Octyl cyanoacrylate skin adhesive with or without subcuticular suture for skin closure after implantable venous port placement for oncology patients: a propensity-score matching analysis.

AIM: To compare peri-operative outcomes of skin closure with octyl cyanoacrylate (OCA) skin adhesive (Dermabond) with or without subcuticular sutures after deep dermal suturing for implantable venous port placement closure. MATERIALS AND METHODS: Seven hundred and ninety-two single-lumen implantable venous port insertions for chemotherapy were reviewed from September 2019 to March 2021 in a retrospective single-centre study. Propensity-score matching by a 1:1 nearest neighbour algorithm was conducted to control for confounding baseline differences. Distances were determined by logistic regression. Propensity-score matching was performed based on the following variables: age at procedure, gender, race, operator's seniority, use of anchoring polypropylene suture (PROLENE), port model, and volume of intra-operative local analgesia. The primary outcome was wound dehiscence at the first follow-up (∼1 week). RESULTS: The 792 port insertions were conducted in 302 males (38.1%), median age 63 years (IQR: 54-69). Of the 656 wounds closed with subcuticular sutures and skin adhesive, 136 were matched in a 1:1 fashion against procedures closed without a subcuticular suture. No significant differences were demonstrated in pain scores, bleeding, swelling, bruising, fever, wound dehiscence, and discharge at postoperative day 1 (POD1) and at first follow-up between the groups (all p>0.05). Of note, no significant differences in wound dehiscence at first follow-up was found in both unmatched (p=0.133) and matched cohorts (McNemar-Bowker's χ2 = 1.167, p=0.761). CONCLUSION: These findings suggest that the omission of subcuticular sutures during implantable venous port closure may not compromise peri-operative outcomes when OCA skin adhesives were used.

Role of pre-operative ureteral stent on outcomes of retrograde intra-renal surgery (RIRS): systematic review and meta-analysis of 3831 patients and comparison of Asian and non-Asian cohorts.

PURPOSE: To evaluate the outcomes of pre-stented (PS) versus non-pre-stented (NPS) patients who have undergone retrograde intrarenal surgery (RIRS) for renal calculi with subgroup analysis of Asian and non-Asian cohorts. METHODS: Protocol is registered in PROSPERO, CRD42021261123. Eligible studies identified from four electronic databases. Meta-analysis was done to enumerate the outcomes of RIRS in between PS and NPS. Secondary sub-analysis was done to look for differences in outcomes in Asian and non-Asian cohorts. RESULTS: Fourteen studies involving 3831 patients (4 prospective, 10 retrospective studies) were included. PS patients experienced higher success rates of ureteral access sheath (UAS) insertion than NPS (RR 1.09, 95% CI 1.05-1.13, p < 0.00001). PS patients had lower risk of ureteral injuries from UAS placement (RR 0.69, 95% CI 0.50-0.96, p = 0.03). No significant differences in intra- and postoperative complications between two groups were found. Stone-free rate (SFR) outcomes for residual fragment (RF) cut-off of < 1 mm and < 4 mm favoured the PS patients (RR 1.10, 95% CI 1.04-1.17, p = 0.002 for < 4 mm, RR1.10, 95% CI 1.02-1.19, p = 0.02 for < 1 mm). In the subgroup analysis, PS Asian patients had similar SFR as NPS patients for SFR(< 4 mm) but non-Asian population showed better outcomes in the PS patients for SFR(< 4 mm) (RR 1.31, 95% CI 1.13-1.52, p = 0.0005). CONCLUSIONS: This meta-analysis suggests that pre-stenting results in a higher success for UAS placement, minimising intraoperative ureteric injury, with higher overall SFR for any RF cut-off in PS cohorts. In non-Asian cohort, significant differences occurred at SFR < 4 mm but not for SFR < 1 mm. No difference was seen in our Asian cohort for any SFR cut-off in both PS and NPS patients.

Prevention of Hepatitis C Virus Infection and Liver Cancer.

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer-related death worldwide.

Review: Revisiting the human cholinergic nucleus of the diagonal band of Broca.

Although the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB) is the second largest cholinergic nucleus in the basal forebrain, after the nucleus basalis of Meynert, it has not generally been a focus for studies of neurodegenerative disorders. However, the nvlDBB has an important projection to the hippocampus and discrete lesions of the rostral basal forebrain have been shown to disrupt retrieval memory function, a major deficit seen in patients with Lewy body disorders. One reason for its neglect is that the anatomical boundaries of the nvlDBB are ill defined and this area of the brain is not part of routine diagnostic sampling protocols. We have reviewed the history and anatomy of the nvlDBB and now propose guidelines for distinguishing nvlDBB from other neighbouring cholinergic cell groups for standardizing future clinicopathological work. Thorough review of the literature regarding neurodegenerative conditions reveals inconsistent results in terms of cholinergic neuronal loss within the nvlDBB. This is likely to be due to the use of variable neuronal inclusion criteria and omission of cholinergic immunohistochemical markers. Extrapolating from those studies showing a significant nvlDBB neuronal loss in Lewy body dementia, we propose an anatomical and functional connection between the cholinergic component of the nvlDBB (Ch2) and the CA2 subfield in the hippocampus which may be especially vulnerable in Lewy body disorders.

