Skeleton-Reorganizing Coupling Reactions of Cycloheptatriene and Cycloalkenones with Amines.

Skeletal reorganization reactions have emerged as an intriguing tool for converting readily available compounds into complicated molecules inaccessible by traditional methods. Herein, we report a unique skeleton-reorganizing coupling reaction of cycloheptatriene and cycloalkenones with amines. In the presence of Rh/acid catalysis, cycloheptatriene can selectively couple with anilines to deliver fused 1,2-dihydroquinoline products. Mechanistic studies indicate that the retro-Mannich type ring-opening and subsequent intramolecular Povarov reaction account for the ring reorganization. Our mechanistic studies also revealed that skeleton-reorganizing amination between anilines and cycloalkenones can be achieved with acid. The synthetic utilization of this skeleton-reorganizing coupling reaction was showcased with a gram-scale reaction, synthetic derivatizations, and the late-stage modification of commercial drugs.

Rhodium-Catalyzed Deuterated Tsuji-Wilkinson Decarbonylation of Aldehydes with Deuterium Oxide.

The recent surge in the applications of deuterated drug candidates has rendered an urgent need for diverse deuterium labeling techniques. Herein, an efficient Rh-catalyzed deuterated Tsuji-Wilkinson decarbonylation of naturally available aldehydes with D2O is developed. In this reaction, D2O not only acts as a deuterated reagent and solvent but also promotes Rh-catalyzed decarbonylation. In addition, decarbonylative strategies for the synthesis of terminal monodeuterated alkenes from α,ß-unsaturated aldehydes are within reach.

Selective C-S Bond Constructions Using Inorganic Sulfurs via Photoinduced Electron Donor-Acceptor Activation.

By complementing traditional transition metal catalysis, photoinduced catalysis has emerged as a versatile and sustainable way to achieve carbon-heteroatom bond formation. This work discloses a visible-light-induced reaction for the formation of a C-S bond from aryl halides and inorganic sulfuration agents via electron donor-acceptor (EDA) complex photocatalysis. Divergent formations of organic sulfide and disulfide have been demonstrated under mild conditions. Preliminary mechanistic studies suggest that visible-light-induced intracomplex charge transfer within the monosulfide-anion-containing EDA complex permits the C-S bond construction reactivity.

Schistosoma japonicum infection associated with membranous nephropathy: a case report.

BACKGROUND: Schistosomiasis is one of the most contagious parasitic diseases affecting humans; however, glomerular injury is a rare complication mainly described with Schistosoma mansoni infection. We report a case of membranous nephropathy associated with Schistosoma japonicum infection in a Chinese man. CASE PRESENTATION: A 51-year-old Chinese male with a long history of S. japonicum infection presented to the hospital with a slowly progressing severe lower limb edema and foaming urine for over 5 months. Serum S. japonicumantigen test was positive and immunohistochemistry showed that the glomeruli were positive for the antigens. The renal pathologic diagnosis was stage III membranous nephropathy. The patient was treated with glucocorticoid, praziquantel, and an angiotensin-converting enzyme inhibitor. The edema in both lower limbs disappeared within 2 weeks, but his renal function declined progressively and proteinuria persisted after 5 months of therapy. CONCLUSIONS: Different classes of schistosomal glomerulopathy have completely different clinical manifestation and prognosis. Therefore, efforts should focus on alleviating symptoms, prevention, and early detection. S. japonicumassociated with membranous nephropathy may show a good curative effect and prognosis. However, it is necessary to monitor the renal function in such patients.

Investigation of Factors Influencing the Fear of Cancer Recurrence in Breast Cancer Patients Using Structural Equation Modeling: A Cross-Sectional Study.

Objective: This study aimed to investigate the fear of cancer recurrence (FCR) in breast cancer patients and develop a structural equation model of influencing factors to help formulate clinical intervention strategies. Methods: A convenience sample of 325 patients was surveyed using a general and disease-related data questionnaire, which combined the Fear of Progression Questionnaire-Short Form, Mishel Uncertainty in Illness Scale, Perceived Social Support Scale, and Medical Coping Modes Questionnaire. Results: The total score of FCR in breast cancer patients was 35.06 ± 10.83, and 53.8% of patients reached the clinical level. The structural equation model demonstrated that illness uncertainty had a direct positive impact on FCR (ß = 0.275, p < 0.05), and it could have an indirect impact through social support and resignation coping methods (ß = 0.254, p < 0.05). Conclusion: The fear of cancer recurrence in breast cancer patients needs further understanding. Medical staff can reduce or buffer FCR in breast cancer patients by strengthening positive influences, such as social support, or weakening negative influences, such as illness uncertainty and resignation coping.

