tiangui huang - Academia.edu (original) (raw)
Papers by tiangui huang
Journal of Investigative Medicine High Impact Case Reports
We report a case of a 60-year-old asymptomatic male with history of consumption of uncooked snake... more We report a case of a 60-year-old asymptomatic male with history of consumption of uncooked snake meat while living in the Congo basin and prior imaging showing multiple abdominal calcifications. Patient had multiple subepithelial colonic lesions identified during screening colonoscopy and microscopic examination of the lesions demonstrated a calcified nodule in the submucosa with overlying normal mucosa. However, no parasite was identified within the calcified nodule. Given the history of consumption of uncooked snake meat and the typical radiographic feature of multiple abdominal calcifications, it is very likely that the patient’s radiographic abnormalities are due to prior Armillifer armillatus infection, a parasitic infection acquired from consumption of uncooked snake meat. Patient was asymptomatic at the time of evaluation and was not given anti-parasitic treatment.
The American journal of surgical pathology, 2015
Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cyto... more Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cytology, which may overlap with benign urothelial lesions such as von Brunn nests, cystitis cystica, cystitis glandularis, and nephrogenic adenoma. Because of the tumor's deceptively bland appearance, these cancers can potentially be misdiagnosed as benign lesions, leading in some cases to a significant delay in correct diagnosis and appropriate treatment. Prior studies suggest that Ki67 and p53 are useful markers in distinguishing NVUC from benign lesions. However, the overlap in the rates of immunoreactivity has prevented pathologists from using these markers as reliable adjunct markers in differentiating NVUC from mimickers. In addition, large nested variant urothelial carcinoma (LNVUC), a relatively new entity, shares features of both the NVUC and papillary urothelial carcinomas with an inverted growth pattern. They also mimic benign lesions, such as proliferation of von Brunn nests...
Journal of Clinical Investigation, 2002
Emerging Infectious Diseases, 2013
Case Reports in Gastroenterology
Ganglioneuromas are very rare clinical entities, and their occurrence in the large bowel lays fur... more Ganglioneuromas are very rare clinical entities, and their occurrence in the large bowel lays further emphasis on their rarity. Ganglioneuromas are benign tumors of undifferentiated neural crest cells. Their clinical presentation is mostly asymptomatic, and if any symptoms are present at all, they are usually nonspecific, with excellent prognosis. We report an asymptomatic, 65-year-old male with a solitary ascending colonic polyp found on screening colonoscopy. Histology revealed benign polypoid spindle-cell proliferation as well as S100 reactivity, consistent with ganglioneuroma. We report on the clinical presentation and discuss the origin, epidemiology, treatment, and management of this lesion.
The American Journal of the Medical Sciences
Case reports in oncological medicine, 2016
Small cell neuroendocrine carcinoma (SNEC) is a rare form of malignancy. It mainly presents as br... more Small cell neuroendocrine carcinoma (SNEC) is a rare form of malignancy. It mainly presents as bronchogenic neoplasm, and the extrapulmonary form accounts for only 0.1% to 0.4% of all cancers. These extrapulmonary tumors have been described most frequently in the urinary bladder, prostate, esophagus, stomach, colon and rectum, gall bladder, head and neck, cervix, and skin. Primary SNEC of the sinonasal tract is extremely rare with only less than 100 cases reported in the literature. Because of extreme rarity and aggressiveness of the tumor, the management for this entity varies considerably mandating multimodality approach. In this paper, we report a patient presented with left-sided facial swelling, and the histopathologic examination confirmed primary SNEC of left sinonasal tract. The tumor involved multiple paranasal sinuses with invasion into the left orbit and left infratemporal fossa and metastasized to cervical lymph nodes and bone. The patient encountered devastating outcome...
