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Although immune checkpoint inhibitors (ICIs) have produced remarkable responses in non-small cell lung cancer (NSCLC) patients, receivers still have a relatively low response rate. Initial response assessment by conventional imaging and evaluation criteria is often unable to identify whether patients can achieve durable clinical benefit from ICIs. Overall, there are sparse effective biomarkers identified to screen NSCLC patients responding to this therapy. A lot of studies have reported that patients with specific gene mutations may benefit from or resist to immunotherapy. However, the single gene mutation may be not effective enough to predict the benefit from immunotherapy for patients. With the advancement in sequencing technology, further studies indicate that many mutations often co-occur and suggest a drastic transformation of tumour microenvironment phenotype. Moreover, co-mutation events have been reported to synergise to activate or suppress signalling pathways of anti-tumour immune response, which also indicates a potential target for combining intervention. Thus, the different mutation profile (especially co-mutation) of patients may be an important concern for predicting or promoting the efficacy of ICIs. However, there is a lack of comprehensive knowledge of this field until now. Therefore, in this study, we reviewed and elaborated the value of cancer mutation profile in predicting the efficacy of immunotherapy and analysed the underlying mechanisms, to provide an alternative way for screening dominant groups, and thereby, optimising individualised therapy for NSCLC patients.
Let $j_n$ be the modular function obtained by applying the nth Hecke operator on the classical j-invariant. For $n>m\ge 2$, we prove that between any two zeros of $j_m$ on the unit circle of the fundamental domain, there is a zero of $j_n$.
Based on hubs of neural circuits associated with addiction and their degree centrality (DC), this study aimed to construct the addiction-related brain networks for patients diagnosed with heroin dependence undertaking stable methadone maintenance treatment (MMT) and further prospectively identify the ones at high risk for relapse with cluster analysis.
Sixty-two male MMT patients and 30 matched healthy controls (HC) underwent brain resting-state functional MRI data acquisition. The patients received 26-month follow-up for the monthly illegal-drug-use information. Ten addiction-related hubs were chosen to construct a user-defined network for the patients. Then the networks were discriminated with K-means-clustering-algorithm into different groups and followed by comparative analysis to the groups and HC. Regression analysis was used to investigate the brain regions significantly contributed to relapse.
Sixty MMT patients were classified into two groups according to their brain-network patterns calculated by the best clustering-number-K. The two groups had no difference in the demographic, psychological indicators and clinical information except relapse rate and total heroin consumption. The group with high-relapse had a wider range of DC changes in the cortical−striatal−thalamic circuit relative to HC and a reduced DC in the mesocorticolimbic circuit relative to the low-relapse group. DC activity in NAc, vACC, hippocampus and amygdala were closely related with relapse.
MMT patients can be identified and classified into two subgroups with significantly different relapse rates by defining distinct brain-network patterns even if we are blind to their relapse outcomes in advance. This may provide a new strategy to optimize MMT.
Different from developed countries, there is a paucity of research examining how the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets relate to lipids in less-developed ethnic minority regions (LEMR). A total of 83 081 participants from seven ethnic groups were retrieved from the baseline data of the China Multi-Ethnic Cohort study, which was conducted in less-developed Southwest China between May 2018 and September 2019. Multivariable linear regression models were then used to examine the associations of the DASH and alternative Mediterranean diet (AMED) scores, assessed by modified DASH score and AMED, as well as their components with total cholesterol (TC), LDL-cholesterol, HDL-cholesterol, TAG and TC/HDL-cholesterol. The DASH scores were negatively associated with TC, HDL-cholesterol and TAG. Comparing the highest quintiles with the lowest DASH scores, TC decreased 0·0708 (95 % CI −0·0923, −0·0493) mmol/l, HDL-cholesterol decreased 0·0380 (95 % CI −0·0462, −0·0299) mmol/l and TAG decreased 0·0668 (95 % CI −0·0994, −0·0341) mmol/l. The AMED scores were negatively associated with TC, LDL-cholesterol and HDL-cholesterol. Comparing the highest quintiles with the lowest AMED scores, TC decreased 0·0816 (95 % CI −0·1035, −0·0597) mmol/l, LDL-cholesterol decreased 0·0297 (95 % CI −0·0477, −0·0118) mmol/l and HDL-cholesterol decreased 0·0275 (95 % CI −0·0358, −0·0192) mmol/l. Although both the DASH diet and the Mediterranean diet were negatively associated with blood lipids, those associations showed different patterns in LEMR, particularly for TAG and HDL-cholesterol.
