Association between specific ultrasound features of joints and impaired kidney function among gout patients.

OBJECTIVE: To investigate the relationship between the specific ultrasonic manifestations of lower limb joints and impaired kidney function in gouty arthritis. METHODS: In this cross-sectional study, 408 patients with gouty arthritis were divided into two groups based on the status of renal function: normal group (n = 240) and renal impairment (n = 168) group. All patients underwent ultrasound examination of the bilateral knee, ankle, and first metatarsophalangeal joints to detect ultrasound features of double-contour sign (DC) and tophus. Multiple logistic regression analysis was conducted to assess the association between kidney dysfunction and ultrasound features. A number of potential clinical confounders were adjusted in the model. RESULTS: Univariable conditional logistic regression produces several significant risk factors of impaired kidney function which were the highest and current lever of serum urate acid, course of disease, frequency of attack, hyperlipidemia, hypertension, diabetes, coronary heart disease, presence of multiple tophus, and DC (P < 0.05). After correcting the course of disease and other risk factors, tophus was still an independent risk factor of impaired kidney function and the multivariable adjusted odds ratios (95% CI) was 1.789 (1.005-3.185, P = 0.05), however, the association was not significant in DC (OR = 1.098, 95% CI: 0.668-1.803, P = 0.71). CONCLUSION: The ultrasound feature of tophus was associated with kidney dysfunction in patients with gout, independent of clinical risk factors, which may be helpful in guiding clinical practice.

Developmental trajectories of health-promoting behaviours among pregnant women: A longitudinal study.

AIMS AND OBJECTIVES: The aim of this study is to estimate differences in health-promoting behaviour levels throughout the pregnancy trimesters, to identify distinct patterns of health-promoting behaviour trajectories during pregnancy and to evaluate predictors of these trajectory group memberships. BACKGROUND: Promoting healthy lifestyle behaviours during pregnancy could decrease devastating outcomes for the mother and foetus. However, there is currently limited insight into the dynamics of health-promoting behaviours during pregnancy. DESIGN: An observational longitudinal study. METHODS: 158 pregnant women were recruited from June 2020 to June 2021 in Qingdao, China. The Health-Promoting Lifestyle Profile was used to assess health-promoting behaviours. Latent growth model was performed to compare health-promoting behaviours at different time points. Group-based trajectory model was applied to identify health-promoting behaviour trajectories. Multinomial logistic regression was adopted to determine the predictors of trajectory group memberships. We used the STROBE checklist to report this study. RESULTS: The entire sample of pregnant women experienced a significant increase in health-promoting behaviours during pregnancy. Three trajectories were identified including a 'low-increase behaviour trajectory (20.1% of sample)', a 'moderate-increase behaviour trajectory (58.0% of sample)' and a 'stable then increased behaviour trajectory (21.9% of sample)'. Low maternal sense of coherence, lack of pre-pregnancy exercise habit, artificial insemination and low monthly family income were significantly associated with the low-increase behaviour trajectory. High self-efficacy and pre-pregnancy exercise habit were significantly associated with the stable then increased behaviour trajectory. CONCLUSIONS: Pregnant women exhibit different health-promoting behaviours throughout the pregnancy trimesters. Meanwhile, three trajectories were identified among pregnant women. Thus, more attentions should be paid on early identification and targeted intervention in a future study. RELEVANCE OF CLINICAL PRACTICE: Healthcare providers should pay closer and earlier attention to identify women in the low-increase trajectory subgroup at the outset of pregnancy. Similarly, increased efforts should be made to improve maternal self-efficacy and develop good pre-pregnancy exercise habit in future study.

Effects of e-health interventions on health outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis.

