Identification of MET fusions in solid tumors: A multicenter, large scale study in China.

MET amplification and exon 14 skipping are well known as oncogenic drivers in multiple cancer types. However, MET fusions in most cancer types are poorly defined. To explore the profile and analyze the characteristics of MET fusions, a large-cohort study was conducted to screen MET fusions in clinical samples (n = 10 882) using DNA-based NGS. A total of 37 potentially functional MET fusions containing the intact tyrosine kinase domain (TKD) of MET were identified in 36 samples. Further, 15 novel MET fusions were identified in five cancer types, and the incidence of novel MET fusions accounted for 40.5% (15/37). Brain cancer had the highest incidence of MET fusion, with PTPRZ1-MET as the most common fusion (37.0%). All MET breakpoints in brain cancer (n = 27) were also located in intron 1, while those in lung cancer (n = 4) occurred in intron 1, intron 11, intron 14 and exon 14, respectively. The positive consistency of the common fusion group was 100% (11/11), while that of the rare fusion group was 53.8% (7/13). In conclusion, we provided a comprehensive genomic landscape of MET rearrangement and updated the MET fusions database for clinical test. In addition, we revealed that DNA-based NGS might serve as the clinical test for common MET fusions; however, rare MET fusions must be validated by both DNA-based NGS and RNA-based NGS. Prospective trials are necessary to confirm the treatment efficacy of MET inhibitors.

Fabrication of 2D/1D Bi2WO6/halloysite nanotubes photocatalyst towards water purification: a support effect onin situconstruction and electron-hole separation.

In this research work, a reusable and efficient 2D/1D heterogeneous structured photocatalyst based on amine-functionalized halloysite nanotubes (MHNTs) and Bi2WO6nanosheet (BWO) was prepared using a facile hydrothermal method for decomposing PPCPs under simulated sunlight. On the degradation of tetracycline hydrochloride (TCH), the effects of composite catalysts prepared under various conditions were discussed. The results showed that over BWO/MHNTs with a mass ratio was 3:1, the synthesizing temperature was 120 °C and the precursor pH value was 1, the TCH (10 mg l-1) degradation efficiency reached 100% after 1 h irradiation of simulated sunlight. Moreover, BWO/MHNTs composites kept good recovery and stable photocatalytic activity after 5 cycles. The excellent dispersion of Bi2WO6on the surface of clay minerals and the oxygen vacancy enhanced electron-hole separation may be responsible for the its high activity and stability. Futhermore, the radical capture test demonstrated that ·O-2was primarily responsible for the photodegradation of TCH. Thus, BWO/MHNTs composites exhibit a good application prospect in the field of sunlight-driven photocatalytic degradation towards PPCPs pollutants in water.

Coordinated Co-NC/CoFe dual active centre embedded three-dimensional ordered macroporous framework as bifunctional catalyst for efficient and stable zinc-air batteries.

Developing efficient and stable multifunctional electrocatalyst is very important for zinc-air batteries in practical. Herein, semiconductive spinel CuFe2O4supported Co-N co-doped carbon (Co-NC) and CoFe alloy nanoparticles were proposed. In this strategy, the three-dimensional ordered macroporous CuFe2O4support provides rich channels for mass transmission, revealling good corrosion-resistance and durability at the same time. ZIF-67 derived Co-NC decoration improves the conductivity of the catalyst. Further, the uniformly distributed Co-NC and CoFe nanoparticles (C/CF) dramatically promote the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) performance. Accordingly, C/CF@CuFe2O4catalyst shows remarkable bifunctional electrocatalytic activity, with an ORR half-wave potential of 0.86 V, and an OER over-potential of 0.46 V at 10 mA cm-2. The zinc-air battery using this catalyst exhibits a power density of 95.5 mW cm-2and a durable cyclability for over 170 h at a current density of 10 mA cm-2, which implies a great potential in practical application.

ZIF-67-derived N-doped double layer carbon cage as efficient catalyst for oxygen reduction reaction.

