Pyrene-Fused Poly-Aromatic Regioisomers: Synthesis, Columnar Mesomorphism, and Optical Properties.

π-Extended pyrene compounds possess remarkable luminescent and semiconducting properties and are being intensively investigated as electroluminescent materials for potential uses in organic light-emitting diodes, transistors, and solar cells. Here, the synthesis of two sets of pyrene-containing π-conjugated polyaromatic regioisomers, namely 2,3,10,11,14,15,20,21-octaalkyloxypentabenzo[a,c,m,o,rst]pentaphene (BBPn) and 2,3,6,7,13,14,17,18-octaalkyloxydibenzo[j,tuv]phenanthro [9,10-b]picene (DBPn), is reported. They were obtained using the Suzuki-Miyaura cross-coupling in tandem with Scholl oxidative cyclodehydrogenation reactions from the easily accessible precursors 1,8- and 1,6-dibromopyrene, respectively. Both sets of compounds, equipped with eight peripheral aliphatic chains, self-assemble into a single hexagonal columnar mesophase, with one short-chain BBPn homolog also exhibiting another columnar mesophase at a lower temperature, with a rectangular symmetry; BBPn isomers also possess wider mesophase ranges and higher mesophases' stability than their DBPn homologs. These polycyclic aromatic hydrocarbons all show a strong tendency of face-on orientation on the substrate and could be controlled to edge-on alignment through mechanical shearing of interest for their implementation in photoelectronic devices. In addition, both series BBPn and DBPn display green-yellow luminescence, with high fluorescence quantum yields, around 30%. In particular, BBPn exhibit a blue shift phenomenon in both absorption and emission with respect to their DBPn isomers. DFT results were in good agreement with the optical properties and with the stability ranges of the mesophases by confirming the higher divergence from the flatness of DBPn compared with BBPn. Based on these interesting properties, these isomers could be potentially applied not only in the field of fluorescent dyes but also in the field of organic photoelectric semiconductor materials as electron transport materials.

Identification of novel rare copy number variants associated with sporadic tetralogy of Fallot and clinical implications.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Highly penetrant copy number variants (CNVs) and genes related to the etiology of TOF likely exist with differences among populations. We aimed to identify CNV contributions to sporadic TOF cases in Han Chinese. Genomic DNA was extracted from peripheral blood in 605 subjects (303 sporadic TOF and 302 unaffected Han Chinese [Control] from cardiac centers in China) and analyzed by genome-wide association study (GWAS). The GWAS results were compared with existing Database of Genetic Variants. These CNVs were further validated by qPCR. Bioinformatics analyses were performed with protein-protein interaction (PPI) network and KEGG pathway enrichment. Across all chromosomes 119 novel "TOF-specific CNVs" were identified with prevalence of CNVs of 21.5% in chromosomes 1-20 and 37.0% including Chr21/22. In chromosomes 1-20, CNVs on 11q25 (encompasses genes ACAD8, B3GAT1, GLB1L2, GLB1L3, IGSF9B, JAM3, LOC100128239, LOC283177, MIR4697, MIR4697HG, NCAPD3, OPCML, SPATA19, THYN1, and VPS26B) and 14q32.33 (encompasses genes THYN1, OPCML, and NCAPD3) encompass genes most likely to be associated with TOF. Specific CNVs found on the chromosome 21 (6.3%) and 22(11.9%) were also identified in details. PPI network analysis identified the genes covering the specific CNVs related to TOF and the signaling pathways. This study for first time identified novel TOF-specific CNVs in the Han Chinese with higher frequency than in Caucasians and with 11q25 and 14q32.33 not reported in TOF of Caucasians. These novel CNVs identify new candidate genes for TOF and provide new insights into genetic basis of TOF.

Preparation of PMMA Electrospun Fibers Bearing Porphyrin Pendants and Photocatalytic Degradation of Organic Dyes.

