Hypomethylation-enhanced CRTC2 expression drives malignant phenotypes and primary resistance to immunotherapy in hepatocellular carcinoma.

The cyclic AMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a crucial regulator of hepatic lipid metabolism and gluconeogenesis and correlates with tumorigenesis. However, the mechanism through which CRTC2 regulates hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that increased CRTC2 expression predicted advanced tumor grade and stage, as well as worse prognosis in patients with HCC. DNA promoter hypomethylation led to higher CRTC2 expression in HCC. Functionally, CRTC2 contributed to HCC malignant phenotypes through the activated Wnt/ß-catenin pathway, which could be abrogated by the small-molecular inhibitor XAV-939. Moreover, Crtc2 facilitated tumor growth while concurrently downregulating the PD-L1/PD-1 axis, resulting in primary resistance to immunotherapy. In immunocompetent mice models of HCC, targeting Crtc2 in combination with anti-PD-1 therapy prominently suppressed tumor growth by synergistically enhancing responsiveness to immunotherapy. Collectively, targeting CRTC2 might be a promising therapeutic strategy to sensitize immunotherapy in HCC.

Computational modeling and minimization of unintended neuronal excitation in a LIFU stimulation.

The neuromodulation effect of low-intensity focused ultrasound (LIFU) is highly target-specific. Unintended off-target neuronal excitation can be elicited when the beam focusing accuracy and resolution are limited, whereas the resulted side effect has not been evaluated quantitatively. There is also a lack of methods addressing the minimization of such side effects. Therefore, this work introduces a computational model of unintended neuronal excitation during LIFU neuromodulation, which evaluates the off-target activation area (OTAA) by integrating an ultrasound field model with the neuronal spiking model. In addition, a phased array beam focusing scheme called constrained optimal resolution beamforming (CORB) is proposed to minimize the off-target neuronal excitation area while ensuring effective stimulation in the target brain region. A lower bound of the OTAA is analytically approximated in a simplified homogeneous medium, which could guide the selection of transducer parameters such as aperture size and operating frequency. Simulations in a human head model using three transducer setups show that CORB markedly reduces the OTAA compared with two benchmark beam focusing methods. The high neuromodulation resolution demonstrates the capability of LIFU to effectively limit the side effects during neuromodulation, allowing future clinical applications such as treatment of neuropsychiatric disorders.

Nitric oxide detection using principal component analysis spectral structure matching to the UV derivative spectrum.

Ultraviolet (UV) spectroscopy is widely applied in real-time environmental monitoring, especially in diesel vehicle nitrogen monoxide (NO) emissions. However, in field experiments, UV absorption spectrum may exist for different degrees of drifts. Spectral jitters may exist for various reasons such as optical power variation, electrical signal drift, and the refractive index jitters of the optical path for an extended period of time, which causes the detection system to be calibrated. And the pulse xenon lamps as the UV source are characterized by specific emission lines that interfere in spectral analysis directly. For these problems, we proposed the spectral structure matching method based on principal component analysis (PCA), which was compared with the conventional polynomial fitting method to observe feasibility and variability. Further, the UV derivative spectrum was applied to the system appropriately, due to the variation of the absorption peak, and was only related to the target gas by using the above method. We validated our method experimentally by performing the NO UV detection system with the calibration and the comparison test. The results suggested that the calibration relative error was less than 9% and the measurement relative error was less than 6% for this wide range by the proposed processes, which optimized the interference of spectral structures and fluctuation to the system and therefore provided better monitoring. This study may provide an alternative spectral analysis method that is unaffected on the specific emission lines of lamps and is not limited to the spectral region and the target gas.

Mutational landscape of paired primary and synchronous metastatic lymph node in chemotherapy naive gallbladder cancer.

BACKGROUND: Comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships in gallbladder cancer (GBC) is limited. METHODS: We performed whole exome sequencing for 5 patients with primary tumor, metastatic lymph node (LNM) and corresponding normal tissue. Mutations, mutation signatures and copy number variations were analyzed with state-of-art bioinformatics methods. Phylogenetic tree was also generated to infer metastatic pattern. RESULTS: Five driver mutations were detected in these patients. Among which, TP53 was the only shared mutation between primary tumor and LNM. Although tumor mutational burden was comparable between primary tumor and LNM, higher mutation burden was observed in LNM of one patient. Copy number variations (CNVs) burden was higher in LNM than their primary tumor. Phylogenetic analysis indicated both linear and parallel progression of metastasis exist in these patients. TP53 mutation and CNVs were homogenously between primary tumor and LNM. CONCLUSIONS: High consistence of genetic landscape were shown between primary tumor and LNM in GBC. However, heterogenicity still exist between primary tumor and LNM in particular patients in term of driver mutation, TMB and CNV burden. Phylogenetic analysis indicated both Linear and parallel progression of metastasis were exist among these patients.

