DNA damage response and repair gene mutations are associated with tumor mutational burden and outcomes to platinum-based chemotherapy/immunotherapy in advanced NSCLC patients.

BACKGROUND: DNA damage response and repair (DDR) genes are crucial for maintaining the integrity of the genome. This study aims to explore the correlation of DDR gene mutations with TMB, clinical characteristics, and outcomes to platinum-based chemotherapy and platinum-based chemotherapy/immunotherapy in non-small cell lung cancer (NSCLC) without EGFR and ALK alterations. METHODS: Tumor tissue from 49 patients with stage III or IV NSCLC who were without EGFR and ALK alterations were analyzed using targeted next-generation sequencing (NGS). Among them, 13 patients received first-line platinum-based chemotherapy, 32 patients received first-line platinum-based chemotherapy/immunotherapy. RESULTS: In these NSCLC patients without EGFR and ALK alterations, the frequently mutated genes included TP53, KMT2D and KRAS, the most frequently mutated DDR gene was FANCG, DDR gene mutations were detected in 20 patients. The mutation frequency of homologous recombination (HR) pathway was significantly higher in lung squamous cell carcinoma (LUSC) than that in lung adenocarcinoma (LUAD) (30.8% vs. 5.7%). Among DDR positive patients, a lower percentage exhibited metastasis. Patients with DDR gene mutations, cell-cycle checkpoint pathway mutations, and BER pathway mutations had significantly higher TMB compared to those without corresponding mutations. In the patients receiving platinum-based chemotherapy/immunotherapy, the disease control rate was significantly lower in the DDR-positive group compared with that in the DDR-negative group (55.6% vs. 100.0%). Among LUAD patients receiving platinum-based chemotherapy/immunotherapy, we observed a worse overall survival (OS) in DDR-positive group, as well as poorer progression-free survival(PFS)and OS in BER-positive and FANCG mutated group. CONCLUSIONS: DDR gene mutations are associated with tumor metastasis, TMB, and outcomes to platinum-based chemotherapy/immunotherapy in advanced NSCLC patients.

Apatinib successfully administered in malignant tumour patients with severe hypotension: a case series, literature review, and considerations for treatment.

The most notable side-effect of apatinib, a novel antiangiogenic agent for the treatment of cancer, is hypertension, but there are few published studies regarding the use of apatinib to treat patients with cancer and severe hypotension. Here, the cases of three patients with tumours and severe hypotension are described: case 1, a 73-year-old male patient with lung squamous cell carcinoma who initially received radiotherapy and chemotherapy, and developed pneumonia and severe hypotension after 6 months; case 2, a 56-year-old male patient with nasopharyngeal carcinoma who was treated with chemotherapy and presented with fever and persistent hypotension; and case 3, a 77-year-old male patient with oesophageal cancer who was admitted with deglutition difficulty and severe hypotension. Apatinib was added to the treatment regimen of all three patients for antitumor therapy. Pneumonia, tumour progression, and severe hypotension improved noticeably in all patients within 1 month after receiving apatinib. Apatinib was associated with a positive effect on blood pressure stability, in synergy with other means of therapy, and the patients achieved satisfactory short-term clinical results. The role of apatinib in treating patients with cancer and hypotension merits further investigation.

EGFR-TKI Combined with Pemetrexed versus EGFR-TKI Monotherapy in Advanced EGFR-mutated NSCLC: A Prospective, Randomized, Exploratory Study.

PURPOSE: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. RESULTS: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. CONCLUSION: EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Genome-Wide Identification and Expression Analysis of the MADS-Box Gene Family in Sweet Potato [Ipomoea batatas (L.) Lam].

