A Bacterial Nanomedicine Combines Photodynamic-Immunotherapy and Chemotherapy for Enhanced Treatment of Oral Squamous Cell Carcinoma.

Bacterial therapy is an emerging hotspot in tumor immunotherapy, which can initiate antitumor immune activation through multiple mechanisms. Porphyromonas gingivalis (Pg), a pathogenic bacterium inhabiting the oral cavity, contains a great deal of pathogen associated molecular patterns that can activate various innate immune cells to promote antitumor immunity. Owing to the presence of protoporphyrin IX (PpIX), Pg is also an excellent photosensitizer for photodynamic therapy (PDT) via the in situ generation of reactive oxygen species. This study reports a bacterial nanomedicine (nmPg) fabricated from Pg through lysozyme degradation, ammonium chloride lysis, and nanoextrusion, which has potent PDT and immune activation performances for oral squamous cell carcinoma (OSCC) treatment. To further promote the tumoricidal efficacy, a commonly used chemotherapeutic drug doxorubicin (DOX) is efficiently encapsulated into nmPg through a simple incubation method. nmPg/DOX thus prepared exhibits significant synergistic effects on inhibiting the growth and metastasis of OSCC both in vitro and in vivo via photodynamic-immunotherapy and chemotherapy. In summary, this work develops a promising bacterial nanomedicine for enhanced treatment of OSCC.

Conteltinib (CT-707) in patients with advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, first-in-human phase 1 study.

BACKGROUND: Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC). METHODS: In this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators. RESULTS: Between April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%]), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%]). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2-78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26-23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06-25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6-57.0), median PFS was 6.73 months (95% CI, 4.73-8.54), and median DoR was 6.60 months (95% CI, 3.77-13.3). CONCLUSIONS: In this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02695550.

The effect of methyltestosterone (MT) on sex differentiation and growth in juvenile yellow perch (Perca flavescens).

A study was conducted to evaluate the gonad differentiation of juvenile yellow perch (YP, Perca flavencens) and determine the latest labile period related to hormone treatment. Juvenile fish were subjected to two dietary concentrations of methyltestosterone (MT; 20 and 50 mg/kg feed) for 60 days in three (3) age groups of 38-, 46-, and 67-days post-hatching (dph), where control group were fed with standard commercial feed. Following a 10-month on-growing period, sex phenotypes were determined by gross and histological gonad morphology. Results showed the juvenile YP responded to the exogenous hormone when it was applied at 38 dph for both 20 and 50 mg/kg feed resulting in 100% males. At 46 dph, only 50 mg/kg feed resulted in 100% males. Both MT-treated at 38 and 46 dph significantly differed (P < 0.01) from the expected normal population of male:female (1:1). MT-treated at 67 dph resulted in 37% and 25% intersex fish for both 20 and 50 mg/kg feed dosage groups, respectively. MT-treated at 38 and 46 dph promoted growth and showed significantly heavier mean body weight (P < 0.05) compared to control. The gonadosomatic index (GSI) of MT-treated at 38 and 46 dph was significantly lower than that in control. This study provides the first evidence that juvenile YP can be successfully masculinized when the treatment is initiated at the age of up to 46 dph. The result is important for sex control in aquaculture.

Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy. METHODS: We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data. RESULTS: We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets. CONCLUSIONS: Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.

A Bayesian network meta-analysis regarding the comparative efficacy of therapeutics for ALK-positive, brain metastatic non-small cell lung cancer.

