Identifying Circulating Tumor DNA Mutations Associated with Neoadjuvant Chemotherapy Efficacy in Local Advanced Breast Cancer.

Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer. Neoadjuvant chemotherapy (NACT) has become standard therapy for local advanced breast cancer (LABC). The aim of our study was to investigate plasma ctDNA as a prognostic marker for outcome in patients with LABC treated with NACT. A total of 56 patients with LABC were involved in this study. ctDNA mutations were investigated by using a 100 gene panel-target capture next-generation sequencing. The patients then received standard NACT therapy: adriamycin and cyclophosphamide and paclitaxel (AC-T) or AC-TH (AC-T+ Trastuzumab) regimen. The efficacy of NACT was evaluated by Miller-Payne grading system. A predictive and weight model was used to screen ctDNA point mutation biomarkers for NACT. The ctDNA mutational profile of LABC patients was identified. For nonsynonymous mutations, the top 5 mutated genes were MTHFR (51/56, 91.1%), XPC (50/56, 89.3%), ABCB1 (48/51, 94.1%), BRCA2 (38/56, 67.9%), and XRCC1 (38/56, 67.9%). In addition, the mutation frequencies of PIK3CA and TP53 were 32.1% (18/56) and 26.8% (15/56), respectively. The predictive model indicated that XRCC1 44055726 (TG>-) mutation (25/56, 44.6%) was significantly associated with Miller-Payne 4-5 and Miller-Payne 3-5 responses. While mTOR 11249132(G>C) mutation (23/56, 41.1%) was associated with Miller-Payne 1-4 or Miller-Payne 1-3 responses. Furthermore, XRCC1 44055726 (TG>-) accompanied by mTOR wild type predicted a good NACT efficacy in all response classification systems. The ROC curves to discriminate good neoadjuvant chemotherapy efficiency (Miller-Payne 4-5) and poor efficiency (Miller-Payne 1-3) were created, and AUC value was 0.77. Our results suggested that ctDNA mutation of XRCC1 44055726 (TG>-) might be a positive biomarker for NACT therapy in LABC, while mTOR 11249132(G>C) mutation was potentially associated with NACT resistance.

Nanocellulose-Reinforced Hydroxyapatite Nanobelt Membrane as a Stem Cell Multi-Lineage Differentiation Platform for Biomimetic Construction of Bioactive 3D Osteoid Tissue In Vitro.

Severe bone defects, especially accompanied by vascular and peripheral nerve injuries, remain a massive challenge. Most studies related to bone tissue engineering have focused on osteogenic differentiation of mesenchymal stem cells (MSCs), and ignored the formation of blood vessels and nerves in the newly generated bone owing to the lack of proper materials and methodology for tuning stem cells differentiated into osteogenic, neuronal, and endothelial cells (ECs) in the same scaffold system. Herein, a nanocellulose-reinforced hybrid membrane with good mechanical properties and control over biodegradation by assembling ultralong hydroxyapatite nanobelts in a bacterial nanocellulose hydrogel is designed and synthesized. Osteogenic, neuronal cells are successfully differentiated on this hybrid membrane. Based on the multi-lineage differentiation property of the membrane, a bioactive 3D osteoid tissue (osteogenic, neural, and ECs) is mimetically constructed in vitro using layer-by-layer culture and integration. The bone regeneration ability of the as-prepared bioactive osteoid tissue is assessed in vivo via heterotopic osteogenesis experiments for eight weeks. The rapid new bone growth and formation of blood capillaries and nerve fibers prove that the hybrid membrane can be universally applied as a stem cell multi-lineage differentiation platform, which has significant applications in bone tissue engineering.

Novel association between FOXO3 rs2232365 polymorphism and late-onset preeclampsia: a case-control candidate genetic study.

BACKGROUND: Both genetic susceptibility and dysregulated lipid metabolism are important susceptibilities to preeclampsia. In the study, we devote to investigate the associations of FOXO3 and TLR7 genetic polymorphisms with preeclampsia in a Chinese population. METHODS: This case-control study involved 335 Han Chinese pregnant women, including 177 pregnant women with preeclampsia and 158 healthy controls. The preeclampsia group was further sub-grouped into early-onset preeclampsia (EOPE, n = 70)and late-onset preeclampsia (LOPE, n = 107. Three single nucleotide polymorphisms (SNPs), including FOXO3 (rs2232365, rs3761548), and TLR7 rs3853839 were genotyped by multiplex PCR for targeted next-generation sequencing. The χ2 test and multiple interaction effect analyses were performed to determine the association of three SNPs with serum lipid levels and thyroid function in women with preeclampsia. RESULTS: The genotype (CC vs. TT + CT) distribution of rs2232365 revealed a significant association with LOPE (P = 0.004, odds ratio = 3.525 (0.95 CI: 1.498-8.164)). No significant difference was found in the genotype and allele frequencies of rs3761548 and rs3853839 between controls and cases (P > 0.05). Moreover, the genotype CT/TT of rs2232365 was significantly correlated with increased TG/HDL levels in the LOPE group (p = 0.014). CONCLUSIONS: The polymorphisms of rs2232365 are associated with the risk of LOPE and may modulate TG/HDL levels in pregnant women with LOPE.

