Pei-hsin Huang - Academia.edu (original) (raw)

Papers by Pei-hsin Huang

Development, 2007

Semaphorin signaling plays integral roles in multiple developmental processes. Branching morphoge... more Semaphorin signaling plays integral roles in multiple developmental processes. Branching morphogenesis is one such role that has not been thoroughly explored. Here, we show in mice that functional blockage of neuropilin 1 (Npn1) inhibits cleft formation in the developing submandibular gland (SMG) cultured ex vivo. This Npn1-dependent morphogenesis is mediated by Sema3A and Sema3C in an additive manner, and can be abolished by decreasing the expression of plexin A2 or plexin D1. VEGF, another known Npn1 ligand, has no apparent effects on SMG development. FGF signaling, which also mediates SMG branching morphogenesis, acts in parallel with semaphorin signaling. Finally,in contrast to the effect of FGF signaling, we find that semaphorins do not stimulate the proliferation of SMG epithelial cells. Instead, the semaphorin signals act locally on the epithelial cells to facilitate SMG cleft formation.

Journal of Neuromuscular Diseases

Background: Whole-exome sequencing (WES) facilitates the diagnosis of hereditary neuromuscular di... more Background: Whole-exome sequencing (WES) facilitates the diagnosis of hereditary neuromuscular disorders. To achieve an accurate diagnosis, physicians should interpret the genetic report carefully along with clinical information and examinations. We described our experience with (1) clinical validation in patients with variants found using WES and (2) a diagnostic approach for those with negative findings from WES. Methods: WES was performed on patients with the clinical impression of hereditary neuromuscular disorders. Information on clinical manifestations, neurological examination, electrodiagnostic studies, histopathology of muscle and nerve, and laboratory tests were collected. Results: Forty-one patients (Male/Female: 18/23, age of onset: 34.5±15.9) accepted WES and were categorized into four scenarios: (1) patients with a positive WES result, (2) patients with an inconclusive WES result but supporting clinical data, (3) negative findings from WES, but a final diagnosis after ...

Translational Psychiatry

Mood disorders are an important public health issue and recent advances in genomic studies have i... more Mood disorders are an important public health issue and recent advances in genomic studies have indicated that molecules involved in neurodevelopment are causally related to mood disorders. BLM-s (BCL-2-like molecule, small transcript isoform), a BH3-only proapoptotic BCL-2 family member, mediates apoptosis of postmitotic immature neurons during embryonic cortical development, but its role in the adult brain is unknown. To better understand the physiological role of Blm-s gene in vivo, we generated a Blm-s-knockout (Blm-s−/−) mouse. The Blm-s−/− mice breed normally and exhibit grossly normal development. However, global depletion of Blm-s is highly associated with depression- and anxiety-related behaviors in adult mutant mice with intact learning and memory capacity. Functional magnetic resonance imaging of adult Blm-s−/− mice reveals reduced connectivity mainly in the ventral dentate gyrus (vDG) of the hippocampus with no alteration in the dorsal DG connectivity and in total hippoc...

eNeurologicalSci, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Neuromuscular Disorders, 2019

Scientific reports, Jan 9, 2018

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact c... more Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is unknown. Dysregulated allele-specific expression (ASE) has been identified in persons with ASD; however, a comprehensive analysis of ASE has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE using genomic DNA from parent and offspring and RNA from offspring's postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing revealed distinct ASE patterns from the PFC of both offspring. However, only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP and ZNF407. We also identified a novel site of RNA-editing in KMT2C in addition to new monoallelically-expressed genes and miRNAs. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights in...