Retracted: Long Noncoding RNA LINC003121 Inhibits Proliferation and Invasion of Thyroid Cancer Cells by Suppression of the Phosphatidylinositol-3-Kinase (PI3K)/Akt Signaling Pathway.

This article is retracted due to serious flaws detected on figures. Reference: Xiang Min, Kai Liu, Hengtao Zhu, Jian Zhang. Long Noncoding RNA LINC003121 Inhibits Proliferation and Invasion of Thyroid Cancer Cells by Suppression of the Phosphatidylinositol-3-Kinase (PI3K)/Akt Signaling Pathway. Med Sci Monit 2018; 24: LBR4592-4601. 10.12659/MSM.908652.

Stiffness Could be a Predictor of AJCC Prognostic Stage Groups in Preoperative Invasive Ductal Carcinoma.

OBJECTIVES: This study aimed to evaluate the stiffness of 2-dimensional (2D) shear wave elastography (SWE) in preoperatively predicting the prognostic stage groups of invasive ductal carcinoma (IDC). METHODS: Eighty-six newly diagnosed lesions on 83 patients with IDCs were analyzed. All parameters from conventional ultrasound and stiffness to virtual touch tissue imaging and quantification were collected, and mean shear wave velocity (SWVmean) was calculated. Data on maximum diameter, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), histologic grading system and Tumor Node Metastasis (TNM) stages were collected. The levels of maximum shear wave velocity (SWVmax), minimum shear wave velocity (SWVmin) and SWVmean were compared. In receiver operating characteristic (ROC) curves analysis, the diagnostic efficacy was found in area under the curve (AUC). Parallel mode was used to improve the predictive value of sensitivity. RESULTS: The median stiffness of SWVmax and SWVmean for IDCs were 9.38 and 6.32 m/s for late stage (stages II, III, IV) and 6.39 m/s and 4.72 m/s for early stage (stage I) of the prognostic stage groups, respectively. The median stiffness values in the late stage were significantly higher than those in the early stage (P = .003, P = .005). The optimal cutoff stiffness of SWVmax and SWVmean were 8.62 and 6.13 m/s, respectively. In ROC curves analysis, the AUC for SWVmax was 0.742, and it showed a better diagnostic value than SWVmean (0.725). In predictive diagnosis, the sensitivity for SWVmax and SWVmean were both 62.50%. The parallel mode improved the prediction power of sensitivity to 68.75%. CONCLUSIONS: Preoperative SWV level may serve as a promising prognostic imaging indicator for breast IDCs.

Visible Light Induced Bifunctional Rhodium Catalysis for Decarbonylative Coupling of Imides with Alkynes.

Transition metal catalyzed decarbonylation offers a distinct synthetic strategy for new chemical bond formation. However, the π-backbonding between CO π* orbitals and metal center d-orbitals impedes ligand dissociation to regenerate the catalyst under mild reaction conditions. Developed here is visible light induced rhodium catalysis for decarbonylative coupling of imides with alkynes under ambient conditions. Initial mechanistic studies suggest that the rhodium complex simultaneously serves as the catalytic center and photosensitizer for decarbonylation. This visible light promoted catalytic decarbonylation strategy offers new opportunities for reviewing old transformations with ligand dissociation as a rate-determining step.

Orthogonal Regulation of Nucleophilic and Electrophilic Sites in Pd-Catalyzed Regiodivergent Couplings between Indazoles and Isoprene.

Depending on the reactant property and reaction mechanism, one major regioisomer can be favored in a reaction that involves multiple active sites. Herein, an orthogonal regulation of nucleophilic and electrophilic sites in the regiodivergent hydroamination of isoprene with indazoles is demonstrated. Under Pd-hydride catalysis, the 1,2- or 4,3-insertion pathway with respect to the electrophilic sites on isoprene could be controlled by the choice of ligands. In terms of the nucleophilic sites on indazoles, the reaction occurs at either the N1 - or N2 -position of indazoles is governed by the acid co-catalysts. Preliminary experimental studies have been performed to rationalize the mechanism and regioselectivity. This study not only contributes a practical tool for selective functionalization of isoprene, but also provides a guide to manipulate the regioselectivity for the N-functionalization of indazoles.

Copper-catalyzed boroacylation of allenes to access tetrasubstituted vinylboronates.