Porphyrins have a large π-π conjugation force between molecules, and they are easy to aggregate in solution, which affects the photoelectric properties of porphyrins. Connecting porphyrins to polymer links through covalent bonds not only retains the mechanical properties and thermal stability of polymer materials, but also has the photoelectric properties and catalytic properties of porphyrins, which improves the availability of materials. In this study, first, a porphyrin ligand with double bonds in the side chain was designed and the corresponding copper and zinc complexes were synthesized by adjusting the metal ions in the center of the pyrrole ring. Then, the metalloporphyrin complexes were copolymerized with methyl methacrylate (MMA), and two metalloporphyrin/PMMA copolymers were obtained: CPTPPCu/PMMA and CPTPPZn/PMMA. The structure of the compounds was characterized by IR, 1H NMR, MS, and UV-Vis spectra. Metalloporphyrin/PMMA copolymers were prepared into electrospun fiber materials by electrospinning. The morphology of the composites was studied by SEM, and the thermal stability and optical properties of electrospun fibers were studied by TGA and FL. The catalytic activity of electrospun fiber materials for the degradation of organic dyes was studied. The results showed that the efficiency of the metalloporphyrin/PMMA copolymer in photocatalytic degradation of methylene blue (MB) was better than that of the PMMA electrospun fiber blended with metalloporphyrin.

Rhodium-Catalyzed Regiodivergent and Enantioselective Hydroboration of Enamides.

Chiral α- and ß-aminoboronic acids exhibit unique biological activities. General methods for the synthesis of these bioisosteres of amino acids are highly desirable. We report a facile preparation of these compounds through rhodium-catalyzed regiodivergent and enantioselective hydroboration of enamides. Catalytic asymmetric synthesis of α- and ß-aminoboronic esters with high regio-, diastereo-, and enantioselectivities were achieved through effective catalyst control and tuning substrate geometry. Starting from easily available materials, this strategy provides a unified synthetic access to both enantioenriched α-boration and ß-boration products. The synthetic utility of these methods was demonstrated by efficient synthesis of an anticancer drug molecule and diverse transformations of the boration products.

Highly Enantioselective Synthesis of Propargyl Amides through Rh-Catalyzed Asymmetric Hydroalkynylation of Enamides: Scope, Mechanism, and Origin of Selectivity.

Chiral propargyl amides are particularly useful structural units in organic synthesis. The enantioselective synthesis of propargyl amide is highly desirable. Conventional approach involves the use of a stoichiometric amount of metal reagent or chiral auxiliary. In comparison, direct alkynylation with terminal alkyne is attractive because it avoids the use of stoichiometric organometallic reagent. The asymmetric coupling of aldehyde, amine, and alkyne (A3-coupling) provides an efficient method for the synthesis of N-alkyl and N-aryl-substituted propargyl amines, but this strategy is not amenable for the direct enantioselective synthesis of propargyl amide. We have developed a new strategy and report here a Rh-catalyzed asymmetric hydroalkynylation of enamides. Alkynylations occur regioselectively at the α position of an enamide to produce chiral propargyl amides. High yield and enantioselectivity were observed. Previous alkynylation methods to prepare chiral propargyl amine involve the nucleophilic addition to an electron-deficient imine. In contrast, our current approach proceeds through regioselective hydroalkynylation of an electron-rich alkene. Kinetic studies indicated that migratory insertion of the enamide to the rhodium hydride is turnover limiting. Computational studies revealed the origin of regio- and enantioselectivities. This novel strategy provides an efficient method to access chiral propargyl amides directly from terminal alkynes.

Synthesis of Amides with Remote Stereocenters by Catalytic Asymmetric γ-Alkynylation of α,ß-Unsaturated Amides.

An iridium-catalyzed enantioselective hydroalkynylation of α,ß-unsaturated amides was described. The selectivity of this reaction is distinct from that observed in many catalytic hydroalkynylations of α,ß-unsaturated carbonyl compounds. It occurs selectively at the γ instead of the ß position. Preliminary mechanistic studies suggest that the reaction proceeds through alkene isomerization followed by hydroalkynylation. This method provides a straightforward route for the synthesis of amides with a remote stereocenter at the γ position.

Iridium-Catalyzed Enantioselective Hydroalkynylation of Enamides for the Synthesis of Homopropargyl Amides.

