Still a Case of “No Pain, No Gain”? An Updated and Critical Review of the Pathogenesis, Diagnosis, and Management Options for Hemorrhoids in 2020

Kheng-Seong Ng,Melanie Holzgang,Christopher Young 대한대장항문학회 2020 Annals of Coloproctolgy Vol.36 No.3

The treatment of haemorrhoids remains challenging: multiple treatment options supported by heterogeneous evidence are available, but patients rightly demand a tailored approach. Evidence for newer surgical techniques that promise to be less painful has been conflicting. We review the current evidence for management options in patients who present with varying haemorrhoidal grades. A review of the English literature was performed utilizing MEDLINE/PubMed, Embase, and Cochrane databases (31 May 2019). The search terms (haemorrhoid OR haemorrhoid OR haemorrhoids OR haemorrhoids OR “Hemorrhoid”[Mesh]) were used. First- and second-degree haemorrhoids continue to be managed conservatively. The easily repeatable and cost-efficient rubber band ligation is the preferred method to address minor haemorrhoids; long-term outcomes following injection sclerotherapy remain poor. Conventional haemorrhoidectomies (Ferguson/Milligan-Morgan/Ligasure haemorrhoidectomy) still have their role in third- and fourth-degree haemorrhoids, being associated with lowest recurrence; nevertheless, posthaemorrhoidectomy pain is problematic. Stapled haemorrhoidopexy allows quicker recovery, albeit at the costs of higher recurrence rates and potentially serious complications. Transanal Haemorrhoidal Dearterialization has been promoted as nonexcisional and less invasive, but the recent HubBLe trial has questioned its overall place in haemorrhoid management. Novel “walk-in-walk-out” techniques such as radiofrequency ablations or laser treatments will need further evaluation to define their role in modern-day haemorrhoid management. There are numerous treatment options for haemorrhoids, each with their own evidence-base. Newer techniques promise to be less painful, but recurrence rates remain an issue. The balance continues to be sought between long-term efficacy, minimisation of postoperative pain, and preservation of anorectal function.

Comparison of Luminex NxTAG Respiratory Pathogen Panel and xTAG Respiratory Viral Panel FAST Version 2 for the Detection of Respiratory Viruses

Chun Kiat Lee,Hong Kai Lee,Christopher Wei Siong Ng,Lily Chiu,Julian Wei-Tze Tang,Tze Ping Loh,Evelyn Siew-Chuan Koay 대한진단검사의학회 2017 Annals of Laboratory Medicine Vol.37 No.3

Owing to advancements in molecular diagnostics, recent years have seen an increasing number of laboratories adopting respiratory viral panels to detect respiratory pathogens. In December 2015, the NxTAG respiratory pathogen panel (NxTAG RPP) was approved by the United States Food and Drug Administration. We compared the clinical performance of this new assay with that of the xTAG respiratory viral panel (xTAG RVP) FAST v2 using 142 clinical samples and 12 external quality assessment samples. Discordant results were resolved by using a laboratory-developed respiratory viral panel. The NxTAG RPP achieved 100% concordant negative results and 86.6% concordant positive results. It detected one coronavirus 229E and eight influenza A/H3N2 viruses that were missed by the xTAG RVP FAST v2. On the other hand, the NxTAG RPP missed one enterovirus/rhinovirus and one metapneumovirus that were detected by FAST v2. Both panels correctly identified all the pathogens in the 12 external quality assessment samples. Overall, the NxTAG RPP demonstrated good diagnostic performance. Of note, it was better able to subtype the influenza A/H3N2 viruses compared with the xTAG RVP FAST v2.

Screening Carica papaya native promoters driving stilbene synthase expression in Arabidopsis thaliana for resveratrol glucoside (piceid) synthesis

Luzminda Carlos-Hilario,Richard Shimshock,Cherie Ng,Jon-Paul Bingham,David A. Christopher 한국식물생명공학회 2015 Plant biotechnology reports Vol.9 No.5

