HIV-1 virological synapse formation enhances infection spread by dysregulating Aurora Kinase B.

HIV-1 spreads efficiently through direct cell-to-cell transmission at virological synapses (VSs) formed by interactions between HIV-1 envelope proteins (Env) on the surface of infected cells and CD4 receptors on uninfected target cells. Env-CD4 interactions bring the infected and uninfected cellular membranes into close proximity and induce transport of viral and cellular factors to the VS for efficient virion assembly and HIV-1 transmission. Using novel, cell-specific stable isotope labeling and quantitative mass spectrometric proteomics, we identified extensive changes in the levels and phosphorylation states of proteins in HIV-1 infected producer cells upon mixing with CD4+ target cells under conditions inducing VS formation. These coculture-induced alterations involved multiple cellular pathways including transcription, TCR signaling and, unexpectedly, cell cycle regulation, and were dominated by Env-dependent responses. We confirmed the proteomic results using inhibitors targeting regulatory kinases and phosphatases in selected pathways identified by our proteomic analysis. Strikingly, inhibiting the key mitotic regulator Aurora kinase B (AURKB) in HIV-1 infected cells significantly increased HIV activity in cell-to-cell fusion and transmission but had little effect on cell-free infection. Consistent with this, we found that AURKB regulates the fusogenic activity of HIV-1 Env. In the Jurkat T cell line and primary T cells, HIV-1 Env:CD4 interaction also dramatically induced cell cycle-independent AURKB relocalization to the centromere, and this signaling required the long (150 aa) cytoplasmic C-terminal domain (CTD) of Env. These results imply that cytoplasmic/plasma membrane AURKB restricts HIV-1 envelope fusion, and that this restriction is overcome by Env CTD-induced AURKB relocalization. Taken together, our data reveal a new signaling pathway regulating HIV-1 cell-to-cell transmission and potential new avenues for therapeutic intervention through targeting the Env CTD and AURKB activity.

Urological complications after COVID 19 vaccine according to age, sex and manufacturer.

OBJECTIVES: To examine the effects of age, sex, and type of COVID-19 vaccine on urological complications after vaccination with COVID-19. MATERIALS AND METHODS: We used the Vaccine Adverse Event Reporting System (VAERS) data from December 2020 to August 2022 to analyze urological symptoms post-vaccination adverse events (AEs) associated with COVID-19 vaccines authorized for the U.S. POPULATION: We collected AEs after 1-2 dose vaccination in VAERS, but not those after an additional booster shot. Age was divided into three groups (< 18 years, 18-64 years, and > 64 years), and compared incidence of AEs after vaccination with either mRNA vaccine (mRNA-1273, Moderna; and BNT162b2, Pfizer-BioNTech) or a viral vector vaccine (JNJ-78436735, Janssen/Johnson and Johnson) as reported in VAERS data. RESULTS: Cumulative incidence rates (CIRs) of LUTS, voiding symptom, storage symptom, infection, and hematuria were 0.057, 0.282, 0.223, 1.245, and 0.214, respectively. By gender, CIRs OF LUTS, storage symptom, and infection were statistically significantly higher in women, whereas CIRs of voiding symptom and hematuria were statistically significantly higher in men. CIRs of AEs per 100,000 in age groups of < 18 years, 18-64 years, and > 64 years were 0.353, 1.403, and 4.067, respectively. All AE types except for voiding symptom displayed the highest CIRs in the Moderna vaccine group. CONCLUSIONS: Based on an updated analysis of available data, the prevalence of urologic complications following administration of COVID-19 vaccines is low. However, specific urologic complications such as gross hematuria are not low in incidence.

Expression and prognostic significance of Niemann-Pick C1-Like 1 in colorectal cancer: a retrospective cohort study.

