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Papers by Patricia Latham

Data from A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Supplementary Table S7 from Identification and Functional Validation of Reciprocal microRNA–mRNA Pairings in African American Prostate Cancer Disparities

Supplementary Table S7. Significant pathways identified by Global test in A) AA PCa vs. EA PCa, B... more Supplementary Table S7. Significant pathways identified by Global test in A) AA PCa vs. EA PCa, B) AA PCa vs AA NP, and C) EA PCa vs EA NP

Supplementary Figure S2 from A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

S2. Common FGFR3 alterations by cancer type.

Supplementary Data_Legends from A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Supplementary Table S2 from A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Supplemental Table S2. Relative phospho-protein expression with and without FGF2 treatment.

Supplementary Table S4 from A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Supplemental Table S4. IC50 values calculated for proliferation, migration, and invasion assays f... more Supplemental Table S4. IC50 values calculated for proliferation, migration, and invasion assays for PC-3 and LNCaP overexpressing cell lines from Fig 3.

Direct effect of endotoxin (LPS) on oxygen consumption (OC) in primary hepatocyte cultures: Role of Kupffer cells

Hepatology, 1982

Supplementary Figure S1 from A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Differential Effects of Specific Deletion of the Dopamine D2 Receptor in Renal Proximal Tubules of Male and Female Mice

The FASEB Journal, 2019

Design of an Online Histopathology Atlas in the New Medical Curriculum

Background The purpose of this project is to help develop a comprehensive histology and pathology... more Background The purpose of this project is to help develop a comprehensive histology and pathology online database that would aid students throughout their pre-clinical years. With the modern systems-based approach that GW’s own medical school adopted, it becomes a necessity that students learn and integrate both normal and disease processes throughout the various organ blocks. Students need a resource they can utilize as a reference to learn these two disciplines, since the curriculum has a heavy component of self-teaching. The Microanatomy and Pathology Atlas (MAPA) helps to address this need as it contains specifically labeled histology and pathology image sets that are cross referenced with the traditional laboratory instructions and objectives from the two courses. These clearly labeled images are made interactive, which allows students to self-test for better assessment and understanding. Future plans to add clinical vignettes will help students consolidate problem solving skills and relevant multidisciplinary information Methods First and second year medical students were sent online surveys that asked a variety of “yes” and “no” questions about the atlas – ease of use, accessibility, and correlation with course material, both in lecture and lab. Students could also submit their own comments as they used the atlas. Results Preliminary results have shown that 92% of students are in favor of using the tool and 62% strongly favor further use. Current data collected in the fall of 2015 shows that the atlas has a positive correlation with the material in classes, both in terms of comprehension and proficiency. 88% of students have stated that the tool has complemented their studies, while another 66% would strongly recommend it to other peers. The data suggests that 50% of students strongly found the level of information appropriate for coursework. Students have already commented on the ease of using the atlas and its utility for self-quizzing in learning microanatomical structure. Conclusions The project is still ongoing with data collection. Preliminary results have been very promising in terms of student feedback and growth for further improvement. The atlas will continue to be updated, based on this input. Other organs systems and vignettes will be incorporated. Current results indicate students identify MAPA as a valuable tool for improving comprehension of histology and pathology. We hope that it will become a central resource that students in upcoming classes can use

Scientific Reports, May 5, 2023

Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arth... more Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of recombinant IL2 (rIL2), an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, CD4 + effector T cells (Teff), and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the rIL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one. Chikungunya virus (CHIKV) is an alphavirus spread by the Aedes aegypti mosquito that is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. For most CHIKV infections, acute symptoms typically resolve within 7 to 10 days; however, multiple studies have reported patients experiencing persistent joint pain months or years after the initial infection. In a study involving 485 CHIKV patients from Colombia, 25% reported persistent joint pain 20 months after infection, and 13% reported pain 40 months after infection 1,2 . The mouse model for post-CHIKV arthritis involves footpad inoculation of wildtype immunocompetent C57BL/6 mice, which causes localized swelling and systemic infection. In a pilot study involving the post-CHIKV arthritis mouse model, we determined that CHIKV footpad infection results in histologic evidence of arthritis, synovitis, periostitis, and myositis that persist to 21 days post-infection (dpi) 3 . Currently, there are no standard treatments available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in the cytokine interleukin-2 (IL2) during the acute stage of infection and the resulting alteration of regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis . Novel lowdose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs and may be of use in CHIKV arthritis flares in humans . The short half-life of IL2 can be prolonged in vivo using various anti-IL2 monoclonal antibodies to form an IL2/anti-IL2 antibody complex . One study found that IL2/anti-IL2 antibody complexes displayed an extended lifespan in vitro and in vivo, with the activity of IL2 alone tapering after 2 and 4 h, while the activity of the complex lasted greater than 24 h and 72 h, respectively 7 . Unlike other IL2 antibodies, the JES6-1 neutralizing antibody complexed with IL2 selectively induces Tregs expansion due to their high constitutive expression of the high-affinity IL2 receptor, IL2R∝ (CD25). The specificity stems from the JES6-1 antibody binding to IL2 in a way that sterically hinders the interaction between IL2 and the low-affinity receptors IL2Rβ (CD122) and IL2Rγ (CD132) found on other immune cells .

