Search

Aim: This study aimed to evaluate the relationship between secreted frizzled-related protein 5 (SFRP5) expression and fluorine 18-fluoro-deoxyglucose (18 F-FDG) uptake imaged with positron emission tomography/tomography (PET/CT) in patients with non-small cell lung cancer (NSCLC). In addition, we sought to elucidate the potential role and mechanism of action of SFRP5 in NSCLC.Materials and methods: The maximum standardized uptake value (SUVmax) of the lesions was calculated. SFRP5 expression was analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The correlation between SFRP5 expression and SUVmax was evaluated using Pearson’s correlation analysis. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, wound healing, and transwell assays were used to analyze cell viability, apoptosis, migration, and invasion, respectively.Results and conclusion: The results indicated that the SUVmax was higher in patients with NSCLC than that in healthy volunteers. Moreover, SFRP5 expression was lower in tissues from the four types of NSCLC than that in the adjacent normal tissues. SUVmax negatively correlated with SFRP5 expression in the four types of NSCLC. In addition, up-regulation of SFRP5 decreased the viability, migration, and invasion abilities, and increased apoptosis of NSCLC cells. Furthermore, SFRP5 inhibited the Wnt/β-catenin pathway in NSCLC cells. In conclusion, SFRP5 modulates the biological behaviors of NSCLC through Wnt/β-catenin pathway.

IntroductionThe H9N2 subtype is a predominant avian influenza virus (AIV) circulating in Chinese poultry, forming various genotypes (A-W) based on gene segment origins. This study aims to investigate the genotypic distribution and pathogenic characteristics of H9N2 isolates from wild birds and domestic poultry in Yunnan Province, China.MethodsEleven H9N2 strains were isolated from fecal samples of overwintering wild birds and proximate domestic poultry in Yunnan, including four from common cranes (Grus grus), two from bar-headed geese (Anser indicus), and five from domestic poultry (Gallus gallus). Phylogenetic analysis was conducted to determine the genotypes, and representative strains were inoculated into Yunnan mallard ducks to assess pathogenicity.ResultsPhylogenetic analysis revealed that five isolates from domestic birds and one from a bar-headed goose belong to genotype S, while the remaining five isolates from wild birds belong to genotype A. These bird-derived strains possess deletions in the stalk domain of NA protein and the N166D mutation of HA protein, typical of poultry strains. Genotype S H9N2 demonstrated oropharyngeal shedding, while genotype A H9N2 exhibited cloacal shedding and high viral loads in the duodenum. Both strains caused significant pathological injuries, with genotype S inducing more severe damage to the thymus and spleen, while genotype A caused duodenal muscle layer rupture.DiscussionThese findings suggest that at least two genotypes of H9N2 are currently circulating in Yunnan, and Yunnan mallard ducks potentially act as intermediaries in interspecies transmission. These insights highlight the importance of analyzing the current epidemiological transmission characteristics of H9N2 among wild and domestic birds in China.

BackgroundThe metabolic score for insulin resistance (METS-IR) has emerged as a noninsulin-based index for the approximation of insulin resistance (IR), yet longitudinal evidence supporting the utility of METS-IR in the primary prevention of type 2 diabetes mellitus (T2DM) remains limited. ObjectiveWe aimed to investigate the longitudinal association between METS-IR, which combines fasting plasma glucose (FPG), lipid profiles, and anthropometrics that can be routinely obtained in resource-limited primary care settings, and the incidence of new-onset T2DM. MethodsWe conducted a closed-cohort analysis of a nationwide, prospective cohort of 7583 Chinese middle-aged and older adults who were free of T2DM at baseline, sampled from 28 out of 31 provinces in China. We examined the characteristics of participants stratified by elevated blood pressure (BP) at baseline and new-onset T2DM at follow-up. We performed Cox proportional hazard regression analysis to explore associations of baseline METS-IR with incident T2DM in participants overall and in participants stratified by baseline BP. We also applied net reclassification improvement and integrated discrimination improvement to examine the incremental value of METS-IR. ResultsDuring a mean follow-up period of 6.3 years, T2DM occurred in 527 participants, among which two-thirds (332/527, 62.9%; 95% CI 58.7%-67.1%) had baseline FPG

