Mechanisms of Phytochemicals in Anti-Inflammatory and Anti-Cancer.

Phytochemicals are chemical compounds that exist in plants and serve various functions such as protecting against pests, UV radiation, and diseases [...].

Unravelling the Complex LiOH-Based Cathode Chemistry in Lithium-Oxygen Batteries.

The LiOH-based cathode chemistry has demonstrated potential for high-energy Li-O2 batteries. However, the understanding of such complex chemistry remains incomplete. Herein, we use the combined experimental methods with ab initio calculations to study LiOH chemistry. We provide a unified reaction mechanism for LiOH formation during discharge via net 4 e- oxygen reduction, in which Li2 O2 acts as intermediate in low water-content electrolyte but LiHO2 as intermediate in high water-content electrolyte. Besides, LiOH decomposes via 1 e- oxidation during charge, generating surface-reactive hydroxyl species that degrade organic electrolytes and generate protons. These protons lead to early removal of LiOH, followed by a new high-potential charge plateau (1 e- water oxidation). At following cycles, these accumulated protons lead to a new high-potential discharge plateau, corresponding to water formation. Our findings shed light on understanding of 4 e- cathode chemistries in metal-air batteries.

A Single-Atom Fe-N-C Catalyst with Ultrahigh Utilization of Active Sites for Efficient Oxygen Reduction.

Fe-N-C single-atom catalysts (SACs) are emerging as a promising class of electrocatalysts for the oxygen reduction reaction (ORR) to replace Pt-based catalysts. However, due to the limited loading of Fe for SACs and the inaccessibility of internal active sites, only a small portion of the sites near the external surface are able to contribute to the ORR activity. Here, this work reports a metal-organic framework-derived Fe-N-C SAC with a hierarchically porous and concave nanoarchitecture prepared through a facile but effective strategy, which exhibits superior electrocatalytic ORR activity with a half-wave potential of 0.926 V (vs RHE) in alkaline media and 0.8 V (vs RHE) in acidic media while maintaining excellent stability. The superior ORR activity of the as-designed catalyst stems from the unique architecture, where the hierarchically porous architecture contains micropores as Fe SAC anchoring sites, meso-/macro-pores as accessible channels, and concave shell for increasing external surface area. The unique architecture has dramatically enhanced the utilization of previously blocked internal active sites, as confirmed by a high turnover frequency of 3.37 s-1 and operando X-ray absorption spectroscopy analysis with a distinct shift of adsorption edge.

Metformin induces caspase-dependent and caspase-independent apoptosis in human bladder cancer T24 cells.

Bladder cancer (BC) is the sixth most common cancer in men. Moreover, chemotherapy for BC leads to various side effects. Metformin is known to induce apoptosis in vitro in many types of cancer. Furthermore, it has feasibility as a drug repositioning used for the treatment of cancer. The molecular mechanism of metformin mediating apoptosis in BC is still unclear. In this study, we showed that metformin stimulated the caspase-dependent apoptotic signaling pathway in T24 cells, a human BC cell line. Moreover, the induced apoptosis was partially inhibited by a general caspase inhibitor, z-VAD-fmk, which suggested that metformin-induced apoptosis in T24 cells is partially caspase-independent. Notably, we observed the nuclear translocation of apoptosis-inducing factors (AIFs) in metformin-promoted apoptosis, which is a typical characteristic of the caspase-independent apoptotic pathway. In addition, we found that metformin-mediated apoptosis occurred via degradation of the cellular FADD-like interleukin-1ß-converting enzyme inhibitory protein (c-FLIP) by facilitating ubiquitin/proteasome-mediated c-FLIPL degradation. Furthermore, treatment with the reactive oxygen species scavenger N-acetylcysteine, failed to suppress metformin-induced apoptosis and c-FLIPL protein degradation in metformin-treated T24 cells. In conclusion, these results indicate that metformin-induced apoptosis was mediated through AIF-promoted caspase-independent pathways as well as caspase-dependent pathways in T24 cells. As such, metformin could be used as a possible apoptotic agent for the treatment of BC.