The slow kinetic of oxygen reduction reaction (ORR) hampers the practical application of energy conversion devices, such as fuel cells, metal-air batteries. Here, an efficient ORR electrocatalyst consists of Co, Ni co-decorated nitrogen-doped double shell hollow carbon cage (Ni-Co@NHC) was fabricated by pyrolyzing Ni-doped polydopamine wrapped ZIF-67. During the preparation, polydopamine served as a protective layer can effectively prevent the aggregation of Co and Ni nanoparticles during the pyrolysis process, and at the same time forming a carbon layer to grow a double layer carbon cage. This unique hollow structure endows the catalyst with a high specific surface area as well as more exposed active sites. Also benefited from the synergistic effect between Ni and Co nanoparticles, the Ni-Co@NHC catalyst leads to an outstanding ORR performance of half-wave potential (E1/2, 0.862 V), outperforms that of commercial Pt/C catalyst. Additionally, when Ni-Co@NHC was used in the cathode for the zinc-air battery, the cell exhibits high power density (108 mW cm-2) and high specific capacity (806 mAh g-1) at 20 mA cm-2outperforming Pt/C. This work offers a promising design strategy for the development of high-performance ORR electrocatalysts.

Study on sleep-wake disorders in patients with genetic and non-genetic amyotrophic lateral sclerosis.

OBJECTIVE: To study the frequency and clinical features of sleep disturbances in amyotrophic lateral sclerosis (ALS) patients and compare sleep disorders between ALS with and without mutations. METHODS: In this case-control study, 204 ALS patients and 206 controls were included. We evaluated sleep quality using Pittsburgh Sleep Quality Index (PSQI). Excessive daytime sleepiness (EDS) was diagnosed according to Epworth Sleepiness Scale (ESS). Other characteristics, including rapid eye movement sleep behaviour disorder, restless legs syndrome (RLS), cognitive and psychological impairments, were also evaluated. All ALS patients underwent whole exome sequencing analysis to screen for ALS mutations and were divided into genetic ALS and non-genetic ALS subgroups based on the genetic testing results. RESULTS: A total of 114 men and 90 women ALS patients, with a mean onset age of 53.5±9.9 years, were included in this study. There were 21 mutations detected, contributing to 46.6% of familial amyotrophic lateral sclerosis (FALS) and 7.4% of sporadic amyotrophic lateral sclerosis (SALS). The PQSI and ESS scores were higher in ALS patients than in controls (PSQI 6.0 (3.0,10.0) vs 3.5 (2.0,5.0) (p<0.01); ESS 6.0 (3.0,10.0) vs 4.0 (3.0,8.0) (p<0.01), respectively). RLS was more frequent in ALS patients than in controls (p<0.01). Genetic ALS patients were more likely to show EDS than non-genetic ALS patients (adjusted OR 5.2, p<0.01). Genetic ALS scored lower on Revised ALS Functional Rating Scale, and higher on PSQI and ESS than non-genetic ALS (p<0.01). CONCLUSIONS: In the current study, ALS patients with mutations were more likely to have sleep-wake disturbances than were those without mutations. The former group may benefit more from sleep management.

[ZRS mutations in two Chinese Han families featuring triphalangeal thumbs and preaxial polydactyly].

OBJECTIVE: To identify the causative mutations in two Chinese Han families featuring triphalangeal thumbs (TPT) and preaxial polydactyly (PPD). METHODS: Blood samples were collected from 9 members (2 affected) from family 1 and 14 members (7 affected) from family 2. After genomic DNA was extracted, the ZPA regulatory sequence (ZRS) region was analyzed with real-time quantitative PCR (qPCR) and Sanger sequencing. For family 1, haplotypes compassing the ZRS were also analyzed with short tandem repeats (STR) and single nucleotide changes. RESULTS: No copy number mutation around the ZRS region was found in both families. Two heterogeneous mutations in the ZRS (406A>G and 105C>G) were found to co-segregate with the TPT/PPD malformation in family 1 and 2, respectively. Neither mutation was detected in 200 healthy individuals. Haplotype analysis and Sanger sequencing of family 1 indicated that the first TPT/PPD patient in the family was both germline and somatic mosaic for the 406A>G mutation. CONCLUSION: Two pathogenic ZRS mutations, 105C>G and 406A>G, have been identified in two Chinese Han families with TPT/PPD, among which the 406A>G mutation was de novo.