Annals of translational medicine, 2015
It is well-known that malignancies, particularly pancreatic and brain cancers, often present as v... more It is well-known that malignancies, particularly pancreatic and brain cancers, often present as venous thromboembolism. However, stroke and angina attributable to arterial occlusion are relatively common presentations as well. We are reporting a patient, with treatment-naïve hepatitis C and multiple liver nodules, was admitted for deep vein thrombosis (DVT) and pulmonary embolism (PE). Subsequently, she developed an ascending paralysis due to spinal cord infarct (SCI) despite adequate anticoagulation. She also had an enlargement of left supraclavicular lymph node, which was confirmed histologically metastatic cholangiocarcinoma. To our best knowledge, this is the first literature report showing the association linking SCI to metastatic cholangiocarcinoma as a consequence of hypercoagulable state of malignancy.
Cancer Investigation, Feb 1, 2001
This study investigated the enhanced antitumor activity of Ad5-p53 in combination with mitomycin ... more This study investigated the enhanced antitumor activity of Ad5-p53 in combination with mitomycin C (MMC) or cisplatin (DDP) in cervical cancer cell lines SiHa and C-33A. MMC and DDP inhibited the growth of SiHa and C-33A cells in a dose-dependent manner, and the combination of MMC or DDP with Ad5-p53 showed a stronger growth inhibition than those treated with either Ad5-p53, MMC, or DDP alone. As evidenced by the formation of the approximately 200 bp DNA ladder and the appearance of sub-G1 peak, both MMC and DDP induced apoptosis in cervical cancer cells. Western blot analysis of p53 showed that MMC/DDP did not induce the increase of p53 protein in SiHa cells nor the increase of the cellular and nuclear p53 protein in Ad5-p53 transfected Saos-2 cells. Taken together, these results suggested that the combination of Ad5-p53 and MMC/DDP may serve as an effective therapeutic regime for human cervical cancer treatment.
Thesis (Ph. D.)--University of Hong Kong, 1999. Includes bibliographical references (leaves 182-2... more Thesis (Ph. D.)--University of Hong Kong, 1999. Includes bibliographical references (leaves 182-218).
Emerging infectious diseases
CTX-M extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae isolates are infreq... more CTX-M extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae isolates are infrequently reported in the United States. In this study, we analyzed nonduplicate ESBL-producing K. pneumoniae and Escherichia coli clinical isolates collected during 2005-2012 at a tertiary care medical center in suburban New York City, USA, for the presence of bla(CTX-M), bla(SHV), bla(TEM), and bla(KPC) genes. Despite a high prevalence of bla(CTX-M) genes in ESBL-producing E. coli since 2005, bla(CTX-M) genes were not detected in K. pneumoniae until 2009. The prevalence of CTX-M-producing K. pneumoniae increased significantly over time from 1.7% during 2005-2009 to 26.4% during 2010-2012 (p<0.0001). CTX-M-15 was the dominant CTX-M genotype. Pulsed-field gel electrophoresis and multilocus sequence typing revealed high genetic heterogeneities in CTX-M-producing K. pneumoniae isolates. This study demonstrates the recent emergence and polyclonal spread of multidrug resistant CTX-M-producin...
Liver International, 2015
Hepatocellular carcinoma (HCC) is the second most lethal cancer due to lack of effective therapie... more Hepatocellular carcinoma (HCC) is the second most lethal cancer due to lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification. HCC classification defined in our previous transcriptome meta-analysis (S1, S2, and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumors (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumors (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined. HCC subclass-predictive indices were: steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-fetoprotein (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;400 ng/mL) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184, and 53 to 30, 43, and 22 for S1, S2, and S3 subclass-targeting therapies, respectively. HCC molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways. This article is protected by copyright. All rights reserved.
Frontiers in bioscience (Landmark edition), 2014
Glioblastoma (GBM), the most common primary brain tumor, has a poor median prognosis despite mode... more Glioblastoma (GBM), the most common primary brain tumor, has a poor median prognosis despite modern surgical, chemotherapeutic, and radiation modalities, which have shown little clinical efficacy. Initially categorized by clinicopathological classification into de novo primary GBM and secondary GBM, which arises from lower-grade glioma, genomic studies have elucidated several distinct genotypes. In addition, distinct patterns of dysregulated epidermal growth factor receptor, platelet-derived growth factor receptor, p53, phosphatase and tensin homolog, cell cycle proteins, and isocitrate dehydrogenase 1, as well as loss of heterozygosity in multiple chromosomes complicate the GBM mutational landscape. Even with the many approaches in targeting these mutations, a long-standing clinical cure remains limited because of the tremendous heterogeneity and challenges in developing targeted treatments. Furthermore, this cancer utilizes ingenious approaches to subvert targeted agents and patho...
