Construction and validation of the prognostic nomogram model for patients with diffuse-type gastric cancer based on the SEER database.

OBJECTIVE: The prognostic factors of diffuse GC patients were screened the prognostic nomogram was constructed, and the prediction accuracy was verified. METHODS: From 2006 to 2018, there were 2877 individuals pathologically diagnosed with diffuse gastric cancer; the clinicopathological features of these patients were obtained from the SEER database & randomly divided into a training cohort (1439) & validation cohort (1438).To create prognostic nomograms & choose independent prognostic indicators to predict the overall survival (OS) of 1, 3, & 5 years, log-rank & multivariate COX analysis were utilized & discrimination ability of nomogram prediction using consistency index and calibration curve. RESULTS: Age, T, N, M, TNM, surgical status, chemotherapy status, & all seven markers were independent predictors of OS (P < 0.05), & a nomogram of OS at 1, 3, & 5 years was created using these independent predictors. The nomogram's c-index was 0.750 (95% CI 0.734 ~ 0.766), greater than the TNM staging framework 0.658 (95%CI 0.639 ~ 0.677); the c-index was 0.753 (95% CI 0.737 ~ 0.769) as well as superior to the TNM staging mechanism 0.679 (95% CI 0.503-0.697). According to the calibration curve, the projected survival rate using the nomogram & the actual survival rate are in good agreement. CONCLUSIONS: Prognostic nomograms are useful tools for physicians to assess every individual's individualised prognosis & create treatment strategies for those with diffuse gastric cancer. They can reliably predict the prognosis for individuals with diffuse gastrointestinal carcinoma.

Genomic Profiling Reveals Immune-Related Gene Differences in Lung Cancer Patients Stratified by PD1/PDL1 Expression: Implications for Immunotherapy Efficacy.

Lung cancer remains a leading cause of global cancer-related mortality, and the exploration of innovative therapeutic approaches, such as PD1/PDL1 immunotherapy, is critical. This study leverages comprehensive data from the Cancer Genome Atlas (TCGA) to investigate the differential expression of PD1/PDL1 in lung cancer patients and explores its implications. Clinical data, RNA expression, somatic mutations, and copy number variations of 1017 lung cancer patients were obtained from TCGA. Patients were categorized into high (HE) and low (LE) PD1/PDL1 expression groups based on mRNA levels. Analyses included differential gene expression, functional enrichment, protein-protein interaction networks, and mutational landscape exploration. The study identified 391 differentially expressed genes, with CD4 and PTPRC among the upregulated genes in the HE group. Although overall survival did not significantly differ between HE and LE groups, enrichment analysis revealed a strong association with immunoregulatory signaling pathways, emphasizing the relevance of PD1/PDL1 in immune response modulation. Notably, TP53 mutations were significantly correlated with high PD1/PDL1 expression. This study provides a comprehensive analysis of PD1/PDL1 expression in lung cancer, uncovering potential biomarkers and highlighting the intricate interplay between PD1/PDL1 and the immune response. The identified upregulated genes, including CD4 and PTPRC, warrant further investigation for their roles in the context of lung cancer and immunotherapy. The study underscores the importance of considering molecular heterogeneity in shaping personalized treatment strategies for lung cancer patients. Limitations, such as the retrospective nature of TCGA data, should be acknowledged.

Acquired ALK G1202R-, ALK I1171N-, or EML4-ALK-mediated resistance to ensartinib in lung adenocarcinoma but responded to lorlatinib: A case report.

ALK rearrangements are identified as driver mutations in non-small-cell lung cancer (NSCLC). EML4 is the most common partner of ALK rearrangements. Here, we reported a patient with lung adenocarcinoma who was identified with EML4-ALK mutations when he progressed on an immune checkpoint inhibitor. The patient was treated with alectinib and obtained a progression-free survival (PFS) of 24 months. Then, next-generation sequencing on circulating tumor DNA identified multiple ALK mutations, including ALK G1202R, I1171N, ALK-ENC1, and EML4-ALK. Ensartinib was given, and the patient achieved a PFS of 5 months. After progression, lorlatinib was administered, and the patient achieved a partial response. Now, the benefit is still ongoing with a PFS over 10 months. Our case may provide evidence for the treatment choice of multiple ALK mutations, including ALK I1171N.

Distinct Roles of Estrogen Receptors in the Regulation of Vitellogenin Expression in Orange-Spotted Grouper (Epinephelus coioides).