MADS-box gene, one of the largest transcription factor families in plants, is a class of transcription factors widely present in eukaryotes. It plays an important role in plant growth and development and participates in the growth and development of flowers and fruits. Sweet potato is the seventh most important food crop in the world. Its tuberous roots, stems, and leaves contain a large number of proteins, lipids, carotenoids, anthocyanins, conjugated phenolic acids, and minerals, which have high edible, forage, and medicinal value, and is also an important energy crop. At present, MADS-box genes in sweet potato have rarely been reported, and there has been no study on the genome-wide identification and classification of MADS-box genes in Ipomoea batatas. This study provided the first comprehensive analysis of sweet potato MADS-box genes. We identified 95 MADS-box genes, analyzed the structure and protein of sweet potato MADS-box genes, and categorized them based on phylogenetic analysis with Arabidopsis MADS-box proteins. Chromosomal localization indicated an unequal number of MADS-box genes in all 14 chromosomes except LG3, with more than 10 MADS-box genes located on chromosomes LG7, LG11, and LG15. The MADS domain and core motifs of the sweet potato MADS-box genes were identified by motif analysis. We identified 19 MADS-box genes with collinear relationships and analyzed duplication events. Cis-acting elements, such as light-responsive, auxin-responsive, drought-inducible, and MeJA-responsive elements, were found in the promoter region of the MADS-box genes in sweet potato, which further indicates the basis of MADS-box gene regulation in response to environmental changes and hormones. RNA-seq suggested that sweet potato MADS-box genes exhibit tissue-specific expression patterns, with 34 genes highly expressed in sweet potato flowers and fruits, and 19 genes highly expressed in the tuberous root, pencil root, or fibrous root. qRT-PCR again validated the expression levels of the 10 genes and found that IbMADS1, IbMADS18, IbMADS19, IbMADS79, and IbMADS90 were highly expressed in the tuberous root or fibrous root, and IbMADS18, IbMADS31, and IbMADS83 were highly expressed in the fruit. In this study, the molecular basis of MADS-box genes of sweet potato was analyzed from various angles. The effects of MADS-box genes on the growth and development of sweet potato were investigated, which may provide a certain theoretical basis for molecular breeding of sweet potato.

Sequential extraction and enrichment of pesticide residues in Longan fruit by ultrasonic-assisted aqueous two-phase extraction linked to vortex-assisted dispersive liquid-liquid microextraction prior to high performance liquid chromatography analysis.

A simple, green and efficient method for extraction, purification and enrichment of pesticide residues of triazoles and pyrethroids in Longan fruit was developed by ultrasonic-assisted aqueous two-phase extraction (UAATPE) coupled to vortex-assisted dispersive liquid-liquid microextraction (VADLLME). Using an aqueous two-phase system (ATPS) of ethanol/K2HPO4 as extraction solvent, the composition of the ATPS, extraction temperature and time were investigated, respectively. Then VADLLME process also was optimized by investigating type and volume of extracting and dispersive solvents, vortex-assisted time and salt addition. The optimum conditions were as follows: the ATPS composition of ethanol concentration 30.0% (w/w) and K2HPO4 concentration 25% (w/w), extraction temperature 70 °C and extraction time 15 min for UAATPE; 1-dodecanol 200 µL as extraction solvent, ethanol 1.25 mL as dispersive solvent, vortex-assisted time 1.5 min and addition of NaCl 4% (w/v) for VADLLME. Ethanol as extraction solvent and dispersive solvent could directly connect UAATPE with VADLLME without extra steps. By means of HPLC-DAD detection, nine pesticides had good linearity ranged from 0.0200 to 13.59 µg/mL (R2 ≥ 0.9957). LODs and LOQs were in the range of 0.005576-0.01740 µg/mL and 0.01859-0.05010 µg/mL, respectively. UAATPE-VADLLME coupled to HPLC was successfully applied to simultaneous determination of multiple pesticides in Longan fruit, and mean recoveries and RSDs were between 76.95% and 98.63%, 1.2% and 9.8%, respectively. Furthermore, myclobutanil, fenpropathrin and deltamethrin were detected in pericarp and pulp of Longan samples from different districts, respectively.

Chromium ion removal from raw water by magnetic iron composites and Shewanella oneidensis MR-1.

In this study, nanoiron active carbon composites (NZVI/GAC) were used to remove chromium ions from raw water. The composites were synthesized from a novel formula of biological activated carbon and characterized by various techniques. The adsorption test data were fit by a pseudo-second-order kinetic model and Langmuir model. The qe and R2 values were 187 mg Cr/g and 0.9960, respectively, with 0.2 g/L NZVI/GAC at an initial concentration of 118 mg/L Cr according to the Langmuir isotherm model. Moreover, a Cr6+ detoxification reactor was constructed with the magnetic iron composite. The results indicated that the synthesized magnetic iron composite was a significant adsorbent for Cr6+ removal from aqueous solutions. The detoxification reactor was able to remove Cr6+ from raw water at an initial concentration of 26.5 mg/L within a short time period (3-5 min), with a removal efficiency of up to 99.90% and a treatment capacity of 45.0 mg Cr6+/g of adsorbent; the Cr6+ concentrations in the outflow met the GB5749-2006 requirements for drinking water. A synergistic effect between NZVI/GAC and a suspension of the bacterium Shewanella oneidensis MR-1 was found, showing that this bacterium can be used as a regeneration agent for iron-depleted activated carbon materials.