Journal of Investigative Dermatology, 2016

Mucosa associated lymphoma antigen 1(MALT1) is frequently activated in lymphoma, and has been cha... more Mucosa associated lymphoma antigen 1(MALT1) is frequently activated in lymphoma, and has been characterized as a favorable therapeutic target for this disease. Yet, the role of MALT1 in other cancers such as melanoma is not well-understood. Here, we demonstrate that MALT1 is expressed at an increased level in malignant melanoma cells. MALT1 inhibition via shRNA-mediated gene silencing or pharmacologically with MI-2 compound inhibited melanoma cell growth and migration of A2058 and A375 cells in vitro. Subcutaneous xenograft analysis revealed that MALT1 gene silencing significantly slowed melanoma growth in vivo and reduced tumor metastasis to the lung. At the molecular level, MALT1-loss diminished induction of JNK/c-Jun and NF-kB signaling pathways by TNFa. Forced expression a constitutively active mutant of the JNK upstream activator MKK7 fully restored melanoma growth and migration. Our findings demonstrate that MALT1 plays a critical role in melanoma growth and metastasis. Currently, we are investigating whether MALT1 regulates melanoma cell survival through NF-kB in reponse to various chemotherapies.

Journal of the Formosan Medical Association, 2016

Laboratory Investigation, 2001

Lymphangioma has long been thought of as congenital malformations resulting from the failure of l... more Lymphangioma has long been thought of as congenital malformations resulting from the failure of lymphatic vessels communicating with the venous system in the fetal period. Alternatively, it is proposed to be true neoplasm originated from the transformation of lymphatic endothelia. To extend the molecular basis of the pathogenesis of lymphangioma, we have characterized the expression of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) in 29 cases of lymphangioma by RNA in situ hybridization. Endothelial cells of lymphangioma co-express transcripts of VEGF-C and its receptors VEGFR-3 (Flt4) and VEGFR-2 (Flk1), which are not detectable in the adjacent connective tissue. In contrast, there is little or no expression of VEGF-C, VEGFR-3, and VEGFR-2 mRNA in endothelial cells of hemangiomas, angiosarcomas, or normal lymphatic vessels of the small or large intestines. The results suggest that VEGF-C and its receptors may take active parts in the formation of lymphangioma by autocrine or paracrine regulation.

Carcinogenesis, 2009

Mucins play a key role in tumorigenesis. MUC15 is a membranebound mucin and the MUC15 messenger R... more Mucins play a key role in tumorigenesis. MUC15 is a membranebound mucin and the MUC15 messenger RNA (mRNA) has been detected in various organs. However, its role in tumor malignancy is still unclear. This study was to investigate the MUC15 expression in colorectal tumors and the role of MUC15 in colon cancer cells. We found that the mRNA expression of MUC15 was significantly higher in 70.8% (51/72) of colorectal tumors compared with their normal counterparts by real-time reverse transcription-polymerase chain reaction. Immunohistochemistry showed that MUC15 expression was increased in 82.6% (43/52) of colorectal tumors. MUC15 overexpression in HCT116 cells enhanced cell proliferation, cell-extracellular matrix adhesion, colonyforming ability and invasion. Furthermore, these effects were significantly reversed by knockdown of MUC15 with short-hairpin RNA. In nude mice models, MUC15 overexpression significantly (P < 0.01) enhanced tumor growth. In addition, treatment of PD98059 significantly (P < 0.01) inhibited MUC15-enhanced invasion, suggesting that the invasion induced by MUC15 in HCT116 cells was primarily mediated through activation of extracellular signal-regulated kinase 1/2. In conclusion, these results suggest that MUC15 is upregulated in colorectal tumors and its expression enhances the oncogenic potential of colon cancer cells.

Proceedings of the National Academy of Sciences, 2018

Significance During neural development, growing axons navigate over long distances to reach their... more Significance During neural development, growing axons navigate over long distances to reach their targets. A critical step in this process is the regulation of its surface receptors on the axon’s growth cone in response to environmental cues. We focus on how the UNC-5 receptor in Ca enorhabditis elegans motor axons is regulated during axon repulsion. By combining C. elegans genetics, biochemistry, and imaging, we found that MAX-1 SUMOylation and AP-3 complex have significant roles in UNC-5–mediated axon repulsion. Our findings reveal how SUMOylation and AP-3–mediated trafficking and degradation interact to help the growing axon find its final target.