Biomarker research, Jan 16, 2013
BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and pa... more BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and papillary carcinoma of thyroid. These mutations provide potentially valuable diagnostic, prognostic and treatment response prediction markers. A sensitive, specific, low-cost assay to detect these mutations is needed. To detect BRAF V600E mutation in formalin-fixed, paraffin-embedded (FFPE) tissue, we developed a method using Amplification Refractory Mutation System (ARMS)-PCR. This method was designed to amplify three products in a single reaction tube: a 200 bp common product serving as an amplification control, a 144 bp BRAF V600E specific product, and a 97 bp wild-type (wt) specific product. The sensitivity of this method was determined to be as low as 0.5% for the BRAF V600E allele in a wild-type background. This method was successfully validated in 72 thyroid tumors. It detected V600E mutation in 22 out of 33 (67%) of the conventional papillary thyroid carcinoma (PTC), 8 out of 12 (7...
Cancer research, 2003
Tumor-targeted replicating viruses are being developed as a novel class of oncolytic agents. Vesi... more Tumor-targeted replicating viruses are being developed as a novel class of oncolytic agents. Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with inherent specificity for replication in tumor cells due to their attenuated antiviral responses. VSV as an oncolytic virus is particularly appealing for its exceptionally rapid replication rate in tumor cells, such that the oncolytic effects could be maximally manifested before the onset of potentially neutralizing antiviral immune responses in the host. To easily monitor VSV replication, we have rescued a recombinant VSV (rVSV) vector expressing the green fluorescent protein (GFP) gene (rVSV-GFP). Using this GFP-expressing virus, we have demonstrated the oncolytic potential of VSV against human and rat hepatocellular carcinoma (HCC). We found that rVSV-GFP replicated efficiently in cultured human and rat HCC cells, whereas normal human and rat hepatocytes were refractory. When a single dose of the vector was injected intra...
Nuclear medicine and biology, 1995
A simple method of preparation of 99mTc-pingyangmycin (PYM) for clinical use has been established... more A simple method of preparation of 99mTc-pingyangmycin (PYM) for clinical use has been established using super-micro-amounts of SnCl2 as a reductant under dark conditions. The labeling efficiency was higher than 96%, and further purification was not necessary. The effect of ascorbic acid on the distribution of 99mTc-PYM had been investigated. Ascorbic acid increased uptake of 99mTc-PYM in the tumor. Tumor uptake increased with increasing concentration of ascorbic acid. Tumor-blood, tumor-liver, tumor-lung ratios at 1.5 h after 99mTc-PYM administration were 5.19 +/- 1.64, 2.71 +/- 0.51 and 4.15 +/- 0.57, respectively. Preliminary clinical trials in nine patients showed that 99mTc-PYM is a potentially useful tracer for tumor detection with good sensitivity and specificity (true positive 7/7, true negative 1/1, and false positive 1/1).
Tumor Biology, 2013
Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a un... more Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a uniformly poor prognosis. Despite decades of research on the topic, limited progress has been made to improve the poor survival associated with this disease. GBM arises de novo (primary GBM) or via dedifferentiation of lower grade glioma (secondary GBM). While distinct mutations are predominant in each subtype, alterations of tumor suppressor p53 are the most common, seen in 25-30 % of primary GBM and 60-70 % of secondary GBM. Various roles of p53 that protect against neoplastic transformation include modulation of cell cycle, DNA repair, apoptosis, senescence, angiogenesis, and metabolism, resulting in an extremely complex signaling network. Mutations of p53 in GBM are most common in the DNA-binding domain, namely within six hotspot mutation sites (codons 175, 245, 248, 249, 273, and 282). These alterations generally result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53, however, the distinct effect of these mutation types in GBM pathogenesis remain unclear. Signaling alterations downstream from p53 (e.g., MDM2, MDM4, INK4/ARF), p53 isoforms (e.g., p63, p73), and microRNAs (e.g., miR-34) also play critical roles in modulating the p53 pathway. Despite novel mouse models of GBM showing that p53 combined with other mutation generate tumors de novo, the role of p53 as a molecular marker of GBM remains controversial with most studies failing to show an association with prognosis. Regarding treatment in GBM, p53 targeted-gene therapy and vaccinations have reached phase I clinical trials while therapeutic drugs are still in preclinical development. This review aims to discuss the most recent findings regarding the impact of p53 mutations on GBM pathogenesis, prognosis, and treatment.
