A radioactive and fluorescent dual modality cysteine cathepsin-B activity-based probe for the detection and treatment evaluation in rheumatoid arthritis.

Activated macrophages are key effector cells and specific markers in patients with rheumatoid arthritis (RA). Cysteine cathepsin B (CTS-B) is highly expressed in macrophages and positively associated with RA activity and severity. This study aims to evaluate an activity-based multi-modality diagnostic agent, 68Ga-BMX2, which targets CTS-B to visualize the arthritis activity and evaluate the treatment efficacy. A CTS-B activity-based probe, BMX2, was labeled efficiently with 68Ga to produce 68Ga-BMX2 for fluorescent and positron emission tomography (PET) multi-modality imaging. The affinity and specificity of BMX2 binding with the CTS-B enzyme in macrophages were determined by radioactive experiment using RAW 264.7 cell lines, with CA074 and BMX5 as the inhibitors to test the specificity of the binding. Then, PET and fluorescence imaging were acquired on collagen-induced arthritis (CIA) mice. Additionally, the treatment monitoring capability of 68Ga-BMX2 PET/CT imaging was tested with methotrexate (MTX). RAW 264.7 macrophage cells showed significant uptake of 68Ga-BMX2. The binding of BMX2 with CTS-B in RAW 264.7 macrophage cells is time-dependent and could be blocked by CA074 and BMX5. In vivo optical and PET imaging showed high signals in the right hind arthritis in CIA mice from 68Ga-BMX2 and BMX2 accumulated for at least 120 h. Additionally, 68Ga-BMX2 signals were significantly reduced in the MTX-treated CIA mice compared to the control group. The 68Ga-BMX2, a radioactive and fluorescent dual-modality diagnostic agent targeting CTS-B, demonstrated a practical approach for CIA PET and fluorescence imaging. The 68Ga-BMX2 multimodality imaging could significantly monitor the treatment response in the CIA mice.

Effect of waiting time for radiotherapy after last induction chemotherapy on prognosis of locally advanced nasopharyngeal carcinoma.

BACKGROUND: The effect of radiotherapy waiting time after last induction chemotherapy (IC-RT) on prognosis of patients with locally advanced nasopharyngeal carcinoma (LANPC) needs further discussion. METHODS: Three hundred and six patients with LANPC diagnosed pathologically by induction chemotherapy (IC) and radiotherapy (RT) from 2013 to 2018 were selected for this study. RESULTS: The IC-RT was a risk factor for the post-treatment progression of LANPC (OR = 1.017 95%CI: 1.003-1.031), For patients with LANPC, the IC-RT > 40 days significantly reduced 5-year PFS (70% vs. 55%; p = 0.0012), 5-year OS (84% vs. 73%; p = 0.028), 5-year DMFS (80% vs. 66%; p = 0.003), 5-year LRFS (77% vs. 67%; p = 0.012). Indicating that patients with stage IVa who IC-RT > 40 days were found to be a significant predictor of aggravated PFS (HR = 2.69; 95%CI: 1.57-4.6), OS (HR = 2.55; 95%CI: 1.29-5.03), DMFS (HR = 3.07; 95%CI: 1.64-5.76) and LRFS (HR = 2.26; 95%CI: 1.21-4.21). CONCLUSION: The prognosis of patients will be adversely affected if the IC-RT exceeds 40 days, especially for stage IVa patients.

Synthesis of glycyrrhizin analogues as HMGB1 inhibitors and their activity against sepsis in acute kidney injury.

