Publications by authors named "Richard A Friedman"

104 Publications

Randomized Controlled Trial of the Gastrin/CCK Receptor Antagonist Netazepide in Patients with Barrett's Esophagus.

Cancer Prev Res (Phila) 2021 Jun 29;14(6):675-682. Epub 2021 Mar 29.

Department of Medicine, Columbia University Irving Medical Center, New York, New York.

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm, SD 620.7; placebo: +307.8 Ki67+ cells/mm, SD 640.3; = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype () and certain cancer-associated markers (), and decreased expression of intestinal markers , and No serious adverse events related to study drug occurred. The gastrin/CCK receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus. Treatment of patients with Barrett's esophagus with a gastrin/CCK receptor antagonist did not have obvious chemopreventive effects.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0050DOI Listing
June 2021

Frailty subtypes and recovery in older survivors of acute respiratory failure: a pilot study.

Thorax 2021 04 9;76(4):350-359. Epub 2020 Dec 9.

Pulmonary, Allergy, and Critical Care, Columbia University Irving Medical Center, New York, New York, USA.

Background: Identifying subtypes of acute respiratory failure survivors may facilitate patient selection for post-intensive care unit (ICU) follow-up clinics and trials.

Methods: We conducted a single-centre prospective cohort study of 185 acute respiratory failure survivors, aged ≥ 65 years. We applied latent class modelling to identify frailty subtypes using frailty phenotype and cognitive impairment measurements made during the week before hospital discharge. We used Fine-Gray competing risks survival regression to test associations between frailty subtypes and recovery, defined as returning to a basic Activities of Daily Living disability count less than or equal to the pre-hospitalisation count within 6 months. We characterised subtypes by pre-ICU frailty (Clinical Frailty Scale score ≥ 5), the post-ICU frailty phenotype, and serum inflammatory cytokines, hormones and exosome proteomics during the week before hospital discharge.

Results: We identified five frailty subtypes. The recovery rate decreased 49% across each subtype independent of age, sex, pre-existing disability, comorbidity and Acute Physiology and Chronic Health Evaluation II score (recovery rate ratio: 0.51, 95% CI 0.41 to 0.63). Post-ICU frailty phenotype prevalence increased across subtypes, but pre-ICU frailty prevalence did not. In the subtype with the slowest recovery, all had cognitive impairment. The three subtypes with the slowest recovery had higher interleukin-6 levels (p=0.03) and a higher prevalence of ≥ 2 deficiencies in insulin growth factor-1, dehydroepiandrostersone-sulfate, or free-testosterone (p=0.02). Exosome proteomics revealed impaired innate immunity in subtypes with slower recovery.

Conclusions: Frailty subtypes varied by prehospitalisation frailty and cognitive impairment at hospital discharge. Subtypes with the slowest recovery were similarly characterised by greater systemic inflammation and more anabolic hormone deficiencies at hospital discharge.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187474PMC
April 2021

Analysis of 16S rRNA genes reveals reduced Fusobacterial community diversity when translocating from saliva to GI sites.

Gut Microbes 2020 11;12(1):1-13

Division of Periodontics, College of Dental Medicine, Columbia University Irving Medical Center , New York, NY, USA.

is a Gram-negative oral commensal anaerobe which has been increasingly implicated in various gastrointestinal (GI) disorders, including inflammatory bowel disease, appendicitis, GI cancers. The oral cavity harbors a diverse group of , and it is postulated that in the GI tract originate from the mouth. It is not known, however, if all oral translocate to the GI sites with equal efficiencies. Therefore, we amplified 16S rRNA genes of and , two closely related oral species from matched saliva, gastric aspirates, and colon or ileal pouch aspirates of three patients with inflammatory bowel disease (IBD) and three healthy controls, and saliva alone from seven patients with either active IBD or IBD in remission. The 16S rRNA gene amplicons were cloned, and the DNA sequences determined by Sanger sequencing. The results demonstrate that fusobacterial community composition differs more significantly between the oral and GI sites than between different individuals. The oral communities demonstrate the highest level of variation and have the richest pool of unique sequences, with certain nodes/strains enriched in the GI tract and others diminished during translocation. The gastric and colon/pouch communities exhibit reduced diversity and are more closely related, possibly due to selective pressure in the GI tract. This study elucidates selective translocation of oral fusobacteria to the GI tract. Identification of specific transmissible clones will facilitate risk assessment for developing -implicated GI disorders.
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http://dx.doi.org/10.1080/19490976.2020.1814120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577115PMC
November 2020

NIMH's Straight and Neural Path: The Road to Killing Clinical Psychiatric Research.

