Environmental pollution arising from plastic waste is a major global concern. Plastic macroparticles, microparticles, and nanoparticles have the potential to affect marine ecosystems and human ...health. It is generally accepted that microplastic particles are not harmful or at best minimal to human health. However direct contact with microplastic particles may have possible adverse effect in cellular level. Primary polystyrene (PS) particles were the focus of this study, and we investigated the potential impacts of these microplastics on human health at the cellular level. We determined that PS particles were potential immune stimulants that induced cytokine and chemokine production in a size-dependent and concentration-dependent manner.
Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential ...for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Furthermore, mouse embryonic fibroblasts cultured from Atg5 transgenic mice are more tolerant to oxidative damage and cell death induced by oxidative stress, and this tolerance was reversible by treatment with an autophagy inhibitor. Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity.
SUMMARY
Background
Tegoprazan is a novel potassium‐competitive acid blocker used to treat acid‐related disorders.
Aim
To compare tegoprazan 25 mg with lansoprazole 15 mg as maintenance therapy in ...healed erosive oesophagitis (EE)
Methods
In this phase 3, double‐blind, multi‐centre study, patients with endoscopically confirmed healed EE were randomised 1:1 to receive tegoprazan 25 mg or lansoprazole 15 mg once daily for up to 24 weeks. The primary efficacy endpoint was the endoscopic remission rate after 24 weeks. The secondary efficacy endpoint was the endoscopic remission rate after 12 weeks. Safety endpoints included adverse events, clinical laboratory results and serum gastrin and pepsinogen I/II levels.
Results
We randomised patients to tegoprazan 25 mg (n = 174) or lansoprazole 15 mg (n = 177). Most had mild EE (Los Angeles (LA) grade A: 57.3%, LA grade B: 37.3%). The endoscopic remission rate after 24 weeks was 90.6% with tegoprazan and 89.5% with lansoprazole. Tegoprazan was not inferior to lansoprazole for maintaining endoscopic remission at 24 weeks and 12 weeks. In subgroup analysis, tegoprazan 25 mg showed no significant difference in maintenance rate according to LA grade (p = 0.47). The maintenance effect of tegoprazan was consistent in CYP2C19 extensive metabolisers (p = 0.76). Increases in serum gastrin were not higher in tegoprazan‐treated than lansoprazole‐treated patients.
Conclusions
Tegoprazan 25 mg was non‐inferior to lansoprazole 15 mg in maintenance of healing of mild EE. In this study, tegoprazan had a similar safety profile to lansoprazole.
In this phase 3, double‐blind, multi‐centre study, patients with endoscopically confirmed healederosive oesophagitis were randomised 1:1 to receive tegoprazan 25 mg or lansoprazole 15 mg once daily for up to 24 weeks. The endoscopic remission rate after 24 weeks was 90.6% for the tegoprazan group and 89.5% for the lansoprazole group. Overall, tegoprazan was not inferior to lansoprazole for maintaining endoscopic remission rates at 24 weeks and 12 weeks, and was well tolerated during the maintenance period.
Summary
Background
Tegoprazan is a novel potassium‐competitive acid blocker that has a fast onset of action and can control gastric pH for a prolonged period, which could offer clinical benefit in ...acid‐related disorders.
Aim
To confirm the non‐inferiority of tegoprazan to esomeprazole in patients with erosive oesophagitis (EE).
Methods
In this multicentre, randomised, double‐blind, parallel‐group comparison study, 302 Korean patients with endoscopically confirmed EE (Los Angeles Classification Grades A‐D) were randomly allocated to either tegoprazan (50 or 100 mg) or esomeprazole (40 mg) treatment groups for 4 or 8 weeks. The primary endpoint was the cumulative proportion of patients with healed EE confirmed by endoscopy up to 8 weeks from treatment initiation. Symptoms, safety and tolerability were also assessed.
Results
The cumulative healing rates at week 8 were 98.9% (91/92), 98.9% (90/91) and 98.9% (87/88) for tegoprazan 50 mg, tegoprazan 100 mg and esomeprazole 40 mg, respectively. Both doses of tegoprazan were non‐inferior to esomeprazole 40 mg. The incidence of adverse events was comparable among the groups, and tegoprazan was well‐tolerated.
