ETV6-NTRK2 Fusion in a Patient With Metastatic Pulmonary Atypical Carcinoid Successfully Treated With Entrectinib: A Case Report and Review of the Literature.

Pulmonary atypical carcinoid (AC) is an extremely rare neuroendocrine tumor. The neurotrophic tropomyosin receptor kinase (NTRK) fusions are reported in only 0.5% of nonsmall cell lung cancer, and are more rare in AC with only one previously reported case. Currently, there is little established evidence on the optimal therapeutic strategies and prognosis for advanced cases. We present a female patient with metastatic AC after complete resection. Due to low expression of somatostatin receptor in this case, somatostatin analogs and peptide receptor radionuclide therapy were not available. After pursuing other alternative treatments, including chemotherapy (ie, carboplatin, etoposide, capecitabine, temozolomide, and paclitaxel), everolimus, and atezolizumab, she returned with significant progression, including innumerable subcutaneous nodules, left pleura metastasis, multiple bone metastases, and brain metastases. New biopsy analysis revealed an ETV6-NTRK2 fusion. She was immediately administered the first-generation tropomyosin receptor kinase inhibitor entrectinib at a dose of 600 mg q.d. A subsequent month of treatment resulted in a complete response in all of the metastatic lung lesions. To date, she has maintained sustained benefit for at least 1 year from initiation of entrectinib. Here, we present the first case of a female patient with metastatic AC harboring the ETV6-NTRK2 fusion, and successfully treated with entrectinib, providing evidence for the application of entrectinib in patients with NTRK-positive AC, and underscoring the critical role of molecular profiling for such cases.

Longitudinal Immune Profiling Highlights CD4+ T Cell Exhaustion Correlated with Liver Fibrosis in Schistosoma japonicum Infection.

Schistosomiasis remains an important public health concern. The eggs deposited in livers invoke a Th2-dominant response, which mediates the fibrotic granulomatous response. However, the mechanisms involved in this immunopathological process are still not perfectly clear. Here, we report a single-cell transcriptional landscape of longitudinally collected BALB/c mouse splenocytes at different time points after Schistosoma japonicum infection. We found that exhausted CD4+ T cells were enriched after infection, changing from coproducing multiple cytokines to predominantly producing the Th2 cytokine IL-4. Regulatory B cells had high expression of Fcrl5, Ptpn22, and Lgals1, potentially regulating exhausted CD4+ T cells via direct PD-1-PD-L2 and PD-1-PD-L1 interactions. Within the myeloid compartment, the number of precursor and immature neutrophils sharply increased after infection. Moreover, dendritic cells, macrophages, and basophils showed inhibitory interactions with exhausted CD4+ T cells. Besides, in mouse livers, we found that exhausted CD4+ T cells were distributed around egg granuloma, promoting collagen expression in primary mouse hepatic stellate cells via IL-4 secretion, resulting in liver fibrosis. Our study provides comprehensive characterization of the composition and cellular states of immune cells with disease progression, which will facilitate better understanding of the mechanism underlying liver fibrotic granulomatous response in schistosomiasis.

Atmospheric aerosol particle size distribution from Lidar data based on the lognormal distribution mode.

Analysis of the atmospheric Aerosol Particle Size Distribution (APSD) retrieved from Light Detection and Ranging (Lidar) data is one of the popular fields in atmospheric remote sensing. An APSD retrieval method based on the lognormal particle size distribution, the Mie theory, and the Second Simulation of the Satellite Signal in the Solar Spectrum (6S) were studied. According to the 6S, this method divides the main body of the aerosols into four basic components and calculates the APSD from Lidar data and the optical and microphysical characteristics of these components. Numerical simulation and experimental observations reveal that this method can obtain the APSD for particle sizes of >0.15 µm in the different vertical layers with good reliability.

6-Valent Virus-Like Particle-Based Vaccine Induced Potent and Sustained Immunity Against Noroviruses in Mice.