BACKGROUND: Colorectal cancer (CRC) is a malignancy of the large intestine, whose development and prognosis have been demonstrated to be associated with altered lipid metabolism. High cholesterol intake is associated with an increased risk of CRC, and elevated serum cholesterol levels are known to be correlated with risk of developing CRC. Niemann-Pick C1-Like 1 (NPC1L1), a target of ezetimibe, plays an essential role in the absorption of intestinal cholesterol. However, whether the altered expression of NPC1L1 affects CRC development and prognosis is currently unknown. METHODS: Data corresponding to patients with CRC were obtained from The Cancer Genome Atlas (TCAG). Datasets from the Genome Data Analysis Center (GDAC) platform were analyzed to compare the expression of NPC1L1 in normal and CRC tissues using the Mann-Whitney U test and chi-square test. Further, the datasets from the Gene Expression Omnibus (GEO) database were analyzed. The log-rank test and multivariate Cox proportional hazard regression analysis were performed to determine whether NPC1L1 significantly affects the prognosis of CRC. RESULTS: The expression of NPC1L1 was found to be upregulated in CRC and was significantly associated with the N and pathological stages but not with the histological type, age, and sex. Increased NPC1L1 expression in CRC was related to poor patient survival, as evidenced by the Kaplan-Meier and multivariate regression analyses. CONCLUSIONS: As high expression of NPC1L1 was associated with CRC development, pathological stage, and prognosis, NPC1L1 can serve as an independent prognostic marker for CRC.

The Gut Microbiota-Derived Immune Response in Chronic Liver Disease.

In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut-liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.

T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.

Augmenting subnetwork inference with information extracted from the scientific literature.

Many biological studies involve either (i) manipulating some aspect of a cell or its environment and then simultaneously measuring the effect on thousands of genes, or (ii) systematically manipulating each gene and then measuring the effect on some response of interest. A common challenge that arises in these studies is to explain how genes identified as relevant in the given experiment are organized into a subnetwork that accounts for the response of interest. The task of inferring a subnetwork is typically dependent on the information available in publicly available, structured databases, which suffer from incompleteness. However, a wealth of potentially relevant information resides in the scientific literature, such as information about genes associated with certain concepts of interest, as well as interactions that occur among various biological entities. We contend that by exploiting this information, we can improve the explanatory power and accuracy of subnetwork inference in multiple applications. Here we propose and investigate several ways in which information extracted from the scientific literature can be used to augment subnetwork inference. We show that we can use literature-extracted information to (i) augment the set of entities identified as being relevant in a subnetwork inference task, (ii) augment the set of interactions used in the process, and (iii) support targeted browsing of a large inferred subnetwork by identifying entities and interactions that are closely related to concepts of interest. We use this approach to uncover the pathways involved in interactions between a virus and a host cell, and the pathways that are regulated by a transcription factor associated with breast cancer. Our experimental results demonstrate that these approaches can provide more accurate and more interpretable subnetworks. Integer program code, background network data, and pathfinding code are available at https://github.com/Craven-Biostat-Lab/subnetwork_inference.

Potential Photoprotective Effect of Dietary Corn Silk Extract on Ultraviolet B-Induced Skin Damage.

Ultraviolet B (UVB) irradiation causes adverse effects on the skin. Corn silk contains flavonoids and other bioactive compounds and antioxidants, which may prevent skin photoaging through antioxidant and anti-inflammatory effects. We aimed to investigate the potential photoprotective effects of dietary corn silk on UVB-induced skin damage in mice and the mechanisms behind these effects on human skin cells. Oral administration of corn silk water extract (CS) (2 or 4 g/kg/day) for 19 weeks decreased epidermal thickness, wrinkle formation, and positive staining for PCNA, Ki67, and 8-OHdG, and increased collagen staining in UVB-irradiated SKH-1 hairless mice compared with controls. The pro-inflammatory NF-κB target genes (IL-1ß, iNOS, and COX-2) and MMP-9 expressions were lower in the CS groups, and TGF-ß/Smad signaling increased. Low skin lipid peroxidation and blood DNA oxidation levels and high blood glutathione were detected. Antioxidant transcription factor Nrf2-related catalase and SOD1 proteins and glutaredoxin mRNA levels increased. The results of CS extract treatment and UVB irradiation in HaCaT cells showed the same results in Nrf2 and NF-κB target genes. An LC-MS/MS analysis showed that the CS extract contained potential antioxidants, which might have contributed to its anti-photoaging effects in tissues and cells. CS extract may reduce UVB-induced skin damage through antioxidant and anti-inflammatory mechanisms.

