[Research Progress of Helicobacter pylori-Associated Extragastric Diseases].

Helicobacter pylori (Hp) is a common Gram-negative bacillus causing gastrointestinal infections.It mainly exists on the surface of gastric epithelial cells and in mucus and is associated with gastric ulcers,gastric cancer,and gastric mucosa-associated lymphomas.Studies have shown that Hp can induce or exacerbate certain extragastric diseases and is associated with the occurrence of coronavirus disease 2019.It is hypothesized that Hp may be indirectly or directly involved in the occurrence and development of diseases by stimulating the production of inflammatory cytokines or inducing cross-immune reactions.In addition,Hp can enter Candida to release toxins continuously and play a role in escaping the recognition of the host immune system and the bactericidal effect of drugs.This article reviews the research progress in Hp-associated extragastric diseases in recent years,aiming to draw the attention of clinical workers to Hp-associated extragastric diseases and enrich the knowledge about Hp infection for formulating countermeasures to avoid the aggravation or triggering of other diseases by Hp.

Circular RNA circ-ERBB2 promotes HER2-positive breast cancer progression and metastasis via sponging miR-136-5p and miR-198.

BACKGROUND: Circular RNAs (circRNAs) are pivotal regulators of various human cancers and circ-ERBB2 is abnormally expressed in breast cancer cells. However, the role and mechanism of circ-ERBB2 in HER2-positive breast cancer are still unknown. METHODS: The circ-ERBB2 expressions in the tumor tissues of HER2-positive breast cancer patients were tested using quantitative real-time PCR. The circ-ERBB2 function was investigated by cell counting kit 8 assay, Transwell, flow cytometry and Western blot. Mechanistically, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and dual-luciferase reporter gene assays were conducted to confirm the interaction between circ-ERBB2 and miR-136-5p or miR-198 in HER2-positive breast cancer cells. RESULTS: Circ-ERBB2 was elevated in the tumor tissues of HER2-positive breast cancer patients. Functionally, the interference with circ-ERBB2 repressed HER2-positive breast cancer cell proliferation, migration, invasion and accelerated cell apoptosis. Furthermore, the mechanistic analysis corroborated that circ-ERBB2 acted as a competing endogenous RNA for miR-136-5p or miR-198 to relieve the repressive influence of miR-136-5p or miR-198 on its target transcription factor activator protein 2C (TFAP2C). Meanwhile, in vivo assays further corroborated the oncogenic function of circ-ERBB2 in HER2-positive breast cancer. CONCLUSIONS: Circ-ERBB2 accelerated HER2-positive breast cancer progression through the circ-ERBB2/miR-136-5p/TFAP2C axis or the circ-ERBB2/miR-198/TFAP2C axis.

Evaluation of the potential effect of dacomitinib, an EGFR tyrosine kinase inhibitor, on ECG parameters in patients with advanced non-small cell lung cancer.

Purpose The study evaluated the potential effect of dacomitinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, on the electrocardiogram (ECG) parameters in adult patients with advanced non-small cell lung cancer enrolled in a multicenter, open-label, phase 2 study. Methods Patients received dacomitinib for six doses of 45 mg every 12 h in a 7-day lead-in cycle (cycle 0), then 60 mg every 12 h for six doses in a 14-day cycle (cycle 1). Clock time-matched triplicate ECGs were performed at 0, 2, 4, 6, 8 and 10 h on day 1 (baseline) and day 4 of cycle 0, and prior to dose on days 1 and 4 of cycle 1. The QT interval was corrected for heart rate using Fridericia's correction (QTcF) and a study specific correction factor (QTcS). Results Thirty-two patients in the study comprised the QTc-evaluable population. Dacomitinib had no effect on the heart rate. The upper limits of the 95% confidence interval (CI) for the mean change from baseline in QTcF and QTcS were < 10 ms at all time points. A lack of relationship between plasma concentrations of dacomitinib or total active moiety on QTcF and QTcS was evidenced. All upper 90% CIs of the PR intervals were < 200 ms, although a small mean increase from baseline (2.7-6.6 ms) was observed. Conclusions There was a lack of a clinically relevant effect of dacomitinib on ECG parameters at dacomitinib concentrations comparable to those obtained at its highest therapeutic dosing regimen of 45 mg once daily. ClinicalTrials.gov identifier: NCT01858389.

Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer.

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.

