RNA-Sequencing Combined With Genome-Wide Allele-Specific Expression Patterning Identifies ZNF44 Variants as a Potential New Driver Gene for Pediatric Neuroblastoma.

INTRODUCTION: Neuroblastoma (NB) is one of the children's most common solid tumors, accounting for approximately 8% of pediatric malignancies and 15% of childhood cancer deaths. Somatic mutations in several genes, such as ALK, have been associated with NB progression and can facilitate the discovery of novel therapeutic strategies. However, the differential expression of mutated and wild-type alleles on the transcriptome level is poorly studied. METHODS: This study analyzed 219 whole-exome sequencing datasets with somatic mutations detected by MuTect from paired normal and tumor samples. RESULTS: We prioritized mutations in 8 candidate genes (RIMS4, RUSC2, ALK, MYCN, PTPN11, ALOX12B, ZNF44, and CNGB1) as potential driver mutations. We further confirmed the presence of allele-specific expression of the somatic mutations in NB with integrated analysis of 127 RNA-seq samples (of which 85 also had DNA-seq data available), including MYCN, ALK, and PTPN11. The allele-specific expression of mutations suggests that the same somatic mutation may have different effects on the clinical outcomes of tumors. CONCLUSION: Our study suggests 2 novel variants of ZNF44 as a novel candidate driver gene for NB.

[Efficient and durable gene delivery of self complementary adeno-associated virus 6 vector and impact of pre-existing immunity].

Recombinant adeno-associated viral (rAAV) vectors are promising vectors for human gene therapy. However, AAV-mediated gene transduction can be hampered because of the pre-existing neutralized natural antibodies (NAbs) in primates. We evaluated transduction efficiency of rAAV6 expressing human alpha-1-anti-trypsin (hAAT) vectors in murine models, and found that these vectors showed stable and high levels of transgene expression. Fluorescence imaging showed that AAV6 expressing enhanced green fluorescent protein (eGFP) by intravenous administration predominantly targeted the liver, but led to self-limited hepatitis. Besides, our study evaluated epidemiology of anti-AAV6 NAb in non-human primates (NHPs) by NAb assay in vitro. The result indicated that 52.17% of NHPs had detectable NAb at 1:5 dilution rate. In vivo passive transfer experiment showed that AAV6 specific neutralizing antibody, even though with low NAb titer, could significantly inhibit rAAV6 transduction.

Chlortetracycline degradation performance and mechanism in the self-biased bio-photoelectrochemical system constructed with an oxygen-defect-rich BiVO4/Ni9S8 photoanode.

Efficient photoelectrodes are highly desired in bio-photoelectrochemical systems (BPES). Herein, in this paper, the oxygen defect-rich BiVO4/Ni9S8 photoanode was developed and coupled with a biocathode for enhanced chlortertracycline (CTC) degradation and current generation in the self-biased BPES. Characterization results showed that the optimized BiVO4/Ni9S8-7 mg-150 °C NF exhibited the best photocatalytic activity, due to that the rich oxygen vacancies and Ni9S8 could significantly improve light absorption, enhance photo-generated carriers separation, and accelerate charges transfer. CTC (20 mg L-1) removal efficiency from the BPES was about 1.3 times (82.3% vs 64.7%) of that from the unilluminated reactor, and current output (0.68 A m-3) was about 7.6 times (0.09 A m-3). The dominant species in genus level was Geobacter, which is capable of reducing nitroaromatics and in favor of reductive dehalogenation of CTC. Besides, Comamonas and Rhodopseudomonas that are capable of degrading antibiotics were also detected. Possible degradation pathways and mechanism of CTC degradation in the BPES were proposed. This research advances the development of photoelectrode materials for light-driven BPESs and enriches antibiotics degradation mechanism.

Hydroxyl radical and carbonate radical facilitate chlortetracycline degradation in the bio-photoelectrochemical system with a bioanode and a Bi2O3/CuO photocathode using bicarbonate buffer.