Hsa_circ_0001361 facilitates the progress of lung adenocarcinoma cells via targeting miR-525-5p/VMA21 axis.

BACKGROUND: Lung adenocarcinoma (LUAD) is a common subtype of lung cancer with high recurrence rate and fatality. Circ_0001361 has been recognized as key regulators in various malignancies, but its roles in LUAD remain ambiguous. METHODS: Circ_0001361, miR-525-5p, and VMA21 levels were assessed by RT-qPCR. The growth and metastasis of LUAD cells were detected by MTT, colony formation, wound scratch, and transwell assays, respectively. The interaction between circ_0001361/VMA21 and miR-525-5p was detected by dual luciferase, RNA immunoprecipitation, and RNA pull-down assays. VMA21 protein level was detected by Western blotting. Nude mouse xenograft model was established to determine the role of circ_0001361 in tumor growth in vivo. RESULTS: Circ_0001361 was up-regulated, while miR-525-5p was down-regulated in LUAD tissues and cells. Functional experiments demonstrated that circ_0001361 drove LUAD cell growth and metastasis. Mechanistically, circ_0001361 functioned as a sponge of miR-525-5p to up-regulate downstream target VMA21 level. MiR-525-5p/VMA21 axis was involved in circ_0001361-mediated malignant phenotypes of LUAD cells. Finally, inhibition of circ_0001361 restrained in vivo xenograft tumor growth via regulating miR-525-5p/VMA21 axis. CONCLUSION: Our findings elucidate that circ_0001361 facilitates the tumorigenesis and development of LUAD through miR-525-5p/VMA21 axis, providing evidence for circ_0001361 as a potential prognosis biomarker and therapeutic target for clinical treatment of LUAD.

Intraoperative identification of persistent left superior vena cava with intracavitary electrocardiogram during venous port insertion: A report of eight cases.

Persistent left superior vena cava is a rare congenital anomaly, occurring in 0.3% to 0.5% of general population and up to 10% in patients with congenital heart disease. This anomaly is usually discovered incidentally during central venous catheterization from left side. Since 2015, we have identified eight cases of persistent left superior vena cava out of a total of 2637 patients who had left sided venous port insertion in our department. The persistent left superior vena cavae were identified with the aid of intracavitary electrocardiogram. The characteristic finding was an initial negative P-wave (in lead II), followed by a biphasic P-wave pattern during catheter insertion. All the ports worked properly, with a total catheter dwelling time of 2586 days (range: 96-756 days, mean: 323.25 days), and no catheter-related complication was observed. However, because of the paucity of clinical evidence, we should still be prudent in the long-term use of venous ports in persistent left superior vena cava.

Subclinical lipohypertrophy--Easily ignored complications of insulin therapy.

AIMS: Subclinical lipohypertrophy is a lesion meeting ultrasonic criteria for lipohypertrophy that was not detected by inspection and palpation. Little information is published on subclinical lipohypertrophy among insulin injection people with diabetes. We aimed to investigate the subclinical lipohypertrophy prevalence, risk factors, and the association between subclinical lipohypertrophy and glycemic control. METHODS: This observational study included 316 people with diabetes who had continuously received insulin therapy for at least one year. We performed ultrasound scanning and clinical examination for evidence of subclinical lipohypertrophy. Demographic characteristics, clinical information, and glycated hemoglobin were measured. RESULTS: The overall prevalence of subclinical lipohypertrophy was 19.9%. By stepwise logistic regression, higher BMI (OR = 1.44, 95%CI: 1.15-1.81, P = 0.002), incorrect rotation of sites (OR = 3.11, 95%CI: 1.02-9.47, P = 0.046), insulin needle reusage for more than four times (OR = 10.00, 95%CI: 3.23-31.02, P = 0.000) and type 1 diabetes (OR = 6.33, 95%CI: 1.32-30.47, P = 0.021) remained associated with subclinical lipohypertrophy. Subclinical lipohypertrophy demonstrated a significant independent correlation with the nonoptimal glycemic control (OR = 9.97, 95% CI: 3.46-28.75, P = 0.000) when accounting for demographic and diabetes-related parameters. CONCLUSIONS: Subclinical lipohypertrophy is common among insulin-injecting patients with diabetes and is related to glycemic control deterioration. Ultrasonography may be an ideal adjunct in the evaluation of easily ignored lipohypertrophy lesions, especially where poor glycemic control, incorrect injection behaviors, overweight or obesity are documented.