Otolaryngology - Head and Neck Surgery, 2008
OBJECTIVE: To assess immune-based gene therapy in a murine floor of mouth (FOM) squamous cell car... more OBJECTIVE: To assess immune-based gene therapy in a murine floor of mouth (FOM) squamous cell carcinoma (SCC) model. STUDY DESIGN: In vitro and in vivo testing of immune therapy for SCC. METHODS: Multiple SCC lines were infected by using advRSV-interleukin-12 (IL-12) and advCMV-interleukin-12/ granulocyte macrophage colony-stimulating factor (IL-12/GM-CSF) and monitored for production of IL-12 and GM-CSF. Intratumoral injections of viral vectors were administered with systemic Ig-4-1BB ligand in an orthotopic murine FOM SCC model and followed for tumor size and survival. RESULTS: In vitro, all cell lines produced substantial levels of IL-12 and GM-CSF. In vivo, tumors treated with advCMV-IL-12/ GM-CSF and Ig-4-1BBL showed a striking reduction in tumor volume (vs control P Ͻ 0.0001) and improved median survival (38 days vs 19 days for control, P Ͻ 0.0001). CONCLUSION: Combination immune-based therapies effectively improve survival in mice bearing FOM SCC over singlemodality therapy.
Journal of Investigative Medicine High Impact Case Reports
We report a case of a 60-year-old asymptomatic male with history of consumption of uncooked snake... more We report a case of a 60-year-old asymptomatic male with history of consumption of uncooked snake meat while living in the Congo basin and prior imaging showing multiple abdominal calcifications. Patient had multiple subepithelial colonic lesions identified during screening colonoscopy and microscopic examination of the lesions demonstrated a calcified nodule in the submucosa with overlying normal mucosa. However, no parasite was identified within the calcified nodule. Given the history of consumption of uncooked snake meat and the typical radiographic feature of multiple abdominal calcifications, it is very likely that the patient’s radiographic abnormalities are due to prior Armillifer armillatus infection, a parasitic infection acquired from consumption of uncooked snake meat. Patient was asymptomatic at the time of evaluation and was not given anti-parasitic treatment.
The American journal of surgical pathology, 2015
Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cyto... more Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cytology, which may overlap with benign urothelial lesions such as von Brunn nests, cystitis cystica, cystitis glandularis, and nephrogenic adenoma. Because of the tumor's deceptively bland appearance, these cancers can potentially be misdiagnosed as benign lesions, leading in some cases to a significant delay in correct diagnosis and appropriate treatment. Prior studies suggest that Ki67 and p53 are useful markers in distinguishing NVUC from benign lesions. However, the overlap in the rates of immunoreactivity has prevented pathologists from using these markers as reliable adjunct markers in differentiating NVUC from mimickers. In addition, large nested variant urothelial carcinoma (LNVUC), a relatively new entity, shares features of both the NVUC and papillary urothelial carcinomas with an inverted growth pattern. They also mimic benign lesions, such as proliferation of von Brunn nests...
