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   Table of Contents - Current issue
Coverpage
July-September 2022
Volume 34 | Issue 3
Page Nos. 255-357

Online since Tuesday, June 28, 2022

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REVIEW ARTICLES - BASIC  

The organoid: A research model for ovarian cancer p. 255
Yu-Hsun Chang, Kun-Chi Wu, Tomor Harnod, Dah-Ching Ding
DOI:10.4103/tcmj.tcmj_63_21  
Epithelial ovarian cancer (EOC) is a heterogeneous disease with a variety of distinct clinical and molecular characteristics. The currently available and common research models for EOC include tumor cell lines and patient-derived xenografts. However, these models have certain shortcomings: establishing a cell line is time-consuming, loss of genetic traits after long-term culture is a possibility, and investment is required in terms of animal care facilities. Therefore, better research models are required. Organoid technology was originally developed from colorectal cancer. Tumor organoid is a three-dimensional culture system and can help accurately recapture the tumor phenotype from the original tumor. Tumor organoid systems can overcome the above-mentioned shortcomings of the currently available research models. The organoid model can be used for culturing ovarian cancer subtypes, screening drugs, assessing genomes, and establishing biobanks. However, the currently available organoid models can only culture one type of cells, epithelial cells. Therefore, an organoid-on-a-chip device can be developed in the future to provide a microenvironment for cell–cell, cell–matrix, and cell–media interactions. Thus, organoid models can be used in ovarian cancer research and can generate a simulated in vivo system, enabling studies on the heterogeneity of ovarian cancer.
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Genetics of hyperuricemia and gout: Insights from recent genome-wide association studies and Mendelian randomization studies p. 261
Yu-Lin Ko
DOI:10.4103/tcmj.tcmj_117_21  
Gout is the most common form of inflammatory arthritis in adults. Elevation serum uric acid (SUA) concentration is known to be the key to gout pathogenesis. Since the first genome-wide association study (GWAS) for SUA was performed in 2007, the number of gene loci known to be associated with hyperuricemia and gout has grown rapidly. GWASs and Mendelian randomization studies have also reported numerous novel results regarding the genetics of hyperuricemia and gout since 2018. We concisely review recent advances in scholarship on the effects of genetics on hyperuricemia and gout risk. We also review data from genetic association studies in Taiwan and perform GWASs of SUA levels among Taiwan Biobank participants.
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Hematopoietic stem cell mobilization p. 270
Hsin-Hou Chang, Yu-Shan Liou, Der-Shan Sun
DOI:10.4103/tcmj.tcmj_98_21  
Hematopoietic stem cell (HSC) transplantation has been used to treat hematopoietic diseases for over 50 years. HSCs can be isolated from bone marrow (BM), umbilical cord blood, or peripheral blood. Because of lower costs, shorter hospitalization, and faster engraftment, peripheral blood has become the predominant source of HSCs for transplantation. The major factors determining the rate of successful HSC transplantation include the degree of human leukocyte antigen matching between the donor and recipient and the number of HSCs for transplantation. Administration of granulocyte colony-stimulating factor (G-CSF) alone or combined with plerixafor (AMD3100) are clinical used methods to promote HSC mobilization from BM to the peripheral blood for HSC transplantations. However, a significant portion of healthy donors or patients may be poor mobilizers of G-CSF, resulting in an insufficient number of HSCs for the transplantation and necessitating alternative strategies to increase the apheresis yield. The detailed mechanisms underlying G-CSF-mediated HSC mobilization remain to be elucidated. This review summarizes the current research on deciphering the mechanism of HSC mobilization.