Hepatitis C-induced hepatocyte apoptosis following liver transplantation is enhanced by immunosuppressive agents.

In recurrent hepatitis C (HCV) post-liver transplantation (OLT), the combination of immunosuppressants and HCV is postulated to increase hepatocyte apoptosis and liver fibrosis. We evaluated hepatocyte apoptosis within the liver tissue of patients with postOLT HCV recurrence compared to HCV-negative individuals and correlated these findings with the effects of immunosuppressants on HCV-induced cell death and its inhibition in primary mouse hepatocytes (PMoH). Liver biopsies from patients with and without HCV were evaluated by immunohistochemistry for markers of apoptosis M30 CytoDEATH (M30) and cleaved PARP (clPARP). PMoH from C57BL/6 mice were infected with recombinant adenoviruses (rAdHCV) that expressed HCV proteins in hepatocytes. Infected cells were treated with cyclosporine, tacrolimus, sirolimus and/or MMF with or without pan-caspase inhibitor Q-VD-Oph. Cell viability and apoptosis were evaluated using crystal violet assays and Western immunoblots probed for cleaved caspase-3 (clCas3) and clPARP. Both M30 and clPARP were increased in the liver biopsies of patients with postOLT HCV recurrence compared to HCV-negative individuals. Treatment of rAdHCV-infected PMoH with cyclosporine, tacrolimus or sirolimus reduced cell viability and increased clCas3 and clPARP compared to rAdHCV infection alone. Addition of MMF to cyclosporine, tacrolimus or sirolimus further reduced cell viability and increased clCas3 and clPARP. Q-VD-Oph improved cell viability in HCV-infected PMoH treated with immunosuppressants alone and in combination and reduced clCas3 and clPARP by approximately 90%. Immunosuppressive agents, especially in combination, enhanced apoptosis in HCV-infected hepatocytes. The finding that Q-VD-Oph reversed hepatocyte death suggests that treatments utilizing apoptosis inhibition might reduce liver injury in postOLT HCV recurrence.

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation.

Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47(phox), a subunit of NOX1 to plasma membrane. Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47(phox)-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCδ, p47(phox) and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCδ, p47(phox) or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKCδ/p47(phox)/NOX1 for ROS generation and consequent malignant cellular transformation.

Prevention of hepatitis C virus infection and liver cancer.

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancer-related death, and its incidence is increasing. The majority of HCC cases are associated with chronic viral hepatitis. With over 170 million individuals chronically infected with hepatitis C virus (HCV) worldwide, HCV is currently a serious global health concern, leading to chronic hepatitis, cirrhosis and HCC, thereby causing significant morbidity and mortality. With the incidence of HCV infection increasing, the problem of HCV-associated HCC is expected to worsen as well, with the majority of HCCs developing in the setting of cirrhosis. Thus, it is imperative to provide antiviral therapy to infected individuals prior to the development of established cirrhosis in order to reduce the risk of subsequent HCC. Indeed, the successful eradication of HCV is associated with clinical and histological improvement as well as a greatly reduced risk of subsequent HCC development. Even after the development of cirrhosis, successful viral clearance is still associated with reduced HCC risk. Current standard of care antiviral treatment consists of pegylated interferon-α and ribavirin, but viral clearance rates are suboptimal with this regimen, especially in difficult to treat cohorts. However, there is a myriad of different classes of HCV-specific direct-acting antiviral agents currently in development, which can be used in combination with one another or with standard of care treatment to improve HCV cure rates. Preventative and therapeutic vaccines against HCV remain an area of ongoing research with good progress towards developing an effective vaccine in the future.

Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells.

Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial-mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, ß-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.

MiR-375 is downregulated in epithelial cells after IL-13 stimulation and regulates an IL-13-induced epithelial transcriptome.

Interleukin 13 (IL-13)-induced epithelial gene and protein expression changes are central to the pathogenesis of multiple allergic diseases. Herein, using human esophageal squamous and bronchial columnar epithelial cells, we identified microRNAs (miRNAs) that were differentially regulated after IL-13 stimulation. Among the IL-13-regulated miRNAs, miR-375 showed a conserved pattern of downregulation. Furthermore, miR-375 was downregulated in the lung of IL-13 lung transgenic mice. We subsequently analyzed miR-375 levels in a human disease characterized by IL-13 overproduction--the allergic disorder eosinophilic esophagitis (EE)--and observed downregulation of miR-375 in EE patient samples compared with control patients. MiR-375 expression levels reflected disease activity, normalized with remission, and inversely correlated with the degree of allergic inflammation. Using a lentiviral strategy and whole-transcriptome analysis in epithelial cells, miR-375 overexpression was sufficient to markedly modify IL-13-associated immunoinflammatory pathways in epithelial cells in vitro, further substantiating interactions between miR-375 and IL-13. Taken together, our results support a key role of miRNAs, particularly miR-375, in regulating and fine-tuning IL-13-mediated responses.

c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells.

Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of 'stemness' in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133(+)/Nestin(+) population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposide- and ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133(+)/Nestin(+) cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.

Current trends in the application of nanoparticles in drug delivery.

The discovery of new biologically active compounds that can be exploited therapeutically to treat disease has stalled, with fewer new drugs entering the market every year. The spotlight has now turned onto nanoparticles (NPs) as a versatile and multifaceted platform for the delivery of drugs. NPs offer better pharmacokinetic properties, controlled and sustained release, and targeting of specific cells, tissues or organs. All these features can improve the efficacy of existing drugs. The use of NPs can dramatically impact the treatment of many diseases. Many potential therapeutics that exist for alleviating brain diseases such as epilepsy, Alzheimer's disease and tumours are not feasible due to a lack of means to deliver drugs across the blood brain barrier. NPs offer an alternative solution, since they can be modified to cross the blood brain barrier. Additionally, NPs can also play a part in alternative methods of non-parental administration of drugs e.g. pulmonary and transdermally. Through active targeting and the enhanced permeation and retention effect, NPs reduce the systemic toxicity of chemotherapeutic drugs by ensuring delivery only to the site of the tumour, thus enhancing cancer treatment. We critically review the literature to provide a summary of current synthesis methodologies and applications of NPs in drug delivery.

Post-liver transplantation multicentric Castleman disease treated with valganciclovir and weaning of immunosuppression.

Multicentric Castleman disease is a lymphoproliferative disorder which when seen in the setting of HIV/AIDS is often associated with human herpes virus 8 (HHV-8) infection. We describe the case of a HIV-negative man who developed HHV-8-associated multicentric Castleman disease 11 years after liver transplantation. The patient presented with fevers and weight loss. Physical examination revealed enlarged cervical, axillary and inguinal lymph nodes. Widespread lymphadenopathy was confirmed on computed tomography (CT) scanning. Histology of an enlarged lymph node showed a polymorphous infiltrate with mature plasma cells, plasmacytoid lymphocytes and occasional blasts within the cortex and paracortex. The diagnosis of Castleman disease was confirmed by the finding of numerous HHV-8-immunopositive cells around the regressed lymph node follicles and the detection of HHV-8 on plasma PCR. Although the conventional treatment for this condition has been combination chemotherapy, in the post-transplant context it was decided to treat the patient with valganciclovir and cessation of immunosuppression. His symptoms resolved rapidly and repeat plasma PCR done 3 months after starting treatment was negative for HHV-8. A follow-up CT scan showed a dramatic reduction in the size and amount of lymphadenopathy. After 15 months of treatment, he remains well with no evidence of graft dysfunction or rejection.

Cervical screening uptake in immunocompromised women in Waikato, New Zealand.

A one-year retrospective case study was undertaken of cervical cytology in two cohorts of immunocompromised women: those with HIV infection or renal transplants in the Waikato region of New Zealand. Uptake of cervical screening in the two groups was compared with national guidelines. The results showed that HIV patients' uptake was close to the national recommendation for annual cytology (84% had a smear in 18 months); they were more likely to have cytology performed in an HIV-related care setting. Renal transplant patients had lower uptake (56% in 18 months), a finding similar to internationally reported data. Local discussions of these results identified potential influencing factors, which included inadequate dissemination of updated guidelines and inadequate documentation of immunocompromised health status on the national cervical screening programme database. This audit supports including cervical cytology as part of an annual review in all immunocompromised patients.

Can text messaging results reduce time to treatment of Chlamydia trachomatis?

We assessed the impact of text messaging as the preferred method of communicating positive Chlamydia trachomatis test results in an urban sexual health clinic. Following the introduction of a text messaging service to communicate positive C trachomatis test results to patients, the time between test and treatment in 293 consecutive patients was compared with 303 historic controls. No significant difference was found in either median time to treatment for all patients (3 days in 2005; 4 days in 2007) or median time to treatment (both 7 days) for those not treated immediately. There was no significant difference in time to treatment between those using a landline or mobile phone. Mobile phone use was significantly higher in 2007. Overall, we treated more cases within 4 weeks in 2007 (98.6% cf 96%). The lack of difference in time to treatment showed the use of this technology is as effective as more traditional means of communication. The increase in cases of C trachomatis treated within 4 weeks may reflect the significant increase in mobile phone use and improved ability to contact people rather than simply the introduction of text messaging.