutive feet that underwent MICA surgery between July 2014 and April 2018. The primary clinical outcome measures included the Manchester-Oxford Foot Questionnaire (MOXFQ), EuroQol-5 Dimensions-5 Level (EQ-5D-5L) Index, EuroQol-visual analogue scale (EQ-VAS), and a VAS for pain (VAS-pain). Secondary outcome measures included radiographic parameters and complication rates.

Results: Preoperative and 2-year postoperative patient-reported outcome measures (PROMs) were collected for 292 feet (87.7%). At a minimum 2-year follow-up, the MOXFQ scores (mean ± standard deviation [SD]) had improved in each domain-i.e., reduced from 44.5 ± 21.0 preoperatively to 9.4 ± 15.8 postoperatively for pain (p < 0.001), from 38.7 ± 23.4 to 6.5 ± 14.6 for walking and standing (p < 0.001), and from 48.0 ± 22.3 to 6.6 ± 13.5 for social interaction (p < 0.001). The VAS-pain score improved from 31.4 ± 22.7 preoperatively to 8.4 ± 16.4 at the 2-year follow-up (p < 0.001), the 1-2 intermetatarsal angle was reduced from 15.3° ± 3.6° preoperatively to 5.7° ± 3.2° at the 2-year follow-up (p < 0.001), and the hallux valgus angle was reduced from 32.9° ± 10.2° to 8.7° ± 5.2° (p < 0.001).

Conclusions: The third-generation MICA provided significant improvement in clinical outcome measures at the 2-year follow-up and can be successfully used for correction of a range of hallux valgus deformities with a low rate of symptomatic recurrence.

Level Of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.20.01178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265548PMC
July 2021

Tracking the U.S. health sector: the impact of the COVID-19 pandemic.

Bus Econ 2020 Nov 9:1-12. Epub 2020 Nov 9.

Altarum Institute, Ann Arbor, MI USA.

Health spending has grown faster than the U.S. economy for decades and currently represents approximately 18% of gross domestic product. As with other sectors of the economy, the COVID-19 pandemic has had a significant impact on this growth of the health sector and the labor force that supports it. This paper examines that impact, describing how health care spending, employment, and prices have evolved since the start of the pandemic, using data from the authors' Health Sector Economic Indicators (HSEI) series. After unprecedented drops in March and April of 2020, both spending and employment have gradually recovered but, by the end of the summer, remained below their pre-COVID levels. Prices, on the other hand, have continued to rise. The paper compares these patterns with those observed in earlier recessions and describes some likely reasons for them.
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http://dx.doi.org/10.1057/s11369-020-00195-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649570PMC
November 2020

Recovering the Opportunity Cost of Excess Prices.

Am J Public Health 2020 12;110(12):1751-1752

The authors are with the Center for Value in Health Care, Altarum, Ann Arbor, MI.

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http://dx.doi.org/10.2105/AJPH.2020.305972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661990PMC
December 2020

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling.

J Exp Med 2021 01;218(1)

Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY.

KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
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http://dx.doi.org/10.1084/jem.20201414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549316PMC
January 2021

SSAT State-of-the-Art Conference: Advancements in the Microbiome.

J Gastrointest Surg 2021 07;25(7):1885-1895

Department of General Surgery, Cleveland Clinic, Cleveland, OH, 44195, USA.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.
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http://dx.doi.org/10.1007/s11605-020-04551-4DOI Listing
July 2021

Lung-derived HMGB1 is detrimental for vascular remodeling of metabolically imbalanced arterial macrophages.

Nat Commun 2020 08 27;11(1):4311. Epub 2020 Aug 27.

Division of Vascular Surgery, Department of Surgery, New York University Langone Health, New York, NY, USA.

Pulmonary disease increases the risk of developing abdominal aortic aneurysms (AAA). However, the mechanism underlying the pathological dialogue between the lungs and aorta is undefined. Here, we find that inflicting acute lung injury (ALI) to mice doubles their incidence of AAA and accelerates macrophage-driven proteolytic damage of the aortic wall. ALI-induced HMGB1 leaks and is captured by arterial macrophages thereby altering their mitochondrial metabolism through RIPK3. RIPK3 promotes mitochondrial fission leading to elevated oxidative stress via DRP1. This triggers MMP12 to lyse arterial matrix, thereby stimulating AAA. Administration of recombinant HMGB1 to WT, but not Ripk3 mice, recapitulates ALI-induced proteolytic collapse of arterial architecture. Deletion of RIPK3 in myeloid cells, DRP1 or MMP12 suppression in ALI-inflicted mice repress arterial stress and brake MMP12 release by transmural macrophages thereby maintaining a strengthened arterial framework refractory to AAA. Our results establish an inter-organ circuitry that alerts arterial macrophages to regulate vascular remodeling.
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http://dx.doi.org/10.1038/s41467-020-18088-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453029PMC
August 2020

Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis.