Reported is an iridium-catalyzed asymmetric hydroalkynylation of enamides with terminal alkynes. The reaction occurs regioselectively at the ß-position of an enamide to produce homopropargyl amides. Good to high enantioselectivity was observed with an iridium complex ligated by a chiral bis(phosphine) ligand. This method provides a straightforward route to synthesize chiral homopropargyl amides with a stereocenter ß to the amide.

Association of monocyte chemoattractant protein-1 (MCP-1)-2518A>G polymorphism with susceptibility to coronary artery disease: a meta-analysis.

We attempted to systematically elucidate the association between monocyte chemoattractant protein-1 (MCP-1) -2518A>G polymorphism and risk of coronary artery disease (CAD). Eligible studies were identified through PubMed, EBSCO, and Web of Science Databases. The magnitude of MCP-1 polymorphism effect and its possible mode of action on CAD were estimated. The odds ratio (OR) with 95% confidence intervals (CI) were pooled in a specific genetic model to assess the association. A total of 21 studies were involved. There was significant gene effect on CAD risk in the overall population (likelihood ratio test: p < 0.0001). Patients with GG and AG genotypes had 1.435 (95% CI: 1.183-1.740) and 1.087 (95% CI: 1.008-1.172) times higher risk of CAD than those with AA genotype. These gene effects suggested a recessive model to be appropriate. The pooled OR was 1.362 (95% CI: 1.137-1.631; puncorrected = 0.001, pFDR = 0.005) in the recessive model. In the ethnicity-stratified analysis, significant association was observed in the Caucasian population (OR = 1.492; 95% CI: 1.106-2.014; puncorrected = 0.009, pFDR = 0.015), whereas no statistical significant association was detected in the Asian population (adjusted p = 0.124). The results suggested that MCP-1 -2518A>G polymorphism may be associated with susceptibility to CAD, especially in Caucasians.

KLF11 promotes the proliferation of breast cancer cells by inhibiting p53-MDM2 signaling.

Abnormal Krüppel-like factor 11 (KLF11) expression is frequently found in tumor tissues and is associated with cancer prognosis, but its biological functions and corresponding mechanisms remain elusive. Here, we demonstrated that KLF11 functions as an oncoprotein to promote tumor proliferation in breast cancer cells. Mechanistically, at the transcription level, KLF11 decreased TP53 mRNA expression. Notably, KLF11 also interacted with and stabilized MDM2 through inhibiting MDM2 ubiquitination and subsequent degradation. This increase in MDM2 in turn accelerated the ubiquitin-mediated proteolysis of p53, leading to the reduced expression of p53 and its target genes, including CDKN1A, BAX, and NOXA1. Accordingly, data from animals further confirmed that KLF11 significantly upregulated the growth of breast cancer cells and was inversely correlated with p53 expression. Taken together, our findings reveal a novel mechanism for breast cancer progression in which the function of the tumor suppressor p53 is dramatically weakened.

Development of a clinical automatic calculation of hypoglycemia during hemodialysis risk in patients with diabetic nephropathy.

BACKGROUND: Hypoglycemia is one of the most common complications in patients with DN during hemodialysis. The purpose of the study is to construct a clinical automatic calculation to predict risk of hypoglycemia during hemodialysis for patients with diabetic nephropathy. METHODS: In this cross-sectional study, patients provided information for the questionnaire and received blood glucose tests during hemodialysis. The data were analyzed with logistic regression and then an automated calculator for risk prediction was constructed based on the results. From May to November 2022, 207 hemodialysis patients with diabetes nephropathy were recruited. Patients were recruited at blood purifying facilities at two hospitals in Beijing and Inner Mongolia province, China. Hypoglycemia is defined according to the standards of medical care in diabetes issued by ADA (2021). The blood glucose meter was used uniformly for blood glucose tests 15 minutes before the end of hemodialysis or when the patient did not feel well during hemodialysis. RESULTS: The incidence of hypoglycemia during hemodialysis was 50.2% (104/207). The risk prediction model included 6 predictors, and was constructed as follows: Logit (P) = 1.505×hemodialysis duration 8~15 years (OR = 4.506, 3 points) + 1.616×hemodialysis duration 16~21 years (OR = 5.032, 3 points) + 1.504×having hypotension during last hemodialysis (OR = 4.501, 3 points) + 0.788×having hyperglycemia during the latest hemodialysis night (OR = 2.199, 2 points) + 0.91×disturbance of potassium metabolism (OR = 2.484, 2 points) + 2.636×serum albumin<35 g/L (OR = 13.963, 5 points)-4.314. The AUC of the prediction model was 0.866, with Matthews correlation coefficient (MCC) of 0.633, and Hosmer-Lemeshow χ2 of 4.447(P = 0.815). The automatic calculation has a total of 18 points and four risk levels. CONCLUSIONS: The incidence of hypoglycemia during hemodialysis is high in patients with DN. The risk prediction model in this study had a good prediction outcome. The hypoglycemia prediction automatic calculation that was developed using this model can be used to predict the risk of hypoglycemia in DN patients during hemodialysis and also help identify those with a high risk of hypoglycemia during hemodialysis.