Norovirus is a major cause of acute gastroenteritis worldwide, and no vaccine is currently available. The genetic and antigenic diversity of Norovirus presents challenges for providing broad immune protection, which calls for a multivalent vaccine application. In this study, we investigated the possibility of developing a virus-like particle (VLP)-based 6-valent Norovirus vaccine candidate (Hexa-VLPs) that covers GI.1, GII.2, GII.3, GII.4, GII.6, and GII.17 genotypes. Hexa-VLPs (30 µg) adjuvanted with 500 µg of aluminum hydroxide (alum) were selected as the optimal immunization dose after a dose-escalation study. Potent and long-lasting blockade antibody responses were induced by 2-or 3-shot Hexa-VLPs, especially for the emerging GII.P16-GII.2 and GII.17 (Kawasaki 2014) genotypes. Hexa-VLPs plus alum elicited Th1/Th2 mixed yet Th2-skewed immune responses, characterized by an IgG1-biased subclass profile and significant IL-4+ T-cell activation. Notably, simultaneous immunization with a mixture of six VLPs revealed no immunological interference among the component antigens. These results demonstrate that Hexa-VLPs are promising broad-spectrum vaccines to provide immunoprotection against major GI/GII epidemic strains in the future.

Genetic profiles of non-syndromic severe-profound hearing loss in Chinese Hans by whole-exome sequencing.

Hereditary hearing loss is highly heterogeneous. Despite over 120 non-syndromic deafness genes have been identified, there are still some of novel genes and variants being explored. In the study, we investigated 105 Chinese Han children with non-syndromic, prelingual, severe-profound hearing loss by whole-exome sequencing on DNA samples. The most common deafness gene was GJB2, mainly in variant c.235delC (p.Leu79CysfsTer3). 14 children were identified with pathogenic mutations in three genes, GJB2, SLC26A4, and OTOF. Two mutations have been identified to be pathogenic and not recorded previously, including c.4691G > A (p.Trp1564Ter) and c.3928_3930dup (p.Lys1310dup) in OTOF. The rare variants c.1349G > A (p.Arg450His) and c.456 T > G (p.Asn152Lys) in GSDME, and c.1595G > T (p.Ser532Ile) in SLC26A4 were detected. The frequency of nonsense variant c.2359G > T (p.Glu787Ter) in OTOA was very high in 17 cases. Four of them were identified to be digenic inheritance, including GJB2 and COL4A4, GJB2 and EYA1, GJB2 and COL4A5, and GJB2 and DFNA5. The findings showed that a novel pathogenic variant and rare variants may be associated with severe and profound hearing loss.

Using Variational Quantum Algorithm to Solve the LWE Problem.

The variational quantum algorithm (VQA) is a hybrid classical-quantum algorithm. It can actually run in an intermediate-scale quantum device where the number of available qubits is too limited to perform quantum error correction, so it is one of the most promising quantum algorithms in the noisy intermediate-scale quantum era. In this paper, two ideas for solving the learning with errors problem (LWE) using VQA are proposed. First, after reducing the LWE problem into the bounded distance decoding problem, the quantum approximation optimization algorithm (QAOA) is introduced to improve classical methods. Second, after the LWE problem is reduced into the unique shortest vector problem, the variational quantum eigensolver (VQE) is used to solve it, and the number of qubits required is calculated in detail. Small-scale experiments are carried out for the two LWE variational quantum algorithms, and the experiments show that VQA improves the quality of the classical solutions.

Distribution and transport characteristics of fine particulate matter in beijing with mobile lidar measurements from 2015 to 2018.

Accurately quantifying the concentration and transport flux of atmospheric fine particulate matter (PM2.5) is vital when attempting to thoroughly identify the pollution formation mechanism. In this study, the mobile lidar measurements in Beijing on heavily polluted days in December from 2015 to 2018 are presented. The lidar was mounted on a vehicle, which could perform measurements along designated routes. On the basis of mobile lidar measurements along closed circuits of the 6th Ring Road around Beijing, the spatial distribution and transport flux of PM2.5 in Beijing were determined with information of wind field. In the spatial distribution, both the concentration and transport of PM2.5 were revealed to be more significant in the southern section of Beijing. The regional transport layer at heights < 1.3 km plays an important role in pollution formation. The maximum transport flux reached 1600 µg/(m2*sec) on 11 December 2016. With the aerosol boundary layer height determined from the image edge detection (IED) method, the inter-annual variations of the aerosol boundary layer height (ABLH) were also analysed. The ABLH decreased from 0.73 to 0.46 km during the same heavy pollution period from 2015 to 2018. Increasingly adverse aerosol boundary layer (ABL) meteorological factors, including lower ABLH, light winds, temperature inversions, and accumulated moisture, have become necessary for pollution formation in Beijing.