Nat Cell Biol 2020 09 24;22(9):1130-1142. Epub 2020 Aug 24.

Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.

Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.
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http://dx.doi.org/10.1038/s41556-020-0560-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484425PMC
September 2020

Targeting Piezo1 unleashes innate immunity against cancer and infectious disease.

Sci Immunol 2020 08;5(50)

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.

Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We found signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 with a peptide inhibitor was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of in myeloid cells protected against cancer and increased survival in polymicrobial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing the retinoblastoma gene We further show that Piezo1-mediated silencing of is regulated via up-regulation of histone deacetylase 2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immunosuppressive myelopoiesis in cancer and infectious disease.
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http://dx.doi.org/10.1126/sciimmunol.abb5168DOI Listing
August 2020

Regulation and modulation of antitumor immunity in pancreatic cancer.

Nat Immunol 2020 10 17;21(10):1152-1159. Epub 2020 Aug 17.

S.A. Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA.

Pancreatic ductal adenocarcinoma carries a dismal prognosis, and outcomes have improved little with modern therapeutics. Checkpoint-based immunotherapy has failed to elicit responses in the vast majority of patients with pancreatic cancer. Alongside tumor cell-intrinsic mechanisms associated with oncogenic KRAS-induced inflammation, the tolerogenic myeloid cell infiltrate has emerged as a critical impediment to adaptive antitumor immune responses. Furthermore, the discovery of an intratumoral microbiome and the elucidation of host-microbe interactions that curtail antitumor immunity also present opportunities for intervention. Here we review the mechanisms of immunotherapy resistance in pancreatic ductal adenocarcinoma and discuss strategies to directly augment T cell responses in parallel with myeloid cell- and microbiome-targeted approaches that may enable immune-mediated control of this malignancy.
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http://dx.doi.org/10.1038/s41590-020-0761-yDOI Listing
October 2020

Epigenetic CRISPR Screens Identify as a Therapeutic Vulnerability in Non-Small Cell Lung Cancer.

Cancer Res 2020 09 9;80(17):3556-3567. Epub 2020 Jul 9.

Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.

Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens and and identified the histone chaperone nucleophosmin 1 () as a potential therapeutic target. Genetic ablation of significantly attenuated tumor progression and . Furthermore, -mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support as a therapeutic vulnerability in NSCLC. SIGNIFICANCE: Epigenome-wide CRISPR knockout screens identify as a novel metabolic vulnerability and demonstrate that targeting is a new therapeutic opportunity for patients with NSCLC.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493834PMC
September 2020

Progress Toward Identifying Exact Proxies for Predicting Response to Immunotherapies.

Front Cell Dev Biol 2020 17;8:155. Epub 2020 Mar 17.

PureTech Health PLC, Boston, MA, United States.

Clinical value and utility of checkpoint inhibitors, a drug class targeting adaptive immune suppression pathways (PD-1, PDL-1, and CTLA-4), is growing rapidly and maintains status of a landmark achievement in oncology. Their efficacy has transformed life expectancy in multiple deadly cancer types (melanoma, lung cancer, renal/urothelial carcinoma, certain colorectal cancers, lymphomas, etc.). Despite significant clinical development efforts, therapeutic indication of approved checkpoint inhibitors are not as wide as the oncology community and patients would like them to be, potentially bringing into question their universal efficacy across tumor histologies. With the main goal of expanding immunotherapy applications, identifying of biomarkers to accurately predict therapeutic response and treatment related side-effects are a paramount need in the field. Specificities surrounding checkpoint inhibitors in clinic, such as unexpected tumor response patterns (pseudo- and hyper-progression), late responders, as well as specific immune mediated toxicities, complicate the management of patients. They stem from the complexities and dynamics of the tumor/host immune interactions, as well as baseline tumor biology. Search for clinically effective biomarkers therefore calls for a holistic approach, rather than implementation of a single analyte. The goal is to achieve dynamic and comprehensive acquisition, analyses and interpretation of immunological and biologic information about the tumor and the immune system, and to compute these parameters into an actionable, maximally predictive value at the individual patient level. Limitation delaying swift incorporation of validated immuno-oncology biomarkers span from standardized biospecimens acquisition and processing, selection of proficient biomarker discovery and validation methods, to establishing multidisciplinary consortiums and data sharing platforms. Multi-disciplinary efforts have already yielded some approved (PDL-1 and MSI-status) and other advanced tests (TMB, neoantigen pattern, and TIL infiltration rate). Importantly, clinical trial taskforces now recognize the imperative of the biomarker-driven trial design and execution, to enable translating biomarker discoveries into the clinical setting. This will ensure we utilize the "conspiracy" between the peripheral and intra-tumoral dynamic markers in shaping responses to checkpoint blockade, for the ultimate patient benefit.
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http://dx.doi.org/10.3389/fcell.2020.00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092703PMC
March 2020

PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Nat Immunol 2020 04 9;21(4):442-454. Epub 2020 Mar 9.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1 T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4 T cells, which prevented activation, reduced T1-polarization and directed T17-differentiation. PD-L1 signaling also induced an anergic T-betIFN-γ phenotype in CD8 T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1 T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1 T cells engaged PD-1 macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1 T cells have diverse tolerogenic effects on tumor immunity.
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http://dx.doi.org/10.1038/s41590-020-0620-xDOI Listing
April 2020

Regulatory T Cells Keep Pancreatic Cancer at Bay.

Cancer Discov 2020 03;10(3):345-347

S. Arthur Localio Laboratory and Department of Surgery, New York University School of Medicine, New York, New York.

Although CD4 FOXP3 T regulatory (Treg) cells are well-known mediators of immunologic tolerance, their influences in the tumor microenviroment are incompletely understood. Writing in this issue of , Zhang and colleagues demonstrate that in pancreatic cancer, Treg cells promote the differentiation of tumor-restraining myofibroblastic cancer-associated fibroblasts, challenging the existing notion that Treg cells enable tumor progression..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0002DOI Listing
March 2020

Open access availability of anatomy papers presented at meetings of the American and British Associations of Clinical Anatomists.

Clin Anat 2021 Jul 6;34(5):660-667. Epub 2020 Mar 6.

Department of Trauma and Orthopaedics, Queen Elizabeth Woolwich, London, UK.

Introduction: Dissemination of research depends on published work being accessible. In many disciplines open access (OA) research is more frequently cited, although this has never before been demonstrated amongst anatomy publications. The objective of this study was to assess a selection of published anatomy papers to determine the effect of gold and bronze OA availability on citation rates.

Materials And Methods: Taken together, 625 peer-reviewed publications were identified from 2927 abstracts presented at meetings of AACA (2003-2010) and BACA (2000-2015).

Results: In total 18.75% (69 of 368) of papers presented at BACA and 21.79% (56 of 257) of those presented at AACA reached OA publication.  Citation rates are significantly higher amongst OA papers as compared to non-OA papers presented at these two anatomy conferences (OA 18.95, Non-OA 15.14 p = 0.047). OA papers were most commonly themed around education and pure anatomy.

Conclusions: The average OA publication rate of 20.0% in anatomical research arising from these conferences is significantly lower than the average rate for scientific research. Citation rates are significantly higher amongst OA anatomy papers presented at these two conferences.
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http://dx.doi.org/10.1002/ca.23580DOI Listing
July 2021

Detection of pancreatic ductal adenocarcinoma with galectin-9 serum levels.

Oncogene 2020 04 13;39(15):3102-3113. Epub 2020 Feb 13.

Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, University of Dresden, Dresden, Germany.

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to checkpoint blockade, such as anti-CTLA-4 and anti-PD-1. Galectin-9, a β-galactoside-binding lectin, promotes immune suppression through T-cell inhibition, and programming of tolerogenic macrophages. Of all cancers tested, PDAC showed the highest expression of LGALS9 (galectin-9) mRNA. We analyzed formalin-fixed and paraffin-embedded specimens from 83 patients with PDAC stained for galectin-9. Using flow cytometry, we determined galectin-9 expression on immune cells from tumor and matched blood samples from 12 patients with resectable PDAC. Furthermore, we analyzed galectin-9 serum levels by enzyme-linked immunosorbent assay using serum samples from 70 patients with PDAC, from 36 individuals with benign pancreatic disease, and from 28 healthy controls. Galectin-9 was highly expressed in human PDAC compared with normal pancreas and present on both tumor and immune cells. Tumor-infiltrating immune cells, especially CD3 T cells, showed upregulation of galectin-9 compared with immune cells from matched blood. Blood γδ T cells from PDAC patients had higher galectin-9 expression than γδ T cells from healthy individuals. Galectin-9 polarized macrophages toward a protumoral M2 phenotype leading to suppressed T-cell cytokine secretion. Furthermore, serum concentration of galectin-9 was able to discriminate PDAC from benign pancreatic disease and healthy individuals, and was prognostic for stage IV patients. Galectin-9 is a new biomarker for the detection of PDAC.
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http://dx.doi.org/10.1038/s41388-020-1186-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142017PMC
April 2020

CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer.