A dynamic transcriptomic atlas of cytokine-induced killer cells.

Several clinical immunotherapy trials with cytokine-induced killer (CIK) cells have been reported. However, molecular evidence of cell expansion, acquisition of tumor cytotoxicity, and safety of CIK cells is required before putting them to clinical use. Here, we performed dynamic transcriptomic analyses of CIKs generated from primary peripheral blood mononuclear cells exposed to interferon-γ, OKT3, and interleukin-2. CIK mRNAs were extracted and sequenced at days 0, 1, 7, and 14 and subjected to bioinformatics analyses. Using weighted correlation network analysis (WGCNA), we identified two major gene modules that mediate immune cell activation and mitosis. We found that activation and cytotoxicity of CIK cells likely rely on cluster of differentiation 8 (CD8) and its protein partner LCK proto-oncogene, Src family tyrosine kinase (LCK). A time-course series analysis revealed that CIK cells have relatively low immunogenicity because of decreased expression of some self-antigens. Importantly, we identified several crucial activating receptors and auxiliary adhesion receptors expressed on CIK cells that may function as tumor sensors. Interestingly, cytotoxicity-associated genes, including those encoding PRF1, GZMB, FASL, and several cytokines, were up-regulated in mature CIK cells. Most immune-checkpoint molecules and inflammatory tumor-promoting factors were down-regulated in the CIK cells, suggesting efficacy and safety in future clinical trials. Notably, insulin-like growth factor 1 (IGF-1) was highly expressed in CIK cells and may promote cytotoxicity, although it also could facilitate tumorigenesis. The transcriptomic atlas of CIK cells presented here may inform efforts to improve CIK-associated tumor cytotoxicity and safety in clinical trials.

Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer.

Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721.

[Impact of Smoking on the Histological Subtype and Outcome of the Primary Lung Adenocarcinoma].

OBJECTIVE: To explore the effect of smoking on the histological subtype and prognosis of patients with lung adenocarcinoma (LAC) in China. METHODS: According to the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society(IASLC/ATS/ERS)classification, 266 donors with primary LAC were reclassified. The correlation between clinicopathological factors including smoking status and the histological subtype was analyzed, and survival analysis was used to analyze the prognosis of primary LAC. RESULTS: There were four main histological subtypes including acinar predominant adenocarcinoma (APA) 30.1%, papillary predominant adenocarcinoma (PPA) 26.7%, solid predominant adenocarcinoma (SPA) 25.9%, and lepidic predominant adenocarcinoma (LPA) 11.7%.Smoking was associated with the histological subtype.The proportion of smokers was significantly higher than non-smokers in the SPA group, and the proportion of non-smokers was higher in other subtypes group. Cox regression model showed that the histological subtype and TNM stage were the independent predictors of prognostic in all patients.TNM stage was the predictor of postoperative survival in both smokers and non-smokers, and histological subtypes was the predictor only in smokers (ß=0.898, RR=2.455). Compared with the non-SPA group, the prognosis of the SPA group was significantly worse. CONCLUSION: Smoking is associated with SPA subtype, which affect the prognosis of primary LAC.

Time Intervals Between Prior Cervical Conization and Posterior Hysterectomy Influence Postoperative Infection in Patients with Cervical Intraepithelial Neoplasia or Cancer.

BACKGROUND This study was conducted to observe the influence of different time intervals between prior cervical conization and posterior hysterectomy on postoperative infection in female patients with cervical intraepithelial neoplasia or cancer. MATERIAL AND METHODS Medical records of 170 patients who underwent hysterectomy following cervical conization between November 2010 and September 2016 at the Zhenjiang 4th Hospital were reviewed. According to the interval between hysterectomy and cervical conization, patients were classified into 1-2-week, 4-5-week, and 6-week groups. The outcomes of 46 patients who underwent conization with iodoform gauze inside the vagina were observed. RESULTS The total postoperative infection rate after hysterectomy was 25.3% (43/170). The expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and high mobility group box 1 (HMGB1) in the cervical secretions and tissues were found to gradually increase, peaking at 2 weeks after conization, then significantly decreasing 3-6 weeks onwards. Compared with the 1-2-week group, the 4-5-week and 6-week groups exhibited significantly lower infection rates (2/42, 4.8%, 4-5-week group; 0%, 0/33, 6-week group; vs. 41/95, 43.2%, 1-2-week group; p<0.001). In the 1-2-week group in particular, the postoperative infection rate after laparoscopic hysterectomy was significantly higher than the rate after abdominal hysterectomy (21/35, 60% vs. 20/60, 33%, p=0.0177). In addition, the vaginal and cervical wound infection rates after conization in patients treated with iodoform were significantly lower than the rates in those without iodoform treatment (p<0.05). CONCLUSIONS Hysterectomy should be performed at least 4 weeks after conization. Treatment with iodoform would be beneficial.