The use of promoters for downstream metabolic engineering in plants requires efficiently screening their transcriptional strength and the resulting levels of the desired metabolite. Carica papaya is a complex slowgrowing tropical tree, which is difficult to rapidly screen for promoter activity. Therefore, we used the simple model system, Arabidopsis thaliana (Columbia), to compare the effectiveness of two native papaya promoters (Cp9 and Cp29) with a positive control (CaMV35S promoter), in driving transcription of the stilbene synthase gene (Vst1) and production of the phytoalexin trans-resveratrol glucoside (piceid). Single transgene copy numbers were verified via Southern analysis of at least three independent transgenic lines for each promoter construct. The Cp29 and control CaMV35S promoters consistently produced high Vst1 mRNA levels, whereas Vst1 mRNA was 50–60 % less in the Cp9:Vst1 lines. The evolutionarily related chalcone synthase (CHS) gene produced 20 and 40 % less mRNAs relative to WT in the Cp29:Vst1 and 35S:Vst1 lines, respectively, but was unchanged in the Cp9:Vst1 lines. The transgenic lines accumulated piceid as identified through RP-HPLC and tandem mass spectrometry. Piceid levels were the highest in the 35S:Vst1 followed by Cp29:Vst1 and Cp9:Vst1 in the studied tissues. No overt deleterious phenotypes were observed in the Cp9:Vst1 and Cp29:Vst1 lines; however, 35S:Vst1 produced smaller plants. The levels of secondary metabolites (anthocyanins) and seed pigments (tannins) decreased in the CaMV35S:Vst1 and Cp29:Vst1 lines, likely due to competition between CHS and stilbene synthase for precursors p-coumaroyl- and malonyl-CoA. The Cp29:Vst1 expression in Arabidopsis produced adequate levels of piceid for future disease-resistance studies.

Resveratrol Arrests Cell Cycle and Induces Apoptosis in Human Hepatocellular Carcinoma Huh-7 Cells

Pei-Chi Liao,Lean-Teik Ng,Liang-Tzung Lin,Christopher D. Richardson,Guey-Horng Wang,Chun-Ching Lin 한국식품영양과학회 2010 Journal of medicinal food Vol.13 No.6

Resveratrol has been shown to possess anticancer, anti-aging, anti-inflammatory, antimicrobial, and neuroprotective activities. In this study, we examined the antiproliferative properties of resveratrol and its molecular mechanism(s) of action in Huh-7 cells, a new human hepatoma cell line system for hepatitis C virus. Results showed that resveratrol significantly inhibited Huh-7 cell proliferation (50% inhibitory concentration=22.4μg/mL) and effectively induced cell cycle arrest and apoptosis. It up-regulated p21/WAF1 expression in a p53-independent manner, but the expressions of cyclin E, cyclin A, and cyclin-dependent kinase 2 were down-regulated. It also caused an increase in the ratio of pro-apoptotic/anti-apoptotic protein, which was associated with the mitochondrial membrane depolarization and the increase in caspase activity. Resveratrol showed no effect on Fas, Fas ligand, extracellular signal regulated kinase (ERK) 1/2, and p38 expression but down-regulated phospho-ERK and phospho-p38 expression. In addition, resveratrol was noted to trigger autophagic cell death through the increased expression of autophagy-related Atg5, Atg7, Atg9, and Atg12 proteins. These results suggest that resveratrol could be an important chemoprevention agent for hepatoma of hepatitis C virus infection.

Incorporation of Smooth Muscle Cells Derived from Human Adipose Stem Cells on Poly(Lactic-co-Glycolic Acid) Scaffold for the Reconstruction of Subtotally Resected Urinary Bladder in Athymic Rats

Salem Salah Abood,Rashidbenam Zahra,Jasman Mohd Hafidzul,Ho Christopher Chee Kong,Sagap Ismail,Singh Rajesh,Yusof Mohd Reusmaazran,Md. Zainuddin Zulkifli,Haji Idrus Ruszymah Bt,Ng Min Hwei 한국조직공학과 재생의학회 2020 조직공학과 재생의학 Vol.17 No.4

Background: The urinary tract can be affected by both congenital abnormalities as well as acquired disorders, such as cancer, trauma, infection, inflammation, and iatrogenic injuries, all of which may lead to organ damage requiring eventual reconstruction. As a gold standard, gastrointestinal segment is used for urinary bladder reconstruction. However, one major problem is that while bladder tissue prevents reabsorption of specific solutes, gastrointestinal tissue actually absorbs them. Therefore, tissue engineering approach had been attempted to provide an alternative tissue graft for urinary bladder reconstruction. Methods: Human adipose-derived stem cells isolated from fat tissues were differentiated into smooth muscle cells and then seeded onto a triple-layered PLGA sheet to form a bladder construct. Adult athymic rats underwent subtotal urinary bladder resection and were divided into three treatment groups (n = 3): Group 1 (“sham”) underwent anastomosis of the remaining basal region, Group 2 underwent reconstruction with the cell-free scaffold, and Group 3 underwent reconstruction with the tissue-engineered bladder construct. Animals were monitored on a daily basis and euthanisation was performed whenever a decline in animal health was detected. Results: All animals in Groups 1, 2 and 3 survived for at least 7 days and were followed up to a maximum of 12 weeks post-operation. It was found that by Day 14, substantial ingrowth of smooth muscle and urothelial cells had occurred in Group 2 and 3. In the long-term follow up of group 3 (tissue-engineered bladder construct group), it was found that the urinary bladder wall was completely regenerated and bladder function was fully restored. Urodynamic and radiological evaluations of the reconstructed bladder showed a return to normal bladder volume and function.Histological analysis revealed the presence of three muscular layers and a urothelium similar to that of a normal bladder. Immunohistochemical staining using human-specific myocyte markers (myosin heavy chain and smoothelin) confirmed the incorporation of the seeded cells in the newly regenerated muscular layers. Conclusion: Implantation of PLGA construct seeded with smooth muscle cells derived from human adipose stem cells can lead to regeneration of the muscular layers and urothelial ingrowth, leading to formation of a completely functional urinary bladder.

