Publications by authors named "Chien-Chin Chen"

53 Publications

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials.

Cells 2021 Jun 29;10(7). Epub 2021 Jun 29.

Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600, Taiwan.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.
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http://dx.doi.org/10.3390/cells10071629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306951PMC
June 2021

COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells.

Oncogene 2021 Jul 11;40(26):4503-4519. Epub 2021 Jun 11.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-β3 activation. The CAF-cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-β3 antibody. Human tumors with high TGF-β3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-β3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.
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http://dx.doi.org/10.1038/s41388-021-01865-8DOI Listing
July 2021

Sonication-Assisted Method for Decellularization of Human Umbilical Artery for Small-Caliber Vascular Tissue Engineering.

Polymers (Basel) 2021 May 22;13(11). Epub 2021 May 22.

Section of Pediatric Cardiology, Department of Pediatrics, Taipei Medical University Hospital, Taipei 11031, Taiwan.

Decellularized vascular grafts are useful for the construction of biological small-diameter tissue-engineered vascular grafts (≤6 mm). Traditional chemical decellularization requires a long treatment time, which may damage the structure and alter the mechanical properties. Decellularization using sonication is expected to solve this problem. The aim of this study was to develop an effective decellularization method using ultrasound followed by washing. Different power values of sonication at 40 kHz were tested for 2, 4, and 8 h followed by a washing procedure. The efficacy of sonication of decellularized human umbilical artery (sDHUA) was evaluated via DNA content, histological staining, mechanical properties, and biocompatibility. The sDHUAs were further implanted into rats for up to 90 days and magnetic resonance angiography (MRA) was performed for the implanted grafts. The results demonstrated that treatment of human umbilical artery (HUA) by sonication at ultrasonic power of 204 W for 4 h followed by washing for 24 h in 2% SDS buffer could eliminate more than 90% of cells and retain similar mechanical properties of the HUA. Recellularization was assessed by scanning electron microscopy (SEM), which indicated that sDHUA provided niches for human umbilical vein endothelial cells (HUVECs) to reside, indicating in vitro cytocompatibility. Further implantation tests also indicated the fitness of the sonication-treated HUA as a scaffold for small-caliber tissue engineering vascular grafts.
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http://dx.doi.org/10.3390/polym13111699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196986PMC
May 2021

NRAS Mutations May Be Involved in the Pathogenesis of Cutaneous Rosai Dorfman Disease: A Pilot Study.

Biology (Basel) 2021 May 2;10(5). Epub 2021 May 2.

Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600, Taiwan.

Background: Purely cutaneous Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder limited to the skin. To date, its pathogenesis remains unclear. Owing to recent findings of specific mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in histiocytic proliferative disorders, it provides a novel perspective on the pathomechanism of cutaneous RDD. We aim to investigate the genomic mutations in MAPK/ERK pathway in cutaneous RDD.

Methods: We retrospectively recruited all cases of cutaneous RDD from two hospitals in Taiwan from January 2010 to March 2020 with the clinicopathologic features, immunohistochemistry, and treatment. Mutations of neuroblastoma RAS viral oncogene homolog () Kirsten rat sarcoma 2 viral oncogene homolog (), and v-raf murine sarcoma viral oncogene homolog B1 () in MAPK/ERK pathway were investigated by the highly sensitive polymerase chain reaction with Sanger sequencing.

Results: Seven patients with cutaneous RDD were recruited with nine biopsy specimens. The median age was 46 years (range: 17-62 years). Four of seven patients (57.1%) received tumor excision, while the other three chose oral and/or topical or intralesional steroids. mutation was detected in 4 of 7 cases (4/7; 51.7%), and A146T was the most common mutant point ( = 4/7), followed by G13S ( = 2/7). There is no or mutation detected.

Conclusions: We report the mutation is common in cutaneous RDD, and A146T was the most frequent mutation in this cohort. Mutations in the gene can activate the RAS/MAPK signaling and have been reported to be associated with various cancers. It indicates that mutation in MAPK/ERK pathway may involve the pathogenesis of cutaneous RDD.
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http://dx.doi.org/10.3390/biology10050396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147632PMC
May 2021

Morphologic Spectrum of Lymphadenopathy in Adult-onset Immunodeficiency (Anti-interferon-γ Autoantibodies).

Am J Surg Pathol 2021 May 20. Epub 2021 May 20.