AIMS AND OBJECTIVES: To evaluate the effects of e-health interventions on disease activity, self-efficacy, pain and quality of life among patients with rheumatoid arthritis (RA). BACKGROUND: Prior systematic reviews have only reported the quality and features of e-health interventions in patients with RA. However, the effect of e-health interventions in patients with RA is unclear. DESIGN: Systematic review and meta-analysis. METHODS: This review was conducted following the PRISMA guideline. We searched 5 databases, including PubMed, EMBASE, CINAHL, Scopus and the Cochrane library. The risk of bias was assessed using the Cochrane risk of bias tool. The quality of the evidence was assessed via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. Using a random-effects model adopted the standardised mean difference (SMD) with a 95% confidence interval (CI). A chi-squared test and an I2 test were used to assess heterogeneity. Subgroup analyses were conducted based on different controls. RESULTS: A total of 9 randomised control trials were included in this study. Compared with the control group, disease activity of the e-health group significantly decreased (SMD with 95% CI: -.17 [-.30, -.04], p = .01, I2  = 1%). Meanwhile, trials with usual care control had a larger effect on disease activity (SMD with 95% CI: -.21 [-.40, -.02], p = .03, I2  = 38%). The effect of e-health interventions on self-efficacy was controversial; pain and quality of life were negative in the currently included studies. The quality of evidence was rated as low for disease activity and very low for pain, self-efficacy and quality of life. CONCLUSIONS: The effect of e-health interventions on disease activity was statistically significant. More well-designed randomised controlled trials are still needed to verify the effects in the future. RELEVANCE TO CLINICAL PRACTICE: This study shows the potential value of e-health in improving health outcomes in patients with RA.

Reduced lung function predicts risk of incident type 2 diabetes: insights from a meta-analysis of prospective studies.

Epidemiological studies have repeatedly investigated the association between reduced pulmonary function and incident type 2 diabetes mellitus (T2DM). However, the results have been inconsistent. This meta-analysis aimed to clarify this association with prospective cohort studies. We searched PubMed, Web of Science (ISI), and Google Scholar for all studies (in English) reporting reduced lung function with a risk of T2DM. The measures of lung function included percentage of forced vital capacity for predicted values (FVC%pre), percentage of forced expiratory volume in the first second after expiration for predicted values (FEV1%pre) and FEV1-to-FVC ratio%. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects meta-analyses. A total of 5,480 incident T2DM patients among 88,799 individuals were identified from nine prospective cohort studies. Compared to the highest category of FVC%pre and FEV1%pre, the lowest category of FVC%pre and FEV1%pre were significantly associated with increased incident T2DM risk (FVC%pre: RR = 1.49, 95% CI: 1.39-1.59; FEV1%pre: RR = 1.52, 95% CI: 1.42-1.62). However, no significant relationship was found between the FEV1/FVC ratio and incident T2DM risk (RR = 1.01, 95% CI: 0.91-1.13). Current evidence suggests that restrictive rather than obstructive impairment of lung function is significantly associated with the incidence of T2DM. Further research is warranted to explore potential mediators of this relationship.

Association between pregnancy intention and smoking or alcohol consumption in the preconception and pregnancy periods: A systematic review and meta-analysis.

AIMS: To investigate the association between pregnancy intention and smoking or alcohol consumption in preconception and pregnancy periods. BACKGROUND: Suboptimal lifestyle such as smoking and alcohol consumption can lead to devastating outcomes on the maternal and foetus. Pregnancy intention exerts a significant effect on promoting healthy lifestyle behaviours. However, no reliable evidences confirmed pregnancy intention was associated with smoking and alcohol consumption before and during pregnancy. DESIGN: Systematic review and meta-analysis. METHODS: We performed a comprehensive search from databases including PubMed, Cochrane, Web of Science, IEEE Xplore, MEDLINE, ProQuest and Scopus from the inception of these databases up to November, 2020. All eligible studies exploring the association between pregnancy intention and smoking or alcohol consumption were included. The fixed- or random effect pooled measure was used to estimate the odds ratio (OR) or risk ratio (RR) and 95% CI. In addition, the PRISMA checklist was used in this meta-analysis. RESULTS: A total of 23 studies were included in this systematic review and meta-analysis. During pregnancy, the findings suggested that women with unplanned pregnancy were 68% more likely to consume cigarettes (OR = 1.68, 95% CI = 1.44-1.95) and 44% more likely to consume alcohol (OR = 1.44, 95% CI = 1.15-1.81) than those women with planned pregnancy. Meanwhile, during preconception, women with unplanned pregnancy were 30% more likely to consume cigarettes (OR = 1.30, 95% CI = 1.10-1.53) and 20% more likely to consume alcohol (OR = 1.20, 95% CI = 1.01-1.42) than those women with planned pregnancy. CONCLUSION: The findings suggested that women with unplanned pregnancy were more likely to follow unhealthy behaviours such as smoking and alcohol consumption before and during pregnancy. Health professionals should consider the women's desire for pregnancy to decrease preconception and pregnancy smoking or alcohol consumption in future studies. RELEVANCE OF CLINICAL PRACTICE: Pregnancy intention is the key determinant of smoking and alcohol consumption during preconception and pregnancy periods. Offering effective contraception in primary healthcare setting could prevent unplanned pregnancy. Meanwhile, popularising minimal alcohol consumption and comprehensive smoke-free legislation would be beneficial to improve reproductive outcomes.

