Is polyethylene glycol loxenatide 100 µg the preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus? A meta-analysis and trial sequential analysis.

OBJECTIVE: This study aimed to systematically evaluate the efficacy, safety and optimal dose of polyethylene glycol loxenatide (PEX168) for treating type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Clinical trials of PEX168 for T2DM were identified in 8 databases, with a build time limit of January 2023. Included studies were subjected to meta-analysis and trial sequential analysis (TSA). RESULTS: On the efficacy endpoint, the meta-analysis showed that PEX168 100 µg significantly reduced 0.86% glycated hemoglobin type A1c (HbA1c) (MD -0.86, 95% CI -1.02 - -0.70,  p<0.00001), 1.11 mmol/L fasting plasma glucose (FPG) (MD -1.11, 95% CI -1.49 - -0.74, p<0.00001) and 1.91 mmol/L 2h postprandial glucose (PPG) (MD -1.91, 95% CI -3.35 - -0.46, p=0.01) compared with placebo. The TSA showed that all these benefits were conclusive. On safety endpoints, total adverse events (AEs), gastrointestinal (GI) AEs, serious AEs, and hypoglycemia were comparable to placebo for PEX168 100 µg (p>0.05). In the dose comparison, the HbA1c, FPG, and 2h PPG of PEX168 200 µg were comparable to 100 µg (p>0.05), while GI AEs were significantly higher than 100 µg (RR=2.84, 95% CI 1.64-4.93,  p=0.0002). CONCLUSIONS: PEX168 100 µg can significantly lower blood glucose and does not increase the risk of total AEs, GI AEs, and hypoglycemia, which may be a preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus.

[Activation of α7 nAChR improves white fat homeostasis and promotes beige adipogenesis and thermogenesis in obese mice].

OBJECTIVE: To investigate the effects of α7 nicotinic acetylcholine receptor (nAChR) agonist on ß3-adrenoceptor agonist-induced impairment of white fat homeostasis and beige adipose formation and heat production in obese mice. METHODS: Forty obese C57BL/6J mice were randomized into high-fat feeding group, ß3-adrenoceptor agonist-treated model group, α7 nAChR agonist group, and α7 nAChR inhibitor group (n=10), with another 10 mice with normal feeding as the blank control group. White adipose tissue from the epididymis of the mice were sampled for HE staining of the adipocytes. The expression levels of TNF-α, IL-1ß, IL-10 and TGF-ß in the white adipose tissue were determined by ELISA, and the mRNA levels of iNOS, Arg1, UCP-1, PRDM-16 and PGC-1α were detected using RT-qPCR. Western blotting was performed to detect the expression levels of NF-κB P65, p-JAK2, p-STAT3 in the white adipose tissue. RESULTS: Compared with those in the blank control group, the mice with high-fat feeding showed significantly increased body weight, more fat vacuoles in the white adipose tissue, increased volume of lipid droplets in the adipocytes, upregulated iNOS mRNA expression and protein expression of TNF-α and IL-1ß, and lowered expression of Arg-1 mRNA and IL-10 and TGF-ß proteins (P < 0.01). Treatment with α7 nAChR significantly reduced mRNA levels of PRDM-16, PGC-1α and UCP-1, lowered TNF-α and IL-1ß expressions, increased IL-10 and TGF-ß expressions, and reduced M1/M2 macrophage ratio in the white adipose tissues (P < 0.05 or 0.01). CONCLUSION: Activation of α7 nAchR improves white adipose tissue homeostasis impairment induced by ß3 agonist, promotes transformation of M1 to M2 macrophages, reduces inflammatory response in white adipose tissue, and promote beige adipogenesis and thermogenesis in obese mice.

[Thinking on ideological and political education in Medical Parasitology teaching].