MiR-1208 Increases the Sensitivity to Cisplatin by Targeting TBCK in Renal Cancer Cells.

MicroRNAs (miRNAs) can be used to target a variety of human malignancies by targeting their oncogenes or tumor suppressor genes. Recent evidence has shown that miRNA-1208 (miR-1208) was rarely expressed in a variety of cancer cells, suggesting the possibility that miR-1208 functions as a tumor suppressor gene. Herein, ectopic expression of miR-1208 induced the accumulation of sub-G1 populations and the cleavage of procaspase-3 and PARP, which could be prevented by pre-treatment with the pan-caspase inhibitor, Z-VAD. In addition, miR-1208 increased the susceptibility to cisplatin and TRAIL in Caki-1 cells. Luciferase reporter assay results showed that miR-1208 negatively regulates TBC1 domain containing kinase (TBCK) expression by binding to the miR-1208 binding sites in the 3'-untranslated region of TBCK. In addition, miR-1208 specifically repressed TBCK expression at the transcriptional level. In contrast, inhibition of endogenous miR-1208 by anti-miRs resulted in an increase in TBCK expression. Downregulation of TBCK induced by TBCK-specific siRNAs increased susceptibility to cisplatin and TRAIL. These findings suggest that miR-1208 acts as a tumor suppressor and targets TBCK directly, thus possessing great potential for use in renal cancer therapy.

Prognostic Impact of Left Atrial Minimal Volume on Clinical Outcome in Patients with Non-Obstructive Hypertrophic Cardiomyopathy.

Maximal left atrial volume (LAVmax) has been suggested to be an important indicator of left ventricular (LV) diastolic function and a prognosticator in patients with hypertrophic cardiomyopathy (HCM). However, LAVmax can be influenced by LV longitudinal systolic function, which causes systolic descent of the mitral plane. We investigated the prognostic role of LAVmin in patients with HCM and tested if LAVmin is better than LAVmax in predicting clinical outcome in these patients. A total of 167 consecutive patients with HCM were enrolled (age = 64.7 ± 13.5 years, male: female = 120:47). Clinical parameters and conventional echocardiographic measurement including tissue Doppler measurement were evaluated. Left atrial maximal and minimal volumes were measured just before mitral valve opening and at mitral valve closure respectively using the biplane disk method. The relationship between LAVmin and the clinical outcome of hospitalization for heart failure (HF), stroke or all-cause mortality was evaluated. During a median follow-up of 25.0 ± 17.8 months, the primary end point of HF hospitalization, stroke or death occurred in 35 patients (21%). Indexed LAVmin was predictive of HF, stroke or death after adjustment for age, diabetes, hypertension, atrial fibrillation, LV ejection fraction, and E/e'in a multivariate analysis (P = 0.001). The model including indexed LAVmin was superior to the model including indexed LAVmax in predicting a worse outcome in patients with HCM (P = 0.02). In conclusion, LAVmin was independently associated with increased risk of HF, stroke, or mortality in patients with HCM and was superior to LAVmax in predicting clinical outcome in this population.

Methylglyoxal-induced apoptosis is dependent on the suppression of c-FLIPL expression via down-regulation of p65 in endothelial cells.