More clinical evidence is needed regarding the ranking priority of interventions for ALK-positive, brain metastatic (BM) non-small cell lung cancer (NSCLC). Eligible randomized controlled trials (RCTs) were identified. Progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) for the intended populations were analyzed with random effects, Bayesian network meta-analysis with the estimated hazard ratio (HR) and odds ratio (OR) with 95% credible interval (95% CrIs). We included 11 RCTs (2687 NSCLC and 991 BM patients) investigating 7 treatments and 5 medication classes. For PFS for BM patients, lorlatinib (hazard ratio (HR): 0.01, 95% CrI: 0.001-0.12), alectinib (HR: 0.05, 95% CrI: 0.01-0.21) and brigatinib (HR: 0.07, 95% CrI: 0.007-0.76) were top-ranking individual treatments; for ORR for BM patients, brigatinib, lorlatinib and alectinib were top-ranking treatments. For PFS for all NSCLC patients, the top-ranking individual treatments were lorlatinib (HR: 0.05, 95% CrI: 0.02-0.13), alectinib (HR: 0.09, 95% CrI: 0.05-0.18) and brigatinib (HR: 0.11, 95% CrI: 0.05-0.28). For OS for all NSCLC patients, we found that no individual treatments were superior to chemotherapy, whereas the following top-ranking interventions were alectinib (HR: 0.29, 95% CrI: 0.03-1.68), lorlatinib (HR: 0.41, 95% CrI: 0.04-4.13), and ceritinib (HR: 0.63, 95% CrI: 0.10-4.25). The results of individual treatments and medication classes were similar. Data were limited in regard to subgroup analyses and adverse events of BM patients. Lorlatinib has the most statistical superiority for BM patients, but ORR differences between third- and second-generation inhibitors are not obvious. All things considered, alectinib is recommended as first-line treatment, followed by lorlatinib, especially after developing drug resistance to alectinib.

Self-assembled nanoparticles containing photosensitizer and polycationic brush for synergistic photothermal and photodynamic therapy against periodontitis.

BACKGROUND: Periodontitis is a chronic inflammatory disease in oral cavity owing to bacterial infection. Photothermal therapy (PTT) and photodynamic therapy (PDT) have many advantages for antibacterial treatment. As an excellent photosensitizer, indocyanine green (ICG) shows prominent photothermal and photodynamic performances. However, it is difficult to pass through the negatively charged bacterial cell membrane, thus limiting its antibacterial application for periodontitis treatment. RESULTS: In this work, self-assembled nanoparticles containing ICG and polycationic brush were prepared for synergistic PTT and PDT against periodontitis. First, a star-shaped polycationic brush poly(2-(dimethylamino)ethyl methacrylate) (sPDMA) was synthesized via atom transfer radical polymerization (ATRP) of DMA monomer from bromo-substituted ß-cyclodextrin initiator (CD-Br). Next, ICG was assembled with sPDMA to prepare ICG-loaded sPDMA (sPDMA@ICG) nanoparticles (NPs) and the physicochemical properties of these NPs were characterized systematically. In vitro antibacterial effects of sPDMA@ICG NPs were investigated in porphyromonas gingivalis (Pg), one of the recognized periodontitis pathogens. A ligature-induced periodontitis model was established in Sprague-Dawley rats for in vivo evaluation of anti-periodontitis effects of sPDMA@ICG NPs. Benefiting from the unique brush-shaped architecture of sPDMA polycation, sPDMA@ICG NPs significantly promoted the adsorption and penetration of ICG into the bacterial cells and showed excellent PTT and PDT performances. Both in vitro and in vivo, sPDMA@ICG NPs exerted antibacterial and anti-periodontitis actions via synergistic PTT and PDT. CONCLUSIONS: A self-assembled nanosystem containing ICG and polycationic brush has shown promising clinical application for synergistic PTT and PDT against periodontitis.

Astragalus membranaceus nanoparticles markedly improve immune and anti-oxidative responses; and protection against Aeromonas veronii in Nile tilapia Oreochromis niloticus.