Journal of Clinical Investigation, 2002
Emerging Infectious Diseases, 2013
Case Reports in Gastroenterology
Ganglioneuromas are very rare clinical entities, and their occurrence in the large bowel lays fur... more Ganglioneuromas are very rare clinical entities, and their occurrence in the large bowel lays further emphasis on their rarity. Ganglioneuromas are benign tumors of undifferentiated neural crest cells. Their clinical presentation is mostly asymptomatic, and if any symptoms are present at all, they are usually nonspecific, with excellent prognosis. We report an asymptomatic, 65-year-old male with a solitary ascending colonic polyp found on screening colonoscopy. Histology revealed benign polypoid spindle-cell proliferation as well as S100 reactivity, consistent with ganglioneuroma. We report on the clinical presentation and discuss the origin, epidemiology, treatment, and management of this lesion.
The American Journal of the Medical Sciences
Case reports in oncological medicine, 2016
Small cell neuroendocrine carcinoma (SNEC) is a rare form of malignancy. It mainly presents as br... more Small cell neuroendocrine carcinoma (SNEC) is a rare form of malignancy. It mainly presents as bronchogenic neoplasm, and the extrapulmonary form accounts for only 0.1% to 0.4% of all cancers. These extrapulmonary tumors have been described most frequently in the urinary bladder, prostate, esophagus, stomach, colon and rectum, gall bladder, head and neck, cervix, and skin. Primary SNEC of the sinonasal tract is extremely rare with only less than 100 cases reported in the literature. Because of extreme rarity and aggressiveness of the tumor, the management for this entity varies considerably mandating multimodality approach. In this paper, we report a patient presented with left-sided facial swelling, and the histopathologic examination confirmed primary SNEC of left sinonasal tract. The tumor involved multiple paranasal sinuses with invasion into the left orbit and left infratemporal fossa and metastasized to cervical lymph nodes and bone. The patient encountered devastating outcome...
Annals of translational medicine, 2015
It is well-known that malignancies, particularly pancreatic and brain cancers, often present as v... more It is well-known that malignancies, particularly pancreatic and brain cancers, often present as venous thromboembolism. However, stroke and angina attributable to arterial occlusion are relatively common presentations as well. We are reporting a patient, with treatment-naïve hepatitis C and multiple liver nodules, was admitted for deep vein thrombosis (DVT) and pulmonary embolism (PE). Subsequently, she developed an ascending paralysis due to spinal cord infarct (SCI) despite adequate anticoagulation. She also had an enlargement of left supraclavicular lymph node, which was confirmed histologically metastatic cholangiocarcinoma. To our best knowledge, this is the first literature report showing the association linking SCI to metastatic cholangiocarcinoma as a consequence of hypercoagulable state of malignancy.
Cancer Investigation, Feb 1, 2001
This study investigated the enhanced antitumor activity of Ad5-p53 in combination with mitomycin ... more This study investigated the enhanced antitumor activity of Ad5-p53 in combination with mitomycin C (MMC) or cisplatin (DDP) in cervical cancer cell lines SiHa and C-33A. MMC and DDP inhibited the growth of SiHa and C-33A cells in a dose-dependent manner, and the combination of MMC or DDP with Ad5-p53 showed a stronger growth inhibition than those treated with either Ad5-p53, MMC, or DDP alone. As evidenced by the formation of the approximately 200 bp DNA ladder and the appearance of sub-G1 peak, both MMC and DDP induced apoptosis in cervical cancer cells. Western blot analysis of p53 showed that MMC/DDP did not induce the increase of p53 protein in SiHa cells nor the increase of the cellular and nuclear p53 protein in Ad5-p53 transfected Saos-2 cells. Taken together, these results suggested that the combination of Ad5-p53 and MMC/DDP may serve as an effective therapeutic regime for human cervical cancer treatment.
Thesis (Ph. D.)--University of Hong Kong, 1999. Includes bibliographical references (leaves 182-2... more Thesis (Ph. D.)--University of Hong Kong, 1999. Includes bibliographical references (leaves 182-218).
