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Papillary thyroid carcinoma (PTC) is a common malignancy worldwide. LncRNA LINC00704 (mitotically associated long non-coding RNA) was reported as a crucial regulator in PTC. However, the biological mechanism of LINC00704 action remains unclear in PTC. The mRNA levels of LINC00704, miR-204-5p, and high-mobility group box 1 (HMGB1) were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay. HMGB1, proliferating cell nuclear antigen (PCNA), and cyclin D1 protein levels were detected using the Western blot assay. The binding relationship between miR-204-5p and LINC00704 or HMGB1 was predicted by LncBase Predicted v.2 or TargetScan, respectively, and then validated by dual luciferase reporter assay. Cell viability, cell cycle, cell migration and invasion, and migration ratio were assessed by MTT, flow cytometry, transwell cell migration and invasion, and wound-healing assays, respectively. Results suggested that LINC00704 and HMGB1 were elevated and miR-204-5p decreased in PTC tissues and cells. Furthermore, rescue experiments demonstrated that the miR-204-5p inhibitor alleviated the inhibitory effects of LINC00704 knockdown on cell proliferation, cell cycle, migration, and invasion. Meanwhile, miR-204-5p overexpression repressed proliferation, migration, and invasion by targeting HMGB1. Mechanical analysis discovered that LINC00704 could act as an miR-204-5p sponge to modulate HMGB1 expression. In conclusion, LINC00704 promoted PTC cell proliferation, cell cycle, migration, and invasion by the miR-204-5p/HMGB1 axis, providing a novel therapeutic target for PTC patients.

Byline: Duan. Xiao, Yihui. Lin, Xiaofeng. Wang, Canhong. Yang, Xiaoyu. Huang, Bo. Fu, Qingzhu. Wei, Tianming. Lü Sir, Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a novel NMDAR-mediated form of autoimmune [...]

N6‐methyladenosine (m6A) and long noncoding RNAs (lncRNAs) are both crucial regulators in non‐small‐cell lung cancer (NSCLC) tumorigenesis. However, the pathological roles of m6A and lncRNAs in NSCLC progression are still limited and undefined. Here, lncRNA ABHD11‐AS1 was upregulated in NSCLC tissue specimens and cells and the ectopic overexpression was closely correlated with unfavorable prognosis of NSCLC patients. Functionally, ABHD11‐AS1 promoted the proliferation and Warburg effect of NSCLC. Mechanistically, m6A profile was analyzed by methylated RNA immunoprecipitation sequencing (MeRIP‐Seq). MeRIP‐Seq presented that there was m6A modification site in ABHD11‐AS1. m6A methyltransferase‐like 3 (METTL3) installed the m6A modification and enhanced ABHD11‐AS1 transcript stability to increase its expression. In conclusion, our findings highlight the function and mechanism of METTL3‐induced ABHD11‐AS1 in NSCLC and inspire the understanding of m6A and lncRNA in cancer biology. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the novel mechanisms of forkhead box protein P3 (foxp3) in T regulatory (Treg) cells in lung cancer behavior. Treg cells were isolated from the peripheral blood of healthy volunteers and then co‑cultured with 95D cells. A plasmid overexpressing foxp3 was constructed and transfected into Treg cells and an MTS assay was performed to assess cell viability. Flow cytometry was performed to evaluate cell apoptosis and reverse transcription‑quantitative polymerase chain reaction was used to measure mRNA expression. A Transwell assay was used to assess cell invasion. Treg cells were successfully isolated from peripheral blood with purity of 94.26%. Foxp3 expression in Treg cells was significantly increased following co‑culture with 95D cells, while matrix metalloproteinase‑9 expression was upregulated in 95D cells co‑cultured with Treg cells. The apoptosis, invasion and migration abilities of 95D cells were suppressed by co‑culture with Treg cells, whereas the adhesive ability was enhanced. Foxp3 overexpression in Treg cells enhanced the viability and invasiveness of 95D cells, whereas cell adhesion and migration were decreased. The results of the present study demonstrate that the viability and invasiveness of 95D cells are enhanced by foxp3 overexpression in Treg cells, indicating that increased levels of foxp3 in the tumor microenvironment may promote tumor cell growth. [ABSTRACT FROM AUTHOR]