Departments of Pathology Infectious Disease, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital School of Medicine, Chung Shan Medical University, Taichung Department of Pathology, National Taiwan University Hospital, Taipei Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi Department of Pathology, E-DA Hospital, I-Shou University Department of Pathology, Kaohsiung Medical University Hospital Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Babina Diagnostics, Imphal, Manipur, India Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-γ autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83 y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus-encoded RNA showed scattered (<1%) to relatively more common (4% to 5%) positive cells in 29 of 30 (97%) tested specimens, reflecting immune dysregulation due to an interferon-γ defect. In the 31 lymph node specimens, 23 (74%) cases showed increased immunoglobulin G4-positive plasma cells (4 to 145/HPF; mean, 49.7/HPF) with focal areas of sclerosis reminiscent of immunoglobulin G4-related lymphadenopathy, 4 (13%) cases resembled, in part, nodular sclerosis Hodgkin lymphoma, and 9 (29%) cases mimicked T-cell lymphoma. Among 33 patients with available clinical follow-up, 20 (61%) showed persistent or refractory disease despite antimycobacterial therapy, and 1 patient died of the disease. We conclude that the presence of ill-defined granulomas, clusters of neutrophils adjacent to the histiocytic aggregates, and some Epstein-Barr virus-positive cells are features highly suggestive of AOIS. A high index of clinical suspicion and awareness of the morphologic features and differential diagnosis of AOIS are helpful for establishing the diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000001736DOI Listing
May 2021

Sole adjuvant intraoperative breast radiotherapy in Taiwan: a single-center experience.

Breast Cancer Res 2021 Apr 1;23(1):43. Epub 2021 Apr 1.

Department of Surgery, Ditmansion Medical Foundation Chia-Yi Christian Hospital, No. 539, Zhongxiao Rd., East District, Chia-Yi City, Taiwan, 60002.

Introduction: Intraoperative radiotherapy (IORT) is more convenient than standard whole breast external beam radiotherapy (EBRT) as a sole adjuvant radiotherapy for breast cancer. The impact of age on breast cancer course and treatment strategy is still under investigation, and the peak age for breast cancer in Taiwan is much younger than that in Western countries. We aimed to review the oncological outcomes of sole IORT compared with standard EBRT in a country with younger breast cancer patients.

Patients And Methods: We reviewed patients with invasive breast cancer who received breast-conserving surgery (BCS) from September 2014 to December 2016. The clinicopathologic characteristics and oncological outcomes of eligible patients who received EBRT or IORT as sole adjuvant radiotherapy after BCS were collected and reviewed.

Results: A total of 170 patients were enrolled with a mean follow-up time of 3.53 ± 0.82 years. The risk of locoregional recurrence was 2.44% for EBRT versus 10.64% for IORT (p = 0.024). IORT was a significant risk factor of locoregional recurrence (p = 0.005). The hazard ratios (HRs) for locoregional recurrence in the IORT group compared with the EBRT group were significantly higher in non-suitable risk group patients (HR = 7.02, p = 0.009) and in patients under 50 years old (HR = 10.42, p = 0.011).

Conclusions: Locoregional recurrence was significantly higher in patients who received IORT than in those who underwent EBRT. IORT should not be used alone in patients under 50 years old who do not belong to a suitable group.
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http://dx.doi.org/10.1186/s13058-021-01421-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017735PMC
April 2021

The Biosafety and Risk Management in Preparation and Processing of Cerebrospinal Fluid and Other Neurological Specimens With Potential Coronavirus Infection.

Front Neurol 2020 20;11:613552. Epub 2021 Jan 20.

Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.

The recent outbreak of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2, has become a global threat. Due to neurological manifestations presented throughout the coronavirus disease process, the potential involvement of COVID-19 in central nervous system has attracted considerable attention. Notably, the neurologic system could be widely affected, with various complications such as acute cerebrovascular events, encephalitis, Guillain-Barré syndrome, and acute necrotizing hemorrhagic encephalopathy. However, the risk assessment of exposure to potential biohazards in the context of the COVID-19 pandemic has not been clearly clarified regarding the sampling, preparation, and processing neurological specimens. Further risk managements and implantations are seldom discussed either. This article aims to provide current recommendations and evidence-based reviews on biosafety issues of preparation and processing of cerebrospinal fluid and neurological specimens with potential coronavirus infection from the bedside to the laboratory.
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http://dx.doi.org/10.3389/fneur.2020.613552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855587PMC
January 2021

Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1.

Int J Mol Sci 2020 Dec 19;21(24). Epub 2020 Dec 19.

Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Dengue virus (DENV) infection is a significant public health threat in tropical and subtropical regions; however, there is no specific antiviral drug. Accumulated studies have revealed that DENV infection induces several cellular responses, including autophagy and apoptosis. The crosstalk between autophagy and apoptosis is associated with the interactions among components of these two pathways, such as apoptotic caspase-mediated cleavage of autophagy-related proteins. Here, we show that DENV-induced autophagy inhibits early cell apoptosis and hence enhances DENV replication. Later, the apoptotic activities are elevated to suppress autophagy through cleavage of Beclin-1, an essential autophagy-related protein. Inhibition of cleavage of Beclin-1 by a pan-caspase inhibitor, Z-VAD, increases both autophagy and viral replication. Regarding the mechanism, we further found that DENV nonstructural protein 1 (NS1) is able to interact with Beclin-1 during DENV infection. The interaction between Beclin-1 and NS1 attenuates Beclin-1 cleavage and facilitates autophagy to prevent cell apoptosis. Our study suggests a novel mechanism whereby NS1 preserves Beclin-1 for maintaining autophagy to antagonize early cell apoptosis; however, elevated caspases trigger apoptosis by degrading Beclin-1 in the late stage of infection. These findings suggest implications for anti-DENV drug design.
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http://dx.doi.org/10.3390/ijms21249702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766445PMC
December 2020

Hydroa Vacciniforme and Hydroa Vacciniforme-Like Lymphoproliferative Disorder: A Spectrum of Disease Phenotypes Associated with Ultraviolet Irradiation and Chronic Epstein-Barr Virus Infection.

Int J Mol Sci 2020 Dec 7;21(23). Epub 2020 Dec 7.

Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Hydroa vacciniforme (HV) is a rare form of photosensitivity disorder in children and is frequently associated with Epstein-Barr virus (EBV) infection, whereas HV-like lymphoproliferative disorders (HVLPD) describe a spectrum of EBV-associated T-cell or natural killer (NK)-cell lymphoproliferations with HV-like cutaneous manifestations, including EBV-positive HV, atypical HV, and HV-like lymphoma. Classic HV occurs in childhood with papulovesicules on sun-exposed areas, which is usually induced by sunlight and ultraviolet irradiation, and mostly resolves by early adult life. Unlike classic HV, atypical or severe HV manifests itself as recurrent papulovesicular eruptions in sun-exposed and sun-protected areas associated occasionally with facial edema, fever, lymphadenopathy, oculomucosal lesions, gastrointestinal involvement, and hepatosplenomegaly. Notably, atypical or severe HV may progress to EBV-associated systemic T-cell or natural killer (NK)-cell lymphoma after a chronic course. Although rare in the United States and Europe, atypical or severe HV and HV-like lymphoma are predominantly reported in children from Asia and Latin America with high EBV DNA levels, low numbers of NK cells, and T cell clones in the blood. In comparison with the conservative treatment used for patients with classic HV, systemic therapy such as immunomodulatory agents is recommended as the first-line therapy for patients with atypical or severe HV. This review aims to provide an integrated overview of current evidence and knowledge of HV and HVLPD to elucidate the pathophysiology, practical issues, environmental factors, and the impact of EBV infection.
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http://dx.doi.org/10.3390/ijms21239314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731420PMC
December 2020

Clinicopathological and molecular characterisation of USP6-rearranged soft tissue neoplasms: the evidence of genetic relatedness indicates an expanding family with variable bone-forming capacity.

Histopathology 2021 Apr 24;78(5):676-689. Epub 2020 Nov 24.

Department of Anatomical Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Aims: USP6 rearrangement underpins self-limiting fibroblastic/myofibroblastic neoplasms, including nodular fasciitis (NF), myositis ossificans (MO), aneurysmal bone cyst (ABC), and related variants. The aim of this study was to characterise UPS6 and fusion partners in order to delineate the clinicopathological, genetic and bone-forming features in such lesions of soft tissue (ST).

Methods And Results: Break-apart fluorescence in-situ hybridisation (FISH) validated USP6 rearrangement in 31 of 35 NF [comprising three of three fasciitis ossificans (FO) cases, seven of eight cellular variant of fibroma of tendon sheath (C-FTS), four of six MO, three of three ST-ABC, and two of two fibro-osseous pseudotumours of digits (FOPD)]. As determined with FISH and reverse transcription polymerase chain reaction, MYH9-USP6 was the commonest fusion in four C-FTS and 20 NF, including one intravascular case and two infantile (one retroperitoneal) cases. The presence of MYH9-USP6 confirmed the diagnosis of two NFs> 50 mm with prominent ischaemic necrosis. COL1A1-USP6 was predominant in ossifying lesions, including all FO, MO, ST-ABC and FOPD with identified partner genes, and was also present in non-ossifying head and neck NF (HN-NF) and C-FTS in two cases each. A cervical NF of a 14-month-old girl harboured the novel COL1A2-USP6. Ossifying lesions showed considerable genetic and morphological overlaps. Sharing COL1A1-USP6, FO and FOPD showed similar central or haphazard bone matrix deposition. Besides zonation of outward bone maturation, four COL1A1-USP6-positive MO had incipient to sieve-like pseudocysts reminiscent of ST-ABC.