Vertical profile of aerosols in the Himalayas revealed by lidar: New insights into their seasonal/diurnal patterns, sources, and transport.

Atmospheric aerosols play a crucial role in climate change, especially in the Himalayas and Tibetan Plateau. Here, we present the seasonal and diurnal characteristics of aerosol vertical profiles measured using a Mie lidar, along with surface black carbon (BC) measurements, at Mt. Qomolangma (QOMS), in the central Himalayas, in 2018-2019. Lidar-retrieved profiles of aerosols showed a distinct seasonal pattern of aerosol loading (aerosol extinction coefficient, AEC), with a maximum in the pre-monsoon (19.8 ± 22.7 Mm-1 of AEC) and minimum in the summer monsoon (7.0 ± 11.2 Mm-1 of AEC) seasons. The diurnal variation characteristics of AEC and BC were quite different in the non-monsoon seasons with enriched aerosols being maintained from 00:00 to 10:00 in the pre-monsoon season. The major aerosol types at QOMS were identified as background, pollution, and dust aerosols, especially during the pre-monsoon season. The occurrence of pollution events influenced the vertical distribution, seasonal/diurnal patterns, and types of aerosols. Source contribution of BC based on the weather research and forecasting chemical model showed that approximately 64.2% ± 17.0% of BC at the QOMS originated from India and Nepal in South Asia during the non-monsoon seasons, whereas approximately 47.7% was from local emission sources in monsoon season. In particular, the high abundance of BC at the QOMS in the pre-monsoon season was attributed to biomass burning, whereas anthropogenic emissions were the likely sources during the other seasons. The maximum aerosol concentration appeared in the near-surface layer (approximately 4.3 km ASL), and high concentrations of transported aerosols were mainly found at 4.98, 4.58, 4.74, and 4.88 km ASL in the pre-monsoon, monsoon, post-monsoon, and winter seasons, respectively. The investigation of the vertical profiles of aerosols at the QOMS can help verify the representation of aerosols in the air quality model and satellite products and regulate the anthropogenic disturbance over the Tibetan Plateau.

Multi-Center in-Depth Screening of Neonatal Deafness Genes: Zhejiang, China.

PURPOSE: The conventional genetic screening for deafness involves 9-20 variants from four genes. This study expands screening to analyze the mutation types and frequency of hereditary deafness genes in Zhejiang, China, and explore the significance of in-depth deafness genetic screening in newborns. METHODS: This was a multi-centre study conducted in 5,120 newborns from 12 major hospitals in the East-West (including mountains and islands) of Zhejiang Province. Concurrent hearing and genetic screening was performed. For genetic testing, 159 variants of 22 genes were screened, including CDH23, COL11A1, DFNA5, DFNB59, DSPP, GJB2, GJB3, KCNJ10, MT-RNR1, MT-TL1, MT-TS1, MYO15A, MYO7A, OTOF, PCDH15, SLC26A4, SOX10, TCOF1, TMC1, USH1G, WFS1, and WHRN using next-generation sequencing. Newborns who failed to have genetic mutations or hearing screening were diagnosed audiologically at the age of 6 months. RESULTS: A total of 4,893 newborns (95.57%) have passed the initial hearing screening, and 7 (0.14%) have failed in repeated screening. Of these, 446 (8.71%) newborns carried at least one genetic deafness-associated variant. High-risk pathogenic variants were found in 11 newborns (0.21%) (nine homozygotes and two compound heterozygotes), and eight of these infants have passed the hearing screening. The frequency of mutations in GJB2, GJB3, SLC26A4, 12SrRNA, and TMC1 was 5.43%, 0.59%, 1.91%, 0.98%, and 0.02%, respectively. The positive rate of in-depth screening was significantly increased when compared with 20 variants in four genes of traditional testing, wherein GJB2 was increased by 97.2%, SLC26A4 by 21% and MT-RNR1 by 150%. The most common mutation variants were GJB2c.235delC and SLC26A4c.919-2A > G, followed by GJB2c.299_300delAT. Homoplasmic mutation in MT-RNR1 was the most common, including m.1555A > G, m.961T > C, m.1095T > C. All these infants have passed routine hearing screening. The positive rate of MT-RNR1 mutation was significantly higher in newborns with high-risk factors of maternal pregnancy. CONCLUSION: The positive rate of deafness gene mutations in the Zhejiang region is higher than that of the database, mainly in GJB2c.235delC, SLC26A4 c.919-2A > G, and m.1555A > G variants. The expanded genetic screening in the detection rate of diseasecausing variants was significantly improved. It is helpful in identifying high-risk children for follow-up intervention.

