Publications by authors named "Joseph F LaComb"

14 Publications

  • Page 1 of 1

Impact of preoperative antibiotics and other variables on integrated microbiome-host transcriptomic data generated from colorectal cancer resections.

World J Gastroenterol 2021 Apr;27(14):1465-1482

Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, United States.

Background: Integrative multi-omic approaches have been increasingly applied to discovery and functional studies of complex human diseases. Short-term preoperative antibiotics have been adopted to reduce site infections in colorectal cancer (CRC) resections. We hypothesize that the antibiotics will impact analysis of multi-omic datasets generated from resection samples to investigate biological CRC risk factors.

Aim: To assess the impact of preoperative antibiotics and other variables on integrated microbiome and human transcriptomic data generated from archived CRC resection samples.

Methods: Genomic DNA (gDNA) and RNA were extracted from prospectively collected 51 pairs of frozen sporadic CRC tumor and adjacent non-tumor mucosal samples from 50 CRC patients archived at a single medical center from 2010-2020. The 16S rRNA gene sequencing (V3V4 region, paired end, 300 bp) and confirmatory quantitative polymerase chain reaction (qPCR) assays were conducted on gDNA. RNA sequencing (IPE, 125 bp) was performed on parallel tumor and non-tumor RNA samples with RNA Integrity Numbers scores ≥ 6.

Results: PERMANOVA detected significant effects of tumor nontumor histology ( = 0.002) and antibiotics ( = 0.001) on microbial β-diversity, but CRC tumor location (left right), diabetes mellitus not diabetic and Black/African Ancestry (AA) not Black/AA, did not reach significance. Linear mixed models detected significant tumor nontumor histology*antibiotics interaction terms for 14 genus level taxa. QPCR confirmed increased abundance in tumor nontumor groups, and detected significantly reduced bacterial load in the (+)antibiotics group. Principal coordinate analysis of the transcriptomic data showed a clear separation between tumor and nontumor samples. Differentially expressed genes obtained from separate analyses of tumor and nontumor samples, are presented for the antibiotics, CRC location, diabetes and Black/AA race groups.

Conclusion: Recent adoption of additional preoperative antibiotics as standard of care, has a measurable impact on -omics analysis of resected specimens. This study still confirmed increased in tumor.
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http://dx.doi.org/10.3748/wjg.v27.i14.1465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047535PMC
April 2021

Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019.

Clin Gastroenterol Hepatol 2020 Oct 1. Epub 2020 Oct 1.

Division of Gastroenterology, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

Background & Aims: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19.

Methods: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19.

Results: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death.

Conclusions: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.
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http://dx.doi.org/10.1016/j.cgh.2020.09.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527302PMC
October 2020

Single-Pass vs 2-Pass Endoscopic Ultrasound-Guided Fine-Needle Biopsy Sample Collection for Creation of Pancreatic Adenocarcinoma Organoids.

Clin Gastroenterol Hepatol 2021 Apr 29;19(4):845-847. Epub 2020 Feb 29.

Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all malignancies, with a 5-year survival rate <8%. Suspicious lesions are typically diagnosed via endoscopic ultrasound-guided fine-needle aspiration or endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). Fewer needle passes decreases the risk of postprocedure complications, including pancreatitis and hemorrhage, while allowing additional needle passes to be used for adjuvant tissue testing, such as organoid creation and DNA sequencing.
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http://dx.doi.org/10.1016/j.cgh.2020.02.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483221PMC
April 2021

Phospho-valproic acid (MDC-1112) reduces pancreatic cancer growth in patient-derived tumor xenografts and KPC mice: enhanced efficacy when combined with gemcitabine.

Carcinogenesis 2020 07;41(7):927-939

Department of Nutrition, University of California, Davis, One Shields Ave, Davis, CA, USA.