Data from Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, an... more RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients.Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.

Genes & Cancer, Jun 6, 2022

Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a major cause of cancer de... more Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a major cause of cancer death worldwide. Early detection is key to effective treatment. Yet, early diagnosis is challenging, especially in patients with cirrhosis, who are at high risk of developing HCC. Dysfunction or loss of function of the transforming growth factor β (TGF-β) pathway is associated with HCC. Here, using quantitative immunohistochemistry analysis of samples from a multi-institutional repository, we evaluated if differences in TGF-β receptor abundance were present in tissue from patients with only cirrhosis compared with those with HCC in the context of cirrhosis. We determined that TGFBR2, not TGFBR1, was significantly reduced in HCC tissue compared with cirrhotic tissue. We developed an artificial intelligence (AI)-based process that correctly identified cirrhotic and HCC tissue and confirmed the significant reduction in TGFBR2 in HCC tissue compared with cirrhotic tissue. Thus, we propose that a reduction in TGFBR2 abundance represents a useful biomarker for detecting HCC in the context of cirrhosis and that incorporating this biomarker into an AI-based automated imaging pipeline could reduce variability in diagnosing HCC from biopsy tissue.

Effects of Tryptophan Related Compounds On Nuclear Regulatory Control

Springer eBooks, 1996

For many years our laboratory has been concerned with the unique effect of L-tryptophan on rat he... more For many years our laboratory has been concerned with the unique effect of L-tryptophan on rat hepatic protein synthesis (Sidransky, 1985). Tryptophan administered alone, but not an administration of other single essential amino acids, induced a stimulatory response of protein synthesis in mice and rats as measured in vivo or in vitro(Sidransky, 1985; Sydransky et al., 1967; Sidransky et al., 1968). Other laboratories have confirmed our findings (Pronezuk et al., 1968; Cammarano et al., 1968; Rothschild et al., 1969; Oravec and Sourkes, 1970; Park et al., 1973; Jorgensen and Majumdar, 1975; Majumdar, 1982). Subsequent studies from our laboratory have enabled us to gain much insight into the mechanism/s by which L-tryptophan stimulates hepatic protein synthesis. Many of these findings will be reviewed in a subsequent section.

1227 a Novel Clinical and Biomarker Model Based on TGF-B Superfamily Signaling Proteins Improves on Afp and the Doylestown Model in Predicting Hepatocellular Carcinoma Across Racial Groups

Gastroenterology

Purpose: African Americans (AA) exhibit higher rates of prostate cancer incidence and mortality c... more Purpose: African Americans (AA) exhibit higher rates of prostate cancer incidence and mortality compared with European American (EA) men. In addition to socioeconomic influences, biologic factors are believed to play a critical role in prostate cancer disparities. We investigated whether population-specific and -enriched miRNA-mRNA interactions might contribute to prostate cancer disparities. Experimental Design: Integrative genomics was used, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis, and functional validation, to map miRNA-mRNA interactions associated with prostate cancer disparities. Results: We identified 22 AA-specific and 18 EA-specific miR-NAs in prostate cancer versus patient-matched normal prostate, and 10 "AA-enriched/-depleted" miRNAs in AA prostate cancer versus EA prostate cancer comparisons. Many of these populationspecific/-enriched miRNAs could be paired with target mRNAs that exhibited an inverse pattern of differential expression. Pathway analysis revealed EGFR (or ERBB) signaling as a critical pathway significantly regulated by AA-specific/-enriched mRNAs and miRNA-mRNA pairings. Novel miRNA-mRNA pairings were validated by qRT-PCR, Western blot, and/or IHC analyses in prostate cancer specimens. Loss/gain of function assays performed in population-specific prostate cancer cell lines confirmed miR-133a/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ ITPR2, and miR-34a/PPP2R2A as critical miRNA-mRNA pairings driving oncogenesis. Manipulating the balance of these pairings resulted in decreased proliferation and invasion, and enhanced sensitization to docetaxel-induced cytotoxicity in AA prostate cancer cells. Conclusions: Our data suggest that AA-specific/-enriched miRNA-mRNA pairings may play a critical role in the activation of oncogenic pathways in AA prostate cancer. Our findings also suggest that miR-133a/MCL1, miR-513c/STAT1, and miR-96/ FOXO3A may have clinical significance in the development of novel strategies for treating aggressive prostate cancer. Clin Cancer Res; 21(21); 4970-84. Ó2015 AACR.