Psychiatr Serv 2020 11 23;71(11):1096-1097. Epub 2020 Sep 23.

Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York (Markowitz); Department of Clinical Therapeutics, New York State Psychiatric Institute, New York (Markowitz); Department of Psychiatry, Weill Cornell Medical College, New York (Friedman).

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http://dx.doi.org/10.1176/appi.ps.202000057DOI Listing
November 2020

DNMT1 and DNMT3B regulate tumorigenicity of human prostate cancer cells by controlling RAD9 expression through targeted methylation.

Carcinogenesis 2021 02;42(2):220-231

Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

Prostate cancer is the second most common type of cancer and the second leading cause of cancer death in American men. RAD9 stabilizes the genome, but prostate cancer cells and tumors often have high quantities of the protein. Reduction of RAD9 level within prostate cancer cells decreases tumorigenicity of nude mouse xenographs and metastasis phenotypes in culture, indicating that RAD9 overproduction is essential for the disease. In prostate cancer DU145 cells, CpG hypermethylation in a transcription suppressor site of RAD9 intron 2 causes high-level gene expression. Herein, we demonstrate that DNA methyltransferases DNMT1 and DNMT3B are highly abundant in prostate cancer cells DU145, CWR22, LNCaP and PC-3; yet, these DNMTs bind primarily to the transcription suppressor in DU145, the only cells where methylation is critical for RAD9 regulation. For DU145 cells, DNMT1 or DNMT3B shRNA reduced RAD9 level and tumorigenicity, and RAD9 ectopic expression restored this latter activity in the DNMT knockdown cells. High levels of RAD9, DNMT1, DNMT3B and RAD9 transcription suppressor hypermethylation were significantly correlated in prostate tumors, and not in normal prostate tissues. Based on these results, we propose a novel model where RAD9 is regulated epigenetically by DNMT1 and DNMT3B, via targeted hypermethylation, and that consequent RAD9 overproduction promotes prostate tumorigenesis.
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http://dx.doi.org/10.1093/carcin/bgaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905840PMC
February 2021

Why Humans Are Vulnerable to Conspiracy Theories.

Psychiatr Serv 2021 01 24;72(1):3-4. Epub 2020 Jul 24.

Department of Psychiatry, Weill Cornell Medical College, New York.

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http://dx.doi.org/10.1176/appi.ps.202000348DOI Listing
January 2021

RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in macrophage inflammation and cholesterol metabolism.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.

Despite advances in lipid-lowering therapies, people with diabetes continue to experience more limited cardiovascular benefits. In diabetes, hyperglycemia sustains inflammation and preempts vascular repair. We tested the hypothesis that the receptor for advanced glycation end-products (RAGE) contributes to these maladaptive processes. We report that transplantation of aortic arches from diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene encoding RAGE) versus WT diabetic recipient mice accelerated regression of atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms principally to the recipient macrophages and linked RAGE to interferon signaling. Specifically, deletion of Ager in the regressing diabetic plaques downregulated interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry studies colocalized IRF7 and macrophages in both murine and human atherosclerotic plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene expression and regulated a host of genes linked to cholesterol efflux and homeostasis. Collectively, this work adds a new dimension to the immunometabolic sphere of perturbations that impair regression of established diabetic atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular repair in diabetes.
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http://dx.doi.org/10.1172/jci.insight.137289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406264PMC
July 2020

Incidence of arrhythmias and electrocardiographic abnormalities in symptomatic pediatric patients with PCR-positive SARS-CoV-2 infection, including drug-induced changes in the corrected QT interval.