The pathogenic mechanism of syndactyly type V identified in a Hoxd13Q50R knock-in mice.

Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifth metacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) of HOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlying pathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed to generate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly and partial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes. Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limb development, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud at E10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibited notable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involved in various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopic expression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both the anterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascade ultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations in homozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may be responsible for the manifestation of human SDTY5.

Multifunctional polylactic acid sensing fabric based on biomass flame retardants for intelligent fire early-warning.

Today, building materials emit many hazardous gases in the event of a fire, causing great harm to human health and the environment. Therefore, it is of great significance to develop bio-based flame retardant materials and to realize preventive measures to reduce fires or their damage. In this work, we fabricated a novel multifunctional fire early-warning polylactic acid-based fabric (MFR-PBF) by coating MXene nanosheet, phytic acid @ furfurylamine (PA@FA) and ammonium polyphosphate (APP) via an eco-friendly layer-by-layer assembly method. MFR-PBF showed outstanding flame retardancy including a limiting oxygen index value of 35 % and better char formation capacity. More importantly, MFR-PBF exhibited sensitive fire early-warning capability (∼1 s) and excellent cyclic alarm stability (>15 cycles) due to the excellent semiconductor responsiveness (light and heat) and the significant catalytic char formation effect. Moreover, MFR-PBF is comfortable, flexible and strong enough to sew onto firefighter uniform to detect a variety of human motions, which can be monitored in the internet by using a LoRa emitter and a gateway. In addition, the controllable heating performance rendered MFR-PBF as a potential portable heater. This work provides new insights into the preparation and application of intelligent fire early-warning fabrics in the smart fire protection and Internet of Things.

Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late-onset cancers.

BACKGROUND: Pathogenic germline variants (PGVs) can play a vital role in the oncogenesis process in carriers. Previous studies have recognized that PGVs contribute to early onset of tumorigenesis in certain cancer types, for example, colorectal cancer and breast cancer. However, the reported prevalence data of cancer-associated PGVs were highly inconsistent due to nonuniform patient cohorts, sequencing methods, and prominent difficulties in pathogenicity interpretation of variants. In addition to the above difficulties, due to the rarity of cases, the prevalence of cancer PGV carriers in young cancer patients affected by late-onset cancer types has not been comprehensively evaluated to date. METHODS: A total of 131 young cancer patients (1-29 years old at diagnosis) were enrolled in this study. The patients were affected by six common late-onset cancer types, namely, lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and head-neck cancer. Cancer PGVs were identified and analyzed. based on NGS-based targeted sequencing followed by bioinformatic screening and strict further evaluations of variant pathogenicity. RESULTS: Twenty-three cancer PGVs in 21 patients were identified, resulting in an overall PGV prevalence of 16.0% across the six included cancer types, which was approximately double the prevalence reported in a previous pancancer study. Nine of the 23 PGVs are novel, thus expanding the cancer PGV spectrum. Seven of the 23 (30.4%) PGVs are potential therapeutic targets of olaparib, with potential implications for clinical manipulation. Additionally, a small prevalence of somatic mutations of some classic cancer hallmark genes in young patients, in contrast to all-age patients, was revealed. CONCLUSION: This study demonstrates the high prevalence of PGVs in young cancer patients with the common late-onset cancers and the potentially significant clinical implications of cancer PGVs, the findings highlight the value of PGV screening in young patients across lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, or head-neck cancer.

Synergistic Binary Fe-Co Nanocluster Supported on Defective Tungsten Oxide as Efficient Oxygen Reduction Electrocatalyst in Zinc-Air Battery.