During their breeding season, estrogen induces vitellogenin (VTG) production in the liver of teleost fish through estrogen receptors (ERs) that support oocyte vitellogenesis. There are at least three ER subtypes in teleost fish, but their roles in mediating E2-induced VTG expression have yet to be ascertained. In this study, we investigated the expression of vtgs and ers in the liver of orange-spotted grouper (Epinephelus coioides). Their expression levels were significantly increased in the breeding season and were upregulated by an estradiol (E2) injection in female fish, except for the expression of erß1. The upregulation of vtgs, erα and erß2 by E2 was also observed in primary hepatocytes, but these stimulatory effects could be abolished by ER antagonist ICI182780 treatment. Subsequent studies showed that ERß antagonist Cyclofenil downregulated the E2-induced expression of vtg, erα, and erß2, while the ERß agonist DPN simulated their expression. Knockdown of erß2 by siRNA further confirmed that ERß2 mediated the E2-induced expression of vtgs and erα. To reveal the mechanism of ERß2 in the regulation of erα expression, the erα promoter was cloned, and its activity was examined in cells. E2 treatment simulated the activity of the erα promoter in the presence of ERß2. Deletions and site-directed mutations showed that the E2 up-regulated transcriptional activity of erα occurs through a classical half-estrogen response element- (ERE) dependent pathway. This study reveals the roles of ER subtypes in VTG expression in orange-spotted grouper and provides a possible explanation for the rapid and efficient VTG production in this species during the breeding season.

Long-Term Survival of a Lynch Syndrome Patient With Eight Primary Tumors: A Case Report.

With the modern technological developments in the diagnosis and treatment of cancer, the survival rate of cancer patients has increased. On the other hand, the incidence of multiple primary tumors is increasing annually. Lynch syndrome (LS), an autosomal dominant disorder with germline mutations in DNA mismatch repair genes, increases the risk of cancer in patients carrying those mutations. In this report, we present an extremely rare case of an 81-year-old male patient with eight primary malignancies and LS. The patient is still alive having survived for more than 41 years since the initial discovery of the first tumor. The eighth and most recently diagnosed primary cancer was a malignant peripheral nerve sheath tumor. Although there have been numerous reports of malignancies in LS, malignant peripheral nerve sheath tumors have not been reported previously with LS. Here, we report, to the best of our knowledge, the first case of a malignant peripheral nerve sheath tumor with LS.

Mutation of spexin2 promotes feeding, somatic growth, adiposity, and insulin resistance in zebrafish.

Spexin2 (spx2) is a newly identified gene in vertebrates, but its biological functions remain unclear. In this study, we cloned the full-length cDNA of spx2 in zebrafish. The 288-bp open reading frame encodes a protein of 95 amino acids that contains a 14 amino acids mature peptide. Spx2 is highly expressed in brain and testis. Its expression was significantly downregulated in the hypothalamus after feeding treatment and 7 days of food deprivation. Using a zebrafish spx2-/- mutant line, we observed a greater amount of food intake and changes in mRNA levels of feeding factors. We found that, SPX2 acts as a satiety factor that inhibits food intake by downregulating the expression of agouti-related neuropeptide (agrp). Moreover, spx2 mutant fish exhibited a larger body size, excessive lipid accumulation, and insulin resistance. Taken together, our results revealed that SPX2 functions as a satiety factor involved in energy metabolic regulation in zebrafish.

Molecular characterization and functional analysis of IKKα in orange-spotted grouper (Epinephelus coioides).

Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) plays crucial roles in regulating activation of nuclear factor kappa-B (NF-κB) in response to pathogens infections. Here, we cloned and identified IKKα gene of orange-spotted grouper (Epinephelus coioides), named as EcIKKα. The gene transcript contained a 2262 bp open reading frame, which encoded 753 amino acids. The typically conserved IKKα structure, including serine kinase domain (KD), leucine chain (LZ) structure, helix-loop-helix (HLH) motif and IKKß-NEMO-binding domain, was identified in EcIKKα. Phylogenetic analysis suggested that EcIKKα had the closest relationship with large yellow croaker (Larimichthy crocea) IKKα. Ecikkα was ubiquitously expressed in all tissues tested and the highest expression level was in ovary. After lipopolysaccharide (LPS), flagellin, polyinosinic-polycytidylic acid (poly I:C), polyadenylic-polyuridylic acid (poly A:U), and Vibrio parahaemolyticus stimulation, the expression of Ecikkα increased in grouper spleen (GS) cells. In the luciferase assay, NF-κB-luc activity was significantly up-regulated when human embryonic kidney 293T (HEK 293T) cells were transfected with EcIKKα plasmid. Moreover, overexpression of EcIKKα significantly increased LPS- and flagellin-induced proinflammatory cytokines (interleukin-6 (il-6) and tumor necrosis factor-α (tnf-α)) expression, but did not significantly affect poly I:C- and poly A:U-induced cytokines (il-6 and tnf-α) expression. Overall, these results suggested that EcIKKα functions like that of mammals to activate NF-κB, and it could be involved in host defense against invading pathogens.