The single-chamber bio-photoelectrochemical system (BPES) with a bioanode and a Bi2O3/CuO photocathode is developed for chlortetracycline (CTC) degradation under simulated solar irradiation, using phosphate buffer solution (PBS) or NaHCO3 as buffer solution. The optimized Bi2O3/CuO photocathode possesses rich vacancies, great photoresponse capability, and exhibits great photocatalytic activity toward CTC degradation due to its Z-scheme structure. Electron spin-resonance spectroscopy (ESR) and reactive species trapping experiments reveal that superoxide radicals/hydroxyl radicals are both the main radicals contributing to CTC degradation. Moreover, carbonate radical plays a more effective role toward CTC degradation, resulting in 40% improvement for CTC degradation in the BPES within 2 h. Higher current density (maximum of 137.6 A m-2) and more negative cathode potential are obtained from the illuminated BPES with NaHCO3 buffer. Possible mechanism and pathways of CTC degradation are proposed. This study contributes to the development of BPESs for antibiotics degradation.

Reply to Schramm, L. Comment on "Li et al. BDP1 Variants I1264M and V1347M Significantly Associated with Clinical Outcomes of Pediatric Neuroblastoma Patients Imply a New Prognostic Biomarker: A 121-Patient Cancer Genome Study. Diagnostics 2021, 11, 2364".

We thank Professor Laura Schramm for her comment on the history and clarification of BDP1 nomenclature, her contribution to gene cloning [...].

B-doped graphene quantum dots implanted into bimetallic organic framework as a highly active and robust cathodic catalyst in the microbial fuel cell.

Developing efficient and durable oxygen reduction reaction (ORR) cathodic catalysts plays an essential role in application of microbial fuel cells (MFCs). Herein, the B-doped graphene quantum dots implanted into bimetallic organic framework (BGQDs/MOF-t) are fabricated by a facile electro-deposition. Results show that, the in-situ growth of FeCoMOF on nickel foam can effectively assist construction of nanoflowers with compact connections, thus improves the conductivity. More importantly, this nano-network can serve as the template for the implantation of BGQDs through powerful interface of M-O-C bonding, avoiding π-π rearrangement and providing efficient charge transfer and abundant edge active sites. Benefitting from the enhanced electrode/electrolyte transport interface, abundant catalytic sites and low charge transfer resistance, the BGQDs/MOF-15 exhibits excellent ORR activity, superior to commercial Pt/C catalyst. In the MFC with the BGQDs/MOF-15 cathode, the maximum power density of 703.55 mW m-2 is achieved, which is 1.53 times of that of the Pt/C cathode. In addition, the BGQDs/MOF-15 cathode maintains great stability over 800 h, while that of Pt/C reduces to 61% of the initial voltage. This work opens new opportunities for developing efficient and durable MOF-derived ORR catalyst.

Synchronous removal of tetracycline and copper (II) over Z­scheme BiVO4/rGO/g-C3N4 photocatalyst under visible-light irradiation.

The combined pollution of heavy metals and organic pollutants in water body has become one of vital environmental issues. Herein, a series of BiVO4/rGO/g-C3N4 nanocomposites were synthesized for concurrent removals of organic pollutant and heavy metal. Results showed that using the optimized photocatalyst BiVO4/rGO/g-C3N4-28, tetracycline (TC) removal of 87.3% and copper (Cu (II)) removal of 90.6% were achieved under visible-light irradiation within 3 h, respectively; much higher than those using BiVO4 and g-C3N4. More importantly, synergistic effect of TC and Cu (II) removals occurred on the surface of BiVO4/rGO/g-C3N4 in the TC-Cu (II) coexistence condition. Additionally, the ·OH and ·O2- were the most important active species for TC oxidation, while photogenerated electrons were the most responsible for Cu (II) reduction. Results of various characterizations and electron spin resonance test demonstrated that BiVO4/rGO/g-C3N4 was a Z-scheme photocatalyst. Based on the identified intermediates, possible degradation pathways and mechanisms for photocatalytic degradation of TC were proposed. This study advances the development and mechanism of photocatalysts for collaborative removal of pollutants.

