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Open Access Publications from the University of California

Scholarly Works (9 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2020)

The composition and metabolic activity of the gut microbiome are implicated in childhood obesity, though etiology of the disease remains unclear. Using 16S bacterial and ITS2 fungal biomarker sequencing, we identify a precocious gut microbiota in more frequently formula fed 1-month-old infants that relates with higher relative risk for overweight or obesity (OW/OB) phenotypes at two years of age. Integrated shotgun metagenomic and untargeted metabolomic profiling revealed that higher-risk infant microbiomes exhibited accelerated functional maturation and broad-ranging metabolic reprogramming, including evidence for increased fermentation and amino acid catabolism. In vitro, exposure of enterocytes to cell-free fecal extracts of higher-risk infants who became OW/OB at 2-years reprogrammed transcription and cellular function, promoting obesity-associated gene expression and increasing triglyceride absorption. Of several microbial species screened, Candida albicans recapitulated accelerated triglyceride trafficking by enterocytes, via a small, secreted polar molecule in an infant formula-dependent manner. Thus, appropriately paced early life development of microbiome function and metabolism appear crucial determinants of childhood obesity.

  • 1 supplemental file
Cover page: Precocious Infant Gut Microbiome Accelerates Triglyceride Absorption and Promotes Childhood Obesity Risk
  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2012)

Prostate cancer is currently the most prevalent noncutaneous cancer in males. An increase in the number of men diagnosed with indolent, organ-confined disease has lead to the increasing numbers of patients and their physicians selecting active surveillance or "delayed definitive treatment" as a viable approach for managing prostate cancer. However, the selection of appropriate patients for active surveillance has been confounded by sampling errors associated with transrectal ultrasound guided biopsies as well as accurate clinical and imaging biomarkers that predict for aggressive, progressive disease at diagnosis. Multiparametric magnetic resonance (MR) imaging may assist in overcoming this problem; it allows for the identification of the whole gland and a combination of T2-weighted MR imaging, proton MR spectroscopic imaging (1H MRSI), and diffusion-weighted imaging (DWI) can be used to better characterize the aggressiveness of intraglandular cancer at diagnosis. In this retrospective study, we quantitatively analyzed multiparametric MR images from a cohort of active surveillance patients (N=119) to determine the combination of MR imaging techniques that best predicted disease progression on active surveillance. Fifty-nine of 119 patients progressed within 43 ± 32 months on active surveillance. Receiver-operator characteristic (ROC) curve analysis indicated that all three techniques (T2 MRI, MRSI, DWI) demonstrated similar modest accuracies in predicting progression on AS (AUC of 0.59, 0.63 and 0.61, respectively). The best prediction of prostate cancer progression in AS patients was when all three techniques were positive for cancer presence, yielding an odds ratio for progression of 2.91 (95% CI 1.19 - 7.08) as compared to all other findings. Whereas a negative finding for all 3 tests for patients that were appropriate for AS yielded an odds ratio for no progression of 2.84 (95% CI = 1.26 - 6.37) as compared to all other findings. In conclusion, multiparametric MR imaging could play a valuable role in better selecting patients for active surveillance.