Journal of Cell Biology, 1997

The key gluconeogenic enzyme, fructose1,6-bisphosphatase (FBPase), is induced when Saccharomyces ... more The key gluconeogenic enzyme, fructose1,6-bisphosphatase (FBPase), is induced when Saccharomyces cerevisiae are starved of glucose. FBPase is targeted from the cytosol to the yeast vacuole for degradation when glucose-starved cells are replenished with fresh glucose. Several vid mutants defective in the glucose-induced degradation of FBPase in the vacuole have been isolated. In some vid mutants, FBPase is found in punctate structures in the cytoplasm. When extracts from these cells are fractionated, a substantial amount of FBPase is sedimentable in the high speed pellet, suggesting that FBPase is associated with intracellular structures in these vid mutants. In this paper we investigated whether FBPase association with intracellular structures also existed in wild-type cells. We report the purification of novel FBPase-associated vesicles from wild-type cells to near homogeneity. Kinetic studies indicate that FBPase association with these vesicles is stimulated by glucose and occurs ...

(A) representative end-point PCR of chromatin immunoprecipitation (ChIP) using an antibo... more (A) representative end-point PCR of chromatin immunoprecipitation (ChIP) using an antibody against SOX4 in PANC-1 cells. Genomic DNAs were amplified with primer sets after bound proteins were digested with proteinase K. The ChIP results showed binding of SOX4 to the genomic region harboring SOX4 binding sites in the predicted promoter of most SEMA3 and Plexin genes. (B) quantification of ChIP results in (A), n> = 3. Each lane in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048637#pone-0048637-g003" target="_blank">figure 3A</a> was given a value measured by densitometry and normalized with the value of IgG. ChIP efficiency is defined as percentage of the value derived from PCR of SOX4-immunoprecipitate relative to that of total genomic input. Error bars, standard deviation (SD) from at least triplicate. (C) increased luciferase activity of constructs containing SEMA3- or Plexin- promoter in the absence (white bars) or presence (gray bars) of co-expressed SOX4 in comparison with the promoterless pGL3-Basic control. The constructs harboring a SOX4-consensus binding site were transiently transfected into SOX4-containing HeLa cells. Shown are ratios of firefly luciferase expression to Renilla luciferase expression (expressed from co-transfected plasmid), measured 48 h after transfection, normalized to the mean ratio from the pGL3-Basic. Error bars show SD, n> = 4. Student's t-test, *, P<0.01; **, P<0.001. In the presence of co-transfected SOX4, luciferase activity driven by each SEMA3- or Plexin- promoter is further augmented (gray bars) compared to mock-transfected (white bars) and controls. (D) Transcriptional activity of PLXNA2 promoter driven by SOX4 is attenuated when the consensus SOX4-binding sites are mutated. Boxed DNA sequence, the consensus SOX4-binding site; Underline with shadow in letters, the mutated SOX4-binding sites. Bar graph shows that mutation of either SOX4-binding site caused significant decrease in luciferase activity driven by PLXNA2 promoter in the presence of overexpressed SOX4. Error bars, SD, n = 5. Student's t-test, *, P<0.01; **, P<0.001. (E) EMSA shows that the migration of a radiolabeled DNA fragment derived from the PLXNA2 promoter is retarded by SOX4-containing HeLa crude nuclear extract in a concentration-dependent manner. The signal of protein-bound retarded band (arrowheads) was specifically diminished by cold probes containing SOX4-binding consensus sequences and was super-shifted by anti-SOX4 antibody (empty arrowhead). Asterisk, non-specific binding signals; arrow, un-bound radiolabeled probe. (F) effective RNAi knockdown of endogenous SOX4 in PANC-1 cells shown by SOX4 immunoblotting. The value indicated is the normalized relative intensity measured by densitometry (The ratio SOX4/Tubulin for scrambled-siRNA cells is defined as 1.). Two stable siSOX4 clones labeled as siSOX4#1 and siSOX4#2 were constructed with the targeting oligonucleotide directed against different nucleotide sequences in SOX4 gene (siSOX4#1, nt.1999–2019 NM_003107.2; siSOX4#2, nt.1362–1382 NM_003107.2). (G) Immunoblotting in SOX4-depleted cells shows a concomitant decrease in the protein amount of NRP1, SEMA3- and Plexin- family members. Tubulin was used as a standard for normalization in the quantification of each lane measured by densitometry. The ratio indicated was the normalized value in siSOX4 cells relative to the normalized value in scrambled-siRNA cells. (H) Real-time PCR to quantify mRNA expression of SEMA3 and PLXN genes in SOX4-depleted cells relative to SOX4-abundant scrambled-siRNA cells (shown by fold-change). Student's t-test, *, P<0.01; **, P<0.001.</p