Emerging infectious diseases
CTX-M extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae isolates are infreq... more CTX-M extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae isolates are infrequently reported in the United States. In this study, we analyzed nonduplicate ESBL-producing K. pneumoniae and Escherichia coli clinical isolates collected during 2005-2012 at a tertiary care medical center in suburban New York City, USA, for the presence of bla(CTX-M), bla(SHV), bla(TEM), and bla(KPC) genes. Despite a high prevalence of bla(CTX-M) genes in ESBL-producing E. coli since 2005, bla(CTX-M) genes were not detected in K. pneumoniae until 2009. The prevalence of CTX-M-producing K. pneumoniae increased significantly over time from 1.7% during 2005-2009 to 26.4% during 2010-2012 (p<0.0001). CTX-M-15 was the dominant CTX-M genotype. Pulsed-field gel electrophoresis and multilocus sequence typing revealed high genetic heterogeneities in CTX-M-producing K. pneumoniae isolates. This study demonstrates the recent emergence and polyclonal spread of multidrug resistant CTX-M-producin...
Liver International, 2015
Hepatocellular carcinoma (HCC) is the second most lethal cancer due to lack of effective therapie... more Hepatocellular carcinoma (HCC) is the second most lethal cancer due to lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification. HCC classification defined in our previous transcriptome meta-analysis (S1, S2, and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumors (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumors (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined. HCC subclass-predictive indices were: steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-fetoprotein (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;400 ng/mL) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184, and 53 to 30, 43, and 22 for S1, S2, and S3 subclass-targeting therapies, respectively. HCC molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways. This article is protected by copyright. All rights reserved.
Frontiers in bioscience (Landmark edition), 2014
Glioblastoma (GBM), the most common primary brain tumor, has a poor median prognosis despite mode... more Glioblastoma (GBM), the most common primary brain tumor, has a poor median prognosis despite modern surgical, chemotherapeutic, and radiation modalities, which have shown little clinical efficacy. Initially categorized by clinicopathological classification into de novo primary GBM and secondary GBM, which arises from lower-grade glioma, genomic studies have elucidated several distinct genotypes. In addition, distinct patterns of dysregulated epidermal growth factor receptor, platelet-derived growth factor receptor, p53, phosphatase and tensin homolog, cell cycle proteins, and isocitrate dehydrogenase 1, as well as loss of heterozygosity in multiple chromosomes complicate the GBM mutational landscape. Even with the many approaches in targeting these mutations, a long-standing clinical cure remains limited because of the tremendous heterogeneity and challenges in developing targeted treatments. Furthermore, this cancer utilizes ingenious approaches to subvert targeted agents and patho...
Biomarker research, Jan 16, 2013
BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and pa... more BRAF mutations occur in approximately 8% of all human cancers and approach 50% in melanoma and papillary carcinoma of thyroid. These mutations provide potentially valuable diagnostic, prognostic and treatment response prediction markers. A sensitive, specific, low-cost assay to detect these mutations is needed. To detect BRAF V600E mutation in formalin-fixed, paraffin-embedded (FFPE) tissue, we developed a method using Amplification Refractory Mutation System (ARMS)-PCR. This method was designed to amplify three products in a single reaction tube: a 200 bp common product serving as an amplification control, a 144 bp BRAF V600E specific product, and a 97 bp wild-type (wt) specific product. The sensitivity of this method was determined to be as low as 0.5% for the BRAF V600E allele in a wild-type background. This method was successfully validated in 72 thyroid tumors. It detected V600E mutation in 22 out of 33 (67%) of the conventional papillary thyroid carcinoma (PTC), 8 out of 12 (7...
Cancer research, 2003
Tumor-targeted replicating viruses are being developed as a novel class of oncolytic agents. Vesi... more Tumor-targeted replicating viruses are being developed as a novel class of oncolytic agents. Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with inherent specificity for replication in tumor cells due to their attenuated antiviral responses. VSV as an oncolytic virus is particularly appealing for its exceptionally rapid replication rate in tumor cells, such that the oncolytic effects could be maximally manifested before the onset of potentially neutralizing antiviral immune responses in the host. To easily monitor VSV replication, we have rescued a recombinant VSV (rVSV) vector expressing the green fluorescent protein (GFP) gene (rVSV-GFP). Using this GFP-expressing virus, we have demonstrated the oncolytic potential of VSV against human and rat hepatocellular carcinoma (HCC). We found that rVSV-GFP replicated efficiently in cultured human and rat HCC cells, whereas normal human and rat hepatocytes were refractory. When a single dose of the vector was injected intra...