An estradiol-17ß/miRNA-26a/cyp19a1a regulatory feedback loop in the protogynous hermaphroditic fish, Epinephelus coioides.

Cyp19a1a is a key gene responsible for the production of estradiol-17ß (E2), the main functional estrogen and a major downstream regulator of reproduction in teleost fish. It is widely known that CYP19 gene expression, aromatase activity, and E2 production can influence gonadal differentiation and sex reversal in teleost fish, but the feedback mechanisms whereby E2 regulates cyp19a1a remain poorly understood, especially regarding the potential roles of endogenous small RNA molecules (miRNAs). Here, we identified miR-26a-5p as a regulatory factor of its predicted target gene (cyp19a1a). In vitro and in vivo studies showed that miR-26a-5p can decrease cyp19a1a expression. Furthermore, high doses of E2 act as a repressor of miR-26a-5p. This study proposes a regulatory feedback loop whereby E2 regulates cyp19a1a through miR-26a-5p, and suggests that this positive feedback is an important aspect of the control of E2 production.

Controllable Co@N-doped graphene anchored onto the NRGO toward electrocatalytic hydrogen evolution at all pH values.

We propose a synthetic strategy to synthesize cobalt nanoparticle cores encapsulated in tunable N-doped graphene shells on N-doped reduced graphene oxide as a highly efficient and stable pH-universal electrocatalyst. The superior performance is mainly attributed to the optimization of the electrocatalytic centre and the improvement of the electronic configuration.

Utilizing o-Quinone Methide Chemistry: Synthesis of d9-Ivacaftor.

Lead time and cost are important factors for any pharmaceutical API. However, these issues become even more important when the drug substance contains an isotope such as deuterium, which has a natural abundance of only ∼0.016% of all hydrogen. Fewer suppliers and logistical barriers both play a role in driving up the cost. These factors can challenge the supply route used to manufacture d9-ivacaftor (17), requiring investigation into alternative routes. By adapting the work from Pettus et al., a synthetic approach utilizing a transient o-quinone methide allowed access to the deuterium-labeled o-tert-butylphenol moiety. This was developed and proven on pilot scale to significantly reduce the number of deuterated reagents used, leading to an overall reduction in cost by a factor of 10, while also providing the substantial benefit of applying prior process knowledge from the parent, nonisotopically enriched API ivacaftor (7).

New Insights Into the Role of Follicle-Stimulating Hormone in Sex Differentiation of the Protogynous Orange-Spotted Grouper, Epinephelus coioides.

Follicle-stimulating hormone (FSH) signaling is considered to be essential for early gametogenesis in teleosts, but its functional roles during sex differentiation are largely unknown. In this study, we investigated the effects of long-term and short-term FSH injection on sex differentiation in the protogynous orange-spotted grouper (Epinephelus coioides). Long-term FSH treatment initially promoted the formation of ovaries but subsequently induced a male fate. The expression of female pathway genes was initially increased but then decreased, whereas the expression of male pathway genes was up-regulated only during long-term FSH treatment. The genes related to the synthesis of sex steroid hormones, as well as serum 11-ketotestosterone and estradiol, were also up-regulated during long-term FSH treatment. Short-term FSH treatment activated genes in the female pathway (especially cyp19a1a) at low doses but caused inhibition at high doses. Genes in the male pathway were up-regulated by high concentrations of FSH over the short term. Finally, we found that low, but not high, concentrations of FSH treatment activated cyp19a1a promoter activities in human embryonic kidney (HEK) 293 cells. Overall, our data suggested that FSH may induce ovarian differentiation or a change to a male sex fate in the protogynous orange-spotted grouper, and that these processes occurred in an FSH concentration-dependent manner.