Glycyrrhizin (GL) is one of the antagonists of highly conserved nuclear protein (HMGB1). The researches have shown that the glycosyl of GL is an important pharmacophore for GL binding to HMGB1, and it is the determinant factor for mechanism of action. To get the HMGB1 inhibitors with higher activity and good pharmacokinetic properties, two classes of GL analogues containing C-N glycoside bond were synthesized, and their anti-inflammatory, anti-oxidative stress and anti-septic kidney injury were evaluated. The results are as follows. First, in the anti-inflammatory assay, all the compounds inhibited NO release in some degree; among them, compound 6 displayed the strongest NO inhibitory effect with IC50 value of 15.9 µM, and compound 15 with IC50 of 20.2 µM. The two compounds not only decreased IL-1ß and TNF-α levels in RAW264.7 cells and HK-2 cells, but also downregulated the levels of NLRP3, P-NF-κB p65 and HMGB1 in activated HK-2 cells in a dose-dependent manner. Second, in the renal protection assay with H2O2-stimulated HK-2 cell line, they reduced MDA level and increased SOD in HK-2 cells; additionally, they also inhibited the HK-2 cell apoptosis and downregulated the Caspase-1 p20 level. Third, in the in vivo activity tests of the septic mouse, they also showed good activities just like in vitro, decreasing the IL-1ß, TNF-α, MDA, blood creatinine (Scr) and urea nitrogen (BUN) in serum, and increasing SOD levels in a dose-dependent manner. The immunoblotting results showed the two compounds downregulated the levels of HMGB1, P-NF-κB p65, NLRP3 and Caspase-1 p20 protein. All in all, the two compounds improved the renal injury of septic mice, and alleviated the tube wall structure damage and renal tubular dilation in kidney, which further proved by H&E staining. This suggests the two compounds have septic acute kidney injury activity, and they will be potential therapeutic drugs for septic acute kidney injury.

Predictive value of machine learning for breast cancer recurrence: a systematic review and meta-analysis.

PURPOSE: Recurrence of breast cancer leads to a high lifetime risk and a low 5 year survival rate. Researchers have used machine learning to predict the risk of recurrence in patients with breast cancer, but the predictive performance of machine learning remains controversial. Hence, this study aimed to explore the accuracy of machine learning in predicting breast cancer recurrence risk and aggregate predictive variables to provide guidance for the development of subsequent risk scoring systems. METHODS: We searched Pubmed, EMBASE, Cochrane, and Web of Science. The risk of bias in the included studies was evaluated using prediction model risk of bias assessment tool (PROBAST). Meta-regression was adopted to explore whether there was a significant difference in the recurrence time by machine learning. RESULTS: Thirty-four studies involving 67,560 subjects were included, among whom 8695 experienced breast cancer recurrence. The c-index of prediction models was 0.814 (95%CI 0.802-0.826) and 0.770 (95%CI 0.737-0.803) in the training and validation sets, respectively; the sensitivity and specificity were 0.69 (95% CI 0.64-0.74), 0.89 (95% CI 0.86-0.92) in the training, and 0.64 (95% CI 0.58-0.70), 0.88 (95% CI 0.82-0.92) in the validation, respectively. Age, histological grading, and lymph node status are the most commonly used variables in model construction. Attention should be paid to unhealthy lifestyles such as drinking, smoking and BMI as modeling variables. Risk prediction models based on machine learning have long-term monitoring value for breast cancer population, and subsequent studies should consider using large-sample and multi-center data to establish risk equations for verification. CONCLUSION: Machine learning may be used as a predictive tool for breast cancer recurrence. Currently, there is a lack of effective and universally applicable machine learning models in clinical practice. We expect to incorporate multi-center studies in the future and attempt to develop tools for predicting breast cancer recurrence risk, so as to effectively identify populations at high risk of recurrence and develop personalized follow-up strategies and prognostic interventions to reduce the risk of recurrence.

Design and synthesis of salidroside analogs and their bioactivity against septic myocardial injury.