Expression of tomato prosystemin gene in Arabidopsis reveals systemic translocation of its mRNA and confers necrotrophic fungal resistance.

Systemin (SYS), an octadecapeptide hormone processed from a 200-amino-acid precursor (prosystemin, PS), plays a central role in the systemic activation of defense genes in tomato in response to herbivore and pathogen attacks. However, whether PS mRNA is transferable and its role in systemic defense responses remain unknown. We created the transgenic tomato PS gene tagged with the green fluorescent protein (PS-GFP) using a shoot- or root-specific promoter, and the constitutive 35S promoter in Arabidopsis. Subcellular localization of PS-/SYS-GFP was observed using confocal laser scanning microscopy and gene transcripts were determined using quantitative real-time PCR. In Arabidopsis, PS protein can be processed and SYS is secreted. Shoot-/root-specific expression of PS-GFP in Arabidopsis, and grafting experiments, revealed that the PS mRNA moves in a bi-directional manner. We also found that ectopic expression of PS improves Arabidopsis resistance to the necrotrophic fungus Botrytis cinerea, consistent with substantial upregulation of the transcript levels of specific pathogen-responsive genes. Our results provide novel insights into the multifaceted mechanism of SYS signaling transport and its potential application in genetic engineering for increasing pathogen resistance across diverse plant families.

Expression of cadR Enhances its Specific Activity for Cd Detoxification and Accumulation in Arabidopsis.

Cadmium (Cd) is a transition metal that is highly toxic in biological systems. Anthropogenic emissions of Cd have increased biogeochemical cycling and the amount of Cd in the biosphere. Here we studied the utility of a bacterial Cd-binding protein, CadR, for the remediation of Cd contamination. CadR was successfully targeted to chloroplasts using a constitutive Cauliflower mosaic virus (CaMV) 35S promoter or a shoot-specific Chl a/b-binding protein 2 gene (CAB2) promoter and an RbcS (small subunit of the Rubisco complex) transit peptide. Under short-term (2 d) exposure to Cd, the cadR transgenic plants showed up to a 2.9-fold Cd accumulation in roots compared with untransformed plants. Under medium term (7 d) exposure to Cd, the concentrations of Cd in leaves began to increase but there were no differences between the wild type and the cadR transgenic plants. Under long-term (16 d) exposure to Cd, the cadR transgenic plants accumulated greater amounts of Cd in leaves than the untransformed plants. Total Cd accumulation (µg per plant) in shoots and roots of the plants expressing cadR were significantly higher (up to 3.5-fold in shoots and 5.2-fold in roots) than those of the untransformed plants. We also found that targeting CadR to chloroplasts facilitated chloroplastic metal homeostasis and Chl b accumulation. Our results demonstrate that manipulating chelating capacity in chloroplasts or in the cytoplasm may be effective in modifying both the accumulation of and resistance to Cd.

Subcellular targeting of bacterial CusF enhances Cu accumulation and alters root to shoot Cu translocation in arabidopsis.