Comparison of thermal ablation and routine surgery for the treatment of papillary thyroid microcarcinoma: a systematic review and Meta-analysis.

BACKGROUND: Thermal ablation (TA), as an alternative to surgery, has shown some benefits in the treatment of papillary thyroid microcarcinoma (PTMC) patients, especially for those who are at high risk for surgery or refuse surgery. We performed a systematic review and meta-analysis to evaluate the efficiency, safety, and economy of TA, compared with those of routine surgery (RS), for the treatment of PTMC. METHODS: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases were retrieved from inception to 10 January 2020 to identify relevant original studies on comparison of TA and RS for treatment of PTMC. The recurrence rate, recurrence-free survival (RFS), complication rate, operation time, postoperative length of stay, and cost during the perioperative period were extracted as main indices. The pooled standardized mean difference (SMD) or odds ratio (OR) with 95% confidence intervals (CI) were calculated and analyzed. Chi-square test and I2 statistic were applied to determine the heterogeneity among studies. The sensitivity analysis was applied to explore the origin of heterogeneity, and the publication bias was evaluated by Egger's test. RESULTS: Seven retrospective studies with a total of 867 patients met the eligibility criteria and were included in the final meta-analysis. Our study demonstrated that TA showed significant reduction in complication with a pooled OR 0.24 (95% CI 0.13 to 0.43), postoperative length of stay with a pooled SMD -3.14 (95% CI -4.77 to -1.51) and cost during the perioperative period with a pooled SMD of -1.69 (95% CI -3.18 to -0.20). It also demonstrated that both TA and RS had similar pooled proportion of recurrence of OR 0.93 (95% CI 0.38 to 2.30) and recurrence-free survive (RFS). The sensitivity analysis showed that each included study had no significant effect on the results and the results were stable and reliable. The Egger's test demonstrated publication bias was acceptable. CONCLUSIONS: TA may not be oncologically inferior to RS, and it is a relatively safe and economical alternative for the treatment of PTMC.

Adaptive monostable stochastic resonance for processing UV absorption spectrum of nitric oxide.

When ultraviolet (UV) absorption spectroscopy technology is used for nitric oxide (NO) detection, the background noise will directly affect the accuracy of concentration inversion, especially in low concentrations. Traditional processing methods attempt to eliminate background noise, which damages the absorption spectrum characteristics. However, stochastic resonance (SR) can utilize the noise to extract a weak characteristic signal. This paper reports a monostable stochastic resonance (MSR) model for processing an UV NO absorption spectrum. By analyzing the characteristics of UV absorption spectrum of NO, the evaluation indexes were constructed, thereby an adaptive MSR method was designed for parameter optimization. The numerical simulation confirmed the absorbance peak can be amplified and spectral signal-to-noise ratio (SNR) can be in the stable range of the proposed method, when noise intensity increased. Finally, this experiment obtained a NO detection limit (3σ) of 1.456 ppm and the maximum relative deviation of concentration is 6.32% by this proposed method, which is satisfactory for processing of the UV NO absorption spectrum.

Comparison of microwave ablation treatments in patients with renal secondary and primary hyperparathyroidism.

Purpose: Microwave ablation (MWA) is feasible for severe renal secondary hyperparathyroidism (SHPT) and primary hyperparathyroidism (PHPT) patients ineligible for parathyroidectomy (PTX). Here we compared the clinical manifestations and characteristics of parathyroid glands in these two groups, and summarized the techniques, safety and efficacy of MWA.Methods: Baseline clinical characteristics, ablation-related techniques, adverse events/complications, and efficacy were recorded.Results: In SHPT group, malnutrition, cardiovascular/pulmonary complications, and abnormal bone metabolism were severe. SHPT patients had more hyperplastic parathyroid glands. The volume of each gland was smaller, and the time of ablation for a single parathyroid was shorter in the SHPT group, although there were no significant differences compared with patients in the PHPT group. Three patients in both groups had recurrent laryngeal nerve injuries and all recovered, except for one SHPT patient. By the end of follow-up, serum iPTH levels had decreased from 2400.26 ± 844.26 pg/mL to 429.39 ± 407.93 pg/mL (p < .01) in SHPT and from 297.73 ± 295.32 pg/mL to 72.22 ± 36.51 pg/mL in PHPT group (p < .01). Hypocalcemia was more common (p < .001) and serum iPTH levels were prone to rebound in SHPT patients after MWA.Conclusion: MWA can be reserved for those who had high surgical risks because of less invasiveness. Injuries of recurrent laryngeal nerves should be noticed. The health status, perioperative, and intraoperative procedures were more complicated and all parathyroids found by ultrasound should be ablated completely in SHPT patients.