Conclusion: MYH9-USP6 is present in some C-FTS and most NF, including rare variants, but is unrelated to bone formation. All bone-forming USP6-rearranged lesions adopt COL1A1 as the 5' partner, indicating close genetic kinships. However, COL1A1/COL1A2 also contributes to the pathogenesis of minor subsets of non-ossifying USP6-rearranged HN-NF and C-FTS.
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http://dx.doi.org/10.1111/his.14268DOI Listing
April 2021

Impact of the COVID-19 pandemic on cytology practice: An international survey in the Asia-Pacific region.

Cancer Cytopathol 2020 Dec 15;128(12):895-904. Epub 2020 Sep 15.

Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.

Background: The purpose of the current study was to examine the impact of coronavirus disease 2019 (COVID-19) on various aspects of cytology practice in the Asia-Pacific region.

Methods: An online questionnaire was distributed to cytopathology laboratories in 24 Asia-Pacific countries to explore the impact of restrictive measures on access to health care, use of general and personal protective equipment (PPE), and changes in cytology workflow and workload from February to April 2020.

Results: A total of 167 cytopathology laboratories from 24 countries responded to the survey; the majority reported that restrictive measures that limited the accessibility of health care services had been implemented in their cities and/or countries (80.8%) and their hospitals (83.8%). The respondents noted that COVID-19 had an impact on the cytologic workflow as well as the workload. Approximately one-half of the participants reported the implementation of new biosafety protocols (54.5%) as well as improvements in laboratory facilities (47.3%). Rearrangement or redeployment of the workforce was reported in 53.3% and 34.1% of laboratories, respectively. The majority of the respondents reported a significant reduction (>10%) in caseload associated with both gynecological (82.0%) and nongynecological specimens (78.4%). Most laboratories reported no significant change in the malignancy rates of both gynecological (67.7%) and nongynecological specimens (58.7%) compared with the same period in 2019.

Conclusions: The results of the survey demonstrated that the COVID-19 pandemic resulted in a significant reduction in the number of cytology specimens examined along with the need to implement new biosafety protocols. These findings underscore the need for the worldwide standardization of biosafety protocols and cytology practice.
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http://dx.doi.org/10.1002/cncy.22354DOI Listing
December 2020

Thyroid fine-needle aspiration cytology in Taiwan: a nationwide survey and literature update.

J Pathol Transl Med 2020 Sep 31;54(5):361-366. Epub 2020 Aug 31.

Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

In Taiwan, thyroid fine-needle aspiration cytology is easily accessible and reliable for evaluating thyroid nodules. The sonographic pattern plays a major role and is the deciding factor for aspiration. We conducted a nationwide survey in 2017 and it revealed that 31% of laboratories had adopted The Bethesda System for Reporting Thyroid Cytopathology. There was a relatively high unsatisfactory rate (24.04%) and low rates of indeterminate diagnoses, including atypia of undetermined significance/follicular lesions of undetermined significance: 4.87%, and follicular neoplasm/suspicious for a follicular neoplasm: 0.35%. Moreover, the risks of malignancy in benign, atypia of undetermined significance, and suspicious for a follicular neoplasm were relatively high. These may reflect strict diagnostic criteria for indeterminate categories and better patient selection for surgery. Improvements in specimen sampling and continuing education programs are crucial. Newly-developed thyroid cytology technologies, such as immunocytochemistry, molecular testing, and computerized cytomorphometry, may further facilitate cytology diagnoses.
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http://dx.doi.org/10.4132/jptm.2020.07.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483030PMC
September 2020

Cytologic diagnosis of medullary thyroid carcinoma in the Asia-Pacific region.

Diagn Cytopathol 2021 Jan 22;49(1):60-69. Epub 2020 Aug 22.

Department of Pathology and Thyroid Disease Center, Izumi City General Hospital, Izumi, Osaka, Japan.

Background: The accurate preoperative identification of medullary thyroid carcinoma (MTC) is challenging due to the rarity of tumor and variable cytologic appearance. The Asian experience with diagnosing MTC by fine-needle aspiration (FNA) was scarcely reported.

Methods: Cases of MTC with available FNA slides were enrolled from 13 hospitals representing 8 Asia-Pacific countries. Clinicopathological information, including sample preparation technique, staining method, original cytologic diagnosis and review diagnosis were collected.

Results: Of a total of 145 MTC cases retrospectively recruited, 99 (68.3%) were initially interpreted as MTC/suspicious for MTC (S-MTC). The distribution of original FNA diagnostic categories was not associated with the staining method or sample preparation technique. The staining methods used were Papanicolaou, hematoxylin-eosin and Romanowsky stains. Liquid-based cytology (LBC) was used only in three countries. After reviewing all cases, the diagnostic rate of MTC/S-MTC increased to 91.7% (133/145). Cases with initially unrecognized MTC had either marked pleomorphism or cytology mimicking papillary carcinoma or follicular neoplasm. Although LBC provided certain benefits, there was no significant difference in diagnostic accuracy between conventional smear and LBC. Immunocytochemistry was available in 38 cases (26.2%), all of which were correctly recognized as MTC.