BackgroundThe automatic generation of radiology reports, which seeks to create a free-text description from a clinical radiograph, is emerging as a pivotal intersection between clinical medicine and artificial intelligence. Leveraging natural language processing technologies can accelerate report creation, enhancing health care quality and standardization. However, most existing studies have not yet fully tapped into the combined potential of advanced language and vision models. ObjectiveThe purpose of this study was to explore the integration of pretrained vision-language models into radiology report generation. This would enable the vision-language model to automatically convert clinical images into high-quality textual reports. MethodsIn our research, we introduced a radiology report generation model named ClinicalBLIP, building upon the foundational InstructBLIP model and refining it using clinical image-to-text data sets. A multistage fine-tuning approach via low-rank adaptation was proposed to deepen the semantic comprehension of the visual encoder and the large language model for clinical imagery. Furthermore, prior knowledge was integrated through prompt learning to enhance the precision of the reports generated. Experiments were conducted on both the IU X-RAY and MIMIC-CXR data sets, with ClinicalBLIP compared to several leading methods. ResultsExperimental results revealed that ClinicalBLIP obtained superior scores of 0.570/0.365 and 0.534/0.313 on the IU X-RAY/MIMIC-CXR test sets for the Metric for Evaluation of Translation with Explicit Ordering (METEOR) and the Recall-Oriented Understudy for Gisting Evaluation (ROUGE) evaluations, respectively. This performance notably surpasses that of existing state-of-the-art methods. Further evaluations confirmed the effectiveness of the multistage fine-tuning and the integration of prior information, leading to substantial improvements. ConclusionsThe proposed ClinicalBLIP model demonstrated robustness and effectiveness in enhancing clinical radiology report generation, suggesting significant promise for real-world clinical applications.

Abstract Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2. Here we report that nelfinavir, an FDA approved drug for the treatment of HIV infection, is effective against SARS-CoV-2 and COVID-19. Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2 (IC50 = 8.26 μM), while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93 μM (EC50). In comparison with vehicle-treated animals, rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals. At necropsy, nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude. A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center, which were randomized (1:1) to nelfinavir and control groups, showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days (9.0 vs. 14.5 days, P = 0.055) and the duration of fever time by 3.8 days (2.8 vs. 6.6 days, P = 0.014) in mild/moderate COVID-19 patients. The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients, together with its well-established good safety profile in almost all ages and during pregnancy, indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.

This study investigates the pass-through of exchange rate shocks to different aggregate prices in China. The baseline analysis is carried out with vector autoregressive models incorporating a distribution chain of pricing, and various modifications are examined for robustness. The central results show an appreciation of the local currency tends to suppress domestic inflation at the early production stages, although the pass-through effect only amounts to a moderate degree for consumer prices. As the contribution of external factors to the persistently low inflation environment mostly has been modest, the paper suggests that the monetary authority can contribute to the permanent component of low exchange rate pass-through to domestic inflation, by continually conducting a credible and efficient stable-inflation policy.

Abstract Background This study compared the survival outcomes of different surgical approaches to determine the optimal approach for gastric cardia adenocarcinoma (GCA) and aimed to standardize the surgical treatment guidelines for GCA. Methods A total of 7103 patients with GCA were enrolled from our previously established gastric cardia and esophageal carcinoma databases. In our database, when the epicenter of the tumor was at or within 2 cm distally from the esophagogastric junction, the adenocarcinoma was considered to originate from the cardia and was considered a Siewert type 2 cancer. The main criteria for the enrolled patients included treatment with radical surgery, no radio- or chemotherapy before the operation, and detailed clinicopathological information. Follow-up was mainly performed by telephone or through home interviews. According to the medical records, the surgical approaches included transthoracic, thoracoabdominal, and transabdominal approaches. Kaplan–Meier and Cox proportional hazards regression models were applied to correlate the surgical approach with survival in patients with GCA. Results There were marked differences in age and tumor stage among the patients who underwent the three surgical approaches (P