Transcriptomic Analysis Revealed the Regulatory Mechanisms of Oocyte Maturation and Hydration in Orange-Spotted Grouper (Epinephelus coioides).

Oocyte maturation and hydration are regulated by a complex interplay of various hormones and local factors. We have investigated the morphological changes of follicles and serum steroid levels during the HCG (human choionic gonadotophin)-induced oocyte maturation in the orange-spotted grouper. For the first time, a large-scale transcriptomic analysis of follicles during the maturation has been conducted in a fish species which produce pelagic oocytes. Eight cDNA libraries of follicle samples, from full-grown immature follicles to mature follicles, were constructed. A total of 402,530,284 high-quality clean reads were obtained after filtering, 79.66% of which perfectly mapped to the orange-spotted grouper genome. Real-time PCR results of 12 representative genes related to oocyte maturation and hydration verified the reliability of the RNA-seq data. A large number of genes related to oocyte maturation and hydration were identified in the transcriptome dataset. And the transcriptomic analysis revealed the dynamic changes of the steroid synthesis pathway and the pathway of hydration during oocyte maturation. The present study will facilitate future study on the oocyte maturation and hydration in the orange-spotted grouper and other marine pelagic egg spawner.

Correlation of MicroRNA 17-92 Cluster Host Gene (MIR17HG) Polymorphisms With Susceptibility and Prognosis for Multiple Myeloma.

PURPOSE: To explore the correlation of MIR17HG polymorphism with susceptibility and prognosis of multiple myeloma (MM). PATIENTS AND METHODS: A total of 217 MM patients treated with high-dose melphalan combined with autologous peripheral blood stem-cell transplantation at our hospital were enrolled as the case group, and 220 healthy people were included as the control group. Sequenom MassARRAY iPLEX Gold single nucleotide polymorphism genotyping was used to detect polymorphisms of MIR17HG, including rs7336610, rs17735387, rs4284505, and rs1428. RESULTS: An increased risk of MM was found in patients who carried the rs7336610 T allele and rs4284505 G allele, and the higher the Durie-Salmon and International Staging System stages were, the more MM patients carrying rs7336610 CT + TT genotype and rs4284505 AG + GG genotype (all P < .05). Haplotype AC (rs4284505-rs1428) and CA (rs7336610-rs4284505) evidently reduce MM risk, whereas haplotype GC (rs4284505-rs1428) significantly elevated MM risk (all P < .05). Kaplan-Meier curve analysis demonstrated that rs7336610 CC genotype carriers had higher 5-year survival rate than CT + TT genotype carriers (P = .034), and the AA genotype carriers of rs4284505 had higher 5-year survival rate than AG + GG genotype carriers (P < .001). CONCLUSION: Polymorphisms of MIR17HG rs7336610 and rs1428 were correlated with MM risk and prognosis.

Socially controlled male-to-female sex reversal in the protogynous orange-spotted grouper, Epinephelus coioides.

Socially controlled sex change in teleosts is a dramatic example of adaptive reproductive plasticity. In many cases, the occurrence of sex change is triggered by a change in the social context, such as the disappearance of the dominant individual. The orange-spotted grouper Epinephelus coioides is a typical protogynous hermaphrodite fish that changes sex from female to male and remains male throughout its life span. In this study, male-to-female sex reversal in male Epinephelus coioides was successfully induced by social isolation. The body length and mass, gonadal change, serum sex steroid hormone levels and sex-related gene expression patterns during the process of socially controlled male-to-female sex reversal in E. coioides were systematically examined. This report investigates the physiological mechanisms of the socially controlled male-to-female sex reversal process in a protogynous hermaphrodite grouper species. The results enable us to study the physiological control of sex change, not only from female to male, but also from male to female.

Amorphous Molybdenum Sulfide/Carbon Nanotubes Hybrid Nanospheres Prepared by Ultrasonic Spray Pyrolysis for Electrocatalytic Hydrogen Evolution.