Crizotinib in ROS1-rearranged non-small-cell lung cancer.

BACKGROUND: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. RESULTS: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS: In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model.

Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

Adiponectin as a potential tumor suppressor inhibiting epithelial-to-mesenchymal transition but frequently silenced in prostate cancer by promoter methylation.

BACKGROUND: Recent evidence suggests a particular role for obesity in prostate cancer (PCa) progression. Adiponectin (ADN) is a hormone secreted by adipose tissue and has a variety of functions including the inhibition of PCa cell proliferation. Although serum ADN levels have been identified to be related with carcinogenesis in a tissue-specific context, the exact role of endogenous ADN in PCa cells remains largely unknown. METHODS: Two tissue microarrays were constructed and immunohistochemistry (IHC) was utilized to detect ADN's expression in a cohort of 96 Chinese PCa patients with radical prostatectomy as well as 15 cases with Benign Prostatic Hyperplasia (BPH). MTS and transwell assays were applied to validate the effects of ADN on proliferation and invasive capacity of PCa cells. Real-time PCR and Western blot were performed to evaluate the expression at transcript and protein levels. Epigenetic modifications of ADN's promoter after TGF-ß1 treatment in 22RV1 cells was monitored by chromatin immunoprecipitation (ChIP). Methylation-Specific PCR (MSP) was performed to determine the methylation status of ADN's promoter. RESULTS: IHC showed decreased levels of ADN in 1 of 15 (6.7%) BPH cases, 6 of 27 (22.2%) PCa cases with low Gleason score (<7), 18 of 26 (69.2%) cases with Gleason score 7, but 32 of 43 (74.4%) cases with high Gleason score (>7). Silencing endogenous ADN could promote proliferation and invasion of 22RV1 cells via orchestrating Epithelial-to-mesenchymal Transition (EMT) process. TGF-ß1, a potent EMT inducer, could decrease levels of chromatin markers associated with active genes (H3K4me3, H4acetylK16), and increase levels of repressive marker (H3K27me3) at ADN promoter in 22RV1 cells. Additionally, 5-aza and TSA treatment restored ADN expression in LNCaP cells in which the ADN expression was almost absent. MSP analysis revealed that methylation in the promoter might be involved in decreased expression of ADN in PCa tissues. CONCLUSION: Our findings indicated that endogenous ADN may function as a tumor suppressor gene through inhibiting EMT of PCa cells but is down-regulated in PCa via promoter hypermethylation.

Estrogen induces androgen-repressed SOX4 expression to promote progression of prostate cancer cells.

BACKGROUND: The sex determing region Y-box 4 (SOX4) gene is a critical developmental transcriptional factor that is overexpressed in prostate cancer (PCa). While we and others have investigated the role of SOX4 overexpression in PCa, the molecular mechanism underlying its aberrant expression remains unclear. METHODS: Immunohistochemistry were utilized to detect SOX4 expression and the correlation between estrogen receptor ß (ERß), androgen receptor (AR) and SOX4 in a cohort of 94 clinical specimens. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Immunofluorescence staining and co-immunoprecipitation were performed to assess the interaction and subcellular location of ERß and AR. Chromatin immunoprecipitation (ChIP) assays and Luciferase reporter assays were performed to explore the binding and transcriptional activities of ERß and AR to the SOX4 promoter. Cellular function was evaluated by MTS, invasion and wound healing assays. RESULTS: SOX4 expression is up-regulated in Castration-Resistant Prostate Cancer (CRPC) tumors compared to hormone-dependent PCa (HDPC) cases. Increased expression was also observed in PCa cells after long-term androgen-deprivation treatment (ADT). In vitro data indicated that SOX4 is an AR transcriptional target and down-regulated by dihydrotestosterone (DHT) via AR. 17ß-estradiol (E2) up-regulates SOX4 expression in the absence of androgen through the formation of a protein complex between ERß and AR. Knockdown of AR or ERß blocks the E2-induced SOX4 expression. ChIP assays confirmed that both ERß and AR bind to the SOX4 promoter in response to E2. Functionally, silencing SOX4 significantly attenuates the proliferative effect, as well as the capacity of migration and invasion of E2 on PCa cells. Clinically, overexpression of SOX4 is significantly associated with ERß expression in PCa. In addition, this association is still retained in CRPC patients with poor prognosis. CONCLUSION: These findings suggest that SOX4 is a novel DHT-repressed AR-target gene. E2 could promote proliferation of PCa cells through the up-regulation of SOX4 under androgen-depleted environment. Our data provides a possible molecular basis for the overexpression of SOX4 in CRPC and may facilitate the detection and prevention of the emergence of CRPC.