AimsTo assess longitudinal changes in blood pressure (BP) and fasting plasma glucose (FPG) in primary care patients with concomitant hypertension and type 2 diabetes mellitus (T2DM), and to explore factors associated with patients' inability to improve BP and FPG at follow-up.MethodsWe constructed a closed cohort in the context of the national basic public health (BPH) service provision in an urbanised township in southern China. Primary care patients who had concomitant hypertension and T2DM were retrospectively followed up from 2016 to 2019. Data were retrieved electronically from the computerised BPH platform. Patient-level risk factors were explored using multivariable logistic regression analysis.ResultsWe included 5,398 patients (mean age 66 years; range 28.9 to 96.1 years). At baseline, almost half [48.3% (2,608/5,398)] of patients had uncontrolled BP or FPG. During follow-up, more than one-fourth [27.2% (1,467/5,398)] of patients had no improvement in both BP and FPG. Among all patients, we observed significant increases in systolic BP [2.31 mmHg, 95% confidence interval (CI): 2.04 to 2.59, p

The motion of magnetic particles under magnetic fields is an object to be solved in association with basic and practical phenomena. Movement phenomena of magnetite-encapsulated graphene particles at air–water interfaces were evaluated by manufacturing a feedback control system of the magnetic field to cause the motion of particles due to magnetic torque. A homogeneous magnetic field was generated using two pairs of electromagnets located perpendicular to each other, which were connected to an electronic switch. The system influenced the translational movement and the self-rotational speed of magnetic particles located at a center on the surface of fluid media in a continuous duty cycle. Operating the particle at a remote control in the same duty cycle at the air–water surface, the short and elongated magnetic particles successfully rotated. In addition, the rotational speed of the curved particle was slower than that of the elongated particle. The results indicate that the translational and self-rotational movements of magnetite-encapsulated graphene particles at the air–water interface under the external magnetic field are size- and shape-dependent for the speed and the direction. A short magnetic particle was used as a target particle to rotate on cancer cell lines, aiming to study the advantage of this method to induce the growth of HeLa cells. It was monitored for up to 4 days with and without magnetic particles by checking the viability and morphology of cells before and after the electromagnetic treatment. As an outcome, the movement of magnetic particles reduced the number of biological cells, at least on HeLa cells, but it was inactive on the viability of HeLa cells.

BackgroundThis study was intended to construct a brand new prognostic nomogram after combine clinical and pathological characteristics to increases prognostic value in patients with esophageal squamous cell carcinoma.MethodsA total of 1,634 patients were included. Subsequently, the tumor tissues of all patients were prepared into tissue microarrays. AIPATHWELL software was employed to explore tissue microarrays and calculate the tumor-stroma ratio. X-tile was adopted to find the optimal cut-off value. Univariate and multivariate Cox analyses were used to screen out remarkable characteristics for constructing the nomogram in the total populations. A novel prognostic nomogram with clinical and pathological characteristics was constructed on the basis of the training cohort (n=1,144). What’s more performance was validated in the validation cohort (n=490). Clinical-pathological nomogram were assessed by concordance index, time-dependent receiver operating characteristic, calibration curve and decision curve analysis.ResultsThe patients can divide into two groups with cut-off value of 69.78 for the tumor-stroma ratio. It is noteworthy that the survival difference was noticeable (P

Fowl adenoviruses (FAdVs) are distributed worldwide in poultry and incriminated as the etiological agents for several health problems in fowls, and are capable of crossing species barriers between domestic and wild fowls. An FAdV strain was, for the first time, isolated from black-necked crane in this study, and was designated as serotype 4 Fowl aviadenovirus C (abbreviated as BNC2021) according to the phylogenetic analysis of its DNA polymerase and hexon gene. The viral genomic sequence analysis demonstrated that the isolate possessed the ORF deletions that are present in FAdV4 strains circulating in poultry fowls in China and the amino acid mutations associated with viral pathogenicity in the hexon and fiber 2 proteins. A viral challenge experiment with mallard ducks demonstrated systemic viral infection and horizontal transmission. BNC2021 induced the typical clinical signs of hepatitis–hydropericardium syndrome (HHS) with swelling and inflammation in multiple organs and showed significant viral replication in all eight organs tested in the virus-inoculated ducks and their contactees at 6 dpi. The findings highlight the importance of surveillance of FAdVs in wild birds.