N, S co-doped carbon quantum dots anchoring on copper-vacancy-rich Cu nanowires/Cu foam as the cathode in microbial fuel cells: Role of C-S-Cu active site.

Oxygen reduction reaction (ORR) electrocatalysts have been considered as one of the key components in microbial fuel cells (MFCs). Heteroatom-doped carbon quantum dots (CQDs) derived from biomass have attracted wide attention due to their rich functional groups, excellent properties, and environmental friendliness. Herein, orange-peels-derived N, S co-doped carbon quantum dots (N, S-CQDs) are in-situ anchored on copper-vacancy-rich Cu nanowires/Cu foam (V-Cu NWs/CF), obtaining the N, S-CQDs/Cu2O-Cu NWs, to catalyze ORR in MFCs. The interaction between N, S-CQDs and V-Cu NWs/CF from the N, S-CQDs/Cu2O-Cu NWs is bridged by the C-S-Cu bond, which is demonstrated to be the active site towards ORR and plays an important role in promoting electron transfer by in-situ Raman and X-ray photoelectron spectroscopy characterizations. In MFCs, the maximum power density (924.5 ± 32.5 mW·m-2) of N, S-CQDs/Cu2O-Cu NWs is 1.34 times that of Pt/C (686.5 ± 28.0 mW·m-2), and its long-term stability also outperforms the Pt/C. This study provides inspiration for synthesis of efficient ORR electrocatalysts with metal-ligand active sites creating by heteroatom-doped CQDs and cationic-metal-vacancy-rich materials.

Molecular Characterization of Differentiated-Resistance MSC Subclones by Single-Cell Transcriptomes.

Background: The mechanism of tumorigenicity potentially evolved in mesenchymal stem cells (MSCs) remains elusive, resulting in inconsistent clinical application efficacy. We hypothesized that subclones in MSCs contribute to their tumorgenicity, and we approached MSC-subclones at the single-cell level. Methods: MSCs were cultured in an osteogenic differentiation medium and harvested on days 12, 19, and 25 for cell differentiation analysis using Alizarin Red and followed with the single-cell transcriptome. Results: Single-cell RNA-seq analysis reveals a discrete cluster of MSCs during osteogenesis, including differentiation-resistant MSCs (DR-MSCs), differentiated osteoblasts (DO), and precursor osteoblasts (PO). The DR-MSCs population resembled cancer initiation cells and were subjected to further analysis of the yes associated protein 1 (YAP1) network. Verteporfin was also used for YAP1 inhibition in cancer cell lines to confirm the role of YAP1 in MSC--involved tumorigenicity. Clinical data from various cancer types were analyzed to reveal relationships among YAP1, OCT4, and CDH6 in MSC--involved tumorigenicity. The expression of cadherin 6 (CDH6), octamer-binding transcription factor 4 (OCT4), and YAP1 expression was significantly upregulated in DR-MSCs compared to PO and DO. YAP1 inhibition by Verteporfin accelerated the differentiation of MSCs and suppressed the expression of YAP1, CDH6, and OCT4. A survey of 56 clinical cohorts revealed a high degree of co-expression among CDH6, YAP1, and OCT4 in various solid tumors. YAP1 inhibition also down-regulated HeLa cell viability and gradually inhibited YAP1 nuclear localization while reducing the transcription of CDH6 and OCT4. Conclusions: We used single-cell sequencing to analyze undifferentiated MSCs and to discover a carcinogenic pathway in single-cell MSCs of differentiated resistance subclones.

BDP1 Variants I1264M and V1347M Significantly Associated with Clinical Outcomes of Pediatric Neuroblastoma Patients Imply a New Prognostic Biomarker: A 121-Patient Cancer Genome Study.