Elevated C-reactive protein level, obesity, and quality of life.

OBJECTIVE: To investigate the association between serum C-reactive protein level and health-related quality of life, and to assess the relationship between the two in terms of controlling for obesity and other covariates. METHODS: The cross-sectional study was conducted retrospectively at university hospital in Yangsan from January to December 2017 using the nationally representative 2015 Korea National Health and Nutrition Examination Survey (KNHANES). High C-reactive protein was defined as level ≥1.0mg/L. Health-related quality of life was assessed using the Euro-Quality of Life-5 dimensions tool. The association between high C-reactive protein and health-related quality of life was analysed using logistic regression analysis and was adjusted for variables. The subjects were categorised into four groups according to the level of C-reactive protein, and the presence of obesity was analysed. RESULTS: Of the 3376 subjects, 1,413(42%) were men and 1,963(58%) were women. C-reactive protein level was <1.0 in 2490(73.7%) subjects and ≥1.0 in 886(26.2%). High CRP level was associated with low health-related quality of life for mobility and usual activities (p<0.05). However, in multivariable logistic model, the associations ceased to be statistically significant (p>0.05) after adjusting for the presence of obesity. CONCLUSIONS: Obesity was found to play an important role in the association between C-reactive protein and healthrelated quality of life in Korean population.

Antioxidant and antigenotoxic effect of dairy products supplemented with red ginseng extract.

The purpose of this study was to evaluate the antioxidant and antigenotoxic effect of dairy products milk (M) and yogurt (Y) after the addition of 2% red ginseng extract to milk (RM) and to yogurt (RY). Total phenolic content, total flavonoid content, 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, oxygen radical absorbance capacity, and total radical trapping antioxidant potential were determined in the samples. Furthermore, antigenotoxic effect of samples was measured, using comet assay in human leukocytes. Total phenolic content and total flavonoid content of RM [38.3 ± 0.8 mg of gallic acid equivalents (GAE)/100 g, 23.6 ± 0.1 mg of quercetin equivalents (QE)/100 g] and RY (41.1 ± 0.9 mg of GAE/100 g, 18.7 ± 0.1 mg of QE/100 g), respectively, were higher than those of M (6.31 ± 0.2 mg of GAE/100 g, 10.4 ± 0.1 mg of QE/100 g) and Y (8.1 ± 0.9 mg of GAE/100 g, 8.4 ± 0.2 mg of QE/100 g), respectively. The 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and oxygen radical absorbance capacity values increased significantly after the addition of 2% red ginseng in both. Additionally, the total radical trapping antioxidant potential in RM (787.7 ± 7.0 µg/mL) was lower than in M (2074.0 ± 28.4 µg/mL). The H2O2-induced DNA damage in RY (0.1 ± 0.0 mg/mL) was less than the damage in Y (0.4 ± 0.0 mg/mL), but we found no significant difference between M and RM. This study indicates that supplementation with red ginseng can fortify the antioxidant and antigenotoxic effects of dairy products effectively.

Combined effects of whey protein hydrolysates and probiotics on oxidative stress induced by an iron-overloaded diet in rats.