New chemotherapeutic agents are needed for pancreatic cancer (PC). We have previously shown that phospho-valproic acid (MDC-1112) is effective in cell-line xenografts of PC. Here, we explored whether MDC-1112 is effective in additional clinically relevant animal models of PC and whether MDC-1112 enhances the anticancer effect of clinically used chemotherapeutic agents. MDC-1112 alone strongly reduced patient-derived pancreatic tumor xenograft growth, and extended survival of LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) mice. In both models, MDC-1112 inhibited STAT3 activation and its downstream signals, including Bcl-xL and cyclin D1. In human PC cell lines, P-V enhanced the growth inhibitory effect of gemcitabine (GEM), Abraxane and 5-FU, but not that of irinotecan. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of MDC-1112/GEM combination. Furthermore, MDC-1112 enhanced GEM's effect on colony formation, apoptosis, cell migration, and cell invasion. In vivo, MDC-1112 and GEM, given alone, reduced patient-derived pancreatic tumor xenograft growth by 58% and 87%, respectively; whereas MDC-1112/GEM combination reduced tumor growth by 94%, inducing tumor stasis. In conclusion, MDC-1112 should be further explored as a potential agent to be used in combination with GEM for treating PC.
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http://dx.doi.org/10.1093/carcin/bgz170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951062PMC
July 2020

Establishment of three novel cell lines derived from African American patients with colorectal carcinoma: A unique tool for assessing racial health disparity.

Int J Oncol 2018 Oct 31;53(4):1516-1528. Epub 2018 Jul 31.

Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

The incidence and mortality rates of colorectal carcinoma (CRC) are higher among African Americans (AAs) compared with Caucasian Americans (CAs). To assess the molecular properties associated with racial health disparity, three cell lines derived from colorectal tumors of three AA subjects were established. Cellular and molecular characterization of the cell lines designated CHTN06, SB501 and SB521 was performed using standard technologies, including immunofluorescence, electron microscopy, karyotyping, reverse transcription-polymerase chain reaction, ELISA and immunoblot analysis. The histology and morphology of CHTN06 xenografts were examined by hematoxylin and eosin staining. A total of three AA CRC cell lines derived from primary tumors were established and characterized. These cell lines were successfully cultured without immortalization and were found to be tumorigenic as mouse xenografts. In the present study, immunoblotting and immunofluorescence confirmed the expression of proteins known to be dysregulated in CRC, such as p53, DNA mismatch repair proteins and villin-1. Oncogenic miRNAs (i.e., miR-17, miR-21, miR-182, miR-210 and miR-222) were overexpressed in the AA CRC lines compared with the CA CRC lines (HT-29, HCT116 and SW480). Additionally, the AA CRC cell lines exhibited a differential inflammatory profile compared with HT-29 (CA CRC cell line); specifically noted was IL-8 secretion in response to inflammatory stimuli. In conclusion, three novel cell lines derived from AA CRC tissues were generated. These cell lines were characterized as epithelial in nature and exhibited differential expression of several miRNAs and inflammatory responses compared with commercially available cell lines of CA origin. The CRC cell lines CHTN06, SB501 and SB521 represent novel tools that may be used to provide diverse in vitro and in vivo models for studying CRC and racial health disparity.
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http://dx.doi.org/10.3892/ijo.2018.4510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086619PMC
October 2018

Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer.

Cancer Discov 2018 09 31;8(9):1112-1129. Epub 2018 May 31.

Memorial Sloan Kettering Cancer Center, New York, New York.

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125219PMC
September 2018

A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras.

Mol Carcinog 2018 09 8;57(9):1130-1143. Epub 2018 May 8.

Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York.

Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (P < 0.02), and the growth of a human patient-derived tumor xenograft by 47.5% (P < 0.03 vs vehicle control). Mechanistically, CMC2.24 inhibited the Ras-RAF-MEK-ERK pathway. Based on Ras Pull-Down Assays, CMC2.24 inhibited Ras-GTP, the active form of Ras, in MIA PaCa-2 cells and in pancreatic acinar explants isolated from Kras mutant mice, by 90.3% and 89.1%, respectively (P < 0.01, for both). The inhibition of active Ras led to an inhibition of c-RAF, MEK, and ERK phosphorylation by 93%, 91%, and 87%, respectively (P < 0.02, for all) in PC xenografts. Furthermore, c-RAF overexpression partially rescued MIA PaCa-2 cells from the cell growth inhibition by CMC2.24. In addition, downstream of ERK, CMC2.24 inhibited STAT3 phosphorylation levels at the serine 727 residue, enhanced the levels of superoxide anion in mitochondria, and induced intrinsic apoptosis as shown by the release of cytochrome c from the mitochondria to the cytosol and the further cleavage of caspase 9 in PC cells. In conclusion, CMC2.24, a potential Ras inhibitor, is an efficacious agent for PC treatment in preclinical models, deserving further evaluation.
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http://dx.doi.org/10.1002/mc.22830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461215PMC
September 2018

Longitudinal microbiome analysis of single donor fecal microbiota transplantation in patients with recurrent Clostridium difficile infection and/or ulcerative colitis.