Heart Rhythm 2020 11 1;17(11):1960-1966. Epub 2020 Jul 1.

Section of Pediatric Cardiology and; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health System, Donald and Barbara Zucker School of Medicine at Hofstra University, New Hyde Park, New York.

Background: There is limited data regarding the electrophysiological abnormalities and arrhythmias in children with COVID-19, including those associated with treatment using potentially proarrhythmic hydroxychloroquine (HCQ) and azithromycin (AZN).

Objectives: To describe the electrophysiologic findings and arrhythmias associated with pediatric COVID-19 and its treatment.

Methods: A single-center retrospective chart review was undertaken and included all patients with (1) symptoms of COVID-19 and (2) PCR-positive nasopharyngeal swabs for SARS-CoV-2 who were placed on continuous telemetry for the duration of their hospitalization during March through May, 2020.

Results: Thirty-six patients were included in the study. Significant arrhythmias were found in 6 (nonsustained ventricular tachycardia in 5 and sustained atrial tachycardia in 1). All were self-resolving and half prompted prophylactic antiarrhythmic therapy. Patients with significant arrhythmias were likely to have noncardiac comorbidities (4/6), but these were not more common than in patients without arrhythmias (20/30, P = 1). The use of HCQ was associated with statistically significant QTc prolongation (413 ± 19 ms vs 425 ± 16 ms, P =.005). QTc was not statistically different in patients with and without arrhythmias (425 ± 15 ms vs 425 ± 15 ms, P = 1).

Conclusions: In pediatric patients with PCR-positive active COVID-19 infection, significant arrhythmias are infrequent, but are more common than expected in a general pediatric population. Comorbidities are not more common in patients with arrhythmias than in patients without arrhythmias. COVID-19 treatment using HCQ is associated with QTc prolongation but was not associated with arrhythmias in pediatric patients.
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http://dx.doi.org/10.1016/j.hrthm.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328618PMC
November 2020

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

Gastroenterology 2020 08 20;159(2):575-590. Epub 2020 Apr 20.

Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Background & Aims: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis.

Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5 (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB.

Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5 cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5 cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5 cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation.

Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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http://dx.doi.org/10.1053/j.gastro.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484392PMC
August 2020

and Mutations Promote 4NQO-Initated Head and Neck Tumor Progression and Metastasis in Mice.

Mol Cancer Res 2020 06 9;18(6):822-834. Epub 2020 Mar 9.

Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.

The PI3K signaling pathway is frequently mutated in head and neck squamous cell carcinoma (HNSCC), often via gain-of-function (GOF) mutations in the gene. Here, we present novel genetically engineered mouse models (GEMM) carrying a GOF allele (E20) alone or in combination with heterozygous - (p53) mutation with tissue-specific expression to interrogate the role of oncogenic in transformation of upper aerodigestive track epithelium. We demonstrated that the GOF mutation promoted progression of 4-nitroquinoline 1-oxide-induced oral squamous cell carcinoma (OSCC) in both E20 single mutant and E20/p53 double mutant mice, with frequent distal metastasis detected only in E20/p53 GEMM. Similar to in human OSCC, loss of p16 was associated with progression of OSCC in these mice. RNA-seq analyses revealed that among the common genes differentially expressed in primary OSCC cell lines derived from E20, p53, and E20/p53 GEMMs compared with those from the wild-type mice, genes associated with proliferation and cell cycle were predominantly represented, which is consistent with the progressive loss of p16 detected in these GEMMs. Importantly, all of these OSCC primary cell lines exhibited enhanced sensitivity to BYL719 and cisplatin combination treatment in comparison with cisplatin alone and , regardless of p53 and/or p16 status. Given the prevalence of mutations in and the PI3K pathways in HNSCC in conjunction with loss of p16 genetically or epigenetically, this universal increased sensitivity to cisplatin and BYL719 combination therapy in cancer cells with mutation represents an opportunity to a subset of patients with HNSCC. IMPLICATIONS: Our results suggest that combination therapy of cisplatin and PI3K inhibitor may be worthy of consideration in patients with HNSCC with mutation.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272268PMC
June 2020

Targeting MEK5 impairs nonhomologous end-joining repair and sensitizes prostate cancer to DNA damaging agents.