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Computer-aided discovery, design, and investigation of COVID-19 therapeutics p. 276
Chun-Chun Chang, Hao-Jen Hsu, Tien-Yuan Wu, Je-Wen Liou
DOI:10.4103/tcmj.tcmj_318_21  
Coronavirus disease 2019 (COVID-19) pandemic is currently the most serious public health threat faced by mankind. Thus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, is being intensively investigated. Several vaccines are now available for clinical use. However, owing to the highly mutated nature of RNA viruses, the SARS-CoV-2 is changing at a rapid speed. Breakthrough infections by SARS-CoV-2 variants have been seen in vaccinated individuals. As a result, effective therapeutics for treating COVID-19 patients is urgently required. With the advance of computer technology, computational methods have become increasingly powerful in the biomedical research and pharmaceutical drug discovery. The applications of these techniques have largely reduced the costs and simplified processes of pharmaceutical drug developments. Intensive and extensive studies on SARS-CoV-2 proteins have been carried out and three-dimensional structures of the major SARS-CoV-2 proteins have been resolved and deposited in the Protein Data Bank. These structures provide the foundations for drug discovery and design using the structure-based computations, such as molecular docking and molecular dynamics simulations. In this review, introduction to the applications of computational methods in the discovery and design of novel drugs and repurposing of existing drugs for the treatments of COVID-19 is given. The examples of computer-aided investigations and screening of COVID-19 effective therapeutic compounds, functional peptides, as well as effective molecules from the herb medicines are discussed.
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REVIEW ARTICLES - CLINICAL Top

Pathogenesis evidence from human and animal models of detrusor underactivity p. 287
Jia-Fong Jhang, Yuan-Hong Jiang, Yung-Hsiang Hsu, Han-Chen Ho, Hann-Chorng Kuo
DOI:10.4103/tcmj.tcmj_284_20  
Detrusor underactivity (DU) is a common urodynamic diagnosis in patients with lower urinary tract symptoms and large post-voiding residual volume. Animal and human studies showed the possible etiologies of DU include central or peripheral nerve injury, bladder outlet obstruction, chronic ischemia, aging, diabetes mellitus, and sympathetic inhibition of micturition reflex. Evidence from animal and human DU studies with various etiologies revealed highly similar gross and histological characteristics in the bladders, including increased bladder weight, bladder wall thickening, inflammation, collagen deposition, and fibrosis. In electron microscopy, smooth muscle destruction, swollen mitochondria, decreased nerve innervation, caveolae, and umbrella cell fusiform vesicles were noted in the DU bladders. Most animal DU models demonstrate detrusor contractility changes from compensatory to the decompensatory stage, and the change was compatible with human DU observation. The cystometry in the DU animal studies is characterized by impaired contractility, prolong intercontraction interval, and hyposensation, while in vitro bladder muscle strips experiment may exhibit normal detrusor contractility. Decreased bladder blood flow and increased oxidative stress in bladders had been proved in different animal DU models, suggesting they should be important in the DU pathogenesis pathway. Sensory receptors mRNA and protein expression changes in DU bladders had been observed in both animal and human studies, including muscarinic receptors M2, M3, adrenergic receptor β3, purinergic receptor P2X1, P2X3, and transient receptor potential vanilloid (TRPV) 1 and TRPV4. Although some of the sensory receptors changes remain controversial, it might be the target for further pharmacologic treatments.
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Emphysematous pyelonephritis: classification, management, and prognosis p. 297
Shu-Yu Wu, Stephen Shei-Dei Yang, Shang-Jen Chang, Chun-Kai Hsu
DOI:10.4103/tcmj.tcmj_257_21  
Urinary tract infections are commonly encountered and managed worldwide, and emphysematous pyelonephritis (EPN) is among the most serious types of urinary tract infections. EPN is an acute necrotizing infection of the kidney, often associated with high rates of renal loss and mortality. The symptoms of EPN infection can be nonspecific, but the clinical triad of fever, flank pain, and nausea represent the most common presentations. The diagnosis and classification are performed with the assistance of computed tomography (CT). The imaging-based classification system created by Huang and Tseng is widely used in clinical assessments. They defined EPN into four different class (1–4), with the higher number the more severe disease. Optimal EPN treatment is controversial, with emergent nephrectomy suggested during early studies, whereas more recent evidence favors more conservative approaches. Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis are most common pathogens. The initial use of broad-spectrum antibiotics such as Third-or fourth-generation cephalosporins and carbapenems are recommended. Diabetes, obstructive uropathy and hypertension are the most common risk factors and often need treatment together. Emergent drainage is indicated with a larger-sized drainage tube to achieve better drainage function. CT guidance has a better success rate than insertion under the guidance of ultrasonography. Nephrectomy should be reserved as the last resort for those who fail to respond to conservative therapy. This review aims to provide comprehensive, evidence-based recommendations for the diagnosis and management of this life-threatening urological infection.