[Chemical Compositions and Sources of n-Alkanes and Saccharides in PM2.5 from Taian City During the Summer].

To investigate the variations and sources of n-alkanes and sugars in Taian City during summer, PM2.5 samples were collected from July 22 to August 19, 2016. The identified n-alkane and sugar sources were investigated using a principal component analysis (PCA) multiple linear regression (MLR) model and a backward trajectory model. The results showed that the mass concentrations of PM2.5 during summer were (37.2±11.5) µg·m-3. The mass concentrations of n-alkanes were (83.3±34.7) ng·m-3, the carbon preference index (CPI) was 1.83, and the relative contribution of wax n-alkanes was 34.7%-69.4%, suggesting that contributions from terrestrial plants were more significant in Taian City. The results showed that the mass concentrations of sugars in Taian City during summer were (73.4±46.6) ng·m-3. Levoglucan, galactosan, and mannosan were the main saccharides, accounting for 64.0%, 7.1%, and 6.3% of the total concentrations of sugars, respectively, indicating that biomass burning is much more significant in Taian City. The results of the PCA-MLR model suggested that n-alkanes and sugars in Taian City during summer were mostly from terrestrial plants, coal burning and biomass burning. The backward trajectory model showed that the pollution mostly came from the native sources of Shandong province and the inland cities in the south.

SARS-CoV-2 infection and stem cells: Interaction and intervention.

The emergence of the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread have created a global health emergency. The resemblance with SARS-CoV in spike protein suggests that SARS-CoV-2 employs spike-driven entry into angiotensin-converting enzyme 2 (ACE2)-expressing cells. From a stem cell perspective, this review focuses on the possible involvement of ACE2+ stem/progenitor cells from both the upper and lower respiratory tracts in coronavirus infection. Viral infection-associated acute respiratory distress syndrome and acute lung injury occur because of dysregulation of the immune response. Mesenchymal stem cells appear to be a promising cell therapy given that they favorably modulate the immune response to reduce lung injury. The use of exogenous stem cells may lead to lung repair. Therefore, intervention by transplantation of exogenous stem cells may be required to replace, repair, remodel, and regenerate lung tissue in survivors infected with coronavirus. Ultimately, vaccines, natural killer cells and induced-pluripotent stem cell-derived virus-specific cytotoxic T lymphocytes may offer off-the-shelf therapeutics for preventing coronavirus reemergence.

[Diurnal Variations and Source Analysis of Water-soluble Compounds in PM2.5 During the Winter in Liaocheng City].

To investigate the diurnal variations and sources of water-soluble compounds in Liaocheng City, PM2.5 samples were collected between January and February 2017. The PM2.5 samples were analyzed for the compositions, concentrations, and sources of water-soluble inorganic ions, oxalic acid, and levoglucosan. The sources of these chemical compound were investigated using principal component analysis (PCA) and multiple linear regression (MLR) modeling. The results showed that the mass concentrations of PM2.5during the nighttime were higher than those during the daytime, and the average concentrations exceeded the National Ambient Air Quality Standard (GB 3095-2012) by more than 1.8 times. Moreover, atmospheric pollution was worse during the day than during the night. SNA (SO42-, NO3-, and NH4+) were the dominant species among the inorganic ions, the relative abundance of which with respect to the total concentrations of inorganic ions was 73.4% and 77.1% during the daytime and nighttime, respectively. The ratios of anion to cation equivalents (AE/CE) were less than one, suggesting that the PM2.5 was slightly alkaline, and the degree of acidity at night was stronger than during the day. The results of the correlation analyses suggested that aqueous-phase oxidation was the major formation pathway of oxalic acid, which is driven by acid-catalyzed oxidation. The oxalic acid was mainly influenced by biomass burning during the winter in Liaocheng City. The results of the PCA-MLR model suggested that water-soluble compounds in Liaocheng City were mostly from vehicular emissions and secondary oxidation, biomass burning, while the impacts of mineral dust and coal burning were relatively minor.

[Source Analysis and Health Risk Assessment of PAHs in PM2.5 During Winter in Liaocheng City].