Esophageal squamous cell carcinoma (ESCC) is one of the most common aggressive malignancies worldwide, particularly in northern China. The absence of specific early symptoms and biomarkers leads to late-stage diagnosis, while early diagnosis and risk stratification are crucial for improving overall prognosis. We performed UPLC-MS/MS on 450 ESCC patients and 588 controls consisting of a discovery group and two validation groups to identify biomarkers for early detection and prognosis. Bioinformatics and clinical statistical methods were used for profiling metabolites and evaluating potential biomarkers. A total of 105 differential metabolites were identified as reliable biomarker candidates for ESCC with the same tendency in three cohorts, mainly including amino acids and fatty acyls. A predictive model of 15 metabolites [all-trans-13,14-dihydroretinol, (±)-myristylcarnitine, (2S,3S)-3-methylphenylalanine, 3-(pyrazol-1-yl)-L-alanine, carnitine C10:1, carnitine C10:1 isomer1, carnitine C14-OH, carnitine C16:2-OH, carnitine C9:1, formononetin, hyodeoxycholic acid, indole-3-carboxylic acid, PysoPE 20:3, PysoPE 20:3(2n isomer1), and resolvin E1] was developed by logistic regression after LASSO and random forest analysis. This model held high predictive accuracies on distinguishing ESCC from controls in the discovery and validation groups (accuracies > 89%). In addition, the levels of four downregulated metabolites [hyodeoxycholic acid, (2S,3S)-3-methylphenylalanine, carnitine C9:1, and indole-3-carboxylic acid] were significantly higher in early cancer than advanced cancer. Furthermore, three independent prognostic markers were identified by multivariate Cox regression analyses with and without clinical indicators: a high level of MG(20:4)isomer and low levels of 9,12-octadecadienoic acid and L-isoleucine correlated with an unfavorable prognosis; the risk score based on these three metabolites was able to stratify patients into low or high risk. Moreover, pathway analysis indicated that retinol metabolism and linoleic acid metabolism were prominent perturbed pathways in ESCC. In conclusion, metabolic profiling revealed that perturbed amino acids and lipid metabolism were crucial metabolic signatures of ESCC. Both panels of diagnostic and prognostic markers showed excellent predictive performances. Targeting retinol and linoleic acid metabolism pathways may be new promising mechanism-based therapeutic approaches. Thus, this study would provide novel insights for the early detection and risk stratification for the clinical management of ESCC and potentially improve the outcomes of ESCC.

The seasonal migration of wild aquatic birds plays a critical role in the maintenance, transmission, and incursion of the avian influenza virus (AIV). AIV surveillance was performed during 2020–2021 in two national nature reserves with abundant wild bird resources in Yunnan, China. Four H5N8 AIVs isolates from the common crane were identified by next-generation sequencing. Phylogenetic analysis demonstrated that all eight gene segments of these H5N8 AIVs belonged to clade 2.3.4.4b high-pathogenic AIV (HPAIV) and shared high nucleotide sequence similarity with the strains isolated in Hubei, China, and Siberia, Russia, in 2020–2021. The H5N8 HPAIVs from common cranes were characterized by both human and avian dual-receptor specificity in the hemagglutinin (HA) protein. Moreover, possessing the substitutions contributes to overcoming transmission barriers of mammalian hosts in polymerase basic 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acid (PA), and exhibiting the long stalk in the neck region of the neuraminidase (NA) protein contributes to adaptation in wild birds. Monitoring AIVs in migratory birds, at stopover sites and in their primary habitats, i.e., breeding or wintering grounds, could provide insight into potential zoonosis caused by AIVs.

Pseudomembranous tracheitis is a rare life-threatening complication of endotracheal intubation. The exact mechanism of its formation is not well known, and it could mimic crusting or retained secretions in the trachea. We encountered a patient with history of recent intubation, presenting with acute stridor requiring emergency airway stabilization, and was eventually found to have pseudomembranous tracheitis.