Nutritional Risk Screening index is a standard tool to assess nutritional risk, but epidemiological data are scarce on controlling nutritional status (CONUT) as a prognostic marker in acute haemorrhagic stroke (AHS). We aimed to explore whether the CONUT may predict a 3-month functional outcome in AHS. In total, 349 Chinese patients with incident AHS were consecutively recruited, and their malnutrition risks were determined using a high CONUT score of ≥ 2. The cohort patients were divided into high-CONUT (≥ 2) and low-CONUT (< 2) groups, and primary outcomes were a poor functional prognosis defined as the modified Rankin Scale (mRS) score of ≥ 3 at post-discharge for 3 months. Odds ratios (OR) with 95 % confidence intervals (CI) for the poor functional prognosis at post-discharge were estimated by using a logistic analysis with additional adjustments for unbalanced variables between the high-CONUT and low-CONUT groups. A total of 328 patients (60·38 ± 12·83 years; 66·77 % male) completed the mRS assessment at post-discharge for 3 months, with 172 patients at malnutrition risk at admission and 104 patients with a poor prognosis. The levels of total cholesterol and total lymphocyte counts were significantly lower in high-CONUT patients than low-CONUT patients (P = 0·012 and < 0·001, respectively). At 3-month post discharge, there was a greater risk for the poor outcome in the high-CONUT compared with the low-CONUT patients at admission (OR: 2·32, 95 % CI: 1·28, 4·17). High-CONUT scores independently predict a 3-month poor prognosis in AHS, which helps to identify those who need additional nutritional managements.
A 1178 J near diffraction limited 527 nm laser is realized in a complete closed-loop adaptive optics (AO) controlled off-axis multi-pass amplification laser system. Generated from a fiber laser and amplified by the pre-amplifier and the main amplifier, a 1053 nm laser beam with the energy of 1900 J is obtained and converted into a 527 nm laser beam by a KDP crystal with 62% conversion efficiency, 1178 J and beam quality of 7.93 times the diffraction limit (DL). By using a complete closed-loop AO configuration, the static and dynamic wavefront distortions of the laser system are measured and compensated. After correction, the diameter of the circle enclosing 80% energy is improved remarkably from 7.93DL to 1.29DL. The focal spot is highly concentrated and the 1178 J, 527 nm near diffraction limited laser is achieved.
We report on the design and first results from experiments looking at the formation of radiative shocks on the Shenguang-II (SG-II) laser at the Shanghai Institute of Optics and Fine Mechanics in China. Laser-heating of a two-layer CH/CH–Br foil drives a $\sim 40$ km/s shock inside a gas cell filled with argon at an initial pressure of 1 bar. The use of gas-cell targets with large (several millimetres) lateral and axial extent allows the shock to propagate freely without any wall interactions, and permits a large field of view to image single and colliding counter-propagating shocks with time-resolved, point-projection X-ray backlighting ($\sim 20$ μm source size, 4.3 keV photon energy). Single shocks were imaged up to 100 ns after the onset of the laser drive, allowing to probe the growth of spatial nonuniformities in the shock apex. These results are compared with experiments looking at counter-propagating shocks, showing a symmetric drive that leads to a collision and stagnation from $\sim 40$ ns onward. We present a preliminary comparison with numerical simulations with the radiation hydrodynamics code ARWEN, which provides expected plasma parameters for the design of future experiments in this facility.
Saraiki (ISO 639-3:skr) is an Indo-Aryan language widely used in Pakistan and India (Bashir, Conners & Hefright 2019). The variety described here is Central Saraiki, spoken in the districts of Multan, Muzaffargarh, Bahawalpur and the northern parts of Dera Ghazi Khan in Pakistan, which form the largest of the Saraiki-speaking areas.1 Geographically, Pakistan is divided into four provinces, Punjab, Sindh, Khyber Pukhton Khaw (KPK) and Balochistan. Punjabi is spoken in Punjab, and Sindhi is the dominant language in Sindh. Most Pashto speakers live in KPK and Balochistan, while the inhabitants of Balochistan speak Balochi, Brahui and Saraiki. Other than Urdu, Saraiki is the only language which is spoken in all four provinces of Pakistan, with a majority of speakers in southern Punjab.
The FNDC5 gene encodes the fibronectin type III domain-containing protein 5 that is a membrane protein mainly expressed in skeletal muscle, and the FNDC5 rs3480 polymorphism may be associated with liver disease severity in non-alcoholic fatty liver disease (NAFLD). We investigated the influence of the FNDC5 rs3480 polymorphism on the relationship between sarcopenia and the histological severity of NAFLD. A total of 370 adult individuals with biopsy-proven NAFLD were studied. The association between the key exposure sarcopenia and the outcome liver histological severity was investigated by binary logistic regression. Stratified analyses were undertaken to examine the impact of FNDC5 rs3480 polymorphism on the association between sarcopenia and the severity of NAFLD histology. Patients with sarcopenia had more severe histological grades of steatosis and a higher prevalence of significant fibrosis and definite non-alcoholic steatohepatitis than those without sarcopenia. There was a significant association between sarcopenia and significant fibrosis (adjusted OR 2·79, 95 % CI 1·31, 5·95, P = 0·008), independent of established risk factors and potential confounders. Among patients with sarcopenia, significant fibrosis occurred more frequently in the rs3480 AA genotype carriers than in those carrying the FNDC5 rs3480 G genotype (43·8 v. 17·2 %, P = 0·031). In the association between sarcopenia and liver fibrosis, there was a significant interaction between the FNDC5 genotype and sarcopenia status (P value for interaction = 0·006). Sarcopenia is independently associated with significant liver fibrosis, and the FNDC5 rs3480 G variant influences the association between sarcopenia and liver fibrosis in patients with biopsy-proven NAFLD.