Rational design of metal oxide supported non-precious metals is essential for the development of stable and high-efficiency oxygen reduction reaction (ORR) electrocatalysts. Here, an efficient ORR catalyst consisting of binary Fe/Co nanoclusters supported by defective tungsten oxide and embedded N-doped carbon layer (NC) with a 3D ordered macroporous architecture (3DOM Fe/Co@NC-WO2- x ) is developed. The oxygen deficient 3DOM WO2- x not only serves as a porous and stable support, but also enhances the conductivity and ensures good dispersion of the binary Fe/Co nanocluster, benefiting its ORR catalytic activity. Theoretical calculation shows that there exists a synergistic effect of electron transfer from Fe to Co in the supported binary Fe/Co cluster, promoting the ORR reaction energetics. Accordingly, the 3DOM Fe/Co@NC-WO2- x catalyst exhibits excellent ORR activity in alkaline medium with a half wave potential (E1/2 ) of 0.87 V higher than that of Pt/C (0.85 V). The zinc-air batteries assembled by 3DOM Fe/Co@NC-WO2- x cathode deliver a higher power density and specific capacity than that of Pt/C. A new strategy of combining synergistic binary-metal nanoclusters and conductive metal oxide support design is provided here to develop efficient and durable ORR electrocatalyst.

Molecular Typing and Clinical Characteristics of Synchronous Multiple Primary Colorectal Cancer.

Importance: Synchronous multiple primary colorectal cancer (sMPCC) is clinically rare, but its incidence has increased over the past decade. However, little is known about the molecular and clinical features of sMPCC, which may differ from those of single primary colorectal cancer (SPCRC). Objective: To evaluate the clinical characteristics and pathogenic variations in lesions and the molecular typing of sMPCC. Design, Setting, and Participants: From November 2012 to April 2021, patients with colorectal cancer (CRC) treated at the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this cohort study. Follow-up ended on January 31, 2022. Main Outcomes and Measures: The primary outcome was mismatch repair (MMR) status of each lesion in all patients examined using immunohistochemistry (IHC). Microsatellite instability (MSI) and tumor mutation burden (TMB) were also calculated. Results: A total of 13 276 patients with CRC were enrolled, and 239 patients with sMPCC (mean [SD] age, 63.3 [12.2] years; 173 men [72.4%]) with available clinical data were evaluated. Seventy-eight patients with sMPCC and 94 with SPCRC also underwent next-generation sequencing (NGS)-based molecular testing. The deficient MMR (dMMR)/MSI-H frequencies in sMPCC were significantly higher than those in SPCRC, which was confirmed by both IHC (50 of 239 patients vs 872 of 13 037 patients) and NGS (17 of 78 patients vs 5 of 94 patients). According to the MMR/MSI status of different lesions in patients with sMPCC, they were further divided into 3 subgroups: all dMMR/MSI-H, dMMR/MSI-H and proficient MMR (pMMR)/microsatellite stability (MSS), and all pMMR/MSS. The EGFR and PIK3CA variants were more common, whereas TP53 variants were less prevalent in patients with sMPCC than in those with SPCRC. Moreover, higher tumor mutation burden was associated with higher MSI in patients with sMPCC rather than in those with SPCRC. Conclusions and Relevance: In this cohort study of sMPCC, the incidence of dMMR/MSI-H in patients with sMPCC was significantly higher than that in patients with SPCRC. These findings suggest that sMPCC can be classified into 3 subgroups according to the MMR/MSI status of each lesion, which might be applied to guide personalized therapies for better disease management.

Association of apolipoprotein E ε4 allele and amyotrophic lateral sclerosis in Chinese population.

Background: Amyotrophic lateral sclerosis (ALS) has a complex genetic origin, and how immune dysregulation may contribute to ALS etiology remain unclear. Given the roles played by apolipoprotein E (APOE) signaling in neuroinflammation and neurodegeneration, an improved knowledge of the association between APOE genotypes and ALS risk in Chinese population may help to understand the underlying etiology of the disease. Methods: A retrospective case-control study with participants of Chinese ancestry was conducted, with a total of 683 ALS patients and 369 healthy controls analyzed for APOE genotypes using Sanger sequencing. In addition, 282 of these patients were further analyzed for known ALS risk variants and rare deleterious variants related to immune disorders via whole exome sequencing. Results: Among the 683 ALS patients analyzed (346 males, 337 females; mean age at onset [SD]: 51.9 [10.9]), 145 patients (21.1%) carried ε4, the proportion of which was significantly higher than 16.0% in controls (59/369; OR, 1.42; 95%CI, 1.02-1.98; p = 0.02). There is no evidence supporting the association between APOE genotypes and disease phenotypes. We also didn't find any enrichment of currently known ALS risk variants or variants in genes related to immune abnormality in specific APOE genotypes. Conclusion: Our study highlighted the importance of trans-ethnic studies in identifying genetic risk factors, and the relevance of APOE in ALS etiopathogenesis in Chinese population.