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High-dose dual therapy versus bismuth-containing quadruple therapy for the treatment of Helicobacter pylori infection – A review of the strengths, weaknesses, and proposed solutions p. 303
Chi-Tan Hu
DOI:10.4103/tcmj.tcmj_185_21  
Helicobacter pylori is the principal cause of peptic ulcers, gastric cancer, and mucosa-associated lymphoid tissue lymphoma. The first treatment to H. pylori infection is dual therapy (a bismuth compound plus metronidazole). On the launch of omeprazole in 1988, dual therapy became omeprazole and amoxicillin (low dose). The poor H. pylori eradication rates by either bismuth-based or low-dose dual therapy drove more combinations of antibiotics were needed. Antibiotic resistance, especially clarithromycin and metronidazole, has made bismuth-containing quadruple therapy (BCQT) a savior for first-line and second-line treatments. However, its complicated dosing regimen commonly causes more adverse events and poor drug compliance. Thus, high-dose dual therapy (HDDT) has been re-arising. This article reviews the strengths and weaknesses of HDDT versus BCQT with proposed solutions.
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ORIGINAL ARTICLES - BASIC Top

Berberine protects cardiac cells against ferroptosis p. 310
Kun-Ta Yang, Tung-Hui Chao, I-Chieh Wang, Yu-Po Luo, Pei-Ching Ting, Jian-Hong Lin, Jui-Chih Chang
DOI:10.4103/tcmj.tcmj_236_21  
Objectives: Cardiovascular diseases are one of the primary causes of death. Cardiomyocyte loss is a significant feature of cardiac injury. Ferroptosis is iron-dependent cell death, which occurs due to excess iron and reactive oxygen species (ROS) accumulation causing lipid peroxidation, and subsequent cell death. Ferroptosis has been confirmed to mediate ischemia/reperfusion-induced cardiomyopathy and chemotherapy-induced cardiotoxicity. Berberine (BBR) has been proven to protect the heart from cardiomyopathies, including cardiac hypertrophy, heart failure, myocardial infarction, and arrhythmias. It protects cardiomyocytes from apoptosis and autophagy. However, the relation between BBR and ferroptosis is still unknown. This study aimed to confirm if BBR reduces cardiac cell loss via inhibiting ferroptosis. Materials and Methods: We used erastin and Ras-selective lethal small molecule 3 (RSL3) to establish a ferroptosis model in an H9c2 cardiomyoblast cell line and rat neonatal cardiomyocytes to prove that BBR has a protective effect on cardiac cells via inhibiting ferroptosis. Results: In H9c2 cardiomyoblasts, the results showed that BBR reduced erastin and RSL3-induced cell viability loss. Moreover, BBR decreased ROS accumulation and lipid peroxidation in cells induced with ferroptosis. Furthermore, quantitative polymerase chain reaction results showed that Ptgs2 mRNA was reduced in BBR-treated cells. In rat neonatal cardiomyocytes, BBR reduced RSL3-induced loss of cell viability. Conclusion: These results indicated that BBR inhibited ferroptosis via reducing ROS generation and reducing lipid peroxidation in erastin and RSL3-treated cardiac cells.
