Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor ...effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib.
Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented.
Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P = 0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P = 0.0471) and T-DM1 (P = 0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, −52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months.
Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy.
NCT02535507.
Melatonin has different functions in plant growth and development, especially in the protection of plants suffering from various forms of abiotic stress. We explored the effect of melatonin priming ...on photosynthetic activity of tomato (
Lycopersicon esculentum
L.) leaves. Our results showed that 100 µM is the optimal concentration used for alleviation of the damage to photosynthetic apparatus. Melatonin priming both in the form of leaf spray and direct root application was found to reduce the damage to photosynthetic apparatus, and increase the electron transfer rate and quantum yield of PSI and PSII photochemistry, to protect the thylakoid membrane from damage caused by low-temperature stress. Our study provides fundamental information for further research on the molecular mechanism of melatonin function in regulating photosynthesis.
Blastocystis
is one common protist inhabiting in gastrointestinal tracts of animals and humans. Examining the subtypes has important implications for assessing the zoonotic potential of
Blastocystis
...and intestinal health of hosts. In the present study, a total of 497 fecal samples collected from 37 wild animal species in Qinling Mountains were investigated for the presence and subtypes of
Blastocystis
. Of them, 200 (40.2%) were positive for
Blastocystis
and 13 subtypes were found, including eight known subtypes (STs1–3, 5, 10, 12–14) and five possible novel subtypes (temporarily named as STs18–22), with ST10 as the predominate subtype and the subtype ST5 was detected in an ostrich for the first time. These findings indicated the wide distribution and specific subtype characteristics of
Blastocystis
in wild animals of Qinling Mountains.
We report on the highest energy photons from the Crab Nebula observed by the Tibet air shower array with the underground water-Cherenkov-type muon detector array. Based on the criterion of a muon ...number measured in an air shower, we successfully suppress 99.92% of the cosmic-ray background events with energies E>100 TeV. As a result, we observed 24 photonlike events with E>100 TeV against 5.5 background events, which corresponds to a 5.6σ statistical significance. This is the first detection of photons with E>100 TeV from an astrophysical source.
Summary
Background
Epithelial barrier dysfunction is critical in the induction of allergy; the aetiology is to be further understood. A recent report indicates that CD98 plays a role in the ...intestinal epithelial barrier dysfunction.
Objectives
This study aimed to investigate the role of overexpression of CD98 in the induction of nasal allergy.
Methods
The nasal epithelium samples were collected from 30 patients with allergic rhinitis and 30 healthy subjects. The contents of CD98 and Staphylococcal enterotoxin B (SEB) in the nasal epithelium samples were evaluated by using Western blotting. The effect of SEB of inducing the expression of CD98 was evaluated with an airway epithelial cell line, the 16HBE14o cells. The epithelial barrier function was assessed with the indicators of transepithelial resistance (TER) and permeability to horseradish peroxidase (HRP). A mouse model was employed to evaluate the role of CD98 in the induction of nasal allergy.
Results
High levels of CD98 and SEB were detected in the nasal epithelium of patients with allergic rhinitis. A positive correlation was identified between CD98 and SEB in nasal epithelium samples. Exposure to SEB could induce the overexpression of CD98 in RPMI 2650 and 16HBE14o cells. The overexpression of CD98 down‐regulated TER and increased the permeability to HRP in 16HBE14o monolayers. Concurrent exposure to SEB and OVA induced nasal allergies in a mouse model that could be blocked by pre‐treatment with anti‐CD98 antibody.
Conclusions and Clinical Relevance
CD98 plays a critical role in compromising the airway epithelial barrier function that contributes to the induction of airway allergy.
Cell-free DNA (cf-DNA)-based liquid biopsy is emerging as a revolutionary new method in individualized cancer treatment and prognosis monitoring, although detecting early-stage cancers using cf-DNA ...remains challenging, partially because of the undefined biological background of cf-DNA.
We investigated somatic mutations in the cf-DNA of 259 cancer-free individuals with a median age of 47 years using an endogenous barcoding duplex method with an ultralow base error rate (2 × 10−7) and compared the variant allele frequencies (VAFs) of these mutations between the cf-DNA and the corresponding blood cell DNA.