    Cover page: Predicting Disease Progression with Multiparametric Magnetic Resonance Imaging of Prostate Cancer Managed with Active Surveillance
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2020)
    The inner nuclear membrane (INM) selectively accumulates proteins that are essential for nuclear functions; however, overaccumulation of INM proteins results in a range of rare genetic disorders. So far, little is known about how defective, mislocalized, or abnormally accumulated membrane proteins are actively removed from the INM, especially in plants and animals. Here, via analysis of a proximity-labeling proteomic profile of INM-associated proteins in Arabidopsis, we identify critical components for an INM protein degradation pathway. We show that this pathway relies on the CDC48 complex for INM protein extraction and 26S proteasome for subsequent protein degradation. Moreover, we show that CDC48 at the INM may be regulated by a subgroup of PUX proteins, which determine the substrate specificity or affect the ATPase activity of CDC48. These PUX proteins specifically associate with the nucleoskeleton underneath the INM and physically interact with CDC48 proteins to negatively regulate INM protein degradation in plants.
      Cover page: Proximity labeling proteomics reveals critical regulators for inner nuclear membrane protein degradation in plants
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2023)
      Heart disease is a worldwide health menace. Both intractable primary and secondary cardiomyopathies contribute to malignant cardiac dysfunction and mortality. One of the key cellular processes associated with cardiomyopathy is cardiomyocyte death. Cardiomyocytes are terminally differentiated cells with very limited regenerative capacity. Various insults can lead to irreversible damage of cardiomyocytes, contributing to progression of cardiac dysfunction. Accumulating evidence indicates that majority of cardiomyocyte death is executed by regulating molecular pathways, including apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Importantly, these forms of regulated cell death (RCD) are cardinal features in the pathogenesis of various cardiomyopathies, including dilated cardiomyopathy, diabetic cardiomyopathy, sepsis-induced cardiomyopathy, and drug-induced cardiomyopathy. The relevance between abnormity of RCD with adverse outcome of cardiomyopathy has been unequivocally evident. Therefore, there is an urgent need to uncover the molecular and cellular mechanisms for RCD in order to better understand the pathogenesis of cardiomyopathies. In this review, we summarize the latest progress from studies on RCD pathways in cardiomyocytes in context of the pathogenesis of cardiomyopathies, with particular emphasis on apoptosis, necroptosis, ferroptosis, autophagy, and pyroptosis. We also elaborate the crosstalk among various forms of RCD in pathologically stressed myocardium and the prospects of therapeutic applications targeted to various cell death pathways.
        Cover page: Regulated cell death pathways in cardiomyopathy.
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2022)
        Metastatic colonization is the primary cause of death from colorectal cancer (CRC). We employed genome-scale in vivo short hairpin RNA (shRNA) screening and validation to identify 26 promoters of CRC liver colonization. Among these genes, we identified a cluster that contains multiple targetable genes, including ITPR3, which promoted liver-metastatic colonization and elicited similar downstream gene expression programs. ITPR3 is a caffeine-sensitive inositol 1,4,5-triphosphate (IP3) receptor that releases calcium from the endoplasmic reticulum and enhanced metastatic colonization by inducing expression of RELB, a transcription factor that is associated with non-canonical NF-κB signaling. Genetic, cell biological, pharmacologic, and clinical association studies revealed that ITPR3 and RELB drive CRC colony formation by promoting cell survival upon substratum detachment or hypoxic exposure. RELB was sufficient to drive colonization downstream of ITPR3. Our findings implicate the ITPR3/calcium/RELB axis in CRC metastatic colony formation and uncover multiple clinico-pathologically associated targetable proteins as drivers of CRC metastatic colonization.
          Cover page: Functional genetic screen identifies ITPR3/calcium/RELB axis as a driver of colorectal cancer metastatic liver colonization
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2019)
          Numerous DNA repair and signaling proteins function at DNA damage sites to protect the genome. Here, we show that fusion of the promiscuous biotin ligase BirAR118G with RAD18 leads to localized protein biotinylation at DNA damage sites, allowing identification of ZPET (zinc finger protein proximal to RAD eighteen)/ZNF280C as a potential DNA damage response (DDR) protein. ZPET binds ssDNA and localizes to DNA double-strand breaks (DSBs) and stalled replication forks. In vitro, ZPET inhibits MRE11 binding to ssDNA. In cells, ZPET delays MRE11 binding to chromatin after DSB formation and slows DNA end resection through binding ssDNA. ZPET hinders resection independently of 53BP1 and HELB. Cells lacking ZPET displayed enhanced homologous recombination (HR), accelerated replication forks under stress, and increased resistance to DSBs and PARP inhibition. These results not only reveal ZPET as an HR repressor but also suggest that localized protein biotinylation at DNA damage sites is a useful strategy to identify DDR proteins.
            Cover page: Localized protein biotinylation at DNA damage sites identifies ZPET, a repressor of homologous recombination
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2019)
            Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with the liver being the main organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection of multiple PDXs for enhanced metastatic colonization capacity upregulated the gluconeogenic enzyme PCK1, which enhanced liver metastatic growth by driving pyrimidine nucleotide biosynthesis under hypoxia. Consistently, highly metastatic tumors upregulated multiple pyrimidine biosynthesis intermediary metabolites. Therapeutic inhibition of the pyrimidine biosynthetic enzyme DHODH with leflunomide substantially impaired CRC liver metastatic colonization and hypoxic growth. Our findings provide a potential mechanistic basis for the epidemiologic association of anti-gluconeogenic drugs with improved CRC metastasis outcomes, reveal the exploitation of a gluconeogenesis enzyme for pyrimidine biosynthesis under hypoxia, and implicate DHODH and PCK1 as metabolic therapeutic targets in CRC metastatic progression.
              Cover page: PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2021)
              Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.
                Cover page: Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2023)

                Background

                Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.

                Aim

                To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.

                Methods

                Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.

                Results

                There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].

                Conclusion

                Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
                  Cover page: Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival
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