Hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles inhibit neuronal death after spinal cord injury by regulating the SIRT1/Nrf2/HO-1 pathway.

Background: Oxidative stress and apoptosis of neurons significantly contribute to the pathophysiological cascade of spinal cord injury (SCI). However, the role of hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles (H-sEVs) in promoting SCI repair remains unclear. Hence, the present study aims to investigate the regulatory effects of H-sEVs on neuronal oxidative stress and apoptotic responses following SCI. Methods: The administration of H-sEVs of SCI rats was assessed using behavioral evaluations such as Basso-Beattie-Bresnahan (BBB) scores, neuroelectrophysiological monitoring, and Catwalk gait analysis. Indices of oxidative stress (including superoxide dismutase [SOD], total antioxidant capacity [T-AOC], and malondialdehyde [MDA]) were measured. Neuronal survival was evaluated through Nissl staining, while the expression level of sirtuin 1 (SIRT1) was examined using immunohistochemical staining. Additionally, histological evaluation of lesion size was performed using hematoxylin-eosin (HE) staining. Tunel cell apoptosis staining and analysis of apoptosis-associated proteins (B-cell lymphoma-2 [Bcl2] and BCL2-Associated X [Bax]) were conducted through immunofluorescence staining and western blot, respectively. Furthermore, the model of oxidative stress was established using PC12 cells, and apoptosis levels were assessed via flow cytometry and western blot analysis. Importantly, to ascertain the critical role of SIRT1, we performed SIRT1 knockout experiments in PC12 cells using lentivirus transfection, followed by western blot. Results: Using those behavioral evaluations, we observed significant functional improvement after H-sEVs treatment. Nissl staining revealed that H-sEVs treatment promoted neuronal survival. Moreover, we found that H-sEVs effectively reduced oxidative stress levels after SCI. HE staining demonstrated that H-sEVs could reduce lesion area. Immunohistochemical analysis revealed that H-sEVs enhanced SIRT1 expression. Furthermore, Tunel cell apoptosis staining and western blot analysis of apoptosis-related proteins confirmed the anti-apoptotic effects of H-sEVs. The PC12 cells were used to further substantiate the neuroprotective properties of H-sEVs by significantly inhibiting neuronal death and attenuating oxidative stress. Remarkably, SIRT1 knockout in PC12 cells reversed the antioxidant stress effects induced by H-sEVs treatment. Additionally, we elucidated the involvement of the downstream Nrf2/HO-1 signaling pathway. Conclusion: Our study provides valuable insights into the effects of H-sEVs on neuronal oxidative stress and apoptosis after SCI. These findings underscore the potential clinical significance of H-sEVs-based therapies for SCI.

The specialized sesquiterpenoids produced by the genus Elephantopus L.: Chemistry, biological activities and structure-activity relationship exploration.

The genus Elephantopus L. is a valuable resource rich in sesquiterpenoids with structural diversity and various bioactivities, showing great potential for applications in medicinal field and biological industry. Up to now, over 129 sesquiterpenoids have been isolated and identified from this plant genus, including 114 germacrane-type, 7 guaianolide-type, 5 eudesmane-type, 1 elemanolide-type, and 2 bis-sesquiterpenoids. These sesquiterpenoids were reported to show a diverse range of pharmacological properties, including cytotoxic, anti-tumor, anti-inflammatory, antimicrobial, and antiprotozoal. Consequently, some of them were identified as active scaffolds in the design and development of drugs. Considering that there is currently no overview available that covers the sesquiterpenoids and their biological activities in the Elephantopus genus, this article aims to comprehensively review the chemical structures, biosynthetic pathways, pharmacological properties, and structure-activity relationship of sesquiterpenoids found in the Elephantopus genus, which will establish a theoretical framework that can guide further research and exploration of sesquiterpenoids from Elephantopus plants as promising therapeutic agents.

Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization.

JOURNAL/nrgr/04.03/01300535-202410000-00027/figure1/v/2024-02-06T055622Z/r/image-tiff Spinal cord injury is a disabling condition with limited treatment options. Multiple studies have provided evidence suggesting that small extracellular vesicles (SEVs) secreted by bone marrow mesenchymal stem cells (MSCs) help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury. Strikingly, hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs (HSEVs) exhibit increased therapeutic potency. We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair. SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation. HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation. HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro. MicroRNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that miR-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1. Reducing miR-146a-5p expression in HSEVs partially attenuated macrophage polarization. Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting miR-146a-5p, which alters macrophage polarization. This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles promote the recovery of spinal cord injury by affecting the phenotype of astrocytes through the miR-21/JAK2/STAT3 pathway.

