Uncommon de novo EGFRT790M-Mutant NSCLC characterized with unique genetic Features: Clinical response and acquired resistance to the third-generation EGFR-TKIs treatment.

INTRODUCTION: The literature on de novo EGFRT790M-mutant patients diagnosed with lung cancer is limited, and there is currently no consensus concerning the most effective treatment protocols. This study aimed to investigate the genomic characteristics of de novoEGFRT790M-mutant non-small cell lung cancer (NSCLC) and provide insights into its clinical response and resistance mechanism to third-generation EGFR-TKIs. METHODS: Next-generation sequencing was utilized to screen a substantial cohort of 4,228 treatment-naïve patients from the Mygene genomic database to identifythe de novo EGFR-T790M mutation. Meanwhile, we recruited 83 individuals diagnosed with lung cancer who harbored de novo EGFRT790M mutation in the real world. In addition, 166 patients who acquired EGFR-T790M mutation after becoming resistant to first- or second-generation EGFR-TKIs were included as a comparison cohort. RESULTS: De novo EGFRT790M mutation identified by next-generation sequencing is rare (∼1.3 %) in Chinese lung cancer patients. The relative variant allele frequency (VAF) of de novo EGFRT790M mutation was either comparable to or significantly lower than those of EGFR-activating mutations. Patients with de novo-T790M mutations exhibited less favorable clinical outcomes when administered third-generation EGFR-TKIs as first-line therapy thanthose with 19del mutationsdue to a high overlap rate in EGFR p.L858R mutation. In patients with a de novo EGFRT790M mutation, no correlation was observed between T790M clonality and treatment outcomes with third-generation EGFR-TKIs. In contrast, the sub-clonality of the T790M mutation detrimentally affected the third-generation EGFR-TKI treatment efficacy in patients with acquired T790M mutation. Potential resistance mechanisms of third-generation EGFR TKIs in NSCLC patients with de novo or acquired EGFRT790M mutations included EGFR p.C797S in cis or EGFR p.E709X mutation, as well as activation of bypass pathways. CONCLUSIONS: The present study characterized the uncommon but unique de novo EGFRT790M-mutant NSCLC and laid a foundation for designing future clinical trials in the setting of uncommon EGFR mutation.

Benefits of Curcumin in the Vasculature: A Therapeutic Candidate for Vascular Remodeling in Arterial Hypertension and Pulmonary Arterial Hypertension?

Growing evidence suggests that hypertension is one of the leading causes of cardiovascular morbidity and mortality since uncontrolled high blood pressure increases the risk of myocardial infarction, aortic dissection, hemorrhagic stroke, and chronic kidney disease. Impaired vascular homeostasis plays a critical role in the development of hypertension-induced vascular remodeling. Abnormal behaviors of vascular cells are not only a pathological hallmark of hypertensive vascular remodeling, but also an important pathological basis for maintaining reduced vascular compliance in hypertension. Targeting vascular remodeling represents a novel therapeutic approach in hypertension and its cardiovascular complications. Phytochemicals are emerging as candidates with therapeutic effects on numerous pathologies, including hypertension. An increasing number of studies have found that curcumin, a polyphenolic compound derived from dietary spice turmeric, holds a broad spectrum of pharmacological actions, such as antiplatelet, anticancer, anti-inflammatory, antioxidant, and antiangiogenic effects. Curcumin has been shown to prevent or treat vascular remodeling in hypertensive rodents by modulating various signaling pathways. In the present review, we attempt to focus on the current findings and molecular mechanisms of curcumin in the treatment of hypertensive vascular remodeling. In particular, adverse and inconsistent effects of curcumin, as well as some favorable pharmacokinetics or pharmacodynamics profiles in arterial hypertension will be discussed. Moreover, the recent progress in the preparation of nano-curcumins and their therapeutic potential in hypertension will be briefly recapped. The future research directions and challenges of curcumin in hypertension-related vascular remodeling are also proposed. It is foreseeable that curcumin is likely to be a therapeutic agent for hypertension and vascular remodeling going forwards.