With the deepening reform of ideological and political education, Medical Parasitology teaching needs to update the teaching concept, change the teaching ideas, as well as keep trying to combine ideological and political education with the curriculum content closely. In addition to teaching students' basic knowledge and practical skills, teachers are needed to cultivate their moral literacy and political awareness through course teaching, so as to provide the basis for students' subsequent adaptations to social environments and jobs. Currently, the study of ideological and political education in Medical Parasitology teaching is still in the exploratory stage. Therefore, colleges and universities need to carry out effective construction of ideological and political education in Medical Parasitology teaching, in order to achieve good teaching outcomes and provide insights into ideological and political education in teaching.

Wildfire particulate exposure and risks of preterm birth and low birth weight in the Southwestern United States.

OBJECTIVES: Wildfire air pollution is a growing concern on human health. The study aims to assess the associations between wildfire air pollution and pregnancy outcomes in the Southwestern United States. STUDY DESIGN: This was a retrospective cohort study. METHODS: Birth records of 627,404 singleton deliveries in 2018 were obtained in eight states of the Southwestern United States and were linked to wildfire-sourced fine particulate matter (PM2.5) and their constituents (black carbon [BC] and organic carbon [OC]) during the entire gestational period. A double-robust logistic regression model was used to assess the associations of wildfire-sourced PM2.5 exposures and preterm birth and term low birth weight, adjusting for non-fire-sourced PM2.5 exposure and individual- and area-level confounder variables. RESULTS: Wildfire-sourced PM2.5 contributed on average 15% of the ambient total PM2.5 concentrations. For preterm birth, the strongest association was observed in the second trimester (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 1.05-1.07 for PM2.5; 1.06, 95% CI: 1.05-1.07 for BC; 1.04, 95% CI: 1.03-1.05 for OC, per interquartile range increment of exposure), with higher risks identified among non-smokers or those with low socio-economic status. For term low birth weight, the associations with wildfire-sourced PM2.5 exposures were consistently elevated for all trimesters except for the exposure averaged over the entire gestational period. Overall, the associations between wildfire-sourced PM2.5 and pregnancy outcomes were stronger than those with total PM2.5. CONCLUSIONS: Wildfire-sourced PM2.5 and its constituents are linked to higher risks of preterm birth and term low birth weight among a significant US population than the effects of ambient total PM2.5.

Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson's disease.

Disrupted sleep has a profound adverse impact on lives of Parkinson's disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD - the MCI-Park mouse - was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities resemble those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.

First report of the within-farm prevalence of bovine digital dermatitis in Chinese Holstein dairy cows in Jiangsu, China: A Bayesian modelling approach.

Digital dermatitis is one of the most important causes of lameness in dairy cattle, particularly in housed, intensively-managed cattle. The number of modern intensive dairy farms in China has increased markedly in recent years; however, we lack research on digital dermatitis in Chinese dairy cattle. This preliminary study aimed to estimate the prevalence of digital dermatitis on three conveniently selected farms in Jiangsu, China. The washed hind feet of all lactating cows on all three farms were examined during milking with the aid of a mobile phone light source. True prevalence was then estimated from the apparent prevalence using a Bayesian superpopulation approach to account for the imperfect nature of identifying digital dermatitis in cows during milking. Despite none of the farms having thought it necessary to implement routine digital dermatitis monitoring or control, the disease was found on all three sampled farms. All lesions observed were either chronic M4 or M4.1 type-lesions, with no M2 lesions (i.e. acute ulcerated lesions) observed. The estimated true prevalences on the farms were 7.3% (95% credible interval [CrI]: 5.4%-9.6%), 8.3% (95%CrI: 6.3%-10.8%), and 29.8% (95%CrI: 22.9%-37.2%).

[Application of "modified double pocket suture" pancreatoenterostomy in laparoscopic pancreatoduodenectomy].