Methylglyoxal (MGO) is a reactive dicarbonyl metabolite of glucose, and its plasma levels are elevated in patients with diabetes. Studies have shown that MGO combines with the amino and sulphhydryl groups of proteins to form stable advanced glycation end products (AGEs), which are associated with vascular endothelial cell (EC) injury and may contribute to the progression of atherosclerosis. In this study, MGO induced apoptosis in a dose-dependent manner in HUVECs, which was attenuated by pre-treatment with z-VAD, a pan caspase inhibitor. Treatment with MGO increased ROS levels, followed by dose-dependent down-regulation of c-FLIPL . In addition, pre-treatment with the ROS scavenger NAC prevented the MGO-induced down-regulation of p65 and c-FLIPL , and the forced expression of c-FLIPL attenuated MGO-mediated apoptosis. Furthermore, MGO-induced apoptotic cell death in endothelium isolated from mouse aortas. Finally, MGO was found to induce apoptosis by down-regulating p65 expression at both the transcriptional and posttranslational levels, and thus, to inhibit c-FLIPL mRNA expression by suppressing NF-κB transcriptional activity. Collectively, this study showed that MGO-induced apoptosis is dependent on c-FLIPL down-regulation via ROS-mediated down-regulation of p65 expression in endothelial cells.

RU486 Induces Pro-Apoptotic Endoplasmic Reticulum Stress Through the Induction of CHOP Expression by Enhancing C/EBPδ Expression in Human Renal Carcinoma Caki Cells.

RU486 (Mifepristone) is known as an antagonist of the progesterone receptor and glucocorticoid receptor. Here, we investigated the mechanism underlying anti-tumor activity of RU486 in renal carcinoma Caki cells. Treatment of Caki cells with RU486 was found to induce several signature ER stress markers; including ER stress-specific XBP1 splicing, and the up-regulation of glucose-regulated protein (GRP)-78 and CCAAT/enhancer-binding protein homologous protein (CHOP) expression. RU486-induced expression of CHOP involves the putative C/EBPδ site within the CHOP promoter region. Using a combination of C/EBPδ cDNA transfection, the luciferase assay with a mutated C/EBPδ binding site and siRNA-mediated C/EBPδ knockdown, we found that the C/EBPδ site is required for RU486-mediated activation of the CHOP promoter. In addition, RU486-induced CHOP expression is down-regulated by inhibition of the p38 MAPK and JNK signaling pathways at the post-translational levels. RU486 dose-dependently induced apoptotic cell death in renal carcinoma cells. Suppression of CHOP expression by CHOP siRNA attenuated RU486-induced apoptosis. Taken together, RU486 induces pro-apoptotic ER stress through the induction of CHOP expression.

Dioscin induces caspase-independent apoptosis through activation of apoptosis-inducing factor in breast cancer cells.

Dioscin, a saponin extracted from the roots of Polygonatum zanlanscianense, shows several bioactivities such as antitumor, antifungal, and antiviral properties. Although, dioscin is already known to induce cell death in variety cancer cells, the molecular basis for dioscin-induced cell death was not definitely known in cancer cells. In this study, we found that dioscin treatment induced cell death in dose-dependent manner in breast cancer cells such as MDA-MB-231, MDA-MB-453, and T47D cells. Dioscin decreased expressions of Bcl-2 and cIAP-1 proteins, which were down-regulated at the transcriptional level. Conversely, Mcl-1 protein level was down-regulated by facilitating ubiquitin/proteasome-mediated Mcl-1 degradation in dioscin-treated cells. Pretreatment with z-VAD fails to attenuate dioscin-induced cell death as well as caspase-mediated events such as cleavages of procaspase-3 and PARP. In addition, dioscin treatment increased the population of annexin V positive cells and induced DNA fragmentation in a dose-dependent manner in MDA-MB-231 cells. Furthermore, apoptosis inducing factor (AIF) was released from the mitochondria and translocated to the nucleus. Suppression in AIF expression by siRNA reduced dioscin-induced apoptosis in MDA-MB-231 cells. Taken together, our results demonstrate that dioscin-induced cell death was mediated via AIF-facilitating caspase-independent pathway as well as down-regulating anti-apoptotic proteins such as Bcl-2, cIAP-1, and Mcl-1 in breast cancer cells.

Enhanced dielectric performance in polymer composite films with carbon nanotube-reduced graphene oxide hybrid filler.