Colonic epithelial mTORC1 promotes ulcerative colitis through COX-2-mediated Th17 responses.

The functional role of colonic epithelium in the pathogenesis of ulcerative colitis (UC) remains unclear. Here, we reveal a novel mechanism by which colonic epithelia recruit T helper-17 (Th17) cells during the onset of UC. mTOR complex 1 (mTORC1) was hyper-activated in colonic epithelia of UC mice. While colonic epithelial TSC1 (mTORC1 negative regulator) disruption induced constitutive mTORC1 activation in the colon epithelia and aggravated UC, RPTOR (essential mTORC1 component) depletion inactivated mTORC1 and ameliorated UC. TSC1 deficiency enhanced, whereas RPTOR ablation reduced the expression of cyclooxygenase 2 (COX-2), interleukin-1 (IL-1), IL-6, and IL-23, as well as Th17 infiltration in the colon. Importantly, inhibition of COX-2 reversed the elevation in the expression of these proinflammatory mediators induced by TSC1 deficiency, and subsequently reduced the symptoms and pathological characteristics of UC in mouse models. Mechanistically, mTORC1 activates COX-2 transcription via phosphorylating STAT3 and enhancing it's binding to the COX-2 promoter. Consistently, enhanced mTORC1 activity and COX2 expression, as well as strong positive correlation between each other, were observed in colonic epithelial tissues of UC patients. Collectively, our study demonstrates an essential role of epithelial mTORC1 in UC pathogenesis and establishes a novel link between colonic epithelium, Th17 responses, and UC development.

Bendable n-Type Metallic Nanocomposites with Large Thermoelectric Power Factor.

Highly bendable n-type thermoelectric nanocomposites are successfully developed by embedding metallic Ni nanowires within an insulating poly(vinylidene fluoride) (PVDF) matrix in solution. These nanocomposites exhibit an abnormal decoupling of the electrical conductivity and Seebeck coefficient as a function of Ni contents. A maximum power factor of 220 µW m-1 K-2 and ZT of 0.15 can thus be obtained with 80 wt% Ni at 380 K.

Structure and Growth Control of Organic-Inorganic Halide Perovskites for Optoelectronics: From Polycrystalline Films to Single Crystals.

Recently, organic-inorganic halide perovskites have sparked tremendous research interest because of their ground-breaking photovoltaic performance. The crystallization process and crystal shape of perovskites have striking impacts on their optoelectronic properties. Polycrystalline films and single crystals are two main forms of perovskites. Currently, perovskite thin films have been under intensive investigation while studies of perovskite single crystals are just in their infancy. This review article is concentrated upon the control of perovskite structures and growth, which are intimately correlated for improvements of not only solar cells but also light-emitting diodes, lasers, and photodetectors. We begin with the survey of the film formation process of perovskites including deposition methods and morphological optimization avenues. Strategies such as the use of additives, thermal annealing, solvent annealing, atmospheric control, and solvent engineering have been successfully employed to yield high-quality perovskite films. Next, we turn to summarize the shape evolution of perovskites single crystals from three-dimensional large sized single crystals, two-dimensional nanoplates, one-dimensional nanowires, to zero-dimensional quantum dots. Siginificant functions of perovskites single crystals are highlighted, which benefit fundamental studies of intrinsic photophysics. Then, the growth mechanisms of the previously mentioned perovskite crystals are unveiled. Lastly, perspectives for structure and growth control of perovskites are outlined towards high-performance (opto)electronic devices.

Elevation of n-3/n-6 PUFAs ratio suppresses mTORC1 and prevents colorectal carcinogenesis associated with APC mutation.