BACKGROUND: Secondary injury after spinal cord injury (SCI) is a major obstacle to their neurological recovery. Among them, changes in astrocyte phenotype regulate secondary injury dominated by neuroinflammation. Hypoxia-preconditioned mesenchymal stem cells (MSCs)-derived extracellular vesicle (H-EV) plays a multifaceted role in secondary injury by interacting with cellular components and signaling pathways. They possess anti-inflammatory properties, regulate oxidative stress, and modulate apoptotic pathways, promoting cell survival and reducing neuronal loss. Given the unique aspects of secondary injury, H-EV shows promise as a therapeutic approach to mitigate its devastating consequences. Our study aimed to determine whether H-EV could promote SCI repair by altering the phenotype of astrocytes. METHODS: Rat bone marrow MSCs (BMSCs) and EVs secreted by them were extracted and characterized. After the SCI model was successfully constructed, EV and H-EV were administered into the tail vein of the rats, respectively, and then their motor function was evaluated by the Basso-Beattie-Bresnahan (BBB) score, Catwalk footprint analysis, and electrophysiological monitoring. The lesion size of the spinal cord was evaluated by hematoxylin-eosin (HE) staining. The key point was to use glial fibrillary acidic protein (GFAP) as a marker of reactive astrocytes to co-localize with A1-type marker complement C3 and A2-type marker S100A10, respectively, to observe phenotypic changes in astrocytes within tissues. The western blot (WB) of the spinal cord was also used to verify the results. We also compared the efficacy differences in apoptosis and inflammatory responses using terminal deoxynucleotidyl transferase dUTP terminal labeling (TUNEL) assay, WB, and enzyme-linked immunosorbent assay (ELISA). Experiments in vitro were also performed to verify the results. Subsequently, we performed microRNA (miRNA) sequencing analysis of EV and H-EV and carried out a series of knockdown and overexpression experiments to further validate the mechanism by which miRNA in H-EV plays a role in promoting astrocyte phenotypic changes, as well as the regulated signaling pathways, using WB both in vivo and in vitro. RESULTS: Our findings suggest that H-EV is more effective than EV in the recovery of motor function, anti-apoptosis, and anti-inflammatory effects after SCI, both in vivo and in vitro. More importantly, H-EV promoted the conversion of A1 astrocytes into A2 astrocytes more than EV. Moreover, miR-21, which was found to be highly expressed in H-EV by miRNA sequencing results, was also demonstrated to influence changes in astrocyte phenotype through a series of knockdown and overexpression experiments. At the same time, we also found that H-EV might affect astrocyte phenotypic alterations by delivering miR-21 targeting the JAK2/STAT3 signaling pathway. CONCLUSION: H-EV exerts neuroprotective effects by delivering miR-21 to promote astrocyte transformation from the A1 phenotype to the A2 phenotype, providing new targets and ideas for the treatment of SCI.

Opium, phencyclidine, and crack cocaine smoking associations with lung and upper aerodigestive tract cancers: exploratory findings from a case-control study in Los Angeles County.

Background: Illicit drug use has become a global epidemic, yet it is unclear if drug smoking increases the risk of tobacco-related cancers.Objectives: We aimed to evaluate hypothesized associations between smoking three drugs - opium, phencyclidine (PCP) and crack cocaine and lung and upper aerodigestive tract (UADT) cancers.Methods: A population-based case-control study with 611 lung cancer cases (50% male), 601 UADT cancers cases (76% male), and 1,040 controls (60% male) was conducted in Los Angeles County (1999-2004). Epidemiologic data including drug smoking histories were collected in face-to-face interviews. Associations were estimated with logistic regressions.Results: Adjusting for potential confounders, ever vs. never crack smoking was positively associated with UADT cancers (aOR = 1.56, 95% CI: 1.05, 2.33), and a dose-response relationship was observed for lifetime smoking frequency (p for trend = .024). Heavy (> median) vs. never crack smoking was associated with UADT cancers (aOR = 1.81, 95% CI: 1.07, 3.08) and lung cancer (aOR = 1.58, 95% CI: 0.88, 2.83). A positive association was also observed between heavy PCP smoking and UADT cancers (aOR = 2.29, 95% CI: 0.91, 5.79). Little or no associations were found between opium smoking and lung cancer or UADT cancers.Conclusion: The positive associations between illicit drug use and lung and/or UADT cancers suggest that smoking these drugs may increase the risk of tobacco-related cancers. Despite the low frequency of drug smoking and possible residual confounding, our findings may provide additional insights on the development of lung and UADT cancers.