Copper (Cu) is an important environmental pollutant that exerts harmful effects on all living organisms when in excess. In an effort to remove this toxin in situ, a bacterial Cu-binding protein gene CusF was engineered to target CusF for secretion to the cell wall and vacuoles and for accumulation in the cytoplasm. Analysis of transgenic Arabidopsis plants showed that CusF was functionally active and that plants expressing cell wall- (CusFcw transgenic lines) or vacuole-targeted CusF (CusFvac transgenic lines) were more resistant to Cu excess than untransformed plants and plants with cytoplasmic CusF (CusFcyto transgenic lines). Under short-term (48 h) exposure to Cu excess, CusFcw transgenic lines showed up to 2-fold increased Cu accumulation in roots compared with the untransformed plants; however, CusFcyto lines and the wild-type plants had similar Cu concentrations in both roots and shoots. Under long-term (40 d) exposure to Cu excess, all transgenic lines accumulated more Cu (up to 3-fold) in roots than the untransformed plants, whereas only CusFcyto lines showed a marked increase (∼3-fold of the wild-type plants) of Cu accumulation in shoots. In addition, expression of CusF in the cytosol dramatically enhanced Cu transport from roots to shoots when compared with plants with secretory pathway-targeted CusF. Our results demonstrate the feasibility of Cu tolerance and accumulation by engineering Cu-binding proteins targetable to subcellular compartments and provide new insights into the multifaceted mechanisms of Cu partitioning between roots and shoots.

Circulating tumor DNA analysis predicts recurrence and avoids unnecessary adjuvant chemotherapy in I-IV colorectal cancer.

Background: Circulating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC. Objectives: To define potentially cured CRC patients through ctDNA monitoring following surgery. Design: A prospective, multicenter, observational study. Methods: We enrolled 309 patients with stages I-IV CRC who underwent definitive surgery. Tumor tissues were sequenced by a custom-designed next-generation sequencing panel to identify somatic mutations. Plasma was analyzed using a ctDNA-based molecular residual disease (MRD) assay which integrated tumor-genotype-informed and tumor-genotype-naïve ctDNA analysis. The turnaround time of the assay was 10-14 days. Results: Postoperative ctDNA was detected in 5.4%, 13.8%, 15%, and 30% of patients with stage I, II, III, and IV disease, respectively, and in 17.5% of all longitudinal samples. Patients with positive postsurgery MRD had a higher recurrence rate than those with negative postsurgery MRD [hazard ratio (HR), 13.17; p < 0.0001], producing a sensitivity of 64.6%, a specificity of 94.8%, a positive predictive value (PPV) of 75.6%, and a negative predictive value (NPV) of 91.5%. Furthermore, patients with positive longitudinal MRD also had a significantly higher recurrence rate (HR, 14.44; p < 0.0001), with increased sensitivity (75.0%), specificity (94.9%), PPV (79.6%), and NPV (93.4%). Subgroup analyses revealed that adjuvant therapy did not confer superior survival for patients with undetectable or detectable MRD. In addition, MRD detection was less effective in identifying lung-only and peritoneal metastases. Conclusion: Postoperative ctDNA status is a strong predictor of recurrence independent of stage and microsatellite instability status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.

Genetic polymorphisms of interleukin 17A and interleukin 17F and their association with inflammatory bowel disease in a Chinese Han population.

OBJECTIVE: Interleukin-17A and interleukin-17F (IL-17A and IL-17F) are candidate genes for chronic inflammatory disease. We investigated the association between IL17A/F gene polymorphisms and susceptibility to and clinical features of inflammatory bowel disease (IBD). METHODS: A total of 270 ulcerative colitis (UC) patients, 82 Crohn's disease (CD) patients and 268 healthy controls were recruited in this study. Genomic DNA was extracted and analyzed for IL17A/F gene polymorphisms using ligase detection reaction allelic technology. RESULTS: Compared to the controls, the mutant allele C for IL17F rs763780 was significantly more common in CD patients [14.0 vs 8.4 %, P = 0.033, odds ratio (OR) 1.18, 95 % confidence interval (CI) 1.41-3.04] and was associated with the disease lesion location. This variant of IL17F rs763780 also had a weak correlation with the age of UC onset (P = 0.05, OR 0.97, 95 % CI 0.94-1.00). The IL17A (rs2275913, G-197A) variant had a weak association with the severity of disease: patients with the mutant allele A tended to suffer mild active UC. The haplotype (GGTT) of IL17A formed with four single nucleotide polymorphisms (rs2275913, rs8193037, rs8193038, and rs3804513) was associated with an increased risk of UC (P = 0.034, OR 4.58, 95 % CI 1.54-13.64). CONCLUSIONS: The IL17F (rs763780, 7488T/C) variant was associated with an increased risk for the development of CD, and affected some clinical features of UC and CD. The IL17A (rs2275913, G-197A) variant had a weak association with the severity of UC. There was a risk haplotype in IL17A which could increase the risk of UC.