Oncogene 2020 03 24;39(12):2467-2477. Epub 2020 Jan 24.

Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that nonhomologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease.
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http://dx.doi.org/10.1038/s41388-020-1163-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085449PMC
March 2020

Meeting the challenges of medical student mental health and well-being today.

Med Educ 2020 03;54(3):183-185

Department of Psychiatry, Weill Cornell Medicine, Cornell University, New York, New York, USA.

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http://dx.doi.org/10.1111/medu.14064DOI Listing
March 2020

A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis.

Cell Rep 2019 07;28(3):773-791.e7

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30(th) Street, New York, NY 10016, USA. Electronic address:

Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager, the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation-processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.
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http://dx.doi.org/10.1016/j.celrep.2019.06.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686683PMC
July 2019

High-resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma.

Int J Cancer 2019 11 2;145(10):2754-2766. Epub 2019 May 2.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center (CUIMC), New York, NY.

The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett's esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of nondysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high-resolution assays. We tested BE tissues from 74 patients, including 42 nonprogressors from two separate groups of 21 patients each and 32 progressors (16 in a longitudinal cohort before DAC/preprogression-BE and 16 with temporally concurrent but spatially separate DAC/concurrent-BE). We interrogated genome-wide somatic copy number alterations (SCNAs) at the exon level with high-resolution SNP arrays in DNA from formalin-fixed samples histologically confirmed as nondysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B or both in 88% longitudinal BE progressors to DAC vs. 24% in both nonprogressor groups (p = 0.0004). Deletions in other genomic regions were found in 56% of preprogression-BE but only in one nonprogressor-BE (p = 0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent-BE but not earlier in preprogression-BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. nonprogressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.
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http://dx.doi.org/10.1002/ijc.32351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750991PMC
November 2019

The receptor for advanced glycation end products (RAGE) and DIAPH1: unique mechanisms and healing the wounded vascular system.

Expert Rev Proteomics 2019 06 13;16(6):471-474. Epub 2019 Jan 13.

a Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine , New York University School of Medicine , New York , NY , USA.

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http://dx.doi.org/10.1080/14789450.2018.1536551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467738PMC
June 2019

Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness.

Cancer Discov 2018 11 5;8(11):1458-1473. Epub 2018 Sep 5.

Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL- ;-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL- ;LSL- ;-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Subdiaphragmatic vagotomy or knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214763PMC
November 2018

Deletion of the formin Diaph1 protects from structural and functional abnormalities in the murine diabetic kidney.

Am J Physiol Renal Physiol 2018 12 22;315(6):F1601-F1612. Epub 2018 Aug 22.

Diabetes Research Program, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University School of Medicine , New York, New York.

Diaphanous 1 (DIAPH1), a member of the formin family, binds to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE) and is required for RAGE signal transduction. Experiments employing genetic overexpression or deletion of Ager (the gene encoding RAGE) or its pharmacological antagonism implicate RAGE in the pathogenesis of diabetes-associated nephropathy. We hypothesized that DIAPH1 contributes to pathological and functional derangements in the kidneys of diabetic mice. We show that DIAPH1 is expressed in the human and murine diabetic kidney, at least in part in the tubulointerstitium and glomerular epithelial cells or podocytes. To test the premise that DIAPH1 is linked to diabetes-associated derangements in the kidney, we rendered male mice globally devoid of Diaph1 ( Diaph1) or wild-type controls (C57BL/6 background) diabetic with streptozotocin. Control mice received equal volumes of citrate buffer. After 6 mo of hyperglycemia, diabetic Diaph1 mice displayed significantly reduced mesangial sclerosis, podocyte effacement, glomerular basement thickening, and urinary albumin-to-creatinine ratio compared with diabetic mice expressing Diaph1. Analysis of whole kidney cortex revealed that deletion of Diaph1 in diabetic mice significantly reduced expression of genes linked to fibrosis and inflammation. In glomerular isolates, expression of two genes linked to podocyte stress, growth arrest-specific 1 ( Gas1) and cluster of differentiation 36 ( Cd36), was significantly attenuated in diabetic Diaph1 mice compared with controls, in parallel with significantly higher levels of nestin (Nes) mRNA, a podocyte marker. Collectively, these data implicate DIAPH1 in the pathogenesis of diabetes-associated nephropathy and suggest that the RAGE-DIAPH1 axis is a logical target for therapeutic intervention in this disorder.
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http://dx.doi.org/10.1152/ajprenal.00075.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336994PMC
December 2018