Background/Aims: Exosomal circulating long non-coding RNAs (lncRNAs) in blood are emerging as clinically useful and non-invasive biomarkers for tumor diagnosis. However, normal cells can also secrete exosomes, so it is a prerequisite to obtain tumor-derived exosomes for better understanding of their diagnostic impacts in cancer. In this study, a dual-antibody-functionalized immunoaffinity system was established to isolate exosomes and investigate their lncRNAs expression pattern and clinical significance in prostate cancer (PCa). Methods: A commercially available kit was used to isolate total exosomes, which were then purified by a dual-antibody-functionalized immunoaffinity system. RT-qPCR was performed to detect the expression of exosomal lncRNAs. Receiver operating characteristic (ROC) curves were plotted to assess the diagnostic value. Results: Expression levels of two lncRNAs in tumor-derived exosomes were significantly higher than those in total exosomes. The levels of SAP30L-AS1 were upregulated in benign prostatic hyperplasia (BPH), and SChLAP1 levels were significantly higher in PCa than in BPH and healthy individuals. The area under the ROC curve indicated that SAP30L-AS1 and SChLAP1 had adequate diagnostic value to distinguish PCa from controls. Two lncRNAs separately combined with prostate specific antigen (PSA) possessed a moderate ability for discrimination. SAP30L-AS1 expression level was related to PSA values and tumor invasion. SChLAP1 expression was significantly higher in patients with higher Gleason scores, and was also effective in differentiating between BPH and PCa when the concentration of PSA was in the gray zone. Conclusion: The isolation of tumor-derived exosomes by dual-antibody-functionalized immunoaffinity systems and detection of their lncRNAs in plasma may lead to the identification of suitable biomarkers, with potential diagnostic utility.

Objective: To investigate the potential biomarkers for venous metastasis of hepatocellular carcinoma (HCC), and briefly discuss their target genes and the signaling pathways they are involved in.Materials and Method: The dataset GSE6857 was downloaded from GEO. Significantly differentially expressed miRNAs were identified using the R package “limma,” After that, the survival analysis was conducted to discover the significance of these up-regulated miRNAs for the prognosis of HCC patients. Additionally, miRNAs which were up-regulated in venous metastasis positive HCC tissues and were significant for the prognosis of HCC patients were further verified in clinical samples using RT-qPCR. The miRNAs were then analyzed for their correlations with clinical characteristics including survival time, AFP level, pathological grade, TNM stage, tumor stage, lymph-node metastasis, distant metastasis, child-pugh score, vascular invasion, liver fibrosis and race using 375 HCC samples downloaded from the TCGA database. The target genes of these miRNAs were obtained using a miRNA target gene prediction database, and their functions were analyzed using the online tool DAVID.Results: 15 miRNAs were differentially expressed in samples with venous metastasis, among which 7 were up-regulated in venous metastasis positive HCC samples. As one of the up-regulated miRNAs, hsa-miR-210 was identified as an independent prognostic factor for HCC. Using RT-qPCR, it was evident that hsa-miR-210 expression was significantly higher in venous metastasis positive HCC samples (p = 0.0036). Further analysis indicated that hsa-miR-210 was positively associated with AFP level, pathological grade, TNM stage, tumor stage and vascular invasion. A total of 168 hsa-miR-210 target genes, which are mainly related to tumor metastasis and tumor signaling pathways, were also predicted in this study.Conclusion: hsa-miR-210 might promote vascular invasion of HCC cells and could be used as a prognostic biomarker.

Accumulating evidence has demonstrated that some single nucleotide polymorphisms (SNPs) existing in miRNAs correlate with the susceptibility to urological cancers. However, a clear consensus still not reached due to the limited statistical power in individual study. Thus, we concluded a meta-analysis to systematically evaluate the association between microRNA SNPs and urological cancer risk. Eligible studies were collected from PubMed, Embase, Web of Science, and CNKI databases. Pooled odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to assess the strength of the relationships between three SNPs (miR-196a2, C>T rs11614913; miR-146a, G>C rs2910164; and miR-499, A>G rs3746444) and the risk of urological cancers. In addition, the stability of our analysis was evaluated by publication bias, sensitivity and heterogeneity analysis. Overall, a total of 17,019 subjects from 14 studies were included in this meta-analysis. We found that CT (miR-196a2, C>T rs11614913) was a risk factor for renal cell carcinoma (CT vs. CC: OR = 1.72, 95%CI = 1.05–2.80, P = 0.03, I2 = 66%), especially in Asian population (CT vs. CC: OR = 1.17, 95%CI = 1.04–1.32, P < 0.01, I2 = 0%). miR-146a G>C rs2910164 was a protective factor of urological cancers (C vs. G: OR = 0.87, 95%CI = 0.81–0.93, P < 0.01, I2 = 0%), especially for bladder cancer. miR-499 A>G rs3746444 was correlated with an increased risk of urological cancers, specifically in Asian population. In conclusion, our meta-analysis suggests that polymorphisms in microRNAs, miR-196a2, C>T rs11614913, miR-146a G>C rs2910164 and miR-499 A>G rs3746444, may be associated with the development of urological cancers and the risks mainly exist in Asian populations.