Progress on methods for acquiring flanking genomic sequence.

Flanking genomic sequences refer to the DNA sequences flanking specific sites of known sequences in chromosome, which contain information such as candidate genes, transcriptional regulation, chromosome structure, and biosafety, and play an important role in genomics research. Flanking sequence acquisition technologies are mainly used in the cloning of regulatory sequences such as promoters and enhancers, identification of T-DNA or transposon insertion sites, chromosome walking, genome-wide gap filling, etc. It is an important means of structural genomics research and functional genomics research. It is applied in the identification of transgenic plants and animals and their safety management. With the development of molecular biology, many methods for obtaining flanking sequences have been established, including plasmid rescue, inverse PCR, ligation-mediated PCR, semi-random primer PCR, whole-genome resequencing etc. In this review, we summarize and compared different methods for acquiring flanking genomic sequence. The principles and research progress of each approach are discussed.

An organic plastic ferroelectric with high Curie point.

Plastic ferroelectrics, featuring large entropy changes in phase transitions, hold great potential application for solid-state refrigeration due to the electrocaloric effect. Although conventional ceramic ferroelectrics (e.g., BaTiO3 and KNbO3) have been widely investigated in the fields of electrocaloric material and catalysis, organic plastic ferroelectrics with a high Curie point (T c) are rarely reported but are of great importance for the sake of environmental protection. Here, we reported an organic plastic ferroelectric, (-)-camphanic acid, which crystallizes in the P21 space group, chiral polar 2 (C2) point group, at room temperature. It undergoes plastic paraelectric-to-ferroelectric phase transition with the Aizu notation of 23F2 and high T c of 414 K, showing large entropy gain (ΔS t = 48.2 J K-1 mol-1). More importantly, the rectangular polarization-electric field (P-E) hysteresis loop was recorded on the thin film samples with a large saturated polarization (P s) of 5.2 µC cm-2. The plastic phase transition is responsible for its multiaxial ferroelectric feature. This work highlights the discovery of organic multiaxial ferroelectrics driven by the motive of combining chirality and plastic phase transition, which will extensively promote the practical application of such unique functional materials.

A narrative review of plant and herbal medicines for delaying diabetic atherosclerosis: an update and future perspectives.

Due to their high prevalence and incidence, diabetes and atherosclerosis are increasingly becoming global public health concerns. Atherosclerosis is one of the leading causes of morbidity and disability in type 1 and/or type 2 diabetes patients. Atherosclerosis risk in diabetic patients is obviously higher than that of non-diabetic individuals. Diabetes-related glycolipid metabolism disorder has been shown to play a central role in atherosclerosis development and progression. Hyperglycemia and dyslipidemia increase the risks for atherosclerosis and plaque necrosis through multiple signaling pathways, such as a prolonged increase in reactive oxygen species (ROS) and inflammatory factors in cardiovascular cells. Notwithstanding the great advances in the understanding of the pathologies of diabetes-accelerated atherosclerosis, the current medical treatments for diabetic atherosclerosis hold undesirable side effects. Therefore, there is an urgent demand to identify novel therapeutic targets or alternative strategies to prevent or treat diabetic atherosclerosis. Burgeoning evidence suggests that plant and herbal medicines are closely linked with healthy benefits for diabetic complications, including diabetic atherosclerosis. In this review, we will overview the utilization of plant and herbal medicines for the treatment of diabetes-accelerated atherosclerosis. Furthermore, the underlying mechanisms of the ethnopharmacological therapeutic potentials against diabetic atherosclerosis are gathered and reviewed. It is foreseeable that the natural constituents from medicinal plants might be a new hope for the treatment of diabetes-accelerated atherosclerosis.

[Spatio-temporal Variation Characteristics Monitored by Remotely Sensed Technique of PM2.5 Concentration and Its Influencing Factor Analysis in Sichuan Basin, China].