Objective: The purpose of this study was to explore the value of the "improved double purse-string suture method" for pancreatojejunostomy in laparoscopic pancreaticoduodene-ctomy. Methods: The clinical data of 273 patients who underwent laparoscopic pancreaticoduode-nectomy in the Department of Hepatobiliary and Pancreatic Surgery of the First Hospital of Jilin University from January 2021 to May 2022 were retrospectively analyzed. According to the method of pancreaticoenteric anastomosis, the patients were divided into two groups: the "improved double purse-string suture method" group and the "Hong's one-stitch method" group. Results: The "improved double purse-string suture method" for pancreaticoenteric anastomosis was performed in a total of 189 patients, including 107 males and 82 females, with a mean age of (59.6±10.2) years. The "Hong's one-stitch method" group" was performed in a group of 84 patients, including 52 males and 32 females, with a mean age of (60.8±9.3) years.The results showed that the "improved double purse-string suture method" group had a lower incidence of postoperative pancreatic fistula (6.88% vs 8.33% for grade B fistula, and 1.58% vs 2.38% for grade C fistula) and a shorter anastomosis time [(25.25±4.73) min vs (25.76±6.71) min] than the "Hong's one-stitch method" group. There was no statistically significant difference between the two groups in terms of postoperative biliary fistula, abdominal bleeding, delayed gastric emptying, and other complications (P>0.05). Conclusion: The "improved double purse-string suture method" for pancreatojejunostomy is safe and feasible in laparoscopic pancreaticoduodenectomy.

[Changes of uterine morphology and endometrial T2 signal intensity in the fibrotic repair secondary to endometrial injury].

Objective: To investigate the value of uterine morphological parameters and endometrial T2 signal intensity (T2-SI) in evaluating the degree of the fibrotic repair secondary to endometrial injury. Methods: From Sep. 2018 to Feb. 2023, this study prospectively enrolled 29 patients with fibrotic repair secondary to severe endometrial injury (severe group), 17 patients with fibrotic repair secondary to mild to moderate endometrial injury (mild to moderate group), and 40 healthy women of reproductive age (control group) in Nanjing Drum Tower Hospital. The length of uterine cavity (LUC), length of cervix and isthmus (LCI), width of upper uterine cavity (WUUC) and width of lower uterine cavity (WLUC) were measured using magnetic resonance imaging. T2-SI of endometrium and subcutaneous fat of buttocks were measured, and endometrial normalized T2-SI (nT2-SI; T2-SI of endometrium/T2-SI of subcutaneous fat of buttocks) was calculated. Statistical analyses of data were performed using one-way analysis of variance, Mann-Whitney U test, intraclass correlation coefficient, Spearman rho test, area under the receiver operating characteristic curve (AUC). Results: LUC, WUUC, WLUC and endometrial nT2-SI of severe group [(19.7±3.5) mm, (26.9±6.4) mm, (7.9±1.4) mm, 0.73±0.11, respectively] were significantly lower than those of the control group (all P<0.01), while LCI and WUUC/LUC [(51.3±7.3) mm and 1.38±0.34] were significantly higher than those of the control group (all P<0.001). LUC and WLUC of severe group were significantly lower than those of mild to moderate group [(32.4±5.1) mm and (8.8±1.2) mm; all P<0.05], while LCI and WUUC/LUC were significantly higher than those of mild to moderate group [(41.8±8.6) mm and 0.94±0.16; all P<0.001]. LUC and endometrial nT2-SI of mild to moderate group were significantly lower than those of the control group [ (32.4±5.1) vs (35.3±3.5) mm, 0.68±0.13 vs 0.80±0.12; all P<0.01]. LUC, WUUC, WLUC and endometrial nT2-SI were significantly negatively correlated to the degree of the fibrotic repair secondary to endometrial injury (Spearman rho:-0.794, -0.441, -0.471 and -0.316, respectively; all P<0.05), while LCI and WUUC/LUC were significantly positively correlated to the degree of the fibrotic repair secondary to endometrial injury (Spearman rho: 0.481 and 0.674, respectively; all P<0.05). LUC and WUUC/LUC showed high value in distinguishing severe group from the control group or mild to moderate group (all AUC>0.9, all P<0.001). Conclusion: As noninvasive and quantitative biomarkers, uterine morphological parameters and endometrial nT2-SI could evaluate the degree of the fibrotic repair secondary to endometrial injury.