Cardiac tissue suffers much from sepsis, and the incidence of myocardial injury is high in septic patients. The treatment of sepsis myocardial injury (SMI) has been the focus of clinical medicine. Salidroside shows myocardial cell protection, anti-oxidation and anti- inflammation effects, and it is thought as one of the potential compounds to treat sepsis myocardial injury. However, its anti-inflammatory activity is lower and its pharmacokinetic properties are not ideal, which is far from clinical application. Here, a series of salidroside analogs were synthesized, and their bioactivities were evaluated from several aspects, including their anti-oxidant and anti-inflammatory activities in vitro and anti-sepsis myocardial injury activities in vivo. Of all the compounds which synthesized, compounds 2 and 3 exhibited stronger anti-inflammatory activities than the others; after treating LPS-stimulated RAW264.7 or H9c2 cells with each of them, the levels of IL-1ß, IL-6 and TNF-α were down-regulated in a dose-dependent manner. In the anti-oxidative stress injury test, compounds 2 and 3 not only markedly increased the survival rate of cells, and but also improved the cellular oxidative stress-related indicators MDA, SOD and cell damage marker LDH in a dose-dependent manner. In the LPS-induced septic rat myocardial injury models (in vivo), the two compounds also showed good bioactivities. They also reduced the expression of IL-1ß, IL-6 and TNF-α, and blocked cell damage by suppressing overhauled oxidation in septic rats. In addition, the myocardial injury was significantly improved and the inflammatory infiltration was reduced after treatment with the two compounds. In conclusion, the salidroside analogs (2 and 3) showed promising therapeutical effect on septic myocardial injury in LPS-model rats, and they could be good candidates for clinical trials against inflammation and septic myocardial injury.

Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review.

We report here the clinical diagnosis and treatment and genetic mutations of an infant with You-Hoover-Fong syndrome (YHFS). The relevant literature review was conducted. A female infant aged 17 months was admitted to Nanhai Affiliated Maternity and Children's Hospital of Guangzhou University of Chinese Medicine due to "global development delay complicated with postnatal growth retardation for more than 1 year." The infant was diagnosed with YHFS due to the onset of extremely severe mental retardation, microcephaly, abnormal hearing, severe protein-energy malnutrition, congenital cataract, cleft palate (I°), congenital atrial septal defect, brain atrophy, hydrocephalus, and brain hypoplasia. The whole exon sequencing revealed two compound heterozygous mutations, including a likely pathogenic TELO2 variant, c.2245A > T (p.K749X) from her mother and an uncertain variant, c.2299C > T (p.R767C) from her father, validated by Sanger sequencing. After bilateral cataract surgery, the infant obtained better visual acuity and showed more responses and interactions with her parents. Diagnosis and treatment of this case prompt that these TELO2 variants have not been reported, deepening the understanding of the molecular and genetic mechanism of YHFS in clinical practice.

Prevalent characteristics of human papillomavirus infection in 29,508 women in Jinshan District, Shanghai.

OBJECTIVE: This study aimed to investigate the prevalence characteristics of human papillomavirus (HPV) infections in 29,508 female cases in Jinshan District, Shanghai. MATERIALS AND METHODS: The current research represents a retrospective study that included 29,508 women who received cervical screening in the Jinshan Branch of Shanghai Sixth People's Hospital from 2010 to 2020. The overall prevalence, distribution types, age-specific prevalence and annual trends were analysed. RESULTS: The overall HPV infection rate among the patients was 21.97%. They were primarily high-risk HPV (HR-HPV) infections (20.30%) and single HPV infections (15.91%). A general decline in HPV and HR-HPV prevalence was observed with time from 33.52% to 25.45% in 2011 to 21.47% and 20.18% in 2020. The most common HPV genotypes were HPV52, HPV16, HPV58, HPV51, HPV53 and HPV68. The infection rates of HPV genotypes, including HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV42, HPV43, HPV66 and HPV68, showed overall declines across different years. The age-specific prevalence of total HPV and HR-HPV infections formed an approximate U-shaped curve with two peaks, one in the ≥55 age group (29.75%, 28.43%) and the other in the <25 age group (22.93%, 20.85%). Both total HPV and HR-HPV infection rates decreased to their lowest in the 25-34-year age groups. CONCLUSIONS: The prevalence of HPV infections showed a downward tendency with time. Single HPV genotype infections and HR-HPV infections were predominantly detected. The after prevalent characteristics of HPV can help to guide HPV vaccinations and cervical cancer screenings: 1) non-HPV16/HPV18 H R-HPV genotypes were prevalent; 2) non-vaccine-covered HPV53, HPV51 and HPV68 were also prevalent; 3) women above the age of 55 years had the highest HPV and HR-HPV infection rates.