Automatic and Fast Recognition of On-Road High-Emitting Vehicles Using an Optical Remote Sensing System.

Optical remote sensing systems (RSSs) for monitoring vehicle emissions can be installed on any road and provide non-contact on-road measurements, that allow law enforcement departments to monitor emissions of a large number of on-road vehicles. Although many studies in different research fields have been performed using RSSs, there has been little research on the automatic recognition of on-road high-emitting vehicles. In general, high-emitting vehicles and low-emitting vehicles are classified by fixed emission concentration cut-points, that lack a strict scientific basis, and the actual cut-points are sensitive to environmental factors, such as wind speed and direction, outdoor temperature, relative humidity, atmospheric pressure, and so on. Besides this issue, single instantaneous monitoring results from RSSs are easily affected by systematic and random errors, leading to unreliable results. This paper proposes a method to solve the above problems. The automatic and fast-recognition method for on-road high-emitting vehicles (AFR-OHV) is the first application of machine learning, combined with big data analysis for remote sensing monitoring of on-road high-emitting vehicles. The method constructs adaptively updates a clustering database using real-time collections of emission datasets from an RSS. Then, new vehicles, that pass through the RSS, are recognized rapidly by the nearest neighbor classifier, which is guided by a real-time updated clustering database. Experimental results, based on real data, including the Davies-Bouldin Index (DBI) and Dunn Validity Index (DVI), show that AFR-OHV provides faster convergence speed and better performance. Furthermore, it is not easily disturbed by outliers. Our classifier obtains high scores for Precision (PRE), Recall (REC), the Receiver Operator Characteristic (ROC), and the Area Under the Curve (AUC). The rates of different classifications of excessive emissions and self-adaptive cut-points are calculated automatically in order to provide references for law enforcement departments to establish evaluation criterion for on-road high-emitting vehicles, detected by the RSS.

The Impact of Frequency Scale on the Response Sensitivity and Reliability of Cortical Neurons to 1/fß Input Signals.

What type of principle features intrinsic inside of the fluctuated input signals could drive neurons with the maximal excitations is one of the crucial neural coding issues. In this article, we examined both experimentally and theoretically the cortical neuronal responsivity (including firing rate and spike timing reliability) to input signals with different intrinsic correlational statistics (e.g., white-type noise, showed 1/f0 power spectrum, pink noise 1/f, and brown noises 1/f2) and different frequency ranges. Our results revealed that the response sensitivity and reliability of cortical neurons is much higher in response to 1/f noise stimuli with long-term correlations than 1/f0 with short-term correlations for a broad frequency range, and also higher than 1/f2 for all frequency ranges. In addition, we found that neuronal sensitivity diverges to opposite directions for 1/f noise comparing with 1/f0 white noise as a function of cutoff frequency of input signal. As the cutoff frequency is progressively increased from 50 to 1,000 Hz, the neuronal responsiveness increased gradually for 1/f noise, while decreased exponentially for white noise. Computational simulations of a general cortical model revealed that, neuronal sensitivity and reliability to input signal statistics was majorly dominated by fast sodium inactivation, potassium activation, and membrane time constants.

US-guided microwave ablation for primary hyperparathyroidism: a safety and efficacy study.

OBJECTIVES: To evaluate the safety and efficacy of microwave ablation (MWA) with the assistance of continuous cool saline injection (CCSI) in patients with primary hyperparathyroidism (PHPT). METHODS: Between November 1, 2014, and February 29, 2016, 22 patients with PHPT were enrolled and treated with ultrasound-guided MWA assisted by CCSI. The levels of parathyroid hormone (PTH) and serum calcium were recorded before and after the MWA. Patients were divided into two groups (normalized and unnormalized groups) according to treatment efficacy. Fisher's exact test and the Mann-Whitney test were used to compare data between the two groups. Timing differences in serum PTH and calcium levels were analyzed with repeated measures analysis of variance. RESULTS: Normalized outcomes for both PTH and calcium levels were achieved in 19 of 22 (86.36%) patients with PHPT. In the normalized group, PTH levels remained normal for 12 months after MWA. PTH levels in the unnormalized group were outside the reference range at six of seven follow-ups within 12 months following MWA. By contrast, serum calcium levels gradually decreased in all patients in both groups. The mean serum PTH and mean calcium levels at 6 months after therapy were significantly lower than those before MWA (both p < 0.05). A transient voice change developed in eight patients. One patient experienced hypocalcaemia, which was corrected by oral calcium supplementation within 2 months. CONCLUSIONS: US-guided MWA assisted by CCSI is safe and effective for destroying parathyroid gland tissue and may serve as a therapeutic alternative for patients with PHPT. KEY POINTS: • Microwave ablation is a new option for patients with hypercalcemic or normocalcemic primary hyperparathyroidism. • Microwave ablation can decrease PTH and calcium levels with sustained efficacy in most patients. • Treatment is safe and causes only transient side effects.