Chemical diversity and biological activities of specialized metabolites from the genus Chaetomium: 2013-2022.

Chaetomium (Chaetomiaceae), a large fungal genus consisting of at least 400 species, has been acknowledged as a promising resource for the exploration of novel compounds with potential bioactivities. Over the past decades, emerging chemical and biological investigations have suggested the structural diversity and extensive potent bioactivity of the specialized metabolites in the Chaetomium species. To date, over 500 compounds with diverse chemical types have been isolated and identified from this genus, including azaphilones, cytochalasans, pyrones, alkaloids, diketopiperazines, anthraquinones, polyketides, and steroids. Biological research has indicated that these compounds possess a broad range of bioactivities, including antitumor, anti-inflammatory, antimicrobial, antioxidant, enzyme inhibitory, phytotoxic, and plant growth inhibitory activities. This paper summarizes current knowledge referring to the chemical structure, biological activity, and pharmacologic potency of the specialized metabolites in the Chaetomium species from 2013 to 2022, which might provide insights for the exploration and utilization of bioactive compounds in this genus both in the scientific field and pharmaceutical industry.

Mesenchymal Stem Cell-Derived Exosomal MiRNAs Promote M2 Macrophages Polarization: Therapeutic Opportunities for Spinal Cord Injury.

Spinal cord injury (SCI) is an enormous public health concern affecting approximately 250,000-500,000 people worldwide each year. It is mostly irreversible considering the limitations of currently available treatments, and its prevention and management have been the prime focus of many studies. Mesenchymal stem cell (MSC) transplantation is one of the most promising treatments for SCI. The role of MSCs in SCI has been studied extensively, and MSCs have been shown to have many limitations. Moreover, the therapeutic effects of MSCs are more likely related to paracrine effects. In SCIs, macrophages from peripheral sources differentiate into M1 macrophages, promoting inflammation and aggravating neuronal damage; however, studies have shown that MSC-derived exosomes can induce the polarization of macrophages from the M1 to the M2 phenotype, thereby promoting nerve function recovery in patients with SCI. In this review, we discussed the research progress of MSC-derived exosomal miRNAs in promoting M2 macrophage differentiation in the SCI, and introduced some exosomal miRNAs that can regulate the differentiation of M2 macrophages in non-SCI; it is hoped that the regulatory role of these exosome-derived miRNAs can be confirmed in SCI.

The Role of Exosomes and Exosomal Noncoding RNAs From Different Cell Sources in Spinal Cord Injury.

Spinal cord injury (SCI) not only affects the quality of life of patients but also poses a heavy burden on their families. Therefore, it is essential to prevent the occurrence of SCI; for unpreventable SCI, it is critical to develop effective treatments. In recent years, various major breakthroughs have been made in cell therapy to protect and regenerate the damaged spinal cord via various mechanisms such as immune regulation, paracrine signaling, extracellular matrix (ECM) modification, and lost cell replacement. Nevertheless, many recent studies have shown that the cell therapy has many disadvantages, such as tumorigenicity, low survival rate, and immune rejection. Because of these disadvantages, the clinical application of cell therapy is limited. In recent years, the role of exosomes in various diseases and their therapeutic potential have attracted much attention. The same is true for exosomal noncoding RNAs (ncRNAs), which do not encode proteins but affect transcriptional and translational processes by targeting specific mRNAs. This review focuses on the mechanism of action of exosomes obtained from different cell sources in the treatment of SCI and the regulatory role and therapeutic potential of exosomal ncRNAs. This review also discusses the future opportunities and challenges, proposing that exosomes and exosomal ncRNAs might be promising tools for the treatment of SCI.