The electrical conductivity and the specific surface area of conductive fillers in conductor-insulator composite films can drastically improve the dielectric performance of those films through changing their polarization density by interfacial polarization. We have made a polymer composite film with a hybrid conductive filler material made of carbon nanotubes grown onto reduced graphene oxide platelets (rG-O/CNT). We report the effect of the rG-O/CNT hybrid filler on the dielectric performance of the composite film. The composite film had a dielectric constant of 32 with a dielectric loss of 0.051 at 0.062 wt% rG-O/CNT filler and 100 Hz, while the neat polymer film gave a dielectric constant of 15 with a dielectric loss of 0.036. This is attributed to the increased electrical conductivity and specific surface area of the rG-O/CNT hybrid filler, which results in an increase in interfacial polarization density between the hybrid filler and the polymer.

A Case of Interstitial Lung Disease-Related Pulmonary Hypertension Successfully Treated with Inhaled Iloprost.

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) (PH-ILD) significantly worsens clinical symptoms and survival, with no effective treatment available. This case report presents the successful treatment of PH-ILD with inhaled iloprost in a patient with idiopathic pulmonary fibrosis (IPF). The patient, a 68-year-old female, was diagnosed with IPF in 2018 and was maintained on pirfenidone. She experienced stable disease until March 2023, when she developed progressive exertional dyspnea, despite stability indicated by a computed tomography (CT) scan, without progression. Transthoracic echocardiography (TTE) and right heart catheterization (RHC) confirmed PH-ILD with a mean pulmonary artery pressure (mPAP) of 43 mmHg. Due to the ineffectiveness of sildenafil and a CT scan indicating stable IPF, a repeat RHC was performed, which showed a worsening of PH (mPAP 62 mmHg). Consequently, inhaled iloprost, at a dosage of 10 mcg every eight hours, was added to the existing antifibrotic agent. After two months, the patient experienced reduced exertional dyspnea and home oxygen requirements. By the seventh month, pulmonary function tests, the six-minute walk test, and RHC parameters (mPAP 37 mmHg) showed marked improvements. This case suggests that inhaled iloprost may be beneficial for managing PH-ILD. Further research is needed to confirm the efficacy of iloprost in PH-ILD treatment.

Recent advances in anticancer mechanisms of molecular glue degraders: focus on RBM39-dgrading synthetic sulfonamide such as indisulam, E7820, tasisulam, and chloroquinoxaline sulfonamide.

Synthetic sulfonamide anticancer drugs, including E7820, indisulam, tasisulam, and chloroquinoxaline sulfonamide, exhibit diverse mechanisms of action and therapeutic potential, functioning as molecular glue degraders. E7820 targets RBM39, affecting RNA splicing and angiogenesis by suppressing integrin α2. Phase I studies have demonstrated some stability in advanced solid malignancies; however, further efficacy studies are required. Indisulam causes G1 cell cycle arrest and delays the G1/S transition by modulating splicing through RBM39 degradation via DCAF15. Despite its limited initial efficacy, it shows promise in combination therapies, particularly for hematopoietic malignancies and gliomas. Tasisulam inhibits VEGF signaling, suppresses angiogenesis, and induces apoptosis. Although early trials indicated broad activity, safety concerns have halted its development. Chloroquinoxaline sulfonamide, initially investigated for cell cycle arrest and topoisomerase II inhibition, was discontinued owing to its limited efficacy and toxicity, despite promising initial results. Recent studies revealed the structural interaction of E7820 with DCAF15 and RBM39, although phase II trials on myeloid malignancies have shown limited efficacy. Indisulam is effective against glioblastoma and neuroblastoma, with potential synergy in combination therapies and metabolic disruption. Recent research on tasisulam reveals its potential in cancer therapy by targeting RBM39 degradation through DCAF15-mediated pathways. Understanding these mechanisms could lead to new treatments that affect alternative splicing and improve cancer therapies Overall, although these drugs exhibit promising mechanisms of action, further research is required to optimize their clinical efficacy and safety.