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Comparing miR-16 and miR-1228 as an optimal endogenous control for quantification of circulating microRNAs in colorectal cancer patients p. 318
Chia-Lin Yang, Fu-Ming Tsai, Chuang-Wei Chen, Kuan-Hong Hsiao, Jia-Hui Chen, Woei-Yau Kao
DOI:10.4103/tcmj.tcmj_240_21  
Objectives: Circulating microRNAs (miRNAs) have been discovered to play a novel role in intercellular communication and cancer biology. They are emerging candidates for noninvasive molecular biomarkers of cancer and other diseases. However, current translational researches have been limited by the lack of consensus on the optimal endogenous control of circulating miRNAs quantitation. In this study, we compared two promising miRNAs, miR-1228 and miR-16, as an endogenous control. The effects of normalizers on the relative quantification of circulating miR-31 in plasma samples of colorectal cancer (CRC) were also assessed. Materials and Methods: The cel-miR-39 was a spiked-in RNA used as an external control and added to plasma samples before RNA extraction. Quantitative real-time polymerase chain reaction technology was used to analyze the expression levels of circulating miRNAs in plasma samples of 4 healthy controls and 14 CRC patients. The expression stability of the candidate controls was compared by Ct analysis and NormFinder algorithms. Results: There was no significant difference in expression level of miR-16 and miR-1228 between healthy control group and before or after therapy of CRC patient groups. The expression of miR-1228 has smaller the range Ct values (28.25-25.64) compared with those of miR-16 (24.91-20.34). The stability value of miR-1228 (0.102) is lower than that of miR-16 (0.350). The expression of miR-1228 endogenous reference candidate has lower stability value and smaller the range Ct values compared with those in miR-16. According to the range Ct values and stability value, miR-1228 is better than miR-16 as endogenous control in CRC patients. There are significant differences in circulating miR-31 expression between healthy control and CRC patients when miR-1228 was used to standardize miR-31 expression. Conclusions: miR-1228 is recommended as a better endogenous control in quantification of circulating miRNAs in CRC patients.
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ORIGINAL ARTICLES - CLINICAL RESEARCH Top

Lumbar-peritoneal shunt for idiopathic normal pressure hydrocephalus and secondary normal pressure hydrocephalus p. 323
Chia-Lin Liao, Pao-Hui Tseng, Hsin-Yi Huang, Tsung-Lang Chiu, Shinn-Zong Lin, Sheng-Tzung Tsai
DOI:10.4103/tcmj.tcmj_125_21  
Objectives: Normal-pressure hydrocephalus is a clinical syndrome consisting of dilated cerebral ventricles with the clinical triad of gait disturbance, cognitive impairment and/or urinary dysfunction. Lumbar-peritoneal (LP) shunt could improve idiopathic normal pressure hydrocephalus (iNPH) while its effectiveness on secondary NPH (sNPH) is elusive. We compared the clinical results of the patients who received LP shunt surgery between iNPH and sNPH. Materials and Methods: We retrospectively analyzed the patients who received LP shunt surgery in a single center from January 1, 2017, to June 30, 2017. Patients selected for LP shunt placement had at least two of three cardinal symptoms of iNPH. The symptoms should persist for more than 3 months with compatible brain magnetic resonance imaging findings. All patients were followed up with iNPH grading scale (iNPHGS) and Modified Rankin Scale (MRS) for evaluation. Results: Thirty-three patients (23 male and 10 female patients) with mean age 76-year-old completed follow-up in this study, and 17 patients received lumbar drainage tests and intracranial pressure measurements. Both iNPH (n = 22) and sNPH (n = 11) groups did not have major complications such as infection, nerve root injury, or shunt failure. Both groups have significant improvement in iNPHGS and MRS. Interestingly, we found the correlation between both opening intracranial pressure and pressure gradient difference to the improvement percentage from LP shunt. Conclusion: The safety and effectiveness for sNPH patients who received LP shunt placement are equivalent to the iNPH patients. Lumbar drainage test provides prerequisite outcome prediction and should be considered to identify NPH patients planned to receive LP shunt.