Clinical Evaluation of Paraspinal Mini-Tubular Lumbar Decompression and Minimally Invasive Transforaminal Lumbar Interbody Fusion for Lumbar Spondylolisthesis Grade I with Lumbar Spinal Stenosis: A Cohort Study.

Objective: To investigate the clinical outcome data and difference in efficacy between paraspinal mini-tubular lumbar decompression (PMTD) and minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) in the treatment of degenerative lumbar spondylolisthesis grade I with lumbar spinal stenosis (DLS-I-LSS). Methods: Patients with DLS-I-LSS, who underwent PMTD or MIS TLIF from September 2017 to March 2020, were included retrospectively. The follow-up period was 24 months after surgery. Outcome measurements included the Oswestry disability index (ODI) score, visual analog scale (VAS) low back pain score, VAS leg pain score, surgical data, and adverse events. Results: A total of 104 patients with DLS-I-LSS were included in this study. The average improvement in ODI at 12 months (2.0%, 95% CI, -5.7% to 1.8%; p = 0.30) and 24 months (1.7%, 95% CI, -2.7% to 6.1%; p = 0.45) after surgery between the two groups were not statistically significant. The improvement in VAS low back pain score after 24 months and improvement in VAS leg pain score were not significantly different between the two groups. Compared with the PMTD group, the MIS TLIF group had more estimated blood loss and longer hospital stays. The cumulative reoperation rates were 5.66% and 1.96% in the MIS TLIF and PMTD groups, respectively (p = 0.68). The results of multivariate analysis showed that BMI, diabetes, and baseline ODI score were the main factors influencing the improvement in ODI in patients with DLS-I-LSS after minimally invasive surgery, accounting for 50.5% of the total variance. Conclusions: The clinical effectiveness of PMTD was non-inferior to that of MIS TLIF for DLS-I-LSS; however, there was a reduced duration of hospital stay, operation time, blood loss, and hospitalization costs in the PMTD group. BMI, presence or absence of diabetes and baseline ODI score were influencing factors for the improvement of ODI (Trial Registration: ChiCTR2000040025).

Comparing the Efficacy and Safety of Cell Transplantation for Spinal Cord Injury: A Systematic Review and Bayesian Network Meta-Analysis.

Objective: To compare the safety and effectiveness of transplanted cells from different sources for spinal cord injury (SCI). Design: A systematic review and Bayesian network meta-analysis. Data Sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials. Study Selection: We included randomized controlled trials, case-control studies, and case series related to cell transplantation for SCI patients, that included at least 1 of the following outcome measures: American Spinal Cord Injury Association (ASIA) Impairment Scale (AIS grade), ASIA motor score, ASIA sensory score, the Functional Independence Measure score (FIM), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), or adverse events. Follow-up data were analyzed at 6 and 12 months. Results: Forty-four eligible trials, involving 1,266 patients, investigated 6 treatments: olfactory ensheathing cells (OECs), neural stem cells/ neural progenitor cells (NSCs), mesenchymal stem cells (MSCs), Schwann cells, macrophages, and combinations of cells (MSCs plus Schwann cells). Macrophages improved the AIS grade at 12 months (mean 0.42, 95% credible interval: 0-0.91, low certainty) and FIM score at 12 months (42.83, 36.33-49.18, very low certainty). MSCs improved the AIS grade at 6 months (0.42, 0.15-0.73, moderate certainty), the motor score at 6 months (4.43, 0.91-7.78, moderate certainty), light touch at 6 (10.01, 5.81-13.88, moderate certainty) and 12 months (11.48, 6.31-16.64, moderate certainty), pinprick score at 6 (14.54, 9.76-19.46, moderate certainty) and 12 months (12.48, 7.09-18.12, moderate certainty), and the IANR-SCIFRS at 6 (3.96, 0.62-6.97, moderate certainty) and 12 months (5.54, 2.45-8.42, moderate certainty). OECs improved the FIM score at 6 months (9.35, 1.71-17.00, moderate certainty). No intervention improved the motor score significantly at 12 months. The certainty of other interventions was low or very low. Overall, the number of adverse events associated with transplanted cells was low. Conclusions: Patients with SCI who receive transplantation of macrophages, MSCs, NSCs, or OECs may have improved disease prognosis. MSCs are the primary recommendations. Further exploration of the mechanism of cell transplantation in the treatment of SCI, transplantation time window, transplantation methods, and monitoring of the number of transplanted cells and cell survival is needed. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD 42021282043.