BACKGROUND: Neuroblastoma (N.B.) is the most common tumor in children. The gene BDP1 (B Double Prime 1) plays a role in cancers but is less known in N.B. Thus, we conducted this study to investigate the value of BDP1 mutations in N.B. METHODS: A dataset of 121 NB patients from the Cancer Genome Atlas database was used to analyze BDP1 gene mutations by RNA sequencing. Kaplan-Meier estimates were performed for overall survival (O.S.) analysis on BDP1 variants, and Cox's proportional hazards regression model was used for multivariate analysis. RESULTS: In 121 NB patients, we identified two variants of BDP1 associated with N.B., located at chr5:71511131 and chr5:71510884. The prevalence of these BDP1 variants, I1264M and V1347M, was 52.9% (64/121) and 45.5% (55/121), respectively. O.S. analysis showed a significant difference between subgroups with or without BDP1 variants (p < 0.05). Multivariate analysis further revealed that BDP1ariants were independent prognostic variables in N.B. (p < 0.05). CONCLUSION: Our results suggest BDP1 variants are associated with significantly improved clinical outcomes in N.B., thus providing clinicians with a new tool.

Visible-light-driven Z-scheme Zn3In2S6/AgBr photocatalyst for boosting simultaneous Cr (VI) reduction and metronidazole oxidation: Kinetics, degradation pathways and mechanism.

It is urgently needed to develop high-performance materials that can synchronously remove heavy metals and organic pollutants. Herein, the visible-light responsive Zn3In2S6/AgBr composites were prepared for concurrent removals of metronidazole (MNZ) and Cr (VI). In the Cr (VI)-MNZ coexisting system, the removals of MNZ and Cr (VI) using the optimized Zn3In2S6/AgBr-15 photocatalyst reached 98.2% and 94.8% within 2 h, respectively; higher than those using counterparts. The radical species trapping and electron spin resonance (ESR) results demonstrated that ·OH was the most dominated species for MNZ oxidation, and photo-generated electrons were responsible for Cr (VI) reduction. Besides, slight competition for ·O2- during the simultaneous MNZ degradation and Cr (VI) reduction occurred. Energy band structure analysis, ESR and the outstanding photocatalytic performance for MNZ and Cr (VI) removals demonstrated that the Zn3In2S6/AgBr-15 was a Z-scheme photocatalyst, which promoted photo-induced carrier's separation. Possible MNZ degradation pathways and mechanism over the Z-scheme Zn3In2S6/AgBr were also proposed based on the identified intermediates. This study could inspire new ideas for design of efficient Z-scheme photocatalysts for wastewater treatment.

Continued gefitinib retreatment beyond progression in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations.

PURPOSE: To evaluate the effectiveness and safety of gefitinib retreatment beyond disease progression in patients with advanced non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations. METHODS: Data from patients with stage III/IV NSCLC were analyzed retrospectively. Patients with sensitive EGFR mutations received first-line treatment with gefitinib followed by retreatment with gefitinib after disease progression. Progression-free survival (PFS) after the first treatment (PFS-1) was defined as the time to progression or death using the Response Evaluation Criteria in Solid Tumors criteria (RECIST) v1.1 criteria. The second PFS (PFS-2) was defined as the interval between the first and second progressions, at the investigator's discretion. Toxicities were recorded in accordance with the National Cancer Institute (NCI)-Common Terminology Criteria (CTC) version 4.0. RESULTS: Sixteen patients aged 53 to 80 years (median 66 years) were included in the analysis. The median PFS-1 and PFS-2 were 10.0 months and 14.0 months, respectively. The median overall survival (OS) was 36.0 months. No toxicity of grade 3 or worse was observed. CONCLUSIONS: Our findings suggest that gefitinib retreatment beyond disease progression may be an effective and tolerable approach for NSCLC patients with sensitive EGFR mutations.

Different refractory organic substances degradation and microbial community shift in the single-chamber bio-photoelectrochemical system.