Case report: Target and immunotherapy of a lung adenocarcinoma with enteric differentiation, EGFR mutation, and high microsatellite instability.

Background: Pulmonary enteric adenocarcinoma (PEAC) is a rare histological subtype of non-small-cell lung cancer (NSCLC) with a predominant (>50%) enteric differentiation component. The frequency of high microsatellite instability (MSI-H) is very low in lung cancer. EGFR tyrosine kinase inhibitors and immunotherapy are standard treatment for NSCLC patients, but their effectiveness in lung adenocarcinoma with pulmonary enteric differentiation is unknown. Case presentation: This report describes a 66-year-old man who was initially diagnosed with metastatic lung adenocarcinoma with EGFR mutation based on pleural fluid. A lung biopsy was obtained after 17 months of first-line icotinib treatment. Histological analysis of biopsy samples and endoscopic examination resulted in a diagnosis of adenocarcinoma with enteric differentiation. Next-generation sequencing of 1,021 genes showed EGFR E19del, T790M, and MSI-H, while immunohistochemical assay showed proficient expression of mismatch repair (MMR) proteins. Consequently, the patient was treated with osimertinib and had a progression-free survival (PFS) of 3 months. His treatment was changed to chemotherapy with/without bevacizumab for 6.5 months. Then, the patient was treated with one cycle of camrelizumab monotherapy and camrelizumab plus chemotherapy, respectively. The tumor continued to grow, and the patient suffered pneumonia, pulmonary fungal infections, and increased hemoptysis. He received gefitinib and everolimus and died 2 months later and had an overall survival of 30 months. Conclusion: In summary, our case describes a rare pulmonary enteric adenocarcinoma with an EGFR-activating mutation and MSI-H, responding to an EGFR tyrosine kinase inhibitor and poorly benefiting from an immune checkpoint inhibitor.

Novel PPFIA1-ALK, ALK-C2orf91(intergenic) double-fusion responded well to alectinib in an advanced lung adenocarcinoma patient: a case report.

Non-small cell lung cancers (NSCLCs) with anaplastic lymphoma kinase (ALK)-rearrangement have favorable responses to ALK inhibitors. However, ALK fusion mutations harbored approximately 90 distinct fusion partners. Patients with different ALK fusions might respond distinctly to different-generation ALK inhibitors. In this case report, we identified a novel non-reciprocal ALK fusion, ALK-C2orf91(intergenic) (A19: intergenic) and PPFIA1-ALK (P2:A20), by next-generation DNA sequencing in an advanced lung adenocarcinoma patient. After 2 months of alectinib, the targeted lung lesion regressed significantly, and evaluation of therapeutic efficiency indicated partial response. To date, the patient had achieved 12 months of progression-free survival from alectinib treatment. Our study extended the spectrum of ALK fusion partners in ALK-positive NSCLC, and we reported a new ALK fusion, PPFIA1-ALK and ALK-C2orf91(intergenic), and its sensitivity to alectinib firstly in lung cancer. We believe that this case report has an important clinical reference.

Case report: Successful sequential therapy of crizotinb and entrectinib in ROS1-positive non-small-cell lung cancer with brain metastasis in later-settings.

RATIONALE: Crizotinib has been approved in many countries for the treatment of patients with advanced ROS1-rearranged non-small cell lung cancers (NSCLC). Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the central nervous system (CNS) and has been recommended as first-line therapy. Few reports have precisely described sequential crizotinb followed by entrectinib in patients with ROS1 fusion in later settings. PATIENT CONCERNS: A 56-year-old man with a history of occasional smoking visited our hospital with cough, sputum, and shortness of breath. DIAGNOSIS: He was diagnosed with right lung adenocarcinoma (T4N2M1a, stage IV) after image and histological examination, without EGFR or ALK fusion mutation. INTERVENTIONS: He received three prior lines of therapies, including chemotherapy, nivolumab monotherapy, and paclitaxel plus anlotinib, with progression-free survival (PFS) of 5, 2, and 11.5 months, respectively. Then the patient began to have headaches and dizziness, and brain magnetic resonance imaging showed multiple brain metastases. Next-generation sequencing (NGS) of the biopsy from neck lymph node identified EZR-ROS1 (1.25% abundance). After 2 months of crizotinib (250 mg daily) plus bevacizumab, all pulmonary and brain lesions decreased, but a small liver lesion was discovered. As treatment went on for another 4 months, the liver lesion continued to grow while other lesions kept decreased or stable state. NGS analysis on the peripheral blood found the disappearance of EZR-ROS1 fusion and a new NTRK2 mutation (c.5C>T, p.Ser2Leu, 0.34% abundance) without other targetable molecular alteration. He received entrectinib (600 mg daily) plus bevacizumab and achieved a partial response. After 7 months of therapy, examination revealed progression of brain lesions. OUTCOMES: The patient had a total PFS of 13 months from sequential crizotinib and entrectinib therapy. LESSONS: A ROS1-rearranged NSCLC with CNS metastases responded to sequential tyrosine kinase inhibitors treatment of crizotinb followed by entrectinib. This report has potential implications in guiding decisions for the treatment after crizotinib resistance.