Genomic and immune characteristics of HER2-mutated non-small-cell lung cancer and response to immune checkpoint inhibitor-based therapy.

The efficacy of immunotherapy in advanced HER2-mutated non-small-cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were retrospectively studied at Guangdong Lung Cancer Institute [GLCI cohort, exon 20 insertions (ex20ins): 71.0%] to compare clinical/molecular features and immune checkpoint inhibitor (ICI)-based therapy efficacy between patients with ex20ins and non-ex20ins. Two external cohorts (TCGA, n = 21; META-ICI, n = 30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death-ligand 1 (PD-L1) expression < 1%. Compared with ex20ins patients, non-ex20ins patients had more concurrent mutations in the GLCI cohort (P < 0.01) and a higher tumour mutation burden in the TCGA cohort (P = 0.03). Under ICI-based therapy, advanced NSCLC patients with non-ex20ins had potentially superior progression-free survival [median: 13.0 vs. 3.6 months, adjusted hazard ratio (HR): 0.31, 95% confidence interval (CI): 0.11-0.83] and overall survival (median: 27.5 vs. 8.1 months, adjusted HR: 0.39, 95% CI: 0.13-1.18) to ex20ins patients, consistent with findings in the META-ICI cohort. ICI-based therapy may serve as an option for advanced HER2-mutated NSCLC, with potentially better efficacy in non-ex20ins patients. Further investigations are warranted in clinical practice.

First-line pyrotinib in advanced HER2-mutant non-small-cell lung cancer: a patient-centric phase 2 trial.

To explore targeted treatment options in patients with non-small-cell lung cancer (NSCLC) with rare genetic mutations in the context of a patient-centric clinical trial, we initiated, in parallel, a phase 2 adaptive umbrella trial consisting of a criteria-fulfilled (CF) cohort and a compassionate use (CU) cohort under expanded eligibility criteria, and a prospective real-world study (RWS). Here, we present efficacy and safety data from 48 patients with treatment-naive, advanced HER2-mutant NSCLC treated with the pan-HER receptor tyrosine kinase inhibitor pyrotinib (CF and CU cohorts) or physician's therapy of choice (RWS cohort). In the phase 2 trial CF cohort (n = 28), the primary endpoint was reached with an objective response rate of 35.7% after pyrotinib treatment. Secondary endpoints included disease control rate (89.3%), median progression-free survival (PFS) (7.3 months), median overall survival (OS) (14.3 months) and toxicity, which was acceptable, with grade 3 or 4 treatment-related adverse events occurring in three patients (10.7%). The phase 2 trial CU cohort (n = 12) showed an objective response rate of 16.7%, disease control rate of 83.4%, median PFS of 4.7 months and median OS of 14.2 months after pyrotinib treatment. The RWS cohort (n = 8) had no responses to physician's therapy of choice, while median PFS and OS were 3.0 and 12.2 months, respectively. Phase 2 umbrella trial, clinicaltrials.gov identifier: NCT03574402 . RWS, clinicaltrials.gov identifier: NCT03605602 .

Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial.

Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding: Chinese Thoracic Oncology Group (CTONG).

Genetic Profiling of Cell-Free DNA From Pleural Effusion in Advanced Lung Cancer as a Surrogate for Tumor Tissue and Revealed Additional Clinical Actionable Targets.

BACKGROUND: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. METHOD: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1PE-sDNA. RESULT: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. CONCLUSION: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.

Podocyte number in the maturing rat kidney.

BACKGROUND/AIMS: The podocyte is an important cell for maintaining the normal structure and function of the glomerulus. In recent years much attention has been given to the number of podocytes in glomeruli. During this time there has been a debate as to whether podocytes can divide after the capillary-loop stage of development. The aim of this study was to use an unbiased counting method to determine if podocyte number increases after the capillary-loop stage of development. METHODS: The fractionator/disector method was used to count podocytes in glomeruli from rats aged 1 day, 5, 12, and 24 weeks. Glomerular volume was also measured with the unbiased Cavalieri principle and used to calculate the density of podocytes per glomerulus. RESULTS: The number of podocytes did not increase from the capillary-loop stage of glomerular development to 24 weeks of age. Glomerular volume increased 3.6-fold during this time, which resulted in a decrease of podocyte density as the rats aged. CONCLUSION: The study documents that the number of podocytes is stable after the capillary-loop stage of glomerular development. The data does not confirm but adds evidence that podocytes do not divide from the capillary-loop stage of glomerular development to 24 weeks of age in the normal rat.

Both N- and C-lobes of calmodulin are required for Ca2+-dependent regulations of CaV1.2 Ca2+ channels.

We investigated the concentration- and Ca(2+)-dependent effects of CaM mutants, CaM(12) and CaM(34), in which Ca(2+)-binding to its N- and C-lobes was eliminated, respectively, on the Ca(V)1.2 Ca(2+) channel by inside-out patch clamp in guinea-pig cardiomyocytes. Both CaM(12) and CaM(34) (0.7-10muM) applied with 3mM ATP produced channel activity after "rundown". Concentration-response curves were bell-shaped, similar to that for wild-type CaM. However, there was no obvious leftward shift of the curves by increasing [Ca(2+)], suggesting that both functional lobes of CaM were necessary for the Ca(2+)-dependent shift. However, channel activity induced by the CaM mutants showed Ca(2+)-dependent decrease, implying a Ca(2+) sensor existing besides CaM. These results suggest that both N- and C-lobes of CaM are required for the Ca(2+)-dependent regulations of Ca(V)1.2 Ca(2+) channels.

Plasma Inter-Alpha-Trypsin Inhibitor Heavy Chains H3 and H4 Serve as Novel Diagnostic Biomarkers in Human Colorectal Cancer.

OBJECTIVE: Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) and inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) are heavy chains of protein members belonging to the ITI family, which was associated with inflammation and carcinogenesis. However, the diagnostic value of ITIH3 and ITIH4 in human colorectal cancer (CRC) remains unknown. METHODS: In total, 101 CRC patients and 156 healthy controls were enrolled. The concentrations of ITIH3 and ITIH4 proteins in plasma samples of participants were assessed using enzyme-linked immunosorbent assay. ITIH3 and ITIH4 expressions in human CRC tissues were additionally assessed via immunohistochemical staining (IHC). Receiver operating characteristic (ROC) was applied to estimate the diagnostic power of the two proteins, and the net reclassification improvement (NRI) was adopted to evaluate the incremental predictive ability of ITIH3/ITIH4 when added to the tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS: The plasma concentration of ITIH3 in CRC patients (median: 4.370 µg/mL; range: 2.152-8.170 µg/mL) was significantly lower than that in healthy subjects (median: 4.715 µg/mL; range: 2.665-10.257 µg/mL; p < 0.001), while the ITIH4 plasma level in subjects with CRC (median: 0.211 µg/mL; range: 0.099-0.592 µg/mL) was markedly increased relative to that in the control group (median: 0.134 µg/mL; range: 0.094-0.460 µg/mL, p < 0.001). Consistently, IHC score assessment showed a dramatic reduction in ITIH3 expression and, conversely, upregulation of ITIH4 in colorectal carcinoma specimens relative to adjacent normal colorectal tissues (p < 0.001 in both cases). The area under the curve (AUC) of the ROC for ITIH4 (AUC = 0.801, 95% CI: 0.745-0.857) was higher than that for ITIH3 (AUC = 0.638, 95% CI: 0.571-0.704, both p values < 0.001). The AUC of the ROC for combined ITIH3 and ITIH4 was even higher than that for carcinoembryonic antigen. NRI results showed that combining ITIH3 and ITIH4 with TIMP-1 significantly improved diagnostic accuracy (NRI = 17.12%, p = 0.002) for CRC patients compared to TIMP-1 alone. CONCLUSIONS: Circulating ITIH3 and ITIH4 levels are associated with carcinogenesis in CRC, supporting their potential diagnostic utility as surrogate biomarkers for colorectal cancer detection.