The effects of dietary administration of Astragalus membranaceus nanoparticles (ANP) on immune and anti-oxidative responses, growth performance and disease resistance of Oreochromis niloticus were evaluated in the present study. Fish were divided into three groups and received the ANP at rates of 0 (control), 1, and 2%/kg diet for four weeks. After the four-week feeding trial, three fish from each replicate were sampled for immune and anti-oxidative responses evaluation, ten fish from each group were challenged with A. veronii, and nine fish from each group were subjected to cold and hypoxia challenges. It was obvious from the results that ANP significantly enhanced lysozyme activity and nitrous oxide (NO) activities, as well as improved superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities. Also, aspartate aminotransferase, alanine transaminase, glucose, and cortisol measurements showed significantly lower levels in incorporated groups compared to the control. Growth performance; and amylase and lipase digestive enzymes activities also showed markedly improved results. Expression of heat shock protein 70 (HSP70) and interleukin 1, beta (IL-1ß) genes were significantly upregulated throughout the entire experimental period. When challenged with A. veronii, the mortality of treated groups was significantly (P < 0.05) lower than the control. Current results proofs that dietary ANP had a synergistic effect on immune and anti-oxidative responses, growth performance and disease resistance of Oreochromis niloticus.

Nano spirulina dietary supplementation augments growth, antioxidative and immunological reactions, digestion, and protection of Nile tilapia, Oreochromis niloticus, against Aeromonas veronii and some physical stressors.

The current study evaluated the effects of nano delivery of Spirulina platensis on growth performance, digestive enzymes, and biochemical, immunological, and antioxidative status, as well as resistance to Aeromonas veronii and some physical stressor challenges in Nile tilapia, Oreochromis niloticus. Three experimental fish groups (n = 270) with mean weights of 26 ± 0.30 g and mean lengths of 10 ± 0.5 cm were used; the first additive-free basal diet served as the control group, whereas the following two groups were supplemented with spirulina nanoparticles (SPNP) at 0 (control), 0.25, and 0.5%/kg diet for 4 weeks. Following the feeding trial, fish were challenged with hypoxia, cold stresses, and pathogenic bacteria (A. veronii) infection (9 × 108 CFU/ml). SPNP supplementation, especially 0.5%, (p < 0.05) significantly increased growth performance (specific growth rate % day-1, feed conversion ratio, and length gain rate %), immunological (plasma lysozyme and liver nitrous oxide) antioxidants (superoxide dismutase, catalase, and glutathione peroxidase in liver), biochemical (aspartate aminotransferase, alanine transaminase, glucose, and cortisol concentrations in plasma) assays, and digestive enzymes (lipase and amylase in plasma). The expression of liver's heat shock protein 70 (HSP70) and interleukin 1, beta (IL-1ß) genes showed a significant upregulation outline of 0.5% SPNP > 0.25% SPNP > 0% SPNP compared with the control. Protection in the incorporated fish groups exposed to A. veronii was 100% compared with the control group, which showed 50% cumulative mortalities. In conclusion, dietary SPNP supplementation improved growth performance, antioxidant activity, immune response, digestive enzymes, related gene expression, and resistance of Nile Tilapia to hypoxia, cold, and A. veronii infection. Thus, SPNP could be used as a natural therapy for controlling those stressors.

Adiponectin Gene Polymorphism and Ischemic Stroke Subtypes in a Chinese Population.

As an adipose tissue-specific protein, adiponectin has been suggested as a protective factor for stroke, acting through anti-inflammatory and antiatherogenic effects. Therefore, we aimed to investigate whether 3 polymorphisms (rs1501299, rs2241767, and rs3774261) in the adiponectin (ADIPOQ) gene and their haplotypes were associated with ischemic stroke (IS) and its subtypes in a Chinese population. ADIPOQ gene rs1501299, rs2241767, and rs3774261 polymorphisms were analyzed in 385 IS patients, including 182 patients with large-artery atherosclerosis (LAA), 203 patients with small-vessel occlusion (SVO), and 418 matched controls. The subjects were genotyped by using polymerase chain reaction-restriction fragment length polymorphism analysis. In univariate logistic analysis, the A allele frequency of rs2241767 was moderately higher in IS and LAA patients than that in controls (P = .028 and P = .017, respectively). Compared with the wide-type AA homozygote, both the genotype GG and the dominant model (GG+AG) of rs2241767 moderately increased the risk of LAA (P = .040 and P = .034, respectively). In multivariate logistic regression analysis, the genotype GG of rs2241767 was independently related to IS and LAA patients (adjusted, odds ratio [OR] = 1.822, 95% confidence interval [CI]: 1.037-3.202, P = .037 and OR = 2.051, 95% CI: 1.041-4.041, P = .038, respectively) rather than SVO. In contrast, no relationship was observed between the polymorphism of rs1501299 and rs3774261 and either subtype of IS using both univariate and multivariate logistic regression analyses. In addition, the Trs1501299-Grs2241767-Ars3774261 haplotype showed a moderately increased risk of IS and LAA (OR = 1.595, 95% CI: 1.058-2.406, P = .025 and OR = 1.709, 95% CI: 1.047-2.789, P = .031, respectively) but not of SVO. In conclusion, this study tentatively demonstrated that the polymorphism of rs2241767 and the Trs1501299-Grs2241767-Ars3774261 haplotype were associated with susceptibility to IS and LAA in a Chinese population.