The spread of atmospheric pollutants in the Sichuan Basin is difficult because of its unique topography, static wind, high humidity, and other meteorological conditions. Owing to the acceleration of urbanization and industrialization, PM2.5 pollution in the region is becoming increasingly severe, and the Sichuan Basin has become one of the key areas of national air pollution prevention and control. In this study, based on the remote sensing inversion product of PM2.5 concentration, spatial autocorrelation and gray correlation analyses are used to evaluate the spatial and temporal distribution characteristics and influencing factors of PM2.5 concentration in the Sichuan Basin. The results show that PM2.5 concentration has significant spatial aggregation; the high-high aggregation types are concentrated, low-low aggregation types are more dispersed, and coniferous forest has a significantly higher inhibitory effect on the absorption of PM2.5 than the shrub, grassland, and other vegetation types. The main meteorological factors affecting PM2.5 concentration in the Sichuan Basin are wind speed and temperature; population density and economic scale are the main human-activity factors affecting PM2.5 concentration in the Sichuan Basin, and the change in the industrial structure and scale also has a certain influence on the PM2.5 concentration.

Target Designing Phase Transition Materials through Halogen Substitution.

Crystalline materials have received extensive attention due to their extraordinary physical and chemical properties. Among them, phase transition materials have attracted great attention in the fields of photovoltaic, switchable dielectric devices, and ferroelectric memories, etc. However, many of them suffer from low phase transition temperatures, which limits their practical application. In this work, we systematically designed crystalline materials, (TMXM)2 PtCl6 (X=F, Cl, Br, I) through halogen substitution on the cations, aiming to improving phase transition temperature. The resulting phase transition of (TMXM)2 PtCl6 (X=F, Cl, Br, I) get a significant enhancement, compared to the parent compound [(CH3 )4 N]2 PtCl6 ((TM)2 PtCl6 ). Such phase transition temperature enhancement can be attributed to the introduction of halogen atoms that increase the potential energy barrier of the cation rotation. In addition, (TMBM)2 PtCl6 and (TMIM)2 PtCl6 have a low symmetry and crystallize in the space group C2 /c and P21 21 21 , respectively. This work highlights the halogen substitution in designing crystal materials with high phase transition temperature.

Lrrc34 Is Highly Expressed in SSCs and Is Necessary for SSC Expansion In Vitro.

Objective To discover critical genes contributing to the stemness and maintenance of spermatogonial stem cells (SSCs) and provide new insights into the function of the leucine-rich repeat (LRR) family member Lrrc34 (leucine-rich repeat-containing 34) in SSCs from mice. Methods Bioinformatic methods, including differentially expressed gene (DEG), gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, were used to uncover latent pluripotency-related genes. Reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence analyses were utilized to verify the mRNA and protein expression levels, respectively. RNA interference of Lrrc34 using siRNA was performed to detect its transient impact on SSCs. Results Eight DEGs between ID4-EGFP+ (G) and ID4-EGFP+/TSPAN8High (TH), eight DEGs between G and ID4-EGFP+/TSPAN8Low (TL) and eleven DEGs between TH and TL were discovered, and eleven protein-protein interaction (PPI) modules were found to be significant in the PPI network of DEGs. One of the DEGs, Lrrc34, was selected as a potential pluripotency-related gene due to its differential expression among ID4-EGFP+ spermatogonia subsets and its interaction with fibroblast growth factor 2 in the fifth module. Immunofluorescence experiments exhibited specific expression of Lrrc34 in a subpopulation of undifferentiated spermatogonia marked by LIN28A, and RT-PCR experiments confirmed the high expression of Lrrc34 in SSCs from P7 and adult mice. The transient knockdown of Lrrc34 in SSCs resulted in reduced colony sizes and significant changes in the transcriptome and apoptotic pathways. Conclusion Lrrc34 is highly expressed in mouse SSCs and is required for SSC proliferation in vitro through effects on transcriptome and signaling transduction pathways.

The wound healing potential of collagen peptides derived from the jellyfish Rhopilema esculentum.