To investigate the mass concentrations, sources, and health effects of polycyclic aromatic hydrocarbons (PAHs) in ambient particulate matter (PM) in Liaocheng City during winter, 14 types of PAHs in PM2.5 were determined from January to February of 2017. The sources of the PAHs were analyzed by using diagnostics ratios and the principal component analysis (PCA)-multiple linear regression (MLR) model,and the health risk of PAHs was assessed by BaP equivalent concentrations (BaPeq) and incremental lifetime cancer risk (ILCR). The results showed that the mass concentrations of PAHs in PM2.5 during winter were (64.89±48.23) ng·m-3, Fla, Pyr, and Chry were predominant species, accounting for 15.5%, 12.8%, and 12.7% of the total concentrations of PAHs, respectively. Moreover, the ring distribution of the PAHs was dominated by four-ring PAHs. The pollution during the pre-Spring Festival and firework Ⅱwere the most severe during the sampling period. The results of the PCA-MLR model suggested that PAHs originated mostly from coal burning, biomass burning, and vehicle emissions. The toxicity exposure index (TEQ) in Liaocheng City during winter was (6.37±4.92) ng·m-3. The results of the risk model revealed that the ILCR of adults was higher than that of children, and both groups of ILCR for winter were in the range of the risk threshold. This suggests that a potential risk in terms of inhalation PAH exposure for residents in Liaocheng City.

[Pollution Characteristics and Source Analysis of n-alkanes and Saccharides in PM2.5 During the Winter in Liaocheng City].

To investigate molecular composition, mass concentrations, and sources of n-alkanes and sugars which are adsorbed in ambient particulate matters in Liaocheng City during winter, PM2.5 samples were collected from January 17 to February 15, 2017 at Liaocheng University. 19 kinds (C18-C36) of n-alkanes and 10 kinds of sugars were determined using GC-MS. The identification of n-alkane and sugar sources were investigated using principal component analysis (PCA). The results showed that the mass concentrations of total n-alkanes in PM2.5 during the winter were (456.9±252.5) ng·m-3. During the haze period, the concentrations of n-alkanes were two times higher than those on clear days. Additionally, the concentrations of n-alkanes during fireworks event I and fireworks event Ⅱ were 0.9 times and 1.2 times higher than those on clear days. During the sampling period, the Carbon preference index (CPI) was 1.2±0.1, and the contribution from plant wax concentrations for n-alkanes (% Wax Cn) was between 3.1%~36.0%, indicating that fossil fuels were the major source of n-alkanes in Liaocheng City during the winter. The mass concentrations of saccharides in PM2.5 during the winter were (415.5±213.8) ng·m-3. Levoglucosan was the most abundant species, followed by galactosan and mannosan, which accounted for more than 91.6% of total saccharides, indicating that biomass burning was much more significant in Liaocheng City. PCA further suggested that n-alkane and saccharide compounds in atmospheric aerosol during the winter in Liaocheng City were primarily derived from fossil fuel and biomass burning.

[Analysis of Seasonal Variations in Chemical Characteristics and Sources of PM2.5 During Summer and Winter in Ji'nan City].

To investigate seasonal variations in the chemical compositions of aerosols in Ji'nan City, PM2.5 samples were collected during summer and winter in 2015. The sampling period lasted one month during each season. PM2.5 samples were analyzed for the composition, concentration, and sources of water-soluble inorganic ions, organic carbon (OC), elemental carbon (EC), and water-soluble organic carbon (WSOC). Results showed that mass concentrations of PM2.5 in winter were about twice those in summer, and concentration levels varied between fine and excellent. The concentrations of total water-soluble inorganic ions were also higher in winter than in summer, with SO42-, NO3-, and NH4+ being the dominant species and well correlated with each other. NH4+ in PM2.5 mostly existed in the form of (NH4)2SO4 and NH4NO3 in both summer and winter. There was strong secondary oxidation of SO2 and NO2. The sulfate oxidizing rate (SOR) was higher in summer than in winter, while the nitrate oxidizing rate (NOR) showed the opposite trend. The ratio of anions to cations in both summer and winter were less than one, suggesting that PM2.5 were slightly alkaline. The ISORROPIA-Ⅱ mode showed that acidity in winter was stronger than in summer. Concentations of OC and EC were both higher in winter than in summer. The ratios of OC to EC and WSOC to OC and estimated concentrations of secondary organic carbon (SOC) showed that secondary pollution was more serious in winter than in summer. Principal component analysis(PCA)indicated that the major sources contributing to inorganic ions were secondary oxidation and biomass burning in summer, and coal combustion and secondary pollutants formed by chemical oxidation of precursors emitted from coal combustion in winter.

[Diurnal Variation of Dicarboxylic Acids and Related SOA in PM2.5 from Heze City in Winter].