Whey proteins possess antioxidant properties, and probiotics have various health-promoting effects. We investigated the effects of whey protein hydrolysates (WPHs) and probiotics in rats exposed to oxidative stress induced by iron-overload diet (IOL). Rats were divided into control (CTRL), IOL (0.2% ferrous sulphate), WPH (10%), probiotic (PB) mixture (Lactococcus lactis NK34 and B. polyfermenticus SCD), and WPH + PB group for 6 weeks. Average leukocytes and colonocytes tail moments were increased in IOL compared to CTRL but decreased in other groups. Conjugated diene was lower in WPH, PB, and WPH + PB than in IOL. Only WPH + PB group could recover glutathione S-transferase (GST) levels. SOD levels were recovered by WPH and PB. PB and WPH + PB increased α-tocopherol and only WPH + PB increased γ-tocopherol. Thus, our data demonstrated that WPH and PB exhibit antioxidant properties in a rat model of high-iron diet-induced oxidative stress and combination of them may provide an enhanced effect.

Antioxidant and anticancer effects of functional peptides from ovotransferrin hydrolysates.

BACKGROUND: Egg white is a good source for making functional peptides that can be used in the food industry. Ovotransferrin (OTF) is one of the major egg white proteins, with many functional properties, including antioxidant, antimicrobial and antiviral activities. However, enzymatic hydrolysis of ovotransferrin is known to further improve the functional activities of OTF. The aim of this study was to investigate the antioxidant and anticancer activities of functional peptides produced by two-step enzyme hydrolysis of OTF. RESULTS: OTF hydrolysates were prepared using promod 278P, thermolysin and a combination of the two enzymes. OTF and OTF hydrolysates showed strong antioxidant activities when analyzed using the DPPH assay. However, only OTF hydrolysates showed a strong free radical scavenging activity when NO- or ABTS-scavenging activity was measured. OTF hydrolysates showed stronger cytotoxic activities than the natural OTF against human cancer cell lines. Furthermore, OTF hydrolysates prepared with promod 278P + thermolysin combination showed the strongest cytotoxic activity, and their IC50 values were 0.79, 0.78, 0.92 and 0.78 mg mL-1 against AGS, LoVo, HT-29 and HeLa, respectively. CONCLUSION: These results indicated that the two-step enzyme hydrolysates of OTF have great potential for use as a food ingredient with antioxidant and anticancer activities. © 2017 Society of Chemical Industry.

Changes of oxidative/antioxidative parameters and DNA damage in firefighters wearing personal protective equipment during treadmill walking training.

[Purpose] The purpose of this study was to investigate the influence of personal protective equipment on the oxidant/antioxidant parameters and DNA damage in firefighters during training and recovery. [Subjects and Methods] Twelve male nonsmoking volunteer firefighters (35.1 ± 7.2 years) underwent two maximal treadmill training (9 METs, 6 km/h), within 2 weeks, one in regular clothes and one in personal protective equipment weighing 22.1 kg. Blood samples were obtained before, right after, and 40 min after training. Plasma conjugated dienes, total radical trapping antioxidant potential, erythrocytes antioxidant enzymes activities, and leukocyte DNA damage were measured. [Results] Wearing personal protective equipment during treadmill walking training resulted in increases of plasma conjugated dienes, total radical trapping antioxidant potential, and leukocyte DNA resistance to oxidative stress, which were recovered after in 40 min of rest. Erythrocyte antioxidant enzymes activities remained unchanged during the training either with regular clothes or personal protective equipment. [Conclusion] These results suggest that wearing personal protective equipment during firefighting work could induce oxidative stress, which was enough to produce DNA damage in leukocytes.

Urinary Malondialdehyde Is Associated with Visceral Abdominal Obesity in Middle-Aged Men.