Derivation and validation of a novel preoperative risk prediction model for surgical site infection in pancreaticoduodenectomy and comparison of preoperative antibiotics with different risk stratifications in retrospective cohort.

BACKGROUND: Surgical site infections (SSIs) are common postoperative complications of pancreaticoduodenectomy. AIM: To develop a model for preoperative identification of the risk of SSI that may improve outcomes and guide preoperative antibiotics. METHODS: The prediction model was built by meta-analysis. After literature search and inclusion, data extraction, and quantitative synthesis, the prediction model was established based on the pooled odds ratio of predictors. A single-centre retrospective cohort was the validation cohort. Receiver operating characteristic curves and area under the curve were used to assess the model's ability. We also created a decision curve and a calibration plot to assess the nomogram. The effects of prophylactic antibiotics on SSI were compared between groups by multivariable logistic regression with different risk stratifications. FINDINGS: Twenty-eight studies were included in the meta-analysis, 17 studies in the derivation cohort. Age, male gender, body mass index, pancreatic duct diameter, high-risk diagnosis, and preoperative biliary drainage were selected to build the prediction model. The model was validated in an external cohort. The cut-off value was 3.5 and area under the curve (AUC) was 0.76 in open pancreaticoduodenectomy (OPD). In laparoscopic pancreaticoduodenectomy, the cut-off value was 4.5 and AUC was 0.69. Decision curve and calibration plot showed good usability of the model, especially in OPD. Multivariable logistic regression did not indicate differences between broad- and narrow-spectrum antibiotics for SSI in different risk stratifications. CONCLUSION: The model can identify patients with a high risk of SSI preoperatively. The choice of prophylactic antibiotics under different risk stratifications should be investigated further.

PRRX1+MSCs Enhance Mandibular Regeneration during Distraction Osteogenesis.

Bone defect (BD) caused by trauma, infection, congenital defects, or neoplasia is a major cause of physical limitation. Distraction osteogenesis (DO) is a highly effective procedure for bone regeneration, while the concrete mechanism remains unknown. In this study, canine DO and BD models of the mandible were established. The results of micro-computed tomography and histological staining revealed that DO led to an increased mineralized volume fraction and robust new bone formation; in contrast, BD demonstrated incomplete bone union. Mesenchymal stem cells (MSCs) from DO and BD calluses were isolated and identified. Compared with BD-MSCs, DO-MSCs were found to have a stronger osteogenic capability. Single-cell RNA sequencing analysis was further performed to comprehensively define cell differences between mandibular DO and BD calluses. Twenty-six clusters of cells representing 6 major cell populations were identified, including paired related homeobox 1-expressing MSCs (PRRX1+MSCs), endothelial cells (ECs), T cells, B cells, neutrophils, and macrophages. Interestingly, 2 subpopulations in PRRX1+MSCs in the DO group were found to express the marker of neural crest cells (NCCs) and were associated with the process of epithelial-mesenchymal transition. The immunofluorescence assay was performed to further corroborate these results in vivo and in vitro, experimentally validating that continuous distraction maintained the PRRX1+MSCs in an embryonic-like state. Finally, we used CRISPR/Cas9 to knock out (KO) PRRX1 in the context of DO, which significantly blunted the capability of jawbone regeneration, resulting in a diminished NCC-like program and reduction of new bone volume. In addition, the ability of osteogenesis, cell migration, and proliferation in cultured PRRX1KO MSCs was inhibited. Taken together, this study provides a novel, comprehensive atlas of the cell fates in the context of DO regeneration, and PRRX1+MSCs act essential roles.

A binary pulsar in a 53-minute orbit.