A study on the prevalence and prognosis of progressive pulmonary fibrosis: A retrospective observational study.

Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 diffuse parenchymal lung diseases with various clinical courses. Disease progression is one of the most important prognostic factors, and, the definition of progressive pulmonary fibrosis (PPF) has recently been established. This study aimed to estimate the prevalence, risk factors, and prognosis of PPF among patients with non-idiopathic pulmonary fibrosis (IPF) in real-world practice. A total of 215 patients were retrospectively analyzed between January 2010 and June 2023 at the Haeundae Paik Hospital in the Republic of Korea. According to the criteria proposed in 2022 by Raghu et al, PPF defined as a condition that satisfies 2 or more of the following in the past year: worsening of respiratory symptoms, physiological evidence of disease progression, and radiological evidence of disease progression. The median age of the subjects was 67 years and 63.7% were female. A total of 40% was diagnosed with PPF and connective tissue disease-associated ILD (52.3%) was the most common type, followed by nonspecific interstitial pneumonitis (NSIP) (25.6%) and cryptogenic organizing pneumonitis (16.3%). In multivariate logistic regression for predicting PPF, both the use of steroids and immunosuppressants (OR: 2.57, 95% CI: 1.41-4.67, P = .002) and home oxygen use (OR: 25.17, 95% CI: 3.21-197.24, P = .002) were independent risk factors. During the follow-up period, the mortality rate was significantly higher in the PPF group than in the non-PPF group (24.4% vs 2.3%, P < .001). In the survival analysis using the Cox proportional hazard regression model, disease progression, older age and lower forced vital capacity (FVC) were independent risk factors for mortality. Our study demonstrated that the prevalence of PPF was 40%. Concomitant therapy of steroids with an immunosuppressants and home oxygen use are risk factors for PPF. PPF itself was significantly associated with high mortality rates. Risk factors for mortality were disease progression, older age, and lower FVC.

Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation.

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations.

Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii.

Colistimethate sodium (CMS) nebulization is associated with reduced systemic toxicity compared to intravenous injection, with potentially enhanced clinical efficacy. This study aimed to assess the pharmacokinetic (PK) properties of colistin during low-dose CMS nebulization in patients with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii. A nonlinear mixed-effects modeling approach was applied to develop population PK models for colistin in both epithelial lining fluid (ELF) and plasma. Twenty patients participated, and 80 ELF and 100 plasma samples were used for model development. Median colistin concentrations measured in ELF were 614-fold, 408-fold, and 250-fold higher than in plasma at 1, 3, and 5 h, respectively. Time courses in both ELF and plasma were best described by a one-compartment model with a Weibull absorption process. When the final model was simulated, the maximum free concentration and area under the free colistin concentration-time curve at steady state over 24 h in the plasma were approximately 1/90 and 1/50 of the corresponding values in ELF at steady state, respectively. For an A. baumannii MIC of 1 mg/L, inhaling 75 mg of CMS at 6 h intervals was deemed appropriate, with dose adjustments needed for MICs exceeding 2 mg/L. Using a nebulizer for CMS resulted in a notably higher exposure of colistin in the ELF than plasma, indicating the potential of nebulization to reduce systemic toxicity while effectively treating VAP.

The association of the Sequential Organ Failure Assessment score at intensive care unit discharge with intensive care unit readmission in the cardiac intensive care unit.