A newly designed ignition method for miniature radio frequency ion thruster.

The ignition methods used by micro-radio frequency (RF) ion thrusters have a disadvantage, that is, the starting voltage and flow rate are obviously higher than the rated value, which will easily damage the grid after long-term use. To decrease the starting voltage and flow and reduce the damage to the grid, a new ignition system is proposed in this paper. This system uses an intake pipe as the ground electrode, has an inductance coil and a pre-ionization chamber, and enables the miniature RF ion thruster (Harbin Institute of Technology's RF Ion Thruster 4, HRIT-4) to ignite at the rated voltage and flow by means of strong electric field breakdown and electromagnetic coupling. The experimental results show that when the flow rate is 1.0 SCCM, the ignition voltage is lower than 1900 V, and when the flow rate is 1.5 SCCM, the ignition voltage is lower than 1400 V.

Comparison of ACR TI-RADS, Kwak TI-RADS, ATA guidelines and KTA/KSThR guidelines in combination with SWE in the diagnosis of thyroid nodules.

OBJECTIVE: To compare the diagnostic efficacy of ACR TI-RADS, Kwak TI-RADS, ATA guidelines and KTA/KSThR guidelines in combination with shear wave elastography (SWE) for thyroid nodules. METHODS: The retrospective study included 566 thyroid nodules with maximum diameter≥5 mm which confirmed by FNA cytology or/and surgical pathology. The sensitivity, specificity, accuracy, Youden index of diagnosis of thyroid nodules by ACR TI-RADS, Kwak TI-RADS, ATA guidelines, KTA/KSThR guidelines and SWE were calculated. The ROC curve was drawn to determine the cut-off values of the four ultrasound classification systems and SWE Emax. The diagnostic efficacy of the four ultrasound classification systems in combination with SWE were calculated and compared with those of pre-combination. RESULTS: The ROC curves indicated that the cut-off value of ACR TI-RADS, Kwak TI-RADS, ATA guidelines, KTA/KSThR guidelines and Emax of SWE was TR5, 4c, high-suspicion, high-suspicion, and 41.7 kPa, respectively, and the area under the ROC curve (AUC) was 0.907(0.879-0.934), 0904(0.876-0.932), 0.894(0.863-0.924), 0.888(0.856-0.919), 0.886(0.859-0.913), respectively. After combination with SWE, the the sensitivities of the four ultrasound classification systems for the diagnosis of nodules were improved, and the differences were statistically significant (all P≤0.001); the specificities were decreased, but the differences were not statistically significant (all P > 0.05); the accuracies were improved, but only the difference of ACR TI-RADS was statistically significant (x2 = 4.45, P = 0.035); the differences in the AUCs were not significant (all P > 0.05). CONCLUSIONS: The four ultrasound classification systems and SWE all had high performance in the diagnosis of thyroid nodules. The four classification systems in combination with SWE were all beneficial to the differential diagnosis of nodules, and ACR TI-RADS in combination with SWE was more effective, especially for TR3 and TR4 nodules.

Hsa_circ_0000515 is a novel circular RNA implicated in the development of breast cancer through its regulation of the microRNA-296-5p/CXCL10 axis.

Cancer metastasis is a major cause of death among women afflicted with breast cancer (BC) and understanding the molecular processes involved is a major focus in BC research. Circular RNAs (circRNAs) have emerged as genomic regulatory molecules in carcinogenesis and metastasis; however, their role in BC is unclear. We characterized a novel circRNA, hsa_circ_0000515, in context of BC. We collected 340 cancerous tissues surgically resected from BC patients and found hsa_circ_0000515 was upregulated in BC tissues and associated with poor prognosis of BC. Silencing of hsa_circ_0000515 impaired cell cycle progression, cell proliferation, and invasion, attenuated inflammatory response, and reduced the proangiogenetic potential of BC cells. RNA pull-down and dual-luciferase reporter gene assays showed that hsa_circ_0000515 binds miR-296-5p, preventing it from repressing CXCL10 expression. We also observed that miR-296-5p inhibition or CXCL10 overexpression promoted cell cycle progression, restored proliferative, invasive and proangiogenetic abilities, and increased inflammatory response in MCF-7 cells in the absence of hsa_circ_0000515. In vivo analyses showed that partial loss of hsa_circ_0000515 reduced the tumor growth of MCF-7 cells in nude mice. The key findings from this study revealed that targeting hsa_circ_0000515 might be an effective strategy to combat BC.