Spider pulsars are neutron stars that have a companion star in a close orbit. The companion star sheds material to the neutron star, spinning it up to millisecond rotation periods, while the orbit shortens to hours. The companion is eventually ablated and destroyed by the pulsar wind and radiation1,2. Spider pulsars are key for studying the evolutionary link between accreting X-ray pulsars and isolated millisecond pulsars, pulsar irradiation effects and the birth of massive neutron stars3-6. Black widow pulsars in extremely compact orbits (as short as 62 minutes7) have companions with masses much smaller than 0.1 M⊙. They may have evolved from redback pulsars with companion masses of about 0.1-0.4 M⊙ and orbital periods of less than 1 day8. If this is true, then there should be a population of millisecond pulsars with moderate-mass companions and very short orbital periods9, but, hitherto, no such system was known. Here we report radio observations of the binary millisecond pulsar PSR J1953+1844 (M71E) that show it to have an orbital period of 53.3 minutes and a companion with a mass of around 0.07 M⊙. It is a faint X-ray source and located 2.5 arcminutes from the centre of the globular cluster M71.

A Passive Noise Attenuation Earplug Designed to Minimise Unwanted Air Turbine Driven High-Speed Dental Drill Noise.

INTRODUCTION: Air turbine dental drill noise contains high-frequency components that are of concern for patients and dental staff. Meanwhile, verbal communication between the dentist and patient is essential. Conventional active noise-cancelling headphones are ineffective for dental drill noise and simply suppress all sound and hinder communication. METHOD: A compact passive earplug device was designed specifically to attenuate broadband high-frequency noise ranges from 5 to 8 kHz employing an array of quarter wavelength (QW) resonators. This device was 3D printed and tested against white noise to enhance the objectivity of analysis, using a calibrated ear and cheek simulator to effectively measure its performance. RESULTS: The results showed that the resonators produced an average reduction of 27 dB across the targeted frequency range. When compared with two proprietary passive earplugs, this developed passive device prototype was able to attenuate an average of 9 dB more across the target frequency range whilst delivering louder speech signals of 14 dB more. The results also show that using an array of resonators exhibits an accumulated effect of individual resonator performance. CONCLUSIONS: This low-cost passive device could have a place in the dental clinic to reduce unwanted drill noise equivalent to the white noise high frequency spectra tested.

[Influencing factors of poor treatment adherence in uncontrolled asthma patients in China].

Objective: To evaluate the influencing factors of poor treatment adherence in patients with uncontrolled asthma in China. Methods: From April 2017 to April 2018, all asthma patients with uncontrolled asthma and poor compliance in 32 third-class hospitals in 28 provinces and cities of China mainland included in the "National Mobile Asthma Assessment and Management Project" were selected as the subjects. A total of 923 patients were enrolled in the study including 388 males and 535 females. By analyzing the baseline data of the patients at the initial visit when enrolled, the influencing factors of poor adherence of adult asthma was analyzed by inter-group comparison and χ2 test. Results: Poor compliance in asthma was related to the following factors: age from 59 to 68 years old, course of disease more than 20 years, low education level, non-local follow-up, having obstructive ventilation dysfunction and low awareness of the disease[P values were 0.026(t=1.20), 0.004(t=3.97), 0.001(t=4.92), 0.003(t=3.98), 0.032(t=1.22) and 0.001(t=4.99), respectively]. Totally, 243 patients (26.33%) answered all the questions about asthma correctly. Their medication adherence rating scale (MARS-A) scores were significantly higher than those who answered incompletely correctly (36.23±5.85 vs. 31.77±5.74, P=0.001). Conclusions: The adherence of adult asthma patients was affected by individual and external environment factors. Clinicians should choose individualized methods based on the characteristics of patients. Patient education should be strengthened to improve patients' awareness of the disease at the same time.

[DNAM-1 regulates the proliferation and function of T regulatory type 1 cells via the IL-2/STAT5 pathway].