A distinct copper-catalyzed boroacylation of allenes with acyl chlorides and bis(pinacolato)diboron is developed. For aromatic acyl chlorides, 1,2-boroacylation of allenes readily takes place, leading to the formation of tetrasubstituted vinylboronates with exclusive (E)-stereoselectivity. In comparison, the employment of alkyl acyl chlorides as electrophiles alters the selectivity to 2,3-boroacylated products. Additionally, the product can easily undergo Suzuki-Miyaura cross-coupling to afford tetrasubstituted alkene with complete retention of the configuration.

Long Noncoding RNA LINC003121 Inhibits Proliferation and Invasion of Thyroid Cancer Cells by Suppression of the Phosphatidylinositol-3-Kinase (PI3K)/Akt Signaling Pathway.

BACKGROUND The aim of this study was to explore the potential effects of long noncoding RNA (lncRNA) LINC003121 on thyroid cancer (TC) cell proliferation and invasion and to explore their possible mechanisms with the involvement of the PI3K/Akt signaling pathway. MATERIAL AND METHODS We enrolled 211 thyroid cancer tissues and 70 adjacent normal tissues in this study. TC cell lines K1, SW579, and 8505C and the human thyroid follicular cell line Nthy-ori3-1 were selected and assigned into blank, control vectors, LINC00312 vectors, si-control, and si-LINC00312 groups. Quantitative real-time PCR was used to determine the levels of LINC003121 and Western blotting was used to detect the protein expression of MMP-9, PI3K, t-Akt, and p-Akt. Cell proliferation was assessed by CCK8 assay and EdU incorporation assay, and cell invasion was assessed by Transwell assay. RESULTS The expression of LINC00312 was significantly decreased in TC tissues and cell lines. In an in vitro experiment, si-LINC00312 significantly promoted the invasion and proliferation of TC cells. Conversely, overexpression of LINC00312 decreased cell proliferation and invasion in vitro, and decreased tumorigenicity in TC xenograft models in nude mice. LINC00312-mediated tumor suppression in TC cells may occur via suppression of activation of the PI3K/Akt signaling pathway and expression of MMP-9, and the role of MMP-9 expression induced by overexpressed LINC00312 or si-LINC00312 could be weakened by LY294002 (PI3K inhibitor). CONCLUSIONS LINC00312 can act as a tumor-suppressor in TC by attenuating the PI3K/Akt signaling pathway, and LINC00312 could be a novel diagnosis biomarker and a promising therapeutic target for TC patients.

RNASET2, GPR174, and PTPN22 gene polymorphisms are related to the risk of liver damage associated with the hyperthyroidism in patients with Graves' disease.

OBJECTIVES: This study was designed to unveil the association of GPR174 rs3827440, PTPN22 rs3789604, and RNASET2 rs9355610 with the onset of liver damage (LD) among the Graves' disease (GD) patients. METHODS: A total of 120 GD patients were divided into the none-LD and LD groups. Several indicators were detected for assessing liver functions, and genotypes of single nucleotide polymorphisms (SNPs) were identified. Logistic regression was introduced for investigating the relationship between risk SNPs and LD-associated hyperthyroidism in GD patients. RESULTS: Significant differences were identified between LD and none-LD groups regarding genotype distributions of rs3827440, rs3789604, and rs9355610. Results from logistic regression indicted that among the GD patients, C carriers of PTPN22 rs3789604 were associated with a higher risk of LD-associated hyperthyroidism, while C carriers of rs3827440 (GPR174) and G carriers of rs9355610 (RNASET2) were associated with a reduced risk of LD-associated hyperthyroidism. CONCLUSIONS: The C allele of rs3789604 (PTPN22) was a significant risk factor for LD-associated hyperthyroidism in GD patients, whereas C allele of GPR174 rs3827440 and G allele of RNASET2 rs9355610 appeared to be a protective factor for this disease.

Carfilzomib Inhibits Constitutive NF-κB Activation in Mantle Cell Lymphoma B Cells and Leads to the Induction of Apoptosis.

Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins. Carfilzomib inhibited growth and induced apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells occurred in a caspase-dependent manner through both intrinsic and extrinsic caspase pathways. In addition, carfilzomib inhibited constitutive activation of the NF-κB signaling cascade, both in MCL cell lines and primary MCL cells, by completely blocking the phosphorylation of IκBα. Our results demonstrate that carfilzomib can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway.

Genome-wide cataloging and analysis of alternatively spliced genes in cereal crops.