PLoS One 2018 31;13(1):e0190997. Epub 2018 Jan 31.

Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America.

Background: Studies of colonoscopic fecal microbiota transplant (FMT) in patients with recurrent CDI, indicate that this is a very effective treatment for preventing further relapses. In order to provide this service at Stony Brook University Hospital, we initiated an open-label prospective study of single colonoscopic FMT among patients with ≥ 2 recurrences of CDI, with the intention of monitoring microbial composition in the recipient before and after FMT, as compared with their respective donor. We also initiated a concurrent open label prospective trial of single colonoscopic FMT of patients with ulcerative colitis (UC) not responsive to therapy, after obtaining an IND permit (IND 15642). To characterize how FMT alters the fecal microbiota in patients with recurrent Clostridia difficile infections (CDI) and/or UC, we report the results of a pilot microbiome analysis of 11 recipients with a history of 2 or more recurrences of C. difficile infections without inflammatory bowel disease (CDI-only), 3 UC recipients with recurrent C. difficile infections (CDI + UC), and 5 UC recipients without a history of C. difficile infections (UC-only).

Method: V3V4 Illumina 16S ribosomal RNA (rRNA) gene sequencing was performed on the pre-FMT, 1-week post-FMT, and 3-months post-FMT recipient fecal samples along with those collected from the healthy donors. Fitted linear mixed models were used to examine the effects of Group (CDI-only, CDI + UC, UC-only), timing of FMT (Donor, pre-FMT, 1-week post-FMT, 3-months post-FMT) and first order Group*FMT interactions on the diversity and composition of fecal microbiota. Pairwise comparisons were then carried out on the recipient vs. donor and between the pre-FMT, 1-week post-FMT, and 3-months post-FMT recipient samples within each group.

Results: Significant effects of FMT on overall microbiota composition (e.g., beta diversity) were observed for the CDI-only and CDI + UC groups. Marked decreases in the relative abundances of the strictly anaerobic Bacteroidetes phylum, and two Firmicutes sub-phyla associated with butyrate production (Ruminococcaceae and Lachnospiraceae) were observed between the CDI-only and CDI + UC recipient groups. There were corresponding increases in the microaerophilic Proteobacteria phylum and the Firmicutes/Bacilli group in the CDI-only and CDI + UC recipient groups. At a more granular level, significant effects of FMT were observed for 81 genus-level operational taxonomic units (OTUs) in at least one of the three recipient groups (p<0.00016 with Bonferroni correction). Pairwise comparisons of the estimated pre-FMT recipient/donor relative abundance ratios identified 6 Gammaproteobacteria OTUs, including the Escherichia-Shigella genus, and 2 Fusobacteria OTUs with significantly increased relative abundance in the pre-FMT samples of all three recipient groups (FDR < 0.05), however the magnitude of the fold change was much larger in the CDI-only and CDI + UC recipients than in the UC-only recipients. Depletion of butyrate producing OTUs, such as Faecalibacterium, in the CDI-only and CDI + UC recipients, were restored after FMT.

Conclusion: The results from this pilot study suggest that the microbial imbalances in the CDI + UC recipients more closely resemble those of the CDI-only recipients than the UC-only recipients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190997PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791968PMC
February 2018

Successful creation of pancreatic cancer organoids by means of EUS-guided fine-needle biopsy sampling for personalized cancer treatment.

Gastrointest Endosc 2018 Jun 9;87(6):1474-1480. Epub 2018 Jan 9.

Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, New York, USA.

Background And Aims: Pancreatic cancer organoids are tumor models of individualized human pancreatic ductal adenocarcinoma (PDA), created from surgical specimens and used for personalized treatment strategies. Unfortunately, most patients with PDA are not operative candidates. Creation of human PDA organoids at the time of initial tumor diagnosis is therefore critical. Our aim was to assess the feasibility of creating human PDA organoids by EUS fine-needle biopsy (EUS-FNB) sampling in patients with PDA.