Nuclear medicine and biology, 1995
A simple method of preparation of 99mTc-pingyangmycin (PYM) for clinical use has been established... more A simple method of preparation of 99mTc-pingyangmycin (PYM) for clinical use has been established using super-micro-amounts of SnCl2 as a reductant under dark conditions. The labeling efficiency was higher than 96%, and further purification was not necessary. The effect of ascorbic acid on the distribution of 99mTc-PYM had been investigated. Ascorbic acid increased uptake of 99mTc-PYM in the tumor. Tumor uptake increased with increasing concentration of ascorbic acid. Tumor-blood, tumor-liver, tumor-lung ratios at 1.5 h after 99mTc-PYM administration were 5.19 +/- 1.64, 2.71 +/- 0.51 and 4.15 +/- 0.57, respectively. Preliminary clinical trials in nine patients showed that 99mTc-PYM is a potentially useful tracer for tumor detection with good sensitivity and specificity (true positive 7/7, true negative 1/1, and false positive 1/1).
Tumor Biology, 2013
Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a un... more Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a uniformly poor prognosis. Despite decades of research on the topic, limited progress has been made to improve the poor survival associated with this disease. GBM arises de novo (primary GBM) or via dedifferentiation of lower grade glioma (secondary GBM). While distinct mutations are predominant in each subtype, alterations of tumor suppressor p53 are the most common, seen in 25-30 % of primary GBM and 60-70 % of secondary GBM. Various roles of p53 that protect against neoplastic transformation include modulation of cell cycle, DNA repair, apoptosis, senescence, angiogenesis, and metabolism, resulting in an extremely complex signaling network. Mutations of p53 in GBM are most common in the DNA-binding domain, namely within six hotspot mutation sites (codons 175, 245, 248, 249, 273, and 282). These alterations generally result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53, however, the distinct effect of these mutation types in GBM pathogenesis remain unclear. Signaling alterations downstream from p53 (e.g., MDM2, MDM4, INK4/ARF), p53 isoforms (e.g., p63, p73), and microRNAs (e.g., miR-34) also play critical roles in modulating the p53 pathway. Despite novel mouse models of GBM showing that p53 combined with other mutation generate tumors de novo, the role of p53 as a molecular marker of GBM remains controversial with most studies failing to show an association with prognosis. Regarding treatment in GBM, p53 targeted-gene therapy and vaccinations have reached phase I clinical trials while therapeutic drugs are still in preclinical development. This review aims to discuss the most recent findings regarding the impact of p53 mutations on GBM pathogenesis, prognosis, and treatment.
Otolaryngology - Head and Neck Surgery, 2008
OBJECTIVE: To assess immune-based gene therapy in a murine floor of mouth (FOM) squamous cell car... more OBJECTIVE: To assess immune-based gene therapy in a murine floor of mouth (FOM) squamous cell carcinoma (SCC) model. STUDY DESIGN: In vitro and in vivo testing of immune therapy for SCC. METHODS: Multiple SCC lines were infected by using advRSV-interleukin-12 (IL-12) and advCMV-interleukin-12/ granulocyte macrophage colony-stimulating factor (IL-12/GM-CSF) and monitored for production of IL-12 and GM-CSF. Intratumoral injections of viral vectors were administered with systemic Ig-4-1BB ligand in an orthotopic murine FOM SCC model and followed for tumor size and survival. RESULTS: In vitro, all cell lines produced substantial levels of IL-12 and GM-CSF. In vivo, tumors treated with advCMV-IL-12/ GM-CSF and Ig-4-1BBL showed a striking reduction in tumor volume (vs control P Ͻ 0.0001) and improved median survival (38 days vs 19 days for control, P Ͻ 0.0001). CONCLUSION: Combination immune-based therapies effectively improve survival in mice bearing FOM SCC over singlemodality therapy.