BACKGROUND: Protein functional diversity at the post-transcriptional level is regulated through spliceosome mediated pre-mRNA alternative splicing (AS) events and that has been widely demonstrated to be a key player in regulating the functional diversity in plants. Identification and analysis of AS genes in cereal crop plants are critical for crop improvement and understanding regulatory mechanisms. RESULTS: We carried out the comparative analyses of the functional landscapes of the AS using the consensus assembly of expressed sequence tags and available mRNA sequences in four cereal plants. We identified a total of 8,734 in Oryza sativa subspecies (ssp) japonica, 2,657 in O. sativa ssp indica, 3,971 in Sorghum bicolor, and 10,687 in Zea mays AS genes. Among the identified AS events, intron retention remains to be the dominant type accounting for 23.5 % in S. bicolor, and up to 55.8 % in O. sativa ssp indica. We identified a total of 887 AS genes that were conserved among Z. mays, S. bicolor, and O. sativa ssp japonica; and 248 AS genes were found to be conserved among all four studied species or ssp. Furthermore, we identified 53 AS genes conserved with Brachypodium distachyon. Gene Ontology classification of AS genes revealed functional assignment of these genes in many biological processes with diverse molecular functions. CONCLUSIONS: AS is common in cereal plants. The AS genes identified in four cereal crops in this work provide the foundation for further studying the roles of AS in regulation of cereal plant growth and development. The data can be accessed at Plant Alternative Splicing Database (http://proteomics.ysu.edu/altsplice/).

Sequencing papaya X and Yh chromosomes reveals molecular basis of incipient sex chromosome evolution.

Sex determination in papaya is controlled by a recently evolved XY chromosome pair, with two slightly different Y chromosomes controlling the development of males (Y) and hermaphrodites (Y(h)). To study the events of early sex chromosome evolution, we sequenced the hermaphrodite-specific region of the Y(h) chromosome (HSY) and its X counterpart, yielding an 8.1-megabase (Mb) HSY pseudomolecule, and a 3.5-Mb sequence for the corresponding X region. The HSY is larger than the X region, mostly due to retrotransposon insertions. The papaya HSY differs from the X region by two large-scale inversions, the first of which likely caused the recombination suppression between the X and Y(h) chromosomes, followed by numerous additional chromosomal rearrangements. Altogether, including the X and/or HSY regions, 124 transcription units were annotated, including 50 functional pairs present in both the X and HSY. Ten HSY genes had functional homologs elsewhere in the papaya autosomal regions, suggesting movement of genes onto the HSY, whereas the X region had none. Sequence divergence between 70 transcripts shared by the X and HSY revealed two evolutionary strata in the X chromosome, corresponding to the two inversions on the HSY, the older of which evolved about 7.0 million years ago. Gene content differences between the HSY and X are greatest in the older stratum, whereas the gene content and order of the collinear regions are identical. Our findings support theoretical models of early sex chromosome evolution.

Variegatusides: new non-sulphated triterpene glycosides from the sea cucumber Stichopus variegates semper.

Four new triterpene glycosides, variegatusides C-F (1-4), together with three structurally known triterpene glycosides, variegatusides A and B (5, 6), and holothurin B (7), were isolated from the sea cucumber Stichopus variegates Semper (Holothuriidae), collected from the South China Sea. Their structures were elucidated on the basis of extensive spectral analysis (nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESIMS)) and chemical evidence. Variegatusides C-F exhibit the same structural feature consisting of the presence of a 23-hydroxyl group at the holostane-type triterpene aglycone side chain. Variegatuside C (1) has a double bond (24, 25) in this same chain, while variegatuside D (2) exhibits a 8(9)-ene bond in the holostane-type triterpene aglycone, which has not been extracted from other sea cucumber species. Compound 4 is a native compound from the sea cucumber S. variegates Semper, which has been reported to be desacetylstichloroside B1. Except for holothurin B, these glycosides have no sulfate group in their sugar chain and show potent antifungal activities in vitro biotests.

Key points for protecting the external branch of the superior laryngeal nerve in open thyroidectomy: A possible exploration technique.