Cancer Cell 2020 01 26;37(1):37-54.e9. Epub 2019 Dec 26.

Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.

Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.
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http://dx.doi.org/10.1016/j.ccell.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277075PMC
January 2020

Upregulation of ZIP14 and Altered Zinc Homeostasis in Muscles in Pancreatic Cancer Cachexia.

Cancers (Basel) 2019 Dec 18;12(1). Epub 2019 Dec 18.

Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY 10032, USA.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type in which the mortality rate approaches the incidence rate. More than 85% of PDAC patients experience a profound loss of muscle mass and function, known as cachexia. PDAC patients with this condition suffer from decreased tolerance to anti-cancer therapies and often succumb to premature death due to respiratory and cardiac muscle wasting. Yet, there are no approved therapies available to alleviate cachexia. We previously found that upregulation of the metal ion transporter, , and altered zinc homeostasis are critical mediators of cachexia in metastatic colon, lung, and breast cancer models. Here, we show that a similar mechanism is likely driving the development of cachexia in PDAC. In two independent experimental metastasis models generated from the murine PDAC cell lines, Pan02 and FC1242, we observed aberrant expression and increased zinc ion levels in cachectic muscles. Moreover, in advanced PDAC patients, high levels of ZIP14 in muscles correlated with the presence of cachexia. These studies underscore the importance of altered ZIP14 function in PDAC-associated cachexia development and highlight a potential therapeutic opportunity for improving the quality of life and prolonging survival in PDAC patients.
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http://dx.doi.org/10.3390/cancers12010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016633PMC
December 2019

Epigenetic CRISPR Screen Identifies as an Immunotherapeutic Target in -Mutant Lung Adenocarcinoma.

Cancer Discov 2020 02 19;10(2):270-287. Epub 2019 Nov 19.

Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with -mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an CRISPR screen in a / LUAD model. Our data showed that loss of the histone chaperone in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy. SIGNIFICANCE: Using an epigenetic CRISPR screen, we identified as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007372PMC
February 2020

Harnessing the Microbiome for Pancreatic Cancer Immunotherapy.

Trends Cancer 2019 11 4;5(11):670-676. Epub 2019 Nov 4.

Department of Surgery, NYU School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA. Electronic address:

Late-stage pancreatic cancer harbors a fibrotic and immune-excluded tumor microenvironment that impedes immunotherapy success. A key to unlocking pancreatic cancer immunotherapy may be treating early-stage pancreatic cancer, when peripancreatic inflammation promoted by the microbiome potentiates oncogenic signaling and suppresses innate and adaptive immunity. Hence, understanding the role of microbiota in pancreatic cancer initiation, progression, and immunosuppression is crucial. We propose that not only are microbiota targets for immunomodulation in this disease, but also that microbiome profiling has a potential role in pancreatic cancer screening. Furthermore, combining microbiome profiling with liquid and tissue biopsy may validate the early pancreatic cancer treatment approach of microbiome modulation and immunotherapy.
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http://dx.doi.org/10.1016/j.trecan.2019.10.005DOI Listing
November 2019

Targeting the interleukin-17 immune axis for cancer immunotherapy.

J Exp Med 2020 01;217(1)

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY.

The role of IL-17 in cancer remains controversial. Emerging evidence suggests that during early oncogenesis IL-17 supports tumor growth, whereas in established tumors IL-17 production by γδ and Th17 cells potentiates antitumor immunity. Consequently, γδ and Th17 cells are attractive targets for immunotherapy in the IL-17 immune axis. To optimize IL-17-based immunotherapy, a deeper understanding of the cytokines dictating IL-17 production and the polarity of γδ and Th17 cells is critical. Here, we delve into the dichotomous roles of IL-17 in cancer and provide insight into the tumor microenvironment conducive for successful IL-17-based γδ and Th17 cell immunotherapy.
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http://dx.doi.org/10.1084/jem.20190456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037254PMC
January 2020

The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL.