Prostate cancer: unmet clinical needs and RAD9 as a candidate biomarker for patient management.

Transl Cancer Res 2018 Jul 14;7(Suppl 6):S651-S661. Epub 2018 Jan 14.

Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, NY, USA.

Prostate cancer is a complex disease, with multiple subtypes and clinical presentations. Much progress has been made in recent years to understand the underlying genetic basis that drives prostate cancer. Such mechanistic information is useful for development of novel therapeutic targets, to identify biomarkers for early detection or to distinguish between aggressive and indolent disease, and to predict treatment outcome. Multiple tests have become available in recent years to address these clinical needs for prostate cancer. We describe several of these assays, summarizing test details, performance characteristics, and acknowledging their limitations. There is a pressing unmet need for novel biomarkers that can demonstrate improvement in these areas. We introduce one such candidate biomarker, RAD9, describe its functions in the DNA damage response, and detail why it can potentially fill this void. has multiple roles in prostate carcinogenesis, making it potentially useful as a clinical tool for men with prostate cancer. was originally identified as a radioresistance gene, and subsequent investigations revealed several key functions in the response of cells to DNA damage, including involvement in cell cycle checkpoint control, at least five DNA repair pathways, and apoptosis. Further studies indicated aberrant overexpression in approximately 45% of prostate tumors, with a strong correlation between RAD9 abundance and cancer stage. A causal relationship between RAD9 and prostate cancer was first demonstrated using a mouse model, where tumorigenicity of human prostate cancer cells after subcutaneous injection into nude mice was diminished when RNA interference was used to reduce the normally high levels of the protein. In addition to activity needed for the initial development of tumors, cell culture studies indicated roles for RAD9 in promoting prostate cancer progression by controlling cell migration and invasion through regulation of ITGB1 protein levels, and anoikis resistance by modulating AKT activation. Furthermore, RAD9 enhances the resistance of human prostate cancer cells to radiation in part by regulating ITGB1 protein abundance. RAD9 binds androgen receptor and inhibits androgen-induced androgen receptor's activity as a transcription factor. Moreover, RAD9 also acts as a gene-specific transcription factor, through binding p53 consensus sequences at target gene promoters, and this likely contributes to its oncogenic activity. Given these diverse and extensive activities, RAD9 plays important roles in the initiation and progression of prostate cancer and can potentially serve as a valuable biomarker useful in the management of patients with this disease.
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http://dx.doi.org/10.21037/tcr.2018.01.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071673PMC
July 2018

Profiling of Stem/Progenitor Cell Regulatory Genes of the Synovial Joint by Genome-Wide RNA-Seq Analysis.

Biomed Res Int 2018 26;2018:9327487. Epub 2018 Jun 26.

Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St., PH7 East CDM, New York, NY 10032, USA.