Effect of health coaching on blood pressure control and behavioral modification among patients with hypertension: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Health coaching has emerged as a potential supporting tool for improving hypertension health behavior. However, health coaching efficacy on hypertension has not been reviewed systematically. OBJECTIVE: To evaluate the effects of health coaching on blood pressure and behavioral changes among patients with hypertension in randomized controlled trials. DESIGN: A systematic review and meta-analysis. METHODS: We searched Medline (via PubMed), Web of Science, Embase, Cochrane Central Register of Controlled Trials, Proquest, and Scopus from inception to November 30, 2021. All randomized controlled trials that estimated the effects of health coaching on blood pressure and behavioral changes in adults with hypertension were included. The Cochrane risk-of-bias tool was used to evaluate the quality of the included studies. Standardized mean differences (SMD) and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects meta-analysis. Sensitivity analysis and subgroup analysis were also conducted. RESULTS: A total of 1655 studies were screened and 12 randomized controlled trials were selected for inclusion, with 2497 participants were included. Most of the studies were at low risk of bias and the quality of evidence was high. The meta-analysis demonstrated that health coaching could significantly reduce systolic blood pressure (SMD: -0.26, 95 % CI: -0.39, -0.13, p < 0.001) and diastolic blood pressure in hypertension (SMD: -0.13, 95 % CI: -0.22, -0.03, p = 0.009). In addition, health coaching showed statistically significant positive effects on dietary behaviors (SMD: 0.76, 95 % CI: 0.08, 1.44, p = 0.02) and self-efficacy (SMD: 0.39, 95 % CI: 0.05, 0.73, p = 0.02). Subgroup analysis indicated that the most common and effective type of health coaching was the phone-based interventions (systolic blood pressure: SMD: -0.27, 95 % CI: -0.44, -0.10, p = 0.002; diastolic blood pressure: SMD: -0.14, 95 % CI: -0.25, -0.03, p = 0.02). The effects of nurse-delivered interventions were larger than other health care professionals (systolic blood pressure: SMD: -0.42, 95 % CI: -0.68, -0.16, p = 0.002; diastolic blood pressure: SMD: -0.19, 95 % CI: -0.35, -0.04, p = 0.02). CONCLUSION: Current evidence suggested that health coaching could reduce blood pressure, improve dietary behaviors, and increase self-efficacy among patients with hypertension and thus could be an effective and alternative method in the management of hypertension. The most common and effective types of health coaching were phone-based and nurse-delivered interventions. Thus, more strategies and policies may be needed to implement these types of interventions to more patients with hypertension.

Protective role of uncoupling protein-2 against dextran sodium sulfate-induced colitis.