IEEE Access, 2021

Globally, liver cancer causes more than 700,000 deaths each year and is the second-leading cause ... more Globally, liver cancer causes more than 700,000 deaths each year and is the second-leading cause of death from cancer. Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and accounts for most deaths in cirrhosis patients. Patients with early-stage liver cancer can be treated by surgical intervention with a good prognosis; thus, early diagnosis, as confirmed by liver pathology examination, is necessary to combat HCC. Conventional manual pathology examination requires considerable time and labor, even with established expertise. It is widely accepted that intelligent classifiers may prove effective in the diagnosis process. In this study, we used a GoogLeNet (Inception-V1)-based binary classifier to classify HCC histopathology images. The classifier achieved 91.37% (±2.49) accuracy, 92.16% (±4.93) sensitivity, and 90.57% (±2.54) specificity in HCC classification. Although the classification accuracy of deep learning is reported to be positively correlated with the amount of training data, it is often uncertain how much training data are required for deep learning to achieve satisfactory performance in clinical diagnosis. Moreover, deep learning methods require annotated data to generate efficient models. However, annotated data are a relatively scarce resource and can be expensive to obtain. Hence, the relationship between classification accuracy and the number of liver histopathology images for training was investigated. An inverse power law function-based estimation model is proposed to evaluate the minimum number of annotated training images required for a desired diagnostic accuracy. INDEX TERMS Convolutional neural network, deep learning, hepatocellular carcinoma, histopathology image classification, inverse power law function-based fitting curve regression.

Thrombosis and Haemostasis

Hepsin, a liver-enriched novel serine protease, has been implicated in participating with normal ... more Hepsin, a liver-enriched novel serine protease, has been implicated in participating with normal cell growth, embryogenesis, and blood coagulation pathway. To study its function in vivo, we have disrupted the mouse hepsin gene by homologous recombination. Targeted disruption of the hepsin gene and ablation of hepsin message were demonstrated by Southern blotting, Northern blotting and RT-PCR analysis. Homozygous hepsin -/- mice were viable, fertile, and exhibited no gross abnormalities, as judged by the size, weight and blood coagulation (PT) assays. However, the serum concentration of the bone form of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase of the hepsin -/- mice was mildly elevated, in spite of no obvious pathological change of hepatocytes. To examine whether hepsin is involved in controlling cell growth in adult tissues, 70% hepatectomy was applied to the hepsin -/- mice. Liver regeneration proceeded normally in the hepsin -/- mice as judged...