AIMS: Unplanned intensive care unit (ICU) readmissions contribute to increased morbidity, mortality, and healthcare costs. The severity of patient illness at ICU discharge may predict early ICU readmission. Thus, in this study, we investigated the association of cardiac ICU (CICU) discharge Sequential Organ Failure Assessment (SOFA) score with unplanned CICU readmission in patients admitted to the CICU. METHODS AND RESULTS: We retrospectively reviewed the hospital medical records of 4659 patients who were admitted to the CICU from 2012 to 18. Sequential Organ Failure Assessment scores at CICU admission and discharge were obtained. The predictive performance of organ failure scoring was evaluated by using area under the receiver operating characteristic (AUROC) curves. The primary outcome was unplanned CICU readmission. Of the 3949 patients successfully discharged from the CICU, 184 (4.7%) had an unplanned CICU readmission or they experienced a deteriorated condition but died without being readmitted to the CICU (readmission group). The readmission group had significantly higher rates of organ failure in all organ systems at both CICU admission and discharge than the non-readmission group. The AUROC of the discharge SOFA score for CICU readmission was 0.731, showing good predictive performance. The AUROC of the discharge SOFA score was significantly greater than that of either the initial SOFA score (P = 0.020) or the Acute Physiology and Chronic Health Evaluation II score (P < 0.001). In the multivariable regression analysis, SOFA score, overweight or obese status, history of heart failure, and acute heart failure as reasons for ICU admission were independent predictors of unplanned ICU readmission during the same hospital stay. CONCLUSION: The discharge SOFA score may identify patients at a higher risk of unplanned CICU readmission, enabling targeted interventions to reduce readmission rates and improve patient outcomes.

A hybrid solar cell fabricated using amorphous silicon and a fullerene derivative.

Hybrid solar cells, based on organic and inorganic semiconductors, are a promising way to enhance the efficiency of solar cells because they make better use of the solar spectrum and are straightforward to fabricate. We report on a new hybrid solar cell comprised of hydrogenated amorphous silicon (a-Si:H), [6,6]-phenyl-C71-butyric acid methyl ester ([71]PCBM), and poly-3,4-ethylenedioxythiophene poly styrenesulfonate (PEDOT:PSS). The properties of these PEDOT:PSS/a-Si:H/[71]PCBM devices were studied as a function of the thickness of the a-Si:H layer. It was observed that the open circuit voltage and the short circuit current density of the device depended on the thickness of the a-Si:H layer. Under simulated one sun AM 1.5 global illumination (100 mW cm(-2)), a power conversion efficiency of 2.84% was achieved in a device comprised of a 274 nm-thick layer of a-Si:H; this is the best performance achieved to date for a hybrid solar cell made of amorphous Si and organic materials.

The Efficacy of Pulmonary Rehabilitation in Patients with Idiopathic Pulmonary Fibrosis.

Background: This study evaluated the efficacy and safety of pulmonary rehabilitation (PR) on functional performance, exercise-related oxygen saturation, and health-related quality of life among patients with idiopathic pulmonary fibrosis (IPF). Methods: A total of 25 patients with IPF (13 in the PR group and 12 in the non-PR group) were enrolled between August 2019 and October 2021 at Haeundae-Paik Hospital in the Republic of Korea. A cardiopulmonary exercise test (CPET), six-minute walk test (6MWT), pulmonary function test (PFT), Saint George's Respiratory Questionnaire (SGRQ), muscle strength test, and bioelectrical impedance analysis were performed in each group at baseline and after eight weeks of PR. Results: The mean age was 68 years of age and most subjects were male. Baseline characteristics were similar between the two groups. The distance during 6MWT after PR was significantly improved in the PR group (inter-group p-value = 0.002). VO2max and VE/VCO2 slopes showed a significant difference after eight weeks only in the PR group, but the rate of change did not differ significantly from the non-PR group. Total skeletal muscle mass, PFT variables, and SGRQ scores did not differ significantly between the groups. Conclusions: PR improved exercise capacity, as measured using CPET and 6 MWT. Further studies in larger samples are needed to evaluate the long-term efficacy of PR in IPF patients.