Development and validation of a smoking rationalization scale for male smokers in China.

The purpose of this study is to develop a smoking rationalization scale for Chinese male smokers. A total of 35 focus groups and 19 one-on-one interviews were conducted to collect items of the scale. Exploratory factor analyses and confirmatory factor analyses were conducted to identify the underlying structure of the scale. Results found a 26-item scale within six dimensions (smoking functional beliefs, risk generalization beliefs, social acceptability beliefs, safe smoking beliefs, self-exempting beliefs, and quitting is harmful beliefs). The scale showed acceptable validity and reliability. Results highlight that smoking rationalization is common among Chinese male smokers, and some beliefs of smoking rationalization seem to be peculiar to China.

Why are male Chinese smokers unwilling to quit? A multicentre cross-sectional study on smoking rationalisation and intention to quit.

OBJECTIVE: We aimed to describe the rationalisation beliefs endorsed by Chinese male smokers and to examine the association between rationalisation and the intention to quit. SETTING: Questionnaires were conducted among male smokers in three cities (Shanghai, Nanning and Mudanjiang) which represent different geographical locations, economic development levels and legislative status of tobacco control in China. DESIGN AND PARTICIPANTS: It was a multicentre cross-sectional survey involved a total of 3710 male smokers over 18 years. OUTCOME MEASURES: Primary outcomes were intention to quit, smoking rationalisation scores and sub scores in six dimensions. Smoking rationalisation was assessed using a newly developed Chinese rationalisation scale. Multivariable logistic regression was performed to examine the relationship between rationalisation and intention to quit. RESULTS: On average, smokers scored 3.3 out of 5 on the smoking rationalisation scale. With a one point increase in total rationalisation scale, the odds for intention to quit in the next 6 months decreased by 48% (OR=0.52, 95% CI: 0.44 to 0.61; p<0.001). Separate logistic regressions for six subscales of rationalisation shown consistent inverse associations with intention to quit (all p values <0.001). Believing that smoking was socially acceptable was the strongest predictor (OR=0.62, 95% CI: 0.55 to 0.71; p<0.001). CONCLUSIONS: Rationalisation beliefs could be important barriers to smoking cessation. Some beliefs have stronger association with quit intention than others. Eroding rationalisation beliefs endorsed by smokers is a potential strategy for smoking cessation intervention.

Associations of tumor suppressor SPARCL1 with cancer progression and prognosis.

SPARC-like protein 1 (SPARCL1), a member of the family of secreted proteins which is acidic and rich in cysteine, is a potential tumor suppressor gene in most types of tumor. A systemic review and bioinformatics analysis was carried out to determine the associations between SPARCL1 and tumor progression and clinical factors. Downregulation of SPARCL1, thought to be regulated by epigenetic modifications including DNA methylation, serves important functions in tumor progression and development, with its regulatory functions on cell viability, migration, invasion, cell adhesion and drug resistance. Downregulation of SPARCL1 was markedly associated with a poor overall survival rate of patients with one of ≥7 solid tumors and predicted increased mortality in patients with one of ≥4 distinct tumor types. The present review indicated that SPARCL1 may be a therapeutic target for cancer treatment and a biomarker to determine prognosis.

Educational disparities in the intention to quit smoking among male smokers in China: a cross-sectional survey on the explanations provided by the theory of planned behaviour.