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells.

Alpha-fetoprotein (AFP) and endoplasmic reticulum (ER) stress play multiple roles in hepatocellular carcinoma. Here, we analyzed the crosstalk between AFP and ER stress in human hepatoma cells. We induced ER stress in human hepatoma cell lines (HepG2 and SK-Hep1 cells) with thapsigargin (TG, an ER stress inducer), and mitigated ER stress with 4-phenylbutyrate acid (4-PBA, an ER stress inhibitor). AFP expression was knocked down by AFP short hairpin RNA and rescued by the pCI-AFP vector. AFP expression and ER stress were examined, and their roles in apoptosis, necroptosis, and proliferation were analyzed. TG significantly induced ER stress, apoptosis, necroptosis, and intracellular AFP protein levels, and reduced proliferation and AFP mRNA expression as well as supernatant AFP protein levels in HepG2 and SK-Hep1 cells. 4-PBA pretreatment partially reversed those changes in HepG2 cells. By contrast to AFP overexpression, knockdown of AFP significantly exacerbated TG-induced ER stress, apoptosis, and necroptosis, and decreased proliferation and the expression of activating transcription factor 6 alpha. In conclusion, ER stress causes the accumulation of AFP protein, which may be related to the reduction of AFP secretion. Accumulated AFP mitigates apoptosis and necroptosis and restores the proliferation of hepatoma cells by reducing ER stress.

In vivo structural characterization of the SARS-CoV-2 RNA genome identifies host proteins vulnerable to repurposed drugs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding of the RNA virus and its interactions with host proteins could improve therapeutic interventions for COVID-19. By using icSHAPE, we determined the structural landscape of SARS-CoV-2 RNA in infected human cells and from refolded RNAs, as well as the regulatory untranslated regions of SARS-CoV-2 and six other coronaviruses. We validated several structural elements predicted in silico and discovered structural features that affect the translation and abundance of subgenomic viral RNAs in cells. The structural data informed a deep-learning tool to predict 42 host proteins that bind to SARS-CoV-2 RNA. Strikingly, antisense oligonucleotides targeting the structural elements and FDA-approved drugs inhibiting the SARS-CoV-2 RNA binding proteins dramatically reduced SARS-CoV-2 infection in cells derived from human liver and lung tumors. Our findings thus shed light on coronavirus and reveal multiple candidate therapeutics for COVID-19 treatment.

Dietary glycemic index, glycemic load, and lung cancer risk: A case-control study in Los Angeles County.

BACKGROUND: Although there is some evidence of positive associations between both the glycemic index (GI) and glycemic load (GL) with cancer risk, the relationships with lung cancer risk remain largely unexplored. We evaluated the associations between GI and GL with lung cancer. METHODS: The analyses were performed using data from a population-based case-control study recruited between 1999 and 2004 in Los Angeles County. Dietary factors were collected from 593 incident lung cancer cases and 1026 controls using a modified food frequency questionnaire. GI and GL were estimated using a food composition table. Adjusted odds ratios (ORs) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders. RESULTS: Dietary GI was positively associated with lung cancer (OR for upper vs. lower tertile = 1.62; 95 % CI: 1.17, 2.25). For histologic subtypes, positive associations were observed between GI and adenocarcinoma (OR for upper vs. lower tertile = 1.82; 95 % CI: 1.22, 2.70) and small cell carcinoma (OR for upper vs. lower tertile = 2.68; 95 % CI: 1.25, 5.74). No clear association between GL and lung cancer was observed. CONCLUSION: These findings suggest that high dietary GI was associated with increased lung cancer risk, and the positive associations were observed for both lung adenocarcinoma and small cell lung carcinoma. Replication in an independent dataset is merited for a broader interpretation of our results.

Chemokine (C-X-C Motif) Ligand 4 Is a Restrictor of Respiratory Syncytial Virus Infection and an Indicator of Clinical Severity.