Mutations of DNAJC7 are rare in Chinese amyotrophic lateral sclerosis patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive injury of both upper and lower motor neurons. Recently, protein-truncating and missense mutations of DNAJC7 have been reported in European ALS cohorts. However, the contribution of DNAJC7 mutations in Asian patients with ALS remains unclear. Methods: DNAJC7 mutation screening was performed in a large Chinese cohort comprising 304 sporadic ALS (SALS), 16 familial ALS (FALS), and 6 ALS patients presenting with concomitant frontotemporal dementia (FTD). Results: Two rare missense variants of uncertain significance were identified. One was c.410A > G (p.K137R) detected in 1 SALS, which was absent in 2445 neurologically normal controls. The other variant, c.1106A > C (p.N369T), which is considered benign was found in 5 SALS patients with a detected frequency of 0.65% in control group. No pathogenic mutations of DNAJC7 were found in Chinese ALS cohort. Conclusions: Our results suggest that pathogenic mutations of DNAJC7 are rare in Chinese ALS patients.

Characteristics of peroxyacetyl nitrate pollution during a 2015 winter haze episode in Beijing.

Peroxyacetyl nitrate (PAN) are effective indicators of photochemical pollution, and also play an important role in regional oxidant balance. Surprisingly, in recent years, PAN have also been detected under conditions that do not favor the photochemical processes. To obtain a better understanding of the mechanisms of formation of atmospheric compound pollution, this study examined the relationships between concentrations of PAN and other pollutants (e.g., ozone [O3] and PM2.5) during a winter haze episode. The observation periods were from December 31, 2015, to February 2, 2016, and from February 19, 2016, to March 4, 2016. The maximum daily concentration of PAN during haze episodes was 4-10 times higher than that during non-haze episodes. The continuous cumulative increase in PAN concentrations was the result of a combination of photochemical production during the daytime and production based on free radical chemical reactions during the nighttime. During the haze episode, the correlation between concentrations of PAN and O3 was weak, while a significant correlation was observed between PAN and PM2.5 concentrations (R2 = 0.82). This may have been due to higher concentrations of particulate matter impairing illumination, which can then inhibit the photochemical reactions that produce PAN and O3. OH radicals can replace the role of light in PAN formation, which can cause concentrations of PAN and O3 to vary independently. During the haze episode, the ratio of PAN/O3 was around 0.3, which was much higher than that during the clean period.

Heterogeneous reaction of peroxyacetyl nitrate (PAN) on soot.

The interaction between photochemical oxidants and aerosol particles has been examined in previous atmospheric pollution studies. The heterogeneous reaction can affect the concentration of gases and free radicals, as well as the morphology and properties of particles. In this report, the interaction between the photochemical oxidant peroxyacetyl nitrate (PAN) and soot particles was investigated using a flow tube system. We used real-time online monitoring equipment to track changes in PAN concentrations. Substances on the soot surface were detected using ion chromatography (IC), x-ray photoelectron spectroscopy (XPS), and other surface analysis methods. At 295 K, the upper and lower limits of the initial uptake coefficients were 1.28 × 10-5 and 9.16 × 10-9, respectively. The heterogeneous reaction of PAN on soot was a first-order reaction to PAN under both dry and wet conditions. The products formed on soot included CH3COO-, HCOO-, NO2-, and NO3-. With an increase in relative humidity, the production of all species decreased and the relative amounts changed.