Investigation of atmospheric ozone during summer and autumn in Guangdong Province with a lidar network.

The overall ozone concentration in China has increased significantly in recent years, as has the atmospheric oxidization, and both of these changes are impacting human activities. Measurements based on differential absorption lidar (DIAL) were conducted from June to October 2019 in order to investigate the vertical distribution of ozone in Guangdong Province. The vertical and horizontal distributions of ozone in six different cities were systematically examined during the summer and autumn and analyzed the two different ozone characteristics (local pollution and regional transport). TrajStat was used to analyze the ozone transport directions and potential contributions of in the summer and autumn, and the following results were obtained. In the cities of Guangzhou and Jiangmen, the ozone concentrations climbed significantly higher in autumn than in summer, with the ozone concentration reaching a height of 1000 m in autumn and 600 m in summer. The diurnal variation of ozone in Yangjiang City in summer was not obvious, whereas in other cities, high levels of ozone were concentrated in the afternoon. The average summer ozone concentration at the Guangzhou site was the highest, approximately 92.57 µg/m3, whereas the average at the Dongguan site was the lowest. The average ozone concentration at the Guangzhou site in autumn was also the highest among the six cities, reaching 133.34 µg/m3. In terms of local pollution, the high-concentration ozone mainly occurred near the ground. The maximum ozone concentration was approximately 162.1 µg/m3 at about 350 m, and the ozone was evenly distributed above 1500 m. The external transport of ozone primarily occurred from 500 to 1100 m and above 1100 m. During summer, the southwest airflow trajectory was dominant, whereas northeast airflow predominated in autumn.

Comprehensive study of regional haze in the North China Plain with synergistic measurement from multiple mobile vehicle-based lidars and a lidar network.

Recently, haze pollution has emerged as a regional characteristic that needs to be monitored and mitigated sensibly in China, particularly in the North China Plain (NCP). Clarifying the distribution and source characteristics of haze is necessary to better understand its formation mechanism on a regional scale. In this study, a comprehensive study of regional haze using synergistic measurement from multiple mobile vehicle-based lidars, a ground-based lidar network, and in suit instruments is presented. To investigate the distribution and source characteristics of regional haze in the NCP during the winter of 2017, simultaneous measurements of aerosol under different wind conditions are conducted. The regional distribution characteristics of the aerosol were observed using three sets of mobile vehicle-based lidars, and the source characteristics were achieved using an analysis of transport flux (with the ground-based lidar network and the WRF-Chem model). High aerosol extinction was observed on the southwest pathway under a southern wind. Backward trajectories also indicated that the air masses at 500 m were primarily from the southwest. The transport flux at the boundary of Beijing (BJ) and Baoding (BD) on the southwest pathway was calculated. Below 500 m, the transport flux from BD to BJ was positive under a southern wind and negative under a northern wind. In addition to the transport layer below 500 m, an upper transport layer was observed both on November 6, 2017 and January 15, 2018. The upper transport layer from 500 m to 1500 m on November 6, 2017 was obviously noticeable, which decreased dramatically with a maximum transport flux of 539.53 µg m2 s. The significant transport layer at 1250 m with a maximum flux of 614.93 µg m2 s was observed on January 15, 2018, while it had no impact on the ground because it had not yet fallen.

Succession of fungal dynamics and their influence on physicochemical parameters during pig manure composting employing with pine leaf biochar.