Feeding Glycyrrhiza glabra (liquorice) and Astragalus membranaceus (AM) alters innate immune and physiological responses in yellow perch (Perca flavescens).

The current work assessed the potential immunomodulatory and growth-promoting effects of Astragalus membranaceus (AM) and Glycyrrhiza glabra (liquorice) in Yellow perch (Perca flavescens). In this regard, fish with an average weight of 31 ± 1.0 g were divided into five groups, and fed daily with an additive-free basal diet (control); 1, 2, and 3% (w/w) Glycyrrhiza glabra, and the fifth diet was incorporated with a combination of 1% G. glabra-AM for a four-week period. Immunological, biochemical and growth parameters were measured; and sub-groups of fish were exposed to 1-week starvation. The results showed that incorporating AM and liquorice in the diet significantly improved Immunological [superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), Lipid peroxidase (LPx) and lysozyme activities], biochemical [Aspartate Aminotransferase (AST) and Alanine Transaminase (ALT) activities; and glucose and cortisol concentrations] and growth performance parameters [body mass gain (BMG), specific growth rate (SGR), length, condition factor (K) and feed conversion ratio (FCR)]. In addition, markedly up-regulated the expression of related genes [Insulin-Like Growth Factor-1 (IGF-1), Serum amyloid A (SAA), Complement Component C3 (CCC3), Alpha 2 Macroglobulin (A2M), SOD and GPx] in treated fish groups compared to the control. Conclusively, feeding AM and liquorice diets significantly increased (P < 0.05) growth performance, antioxidant and immune response profiles throughout the entire experiment, suggesting their beneficial rule as natural anti-stress agents.

Diffuse Cystic Lung Diseases: Diagnostic Considerations.

Diffuse cystic lung disease (DCLD) is a group of heterogeneous diseases that present as diffuse cystic changes in the lung on computed tomography of the chest. Most DCLD diseases are rare, although they might resemble common diseases such as emphysema and bronchiectasis. Main causes of DCLD include lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, pulmonary Langerhans cell histiocytosis, lymphoid interstitial pneumonia, amyloidosis, light-chain deposition disease, Sjögren syndrome, and primary or metastatic neoplasm. We discuss clinical factors that are helpful in the differential diagnosis of DCLDsuch as sex and age, symptoms and signs, extrapulmonary presentations, cigarette smoking, and family history. Investigations for DCLD include high-resolution computed tomography, biochemical and histopathological studies, genetic tests, pulmonary function tests, and bronchoscopic and video-assisted thoracoscopic biopsies. A proposed diagnostic algorithm would enhance ease of diagnosing most cases of DCLD.