The effects of ketoconazole and rifampin on the single-dose pharmacokinetics of crizotinib in healthy subjects.

PURPOSE: To investigate the potential effects of strong CYP3A inhibitor ketoconazole and strong CYP3A inducer rifampin on the pharmacokinetics of crizotinib in human. METHODS: Two separate open-label, 2-period, 2-treatment, 1-sequence, crossover, single-dose studies were conducted in healthy subjects with and without ketoconazole or rifampin. Series of plasma samples were collected after each crizotinib dose to determine concentration of crizotinib and its metabolite PF-06260182. Relevant pharmacokinetic (PK) parameters for crizotinib and PF096269182 were estimated by standard non-compartmental analysis (NCA) method. RESULTS: Co-administration of a single 150-mg oral dose of crizotinib with the strong CYP3A inhibitor ketoconazole resulted in an area under the plasma-concentration curve extrapolated to infinity (AUC0-inf) 3.2-fold that for crizotinib alone. Co-administration of a single 250-mg crizotinib dose with the strong CYP3A inducer rifampin caused an 82 % decrease in crizotinib AUC0-inf. Respective increases and decreases in systemic exposure to the crizotinib metabolite PF-06260182 following co-administration of ketoconazole and rifampin were greater than those seen for crizotinib. CONCLUSIONS: These findings suggest that CYP3A plays an important role in the metabolism of both crizotinib and PF-06260182, with the extent of this role being greater for PF-06260182. There were no serious adverse events or deaths and no dose reductions or temporary or permanent discontinuations due to drug-related adverse events in either study.

Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects.

1. Crizotinib (XALKORI®), an oral inhibitor of anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor kinase (c-Met), is currently approved for the treatment of patients with non-small cell lung cancer that is ALK-positive. 2. The metabolism, excretion and pharmacokinetics of crizotinib were investigated following administration of a single oral dose of 250 mg/100 µCi [(14)C]crizotinib to six healthy male subjects. 3. Mean recovery of [(14)C]crizotinib-related radioactivity in excreta samples was 85% of the dose (63% in feces and 22% in urine). 4. Crizotinib and its metabolite, crizotinib lactam, were the major components circulating in plasma, accounting for 33% and 10%, respectively, of the 0-96 h plasma radioactivity. Unchanged crizotinib was the major excreted component in feces (∼ 53% of the dose). In urine, crizotinib and O-desalkyl crizotinib lactam accounted for ∼ 2% and 5% of the dose, respectively. Collectively, these data indicate that the primary clearance pathway for crizotinib in humans is oxidative metabolism/hepatic elimination. 5. Based on plasma exposure in healthy subjects following a single dose of crizotinib and in vitro potency against ALK and c-Met, the crizotinib lactam diastereomers are not anticipated to contribute significantly to in vivo activity; however, additional assessment in cancer patients is warranted.

Serine protease inhibitor Kazal type 1 promotes epithelial-mesenchymal transition through EGFR signaling pathway in prostate cancer.