To identify the diurnal variation and formation mechanism of dicarboxylic acids and related compounds in PM2.5 from Heze City, PM2.5 samples were collected in the winter (December) of 2017, which were subsequently analyzed for dicarboxylic acids, ketocarboxylic acids, α-dicarbonyls, and levoglucosan (Levo). The results showed that the total concentrations of dicarboxylic and ketocarboxylic acids were higher during daytime than those during nighttime. In contrast to the diurnal variation of dicarboxylic and ketocarboxylic acids, the total concentrations of α-dicarbonyls exhibited higher concentrations in nighttime than in daytime. Because α-dicarbonyls are the major precursors of dicarboxylic acids, the opposing patterns suggest that the photochemical oxidation in daytime is stronger than that in nighttime. Oxalic acid (C2) is the dominant species during both day-and nighttime, followed by phahalic acid (Ph), succinic acid (C4), and malonic acid (C3), which is consistent with that in other urban regions. The mass ratios of C3/C4 (R2>0.7) correlated strongly with temperature, indicating that organic compounds in the atmosphere of Heze City are mainly derived from the photochemical oxidation of local emissions rather than long-range transport in winter. C2 correlated with in-situ pH and SO42-, suggesting that aqueous-phase oxidation was the major formation pathway of C2, which is driven by acid-catalyzed oxidation. Since the major SOA (C2, glyoxal, and methyglyoxal, secondary organic aerosol) correlated with Levo and the average mass rations of K+/organic carbon was 0.06 (ranging from 0.03 to 0.13), it can be concluded that the dicarboxylic acids and related SOA and K+ in Heze City were significantly influenced by biomass burning in winter.

Association between the p73 gene G4C14-to-A4T14 single nucleotide polymorphism and risk of cervical cancer by high resolution melting and PCR with confronting two-pair primers in a Chinese population.

As a member of the p53 gene family, the p73 gene can affect an individual's susceptibility to cancer through a p53-like manner. DNA sequence variation in the p73 gene has been reported to be associated with cancer risk. The present study aimed to identify whether the p73 gene G4C14-to-A4T14 single nucleotide polymorphism (SNP) is associated with risk of cervical cancer in a Chinese population. The p73 G4C14-to-A4T14 polymorphism was genotyped in 175 cervical cancer and 189 healthy control peripheral blood DNA samples using high resolution melting, polymerase chain reaction with confronting two-pair primers and direct DNA sequencing. The results demonstrated that carriers of the AT/AT genotype were associated with a significantly increased risk of cervical cancer (P=0.042; χ2=4.122; odds ratio = 2.241; 95% confidence interval = 1.013-4.956) compared with the GC/GC genotype carriers. In addition, there was a significant association between p73 genotypes and tumor size in patients with cervical cancer (P=0.014; χ2=8.607). However, no association was identified between p73 genotypes and tumor stage, histological type or lymph node metastasis in patients with cervical cancer. These results suggest that the p73 G4C14-to-A4T14 SNP may function as a marker of genetic susceptibility to cervical cancer in the Chinese population.

Association of miR-502-binding site single nucleotide polymorphism in the 3'-untranslated region of SET8 and TP53 codon 72 polymorphism with non-small cell lung cancer in Chinese population.

The objective of this study was to identify whether the miR-502-binding site single nucleotide polymorphism (SNP) in the 3'-untranslated region (3'-UTR) of set domain-containing protein 8 (SET8) and the tumor protein p53 (TP53) codon 72 polymorphism were associated with the risk for non-small cell lung cancer (NSCLC), either independently or jointly, among Chinese people from southern Han. The genotypes of SET8 and TP53 codon 72 polymorphisms of peripheral blood DNA were detected using polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequencing in a case-control study on 164 NSCLC cases and 199 controls. The SET8 TT (odds ratio, OR = 2.173, 95% confidence interval, CI = 1.0454.517) or TP53 GG (OR = 2.579, 95% CI = 1.366-4.870) genotype was associated with an increased risk of NSCLC by comparing with the SET8 CC or TP53 CC genotype, respectively. Similar results were obtained in SET8 recessive model (OR = 2.074, 95% CI = 1.019-4.221, P < 0.05), and the dominant and recessive model of TP53 codon 72 were performed, respectively (OR = 1.809, 95% CI = 1.159-2.825, P < 0.05; OR = 1.933, 95% CI = 1.096-3.409, P < 0.05). In addition, interaction between the SET8 and TP53 polymorphisms increased the risk of NSCLC in a multiply manner, with the OR being 3.032 (95%CI = 1.580-5.816) for subjects carrying both SET8 TT and TP53 GG genotypes. Therefore, the miR-502-binding site SNP in the 3'-UTR of SET8 and the TP53 codon 72 polymorphism may be markers of genetic susceptibility to NSCLC in Chinese population, and there is a possible gene-gene interaction in the incidence of NSCLC.