Developing cost-effective electrocatalysts with high activity and stability for hydrogen evolution reaction (HER) plays an important role in modern hydrogen economy. Amorphous molybdenum sulfide (MoSx ) has recently emerged as one of the most promising alternatives to Pt-based catalysts in HER, especially in acidic electrolytes. Here this study reports a simple ultrasonic spray pyrolysis method to synthesize hybrid HER catalysts composed of MoSx firmly attached on entangled carbon nanotube nanospheres (MoSx /CNTs). This synthetic process is fast, continuous, highly durable, and amenable to high-volume production with high yields and exceptional quality. The MoSx /CNTs hybrid catalyst prepared at 300 °C exhibits a low overpotential of 168 mV at the current density of 10 mA cm-2 with a small Tafel slope of 36 mV dec-1 . Electrochemical measurements and X-ray photoelectron spectroscopy analyses reveal that the CNT network not only promotes the charge transfer in corresponding HER process but also enhances the stability of the active sites in MoSx . This work demonstrates that ultrasonic spray pyrolysis is a reliable and versatile approach for synthesizing amorphous MoSx -based HER catalysts.

The complete mitochondrial genome of the hybrid grouper (Cromileptes altivelis♀ × Epinephelus lanceolatus♂) with phylogenetic consideration.

The complete mitochondrial genome of the Hybrid grouper (Cromileptes altivelis♀ × Epinephelus lanceolatus♂) was presented in this study. The mitochondrial genome is 16,501 bp long and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region. The gene order and composition of Hybrid grouper mitochondrial genome was similar to that of most other vertebrates. The nucleotide compositions of the light strand are 26.24% of A, 15.68% of C, 29.07% of T, and29.01% of G. With the exception of the NADH dehydrogenase subunit 6 (ND6) and eight tRNA genes, all other mitochondrial genes are encoded on the heavy strand. The phylogenetic analysis by maximum-likelihood (ML) method shows that the hybrid grouper has closer relationship to C. altivelis.

Facile preparation and applications of graphitic carbon nitride coating in solid-phase microextraction.

In this study, graphitic carbon nitride (g-C3N4) was used as a coating material for solid-phase microextraction (SPME) applications. Coupled to gas chromatography (GC), the extraction ability of the SPME fiber was investigated and compared with the commercial fibers of 100 µm PDMS and 85 µm CAR/PDMS using six target analytes including deltamethrin, nerolidol, amphetamine, dodecane, ametryn and acrylamide. The g-C3N4 coating revealed excellent extraction ability and durability comparing with those of the commercial fibers due to its loose structure and unique physicochemical properties. The repeatability for each single fiber was found to be 3.46% and reproducibility for fiber to fiber was 8.53%. The g-C3N4 SPME fiber was applied to the determination of acrylamide in potato chips, the linearity and detection limit was 0.5-250 µg g(-1) and 0.018 µg g(-1), respectively.

Static feedback stabilization of nonlinear systems with single sensor and single actuator.

This paper considers a single sensor and single actuator approach to the static feedback stabilization of nonlinear systems. This is essentially a remote control problem that is present in many engineering applications. The proposed method solves this problem that is less expensive to implement and more reliable in practice. Significant results are obtained on the design of controllers for stabilizing the nonlinear systems. Important issues on control implementation are also discussed. The proposed design method is validated through its application to nonlinear control of aircraft engines.

Asymmetric glycolate aldol reactions using cinchonium phase-transfer catalysts.

Cinchona phase-transfer catalysts (PTC) were developed for glycolate aldol reactions to give differentially protected 1,2-diol products. Silyl enol ether 9 reacted to generate benzhydryl-protected products. O-Allyl trifluorobenzyl cinchonium hydrofluoride CN-4 (20 mol %) catalyzed the addition of 9 to benzaldehyde to give 8 as a single syn-product in 76% yield and 80% ee. Recrystallization enriched the product to 95% ee, and a Baeyer-Villiger reaction transformed the product into useful ester intermediates. [reaction: see text]

Studies on Mixed Monolayers and Langmuir-Blodgett Films of Schiff-Base Complex Cu(SBC(18))(2) and Calix

Mixed monolayers of Schiff-base complex Cu(SBC(18))(2) with an octadecyl hydrocarbon chain and Calix[4]arene without a long alkyl chain at an air/water interface were studied in ultrapure water at different temperatures. Interface behavior and thermodynamic estimation of the mixed monolayer indicate that a strong intermolecular interaction exists between the mixed components (Cu(SBC(18))(2) and calix[4]arene) and the two-dimensional miscibility decreases with the molar fraction of Cu(SBC(18))(2). It is noticeable that the calix[4]arene monolayer can be transferred successfully onto solid substrates due to the introduction of Cu(SBC(18))(2). FTIR transmission and UV-Vis absorption spectra of mixed LB films provide further evidence of molecular interaction between the headgroups. Copyright 2001 Academic Press.