The effects of pine leaf biochar (PLB) on fungal community during pig manure composting were investigated. Five different doses of PLB [0% (T1), 2.5% (T2), 5% (T3), 10% (T4) and 15% (T5)] were mixed with mixture of pig manure and sawdust (2:1) for 50 days of composting. The present results indicated that fungal diversity increased more obvious in biochar amendment treatments than control (T1) and that the highest was recorded in T4 treatment. Basidiomycota, Ascomycota and Mucoromycota were the most three abundant phyla in all the treatments, while Heterobasidion, Pezoloma, Mucor, Geastrum, Talaromyces and Cystofilobasidium were the richness genera. In addition, network analysis indicated that fungal community abundance was significantly (p < 0.05) associated with temperature, pH, CO2 and CH4 emission and the seed germination index. In summary, the 10% PLB amendment (T4) was a potential option to strengthen fungal diversity and improve the composting efficiency as well as compost quality.

A Perfused Microfluidic System to Study the Differentiation of Neural Stem Cells in vitro.

INTRODUCTION: Due to the ability to mimic in vivo cellular microenvironments, the development of multicell culture systems has received increasing interest for use as research models and serving as platforms for drug evaluation. METHODS: In this study, we developed a perfused microfluidic system to resemble the in vivo intercellular environment and applied it to study the differentiation from neural stem cells into neurons. RESULTS: As determined by immunofluorescence chemistry and quantitative real-time PCR, the neural stem cells grown in this microfluidic system showed an elevated differentiation rate toward the formation of neurons as determined by the increased level of ßIII-tubulin production, which is 4 times higher than that of culturing neural stem cells only. CONCLUSION: These results revealed that some factors secreted into the intercellular microenvironment by adult neuron cells can stimulate the differentiation of neural stem cells, pointing to the importance of developing multicellular culture systems such as the perfused microfluidic system we report here to better resemble the in vivo situation.

Intrabullous Adhesion Pexia (IBAP) by Percutaneous Pulmonary Bulla Centesis: An Alternative for the Surgical Treatment of Giant Pulmonary Bulla (GPB).

Background and Objective: Most patients with giant pulmonary bulla (GPB) are treated by surgery; however, there is a subset for whom surgery is not a viable option, such as those with contraindications, or those unwilling to undergo operation. Therefore, an alternative minimally invasive method is desired for this subpopulation. The aim of this study was to explore an alternative procedure for treating GPB. Methods: This was a prospective, nonrandomized, single-arm, unblinded study evaluating the efficacy and safety of intrabulla adhesion pexia (IBAP) procedure in GPB patients. The study was conducted between December 2004 and April 2017. Results: There were 38 cases in 36 patients (33 males and 3 females) with the target GPB cavities varying in size (range, 10 cm × 7 cm × 5 cm to 15 cm × 8 cm × 30 cm (anteroposterior diameter × medial-lateral diameter × superoinferior diameter)). After IBAP treatment, the closure ratio of GPB in one month was 86.84% (33/38), while the dyspnea index significantly decreased from 4.11 ± 1.11 to 2.24 ± 1.15 (P < 0.01). In addition, the mean FEV1 (L) increased from 1.06 ± 0.73 to 1.57 ± 1.13 (P < 0.01), while RV (L) decreased from 2.77 ± 0.54 to 2.36 ± 0.38 (P < 0.01) and TLC (L) decreased from 6.46 ± 1.21 to 5.86 ± 1.08 (P < 0.01). Moreover, PaO2 (mmHg) increased from 52.18 ± 8.31 to 68.29 ± 12.34, while the 6 MWD increased by 129.36% from 131.58 ± 105.24 to 301.79 ± 197.90 (P < 0.01). Collectively, these data indicated significant improvement in pulmonary function and exercise tolerance after IBAP treatment. Furthermore, no deaths occurred during IBAP treatment, and no cases of aggravated GPB relapse were reported during the 12-month follow-up period. Conclusions: IBAP is a promising strategy for the treatment of GPB. Our findings demonstrated that IBAP had a noteworthy therapeutic effect, desirable safety, and ideal long-term efficacy for GPB.

Secreted protein acidic and rich in cysteine enhances the chemosensitivity of pancreatic cancer cells to gemcitabine.

It has been previously shown that the simultaneous exposure of colon cancer cells MIP to irinotecan and secreted protein acidic and rich in cysteine (SPARC) enhances anticancer activity. However, whether there is same effect of SPARC in pancreatic cancer remains largely unknown. Therefore in this study, we aimed to investigate the role of SPARC played in the sensitivity of pancreatic cancer to gemcitabine. We first treated MIAPaCa2 and MIAPaCa2/SPARC69 cells with different concentrations of gemcitabine (2, 5, 10, and 20 µM) for 24, 48, and 72 h and selected the appropriated concentration for further study. Then we analyzed cell viability, cell cycle, and apoptosis and the levels of apoptosis-related proteins by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting and Western blot were used, respectively. In this study, we found that gemcitabine inhibited the proliferation of pancreatic cancer cells in a time- and dose-dependent manner. Overexpression of SPARC increased the inhibiting effect of gemcitabine on pancreatic cancer cells. The colony size of MIAPaCa2/SPARC69 was much smaller than that of MIAPaCa2/V. There was a G0/G1 arrest with significant increase of apoptosis after gemcitabine treatment in MIAPaCa2/SPARC69 cells. Furthermore, our results demonstrated that overexpression of SPARC markedly increased the levels of pro-apoptotic proteins in gemcitabine-treated pancreatic cancer cells. The SPARC can enhance the chemosensitivity of pancreatic cancer cells to gemcitabine via regulating the expression of apoptosis-related proteins. These results have shown that the SPARC/ gemcitabine combination treatment may be a potentially useful therapeutic option for individuals diagnosed with pancreatic cancer.

Soluble expression of active recombinant human tissue plasminogen activator derivative (K2S) in Escherichia coli.

CONTEXT: The kringle 2 plus serine protease domains (K2S) of human tissue plasminogen activator (tPA) is an efficacious thrombolytic drug, which has been used to treat heart attacks and strokes by breaking up the clots that cause them. It has nine disulfide bridges, which are needed for proper folding and be the bottleneck in improving the production in the Escherichia coli system. So far, few reports have described the production of soluble active K2S from E. coli. OBJECTIVE: To achieve high-level expression of active K2S in the E. coli system. MATERIALS AND METHODS: The DNA fragment coding for K2S was fused with the E. coli disulfide isomerase DsbC. The constructed fusion protein was expressed in E. coli, and then purified with the Ni(2+)-chelating affinity chromatography. K2S was released by cleavage with Factor Xa protease, and the thrombolytic activity was determined using the fibrin plate assay. RESULTS: The fusion protein DsbC-K2S was found in the culture supernatant of recombinant E. coli as a soluble form of ~40%. The result of fibrinolysis fibrin plate assay showed that the purified recombinant K2S exhibited significant fibrinolysis activity in vitro. DISCUSSION AND CONCLUSION: These works provided a novel approach for the production of active K2S in E. coli without the requirements of in vitro refolding process, and might establish a significant foundation for the following production of K2S.

High-level expression of the antimicrobial peptide plectasin in Escherichia coli.

Plectasin is a defensin-like antimicrobial peptide isolated from a fungus, the saprophytic ascomycete Pseudoplectania nigrella. Plectasin showed marked antibacterial activity in vitro against Gram-positive bacteria, especially Streptococcus pneumoniae, including strains resistant to conventional antibiotics. Plectasin could kill the sensitive strain as efficaciously as vancomycin and penicillin and without cytotoxic effects on mammalian cell viability. In order to establish a bacterium-based plectasin production system, in the present study, the coding sequence of plectasin was optimized, and then cloned into pET32a (+) vector and expressed as a thioredoxin (Trx) fusion protein in Escherichia coli. The soluble fusion protein collected from the supernatant of the cell lysate was separated by Ni(2+)-chelating affinity chromatography. The purified protein was then cleaved by Factor Xa protease to release mature plectasin. Final purification was achieved by Ni(2+)-chelating chromatography again. The recombinant plectasin exhibited the same antimicrobial activity as reported previously. This is the first study to describe the expression of plectasin in E. coli expression system, and these works might provide a significant foundation for the following production or study of plectasin, and contribute to the development and evolution of novel antimicrobial drugs in clinical applications.