Effect of dapagliflozin on obstructive sleep apnea in patients with type 2 diabetes: a preliminary study.

OBJECTIVE: The aim of this case-control study was to assess the efficacy of dapagliflozin combined with metformin for type-2 diabetes mellitus (T2DM) with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: A total of 36 patients with newly-diagnosed T2DM and OSAHS were randomized divided into two groups. Eighteen OSAHS patients with T2DM, who were treated with dapagliflozin and metformin, were assigned as the dapagliflozin group. These patients were given dapagliflozin and metformin for 24 weeks between February 2017 and February 2018. Another 18 OSAHS patients with T2DM, who were treated with glimepiride and metformin for 24 weeks, were assigned as the control group. Fasting plasma glucose (FPG) level, postprandial blood glucose (PPG), hemoglobin A1C (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), blood lipids, body mass index (BMI), blood pressure, apnea-hypopnea index (AHI), minimum oxygen saturation (LSpO2), and Epworth Somnolence Scale (ESS) score were measured before and at 24 weeks after the initiation of treatment. RESULTS: In the dapagliflozin group, triglyceride (TG), systolic pressure (SBP) and diastolic pressure (DBP) significantly decreased following treatment, while high-density lipoprotein cholesterol (HDL-C) significantly increased (P < 0.05). Furthermore, a reduction in AHI, an increase in LSpO2 and a decrease in ESS score were observed in the dapagliflozin group (P < 0.05), but not in the control group. Moreover, blood glucose, HbA1c, HOMA-IR, and BMI significantly decreased in these two groups, and the decrease was more significant in the dapagliflozin group. CONCLUSION: These present results indicate that dapagliflozin can significantly reduce glucose, BMI, blood pressure and AHI, and improve hypoxemia during sleep and excessive daytime sleepiness, which thereby has potential as an effective treatment approach for OSAHS.

Analysis of resistance mechanisms to abivertinib, a third-generation EGFR tyrosine kinase inhibitor, in patients with EGFR T790M-positive non-small cell lung cancer from a phase I trial.

BACKGROUND: Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC). Here, we report resistance mechanisms to abivertinib, a novel third-generation EGFR TKI, from a phase I dose-escalation/expansion study (NCT02330367). METHODS: Patients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR TKIs received abivertinib in dose escalation (50-350 mg twice daily [BID]) or expansion (300 mg BID) cohorts. Patients enrolled at Guangdong Lung Cancer Institute who underwent next-generation sequencing (NGS)-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis. FINDINGS: Thirty of 73 patients enrolled were eligible for resistance analysis. Upon abivertinib progression, 27 patients provided plasma samples (six patients also provided paired samples from the progression sites) and three patients only provided tissue samples from the progression sites for NGS. A heterogeneous landscape of resistance to abivertinib was observed: 15% (4/27) experienced EGFR T790M loss and 13% (4/30) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (37%), and considered a putative resistance mechanism in seven (23%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation. INTERPRETATION: Our findings reveal a heterogenous pattern of resistance mechanisms to abivertinib which is distinct from that previously reported with osimertinib. EGFR amplification was the most common resistance mechanism in this cohort. FUND: The National Key R&D Program of China (Grant No. 2016YFC1303800), Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120).