The purpose of the present study was to investigate multiple anthropometric parameters used to evaluate obesity, particularly visceral abdominal fat area, and various metabolic parameters including malondialdehyde (MDA) as an oxidative stress marker. We evaluated various measures of obesity, including body mass index (BMI), waist circumference (WC), sagittal abdominal diameter, fat percentages using dual-energy X-ray absorptiometry, visceral fat area (VFA), subcutaneous fat area, multiple biomarkers related to metabolic disease, and urinary MDA, in 73 asymptomatic middle-aged men who were not severely obese. We examined relationships between multiple measures of obesity, metabolic markers, and urinary MDA levels and evaluated associations between VFA and urinary MDA. In the visceral obesity group, γ-glutamyl transferase (GGT), uric acid, and urinary MDA levels were significantly higher than in the nonvisceral obesity group (P = 0.008, P = 0.002, and P = 0.018). Urinary MDA (r = 0.357, P = 0.002) and uric acid (r = 0.263, P = 0.027) levels were only significantly positively correlated with VFA among measures of obesity. Urinary MDA, serum GGT, and serum CRP were significantly positively associated with VFA (P = 0.001, P = 0.046, and P = 0.023, resp.), even after adjusting for BMI and WC.

Cytotoxic and antigenotoxic activities of phosvitin from egg yolk.

Egg yolk phosvitin is one of the most phosphorylated proteins in nature, and thus has a strong metal-binding ability. The objective of this study was to evaluate the cytotoxic and antigenotoxic activities of phosvitin in vitro. Using the 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicity of phosvitin was evaluated in human cancer cell lines of various tissue origins, including the cervix (HeLa), breast (MCF-7), stomach (AGS), lung (A549 and SK-MES-1), liver (HepG2), and larynx (Hep-2). The growth of all cancer cell lines was inhibited in a dose-dependent manner by phosvitin. Among the cancer cell lines tested, MCF-7 and SK-MES-1 were the least sensitive and HeLa, AGS, and HepG2 were the most sensitive to phosvitin. The 50% inhibition of cell viability values of phosvitin were 5.38, 11.57, 4.78, 6.98, 11.82, 3.93, and 9.97 mg/mL for HeLa, MCF-7, AGS, A549, SK-MES-1, HepG2, and Hep-2, respectively. The protective effects of phosvitin against DNA damage in human leukocytes indicated that phosvitin showed protective effects against the oxidative stress-induced DNA damages in human leukocytes. These results suggested that phosvitin has a high potential to be used as an anticancer agent for humans.

Automatic delirium prediction system in a Korean surgical intensive care unit.

BACKGROUND: In Korea, regular screening for delirium is not considered essential. In addition, delirium is often associated with vague concepts, making it harder to identify high-risk patients and impeding decision-making. AIMS: To assess the impact of the Automatic PREdiction of DELirium in Intensive Care Units (APREDEL-ICU) system on nursing-sensitive and patient outcomes for surgical ICU patients and to evaluate nurse satisfaction with the system and its usability. METHODS: A pre-post research design was adopted. Our study included 724 patients admitted before the implementation of the APREDEL-ICU (January to December 2010) and 1111 patients admitted after the system was installed (May 2011 to April 2012). The APREDEL-ICU uses a pop-up window message to inform the nursing staff of patients at risk for delirium, allowing evidence-based nursing interventions to be applied to the identified patients. A total of 42 nurses were surveyed to determine the system's usability and their level of satisfaction with it. RESULTS: After the implementation of APREDEL-ICU, high-risk patients, determined using a prediction algorithm, showed a slight decrease in the incidence of delirium, but the changes were not significant. However, significant decreases in the number and duration of analgesic/narcotic therapies were observed after the implementation of the system. Nurse self-evaluation results showed an improvement in all categories of knowledge regarding delirium care. CONCLUSION: The use of a prediction and alerting system for ICU patients at high risk of delirium showed a potential increase in the quality of delirium care, including early detection and proper intervention.

Heat-Killed Lactococcus Lactis KC24 Ameliorates Scopolamine-Induced Memory Impairment in ICR Mice.