Tumor cells often aberrantly re-express molecules that mediate proper embryonic development for a... more Tumor cells often aberrantly re-express molecules that mediate proper embryonic development for advantageous growth or survival. Here we report that ARMS (ankyrin repeat-rich membrane spanning), a transmembrane protein rich in the developing and adult neural tissues, was overexpressed in melanoma, a tumor ontogenetically originating from neural crest. Immunohistochemistry study of 79 melanocytic lesions showed significantly increased expression of ARMS in primary malignant melanomas (92.9%) and metastatic melanoma (60.0%). To investigate the role of ARMS in melanoma formation, mouse melanoma cell line B16F0 cells with stable knockdown of ARMS was established by RNA interference. Down-regulation of ARMS resulted in a significant inhibition on anchorage-independent growth in soft agar and a restrictive growth of melanoma in SCID mice. Importantly, depletion of ARMS facilitated UVB-induced apoptosis in melanoma cells through inactivation of MEK/ERK. Addition of MEK inhibitor PD98059 further sensitized ARMS-depleted melanoma cells to UVB-induced apoptosis, whereas constitutively active MEK rescued cells from apoptosis. Interestingly, BRAF mutation, which underlies most melanoma by constitutively activating MAPK, was not detected in most of the representative cases we analyzed. Our study suggests that overexpression of ARMS serves as one possible mechanism to promote melanoma formation by preventing stress-induced apoptotic death mediated by the MEK/ERK signaling pathway.

2013 IEEE Globecom Workshops (GC Wkshps), 2013

ABSTRACT Energy detection (ED) is a popular spectrum sensing technique for cognitive radios. The ... more ABSTRACT Energy detection (ED) is a popular spectrum sensing technique for cognitive radios. The study of ED which takes into account the dynamic of traffic patterns of primary users, in the form of random signal arrival and departure, is of both theoretical and practical importance. Some of the existing works, however, resort to certain approximation techniques to characterize the detection performance. In this paper, given a pair of arrival and departure time instants, we first derive an exact expression for the conditional detection probability. The exact mean detection probability is then obtained via an average operation over the random arrival and departure times. To improve the robustness of the detection performance against random signal arrival and departure, we further propose a Bayesian-based ED scheme. We present simulation results to validate our analytic study, and show the performance gain of our proposed Bayesian approach.

Laboratory Investigation, 2002

Gastric cancer of youth is predominantly a disease of women, usually of the signet-ring cell subt... more Gastric cancer of youth is predominantly a disease of women, usually of the signet-ring cell subtype, with a predilection for metastasizing to the ovaries. The metastatic ovarian tumor is named a Krukenberg tumor. However, the characteristic genetic alterations between the primary gastric cancer and its metastatic ovarian tumor have not been studied. We used laser capture microdissection to procure tissues from 7 patients with gastric cancer who had ovarian metastases (Krukenberg tumor) and tissues from 14 patients with gastric cancer without ovarian metastases. Loss of heterozygosity (LOH) analysis was performed by use of 16 polymorphic markers, which are mapped to the FHIT, APC, p16, BRCA2, E-cadherin, p53, BRCA1, and DPC4 loci. Immunohistochemical staining with anti-Fhit antibody was performed in 7 Krukenberg tumors and 92 gastric cancers without ovarian metastases. LOH at the FHIT locus was observed in six (85.7%) of the seven Krukenberg tumors. In contrast, the gastric cancers without ovarian metastases showed a lower frequency (28.6%, 4/14) of LOH at the FHIT locus (p Ͻ 0.05, odds ratio ϭ 1/15). Anti-Fhit antibody showed that expression of Fhit was lost in each of the 7 (100%) Krukenberg tumors but in only 41 (44.6%) of the 92 patients who had gastric cancer without ovarian metastases (p Ͻ 0.05; odds ratio ϭ 1/18.614). Further analysis showed that loss of Fhit expression is highly associated with signet-ring cell type gastric cancer (p Ͻ 0.0001, odds ratio ϭ 62.5) but is not correlated with prognosis. Alteration of the FHIT gene is a characteristic of signet-ring cell type gastric cancer and

... Role of lmmunohistochemical Expression of Caveolin-1 in Lung Carcinoma Chao-Chi Ho, Pei-Hsin ... more ... Role of lmmunohistochemical Expression of Caveolin-1 in Lung Carcinoma Chao-Chi Ho, Pei-Hsin Huang, Pan-Chyr Yang, and Su ... the local nitric oxide concentration through its participation in degradation of nitric oxide synthase via the proteosome pathway (Felley-Bosco ...