Synovial joints suffer from arthritis and trauma that may be severely debilitative. Despite robust investigations in the roles of individual genes in synovial joint development and arthritis, little is known about global profiles of genes that regulate stem/progenitor cells of a synovial joint. The temporomandibular joint is a poorly understood synovial arthrosis with few clinical treatment options. Here, we isolated the articular and mature zones of the mandibular condyle by laser capture microdissection, performed genome-wide profiling, and analyzed molecular signaling pathways relevant to stem/progenitor cell functions. A total of 804 genes were differentially expressed between the articular and mature zones. Pathway analyses revealed 29 enriched signaling pathways, including the PI3K-Akt, Wnt, and Toll-like receptor signaling pathways that may regulate stem/progenitor cell homeostasis and differentiation into the chondrocyte lineage. Upstream regulator analyses further predicted potential upstream key regulators such as Xbp1, Nupr1, and Hif1a, and associated underlying mechanism networks were described. Among the multiple candidates of growth and transcriptional factors that may regulate stem/progenitor cells, we immunolocalized Sox9, Ihh, Frzb, Dkk1, Lgr5, and TGF3 in the articular and mature zones. These findings provide a comprehensive genetic mapping of growth and transcriptional genes in the articular and mature zones of a synovial joint condyle. Differentially expressed genes may play crucial roles in the regulation of stem/progenitor cells in development, homeostasis, and tissue regeneration.
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http://dx.doi.org/10.1155/2018/9327487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038687PMC
January 2019

Overcoming Tribalism.

Psychiatr Serv 2018 09 26;69(9):946-947. Epub 2018 Jul 26.

Dr. Friedman is with the Department of Psychiatry, Weill Cornell Medical College, New York.

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http://dx.doi.org/10.1176/appi.ps.201800259DOI Listing
September 2018

HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis.

J Clin Invest 2018 06 7;128(6):2436-2451. Epub 2018 May 7.

Department of Medicine, Columbia University, New York, New York, USA.

Cell death is a key driver of disease progression and carcinogenesis in chronic liver disease (CLD), highlighted by the well-established clinical correlation between hepatocellular death and risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Moreover, hepatocellular death is sufficient to trigger fibrosis and HCC in mice. However, the pathways through which cell death drives CLD progression remain elusive. Here, we tested the hypothesis that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) with key roles in acute liver injury, may link cell death to injury responses and hepatocarcinogenesis in CLD. While liver-specific HMGB1 deficiency did not significantly affect chronic injury responses such as fibrosis, regeneration, and inflammation, it inhibited ductular/progenitor cell expansion and hepatocyte metaplasia. HMGB1 promoted ductular expansion independently of active secretion in a nonautonomous fashion, consistent with its role as a DAMP. Liver-specific HMGB1 deficiency reduced HCC development in 3 mouse models of chronic injury but not in a model lacking chronic liver injury. As with CLD, HMGB1 ablation reduced the expression of progenitor and oncofetal markers, a key determinant of HCC aggressiveness, in tumors. In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor signature, and hepatocarcinogenesis in CLD.
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http://dx.doi.org/10.1172/JCI91786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983315PMC
June 2018

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer.

Cancer Cell 2018 01 14;33(1):75-90.e7. Epub 2017 Dec 14.

Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address:

Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras;LSL-Trp53;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.
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http://dx.doi.org/10.1016/j.ccell.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760435PMC
January 2018

Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop.

Cell Stem Cell 2017 Dec 30;21(6):747-760.e7. Epub 2017 Nov 30.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, University of Western Ontario, London, ON N6A 5W9, Canada.

Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here we describe an auto-/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc myeloid cells lie in close anatomical proximity to MB-HSCs and produce histamine, which activates the H receptor on MB-HSCs to promote their quiescence and self-renewal. Depleting histamine-producing cells enforces cell cycle entry, induces loss of serial transplant capacity, and sensitizes animals to chemotherapeutic injury. Increasing demand for myeloid cells via lipopolysaccharide (LPS) treatment specifically recruits MB-HSCs and progenitors into the cell cycle; cycling MB-HSCs fail to revert into quiescence in the absence of histamine feedback, leading to their depletion, while an H agonist protects MB-HSCs from depletion after sepsis. Thus, histamine couples lineage-specific physiological demands to intrinsically primed MB-HSCs to enforce homeostasis.
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http://dx.doi.org/10.1016/j.stem.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975960PMC
December 2017

MicroRNA-21 and Dicer are dispensable for hepatic stellate cell activation and the development of liver fibrosis.