BACKGROUND: Overexpression of serine protease inhibitor Kazal type 1 (SPINK1) defines an aggressive molecular subtype of ETS fusion-negative prostate cancer (PCa) patients in western countries. However, how SPINK1 contributes to PCa invasion and metastasis is largely unknown. METHODS: Fluorescence in situ hybridization and immunohistochemistry were utilized to detect ERG rearrangement, SPINK1 expression, and EGFR aberrations in a cohort of 211 PCa patients with radical prostatectomy. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Cellular distribution of E-cadherin and vimentin were observed by immunofluorescence. Cellular function was evaluated by siRNA, transwell, and wound healing assay, respectively. RESULTS: SPINK1-induced Epithelial-mesenchymal transition (EMT) in benign prostate RWPE cells, manifested by acquisition of mesenchymal morphology, alternation of EMT markers as well as migration and invasion capabilities. Knockdown of SPINK1 in 22RV1 PCa cells results in up-regulation of E-cadherin and down-regulation of vimentin. SPINK1-induced EMT is mediated by EGFR, in which MAPK/MEK/ERK pathway is mainly involved. Connective tissue growth factor (CTGF) might be an important down-stream molecule of SPINK1-EGFR axis. Clinically, SPINK1 and EGFR were significantly co-overexpressed in a cohort of Chinese PCa patients (n > 200). SPINK1 is an unfavorable prognostic factor in Chinese PCas (P = 0.025). CONCLUSIONS: These findings suggest that SPINK1 promotes EMT through EGFR signaling pathway in PCa and SPINK1 could be a new prognostic marker in Chinese PCas.

Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib.

Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutations. Proton-pump inhibitors decreased dacomitinib exposure. This analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (Ctrough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib's PKs. The adjusted geometric mean of the dacomitinib Ctrough,ss of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (p > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (Cmax) and area under the drug concentration-time curve (AUC) over 0-24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.

Space-Efficient 3D Microalgae Farming with Optimized Resource Utilization for Regenerative Food.

Photosynthetic microalgae produce valuable metabolites and are a source of sustainable food that supports life without compromising arable land. However, the light self-shading, excessive water supply, and insufficient space utilization in microalgae farming have limited its potential in the inland areas most in need of regenerative food solutions. Herein, this work develops a 3D polysaccharide-based hydrogel scaffold for vertically farming microalgae without needing liquid media. This liquid-free strategy is compatible with diverse microalgal species and enables the design of living microalgal frameworks with customizable architectures that enhance light and water utilization. This approach significantly increases microalgae yield per unit water consumption, with an 8.8-fold increase compared to traditional methods. Furthermore, the dehydrated hydrogels demonstrate a reduced size and weight (≈70% reduction), but readily recover their vitality upon rehydration. Importantly, valuable natural products can be produced in this system including proteins, carbohydrates, lipids, and carotenoids. This study streamlines microalgae regenerative farming for low-carbon biomanufacturing by minimizing light self-shading, relieving water supply, and reducing physical footprints, and democratizing access to efficient aquatic food production.

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Correlations and comparisons of quantitative trait loci with family per se and testcross performance for grain yield and related traits in maize.

Simultaneous improvement in grain yield and related traits in maize hybrids and their parents (inbred lines) requires a better knowledge of genotypic correlations between family per se performance (FP) and testcross performance (TP). Thus, to understand the genetic basis of yield-related traits in both inbred lines and their testcrosses, two F (2:3) populations (including 230 and 235 families, respectively) were evaluated for both FP and TP of eight yield-related traits in three diverse environments. Genotypic correlations between FP and TP, [Formula: see text] (FP, TP), were low (0-0.16) for grain yield per plant (GYPP) and kernel number per plant (KNPP) in the two populations, but relatively higher (0.32-0.69) for the other six traits with additive effects as the primary gene action. Similar results were demonstrated by the genotypic correlations between observed and predicted TP values based on quantitative trait loci positions and effects for FP, [Formula: see text] (M (FP), Y (TP)). A total of 88 and 35 QTL were detected with FP and TP, respectively, across all eight traits in the two populations. However, the genotypic variances explained by the QTL detected in the cross-validation analysis were much lower than those in the whole data set for all traits. Several common QTL between FP and TP that accounted for large phenotypic variances were clustered in four genomic regions (bin 1.10, 4.05-4.06, 9.02, and 10.04), which are promising candidate loci for further map-based cloning and improvement in grain yield in maize. Compared with publicly available QTL data, these QTL were also detected in a wide range of genetic backgrounds and environments in maize. These results imply that effective selection based on FP to improve TP could be achieved for traits with prevailing additive effects.

Impact of posaconazole and diltiazem on pharmacokinetics of encorafenib, a BRAF V600 kinase inhibitor for melanoma and colorectal cancer with BRAF mutations.

Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug-drug interactions when co-administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50-mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co-administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half-life (t½ ) of encorafenib increased from 4.3 to 7.3 h. The AUCinf and Cmax geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co-administered with diltiazem, and plasma t½ of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co-administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.