Sixty percent (155/259) of the samples showed at least one nonsynonymous mutation on either of two similar target panels covering 508 and 559 cancer-related genes. For individuals older than 50 years of age, the positive rate increased to 76%. Most cf-DNA mutations were also present at similar VAFs in the paired blood cell DNA. The most frequently mutated genes were driver genes of hematologic malignancies, including DNMT3A, TET2, AXSL1, and JAK2. However, the other 58.4% (192/329) of the mutations were likely ‘passenger mutations’ of clonal hematopoiesis, including mutations in NOTCH2, FAT3, EXT2, ERBB4, and ARID2, which are driver genes of solid tumors.
Hematopoietic clone-derived mutations, including ‘driver mutations’ and ‘passenger mutations’, are prevalent in the cf-DNA of both healthy individuals and cancer patients and may be a potential source of false positives in the liquid biopsy. Our results also suggest the ineffectiveness for distinguishing clonal hematopoietic mutations of low VAF (≤0.1%) from tumor-derived mutations using conventional next-generation sequencing of blood cell DNA. However, an error correction model with an ultralow error rate and high coverage depth is required for blood cell DNA sequencing, which is difficult and costly to achieve with current technologies.
The aim of this study is to present our institutional experience in living donor liver transplantation (LDLT) as a treatment for end‐stage liver disease in children with biliary atresia (BA). A ...retrospective review of transplant records was performed. One hundred BA patients (52 males and 48 females) underwent LDLT. The mean follow‐up period was 85.5 months. The mean age was 2.4 years. The mean preoperative weight, height, and computed GFR were 12.2 kg, 82.5 cm, and 116.4 ml/min/1.73 m2, respectively. Twenty‐seven patients were below 1 year of age, and 49 patients were below 10 kg at the time of transplantation. Ninety‐six had had previous Kasai operation prior to transplant. The mean recipient operative time was 628 min. The mean recipient intraoperative blood loss was 176 ml. Thirty‐five did not require blood or blood component transfusion. The left lateral segment (64) was the most common type of graft used. There were 27 operative complications which included 3 reoperations for postoperative bleeding, 9 portal vein, 4 hepatic vein, 4 hepatic artery, and 7 biliary complications. There was one in‐hospital mortality and one retransplantation. The overall rejection rate was 20%. The overall mortality rate was 3%. The 6‐month, 1‐year and 5‐year actual recipient survival rates were 99%, 98% and 98%, respectively.
In 100 biliary atresia patients undergoing living donor liver transplantation at a single center, the overall mortality rate was 3% and the 5 year actual recipient survival rate was 98%.
•Japanese flounder has a low tolerance to high temperatures.•High variability in high-temperature tolerance among Japanese flounder.•Identification of significant molecular markers linked to ...high-temperature tolerance.•Potential influence of traf4 and ppm1l on Japanese flounder’s heat resilience.•Breeding heat-tolerant Japanese flounder using Molecular markers.
This study addresses the critical issue of high-temperature stress in Japanese flounder (Paralichthys olivaceus), a factor threatening both their survival and the growth of the aquaculture industry. The research aims to identify genetic markers associated with high-temperature tolerance, unravel the genetic regulatory mechanisms, and lay the foundation for breeding Japanese flounder with increased resistance to high temperatures. In this study, using a genome-wide association study was performed to identify single nucleotide polymorphisms (SNPs) and genes associated with high−temperature tolerance for Japanese flounder using 280 individuals with 342 311 high-quality SNPs. The traits of high-temperature tolerance were defined as the survival time and survival status of Japanese flounder at high water temperature (31℃) for 15 days cultivate. A genome-wide association study identified six loci on six chromosomes significantly correlated with survival time under high-temperature stress. Six candidate genes were successfully annotated. Additionally, 34 loci associated with survival status were identified and mapped to 15 chromosomes, with 22 candidate genes annotated. Functional analysis highlighted the potential importance of genes like traf4 and ppm1l in regulating apoptosis, impacting high-temperature tolerance in Japanese flounder. These findings provide a valuable theoretical framework for integrating molecular markers into Japanese flounder breeding programmes, serving as a molecular tool to enhance genetic traits linked to high-temperature tolerance in cultured Japanese flounder.