Biopsy-proven IgG4-related lung disease.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder that may involve single or multiple organs. Biopsy-proven lung involvement of this disease is occasionally reported, but not well understood. METHODS: Patients with the diagnosis of biopsy-proven IgG4-related lung disease (IgG4-RLD) from Peking Union Medical College Hospital between January 2011 and July 2015 were retrospectively analyzed. Age, sex, clinical symptoms, laboratory findings, pulmonary function test results, chest CT tests, positron emission tomography (PET) examinations, treatments and prognoses were retrieved from medical records and analyzed. RESULTS: Seventeen patients were included in this study (mean age: 44.8 ± 15.0 years). Ten patients were diagnosed via surgery, and 7 patients were diagnosed via percutaneous transthoracic core-needle lung biopsy. Extrapulmonary involvement was observed in only one patient. The clinical symptoms included cough, fever, dyspnea, chest pain and hemoptysis. The serum IgG4 concentration was elevated in 7/13 patients (mean: 1955 ± 1968 mg/L). The chest CT findings included mainly nodules and masses with spiculated borders, alveolar consolidations with air bronchograms, and ground glass opacities with or without reticular opacities. PET scans indicated increased standardized uptake values, and 7/8 patients were correctly diagnosed with benign inflammation. Corticosteroids and immunosuppressants were administered to 14/17 patients and effectively alleviated the disease. CONCLUSIONS: In biopsy-proven IgG4-RLD, a normal serum IgG4 concentration is commonly seen, while extrapulmonary involvement is infrequent. Alveolar consolidation with air bronchograms is an important imaging finding of IgG4-RLD, which has not been emphasized before.

Astragalus membranaceus (AM) enhances growth performance and antioxidant stress profiles in bluegill sunfish (Lepomis macrochirus).

This study was designed to assess the potential effects of Astragalus membranaceus (AM) on the growth performance and antioxidative stress response in bluegill sunfish (Lepomis macrochirus) exposed to challenging cold water temperature conditions. In this regard, fish with an average weight of 43 ± 1 g were divided into four groups and fed daily with an AM-free diet (control), and 1.5, 3, and 4.5 % (w/w) AM-incorporated diets for an 8-week period. Oxidative stress response, biochemical, and growth parameters were measured, and subgroups of fish were exposed to the outside challenging cold pond water temperature (1.6-9.9 °C) with an average of 7.0 ± 0.1 °C beyond the optimal temperature. The results showed that incorporating AM in the diet significantly improved growth performance parameters (body mass gain, specific growth rate, length, condition factor, and feed conversion ratio) and biochemicals (aspartate aminotransferase and alanine transaminase activities, and glucose and cortisol concentrations). In addition, markedly up-regulated superoxide dismutase, glutathione peroxidase, and catalase activities were observed in AM-treated fish groups over the control. Conclusively, feeding AM diets significantly increased (P < 0.05) growth performance and antioxidative stress profiles throughout the entire experiment, and this increase was much more pronounced at 8 weeks after the water temperature began to rise, which can be related to the nature of Bluegill fish as it is known to be a warm water fish. These findings are considered to be of great importance for sustainable aquaculture.

Relationship between icotinib hydrochloride exposure and clinical outcome in Chinese patients with advanced non-small cell lung cancer.