BACKGROUND AND AIMS: Uncoupling protein-2 (UCP-2) is a negative regulator of reactive oxygen species (ROS) production. We investigated the effect of UCP-2 on disease progression in a murine dextran sodium sulfate (DSS)-induced colitis model, and the expression and distribution of tight junction (TJ) proteins, such as occludin, zonula-1 (ZO-1), claudin-4, and junctional adhesion molecule-1 (JAM-1). METHODS: Male UCP-2(-/-) mice and wild-type littermates were divided into four groups: groups I and II, which comprised each type of mouse, were administered 2.5% DSS dissolved in drinking water to create a colitis model. The control groups (groups III and IV, which comprised each type of mouse) were given normal drinking water. Disease progression was evaluated according to colon length and the disease activity index. The distribution of TJ proteins was detected by immunohistochemical analysis. RESULTS: Compared with wild-type littermates, UCP-2(-/-) mice treated with DSS developed more severe diarrhea, body weight loss (P < 0.01), significantly short colon length, and more inflammatory cell infiltration into the mucosa and submucosa. The level of malondialdehyde in colonic mucosa increased in UCP-2(-/-) mice treated with DSS compared with the wild-type littermates (P < 0.001). The distribution of the ZO-1 and JAM-1 proteins was significantly decreased in the colonic mucosa of UCP-2(-/-) mice compared with the wild-type littermates, whereas occludin and claudin-4 distribution were not different between the UCP-2(-/-) mice and wild-type littermates. CONCLUSIONS: UCP-2 might reduce intestinal inflammatory response through the negative regulation of ROS, and affects the expression and distribution of TJ proteins.

Serial Circulating Tumor DNA in Monitoring the Effect of Neoadjuvant and Adjuvant Immunotherapy in Patients With Colon Cancer: Case Series and Review of the Literature.

Although programmed death 1 blockade has significantly improved the survival of advanced colorectal cancer patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), clinical data in neoadjuvant and adjuvant setting are limited. The role of circulating tumor DNA (ctDNA) in precision oncology is promising, but its clinical significance in immunotherapy needs to be validated. We report a case series of 3 colon patients who received neoadjuvant and adjuvant immunotherapy and serial ctDNA analysis. This report summarizes clinical and molecular details for 3 patients with locally advanced or recurrent dMMR/MSI-H/polymerase epsilon ( POLE ) mutation-positive tumors treated with neoadjuvant/adjuvant immunotherapy. One stage IV recurrent colon cancer patient diagnosed with Lynch syndrome received adjuvant sintilimab monotherapy and had a progression-free survival (PFS) over 16 months, one stage Ⅲc colon cancer patient with MSI-H/high tumor mutation burden received neoadjuvant toripalimab monotherapy, was assessed as clinical complete response before surgery, continued with adjuvant sintilimab monotherapy and had a PFS over 17 months, one stage Ⅱ colon cancer patient with POLE P286R also received adjuvant sintilimab monotherapy and had a PFS over 17 months. All patients had detectable ctDNA after radical surgery and clearance of ctDNA during adjuvant immunotherapy. All 3 patients are free of tumor disease at the time of this report. Further studies are warranted to evaluate the long-term efficacy of neoadjuvant and adjuvant programmed death 1 blockade in locally advanced and metastasis in dMMR/MSI-H/ POLE mutated colorectal cancer and the role of ctDNA monitoring.

Assessment of durable chemoimmunotherapy response via circulating tumor DNA in advanced esophageal squamous cell carcinoma.

Immune checkpoint inhibitor (ICI)-based therapies have shown promising advances for the first-line treatment of advanced or metastatic esophageal cancer (EC). However, few studies concerning the identification of patients who achieve durable response from ICIs have been previously reported. In the present study, pre- and on-treatment plasma circulating tumor DNA (ctDNA) were analyzed in 10 patients with advanced esophageal squamous cell cancer (ESCC) receiving first-line chemoimmunotherapy. Patients with decreased molecular tumor burden index (mTBI) >7% experienced longer progression-free survival (PFS) and durable clinical benefit (DCB, PFS ≥ 6 months). In addition, five patients showed stable disease at first scan, all three patients with decreased mTBI > 7% achieved DCB, while two cases with decreased mTBI ≤ 7% experienced non-DCB. Our results demonstrate that ctDNA monitor might help identify which ESCC patients respond to chemoimmunotherapy.

Correlation of KMT2 family mutations with molecular characteristics and prognosis in colorectal cancer.