Conclusion: Our report summarizes how MTC is handled in contemporary Asian thyroid FNA practice. Although the detection rate of MTC by cytology alone is less satisfactory, integration with ancillary tests could achieve an excellent performance. The recognition of constitutive cytomorphologic features is needed for each cytopreparatory method, which may result in a lower threshold to initiate further workup for MTC.
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http://dx.doi.org/10.1002/dc.24586DOI Listing
January 2021

Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis.

Sci Rep 2020 08 12;10(1):13582. Epub 2020 Aug 12.

Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan.

In many human cancers, including hepatocellular carcinoma (HCC), high density of infiltrating tumor-associated macrophages (TAM) is associated with poor prognosis. Most TAMs express a M2 phenotype subsequently supporting tumor growth. How tumor cells polarize these TAMs to a pro-tumor M2 phenotype is still poorly understood. Our previous studies have revealed that a Toll-like receptor 2 (TLR2)-dependent autophagy triggered by hepatoma-derived factors down-regulates NF-κB p65 and drives M2 macrophage differentiation. However, the underlying mechanisms and potential hepatoma-derived TLR2 ligands are not clear. Here, we provide evidence to reveal that NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation is crucial for HCC-induced autophagy, NF-κB p65 down-regulation and M2 phenotype polarization in primary macrophages. This NOX2-generated ROS production in abolished in TLR2-deficient macrophages. HCC-derived or recombinant high-mobility group box 1 (HMGB1) is able to trigger this TLR2-mediated M2 macrophage polarization. Blockage of HMGB1 and ROS by inhibitors, ethyl pyruvate and N-acetylcysteine amide, respectively, significantly reduces both M2 macrophage accumulation and liver nodule formation in HCC-bearing mice. Our findings uncover a HMGB1/TLR2/NOX2/autophagy axis to trigger M2 macrophage polarization in HCC that can be considered as a novel therapeutic target for treating HCC.
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http://dx.doi.org/10.1038/s41598-020-70137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423894PMC
August 2020

Characterization of Driver Mutations in Anaplastic Thyroid Carcinoma Identifies and Mutations as Negative Survival Predictors.

Cancers (Basel) 2020 Jul 20;12(7). Epub 2020 Jul 20.

Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan.

Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive. We investigated the association of selected driver mutations, including , , promoter, , , and mismatch repair deficiency (MMR-D) with the clinicopathological features of ATC to identify prognostic and predictive biomarkers. Thirty-nine retrospective cases from pathology archives were enrolled for clinicopathology analysis and immunohistochemistry, and 27 cases had sufficient specimens for further molecular testing using targeted next-generation sequencing and mass spectrometry. and mutations were identified in 25.9% and 40.7% of ATC, respectively. mutation was significantly associated with coexisting papillary thyroid carcinoma ( = 0.009) and mutations with female gender ( = 0.012). In univariant analysis, the non- tumors were significantly associated with the presence of a sarcomatoid pattern ( = 0.045). , promoter, and mutations were identified in 14.8%, 81.5%, and 70.4% of cases, respectively. No MMR-D or mutations were detected. In survival analyses, and mutations were significantly associated with inferior outcomes ( = 0.03 and = 0.006, respectively). In conclusion, driver mutations in ATC are associated with distinct clinicopathological features. and mutations were negative predictors for patient survival. Emerging therapeutic agents targeting BRAF, RAS, and PI3 kinase may benefit a substantial proportion of ATC patients.
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http://dx.doi.org/10.3390/cancers12071973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409295PMC
July 2020

Fine-needle aspiration cytology of melanotic schwannoma in the submandibular gland.

Diagn Cytopathol 2021 Jan 24;49(1):142-145. Epub 2020 Jun 24.

Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.

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http://dx.doi.org/10.1002/dc.24534DOI Listing
January 2021

Reply to Rapid on-site evaluation and the COVID-19 pandemic.

Cancer Cytopathol 2020 12 5;128(12):910-912. Epub 2020 Jun 5.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.

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http://dx.doi.org/10.1002/cncy.22296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300869PMC
December 2020

Biosafety in the preparation and processing of cytology specimens with potential coronavirus (COVID-19) infection: Perspectives from Taiwan.

Cancer Cytopathol 2020 05 7;128(5):309-316. Epub 2020 Apr 7.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.

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http://dx.doi.org/10.1002/cncy.22280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262216PMC
May 2020

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment.