We present a first-principles density functional theory study focused on how the chemical and electronic properties of polyaniline are adjusted by introducing suitable substituents on a polymer ...backbone. Analyses of the obtained energy barriers, reaction energies and minimum energy paths indicate that the chemical reactivity of the polyaniline derivatives is significantly enhanced by protonic acid doping of the substituted materials. Further study of the density of states at the Fermi level, band gap, HOMO and LUMO shows that both the unprotonated and protonated states of these polyanilines are altered to different degrees depending on the functional group. We also note that changes in both the chemical and electronic properties are very sensitive to the polarity and size of the functional group. It is worth noting that these changes do not substantially alter the inherent chemical and electronic properties of polyaniline. Our results demonstrate that introducing different functional groups on a polymer backbone is an effective approach to obtain tailored conductive polymers with desirable properties while retaining their intrinsic properties, such as conductivity.
Hepatic metastasis frequently occurs in patients who have undergone radical pancreatic resection for pancreatic cancer. Besides chemotherapy, various local treatment approaches targeting hepatic ...lesions have been explored. However, research on radiofrequency ablation (RFA) as a localized therapy for hepatic metastasis is limited. Therefore, we conducted this retrospective study to provide clinical evidence.PURPOSEHepatic metastasis frequently occurs in patients who have undergone radical pancreatic resection for pancreatic cancer. Besides chemotherapy, various local treatment approaches targeting hepatic lesions have been explored. However, research on radiofrequency ablation (RFA) as a localized therapy for hepatic metastasis is limited. Therefore, we conducted this retrospective study to provide clinical evidence.This is a single-center, retrospective, cohort study. After radical pancreaticoduodenectomy, 32 patients developed metachronous hepatic metastasis with fewer than 3 lesions, the largest of which was less than 3 cm in diameter. These patients underwent combined treatment with chemotherapy and RFA. After 8 weeks of chemotherapy, patients received RFA for hepatic lesions. Additional chemotherapy was administered, and the patients' tumor status and survival were monitored. The primary endpoint of this study was overall survival (OS). Factors affecting OS were analyzed using the Cox risk model.METHODSThis is a single-center, retrospective, cohort study. After radical pancreaticoduodenectomy, 32 patients developed metachronous hepatic metastasis with fewer than 3 lesions, the largest of which was less than 3 cm in diameter. These patients underwent combined treatment with chemotherapy and RFA. After 8 weeks of chemotherapy, patients received RFA for hepatic lesions. Additional chemotherapy was administered, and the patients' tumor status and survival were monitored. The primary endpoint of this study was overall survival (OS). Factors affecting OS were analyzed using the Cox risk model.Among the 32 patients, the mean OS was 28.4 months. Univariate and multivariate Cox regression analysis revealed that the time (in months) of liver metastasis (HR = 0.04, 95% CI: 0.01 to 0.19; P < 0.001), the number of liver metastases (HR = 7.08, 95% CI: 1.85 to 27.08, P = 0.004), and PD (progressive disease) response to the second round of chemotherapy (HR = 29.50, 95% CI: 1.46 to 597.27; P = 0.027) were independent predictors of poorer survival.RESULTSAmong the 32 patients, the mean OS was 28.4 months. Univariate and multivariate Cox regression analysis revealed that the time (in months) of liver metastasis (HR = 0.04, 95% CI: 0.01 to 0.19; P < 0.001), the number of liver metastases (HR = 7.08, 95% CI: 1.85 to 27.08, P = 0.004), and PD (progressive disease) response to the second round of chemotherapy (HR = 29.50, 95% CI: 1.46 to 597.27; P = 0.027) were independent predictors of poorer survival.Combined therapy with RFA and chemotherapy is safe in patients with hepatic metastasis after radical pancreaticoduodenectomy. Early recurrence (≤12 months), three liver metastatic lesions, and a poor response to the second round of chemotherapy were associated with poor survival.CONCLUSIONCombined therapy with RFA and chemotherapy is safe in patients with hepatic metastasis after radical pancreaticoduodenectomy. Early recurrence (≤12 months), three liver metastatic lesions, and a poor response to the second round of chemotherapy were associated with poor survival.
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