Conclusion
Once daily administration of tegoprazan 50 or 100 mg showed non‐inferior efficacy in healing EE and tolerability to that of esomeprazole 40 mg.
Nasal obstruction caused by nasal septal deviation is very bothersome and, therefore, can affect the patient's emotional state. However, little is known about the effect of nasal septal deviation ...(NSD) on the neuropsychiatric aspects of patients. Therefore, this study aims to verify the higher incidence of anxiety, depression, and migraine in patients diagnosed with NSD compared to general populations using big data.
This retrospective cohort study collected subjects from the Korean National Health Insurance Service (NHIS) database. Adjustments were made to minimize the confounding of variables for age, sex, residence type, income levels, hypertension, diabetes, dyslipidemia, rhinitis, and chronic rhinosinusitis between the two groups. The primary endpoint of this study was newly diagnosed anxiety, depression, and migraine between January 2009 and December 2018. Kaplan-Meier survival curves, logarithmic rank test, and Cox proportional regression test were used for statistical analysis.
Among a total of 135,769 subjects in the NHIS database, 48,495 patients with NSD (NSD group) and 54,475 control subjects (control group) were selected. Patients with NSD had an increased risk of anxiety, depression, and migraine compared to the control group. In the NSD group, the adjusted hazard ratios (HR) were 1.236 (95% CI, 1.198-1.276) for anxiety, 1.289 (95% CI, 1.238-1.343) for depression, and 1.251 (95% CI, 1.214-1.290) for migraine.
NSD is associated with a higher incidence of anxiety, depression, and migraine. Therefore, it is suggested that physicians carefully consider psychoneurological distress and employ therapeutic strategies to minimize these conditions.
Patients with end‐stage liver disease show sarcopenia, and preoperative sarcopenia is independently associated with patient mortality after liver transplantation. However, few studies have examined ...the relationship between perioperative loss of core muscle and patient mortality in living donor liver transplantation (LDLT). This study was performed to investigate the association between a perioperative decrease in the psoas muscle index (PMI) and patient mortality after LDLT. Adult patients (age ≥ 18 years) undergoing LDLT between January 2009 and December 2016 were classified into low‐loss (>25th quartile) versus high‐loss (≤25th quartile) groups according to PMI change between the day before surgery and postoperative day (POD) 7. Patient survival was compared between the 2 groups, and factors affecting survival were analyzed. The median (interquartile range) level of PMI change from the day before surgery to POD 7 was −4.8% (−11.7%‐1.2%). Although there was no preoperative difference in PMI between the low‐loss and high‐loss groups, patients with PMI change ≤−11.7% showed poorer survival than those with PMI change >−11.7% during the follow‐up period. A PMI decrease ≤−11.7% between the day before surgery and POD 7 is an independent predictor of patient mortality after LDLT. In addition, intraoperative packed red blood cell transfusion, graft fat percentage, and reoperation and infection after surgery were significantly associated with patient mortality. In conclusion, a PMI decrease ≤−11.7% between the day before surgery and POD 7 is an independent predictor of patient mortality after LDLT. It is necessary to identify the factors responsible for the perioperative decrease in skeletal muscle mass and to ascertain if they are modifiable to improve patient survival after LDLT. Liver Transplantation 24 623–633 2018 AASLD.
Antibiotic use preceding immune checkpoint inhibitor (ICI) treatment has been associated with a decreased efficacy of ICI in solid tumors. In this study, we evaluated the effect of antibiotic use ...before ICI therapy on oncological outcomes.
We examined patients with recurrent gynecologic malignancies at two academic institutions. The clinical data, including antibiotic use within 60 days of ICI initiation, type of antibiotics, reasons for antibiotic use, body mass index, tumor site, chemotherapy-free interval, prior history of radiotherapy, disease control rate (DCR), and overall survival (OS), were assessed.