Efficacy of Pirfenidone According to Dose in Patients with Idiopathic Pulmonary Fibrosis: A Prospective, Observational, Single-Center Cohort Study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a poor prognosis. Pirfenidone is approved and widely used for the treatment of IPF and reduces lung function decline. The aim of this study was to evaluate the efficacy of different doses of pirfenidone for the prevention of disease progression in patients with IPF. METHODS: This was a prospective, observational, single-center cohort study conducted in Haeundae Paik Hospital, Republic of Korea, from April 2021 to March 2023. IPF patients were assigned to three groups according to the dose of pirfenidone (600 mg, 1200 mg, 1800 mg). Disease progression was defined as an absolute decline to ≥5% of forced vital capacity (FVC) (% predicted value) or an absolute decline to ≥10% of diffusing capacity of the lung for carbon monoxide (DLco) (% predicted value) over 12 months. The primary endpoint was to evaluate the clinical effects of pirfenidone of each dosage on disease progression in IPF patients by comparing the FVC (% predicted value) and DLco (% predicted value) values over 12 months. The secondary endpoint was to evaluate the prognostic value of Krebs von den Lungen-6 (KL-6) in the disease progression in IPF patients using the baseline KL-6 value and the change in KL-6 values between the baseline and 12 months. RESULTS: A total of 44 patients were enrolled, of whom 39 completed the study, with 13 patients assigned to each of the three groups. The median age was 71.7 years, and 79.5% of patients were men. The baseline characteristics were similar across groups, except the 600 mg group was older (75.9 vs. 69.2 vs. 68.2 years, p = 0.016). The overall median change in FVC and DLco over 12 months was -2.7% (IQR: -9.1%, -1.2%) and -3.8% (IQR: -13.6%, -3.7%), respectively. There was no difference in the decline in FVC (change in FVC, % predicted value: -3.23 vs. -4.08 vs. -1.54, p = 0.621) and DLco (change in DLco, % predicted value: 0.00 vs. -3.62 vs. -3.15, p = 0.437) among the three groups. Fourteen patients (35.9%) suffered disease progression. The rate of disease progression did not differ according to the dose of pirfenidone (38.5 vs. 38.5 vs. 30.8%, p = 1.000). In multivariable logistic regression analysis, KL-6 was not a statistically significant predictor of disease progression. CONCLUSIONS: In our study, regardless of dose, consistent pirfenidone use for 12 months resulted in similar efficacy for the prevention of disease progression in patients with IPF. Large-scale, randomized, double-blind, placebo-controlled clinical trials are needed.

Suppression of TBCK enhances TRAIL-mediated apoptosis by causing the inactivation of the akt signaling pathway in human renal carcinoma Caki-1 cells.

BACKGROUND: TBC1 domain-containing kinase (TBCK) protein functions as a growth suppressor in certain cell types and as a tumor promoter in others. Although TBCK knockdown increases the responsiveness of cancer cells to anticancer drugs, the detailed mechanisms by which TBCK knockdown increases susceptibility to anticancer drugs remain unknown. OBJECTIVE: This study analyzed the role of TBCK in sensitivities to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and doxorubicin in human renal cancer cells. METHODS: Flow cytometry was employed to evaluate the extent of apoptosis. Western blotting, transient transfection, and lentiviral infection techniques were conducted to investigate the impact of TBCK on apoptosis-related protein expression and mitogen-activated protein kinase (MAPK). RESULTS: TBCK knockdown in renal cancer cells inhibits ERK and Akt signaling pathways and increases TRAIL and doxorubicin sensitivity. In TBCK-knockdown Caki-1 cells, ERK and Akt phosphorylation was suppressed compared to control cell lines, and TRAIL and doxorubicin sensitivities were increased in these cells. In addition, the phosphorylation of PDK1 was suppressed in TBCK-suppressed cells, indicating that TBCK may be involved in the PDK1 and Akt signaling pathways. The introduction of dominantly active Akt into TBCK-suppressed cells restored their sensitivity to TRAIL. In addition, TBCK downregulation enhanced TRAIL sensitivity in different renal cancer cell lines. CONCLUSIONS: These data suggest that TBCK could potentially have a crucial function in influencing the effects of anti-cancer drugs including TRAIL by modulating the signaling pathway involving Akt and PDK1 in human renal cancer cells.