BACKGROUND: The current study was conducted to explore the relationship between icotinib hydrochloride exposure and therapeutic effects in Chinese patients with advanced non-small cell lung cancer (NSCLC) who were treated with icotinib hydrochloride. METHODS: A total of 30 patients with NSCLC who were treated with icotinib hydrochloride were chosen from a single-center, open-label, phase 1 dose escalation clinical trial. Different doses of icotinib hydrochloride were administered orally for 28 consecutive days in different groups until disease progression or unacceptable toxicities occurred. Blood samples were collected during the first treatment cycle (day 1-28) for the pharmacokinetic analysis. Tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). The plasma concentrations of icotinib hydrochloride were assessed by liquid chromatography-mass spectrometry. RESULTS: Thirty patients with a median age of 56 years old (50% of whom were female) were enrolled. For single-dose treatment, the plasma pharmacokinetics demonstrated a median time to maximum concentration of 0.5 to 4 hours and a mean terminal elimination half-life of 6.21±3.44 hours at the 150-mg dose and 10.1±12.18 hours at the 200-mg dose. For multiple-dose treatment, the last measurable concentration (Clast ) was 708±368.67 ng/mL at the 150-mg every 12 hours, 782.73±618.18 ng/mL at the 200-mg every 12 hours, and 1162±658.44 ng/mL at the 125-mg every 8 hours; the under the concentration curve from time 0 to Clast was 14.5±2.43 hour*mg/mL, 13.2±2.5 hour*mg/mL, and 12.19±2.47 hour*mg/mL, respectively. At the dose of 150 mg every 12 hours, 1 patient with an epidermal growth factor receptor (EGFR) exon 19 deletion achieved a complete response for 10 months; another patient who carried the EGFR exon 19 deletion achieved stable disease for 6 months. Univariate analysis demonstrated that the time to maximum plasma concentration (Tmax ) after a single dose of icotinib hydrochloride was significantly correlated with the overall survival (OS) (Spearman correlation coefficient, 0.441; P = .012). The disease control rate was correlated with Tmax after a single dose (Spearman correlation coefficient, 0.518; P = .011). Multivariate analysis demonstrated that the area under the concentration-time curve from 0 to last determination time and the area under the curve from 0 to infinite time after a single dose of icotinib hydrochloride were correlated with OS (P = .037 and .042, respectively). The Clast was found to affect progression-free survival (P = .016). Stratification of these patients according to smoking status indicated significant correlation between OS and the area under the concentration-time curve from 0 to last determination time (Spearman correlation coefficient, -0.709; P = .015). CONCLUSIONS: Patients with a longer Tmax and higher exposure might experience longer OS and a higher disease control rate. In addition, the increased Clast might prolong the progressive-free survival of patients. However, the relationships between EGFR mutation, pharmacokinetics, and clinical outcomes require further research.

Molecular players involved in temperature-dependent sex determination and sex differentiation in Teleost fish.

The molecular mechanisms that underlie sex determination and differentiation are conserved and diversified. In fish species, temperature-dependent sex determination and differentiation seem to be ubiquitous and molecular players involved in these mechanisms may be conserved. Although how the ambient temperature transduces signals to the undifferentiated gonads remains to be elucidated, the genes downstream in the sex differentiation pathway are shared between sex-determining mechanisms. In this paper, we review recent advances on the molecular players that participate in the sex determination and differentiation in fish species, by putting emphasis on temperature-dependent sex determination and differentiation, which include temperature-dependent sex determination and genetic sex determination plus temperature effects. Application of temperature-dependent sex differentiation in farmed fish and the consequences of temperature-induced sex reversal are discussed.

Carbon sequestration in the soils of aquaculture ponds, crop land, and forest land in southern Ohio, USA.

Soil samples were collected from four aquaculture ponds (yellow perch culture), a control pond (without aquaculture activities, fallow pond), crop land (under corn), and forest land to estimate the carbon (C) sequestration potential in the Piketon county, Ohio, USA. The averaged total of C was 6.5 ± 2, 8.8 ± 2, 8.53 ± 0.2 and 10.49 ± 1.1 Mg/ha (Mg=10(6)g) in < 0.25 mm fraction; 15.2 ± 2, 16.0 ± 3, 11.49 ± 0.8 and 17.23 ± 3.4 Mg/ha in micro aggregates (0.25-2.5 mm); and 22.1 ± 3, 26.4 ± 3, 12.16 ± 1.6 and 18.51 ± 4.3 Mg/ha in macro aggregates ( > 2.5mm), for aquaculture ponds, control ponds, cropland and forest land, respectively. The soil/sediment C pool followed the order of forest > crop land soils > aquaculture pond soils.

Equivalent Input Disturbance-Based Control: Analysis, Development, and Applications.

This article reviews the concept, analysis, development, and applications of the equivalent-input-disturbance (EID) approach. First, the definition and existence of the EID are given, and the configuration of the EID estimator is provided. Next, estimation errors in the conventional EID approach are explained, and error-suppression methods are exhibited, which improve the disturbance-rejection performance. Then, this article describes how to apply the EID approach and associate challenges in dealing with nonlinearities, time delays, and uncertainties. Moreover, this article reviews some additional meaningful studies that cannot be categorized into the above-mentioned classes. Finally, some conclusions and future directions are given. The EID approach has been successfully used to suppress the influences of exogenous disturbances, nonlinearities, time delays, and uncertainties in many control systems to improve control performance and robustness. Studies can further rich the theory of the EID approach in the future, such as designing evaluation index, improving disturbance-rejection performance, developing new applications, and combining with other control theory.