PURPOSE: Wound represents a major health challenge as they consume a large amount of healthcare resources to improve patient's quality of life. Many scientific studies have been conducted in search of ideal biomaterials with wound-healing activity for clinical use and collagen has been proven to be a suitable candidate biomaterial. This study intended to investigate the wound healing activity of collagen peptides derived from jellyfish following oral administration. METHODS: In this study, collagen was extracted from the jellyfish--Rhopilema esculentum using 1% pepsin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fourier transform infrared (FTIR) were used to identify and determine the molecular weight of the jellyfish collagen. Collagenase II, papain and alkaline proteinase were used to breakdown jellyfish collagen into collagen peptides. Wound scratch assay (in vitro) was done to determine migration potential of human umbilical vein endothelial cells (HUVEC) covering the artificial wound created on the cell monolayer following treatment with collagen peptides. In vivo studies were conducted to determine the effects of collagen peptides on wound healing by examining wound contraction, re-epithelialization, tissue regeneration and collagen deposition on the wounded skin of mice. Confidence level (p < 0.05) was considered significant using GraphPad Prism software. RESULTS: The yield of collagen was 4.31%. The SDS-PAGE and FTIR showed that extracted collagen from jellyfish was type I. Enzymatic hydrolysis of this collagen using collagenase II produced collagen peptides (CP1) and hydrolysis with alkaline proteinase/papain resulted into collagen peptides (CP2). Tricine SDS-PAGE revealed that collagen peptides consisted of protein fragments with molecular weight <25 kDa. Wound scratch assay showed that there were significant effects on the scratch closure on cells treated with collagen peptides at a concentration of 6.25 µg/mL for 48 h as compared to the vehicle treated cells. Overall treatment with collagen peptide on mice with full thickness excised wounds had a positive result in wound contraction as compared with the control. Histological assessment of peptides treated mice models showed remarkable sign of re-epithelialization, tissue regeneration and increased collagen deposition. Immunohistochemistry of the skin sections showed a significant increase in ß-fibroblast growth factor (ß-FGF) and the transforming growth factor-ß1 (TGF-ß1) expression on collagen peptides treated group. CONCLUSION: Collagen peptides derived from the jellyfish-Rhopilema esculentum can accelerate the wound healing process thus could be a therapeutic potential product that may be beneficial in wound clinics in the future.

[Clinical Analysis on the Therapeutic Efficacy of Autologous Hematopoietic Stem Cell Transplantation in 56 Multiple Myeloma Patients].

OBJECTIVE: To evaluate the therapeutic efficacy and prognosis of autologous stem Hematopoietic cell transplantation (auto-HSCT) in multiple myeloma (MM) patients. METHODS: A retrospective study was conducted for 56 patients diagnosed with MM and then received auto-HSCT in our hospital from December 2008 to September 2016. RESULTS: All the patients successfully underwent hematopoietic reconstruction without transplantation-related mortality (TRM). The complete response (CR) rate of all the patients after induction chemotherapy was 23.2% (13/56), while the CR rate of these patients with auto-HSCT increased to 78.6% (44/56) (P<0.01). The CR plus VGPR (very good partial response) rates of these 56 patients after induction chemotherapy and auto-HSCT were 53.6%（30/56）and 94.6%（53/56） respectively (P<0.01). The median progression-free survival (PFS) time and median overall survival (OS) time were 37 and 71 months, respectively. The median PFS time in the patients with induction therapy containing bortezomib was 37 months, however, the median OS time did not reach to 71 months; the median PFS (P<0.01) and the median OS (P<0.01) in the patients with the induction chemotherapy without bortezomib was 27 and 51 months, respectively. Univariate analysis demonstrated that the patients maintained CR or VGPR after auto-HSCT or with less than 6 cycles of induction chemotherapy significantly correlated with PFS (P<0.01). CONCLUSION: auto-HSCT can further increase the CR rate, prolong PFS and OS time. Sequential auto-HSCT after bortezomib-based therapy is the first line therapy for the transplant-eligible MM patients. Maintenance treatment is beneficial to the sustained CR+VGPR patients after auto-HSCT.