OBJECTIVE: To explore the role of DNAM-1 in the activation, proliferation and function of type Ⅰ regulatory T cells (Tr1 cells). METHODS: Anti-CD3/CD28 antibodies were used to stimulate mouse T cells derived from the spleen of wild-type (WT) mice, and the expression level of DNAM-1 in resting and activated Tr1 cells was evaluated with flow cytometry. Na?ve CD4+ T cells isolated by magnetic cell sorting from the spleens of WT mice and DNAM-1 knockout (KO) mice were cultured in Tr1 polarizing conditions for 3 days, after which CD25 and CD69 expressions were measured using flow cytometry. The induced Tr1 cells were labelled with CFSE and cultured in the presence of anti-CD/CD28 antibodies for 3 days, and their proliferative activity was analyzed. The expressions of IL-10 and p-STAT5 in DNAM-1-deficient Tr1 cells were detected before and after IL-2 stimulation. RESULTS: The expression level of DNAM-1 was significantly upregulated in CD4+ T cells and Tr1 cells after stimulation with anti-CD3/CD28 antibodies (P < 0.05). DNAM-1 knockout did not cause significant changes in the number or proportion of Tr1 cells, but but significantly increased the expression levels of the activation markers CD69 and CD25 (P < 0.05). Compared with WT Tr1 cells, DNAM-1-deficient Tr1 cells exhibited reduced proliferative activity in vitro (P < 0.05) with downregulated IL-10 production (P < 0.05) and decreased expressions of Il-10 and Gzmb mRNA (P < 0.05). In DNAM-1-deficient Tr1 cells, IL-2 stimulation significantly reduced IL-10 secretion level and the expression of p-STAT5 as compared with WT Tr1 cells. CONCLUSION: DNAM-1 participate in the activation and proliferation of Tr1 cells and affect the biological functions of Tr1 cells through the IL-2/STAT5 pathway.

A fast radio burst source at a complex magnetized site in a barred galaxy.

Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin of cosmological FRBs is still not settled. Here we report the detection of 1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref. 9). These observations show irregular short-time variation of the Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (AU; Earth-Sun distance) of the source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.

[Research progress on physiological changes caused by wearing N95 mask in patients with chronic obstruction pulmonary disease].

N95 mask has been shown to reduce lower airway infections requiring hospitalization, mortality and exacerbation frequency in patients with chronic obstructive pulmonary disease(COPD), and therefore is recommended for all COPD patients by guidelines. However, the coverage of influenza vaccination in Chinese COPD patients is far from satisfactory. The large-scale COVID-19 vaccination may have a positive impact on the attitude towards influenza vaccines, and healthcare professionals should take active measures to improve the physical activation in patients with COPD.

Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma.

BACKGROUND: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. PATIENTS AND METHODS: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. RESULTS: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. CONCLUSION: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer.

BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Molecular cloning and characterization of a novel aspartyl aminopeptidase from Trichinella spiralis.

Trichinellosis is an important zoonotic parasitic disease worldwide and is principally caused by ingesting animal meat containing Trichinella infective larvae. Aspartyl aminopeptidase is an intracytoplasmic metalloproteinase that specifically hydrolyzes the N-terminus of polypeptides free of acidic amino acids (aspartic acid and glutamate), and plays an important role in the metabolism, growth and development of organisms. In this study, a novel T. spiralis aspartyl aminopeptidase (TsAAP) was cloned and expressed, and its biological properties and roles in worm growth and development were investigated. The results revealed that TsAAP transcription and expression in diverse T. spiralis stages were detected by RT-PCR and Western blotting, and primarily localized at cuticle, stichosome and intrauterine embryos of this nematode by immunofluorescence test. rTsAAP has the enzymatic activity of native AAP to hydrolyze the substrate H-Glu-pNA. There was a specific binding between rTsAAP and murine erythrocyte, and the binding site was localized in erythrocyte membrane proteins. Silencing of TsAAP gene by specific dsRNA significantly reduced the TsAAP expression, enzymatic activity, intestinal worm burdens and female fecundity. The results demonstrated that TsAAP participates in the growth, development and fecundity of T. spiralis and it might be a potential target molecule for anti-Trichinella vaccines.