Men’s Health Index: A Pragmatic Approach to Stratifying and Optimizing Men’s Health

Hui Meng Tan,Wei Phin Tan,Jun Hoe Wong,Christopher Chee Kong Ho,Chin Hai Teo,Chirk Jenn Ng 대한비뇨의학회 2014 Investigative and Clinical Urology Vol.55 No.11

Purpose: The proposed Men’s Health Index (MHI) aims to provide a practical and systematicframework for comprehensively assessing and stratifying older men with theintention of optimising their health and functional status. Materials and Methods: A literature search was conducted using PubMed from 1980to 2012. We specifically looked for instruments which: assess men’s health, frailty andfitness; predict life expectancy, mortality and morbidities. The instruments were assessedby the researchers who then agreed on the tools to be included in the MHI. Whenthere was disagreements, the researchers discussed and reached a consensus guidedby the principle that the MHI could be used in the primary care setting targetting menaged 55-65 years. Results: The instruments chosen include the Charlson’s Combined Comorbidity-AgeIndex; the International Index of Erectile Function-5; the International ProstateSymptom Score; the Androgen Deficiency in Aging Male; the Survey of Health, Ageingand Retirement in Europe Frailty Instrument; the Sitting-Rising Test; the SeniorFitness Test; the Fitness Assessment Score; and the Depression Anxiety StressScale-21. A pilot test on eight men was carried out and showed that the men’s healthindex is viable. Conclusions: The concept of assessing, stratifying, and optimizing men’s health shouldbe incorporated into routine health care, and this can be implemented by using the MHI. This index is particularly useful to primary care physicians who are in a strategic positionto engage men at the peri-retirement age in a conversation about their life goalsbased on their current and predicted health status.

Promoter methylation of the Wnt/β‐catenin signaling antagonist <i>Dkk‐3</i> is associated with poor survival in gastric cancer

Yu, Jun,Tao, Qian,Cheng, Yuen Y.,Lee, Kwan Y.,Ng, Simon S. M.,Cheung, Kin F.,Tian, Linwei,Rha, Sun Y.,Neumann, Ulf,Rö,cken, Christoph,Ebert, Matthias P. A.,Chan, Francis K. L.,Sung, Joseph J. Y. Wiley Subscription Services, Inc., A Wiley Company 2009 Cancer Vol.115 No.1

<P><B>Abstract</B></P><P><B>BACKGROUND:</B></P><P>Abnormal activation of the Wnt/β‐catenin signaling pathway is common and critical in the pathogenesis of digestive cancers. In this study, the authors investigated the promoter methylation of the dickkopf homolog 3 gene <I>Dkk‐3</I> in these cancers and its prognostic significance in gastric cancer.</P><P><B>METHODS:</B></P><P><I>Dkk‐3</I> methylation was assessed in 173 patients with gastric cancers (including 104 patients who were followed for up to 4090 days) and in 128 patients with colorectal cancer. Cell growth was evaluated by using a colony‐formation assay. For survival analyses, the authors used Kaplan‐Meier plots, the log‐rank test, and Cox proportional regression.</P><P><B>RESULTS:</B></P><P><I>Dkk‐3</I> was silenced or down‐regulated in 12 of 17 gastric cancer cell lines (70.6%) and in 3 of 9 colon cancer cell lines (33.3%). The loss of gene expression was associated with promoter methylation, which could be restored by demethylating agents. Ectopic expression of <I>Dkk‐3</I> suppressed colony formation. Moreover, methylation of <I>Dkk‐3</I> was detected in 117 of 173 primary gastric tumors (67.6%) and in 67 of 128 colorectal tumors (52.3%). The clinical significance and the prognostic value of <I>Dkk‐3</I> methylation also were examined in 104 gastric cancers and in 84 colorectal cancers. Multivariate analysis indicated that <I>Dkk‐3</I> methylation was associated significantly and independently with poor disease survival (relative risk, 2.534; 95% confidence interval, 1.54–4.17; <I>P</I> = .002) in gastric cancer, but not in colorectal cancer. Kaplan‐Meier survival curves revealed that patients who had <I>Dkk‐3</I> methylated gastric cancers had a significantly shorter survival (median, 0.76 years) compared with patients who did not have <I>Dkk‐3</I> methylation (median, 2.68 years; <I>P</I> < .0001; log‐rank test).</P><P><B>CONCLUSIONS:</B></P><P>Epigenetic silencing of the <I>Dkk‐3</I> gene by promoter methylation was a common event in gastric cancer and was associated with a poor outcome in such patients. Cancer 2009. © 2008 American Cancer Society.</P>