Methods: In this prospective clinical trial in patients referred to evaluate a pancreatic mass, EUS-FNA was performed for initial onsite diagnosis. Two additional needle passes were performed with a 22-gauge FNB needle for organoid creation. Primary outcome was successful isolation of organoids within 2 weeks of EUS-FNB sampling (P0, no passages), confirmed by organoid morphology and positive genotyping.

Results: Thirty-seven patients with 38 PDA tumors were enrolled. Successful isolation of organoids (P0) was achieved in 33 of 38 tumors (87%). Establishment of PDA organoid lines for ≥5 passages of growth (P5, five passages) was reached in 25 of 38 tumors (66%). In the single patient with successful P5 FNB sampling-derived and P5 surgically derived organoids, there was identical matching of specimens. There were no serious adverse events. Two patients developed bleeding at the EUS-FNB puncture site requiring hemostasis clips.

Conclusions: Pancreatic cancer organoids can be successfully and rapidly created by means of EUS-FNB sampling using a 22-gauge needle at the time of initial diagnosis. Successful organoid generation is essential for precision medicine in patients with pancreatic cancer in whom most are not surgically resectable. (Clinical trial registration number: NCT03140592.).
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http://dx.doi.org/10.1016/j.gie.2017.12.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143289PMC
June 2018

Aberrant DNA Methylation: Implications in Racial Health Disparity.

PLoS One 2016 25;11(4):e0153125. Epub 2016 Apr 25.

Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, 11794, United States of America.

Background: Incidence and mortality rates of colorectal carcinoma (CRC) are higher in African Americans (AAs) than in Caucasian Americans (CAs). Deficient micronutrient intake due to dietary restrictions in racial/ethnic populations can alter genetic and molecular profiles leading to dysregulated methylation patterns and the inheritance of somatic to germline mutations.

Materials And Methods: Total DNA and RNA samples of paired tumor and adjacent normal colon tissues were prepared from AA and CA CRC specimens. Reduced Representation Bisulfite Sequencing (RRBS) and RNA sequencing were employed to evaluate total genome methylation of 5'-regulatory regions and dysregulation of gene expression, respectively. Robust analysis was conducted using a trimming-and-retrieving scheme for RRBS library mapping in conjunction with the BStool toolkit.

Results: DNA from the tumor of AA CRC patients, compared to adjacent normal tissues, contained 1,588 hypermethylated and 100 hypomethylated differentially methylated regions (DMRs). Whereas, 109 hypermethylated and 4 hypomethylated DMRs were observed in DNA from the tumor of CA CRC patients; representing a 14.6-fold and 25-fold change, respectively. Specifically; CHL1, 4 anti-inflammatory genes (i.e., NELL1, GDF1, ARHGEF4, and ITGA4), and 7 miRNAs (of which miR-9-3p and miR-124-3p have been implicated in CRC) were hypermethylated in DNA samples from AA patients with CRC. From the same sample set, RNAseq analysis revealed 108 downregulated genes (including 14 ribosomal proteins) and 34 upregulated genes (including POLR2B and CYP1B1 [targets of miR-124-3p]) in AA patients with CRC versus CA patients.

Conclusion: DNA methylation profile and/or products of its downstream targets could serve as biomarker(s) addressing racial health disparity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153125PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844165PMC
February 2017

The novel agent phospho-glycerol-ibuprofen-amide (MDC-330) inhibits glioblastoma growth in mice: an effect mediated by cyclin D1.

Carcinogenesis 2016 Apr 10;37(4):420-429. Epub 2016 Feb 10.

Department of Family, Population and Preventive Medicine.