Multivariate analysis within central composite design is applied to simplify an optimization procedure and explore the interactions among experimental parameters in analytical chemistry. In this study, central composite design was used to identify the optimal capillary electrophoresis conditions with electroosmotic flow modulation to determine seven exfoliating agents in cosmetics. The influence of phosphate concentration, cetyltrimethylammonium bromide concentration, and methanol percentage on the response was evaluated by the use of the chromatographic exponential function to simultaneously investigate the resolution and separation under sixteen sets of capillary electrophoresis conditions. The optimized conditions were 150 mM phosphate solution (pH = 7) containing 0.5 mM cetyltrimethylammonium bromide, 3 mM γ-cyclodextrin, and 25% methanol as the running buffer. To shorten the analysis time, an electroosmotic flow modulating agent (cetyltrimethylammonium bromide) was added to the separation buffer. Calibration plots were linear (r ≧ 0.998) with high precision and accuracy in the homemade cosmetic matrix. The exfoliating agents in two commercial cosmetic products were determined using the optimized conditions, and the results correlated well with results obtained by high-performance liquid chromatography–mass spectrometry. [ABSTRACT FROM AUTHOR]

Using laser 40Ar/39Ar dating method, we have gotten the metamorphic ages of lawsonite blueschist and epidote blueschist from Jiuquan, northern Qilian Mountain, NW China. The high quality laser 40Ar/39Ar dating of glaucophane from lawsonite blueschist gives an isochron age of 413±5 Ma. The isochron age obtained from phengite in epidote blueschist is 415±7 Ma. These data, combining with peak metamorphic P-T conditions and regional geological setting, allow us to infer that the lower limit of the ages of the prograde subduction metamorphism from lawsonite blueschist facies to epidote blueschist facies occurred at ca. 413--415 Ma, which also suggests that the formation of lawsonite blueschist in the northern Qilian Mountain maybe resulted from the corner flow in the cold subduction zone. This study shows that the final closing time of the northern Qilian remnant oceanic basin is about 413--415 Ma, which also represents the convergent age between the North China Craton and the Qaidam block. [ABSTRACT FROM AUTHOR]

Water transport time scales are important indicators to assess the renewal of substance inside coastal embayments. Estimates of water renewal efficiency represented by residence and influence times in Xiamen Bay were made via a series of numerical experiments, using the instantaneous tracer injection method. It was found that the average e -folding threshold residence time in the bay is approximately 16.5 days, and that the residence time increases near the entrances to land because water exchange between the bay and the Taiwan Strait is the dominant water-renewal process. The seawater influence time has a similar spatial distribution to the residence time. The freshwater influence time is much shorter in the western region of the bay than in the eastern region, which shows that the influence of Jiulong River freshwater is largely restricted to the western region. The changes in the residence and influence times reveal that increased river discharge mainly accelerates water renewal in the western region of the bay, whereas increased tides mainly accelerate water renewal in the eastern region and the northern part of the western region. The drivers of water renewal were examined using effective transport velocities that were defined based on the decomposition of tracer flux, and showed that tidal residual flow determines the extent of water renewal in Xiamen Bay. The estimation of residence time is sensitive to the operation of instantaneous method. The release of tracer at spring tide results in a shorter residence time and the use of a small threshold can improve the consistency of estimated threshold residence times. • Residence time is 16.5 days over Xiamen Bay and increases from entrances to land. • Seawater influence time has a similar distribution to that of residence time. • Freshwater influence time is shorter in the western region than in the eastern region. • Increasing river discharge mainly accelerates water renewal in the western region. • Increasing tides mainly accelerate water renewal in the eastern region. [ABSTRACT FROM AUTHOR]

Purpose: Bulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART., Methods and Materials: We defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV's border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents., Results: 21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14 - 85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009)., Conclusion: SCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Lu, Qi, Kolb, Wang, Li, Li, Lin, Liu, Mourad, MirkhaghaniHaghighi, Slavisa, Wu, You, Yang, Hanlon, Zhu and Yan.)

We tried to unveil the clinical significance of miR-146a as a biomarker in M2 macrophage polarization in diabetic wound healing. Initially, we found reduced miR-146a in macrophages of diabetic patients. Next, dual-luciferase assay verified that toll-like receptor 4 (TLR4) was a target gene of miR-146 and was negatively regulated by miR-146. Moreover, after ectopic expression and depletion experiments of miR-146 and/or TLR4, lipopolysaccharide-induced inflammatory response of macrophages was detected. The results revealed that overexpression of miR-146a promoted the M2 macrophage polarization by suppressing the TLR4/nuclear factor-kappaB (NF-κB) axis, so as to enhance wound healing in diabetic ulcers. Further, mouse models with diabetic ulcers were established to investigate the effects of miR-146a on diabetic wound healing in vivo, which revealed that miR-146a promoted wound healing in diabetic ulcers by inhibiting the TLR4/NF-κB axis. In conclusion, we demonstrate that miR-146a can induce M2 macrophage polarization to enhance wound healing in diabetic ulcers by inhibiting the TLR4/NF-κB axis.