OBJECTIVE: Injury of the external branch of the superior laryngeal nerve (EBSLN) is easily overlooked in thyroidectomy, and voice changes caused by the injury have a negative effect on an increasing number of patients. This study aimed to reduce the injury rate of EBSLN by expanding the sternothyroid-laryngeal triangle and standardizing the exploration procedure. METHODS: A total of 520 patients who had undergone thyroidectomy at the First Affiliated Hospital of Nanchang University between September 2021 and April 2022 were analyzed. During the operation, the exposure rate of the EBSLN before and after sternothyroid-laryngeal triangle expansion was compared, and all EBSLNs were anatomically classified. RESULTS: The exposure rate of EBSLN after sternothyroid-laryngeal triangle expansion reached 82.7%, which is much higher than that before sternothyroid-laryngeal triangle expansion (33.7%), and voice change caused by injury of the EBSLN was reported in one case (the injury rate was 0.2%). The classification and proportion of the EBSLN were as follows: Type 1 (55.3%), the nerve ran within 1 cm above the STP, but no coincidence or crossover with blood vessels was observed in this region; Type 2 (14.7%), the nerve travelled within 1 cm above the STP and overlapped or intersected with blood vessels in this region; Type 3 (12.7%), the EBSLN ran below the level of the STP; and Type 4 (17.3%), no EBSLN was observed within 1 cm above the STP. CONCLUSION: In thyroidectomy, injury to the EBSLN can be effectively reduced by expanding the sternothyroid-laryngeal triangle and exploring the upper pole area of the thyroid as far as possible, which has great clinical significance in reducing postoperative voice box injury.

GPX4 inhibits apoptosis of thyroid cancer cells through regulating the FKBP8/Bcl-2 axis.

GPX4 has attracted much attention as a key molecule of cell ferroptosis, but its role in cell apoptosis is rarely reported, and its role in apoptosis of thyroid cancer (TC) cell has not been reported. The analysis of TCGA database showed that both GPX4 and FKBP8 were highly expressed in TC tumor tissues; The expression of GPX4 and FKBP8 were positively correlated. The immunohistochemical analysis further confirmed that GPX4 and FKBP8 were highly expressed in TC tumor tissues. In addition, the high expression of GPX4 and FKBP8 were both significantly correlated with the poor prognosis of TC. Silencing GPX4 significantly inhibited the proliferation, induced apoptosis of TC cells, and reduced tumor growth in mice. The co-immunoprecipitation assay revealed a physical interaction between GPX4 and FKBP8 observed in the TC cells. Knockdown of FKBP8 significantly inhibited the proliferation and induced apoptosis of TC cells. Rescue experiments suggested that knockdown of FKBP8 could reverse the strengthens of cell proliferation and apoptosis and the higher expression of FKBP8 and Bcl-2 caused by overexpression of GPX4. Our results suggest that the GPX4/FKBP8/Bcl-2 axis promotes TC development by inhibiting TC cell apoptosis, which provides potential molecular targets for TC therapeutic strategies.

[The design and baseline characteristics of a phase III study to evaluate the efficacy and safety of alogliptin versus placebo in type 2 diabetes mellitus in Mainland China].

OBJECTIVE: To assess the design and the Mainland China subgroup baseline characteristics of the study to evaluate the efficacy and safety of alogliptin versus placebo in subjects with type 2 diabetes (T2DM) as monotherapy, add-on to metformin or add-on to pioglitazone. METHODS: This was a multi-center, randomized, double-blind, placebo-controlled, 16-week study comparing alogliptin (ALO, 25 mg, 1/d) versus placebo (PLA) as monotherapy (A), add-on to metformin (B) or add-on to pioglitazone ± metformin (C). The T2DM subjects with glycosylated hemoglobin A1c(HbA1c) between 7% and 10% and aged between 18 years and 75 years were enrolled and randomized to the alogliptin group and the placebo group in 1: 1 ratio with 16 weeks treatment. All patients were followed up every 4 weeks. The safety endpoints consisted of the incidence of hypoglycemia and other adverse events. RESULTS: A total of 491 patients were enrolled in the Mainland China subgroup of the study (181 in group A, 186 in group B and 124 in group C). In each treatment group, the baseline characteristics including age, gender, body mass index, diabetes duration, HbA1c, fasting plasma glucose, body weight, daily dosage of metformin and daily dosage of pioglitazone were all well balanced. CONCLUSION: The demographic data, medical history, glycemic profile and treatment regimen at baseline in Mainland China subgroup are well balanced. The result of this study will provide the clinical evidence for the use of alogliptin in Chinese T2DM patients.

Disproportionation-Inspired Construction of Highly Functionalized Bicyclo[3.2.1]octanes.

The formation of one unavoidable byproduct in traditional disproportionation reactions limits their applications in synthesis. Inspired by convergent disproportionation, we develop an iodine-induced cyclization and oxidation of allylic alcohols to produce highly functionalized bicyclo[3.2.1]octanes through creation of six new bonds. Guided by the mechanism, we elaborated a variety of other bicyclo[3.2.1]octanes bearing distinct groups with presynthesized dienes and enones as the starting materials. This work provides a divergent access to bicyclo[3.2.1]octane frameworks.