Heat-killed Lactococcus lactis KC24 (H-KC24) has been examined for its neuroprotective effects in SH-SY5Y cells. We hypothesized that H-KC24 could alleviate memory impairment through the gut-brain axis. Scopolamine (1 mg/kg/day) was administered to ICR mice to induce memory impairment. Low- and high-dose H-KC24 cells (1 × 109 and 2 × 109 CFU/day, respectively) or donepezil (DO, 2 mg/kg) were administered for 14 days. H-KC24 treatment alleviated the deleterious scopolamine-induced memory effects on the recognition index and object recognition ability in the novel object recognition test and the Y-maze test. Changes in neurotransmitters and synaptic plasticity were confirmed by measuring acetylcholine, acetylcholinesterase, choline acetyltransferase, brain-derived neurotrophic factor, cyclic AMP response element-binding protein, and phosphorylated cyclic AMP response element-binding protein expression in brain tissues. In the H-KC24 and DO groups, ß-secretase levels increased, whereas amyloid ß levels decreased, demonstrating that H-KC24 can improve memory impairment caused by oxidative stress. This study demonstrated the positive effects of H-KC24 in a scopolamine-induced memory impairment mouse model.

Relationship between Pulse Pressure and Handgrip Strength in the Korean Population: A Nationwide Cross-Sectional Study.

Background: Sarcopenia is defined as the loss of muscle mass and strength and low physical performance, and it is closely related to the risk of cardiovascular disease and mortality. Pulse pressure (PP) is a biomarker of arterial stiffness and compliance. Elevated PP levels increase the risk of cardiovascular diseases and all-cause mortality. Nevertheless, the association between PP and sarcopenia has not yet been clearly established. Methods: Participant data were extracted from the Korea National Health and Nutrition Examination Survey conducted from 2014 to 2020. The study population was classified into three groups (PP < 40 mmHg, 40 mmHg ≤ PP < 60 mmHg, and PP ≥ 60 mmHg). PP was calculated by deducting the diastolic blood pressure from the systolic blood pressure. For handgrip strength, the maximum value measured with a grip dynamometer was adopted (weak handgrip strength: <28 kg for men, <18 kg for woman; normal handgrip strength: ≥28 kg for men, ≥18 kg for women). To determine the relationship between PP and the prevalence of weak handgrip strength, multiple logistic regression analysis was performed after adjusting for possible confounding factors. Results: The higher PP group had a higher age, body mass index; systolic blood pressure, prevalence of hypertension, diabetes, hyperlipidemia, and metabolic syndrome, and maximum handgrip strength. In all models, the prevalence of weak handgrip strength was significantly higher in the group with PP ≥ 60 mmHg compared to the control group (PP < 40 mmHg). Conclusions: Elevated PP was significantly associated with a higher prevalence of weak muscle strength. Thus, PP monitoring may be used to identify individuals at risk of sarcopenia and is helpful in improving health outcomes.

Hepatoprotective Effect of Lactiplantibacillus plantarum DSR330 in Mice with High Fat Diet-Induced Nonalcoholic Fatty Liver Disease.

Lactiplantibacillus plantarum DSR330 (DSR330) has been examined for its antimicrobials production and probiotics. In this study, the hepatoprotective effects of DSR330 were examined against non-alcoholic fatty liver disease (NAFLD) in a high-fat diet (HFD)-fed C57BL/6 mouse model. To induce the development of fatty liver, a HFD was administered for five weeks, and then silymarin (positive control) or DSR330 (108 or 109 CFU/day) was administered along with the HFD for seven weeks. DSR330 significantly decreased body weight and altered serum and hepatic lipid profiles, including a reduction in triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels compared to those in the HFD group. DSR330 significantly alleviated HFD-related hepatic injury by inducing morphological changes and reducing the levels of biomarkers, including AST, ALT, and ALP. Additionally, DSR330 alleviated the expression of SREBP-1c, ACC1, FAS, ACO, PPARα, and CPT-1 in liver cells. Insulin and leptin levels were decreased by DSR330 compared to those observed in the HFD group. However, adiponectin levels were increased, similar to those observed in the ND group. These results demonstrate that L. plantarum DSR330 inhibited HFD-induced hepatic steatosis in mice with NAFLD by modulating various signaling pathways. Hence, the use of probiotics can lead to hepatoprotective effects.