Given that glioblastoma multiforme (GBM) is associated with poor prognosis, new agents are urgently needed. We developed phospho-glycerol-ibuprofen-amide (PGIA), a novel ibuprofen derivative, and evaluated its safety and efficacy in preclinical models of GBM, and its mechanism of action using human GBM cells and animal tumor models. Furthermore, we explored whether formulating PGIA in polymeric nanoparticles could enhance its levels in the brain. PGIA was 3.7- to 5.1-fold more potent than ibuprofen in suppressing the growth of human GBM cell lines. PGIA 0.75× IC50 inhibited cell proliferation by 91 and 87% in human LN-229 and U87-MG GBM cells, respectively, and induced strong G1/S arrest.In vivo, compared with control, PGIA reduced U118-MG and U87-MG xenograft growth by 77 and 56%, respectively (P< 0.05), and was >2-fold more efficacious than ibuprofen. Normal human astrocytes were resistant to PGIA, indicating selectivity. Mechanistically, PGIA reduced cyclin D1 levels in a time- and concentration-dependent manner in GBM cells and in xenografts. PGIA induced cyclin D1 degradation via the proteasome pathway and induced dephosphorylation of GSK3β, which was required for cyclin D1 turnover. Furthermore, cyclin D1 overexpression rescued GBM cells from the cell growth inhibition by PGIA. Moreover, the formulation of PGIA in poly-(L)-lactic acid poly(ethylene glycol) polymeric nanoparticles improved its pharmacokinetics in mice, delivering PGIA to the brain. PGIA displays strong efficacy against GBM, crosses the blood-brain barrier when properly formulated, reaching the target tissue, and establishes cyclin D1 as an important molecular target. Thus, PGIA merits further evaluation as a potential therapeutic option for GBM.
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http://dx.doi.org/10.1093/carcin/bgw017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006213PMC
April 2016

Mitochondrial ribosomal RNA (rRNA) methyltransferase family members are positioned to modify nascent rRNA in foci near the mitochondrial DNA nucleoid.

J Biol Chem 2013 Oct 13;288(43):31386-99. Epub 2013 Sep 13.

From the Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794-8651.

We have identified RNMTL1, MRM1, and MRM2 (FtsJ2) as members of the RNA methyltransferase family that may be responsible for the three known 2'-O-ribose modifications of the 16 S rRNA core of the large mitochondrial ribosome subunit. These proteins are confined to foci located in the vicinity of mtDNA nucleoids. They show distinct patterns of association with mtDNA nucleoids and/or mitochondrial ribosomes in cell fractionation studies. We focused on the role of the least studied protein in this set, RNMTL1, to show that this protein interacts with the large ribosomal subunit as well as with a series of non-ribosomal proteins that may be involved in coupling of the rate of rRNA transcription and ribosome assembly in mitochondria. siRNA-directed silencing of RNMTL1 resulted in a significant inhibition of translation on mitochondrial ribosomes. Our results are consistent with a role for RNMTL1 in methylation of G(1370) of human 16 S rRNA.
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http://dx.doi.org/10.1074/jbc.M113.515692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829452PMC
October 2013

Ablation of Iqgap2 protects from diet-induced hepatic steatosis due to impaired fatty acid uptake.

Regul Pept 2012 Jan 1;173(1-3):36-46. Epub 2011 Oct 1.

Program in Genetics, Stony Brook University, Stony Brook, NY 11794, USA.

Unlabelled: Long-chain fatty acids (LCFA) serve as structural components for membrane biogenesis and as primary energy sources during mitochondrial β-oxidation reactions. Hepatic LCFA uptake is complex, with characteristics suggestive of a dual-kinetic model manifested by rapid (carrier-assisted/facilitated) and delayed (passive diffusional) phases. Our previous work using mice deficient of the Iqgap2 gene established a highly novel link between IQGAP2, a putative GTPase-activating protein, and hepatocarcinogenesis. Now we report that Iqgap2 deficiency also results in selective loss of the facilitated phase of hepatocyte LCFA uptake with preservation of the diffusional component. This molecular defect was seen in Iqgap2(-/-) hepatocytes of all ages studied (1-, 4-, 8-months). The loss of facilitated LCFA uptake protected against development of hepatic triglyceride accumulation in Iqgap2-deficient mice fed high-fat diet, consistent with a fundamental role in physiological fat partitioning. These phenotypic changes could not be explained by genetic loss of fatty acid processing proteins known to regulate lipid uptake or metabolic processing pathways. Iqgap2-deficient livers also displayed enhanced insulin sensitivity.

Conclusion: These observations identify a novel property of the putative GTPase-activating protein IQGAP2 in LCFA uptake in vitro and in vivo, and implicate IQGAP2 in an intracellular signaling pathway necessary for functional fatty acid uptake, lipid processing, and, possibly, glucose homeostasis.
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http://dx.doi.org/10.1016/j.regpep.2011.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237762PMC
January 2012