N 6 -methyladenosine (m 6 A) and long noncoding RNAs (lncRNAs) are both crucial regulators in non-small-cell lung cancer (NSCLC) tumorigenesis. However, the pathological roles of m 6 A and lncRNAs in NSCLC progression are still limited and undefined. Here, lncRNA ABHD11-AS1 was upregulated in NSCLC tissue specimens and cells and the ectopic overexpression was closely correlated with unfavorable prognosis of NSCLC patients. Functionally, ABHD11-AS1 promoted the proliferation and Warburg effect of NSCLC. Mechanistically, m 6 A profile was analyzed by methylated RNA immunoprecipitation sequencing (MeRIP-Seq). MeRIP-Seq presented that there was m 6 A modification site in ABHD11-AS1. m 6 A methyltransferase-like 3 (METTL3) installed the m 6 A modification and enhanced ABHD11-AS1 transcript stability to increase its expression. In conclusion, our findings highlight the function and mechanism of METTL3-induced ABHD11-AS1 in NSCLC and inspire the understanding of m 6 A and lncRNA in cancer biology., (© 2020 Wiley Periodicals LLC.)

Previously reported haemostatic reference intervals in normal pregnancy displayed considerable contradictions to establish convince gestational age-related haemostatic reference values. 30 clinical reports were recruited to collect and assemble existing clinical reports from the database D-dimer levels increased progressively with gestational ages and exceeded conventional value of 1 mg/L after 29-36 weeks, and reached a peak at 24 h postpartum with mean value of 6.44 mg/L [95% confidence interval (CI): 5.84 to 7.05] and returned to 0.79 mg/L (95% CI: 0.43 to 1.16) at 1-8 weeks postpartum. Analogously, the level of fibrinogen gradually increased throughout the pregnancy, and peaked at 48-72 h after birth, with mean value of 9.05 g/L (95% CI: 2.22 to 15.89) and then returned to 3.62 g/L (95% CI: 3.03 to 4.20) at 1-8 weeks postpartum. However, in the middle trimester, asynchronously prothromb in fragments 1 + 2 (F1+2) level elevated and reached a peak at 28-36 weeks with mean value of 3.05 nmol/L (95% CI: 2.41 to 3.70), and then decreased in the later trimester, and reached 1.92 nmol/L (95% CI: 0.58 to 3.27) at 48-72 h post-partum, close to normal levels. Previously reported gestational age-related haemostatic reference intervals in pregnancy could not be used as a standard., (Copyright © 2018. Published by Elsevier B.V.)

Bispecific antibodies provide an efficient tool for combinational clinical therapy. Here we have engineered a heterodimeric Fc for bispecific antibodies production by combining the knob-into-hole and electrostatic steering strategies where a bulky hydrophobic residue Phe405 of the IgG CH3 interface is mutated to a charged residue Lys and Lys409 of the corresponding CH3 domain is mutated to Ala. The crystal structure of this Fc heterodimer solved here at 2.7Å resolution revealed how these two mutations resulted a complementary binding interface and explained why F405K mutation could effectively inhibit Fc homodimer formation during protein expression. An anti-HER2 bispecific antibody derived from trastuzumab and pertuzumab was generated by this heterodimeric Fc. It showed comparable or improved efficacy than the combination of trastuzumab and pertuzumab in inhibiting proliferation of cancer cells in vitro and in vivo . Overall this study shows that the heterodimeric Fc engineered here provides an efficient platform for generating active bispecific antibody for cancer treatment., Competing Interests: CONFLICTS OF INTEREST Y. L is an employee of 3D Medicines Corporation.