Evaluation of the Luminex ARIES HSV 1&2 Assay and Comparison with the FTD Neuro 9 and In-house Real-Time PCR Assays for Detecting Herpes Simplex Viruses

Chun Kiat Lee,Chean Nee Chai,Sharah Mae Capinpin,Alynn Ang,Sau Yoke Ng,Peak Ling Lee,Christopher Wai Siong Ng,Gabriel Yan,Hong Kai Lee,Lily-Lily Chiu,Roland Jureen,Benedict Yan,Tze Ping Loh 대한진단검사의학회 2018 Annals of Laboratory Medicine Vol.38 No.5

Background: Human herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are responsible for a plethora of human diseases, of which cutaneous and mucocutaneous infections are the most prevalent. In its most severe form, HSV infection can cause meningitis/encephalitis. We compared the Luminex ARIES HSV 1&2 assay (Luminex Corp., Austin, TX, USA), an automated sample-to-result molecular solution, to two non-automated HSV DNA assays. Methods: A total of 116 artificial controls were used to determine the analytical performance of the ARIES assay. Controls were prepared by spiking universal transport medium (UTM) and cerebrospinal fluid (CSF) samples from patients who tested negative for HSV by an in-house HSV-1 and -2 DNA assay with reference materials (SeraCare Life Sciences, MA, USA; ZeptoMetrix Corp., MA, USA). Another 117 clinical samples were then used to compare the clinical performance of the ARIES assay with those of an in-house assay and the FTD Neuro 9 assay (Fast Track Diagnostics, Junglinster, Luxembourg). Results: The analytical sensitivity (95% limit of detection) of the ARIES assay was 318 copies/mL (UTM samples) and 935 copies/mL (CSF samples) for HSV-1 strain 96 and 253 copies/mL (UTM samples) and 821 copies/mL (CSF samples) for HSV-2 strain 09. No cross-reactivity was observed in samples spiked with 14 non-HSV microorganisms. Compared with the reference result (agreement between the in-house and FTD Neuro 9 results), the ARIES assay had overall concordance rates of 98.2% (111/113) and 100% (113/113) for HSV-1 and HSV-2, respectively. Conclusions: The ARIES assay appears to be an excellent alternative for rapid detection and differentiation of HSV in skin and genital infections, meningitis, and encephalitis.

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in <i>RAS</i> mutant cancers

Sun, Chaoyang,Fang, Yong,Yin, Jun,Chen, Jian,Ju, Zhenlin,Zhang, Dong,Chen, Xiaohua,Vellano, Christopher P.,Jeong, Kang Jin,Ng, Patrick Kwok-Shing,Eterovic, Agda Karina B.,Bhola, Neil H.,Lu, Yiling,Wes American Association for the Advancement of Scienc 2017 Science translational medicine Vol.9 No.392

<P>Mutant <I>RAS</I> has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple <I>RAS</I> mutant tumor models across tumor lineages where <I>RAS</I> mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of <I>BRCA1/2</I> and <I>p53</I> mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in <I>RAS</I> mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor–induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant <I>RAS</I> to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in <I>RAS</I> mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with <I>RAS</I> mutant tumors where there are few effective therapeutic options.</P>

Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Disoproxil Fumarate in Asian Subjects with Human Immunodeficiency Virus 1 Infection: A Sub- Analysis of Phase 3 Clinical Trials

최준용,Somnuek Sungkanuparph,Thanomsak Anekthananon,Paul Sax,Edwin DeJesus,Howard Edelstein,Mark Nelson,Jennifer DeMorin,Hui C. Liu,Raji Swamy,반준우,황선진,양상윤,Christopher Ng,David Piontkowsky 대한감염학회 2016 Infection and Chemotherapy Vol.48 No.3

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/ F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GSUS- 236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens. The E/C/F/TDF appeared to have sustained efficacy and safety and was well tolerated in the small number of ARTnaïve and ART-experienced Asian subjects.