The single-chamber bio-photoelectrochemical system (BPES) with a BiOBr photocathode was developed for acid orange 7 (AO7), 2,4 dichlorophenol (2,4-DCP) and chloramphenicol (CAP) degradation under solar irradiation. Photoelectrochemical characterizations showed that the optimized BiOBr-photocathode exhibited great light-response property and excellent electrochemcial performance. Moreover, desired TOC removals were achieved for various organic pollutants, with the values of 90.97% (AO7), 81.41% (2,4-DCP) and 78.47% (CAP). Besides, the lower cathode potentials in the illuminated BPESs were favorable to efficient pollutants degradation. Significant microbial community shifts were observed among the inoculation and anodic biofilms from the BPES, and the most dominated species in anodic biofilms acclimated to various pollutants were Geobacter and Pseudomonas, which have the abilities of extracellular electrons transfer and organics degradation. Some other species that different from the inoculation were also identified from the BPES biofilms. This study suggested that BPES had great potential for refractory organics degradation.

Nitrofurazone degradation in the self-biased bio-photoelectrochemical system: g-C3N4/CdS photocathode characterization, degradation performance, mechanism and pathways.

In this study, a self-biased bio-photoelectrochemical system (SB-BPES) was constructed using a bioanode and the g-C3N4/CdS heterojunction photocathode for nitrofurazone (NFZ) degradation under solar irradiation. The physio-chemical properties and optical performance of photocatalysts were characterized, and photo-electrochemical properties of various photocathodes were analyzed. Results showed that g-C3N4/CdS exhibited the broadest visible light absorption range (to 594 nm) and the most efficient e--h+ separation; and its corresponding photocathode showed the highest photocurrent (9.8 µA), and the lowest charge transfer resistance (5.43 ☓ 103 Ω). In the solar-illuminated SB-BPES with g-C3N4/CdS photocathode, about 80% of NFZ removal rate was achieved within 10 h. More importantly, TOC removal of 62.6% was achieved in 24 h, which was 1.8 times of that from the open circuit SB-BPES, and 4.3 folds of that from microbial degradation; also, about 1.5 times of those from SB-BPES with g-C3N4 and CdS photocathodes. Besides, reproducible current generations (∼1.0 mA) were produced. These verified that it was a self-sustained system for spontaneously pollutants degradation and electricity generation. Moreover, possible degradation mechanism and pathways were proposed according to the identified intermediates. This study provides inspiration for synchronic improving refractory organics degradation and net energy recovery.

Bio-photoelectrochemcial system constructed with BiVO4/RGO photocathode for 2,4-dichlorophenol degradation: BiVO4/RGO optimization, degradation performance and mechanism.

A single-chamber bio-photoelectrochemical system (BPES) constructed with BiVO4/reduced graphene oxide (RGO) photocathode was proposed for 2,4-dichlorophenol (2,4-DCP) degradation under simulated solar irradiation. The BiVO4/RGO (B/G) composites were synthesized, optimized and characterized by various techniques to analyze their physico-chemical and photocatalytic properties. Results showed that B/G (5 wt% - 9 h - 150 °C) exhibited the best photocatalytic activity for 2,4-DCP degradation, which was 1.5 times of that of BiVO4, due to its better light absorption, faster electrons transfer, and more efficient photo-generated e- - h+ separation. Reactive species trapping experiments revealed that ·OH was the main radical leading to 2,4-DCP degradation, and h+ also influenced 2,4-DCP removal. The 2,4-DCP (20 mg/L) removal rate and current output from the illuminated BPES were much higher than those of the unilluminated reactor (68.5 % vs. 41.8 %, 60.31 A/m3 vs. 40.07 A/m3) in 24 h, and the cathode potential was more negative, indicating that photocathode catalytic process was favorable to pollutants degradation and energy generation. Intermediates of 2,4-DCP degradation in the BPES were identified, and accordingly, possible degradation pathway and mechanism were proposed. This research advanced the development of efficient photocathode and mechanism of recalcitrant wastewater treatment in the BPES.