The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) to identify malnutrition risk in patients with liver disease. However, little is known about the application of the RFH-NPT to screen for the risk of malnutrition in China, where patients primarily suffer from hepatitis virus-related cirrhosis. A total of 155 cirrhosis patients without liver cancer or uncontrolled co-morbid illness were enrolled in this prospective study. We administered the Nutritional Risk Screening 2002 (NRS-2002), RFH-NPT, Malnutrition Universal Screening Tool (MUST) and Liver Disease Undernutrition Screening Tool (LDUST) to the patients within 24 h after admission and performed follow-up observations for 1·5 years. The RFH-NPT and NRS-2002 had higher sensitivities (64·8 and 52·4 %) and specificities (60 and 70 %) than the other tools with regard to screening for malnutrition risk in cirrhotic patients. The prevalence of nutritional risk was higher under the use of the RFH-NPT against the NRS-2002 (63 v. 51 %). The RFH-NPT tended more easily to detect malnutrition risk in patients with advanced Child–Pugh classes (B and C) and lower Model for End-stage Liver Disease scores (<15) compared with NRS-2002. RFH-NPT score was an independent predictive factor for mortality. Patients identified as being at high malnutrition risk with the RFH-NPT had a higher mortality rate than those at low risk; the same result was not obtained with the NRS-2002. Therefore, we suggest that using the RFH-NPT improves the ability of clinicians to predict malnutrition risk in patients with cirrhosis primarily caused by hepatitis virus infection at an earlier stage.
We describe 14 yr of public data from the Parkes Pulsar Timing Array (PPTA), an ongoing project that is producing precise measurements of pulse times of arrival from 26 millisecond pulsars using the 64-m Parkes radio telescope with a cadence of approximately 3 weeks in three observing bands. A comprehensive description of the pulsar observing systems employed at the telescope since 2004 is provided, including the calibration methodology and an analysis of the stability of system components. We attempt to provide full accounting of the reduction from the raw measured Stokes parameters to pulse times of arrival to aid third parties in reproducing our results. This conversion is encapsulated in a processing pipeline designed to track provenance. Our data products include pulse times of arrival for each of the pulsars along with an initial set of pulsar parameters and noise models. The calibrated pulse profiles and timing template profiles are also available. These data represent almost 21 000 h of recorded data spanning over 14 yr. After accounting for processes that induce time-correlated noise, 22 of the pulsars have weighted root-mean-square timing residuals of
in at least one radio band. The data should allow end users to quickly undertake their own gravitational wave analyses, for example, without having to understand the intricacies of pulsar polarisation calibration or attain a mastery of radio frequency interference mitigation as is required when analysing raw data files.
The effect of maternal folate intake on small-for-gestational-age (SGA) births remains inconclusive. The present study aimed to investigate the associations of maternal folate intake from diet and supplements with the risk of SGA births using data from a cross-sectional study in Shaanxi Province of Northwest China. A total of 7307 women who were within 12 months (median 3; 10th–90th percentile 0–7) after delivery were included. Two-level models were adopted to examine the associations of folate (dietary folate, supplemental folic acid and total folate) intake with the risk of SGA births and birth weight Z score, controlling for a minimum set of confounders that were identified in a directed acyclic graph. Results showed that a higher supplemental folic acid intake during the first trimester was negatively associated with the risk of SGA births (≤60 d v. non-use: OR 0·80; 95 % CI 0·66, 0·96; >60 d v. non-use: OR 0·78; 95 % CI 0·65, 0·94; Ptrend = 0·010; per 10-d increase: OR 0·97; 95 % CI 0·95, 0·99). A higher total folate intake during pregnancy was associated with a reduced risk of SGA births (highest tertile v. lowest tertile: OR 0·77; 95 % CI 0·64, 0·94; Ptrend = 0·010; per one-unit increase in the log-transformed value: OR 0·81; 95 % CI 0·69, 0·95). A similar pattern was observed for the birth weight Z score. Our study suggested that folic acid supplementation during the first trimester and a higher total folate intake during pregnancy were associated with a reduced risk of SGA births.