BACKGROUND: Lysine methyltransferase 2 (KMT2) family proteins methylate lysine 4 on histone H3 (H3K4) to promote genome accessibility and transcription. Dysregulation or mutation of KMT2 family have been observed frequently in various types of human cancers. Colorectal cancer is the third most common cancer worldwide. However, few studies have evaluated the role of KMT2 family mutations in colorectal cancer. The present study aimed to explore the impact of KMT2 family mutations on clinicopathological, molecular characteristics and prognosis in colorectal cancer. METHODS: A total of 316 colorectal cancer patients were enrolled; tumor tissue and matched peripheral blood samples were collected and subjected to targeted sequencing with a panel of 1021 cancer-related genes. The association of clinical pathological features and molecular characteristics in patients were then analyzed. The cBioPortal dataset was used for investigating the KMT2 family mutations data and their correlation with clinical outcomes. RESULTS: The overall mutation frequencies of KMT2A-D were 9.5%, 0.5%, 13%, and 13%, respectively, which were more often present at right-sided primary and earlier stage tumors. KMT2A-D mutations are associated with enhanced genomic instability, including a higher level of microsatellite instability (MSI-H) and tumor mutational burden (TMB-H). In addition, our results highlight the co-occurring gene mutations within the Wnt signaling, ERBB2/4, TGF-ß superfamily pathway, and PI-3-kinase pathway in KMT2-mutant colorectal cancer. KMT2 family mutations were predictive biomarker for better overall survival in metastatic colorectal cancer. CONCLUSIONS: Collectively, we identified that KMT2 family mutations were correlated with higher-TMB and higher-MSI, thus resulting in a better outcome for colorectal cancer patients.

Construction of the subtracted cDNA library of striatal neurons treated with long-term morphine.

OBJECTIVE: To construct a morphine tolerance model in primarily cultured striatal neurons, and screen the differentially expressed genes in this model using suppression subtractive hybridization (SSH). METHODS: Sbtracted cDNA libraries were constructed using SSH from normal primarily cultured striatal neurons and long-term morphine treated striatal neurons (10-5 mol/L for 72 hours). To check reliability of the cell culture model, RT-PCR was performed to detect the cAMP-responsive element-binding protein (CREB) mRNA expression. The subtracted clones were prescreened by PCR. The clones containing inserted fragments from forward libraries were sequenced and submitted to GenBank for homology analysis. And the expression levels of genes of interest were confirmed by RT-PCR. Results CREB mRNA expression showed a significant increase in morphine treated striatal neurons (62.85 ± 1.98) compared with normal striatal neurons (28.43 ± 1.46, P < 0.01). Thirty-six clones containing inserted fragments were randomly chosen for sequence analysis. And the 36 clones showed homology with 19 known genes and 2 novel genes. The expression of 2 novel genes, mitochondrial carrier homolog 1 (Mtch1; 96.81 ± 2.04 vs. 44.20 ± 1.31, P < 0.01) and thymoma viral proto-oncogene 1 (Akt1; 122.10 ± 2.17 vs. 50.11 ± 2.01, P < 0.01), showed a significant increase in morphine-treated striatal neurons compared with normal striatal neurons. CONCLUSIONS: A reliable differential cDNA library of striatal neurons treated with long-term morphine is constructed. Mtch1 and Akt1 might be the candidate genes for the development of morphine tolerance.

Distinct Patterns of Urban-Rural and Sex Disparities in Children's BMI Trajectories From 2013 to 2018.

Background: To identify distinct trajectories of body mass index (BMI) in a large sample of Chinese children by urban-rural and sex disparities. Methods: Data for this study were obtained from the National Surveys on Chinese Students' Constitution and Health among 16,060 children aged 6-11 years. Weight and height data were used to calculate BMI. Group-based trajectory modeling (GBTM) was used to identify distinct BMI trajectories. Results: Seven distinct trajectories were identified, "sustained healthy weight" (46.01%), "sustained obesity" (17.26%), "sustained underweight" (4.50%), "obesity to overweight" (6.45%), "obesity to healthy weight" (11.75%), "healthy weight to overweight" (8.67%), and "healthy weight to obesity" (5.36%). The proportions of "sustained obesity," "healthy weight to obesity," and "healthy weight to overweight" trajectories were much higher among boys compared with girls (P < 0.001). Meanwhile, children living in rural areas were more represented in the "healthy weight to obesity" trajectory (P < 0.001). Conclusion: In this study, the proportions of BMI development trajectories among 6-11-year-old children varied by sex and urban-rural areas, which may require tailored interventions specifically toward these at-risk trajectories.