Rationale: Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory infections worldwide; however, no vaccine is available, and treatment options are limited. Identification of host factors pivotal to viral replication may inform the development of novel therapies, prophylaxes, or diagnoses.Objectives: To identify host factors involved in RSV replication and to evaluate their potential for disease management.Methods: A gain-of-function screening was performed on the basis of a genome-wide human complementary DNA library screen for host factors involved in RSV replication. The antiviral mechanism of CXCL4 (chemokine [C-X-C motif] ligand 4) was analyzed. Its clinical role was evaluated via nasopharyngeal aspirates and plasma samples from patients with RSV infection and different disease severities.Measurements and Main Results: Forty-nine host factors restricting RSV replication were identified by gain-of-function screening, with CXCL4 showing the strongest antiviral effect, which was secretion dependent. CXCL4 blocked viral attachment through binding to the RSV main receptor heparan sulfate, instead of through interacting with RSV surface proteins. Intranasal pretreatment with CXCL4 alleviated inflammation in RSV-infected mice, as shown by decreased concentrations of tumor necrosis factor and viral load in BAL fluid samples as well as by viral nucleocapsid protein histological staining in lungs. Compared with non-RSV infections, RSV infections induced elevated CXCL4 concentrations both in plasma and airway samples from mice and pediatric patients. The airway CXCL4 concentration was correlated with viral load and disease severity in patients (P < 0.001).Conclusions: Our results suggest that CXCL4 is an RSV restriction factor that can block viral entry and serve as an indicator of clinical severity in RSV infections.

Modified Circumcision Using the Disposable Circumcision Suture Device in Children: A Randomized Controlled Trial.

OBJECTIVE: To evaluate and compare the surgical outcomes and complications of the modified circumcision using disposable circumcision suture device (device group) and the conventional dorsal slit circumcision (conventional group) in children. METHODS: A total of 284 patients were randomized to either device group or conventional group. All patients were preoperatively assessed and evaluated at 4 weeks after surgery. The perioperative data and postoperative outcomes were compared between the 2 groups. RESULTS: No statistical differences were observed in the average age and indications between the 2 groups preoperatively (P > .05). Compared with the conventional group, patients in the device group were shorter mean operative time, less blood loss, lower intraoperative and postoperative pain score, faster incision healing time and a higher satisfaction rate of penile cosmetic appearance (P < .01). Similarly, the incidences of complication were significantly lower in the device group than in the conventional group (4.3% vs 12.3%, P < .05). CONCLUSIONS: The modified circumcision using disposable circumcision suture device is a simple, safe, faster, and effective procedure and may become the attractive alternative to the conventional technique for the children, with a relatively lower complication rate and better cosmetic results. With the improvement of disposable circumcision suture device, the modified circumcision using disposable circumcision suture device has the potential to be widely used in the world.

Comprehensive genomic profiling of recurrent endometrial cancer: Implications for selection of systemic therapy.

OBJECTIVES: To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. METHODS: Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. RESULTS: Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3-69 months). CONCLUSIONS: CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.

Comparison of nylon-flocked swab and Dacron swab cytology for anal HSIL detection in transgender women and gay, bisexual, and other men who have sex with men.

BACKGROUND: An anal histological high-grade squamous intraepithelial lesion (hHSIL) is an anal cancer precursor. Experts recommend Dacron swab anal cytology as a primary screen for anal hHSILs, especially among human immunodeficiency virus-infected and -uninfected men who have sex with men (MSM). Studies have shown that Dacron cytology inaccurately predicts anal hHSILs and results in unnecessary diagnostic procedures. Nylon-flocked (NF) swabs have been shown to trap pathogens and cells well. Thus, this study compared test characteristics of anal cytology using NF and Dacron swab collection protocols to predict anal hHSILs. METHODS: A single-visit, randomized clinical trial compared NF and Dacron swab anal cytology specimens to predict high-resolution anoscopy and biopsy-diagnosed anal hHSILs. Data for 326 gay men, bisexual men, other MSM, and male-to-female transgender women contributed descriptive and tabular statistics with which unadjusted and fully adjusted logistic regression models were constructed. The models estimated the odds of hHSILs, test accuracy (area under the curve [AUC]) and sensitivity, and specificity as well as the positive and negative predictive values of abnormal NF and Dacron cytology for predicting hHSILs. RESULTS: In the fully adjusted model, the sensitivities for NF and Dacron cytology were nearly equal (48% vs 47%), but the specificity was higher with NF cytology (76% vs 69%). Comparisons of the areas under receiver operating characteristic curves showed that NF cytology alone predicted hHSILs better than the covariate model (AUC, 0.69 vs 0.63; P = .02), but NF and Dacron cytology comparisons showed no statistically significant differences (AUC, 0.69 vs 0.67; P = .3). CONCLUSIONS: NF cytology and Dacron cytology provide modest sensitivity, but NF cytology has higher specificity and accuracy, and this is important for lowering the costs of population-based screening.