Front Pharmacol 2020 3;11:206. Epub 2020 Mar 3.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.
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http://dx.doi.org/10.3389/fphar.2020.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063971PMC
March 2020

First Glance of Molecular Profile of Atypical Cellular Angiofibroma/Cellular Angiofibroma with Sarcomatous Transformation by Next Generation Sequencing.

Diagnostics (Basel) 2020 Jan 9;10(1). Epub 2020 Jan 9.

Department of Pathology, University of Debrecen, Clinical Center, 4032 Debrecen, Hungary.

Cellular angiofibroma is a rare benign mesenchymal neoplasm most commonly occurring in the vulvovaginal region in women and the inguinoscrotal region in men with specific genetic deletion involved in the gene in chromosome 13q14 region. Atypical cellular angiofibroma and cellular angiofibroma with sarcomatous transformation are recently described variants showing worrisome morphological features and strong, diffuse p16 expression. Nevertheless, the molecular profile of these tumor entities is largely unknown. We carried out a next generation sequencing (NGS) study from six cases of atypical cellular angiofibroma and cellular angiofibroma with sarcomatous transformation. We were able to identify oncogenic gene mutations (33%) which may contribute to pathogenesis also resulting in p16 overexpression. In addition, gene alterations generally present were identified. Since it is a recently described and rare entity, the whole molecular signaling pathway is still largely obscured and the analysis of larger cohorts is needed to elucidate this issue.
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http://dx.doi.org/10.3390/diagnostics10010035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169459PMC
January 2020

Lysophosphatidic acid receptor LPA prevents oxidative stress and cellular senescence in Hutchinson-Gilford progeria syndrome.

Aging Cell 2020 01 12;19(1):e13064. Epub 2019 Nov 12.

Department of Life Science, National Taiwan University, Taipei, Taiwan.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare laminopathy that produces a mutant form of prelamin A, known as Progerin, resulting in premature aging. HGPS cells show morphological abnormalities of the nuclear membrane, reduced cell proliferation rates, accumulation of reactive oxygen species (ROS), and expression of senescence markers. Lysophosphatidic acid (LPA) is a growth factor-like lipid mediator that regulates various physiological functions via activating multiple LPA G protein-coupled receptors. Here, we study the roles of LPA and LPA receptors in premature aging. We report that the protein level of LPA was highly downregulated through internalization and the lysosomal degradation pathway in Progerin-transfected HEK293 cells. By treating Progerin HEK293 cells with an LPA agonist (OMPT, 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate) and performing shRNA knockdown of the Lpa3r transcript in these cells, we showed that LPA activation increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. LPA was shown to be downregulated in HGPS patient fibroblasts through the lysosomal pathway, and it was shown to be crucial for ameliorating ROS accumulation and cell senescence in fibroblasts. Moreover, in a zebrafish model, LPA deficiency was sufficient to cause premature aging phenotypes in multiple organs, as well as a shorter lifespan. Taken together, these findings identify the decline of LPA as a key contributor to the premature aging phenotypes of HGPS cells and zebrafish.
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http://dx.doi.org/10.1111/acel.13064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974717PMC
January 2020

Dietary Supplementation with Hazelnut Oil Reduces Serum Hyperlipidemia and Ameliorates the Progression of Nonalcoholic Fatty Liver Disease in Hamsters Fed a High-Cholesterol Diet.

Nutrients 2019 Sep 14;11(9). Epub 2019 Sep 14.

Department of Pediatrics, Taipei Veterans General Hospital, Taipei 11217, Taiwan.

: Hazelnut oil (HO) is rich in monounsaturated fatty acids and polyunsaturated fatty acids. This study intended to analyze the effects of hazelnut oil supplementation on the serum lipid profile and nonalcoholic fatty liver disease in hamsters fed a high-cholesterol (HC) diet. : Hamsters were fed a basic diet (control group) and an HC diet (HC group) for 16 weeks ( = 10 in each group). Hamsters were fed an HC diet for four weeks to induce hyperlipidemia and were then fed an HC diet enriched with 5% (low-dose HC + HO group; = 10) and 10% HO (high-dose HC + HO group; = 10) for 12 weeks. Serum lipid levels, hepatic changes (including steatosis, inflammation, and fibrosis), and hepatic prooxidant-antioxidant status (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST)) were evaluated after the treatment period. : Hamsters in the control group showed normal serum lipid profiles, normal liver function, and moderate glycogen storage without hepatic steatosis. Hamsters in the HC group showed severe hyperlipidemia, severe hepatic steatosis, and moderate steatohepatitis (mononuclear cell and neutrophil infiltration, oval cell hyperplasia, and fibrosis). Compared to the HC group, both the low-dose and the high-dose HC + HO groups showed a significant reduction of hyperlipidemia (serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C levels)) and improved liver function (serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT)). Additionally, compared to the HC group, intrahepatic triglyceride accumulation (IHTC) was significantly higher in the HC + HO group, while the incidence of steatohepatitis was significantly lower. The intake of the HC diet was associated with a higher level of lipid peroxidation (malondialdehyde, MDA) and a lower concentration of hepatic antioxidant enzymes (SOD, GPx, and GST), and all these factors were partially improved in the low-dose and high-dose HC + HO groups. Our findings indicate that the intake of HO reduced serum hyperlipidemia and oxidative stress and ameliorated the progression of nonalcoholic fatty liver disease in hamsters fed a high-cholesterol diet.
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http://dx.doi.org/10.3390/nu11092224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770627PMC
September 2019

Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma.