Analyzing circulating tumor cells and epithelial-mesenchymal transition status of papillary thyroid carcinoma patients following thyroidectomy: a prospective cohort study.

BACKGROUND: This study investigated the prevalence and subtype distribution of circulating tumor cells (CTCs) in patients with papillary thyroid cancer (PTC) before and after thyroidectomy to determine the potential of CTC count as a noninvasive marker of the efficacy of surgical treatment in PTC. MATERIALS AND METHODS: Between January 2021 and January 2022, 62 PTC patients who underwent thyroidectomy at Seoul National University Bundang Hospital were prospectively evaluated. Peripheral blood samples (7.5 ml) were collected from each patient for CTC analysis before surgery and at 2 weeks and 3 months after surgery. CTC count and the distribution of CTC subtypes, including epithelial, epithelial-mesenchymal, and mesenchymal phenotypes, were analyzed using the negative selection method and immunofluorescence staining. The relationship between CTC count and clinicopathological characteristics was analyzed before and after surgery. RESULTS: Before surgery, CTCs were detected in 87% (54/62) of patients; the mean CTC count was 8.0 and the median was 5.0 in 7.5 ml of peripheral blood. The mesenchymal or epithelial-mesenchymal phenotypes were predominant. After thyroidectomy, the mean and median CTC count values decreased to 5.3 and 2.5, respectively, at 2 weeks and to 4.3 and 3.0, respectively, at 3 months. This postoperative reduction in CTCs was more pronounced in patients with lymphatic invasion, lymph node metastasis, or BRAF V600E mutation. CONCLUSION: CTCs were detected in patients with PTC with a predominance of cells undergoing epithelial-mesenchymal transition. The CTC count decreased postoperatively, suggesting that liquid biopsy with CTC detection could be a valuable noninvasive tool for monitoring the efficacy of surgery in PTC.

A Phase II Study About Efficacy and Safety of the Continuous IntraVenous Infusion of Ketamine as Adjuvant to Opioids in Terminally Ill Cancer Patients With Refractory Cancer Pain (CIVIK Trial).

BACKGROUND: Ketamine has been used to control refractory cancer pain as an adjuvant to opioids. We conducted a prospective phase II study to investigate the efficacy and safety of 5-day continuous intravenous infusion (CIVI) of Ketamine in terminally ill cancer patients with refractory cancer pain. METHODS: Hospitalized terminally ill cancer patients with refractory cancer pain were enrolled. Refractory cancer pain was indicated by requirements for 4 or more rescue opioids or pain intensity using numerical rating scale > personalized pain goal (PPG) despite of intravenous morphine equivalent daily dose (IV MEDD) ≥ 120 mg/day. The CIVI of ketamine was increased from .05 mg/kg/hour to .5 mg/kg/hour by .05 every 8 hours if pain intensity exceeded PPG or if number of rescue opioids ≥2 during prior 8 hours was required. The primary end-point was overall pain response rate, which indicates complete response (both rescue opioid ≤3/day and pain intensity ≤ PPG) plus partial response (rescue opioid ≤3/day), without unacceptable toxicities. RESULTS: Among 21 eligible patients enrolled between September 2019 and January 2023, 20 were analyzed. Most pain mechanisms were mixed type (n = 15, 75%), with neuropathic component (n = 17, 85%). The baseline background opioids were IV MEDD 186 mg/24hour (range, 124-592), number of rescue opioids was 6 (IQR, 5-9), and median PPG was 4 (IQR, 3-4). The overall pain response rate was 50% (n = 10) including 40% (n = 8) for complete pain response and 10% (n = 2) for partial pain response. CONCLUSION: This study showed efficacy of gradually increasing CIVI of ketamine for terminally ill cancer patients with refractory cancer pain. CIVI of ketamine could be a useful tool in these patients considering the limited treatment options. (NCT03362073, Initial Release: November 15, 2017).