Of 215 patients, 22.9% (
= 47) received antibiotics before ICI treatment. The most common cancer was ovarian (52.1%,
= 112), followed by cervical (24.7%,
= 53) and endometrial (16.7%,
= 36). When we divided the cohort based on antibiotic use before ICIs, there were no significant differences in the DCR and baseline characteristics between the two groups. On multivariate analyses, the variables associated with poor OS were previous use of antibiotics for a cumulative duration of >14 days (HR 2.286, 95% CI 1.210-4.318;
= 0.011); Eastern Cooperative Oncology Group 2 or 3 (HR 4.677, 95% CI 2.497-8.762;
< 0.001); and chemotherapy-free interval of <6 months (HR 2.007, 95% CI 1.055-3.819;
= 0.034).
Prior use of antibiotics for a cumulative duration of >14 days was associated with reduced survival in recurrent gynecologic malignancies.
Background
We investigated the combined effects of sarcopenia and inflammation on outcomes in patients with HCC treated with nivolumab.
Materials and Methods
We reviewed 102 patients treated with ...nivolumab between 2017 and 2018. Sarcopenia was diagnosed when the L3 skeletal muscle indices were < 42 cm
2
/m
2
and < 38 cm
2
/m
2
in men and women, respectively. Baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count were used as surrogate markers of inflammation and immune cell reservoir. High NLR (hNLR) was defined as NLR ≥ 3, and severe lymphopenia (sLP) was defined as lymphocyte < 800/μL. The overall survival (OS) and progression-free survival (PFS) were analyzed.
Results
With a median follow-up of 21.9 (interquartile range, 8.3–58.3) months, patients with sarcopenia showed shorter OS than those without sarcopenia (median, 2.9 vs. 7.5 months, respectively). Patients with either hNLR or sLP exhibited inferior survival than those without risk factor (median OS, 2.8 vs. 14.5 months; median PFS, 1.3 vs. 3.7 months, respectively). Among 70 patients treated with RT, benefit of RT was observed in patients with sarcopenia or those without hNLR/sLP (all
p
< 0.05). After multivariable analysis, RT, hNLR/sLP, albumin–bilirubin (ALBI) grade, and alpha-fetoprotein were significantly associated with OS (all
p
< 0.05), and hNLR/sLP was also associated with decreased PFS together with ALBI grade, alpha-fetoprotein, and RT (all
p
< 0.05).
Conclusion
The current study hypothetically demonstrated that the risk group stratified by hNLR/sLP outweighs the significance of sarcopenia in predicting outcomes after nivolumab. Furthermore, patients with sarcopenia might benefit from RT, especially those without risk factors of hNLR/sLP.
A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy.
Herein, we performed comprehensive molecular ...characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells.
The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% (6/60 95% CI, 2.4-17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways.
Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment.
NCT#03163992 (first posted: May 23, 2017).
Abstract In neurodegenerative diseases like AD, tau forms neurofibrillary tangles, composed of tau protein. In the AD brain, activated caspases cleave tau at the 421th Asp, generating a ...caspase-cleaved form of tau, TauC3. Although TauC3 is known to assemble rapidly into filaments in vitro , a role of TauC3 in vivo remains unclear. Here, we generated a transgenic mouse expressing human TauC3 using a neuron-specific promoter. In this mouse, we found that human TauC3 was expressed in the hippocampus and cortex. Interestingly, TauC3 mice showed drastic learning and spatial memory deficits and reduced synaptic density at a young age (2–3 months). Notably, tau oligomers as well as tau aggregates were found in TauC3 mice showing memory deficits. Further, i.p. or i.c.v . injection with methylene blue or Congo red, inhibitors of tau aggregation in vitro , and i.p. injection with rapamycin significantly reduced the amounts of tau oligomers in the hippocampus, rescued spine density, and attenuated memory impairment in TauC3 mice. Together, these results suggest that TauC3 facilitates early memory impairment in transgenic mice accompanied with tau oligomer formation, providing insight into the role of TauC3 in the AD pathogenesis associated with tau oligomers and a useful AD model to test drug candidates.
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