Thermal imaging diagnostics was used as a surface temperature mapping tool to characterize the energy density distribution of a high-intensity pulsed ion beam. This approach was tested on the TEMP-6 accelerator (200–250 kV, 150 ns). The beam composition included carbon ions (85%) and protons, and the energy density in the focus was 5–12 J/cm2. Targets of stainless steel, titanium, brass, copper, and tungsten were examined. Our observations show that the maximum energy density measured with the thermal imaging diagnostics considerably exceeds the ablation threshold of the targets. An analysis of the overheating mechanisms of each target was carried out, including metastable overheating of the target to above its boiling temperature during rapid heating; formation, migration, and the subsequent annealing of fast radiation-induced defects in the target under ion beam irradiation. This expands the range of energy density measurement for this thermal imaging diagnostics from 2–3 J/cm2 up to 10–12 J/cm2 but introduces error into the results of measurement. For a stainless steel target, this error exceeds 15% at an energy density of more than 4 J/cm2. A method of correcting the results of the thermal imaging diagnostics is developed for a pulsed ion beam under conditions of intense ablation of the target material.
Alzheimer’s Disease (AD), characterized by deficits in memory and cognition and by behavioral impairment, is a progressive neurodegenerative disorder that influences more than 47 million people worldwide. Currently, no available drug is able to stop AD progression. Therefore, novel therapeutic strategies need to be investigated.
We analyzed the RNA sequencing data (RNA-seq) derived from the Gene Expression Omnibus (GEO) database to identify the differentially expressed mRNAs in AD. The AD mouse model Tg2576 was used to verify the effects of IGF-2. The Morris Water Maze was administered to test the role of IGF-2 in memory consolidation. In addition, we quantified cell apoptosis by the TUNEL assay. The levels of amyloid plaques and the levels of Aβ40 and Aβ42 in the hippocampus were also determined by immunohistochemistry and ELISA, respectively.
RNA-seq analysis revealed that IGF-2 was remarkably reduced in AD. The expression of the upstream genes PI3K and AKT and the downstream gene CREB in the PI3K signaling pathway was significantly increased in the hippocampus of Tg2576 mice cells treated with IGF-2. The Morris water maze test showed that IGF-2 improved memory consolidation in Tg2576 mice. The activity of caspase-3 was decreased in Tg2576 mice treated with IGF-2. Amyloid plaques in the hippocampus were reduced, and the levels of Aβ40 and Aβ42 were decreased. The above effects of IGF-2 on AD were blocked when the PI3K signaling pathway inhibitor wortmannin was added.
IGF-2 attenuates memory decline, oxidative stress, cell apoptosis and amyloid plaques in the AD mouse model Tg2576 by activating the PI3K/AKT/CREB signaling pathway.
Estimating the robot state within a known map is an essential problem for mobile robot; it is also referred to “localization”. Even LiDAR-based localization is practical in many applications, it is difficult to achieve global localization with LiDAR only for its low-dimension feedback, especially in environments with repetitive geometric features. A sensor-fusion-based localization system is introduced in this paper, which has the capability of addressing the global localization problem. Both LiDAR and vision sensors are integrated, making use of the rich information introduced by vision sensor and the robustness from LiDAR. A hybrid grid-map is built for global localization, and a visual global descriptor is applied to speed up the localization convergence, combined with a pose refining pipeline for improving the localization accuracy. Also, a trigger mechanism is introduced to solve kidnapped problem and verify the relocalization result. The experiments under different conditions are designed to evaluate the performance of the proposed approach, as well as a comparison with the existing localization systems. According to the experimental results, our system is able to solve the global localization problem, and the sensor-fusion mechanism in our system has an improved performance.
In this article, we propose two asymmetry measures for stock returns. Unlike the popular skewness measure, our measures are based on the distribution function of the data rather than just the third central moment. We present empirical evidence that the greater upside asymmetries calculated using our new measures imply lower average returns in the cross section of stocks. In contrast, when using the skewness measure, the relationship between asymmetry and returns is inconclusive.
The paper presents the results of a study on propagation and focusing of high-intensity pulsed ion beams, produced by a self-magnetically insulated diode of semi-cylindrical geometry at the TEMP-6 accelerator (120 ns, 200–250 kV). We examined the space-charge neutralization of the beam, the energy density in the focus, the divergence of the beam, and its shot-to-shot displacement in the focal plane. It is found that the concentration of low-energy electrons in the beam is 1.3–1.5 times higher than the concentration of ions. We observed additional ion focusing by its own space charge. With an increase in the density of the net negative (electrons and ions) charge of the beam from 3.6 to 9 µC/cm2, the total divergence (the sum of the beam divergence in the vertical and horizontal planes) decreases from 11.4 to 4.5°. It leads to an increase in the energy density in the focus from 4 up to 10–12 J/cm2. To increase the electrons concentration in the beam, a metal grid installed in the ion beam transport region was used.