Although epidemiological and preclinical studies have shown the preventative effect of n-3 polyunsaturated fatty acids (PUFAs) on colorectal cancer (CRC), the underlying molecular mechanisms are not clear. In this study, we revealed that elevation of n-3/n-6 PUFAs ratio suppress the mechanistic target of rapamycin complex 1 (mTORC1) and prevent colorectal tumorigenesis. The transgenic expression of fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously, repressed colorectal tumor cell growth and remarkably reduced tumor burden, and alleviated anemia as well as hyperlipidemia in APCMin/+ (adenomatous polyposis coli) mice, a classic CRC model that best simulates most clinical cases. In contrast to arachidonic acid (AA, C20:4 n-6), either Docosahexaenoic acid (DHA, C22:6 n-3), eicosapentaenoic acid (EPA, C20:5 n-3), or a combination of DHA and AA, efficiently inhibited the proliferation of CRC cell lines and promoted apoptosis in these cells. The ectopic expression of fat-1 had similar effects in colon epithelial cells with APC depletion. Mechanistically, elevation of n-3/n-6 ratio suppressed mTORC1 activity in tumors of APCMin/+ mice, CRC cell lines with APC mutation, and in normal colon epithelial cells with APC depletion. In addition, elevation of n-3/n-6 ratio repressed mTORC1 activity and inhibited adipogenic differentiation in preadipocytes with APC knockdown, as well as alleviated hyperlipidemia in APCMin/+ mice. Taken together, our findings have provided novel insights into the potential mechanism by which increase in n-3/n-6 PUFAs ratio represses CRC development, and also a new rationale for utilizing n-3 PUFAs in CRC prevention and treatment.

3D Printing Fabrication of Amorphous Thermoelectric Materials with Ultralow Thermal Conductivity.

Thermoelectric materials are prepared by developing 3D printing technology. The 3D fabricated Bi0.5 Sb1.5 Te3 samples exhibit amorphous characteristics and thus show an ultralow thermal conductivity of 0.2 W m(-1) K(-1) . 3D printing fabrication readily generates bulk thermoelectric samples of any shape, which is not the case with traditional hot-pressing and spark plasma sintering methods.

Chemical decoration of CH3NH3PbI3 perovskites with graphene oxides for photodetector applications.

A facile in situ solution method was developed for chemical decoration of CH3NH3PbI3 perovskites with reduced graphene oxides (rGOs) to significantly improve the photodetector performance. Such CH3NH3PbI3/rGO molecular hybrids show a 6 times higher ON/OFF ratio and notably faster response speed than neat CH3NH3PbI3.

Inhibition of endometrial cancer by n-3 polyunsaturated fatty acids in preclinical models.

Although preclinical and epidemiologic studies have shown the importance of n-3 polyunsaturated fatty acids (PUFA) in the prevention of hormone-responsive cancers such as breast cancer, evidence of the association between n-3 PUFAs and endometrial cancer risk is limited and no previous study has examined the effect of n-3 PUFAs on endometrial cancer in cellular and animal models. In this study, we demonstrated that docosahexenoic acid (DHA) dose- and time-dependently inhibited endometrial cancer cell proliferation, colony formation, and migration and promoted apoptosis. Dietary n-3 PUFAs efficiently prevented endometrial cancer cell growth in xenograft models. Moreover, ectopic expression of fat-1, a desaturase, catalyzed the conversion of n-6 to n-3 PUFAs and produced n-3 PUFAs endogenously, also suppressed endometrial tumor cell growth and migration, and potentiated apoptosis in endometrial cancer cell lines. Interestingly, implanted endometrial cancer cells were unable to grow in fat-1 transgenic SCID mice. Further study revealed that mTOR signaling, which plays an essential role in cell proliferation and endometrial tumorigenesis, is a target of n-3 PUFAs. Exogenous or endogenous n-3 PUFAs efficiently suppressed both mTOR complex 1 (mTORC1) and mTORC2 in vitro and in vivo. Moreover, both dietary n-3 PUFAs and transgenic expression of fat-1 in mice effectively repressed mTORC1/2 signaling and endometrial growth elicited by unopposed estrogen. Taken together, our findings provide comprehensive preclinical evidences that n-3 PUFAs efficiently prevent endometrial cancer and establish mTORC1/2 as a target of n-3 PUFAs.