Cancer Res 2019 Nov 20;79(21):5550-5562. Epub 2019 Aug 20.

Department of Life Science, National Taiwan University, Taipei, Taiwan.

Neuroblastoma is the most common malignant disease of infancy, and amplification of the oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation and . kynurenine treatment also upregulated the expression of , a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that expression positively correlated with , and high expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. SIGNIFICANCE: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3272DOI Listing
November 2019

Modified Sauve-Kapandji Procedure Using Iliac Bone Graft for Giant Cell Tumor of the Distal Ulna: Stabilizing With Two-Screw Fixation: A Case Report.

JBJS Case Connect 2019 Apr-Jun;9(2):e0299

Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan.

Case: We describe a 33-year-old man who had a giant cell tumor in the ulnar head treated with wide resection and reconstructed using the modified Sauve-Kapandji procedure with an iliac crest bone graft as ulnar support.

Conclusions: Due to the destructive nature of the tumor and the important role played by the ulnar head in the distal radioulnar joint (DRUJ), treatment of the giant cell tumor in the distal ulna is a challenge. The modified Sauve-Kapandji procedure is an effective technique to restore DRUJ function, which is performed as an ulnar support arthroplasty. Using an iliac crest bone graft as ulnar support in reconstruction surgery could be a practical method after the ulnar head has been resected.
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http://dx.doi.org/10.2106/JBJS.CC.18.00299DOI Listing
June 2020

Anaplastic sarcoma of the kidney: Case report and literature review.

Ci Ji Yi Xue Za Zhi 2019 Apr-Jun;31(2):129-132

Department of Pathology, Ditmanson Medical Foundation, Chiayi Christian Hospital, Chiayi, Taiwan.

We present a case of a 22-year-old female with gross hematuria for 1 month. A 9.5-cm tumor was found at her left kidney. On suspicion of a renal cancer, she received left nephrectomy. Histologically, it was a hypercellular tumor with undifferentiated anaplastic neoplastic cells in fascicular sheets intermixed with chondroid nodules. The differential diagnoses included anaplastic sarcoma of the kidney (ASK), anaplastic Wilms tumor, mesenchymal chondrosarcoma, sarcomatoid renal cell carcinoma, clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, congenital mesoblastic nephroma, and synovial sarcoma. Based on the results of the work-up and literature review, ASK was diagnosed. The postoperative recovery was uneventful, and the patient began adjuvant chemotherapy (Ifosfamide [1800 mg/m] and Epirubicin [60 mg/m]) 5 weeks after the operation. Herein, we present this case to share the experience on an extremely rare entity.
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http://dx.doi.org/10.4103/tcmj.tcmj_194_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450149PMC
April 2019

Sphingosine-1-phosphate in Endothelial Cell Recellularization Improves Patency and Endothelialization of Decellularized Vascular Grafts In Vivo.

Int J Mol Sci 2019 Apr 2;20(7). Epub 2019 Apr 2.

Department of Pediatrics, Taipei Veterans General Hospital, Taipei 11217, Taiwan.

Background: S1P has been shown to improve the endothelialization of decellularized vascular grafts in vitro. Here, we evaluated the potential of tissue-engineered vascular grafts (TEVGs) constructed by ECs and S1P on decellularized vascular scaffolds in a rat model.

Methods: Rat aorta was decellularized mainly by 0.1% SDS and characterized by histology. Rat ECs, were seeded onto decellularized scaffolds, and the viability of the ECs was evaluated by biochemical assays. Then, we investigated the in vivo patency rate and endothelialization for five groups of decellularized vascular grafts (each = 6) in a rat abdominal aorta model for 14 days. The five groups included (1) rat allogenic aorta (RAA); (2) decellularized RAA (DRAA); (3) DRAA with S1P (DRAA/S1P); (4) DRAA with EC recellularization (DRAA/EC); and (5) DRAA with S1P and EC recellularization (DRAA/EC/S1P).