Novel roles of microRNA-200b in reversing the chemoimmunoresistance by inhibiting BRCA1 nuclear export in triple negative breast cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen ... more Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2). It is typically associated with high rate of metastasis and limited targeted treatment options. Chemotherapy is the standard treatment for metastatic TNBC. However, the development of chemo-resistance limits its clinical application. Elevated expression of immune-related genes in TNBC suggests that immunotherapy strategies may provide new therapeutic options for TNBC. Programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors have been approved by the FDA for TNBC treatment. However, tumor immune evasion is considered an important obstacle. BRCA1 is a nuclear–cytoplasmic shuttling protein that plays a key role in preventing the development of a malignant phenotype. BRCA1 dysregulation and nuclear export are an important mechanism in cancer development and chemoresistance especially in TNBC. Blocking BRCA1 nuclear export could be used as a strategy to prevent resistance. BRCA1 nuclear export has been reported to be mediated by several proteins such as BRCA1-binding protein 2 (BRAP2) and chromosomal maintenance 1 (CRM1, also known as exportin 1, XPO1). CRM1-mediated events have been implicated in breast cancer and involved in chemoimmunotherapy. microRNA-200b (miR-200b) is a cell-autonomous suppressor of EMT (epithelial–mesenchymal transition) and involved in tumor metastasis. In our present work, we discovered that miR-200b overexpression resulted in significant BRCA1 nuclear retention accompanied by down-regulated expression of CRM1 and STAT1 (signal transducer and activator of transcription 1). Bioinformatics analysis indicated that miR-200b directly targets STAT1, which was confirmed by luciferase assay. We demonstrated that STAT1 is a transcription factor (TF) of CRM1, by both Transfac analysis and chromatin immunoprecipitation (ChIP)-qPCR assay. In patient tissue samples, we found that miR-200b expression was relatively lower in TNBC compared to non-TNBCs. Furthermore, we demonstrated that miR-200b-mediated BRCA1 nuclear retention is associated with significant PD-L1 downregulation, and sensitizes the TNBC cells to chemotherapeutic agents. In addition, high level PD-L1 expression is associated with not only chemoimmunoresistance but also tumor metastasis. These data provide strong evidence that miR-200b-mediated regulation of BRCA1 nucleus retention is through transcriptional regulation of CRM1 by STAT1, and miR-200b regulates PD-L1 expression in TNBC. In conclusion, this novel dual roles of miR-200b may serve as a strategy in metastatic TNBC therapy by repressing STAT1-mediated CRM1 transcription regulation, and reversing the chemoimmunoresistance via PD-L1 inhibition

microRNA-196b promotes esophageal squamous cell carcinogenesis and chemoradioresistance by inhibiting EPHA7, thereby restoring EPHA2 activity

American journal of cancer research, 2021

Esophageal cancer (EC) is extremely aggressive and has a very poor survival rate. Esophageal squa... more Esophageal cancer (EC) is extremely aggressive and has a very poor survival rate. Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all ECs worldwide, with the majority of the remaining 20% being esophageal adenocarcinoma (EAC). Due to its occult and insidious presentation, ESCC is typically diagnosed and treated in its advanced stages, thereby limiting the success of present therapeutic modalities. microRNAs (miRNAs) can function as tumor suppressors or oncogenes, playing critical roles in cancer initiation and progression by regulating target genes in oncogenic pathways. In the current study, we demonstrated that microRNA-196b (miR-196b) is one of the most upregulated miRNAs in both ESCC and EAC. miR-196b was overexpressed in ESCC and EAC cell lines, cellular exosomal RNAs, and ESCC tissue samples. Functional studies revealed that miR-196b acted as an oncomiR by directly targeting a tumor suppressor, ephrin type-A receptor 7 (EPHA7). EPHA7 abrogates the activity of eph...

Abstract 498: Dual functions of miR-200b in triple-negative breast cancer metastasis and chemoimmuno-resistance

Cancer Research, 2018