Research on the spectral phase correction method for the atmospheric detection in open space.

During the atmospheric detection process in open space, the excessive phase noise is introduced into the signal, due to the atmospheric turbulence, which causes the intensity and phase fluctuation. In the previous study, a spectral data processing method based on the co-frequency and dual-wave has been used to reduce the influence of the scintillation noise from the atmospheric turbulence in open space, while the influence of the phase noise remains to be solved. So the wavelength modulated signal is theoretically analyzed at first. On studying the relationship between the dual-waves in one cycle to eliminate the phase fluctuation and reduce the phase fluctuation caused by the atmospheric turbulence, a new method of the spectral phase correction for the open space atmospheric detection has been proposed. An atmospheric detection experiment on the phase correction in the open space based on co-frequency and dual-wave has been carried out. The results show that the maximum fluctuation of the spectral signal processed with this method is 1.06%, while the power spectral density fluctuation is suppressed below 50Hz, and the Allan analysis result is 8.8 × 10-8(1s). Compared with the traditional concentration inversion method using 2f-wavelength modulation and the classical light intensity elimination, the proposed phase correction method can effectively reduce the fluctuation of random noise caused by the short-term atmospheric turbulence and the laser flashing to improve the stability of the concentration measurement, which has practical engineering value.

Handgrip exercise reduces peripherally-inserted central catheter-related venous thrombosis in patients with solid cancers: A randomized controlled trial.

BACKGROUND: Peripherally-inserted central catheter-related venous thrombosis has serious complications including the loss of vascular access, recurrent venous thrombosis, and post-thrombotic syndrome. Current guidelines recommend non-pharmacological strategies to prevent peripherally-inserted central catheter-related venous thrombosis. There is little evidence for the effectiveness of handgrip exercise on the prevention of peripherally-inserted central catheter-related venous thrombosis. OBJECTIVES: To examine the effectiveness of handgrip exercise using an elastic ball to prevent peripherally-inserted central catheter-related venous thrombosis in patients with solid cancers. DESIGN: A randomized controlled trial. SETTINGS: One teaching hospital in Nanjing, China. PARTICIPANTS: In total, 120 subjects with solid cancers were eligible; each had a new peripherally-inserted central catheter. They were recruited and randomly assigned into two exercise groups and one control group. METHODS: Subjects from exercise groups 1 and 2 performed a 3-week, 25-repetition handgrip exercise, 3 and 6 times daily, respectively. The control group subjects performed a gentle limb exercise with no frequency and intensity requirements. Ultrasound was used to detect venous thrombosis development and examine axillary vein blood flow over the three points. RESULTS: There were 32 cases of peripherally-inserted central catheter-related venous thrombosis detected. Two venous thrombosis cases in the control group were symptomatic, but all venous thrombosis cases in the exercise groups were asymptomatic. All venous thromboses were partial. There were significant differences in the incidence of venous thrombosis among the three groups (χ2 = 12.813, p = 0.002; χ2 = 9.340, p = 0.009; χ2 = 11.480, p = 0.003; and χ2 = 10.534, p = 0.005, respectively) at days 2, 3 and 21. The incidence of venous thrombosis in the two exercise groups was lower than that in the control group over the 3 time points (all, p < 0.05). The between-group effects and interaction effect in vein maximum velocity and time-mean flow velocity showed significant differences (F = 4.180, p = 0.025; F = 4.010, p = 0.045; and F = 2.928, p = 0.025) at days 2, 3, and 21, respectively. The axillary vein blood flow parameters in the control group were lower than those in the two exercise groups at day 21 (all, p < 0.05). However, no significant differences occurred in the incidence of venous thrombosis and axillary vein blood flow parameters between the two exercise groups. CONCLUSION: Handgrip exercise using an elastic ball daily for three weeks could decrease the incidence of peripherally-inserted central catheter-related venous thrombosis. The method is simple, with no negative consequence reported. Further studies are required to confirm this conclusion and to explore the optimal frequency of handgrip exercise.