Duoculture diminishes social interaction costs and improves growth rates of two fish species at different temperatures.

Duoculture has been reported to increase growth rates of some fishes when reared in combination, due to "shading" effects between the species. Two experiments, one involving outdoor cage-rearing in a reservoir, and the other, indoor tank-rearing, were conducted within each of three temperatures ranges (means of ~18.0°C, ~22.0°C and ~26.5°C), to determine whether duoculture of bluegill (BG) Lepomis macrochirus and yellow perch (YP) Perca flavescens would lead to improved growth relative to when the two species were reared separately. Juvenile bluegill and yellow perch were reared in triplicated groups each involving monoculture sets of 100% BG and 100% YP, and a duoculture set of 50% BG + 50% YP. Experiments in cages (Exp. 1) ran for 150 days while those in tanks ran for 126 days (Exp. 2). In Experiment 1, bluegill exhibited significantly greater (P<0.05) mean weight (P<0.05) in duoculture than in monoculture, under the high summer-like range of temperature (~26.5°C) over most of the experiment, whereas yellow perch showed no significant difference in mean weight in duoculture versus monoculture. By the end of a 150-d experiment, bluegill in duoculture outweighed those in monoculture by 62.5%. In Experiment 2, yellow perch in duoculture grew significantly larger than in monoculture (P<0.05) under the warm thermal regime (mean of ~22°C), while no significant differences were detected in mean weight of bluegill in monoculture versus duoculture. Yellow perch in duoculture outweighed those in monoculture by 33.1% at the end of the experiment. Yellow perch performed better in duoculture than in monoculture under the low thermal regime (mean of ~18°C) in both experiments. A significantly greater reduction of CVwt was observed for both bluegill and yellow perch in duoculture than in monoculture in Experiment 1, while no differences in CVwt reduction were detected for bluegill in Experiment 2. Feed conversion ratios (FCR) of bluegill and yellow perch reared in duoculture were significantly lower than for both fishes reared in monoculture in Experiment 1, while there were no significant differences in FCR among the three groups throughout most of Experiment 2. Findings indicate that duoculture of yellow perch and bluegill holds good potential to improve growth and FCR, and to reduce size variation by diminishing social interaction costs.

Management and treatment of severe immune-related hepatotoxicity based on clinical and pathological characteristics.

BACKGROUND: The management of severe immune-related hepatotoxicity (irH) needs to be further optimized. This study aims to analyze the clinical characteristics of severe irH; improve the therapeutic strategy, especially salvage treatment in steroid-refractory irH; and determine the safety of immune checkpoint inhibitor (ICPi)-rechallenge. METHODS: This multicenter retrospective study included patients who developed severe irH and those without irH after immunotherapy between May 2019 and June 2023. Propensity score matching was used to match these two cohorts with similar baseline characteristics. RESULTS: Among 5,326 patients receiving ICPis, 51 patients developed severe irH. irH occurred after a median duration of 36 days and a median of two doses after the first ICPi administration. Patients receiving PD-L1 inhibitors faced a lower risk of developing severe irH. A higher dose of glucocorticoids (GCS) was administered to grade 4 irH than grade 3 irH. For steroid-sensitive patients, grade 4 irH individuals received a higher dosage of GCS than those with grade 3 irH, with no difference in time to resolution. Meanwhile, a significantly higher dose of GCS plus immunosuppression was needed in the steroid-refractory group. Liver biopsy of the steroid-refractory patients exhibited heterogeneous histological features. Twelve patients were retreated with ICPi. No irH reoccurred after a median follow-up of 9.3 months. CONCLUSION: irH requires multidimensional evaluation. PD-L1 inhibitors correlated with a lower risk of severe irH. Grade 4 irH demands a higher dose of GCS than recommended. Pathology may guide the salvage treatment for steroid-refractory irH. ICPi rechallenge in severe irH is feasible and safe.