Photocathode optimization and microbial community in the solar-illuminated bio-photoelectrochemical system for nitrofurazone degradation.

To further enhance the bio-photoelectrochemical system (BPES) performance for nitrofurazone (NFZ) degradation and current output, the g-C3N4/CdS photocathode was optimized, and microbial community shift from inoculation to the BPES was analyzed. Results showed that photocathode with g-C3N4/CdS (mass ratio of 1:9) loading of 7.5 mg/cm2 exhibited the best performance, with NFZ removal of 83.14% (within 4 h) and current of ~9 mA in the BPES. Proteobacteria accounted for the largest proportion: 66.53% (inoculation), 71.89% (microbial electrolysis cell (MEC) anode), 74.67% (BPES anode) and 57.31% (BPES cathode), respectively. In addition, Geobacter was the most dominant genus in MEC and BPES anode and cathode, which occupied 31.64%, 67.73% and 41.34%, respectively. The microbial compositions of BPES anode and cathode were similar, but different from that of MEC anode. Notably, Rhodopseudomonas, a photosynthetic species, was detected in the BPES. Cognition of microbial community in the BPES is important for advancing its development.

Endostar, a recombined humanized endostatin, enhances the radioresponse for human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts in mice.

The purpose of this paper is to determine the efficacy of combining radiation therapy with endostar, a recombined humanized endostatin, in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts. Tumor xenografts were established in the hind limb of male athymic nude mice (BALB/c-nu) by subcutaneous transplantation. The tumor-bearing mice were assigned into four treatment groups: sham therapy (control), endostar (20 mg/kg, once daily for 10 days), radiation therapy (6 Gray per day to 30 Gray, once a day for 1 week), and endostar plus radiation therapy (combination). The experiment was repeated and mice were killed at days 3, 6, and 10 after initiation therapy, and the tumor tissues and blood samples were collected to analyze the kinetics of antitumor, antiangiogenesis, and antivascularization responses of different therapies. In human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts, endostar significantly enhanced the effects of tumor growth inhibition, endothelial cell and tumor cell apoptosis induction, and improved tumor cell hypoxia of radiation therapy. Histological analyses demonstrated that endostar plus radiation also induced a significant reduction in microvascular density, microvascular area, and vascular endothelial growth factor and matrix metalloproteinase-2 expression compared with radiation and endostar alone respectively. We concluded that endostar significantly sensitized the function of radiation in antitumor and antiangiogenesis in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts by increasing the apoptosis of the endothelial cell and tumor cell, improving the hypoxia of the tumor cell, and changing the proangiogenic factors. These data provided a rational basis for clinical practice of this multimodality therapy.

Tyrosine kinase inhibitors re-treatment beyond progression: choice and challenge.

Tyrosine kinase inhibitors (TKIs) are highly effective agents for the treatment of lung cancer which harbors activated gene mutation. However, for patients with failure of TKI, TKI re-treatment beyond progression (TRBP) is still a potential option that has been proven by many literatures. In this review, we summarize the clinical evidence of TRBP and discuss the potential mechanisms to overcome TKI-acquired resistance.

Management of rectal inflammatory myofibroblastic tumor recurrence.

Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm of intermediate malignant potential. It may occur in various anatomic locations, but rarely in the rectum. This is a case discussion of a 36-year-old male patient with IMT of the rectum. After the patient underwent radical surgery, recurrence was seen after 18 months. Because the tumor was very close to the surrounding tissue, palliative tumor resection was performed followed by concurrent chemo-radiation and non-steroidal anti-inflammatory drugs (NSAID). After 2-year follow-up, the patient has no evidence of recurrence or metastasis. Surgical resection is very important for patient with rectal IMT, even in relapse cases. And adjuvant chemoradiotherapy and NSAID are in favor of the incompletely resected tumors as our case. But perhaps, the adjuvant treatments could be helpful after radical resection of rectal tumor.