Purpose: Gallbladder sarcomatoid carcinoma is a rare cancer with no clinical standard treatment. With the rapid development of next generation sequencing, it has been able to provide reasonable treatment options for patients based on genetic variations. However, most cancer drugs are not approval for gallbladder sarcomatoid carcinoma indications. The correlation between drug response and a genetic variation needs to be further elucidated., Experimental Design: Three patient-derived cells-JXQ-3D-001, JXQ-3D-002, and JXQ-3D-003, were derived from biopsy samples of one gallbladder sarcomatoid carcinoma patient with progression and have been characterized. In order to study the relationship between drug sensitivity and gene alteration, genetic mutations of three patient-derived cells were discovered by whole exome sequencing, and drug screening has been performed based on the gene alterations and related signaling pathways that are associated with drug targets., Results: It has been found that there are differences in biological characteristics such as morphology, cell proliferation, cell migration and colony formation activity among these three patient-derived cells although they are derived from the same patient. Their sensitivities to the chemotherapy drugs-Fluorouracil, Doxorubicin, and Cisplatin are distinct. Moreover, none of common chemotherapy drugs could inhibit the proliferations of all three patient-derived cells. Comprehensive analysis of their whole exome sequencing demonstrated that tumor-associated genes TP53, AKT2, FGFR3, FGF10, SDHA, and PI3KCA were mutated or amplified. Part of these alterations are actionable. By screening a set of compounds that are associated with the genetic alteration, it has been found that GDC-0941 and PF-04691502 for PI3K-AKT-mTOR pathway inhibitors could dramatically decrease the proliferation of three patient-derived cells. Importantly, expression of phosphorylated AKT and phosphorylated S6 were markedly decreased after treatments with PI3K-AKT-mTOR pathway inhibitors GDC-0941 (0.5 μM) and PF-04691502 (0.1 μM) in all three patient-derived cells. These data suggested that inhibition of the PI3K-AKT-mTOR pathway that was activated by PIK3CA amplification in all three patient-derived cells could reduce the cell proliferation., Conclusions: A patient-derived cell model combined with whole exome sequencing is a powerful tool to elucidate relationship between drug sensitivities and genetic alternations. In these gallbladder sarcomatoid carcinoma patient-derived cells, it is found that PIK3CA amplification could be used as a biomarker to indicate PI3K-AKT-mTOR pathway activation. Block of the pathway may benefit the gallbladder sarcomatoid carcinoma patient with this alternation in hypothesis. The real efficacy needs to be confirmed in vivo or in a clinical trial.

Propionylation has been identified recently as a new type of protein post-translational modification. Bacterial propionyl-CoA synthetase and human histone H4 are propionylated at specific lysine residues that have been known previously to be acetylated. However, other proteins subject to this modification remain to be identified, and the modifying enzymes involved need to be characterized. In this work, we report the discovery of histone H3 propionylation in mammalian cells. Propionylation at H3 lysine Lys(23) was detected in the leukemia cell line U937 by mass spectrometry and Western analysis using a specific antibody. In this cell line, the propionylated form of Lys(23) accounted for 7%, a level at least 6-fold higher than in other leukemia cell lines (HL-60 and THP-1) or non-leukemia cell lines (HeLa and IMR-90). The propionylation level in U937 cells decreased remarkably during monocytic differentiation, indicating that this modification is dynamically regulated. Moreover, in vitro assays demonstrated that histone acetyltransferase p300 can catalyze H3 Lys(23) propionylation, whereas histone deacetylase Sir2 can remove this modification in the presence of NAD(+). These results suggest that histone propionylation might be generated by the same set of enzymes as for histone acetylation and that selection of donor molecules (propionyl-CoA versus acetyl-CoA) may determine the difference of modifications. Because like acetyl-CoA, propionyl-CoA is an important intermediate in biosynthesis and energy production, histone H3 Lys(23) propionylation may provide a novel epigenetic regulatory mark for cell metabolism.

Epigenetic modifications play an important role in human cancer. One such modification, histone methylation, contributes to human cancer through deregulation of cancer-relevant genes. The yeast Dot1 and its human counterpart, hDOT1L, methylate lysine 79 located within the globular domain of histone H3. Here we report that hDOT1L interacts with AF10, an MLL (mixed lineage leukemia) fusion partner involved in acute myeloid leukemia, through the OM-LZ region of AF10 required for MLL-AF10-mediated leukemogenesis. We demonstrate that direct fusion of hDOT1L to MLL results in leukemic transformation in an hDOT1L methyltransferase activity-dependent manner. Transformation by MLL-hDOT1L and MLL-AF10 results in upregulation of a number of leukemia-relevant genes, such as Hoxa9, concomitant with hypermethylation of H3-K79. Our studies thus establish that mistargeting of hDOT1L to Hoxa9 plays an important role in MLL-AF10-mediated leukemogenesis and suggests that the enzymatic activity of hDOT1L may provide a potential target for therapeutic intervention.