OBJECTIVES: We aim to describe the intention to quit smoking among Chinese male smokers from different educational backgrounds and to explain this intention from their attitude, perceived social norms and self-efficacy regarding smoking cessation. SETTING: Participants were recruited from workplaces and communities to reflect the occupational distribution in three cities (Shanghai, Nanning and Mudanjiang) in China. DESIGN AND PARTICIPANTS: In 2013 interviews were conducted with 3676 male smokers aged 18 years and older. OUTCOME MEASURES: Multivariate logistic regression analyses calculated educational differences in the intention to quit smoking as well as the association between the intention to quit smoking and attitude, subjective norms, and self-efficacy. Bootstrapping estimated to what extent the educational disparities in the intention to quit smoking were mediated by these three determinants. RESULTS: No educational disparities in the intention to quit smoking within 1 or 6 months were observed among male Chinese smokers (p=0.623 and p=0.153, respectively). A less negative attitude, a higher perceived subjective norm towards smoking cessation, and a higher perceived self-efficacy to quit smoking were all associated with intention to quit (all p values <0.001). Perceived subjective norms were the only component of the theory of planned behaviour that statistically significantly mediated the differences in the intention to quit smoking (within 1 or 6 months) between the lowest educated Chinese men and the groups with lower (ß=0.039, 95% CI 0.017 to 0.071 and ß=0.043, 95% CI 0.019 to 0.073), higher (ß=0.041, 95% CI 0.017 to 0.075 and ß=0.045, 95% CI 0.019 to 0.077) and the highest education (ß=0.045, 95% CI 0.019 to 0.080 and ß=0.050, 95% CI 0.023 to 0.083). CONCLUSIONS: In order to prevent future socioeconomic disparities in smoking cessation, investment in a more stimulating social environment and norms towards smoking cessation among particularly the lowest educated Chinese men is warranted.

Smoke-free homes and home exposure to secondhand smoke in Shanghai, China.

Few studies have examined home exposure to secondhand smoke (SHS) in China. This study aimed to document: (1) the prevalence and correlates of exposure to SHS in homes (in adult non-smokers) in Shanghai, and (2) enforcement of rules, harm reduction behaviors, and self-efficacy for maintaining smoke-free homes in Shanghai. A total of 500 participants were recruited using a multistage proportional random sampling design in an urban and suburban district to complete a survey. Among the total 355 nonsmokers, 127 (35.8%) participants reported being exposed to SHS in the past 7 days. Participants living with smokers in the home, with no smoking restriction at home, and having children younger than 18 were more likely to be exposed to SHS at home. Higher self-efficacy in maintaining a smoke-free home was negatively associated with home SHS exposure. Having visitors who smoke was the greatest policy enforcement challenge. Ineffective measures such as opening windows were more commonly used in homes with partial bans. Educational initiatives to protect against SHS exposure in the home should promote smoke-free homes, address challenges to implementing such policies, and address misconceptions regarding the effectiveness of supposed harm reduction behaviors.

Correlates of smoke-free home policies in Shanghai, China.

BACKGROUND: Approximately 63.7% of nonsmokers in China are exposed to secondhand smoke (SHS) in their homes. The current study documents the prevalence and correlates of smoke-free home policies in Shanghai, as well as reasons for implementing such a policy and places where smoking is most commonly allowed. METHODS: We conducted in-person surveys of 500 participants using a multistage proportional random sampling design in an urban and suburban district. RESULTS: Overall, 35.3% had a smoke-free home policy. In the logistic regression, having higher income, not having smokers in the home, having children in the home, having fewer friends/relatives who permit smoking at home, and not being a current smoker were correlates of having a smoke-free home policy (P < 0.05). Concern about the health impact of SHS was reportedly the most important reason for establishing a smoke-free home. Among participants with no or partial bans, the most common places where smoking was allowed included the living room (64.2%), kitchen (46.1%), and bathroom (33.8%). CONCLUSIONS: Smoke-free home policies were in place for a minority of households surveyed. Establishing such a policy was influenced by personal smoking behavior and social factors. These findings suggest an urgent need to promote smoke-free home policies through tobacco control programs.