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Correlation between placental histopathology and perinatal outcome in COVID-19 p. 329
Devendra Arora, KS Rajmohan, Sanjay Singh, Vinod Nair, Sanghita Barui, Madhusudan Dey, Abhijeet Kumar
DOI:10.4103/tcmj.tcmj_233_21  
Objectives: An alarming rate of adverse perinatal outcomes as well as maternal deaths has been reported worldwide during this pandemic. It would be prudent to start thinking on the lines of acute or chronic intrauterine fetal hypoxia due to placental microvascular pathology or villitis caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Autopsy studies of deceased patients with severe COVID-19 have revealed the presence of diffuse pulmonary alveolar damage, thrombosis, and microvascular injuries. It is expected that similar pathological features such as microvascular injuries could be found in the placenta of infected pregnant women. Materials and Methods: Placentas of singleton pregnancies from 42 SARS-CoV-2 positive mothers delivered at term were submitted for histopathological examination. Those with multifetal gestation, hypertensive disorder, fetal growth restriction, structural or chromosomal anomalies in the fetus, thrombophilia, prolonged prelabor rupture of membranes, and placenta accreta spectrum were excluded from the study. Histopathological examination was done by two pathologists independently and only those results concurred by both were reported. Histopathological features and corresponding neonatal outcome were analyzed. Results: Reports of 42 placentas from patients with SARS-CoV-2, delivered at term (37–40 weeks) were analyzed in our study. Features of maternal vascular malperfusions (MVM) were present in 45% (n = 19) cases. Features of fetal vascular malperfusions (FVM) were present in 23.8% (n = 10) cases. There were 47.6% (n = 20) cases showing at least one feature of acute inflammatory pathology (AIP) and 42.8% (n = 18) showing features of chronic inflammatory pathology (CIP). Neonatal respiratory distress syndrome was found in 19% (n = 8) of the neonates. Correspondingly, nearly all placentas (n = 7) of these neonates showed features of MVM, FVM, AIP and CIP. There was no maternal or neonatal mortality in our study group. Conclusion: The main findings of our study include maternal as well as fetal vascular malperfusions and placental inflammatory pathology. These findings provide an outline for better understanding of etiological factors and pathogenesis of adverse perinatal outcomes in SARS-CoV-2 infection.
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Sociodemographic, clinical profile, and treatment characteristics of oncology patients developing radiation recall phenomenon: Two tertiary care center's experience of an eternal unpredictable phenomenon of cancer treatment p. 337
Abhishek Purkayastha, Neelam Sharma, Sachin Taneja, Virender Suhag, Nishant Lohia
DOI:10.4103/tcmj.tcmj_163_21  
Objectives: To determine the socio-demographic and clinical profile of cancer patients developing radiation recall phenomenon or radiation recall dermatitis following chemotherapy administration, previously treated with external irradiation. We assessed its incidence, severity, frequency, differentiation from radio-sensitization and radiation-dermatitis, its correlation with radiation dose and chemotherapeutic agent, and various parameters affecting its occurrence. Materials and Methods: This observational prospective study was designed for 1092/2676 (50.2%) patients of histologically proven carcinoma breast, carcinoma lung, lymphomas, chest wall sarcomas, thymomas, thymic carcinomas, nasopharyngeal cancer, bladder carcinoma, rectal cancer, and metastatic cases who received radiation therapy followed by chemotherapy. Intake, treatment, observation, and follow-up were done from July 2014 to July 2021 for 7 years in two tertiary care cancer institutes of government setup. Results: In our study, majority of recall phenomena were reported in breast carcinoma 43/71 (60.5%) followed by carcinoma esophagus with 07/71 (9.8%) cases. Females developed 54.9% grade-I/II and 90% grade-III/IV recall cases compared to males with 45.1% and 10% cases, respectively (P = 0.005). Median radiation dose used was 45 Gy (dose range 8–70 Gy) (P = 0.656). Docetaxel resulted in 55% recall cases followed by paclitaxel with 12.7% of cases. Combination therapy reported 71.8% of cases compared to monotherapy with 28.2% of cases. Recall-cases recorded in the time period of 3–4 weeks between radiation and chemotherapy were 59/71 (83%) and those reported in >4 weeks were 12/71 (17%). Time-gap between 3 and 4 weeks reported 49% grade-I/II and 100% grade-III/IV recall-cases while time-gap >4 weeks resulted in 26% and 0% cases respectively (P = 0.000). Conclusion: In this study, taxanes and platinum-agents were the most common chemotherapeutic drugs involved in the occurrence of the recall phenomenon. Multi-drug regimens resulted in higher recall cases compared to monotherapy. Radiation dosage did not cause any significant impact. The risk and severity of recall reactions increased with female gender and shorter time-interval between radiation and systemic therapy, while early-onset recall cases displayed greater severity. This precedented but unpredictable phenomenon ceases to be a topic to be discarded in this modern era of highly conformal radiation therapy techniques and targeted cancer therapy.