Programmed death ligand-1/programmed death-1 inhibition therapy and programmed death ligand-1 expression in urothelial bladder carcinoma.

After two decades of unchanged paradigms, the treatment strategies for advanced urothelial bladder cancer have been revolutionized by emerging programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) inhibition therapy. Increased evidence is demonstrating the efficacy of PD-L1/PD1 inhibition therapy in both second-line and first-line settings. However, the percentage of patients who benefit from anti-PD-L1/anti-PD1 therapy is still low. Many questions have been raised in the development of biomarker-driven approaches for disease classification and patient selection. In this perspective, we discuss PD-L1/PD1 expression in urothelial bladder carcinoma, review approved anti-PD-L1/anti-PD1 agents for bladder cancer treatment and current ongoing studies investigating combination treatment strategies, and explore PD-L1 expression status for the evaluation of bladder cancer immunotherapy.

International telecytology: Current applications and future potential.

International telecytology can improve patient care by increasing access to regional and international expertise in cytopathology. The majority of international telecytology studies published to date have been based on static telepathology platforms. Overall concordance rates for these studies ranged from 71% to 93%. This is comparable to the concordance rates published for other studies comparing diagnoses made by digital still images to reference glass slides, which vary from 80% to 95%. Static telepathology systems are relatively cheap and easy to use, and have the potential to increase access to international experts in developing countries with limited resources. In contrast, resource-rich academic and private medical centers can use whole slide digital imaging (WSI) for telecytology consultation, though few studies have been published addressing this topic. International telepathology consultation services with digital whole slide image capabilities have been established at several academic medical centers including the University of Pittsburgh Medical Center (UPMC) and the University of California at Los Angeles (UCLA), through the UCLA Center for Telepathology and Digital Pathology. In a small series of 20 telecytology cases submitted to UCLA from 2014 to 2017 (10 gynecologic and 10 fine needle aspiration cases), a meaningful diagnosis was rendered for 100% of cases, with 100% concordance between the submitting institution, versus consultation diagnosis provided by UCLA. These limited results are promising, and in the future both WSI and static telecytology consultation may have a place serving clinical needs in different practice settings.

Effects of multimodal fast-track surgery on liver transplantation outcomes.

BACKGROUND: Fast-track surgery and enhanced recovery after surgery have been applied to many surgical procedures; however, data on fast-track surgery and enhanced recovery after surgery following liver transplantation is limited. This study aimed to conduct a prospective study to determine the effects of fast-track surgery on prognosis after liver transplantation. METHODS: This was a prospective, single-blinded, randomized study. One hundred twenty-eight patients undergoing liver transplantation were selected for the fast-track (FT group, n=54) or conventional process (NFT group, n=74). The primary endpoints were intensive care unit (ICU) stay and hospital stay. The secondary endpoints were as follows: operative time, anhepatic phase time, intraoperative blood loss, intraoperative blood transfusion volume, postoperative complications, readmission rate, and postoperative mortality. RESULTS: There was no significant difference in preoperative demographics between the two groups. The median ICU stay was 2 days (range 1-7 days) in the FT group and 5 days (range 3-12 days) in the NFT group (P<0.01). Furthermore, the hospital stay was also significantly reduced in the FT group (P<0.01). The operative time, anhepatic phase time, intraoperative blood loss, and intraoperative blood transfusion volume were decreased in the FT group compared with the NFT group (P<0.05). Based on Spearman correlation analysis, the ICU stay and hospital stay may be positively correlated with operative time, anhepatic phase time and intraoperative blood loss. There were no differences in the incidence of postoperative complications, readmissions, and postoperative mortality between the two groups. CONCLUSION: Fast-track procedures effectively reduce the ICU stay and hospital stay without adversely affecting prognosis. This study demonstrated that fast-track protocols are safe and feasible in liver transplantation.