Hepatology 2018 06 18;67(6):2414-2429. Epub 2018 Jan 18.

Department of Medicine, Columbia University, New York, NY.

Fibrosis and cancer represent two major complications of chronic liver disease. MicroRNAs have been implicated in the development of fibrosis and cancer, thus constituting potential therapeutic targets. Here, we investigated the role of microRNA-21 (miR-21), a microRNA that has been implicated in the development of fibrosis in multiple organs and has also been suggested to act as an "oncomir." Accordingly, miR-21 was the microRNA that showed the strongest up-regulation in activated hepatic stellate cells (HSCs) in multiple models of fibrogenesis, with an 8-fold to 24-fold induction compared to quiescent HSCs. However, miR-21 antisense inhibition did not suppress the activation of murine or human HSCs in culture or in liver slices. Moreover, genetic deletion of miR-21 in two independently generated knockout mice or miR-21 antisense inhibition did not alter HSC activation or liver fibrosis in models of toxic and biliary liver injury. Despite a strong up-regulation of miR-21 in injury-associated hepatocellular carcinoma and in cholangiocarcinoma, miR-21 deletion or antisense inhibition did not reduce the development of liver tumors. As inhibition of the most up-regulated microRNA did not affect HSC activation, liver fibrosis, or fibrosis-associated liver cancer, we additionally tested the role of microRNAs in HSCs by HSC-specific Dicer deletion. Although Dicer deletion decreased microRNA expression in HSCs and altered the expression of select genes, it only exerted negligible effects on HSC activation and liver fibrosis.

Conclusion: Genetic and pharmacologic manipulation of miR-21 does not inhibit the development of liver fibrosis and liver cancer. Moreover, suppression of microRNA synthesis does not significantly affect HSC phenotype and activation. (Hepatology 2018;67:2414-2429).
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http://dx.doi.org/10.1002/hep.29627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930143PMC
June 2018

Histidine decarboxylase (HDC)-expressing granulocytic myeloid cells induce and recruit Foxp3 regulatory T cells in murine colon cancer.

Oncoimmunology 2017;6(3):e1290034. Epub 2017 Feb 10.

Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York, NY, USA.

The colorectal tumor microenvironment contains a diverse population of myeloid cells that are recruited and converted to immunosuppressive cells, thus facilitating tumor escape from immunoediting. We have identified a genetically and functionally distinct subset of dynamic bone marrow myeloid cells that are characterized by histidine decarboxylase (HDC) expression. Lineage tracing in Hdc-CreERT2;R26-LSL-tdTomato mice revealed that in homeostasis, there is a strong bias by HDC myeloid cells toward the CD11bLy6G granulocytic lineage, which was accelerated during azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colonic carcinogenesis. More importantly, HDC myeloid cells strongly promoted colonic tumorigenesis, and colon tumor progression was profoundly suppressed by diphtheria toxin A (DTA)-mediated depletion of HDC granulocytic myeloid cells. In addition, tumor infiltration by Foxp3 regulatory T cells (Tregs) was markedly impaired following HDC myeloid cell depletion. We identified an HDC myeloid-derived Cxcl13/Cxcr5 axis that mediated Foxp3 expression and Treg proliferation. Ablation of HDC myeloid cells or disruption of the Cxcl13/Cxcr5 axis by gene knockdown impaired the production and recruitment of Tregs. Cxcl13 induction of Foxp3 expression in Tregs during tumorigenesis was associated with Stat3 phosphorylation. Overall, HDC granulocytic myeloid cells affect CD8 T cells directly and indirectly through the modulation of Tregs and thus appear to play key roles in suppressing tumoricidal immunity.
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http://dx.doi.org/10.1080/2162402X.2017.1290034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384347PMC
February 2017

MC4R-dependent suppression of appetite by bone-derived lipocalin 2.

Nature 2017 03 8;543(7645):385-390. Epub 2017 Mar 8.

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.

Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood-brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone.
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http://dx.doi.org/10.1038/nature21697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975642PMC
March 2017
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