Nature 2019 10 2;574(7777):264-267. Epub 2019 Oct 2.

S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, NY, USA.

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA). However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species-but not species in the genera Candida, Saccharomyces or Aspergillus-accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment-or knockdown of C3aR in tumour cells-were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl- (also known as Mbl2) or C3-deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.
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http://dx.doi.org/10.1038/s41586-019-1608-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858566PMC
October 2019

Microbes as biomarkers and targets in pancreatic cancer.

Nat Rev Clin Oncol 2019 11;16(11):665-666

S.A. Localio Laboratory, Department of Surgery, NYU School of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41571-019-0276-3DOI Listing
November 2019

γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming.

Hepatology 2020 02 31;71(2):477-494. Epub 2019 Dec 31.

Department of Surgery, S.A. Localio Laboratory, New York University School of Medicine, New York, NY.

Background And Aims: The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH).

Approach And Results: We found that in SH, γδT cells are recruited to the liver by C-C chemokine receptor (CCR) 2, CCR5, and nucleotide-binding oligomerization domain-containing protein 2 signaling and are skewed toward an interleukin (IL)-17A phenotype in an inducible costimulator (ICOS)/ICOS ligand-dependent manner. γδT cells exhibit a distinct Vγ4 , PD1 , Ly6C CD44 phenotype in SH. Moreover, γδT cells up-regulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced SH and accelerates disease resolution.

Conclusions: We demonstrate that hepatic γδT cells exacerbate SH, independent of IL-17 expression, by mitigating conventional CD4 T-cell expansion and modulating their inflammatory program by CD1d-dependent vascular endothelial growth factor expression.
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http://dx.doi.org/10.1002/hep.30952DOI Listing
February 2020

Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

Cancer Discov 2019 09 2;9(9):1288-1305. Epub 2019 Jul 2.

Department of Medicine, New York University School of Medicine, New York, New York.

Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβCD4CD8NK1.1 innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17 cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4 and CD8 T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726581PMC
September 2019

Failure Rates of Base of Thumb Arthritis Surgery: A Systematic Review.

J Hand Surg Am 2019 Sep 28;44(9):728-741.e10. Epub 2019 Jun 28.

Department of Plastic, Reconstructive and Hand Surgery, Peninsula Health, Frankston; Peninsula Clinical School, Central Clinical School, Monash University, The Alfred Centre, Melbourne; Department of Surgery, School of Clinical Sciences, Monash Medical Centre, Clayton, Victoria, Australia. Electronic address:

Purpose: The purpose of the current review was to estimate failure rates of trapeziometacarpal (TMC) implants and compare against failure rates of nonimplant techniques for surgical treatment of TMC joint (basal thumb joint) arthritis.

Methods: A systematic review was conducted to identify articles reporting on thumb implant arthroplasty and on nonimplant arthroplasty techniques for treatment of base of thumb arthritis in the English literature. The collected data were combined to calculate failure rates per 100 procedure-years. Failure was defined by the requirement for a secondary salvage procedure. The failure rates between different implant and nonimplant arthroplasty groups were compared directly and implants with higher than anticipated failure rates were identified.

Results: One hundred twenty-five articles on implant arthroplasty and 33 articles on the outcome of nonimplant surgical arthroplasty of the TMC joint were included. The implant arthroplasty failure rates per 100 procedure-years were total joint replacement (2.4), hemiarthroplasty (2.5), interposition with partial trapezial resection (4.5), interposition with complete trapezial resection (1.7), and interposition with no trapezial resection (4.5). The nonimplant arthroplasty failure rates per 100 procedure-years were: trapeziectomy (0.49), joint fusion (0.52), and trapeziectomy with ligament reconstruction ± tendon interposition (0.23).

Conclusions: Several implant designs (arthroplasties) had high rates of failure due to aseptic loosening, dislocation, and persisting pain. Furthermore, some implants had higher than anticipated failure rates than other implants within each class. Overall, the failure rates of nonimplant techniques were lower than those of implant arthroplasty.

Type Of Study/level Of Evidence: Therapeutic IV.
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http://dx.doi.org/10.1016/j.jhsa.2019.05.003DOI Listing
September 2019

Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.

ACS Med Chem Lett 2019 Jun 9;10(6):857-862. Epub 2019 May 9.

Pattern Recognition Receptor DPU and Medicinal Science & Technology, GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania 19426, United States.

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound ). Compound potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580371PMC
June 2019
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