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A study on origin, termination, and course characteristics of internal thoracic artery relevant to coronary surgeries and reconstructive procedures p. 348
Gaurav Agnihotri, Anureet Mitra
DOI:10.4103/tcmj.tcmj_195_21  
Objectives: The internal thoracic artery is a favored vessel for coronary artery bypass grafting and is utilized for breast reconstructive surgeries. Our study focuses on the origin, termination, and course characteristics of the internal thoracic artery. A comprehension of these morphological features and possible variations will definitely aid a clinician in appropriate harvesting of the artery for clinical procedures. Materials and Methods: 200 thoracic halves (from 100 embalmed adult human cadavers of either sex) were obtained from the department of anatomy. The origin, course characteristics, termination levels, and patterns for the internal thoracic artery were studied. Results: The internal thoracic artery originated from the first part of subclavian artery. The most common course pattern observed was medial concavity (88.5%). In 10% of cases, a tortuous course was observed. No artery with lateral concavity or rectilinear course pattern was documented. The artery terminated in the sixth space in 93.5% of cases. In 98% of cases, bifurcation in termination was observed. Trifurcation in termination was also observed in 2% of cases. The average length of variant artery (third terminating branch) was documented to be 5.5 cm. Conclusion: The increased utilization of the internal thoracic artery for coronary bypass arterial surgery and its role in sternal wound healing has made it imperative for clinicians to keep in mind its anatomical characteristics and local variations.This knowledge definitely will improve prognosis and decrease intraoperative/postoperative complications in patients undergoing coronary surgeries, percutaneous subclavian catheterizations, and reconstructive procedures.
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Development and validation of a brief version of the traditional Chinese Stressors in Nursing Students scale among college nursing students in Taiwan p. 353
Shoa-Jen Perng, Roger Watson, Graeme D Smith, Chen-Jung Chen, Tzu-Ying Lee, Malcolm Koo, Huei-Chuan Sung
DOI:10.4103/tcmj.tcmj_217_21  
Objective: The 43-item Stressors in Nursing Students (SINS) scale has been evaluated among nursing students in several countries, including China, Hong Kong, Japan, Pakistan, and Spain. However, the original four-factor structure has not been consistently replicated in all of these populations. The aim of this study was to develop a brief version of the traditional Chinese SINS (TC-SINS) scale and to validate it in Taiwanese nursing students. Materials and Methods: Data obtained from a cross-sectional survey study of 814 nursing students in a nursing college and a university in Taiwan were randomly divided into two parts. The first part was used to conduct an exploratory factor analysis using principal axis factoring with oblique rotation. After the removal of cross-loading items, the resulting scale was validated with the data from the second part using confirmatory factor analysis. Results: A three-factor solution (social, clinical, and education) with 23 items accounting for 54.5% of variance was obtained in the exploratory factor analysis. The confirmatory factor analysis further reduced the number of items to 20. The goodness-of-fit indexes were good (Root Mean Square Error of Approximation = 0.075 and Comparative Fit Index = 0.90). Conclusions: The number of items in the TC-SINS could be reduced from 43 to 20, without sacrificing its psychometric properties. The brief version of TC-SINS might be able to reduce respondent burden.
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