Results: In vitro, ECs were identified by the uptake of Dil-Ac-LDL. S1P enhanced the expression of syndecan-1 on ECs and supported the proliferation of ECs on decellularized vascular grafts. In vivo, RAA and DRAA/EC/S1P both had 100% patency without thrombus formation within 14 days. Better endothelialization, more wall structure maintenance and less inflammation were noted in the DRAA/EC/S1P group. In contrast, there was thrombus formation in the DRAA, DRAA/S1P and DRAA/EC groups.

Conclusion: S1P could inhibit thrombus formation to improve the patency rate of EC-covered decellularized vascular grafts in vivo and may play an important role in the construction of TEVGs.
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http://dx.doi.org/10.3390/ijms20071641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480112PMC
April 2019

Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression.

Cell Death Dis 2019 04 11;10(4):322. Epub 2019 Apr 11.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels, as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66-sensitized chemoresistant cells to cisplatin and paclitaxel treatment, and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPβ), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin. This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance, and supports the application of SC66 as a therapy for ovarian cancer.
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http://dx.doi.org/10.1038/s41419-019-1555-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459878PMC
April 2019

Anastomosing Hemangioma of the Nasal Cavity.

Laryngoscope 2020 02 8;130(2):354-357. Epub 2019 Apr 8.

Babina Diagnostics, Imphal, India.

Anastomosing hemangioma (AH) is an uncommon benign vascular neoplasm first described in the genitourinary tract. Symptomatically and histologically mimicking malignant angiosarcoma, a few rare cases have been described in the nonrenal genitourinary tract. Here, we report a 37-year-old man with a nasal AH and epistaxis. To the best of our knowledge, this is the first case of AH reported in the nasal cavity. Awareness of this entity in the nasal cavity can be helpful in diagnosis and distinction from angiosarcoma. Laryngoscope, 130:354-357, 2020.
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http://dx.doi.org/10.1002/lary.27998DOI Listing
February 2020

Recurrent tertiary hyperparathyroidism due to supernumerary parathyroid glands in a patient receiving long-term hemodialysis: a case report.

BMC Endocr Disord 2019 Jan 28;19(1):16. Epub 2019 Jan 28.

Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539 Chung Hsiao Rd, Chiayi, 600, Taiwan.

Background: Renal hyperparathyroidism is a common complication of chronic kidney disease (CKD) or end-stage renal disease (ESRD) characterized by elevated parathyroid hormone levels secondary to derangements in the homeostasis of calcium, phosphate, and vitamin D. Rapid correction of severe and prolonged hyperparathyroidism by surgical parathyroidectomy in long-term hemodialysis patients occasionally causes hungry bone syndrome. These patients then exhibit severe and long-lasting secondary or tertiary hyperparathyroidism with high bone turnover.

Case Presentation: We report a case of recurrent tertiary hyperparathyroidism after total parathyroidectomy due to supernumerary parathyroid gland in a patient with long-term hemodialysis. Supplementation with intravenous calcium, oral calcium, and vitamin D immediately after patient surgery helps to prevent and treat hungry bone syndrome.

Conclusions: We should prompt a search for the supernumerary parathyroid glands in ESRD patients, who have recurrent or persistent hyperparathyroidism after total parathyroidectomy. ESRD patients are more likely to develop hungry bone syndrome after parathyroidectomy. Prevention and treatment of hungry bone syndrome may be required after ectopic parathyroidectomy in clinical practice.
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http://dx.doi.org/10.1186/s12902-019-0346-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350335PMC
January 2019

Mechanisms of Lysophosphatidic Acid-Mediated Lymphangiogenesis in Prostate Cancer.

Cancers (Basel) 2018 Oct 31;10(11). Epub 2018 Oct 31.

Department of Life Sciences, National Taiwan University, Taipei 10617, Taiwan.

Prostate cancer (PCa) is the most common noncutaneous cancer in men worldwide. One of its major treatments is androgen deprivation therapy, but PCa frequently relapses as aggressive castration resistant local tumors and distal metastases. Hence, the development of novel agents or treatment modalities for advanced PCa is crucial. Many tumors, including PCa, first metastasize to regional lymph nodes via lymphatic vessels. Recent findings demonstrate that the bioactive lipid lysophosphatidic acid (LPA) promotes PCa progression by regulating vascular endothelial growth factor-C (VEGF-C), a critical mediator of tumor lymphangiogenesis and lymphatic metastasis. Many of the underlying molecular mechanisms of the LPA⁻VEGF-C axis have been described, revealing potential biomarkers and therapeutic targets that may aid in the diagnosis and treatment of advanced PCa. Herein, we review the literature that illustrates a functional role for LPA signaling in PCa progression. These discoveries may be especially applicable to anti-lymphangiogenic strategies for the prevention and therapy of metastatic PCa.
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http://dx.doi.org/10.3390/cancers10110413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266502PMC
October 2018
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