The paper proposed a design scheme of full range speed-regulation system based on bivariate 6-pulse wave AC-AC converter. It analyzed control principle of bivariate 6-pulse wave AC-AC converter, introduced characteristics and design of main circuit and speed-regulation principle of the system. The results of simulation and loading test showed that the system can realize full range speed-regulation with high-efficiency.

In this paper, we present a design of the linear polarization conversion metasurface (MS) for the broadband radar cross section (RCS) reduction based on split-ring resonator (SRR) structure in microwave region. The corresponding phase gradient can be obtained through the stable phase difference of basic units of polarization conversion MS. The designed polarization conversion MS is applied in coded electromagnetic (EM) matrix by defining two basic units “0” and “1”, respectively. Based on the principle of planar array theory, a new random coding method named by matrix-type coding is proposed. Correlative RCS reduction mechanism is discussed and verified, which can be used to explore the RCS reduction characteristic. The simulated linear polarization conversion rate of the designed structure is up to 90% in the frequency range of 6–15 GHz, and the RCS reduction results verify the theoretical assumptions. Two kinds of matrix-type coding MS samples are prepared and measured. The experimental results indicate that the reflectance of MS is less than –10 dB on average under normal incidence in frequency range of 5.8–15.5 GHz. The average RCS reduction is essentially more than 10 dB in frequency range of 5.5–15 GHz and the corresponding relative bandwidth is 92.7%, which reasonably agrees with simulation. In addition, excellent RCS reduction characteristic of the designed MS can also be achieved over a wide incident angle.

A class of linear polarization conversion coding metasurfaces (MSs) based on a metal cut-wire structure is proposed, which can be applied to the reduction properties of radar cross section (RCS). We firstly present a hypothesis based on the principle of planar array theory, and then verify the RCS reduction characteristics using linear polarization conversion coding MSs by simulations and experiments. The simulated results show that in the frequency range of 6–14 GHz, the linear polarization conversion ratio reaches a maximum value of 90%, which is in good agreement with the theoretical predictions. For normal incident x- and y-polarized waves, RCS reduction of designed coding MSs 01/01 and 01/10 is essentially more than 10 dB in the above-mentioned frequency range. We prepare and measure the 01/10 coding MS sample, and find that the experimental results in terms of reflectance and RCS reduction are in good agreement with the simulated ones under normal incidence. In addition, under oblique incidence, RCS reduction is suppressed as the angle of incidence increases, but still exhibits RCS reduction effects in a certain frequency range. The designed MS is expected to have valuable potential in applications for stealth field technology.

Let ℳ be any von Neumann algebra without central summands of type I1 and P a core-free projection with the central carrier I. For any scalar ξ, it is shown that every additive map L on ℳ satisfies L(AB-ξBA)=L(A)B-ξBL(A)+AL(B)-ξL(B)A whenever AB=P if and only if (1) ξ=1, L=φ+h, where φ is an additive derivation and h is a central valued additive map vanishing on AB-BA with AB=P; (2) ξ≠1, L is a derivation with L(ξA)=ξL(A) for each A∈ℳ.

Older chronic lymphocytic leukemia patients have poor outcomes with standard treatments and are underrepresented in clinical trials. We retrospectively reviewed outcomes of refractory chronic lymphocytic leukemia patients in two age categories (≥70 and 0.80). Although overall survival was worse in older patients (median 2.1 vs. 2.4 years, P=0.02); when adjusted for other factors this difference was no longer significant (P≥0.10). With the exception of infections (older 29% vs. younger 62%) no significant association with toxicity was observed. These data demonstrate that flavopiridol administration to older chronic lymphocytic leukemia patients is feasible, tolerable, and may have similar efficacy to that in younger patients. Development of treatment approaches including flavopiridol should be considered for these older patients.

Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy.