Identification of bZIP Transcription Factors That Regulate the Development of Leaf Epidermal Cells in Arabidopsis thaliana by Single-Cell RNA Sequencing.

Epidermal cells are the main avenue for signal and material exchange between plants and the environment. Leaf epidermal cells primarily include pavement cells, guard cells, and trichome cells. The development and distribution of different epidermal cells are tightly regulated by a complex transcriptional regulatory network mediated by phytohormones, including jasmonic acid, and transcription factors. How the fate of leaf epidermal cells is determined, however, is still largely unknown due to the diversity of cell types and the complexity of their regulation. Here, we characterized the transcriptional profiles of epidermal cells in 3-day-old true leaves of Arabidopsis thaliana using single-cell RNA sequencing. We identified two genes encoding BASIC LEUCINE-ZIPPER (bZIP) transcription factors, namely bZIP25 and bZIP53, which are highly expressed in pavement cells and early-stage meristemoid cells. Densities of pavement cells and trichome cells were found to increase and decrease, respectively, in bzip25 and bzip53 mutants, compared with wild-type plants. This trend was more pronounced in the presence of jasmonic acid, suggesting that these transcription factors regulate the development of trichome cells and pavement cells in response to jasmonic acid.

Safety and Pharmacokinetics of Lopinavir/Ritonavir Oral Solution in Preterm and Term Infants Starting Before 3 Months of Age.

BACKGROUND: Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months. RESULTS: Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13-121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months. CONCLUSIONS: LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies.

Heteroplasmy and Individual Mitogene Pools: Characteristics and Potential Roles in Ecological Studies.

The mitochondrial genome (mitogenome or mtDNA), the extrachromosomal genome, is a multicopy circular DNA with high mutation rates due to replication and repair errors. A mitochondrion, cell, tissue, organ, or an individual body may hold multiple variants, both inherited and developed over a lifetime, which make up individual mitogene pools. This phenomenon is also called mtDNA heteroplasmy. MtDNA variants influence cellular and tissular functions and are consequently subjected to selection. Although it has long been recognized that only inheritable germline heteroplasmies have evolutionary significance, non-inheritable somatic heteroplasmies have been overlooked since they directly affect individual fitness and thus indirectly affect the fate of heritable germline variants. This review focuses on the characteristics, dynamics, and functions of mtDNA heteroplasmy and proposes the concept of individual mitogene pools to discuss individual genetic diversity from multiple angles. We provide a unique perspective on the relationship between individual genetic diversity and heritable genetic diversity and guide how the individual mitogene pool with novel genetic markers can be applied to ecological research.

An antifouling electrochemical biosensor based on chondroitin sulfate-functionalized polyaniline and DNA-peptide conjugates for cortisol determination in body fluids.

An antifouling electrochemical biosensor was constructed based on chondroitin sulfate (CS)-functionalized polyaniline (CS/PANI) and DNA-peptide conjugates that is capable of assaying cortisol directly in human fluids. First, a CS-doped PANI nanocomposite (sensing substrate) was electrodeposited onto a bare glassy carbon electrode to promote electron transport, providing the sensing signal from high peak currents of PANI to improve the sensitivity of the biosensor. Dendritic DNA-peptide conjugates were assembled onto the CS/PANI by exploiting the highly specific and strong interactions between biotin and streptavidin, which amplified the sensing signals toward cortisol. The integration of the DNA-peptide conjugates into the CS/PANI nanocomposite ensured that the biosensor had a synergistic antifouling effect and was capable of detecting cortisol directly in body fluids (sweat, saliva, and tears). When assaying cortisol levels, the biosensor exhibited a linear range over the cortisol concentrations of 1 × 10-12-1 × 10-7 M and a low limit of detection (0.333 × 10-12 M). In the detection of cortisol in real samples, the relative standard deviation (RSD) of the biological samples ranged from 2.94 to 4.23%, and the recovery were calculated to be in the range 95.2-103.2%.

FLS2-RBOHD module regulates changes in the metabolome of Arabidopsis in response to abiotic stress.

Through crosstalk, FLAGELLIN SENSITIVE 2 (FLS2) and RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD) are involved in regulating the homeostasis of cellular reactive oxygen species (ROS) and are linked to the metabolic response of plants toward both biotic and abiotic stress. In the present study, we examined the metabolome of Arabidopsis seedlings under drought and salt conditions to better understand the potential role of FLS2 and RBOHD-dependent signaling in the regulation of abiotic stress response. We identified common metabolites and genes that are regulated by FLS2 and RBOHD, and are involved in the response to drought and salt stress. Under drought conditions, D-aspartic acid and the expression of associated genes, such as ASPARAGINE SYNTHASE 2 (ASN2), increased in both fls2 and robed/f double mutants. The accumulation of amino acids, carbohydrates, and hormones, such as L-proline, D-ribose, and indoleacetaldehyde increased in both fls2 and rbohd/f double mutants under salt conditions, as did the expression of related genes, such as PROLINE IMINOPEPTIDASE, PHOSPHORIBOSYL PYROPHOSPHATE SYNTHASE 5, and NITRILASE 3. Collectively, these results indicate that the FLS2-RBOHD module regulates plant response to drought and salt stress through ROS signaling by adjusting the accumulation of metabolites and expression of genes related to metabolite synthesis.

Comprehensive Analysis of Diabetes Mellitus-related Gene Expression and Associated Prognoses in Human Lung Cancer.

INTRODUCTION: Diabetes mellitus (DM) is a major public health problem worldwide. Cancer is the second most common cause of death in the United States and the leading cause of death in China. There is compelling evidence that individual risk for type 2 diabetes mellitus (T2DM) is strongly influenced by genetic factors. DM and cancer may interact with one another; some kinds of cancer accompany DM, and DM can also promote cancer. METHODS: An analysis was conducted of diabetes mellitus-related gene (DM-gene) expression levels in tumor and normal tissues, clinical parameters, tumor stages, mutations, copy number variations (CNVs), immune cell infiltration, survival, gene enrichment, and gene ontology annotations. RESULTS: This analysis revealed six genes that appear to play key roles in lung cancer survival: MTMR3 (in lung adenocarcinoma [LUAD]) and COBLL1, PPARG, PPIP5K2, RREB1, and WFS1 (in lung squamous cell carcinoma [LUSC]). CONCLUSION: The results suggested that clinical practitioners and researchers should account for PPARG and RREB1 expression when selecting or testing chemotherapy drugs.

Improved cotton yield: Can we achieve this goal by regulating the coordination of source and sink?

Cotton is one of the major cash crops globally. It is characterized by determinate growth and multiple fruiting, which makes the source-sink contradiction more obvious. Coordination between source and sink is crucial for normal growth, yield, and quality of cotton. Numerous studies reported how the assimilate transport and distribution under varying environmental cues affected crop yields. However, less is known about the functional mechanism underlying the assimilate transport between source and sink, and how their distribution impacts cotton growth. Here, we provided an overview of the assimilate transport and distribution mechanisms , and discussed the regulatory mechanisms involved in source-sink balance in relation to cotton yield. Therefore, this review enriched our knowledge of the regulatory mechanism involved in source-sink relationship for improved cotton yield.

Dosing of 3 Targeted Agents in Novel Drug Combinations Used at the Precision Medicine Clinic of the University of California San Diego.

BACKGROUND: The diversity in the genomic landscape of advanced and metastatic tumors calls for combination therapies based on the genomic signature associated with each tumor. Determining safe and tolerable doses for novel combinations of oncology drugs is essential for a precision medicine approach, but can also require dose reductions. Trametinib, palbociclib, and everolimus are among the targeted therapies most often used in novel combinations at our precision medicine clinic. OBJECTIVE: To evaluate the safe, tolerable dosing of trametinib, palbociclib, and everolimus when used as part of novel combinations with other agents for the treatment of advanced or metastatic solid tumors. METHODS: This retrospective study included adult patients with advanced or metastatic solid tumors who received trametinib, everolimus, or palbociclib plus other therapies as a part of novel combinations between December 2011 and July 2018 at the University of California San Diego. Patients were excluded if they received trametinib, everolimus, or palbociclib in standard combinations, such as dabrafenib plus trametinib, everolimus plus fulvestrant, everolimus plus letrozole, and palbociclib plus letrozole. Dosing and adverse events were determined through a review of the electronic medical records. A safe, tolerable drug combination dose was defined as being tolerated for at least 1 month, with no clinically significant serious adverse events. RESULTS: A safe, tolerable dose was determined for 76% of the 71 patients who received trametinib, 88% of the 48 patients who received everolimus, and 73% of the 41 patients receiving palbociclib when used in combination with other therapies. For patients with clinically significant adverse events, dose reductions were attempted in 30% of the trametinib recipients, in 17% of everolimus recipients, and in 45% of palbociclib recipients. When used in combination with other therapies, the optimal dosing of trametinib, palbociclib, and everolimus was lower than the standard single-agent dosing: it was 1 mg daily for trametinib; 5 mg daily for everolimus; and 75 mg daily, for 3 weeks on and 1 week off for palbociclib. Of note, everolimus could not be given concomitantly with trametinib at these doses. CONCLUSION: Safe and tolerable dosing of novel combination therapies that includes trametinib, everolimus, or palbociclib is feasible for a precision medicine approach. However, neither results from this study nor results from previous studies could support the use of everolimus in combination with trametinib, even at reduced doses.

Recent advances in SN-38 drug delivery system.

DNA topoisomerase I plays a key role in lubricatingthe wheels of DNA replication or RNA transcription through breaking and reconnecting DNA single-strand. It is widely known that camptothecin and its derivatives (CPTs) have inhibitory effects on topoisomerases I, and have obtained some clinical benefits in cancer treatment. The potent cytotoxicity makes 7-ethyl-10-hydroxycamptothecin (SN-38) become a brilliant star among these derivatives. However, some undesirable physical and chemical properties of this compound, including poor solubility and stability, seriously hinder its effective delivery to tumor sites. In recent years, strategies to alleviate these defects have aroused extensive research interest. By focusing on the loading mechanism, basic nanodrug delivery systems with SN-38 loaded, like nanoparticles, liposomes and micelles, are demonstrated here. Additionally, functionalized nanodrug delivery systems of SN-38 including prodrug and active targeted nanodrug delivery systems and delivery systems designed to overcome drug resistance are also reviewed. At last, challenges for future research in formulation development and clinical translation of SN-38 drug delivery system are discussed.

PIN1 regulates epidermal cells development under drought and salt stress using single-cell analysis.

Over the course of evolution, plants have developed plasticity to acclimate to environmental stresses such as drought and salt stress. These plant adaptation measures involve the activation of cascades of molecular networks involved in stress perception, signal transduction and the expression of stress related genes. Here, we investigated the role of the plasma membrane-localized transporter of auxin PINFORMED1 (PIN1) in the regulation of pavement cells (PCs) and guard cells (GCs) development under drought and salt stress conditions. The results showed that drought and salt stress treatment affected the development of PCs and GCs. Further analysis identified the different regulation mechanisms of PIN1 in regulating the developmental patterns of PCs and GCs under drought and salt stress conditions. Drought and salt stress also regulated the expression dynamics of PIN1 in pif1/3/4/5 quadruple mutants. Collectively, we revealed that PIN1 plays a crucial role in regulating plant epidermal cells development under drought and salt stress conditions, thus contributing to developmental rebustness and plasticity.

Machine Learning for Predicting Hyperglycemic Cases Induced by PD-1/PD-L1 Inhibitors.

Objective: Immune checkpoint inhibitors, such as programmed death-1/ligand-1 (PD-1/L1), exhibited autoimmune-like disorders, and hyperglycemia was on the top of grade 3 or higher immune-related adverse events. Machine learning is a model from past data for future data prediction. From post-marketing monitoring, we aimed to construct a machine learning algorithm to efficiently and rapidly predict hyperglycemic adverse reaction in patients using PD-1/L1 inhibitors. Methods: In original data downloaded from Food and Drug Administration Adverse Event Reporting System (US FAERS), a multivariate pattern classification of support vector machine (SVM) was used to construct a classifier to separate adverse hyperglycemic reaction patients. With correct core SVM function, a 10-fold 3-time cross validation optimized parameter value composition in model setup with R language software. Results: The SVM prediction model was set up from the number type/number optimization method, as well as the kernel and type of "rbf" and "nu-regression" composition. Two key values (nu and gamma) and case number displayed high adjusted r 2 in curve regressions (nu = 0.5649 × e (- (case/6984)), gamma = 9.005 × 10-4 × case - 4.877 × 10-8 × case2). This SVM model with computable parameters greatly improved the assessing indexes (accuracy, F1 score, and kappa) as well as coequal sensitivity and the area under the curve (AUC). Conclusion: We constructed an effective machine learning model based on compositions of exact kernels and computable parameters; the SVM prediction model can noninvasively and precisely predict hyperglycemic adverse drug reaction (ADR) in patients treated with PD-1/L1 inhibitors, which could greatly help clinical practitioners to identify high-risk patients and perform preventive measurements in time. Besides, this model setup process provided an analytic conception for promotion to other ADR prediction, such ADR information is vital for outcome improvement by identifying high-risk patients, and this machine learning algorithm can eventually add value to clinical decision making.

Cervical Sagittal Alignment in Patients With Basilar Invagination.

STUDY DESIGN: Retrospective study. OBJECTIVE: To present a morphological map of cervical sagittal alignment in basilar invagination (BI), a congenital anomaly of the craniovertebral junction, and contribute to a comprehensive understanding of cervical sagittal alignment in congenital cervical deformities. SUMMARY OF BACKGROUND DATA: Ideal cervical sagittal alignment and surgical targets are debated by scholars. However, most of the literature focuses on the description of cervical sagittal alignment in acquired cervical diseases and normal subjects and few on congenital cervical spine deformities. MATERIALS AND METHODS: This study analyzed cervical spine lateral radiographs of 87 BI patients and 98 asymptomatic subjects. They were analyzed for cranial, cervical spine, and thoracic inlet parameters. RESULTS: Patients with BI manifested significantly larger values for the following parameters than asymptomatic subjects: cranial tilt, cranial incidence angle, sagittal vertical axis (SVA) CGH-C7, C2-C7 angle, cervical tilt, and significantly smaller values for the following parameters: cranial slope, C0-C2 angle, C0-C7 angle, SVA C2-C7, spine tilt, thoracic inlet angle, and neck tilt. In the BI group, SVA C2-C7 was the cervical parameter most strongly correlated with the cranial, cervical spine, and thoracic inlet parameters, and was smaller in BI patients with fusion (atlanto-occipital assimilation) than in those without. CONCLUSION: A significant difference was observed between BI patients and asymptomatic subjects. BI patients have craniums tilted forward and downward, smaller upper cervical lordosis, larger lower cervical lordosis, and smaller thoracic inlet angle. In BI patients, the SVA C2-C7 is an important parameter in cervical sagittal alignment. In both individuals with congenital anomalies of the craniovertebral junction and the asymptomatic population, cervical spine alignment is significantly associated with cranial alignment, particularly thoracic inlet alignment.

Research strategies for single-cell transcriptome analysis in plant leaves.

The recent and continuous improvement in single-cell RNA sequencing (scRNA-seq) technology has led to its emergence as an efficient experimental approach in plant research. However, compared with single-cell research in animals and humans, the application of scRNA-seq in plant research is limited by several challenges, including cell separation, cell type annotation, cellular function analysis, and cell-cell communication networks. In addition, the unavailability of corresponding reliable and stable analysis methods and standards has resulted in the relative decentralization of plant single-cell research. Considering these shortcomings, this review summarizes the research progress in plant leaf using scRNA-seq. In addition, it describes the corresponding feasible analytical methods and associated difficulties and problems encountered in the current research. In the end, we provide a speculative overview of the development of plant single-cell transcriptome research in the future.

Significant emission reductions of carbonaceous aerosols from residential coal burning by a novel stove.

Carbonaceous aerosols (CA) are crucial components in the atmospheric PM2.5 and derived from diverse sources. One of the major sources for CA is from the incomplete combustion of bituminous coal that has been prevailingly used by household stoves in rural areas for heating during winter. To efficiently eliminate the CA emission, a new household stove (NHS) was developed based on a novel combustion technology and CA emissions from the NHS and a traditional household stove (THS) were comparably investigated under the actual stove operation conditions in a farmer's house. Compared with the THS, the emission factors of organic carbon (OC), elemental carbon (EC), and water-soluble organic carbon (WSOC) from the NHS were reduced by 96%±1%, 98%±1%, and 91%±1% under the flaming process and 95%±1%, 96%±2%, and 83%±4% under the smoldering process, respectively. Additionally, the mass absorption efficiency of WSOC from the NHS reduced by 3 folds and the radiative forcing by WSOC relative to EC shrank remarkably by a factor of 3-8. Based on the reduction of emissions and light absorption of WSOC, the promotion of the NHS offers a possible solution to achieve the clean combustion of residential solid fuel.

Anatomical analysis of the C2 pedicle in patients with basilar invagination.

PURPOSE: To evaluate and describe the morphologic features of the C2 pedicle in patients with basilar invagination (BI) for informing the placement of pedicle screws. C2 pedicle screw placement is an important surgical technique for the treatment of atlantoaxial instability in patients with BI. However, no systematic and comprehensive anatomical study of the C2 pedicle in patients with BI has been reported. METHODS: The data from 100 patients diagnosed with BI (BI group) and 100 patients without head or cervical disease (control group) were included in the study. Radiographic parameters, including the pedicle width, length, height, transverse angle, lamina angle, and superior angle, were measured and analyzed on CT images. After summary analysis, the effect of C2-3 congenital fusion on C2 pedicle deformity in patients with BI was also investigated. RESULTS: The width, length, and height of the C2 pedicle of the BI patients were smaller than those of the control group. The pedicle cancellous bone was smaller in the BI group, while no significant difference in cortical bone was observed. In total, 44% of the pedicles were smaller than 4.5 mm in the BI group. Patients with C2-3 congenital fusion presented with smaller pedicle transverse angles and larger pedicle superior angles than those without fusion. Wide variations in the left and right angles of the pedicle were observed in the BI group with atlantoaxial dislocation or atlantooccipital fusion. CONCLUSION: The C2 pedicle in the BI group was thinner than that in the control group due to a smaller cortical bone. Cases of C2-3 congenital fusion, atlantoaxial dislocation, and atlantooccipital fusion displayed variation in the angle of the C2 pedicle.

Bindarit Reduces Bone Loss in Ovariectomized Mice by Inhibiting CCL2 and CCL7 Expression via the NF-κB Signaling Pathway.

OBJECTIVE: To investigate the changes in proinflammatory cytokines and chemokines, namely, C-C motif ligand (CCL) 2 and CCL7, in postmenopausal osteoporosis (PMOP) and to develop a new drug, bindarit (Bnd), for PMOP in an ovariectomized (OVX) mouse model. METHODS: Bone marrow macrophages (BMMs) from the femurs of five women with PMOP and five premenopausal women without osteoporosis were detected by RNA sequencing. BMMs from mice were differentiated into osteoclasts and treated with a synthetic inhibitor of CCL2 and CCL7, Bnd, or 17 beta estradiol (E2 ). Mouse BMMs were differentiated into osteoclasts with or without Bnd for 7 days and analyzed by RNA sequencing. Osteoblasts of mice were induced to undergo osteoblastogenesis and treated with Bnd. OVX mice were treated with E2 or Bnd after surgery. The protein and mRNA expression of CCL2 and CCL7 was detected using immunostaining and qPCR, respectively, in OVX and aged mice and in cells cultured in vitro. Osteoclast formation was detected using a tartrate-resistant acid phosphatase (TRAP) assay in vitro and in vivo. Alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) were detected using immunostaining to evaluate osteogenesis. Microcomputed tomography was conducted to analyze trabecular bone parameters, the structure model index, bone mineral density and other variables. Nuclear factor-κB (NF-κB) signaling pathway-related protein phosphorylation of IKKα/ß (p-IKKα/ß) and p-NFκB p65 was examined using western blotting. RESULTS: CCL2, CCL7 and their receptor of C-C chemokine receptor-2 (CCR2), and the NF-κB signaling pathway, were significantly increased in women with PMOP. CCL2 and CCL7 protein and mRNA expression was increased in OVX mice and aged female mice, but the increases were attenuated by E2 and Bnd. E2 and Bnd effectively inhibited osteoclastogenesis and the protein expression of CCL2 and CCL7 both in vitro and in vivo and reduced bone loss in OVX mice. Bnd did not affect the mineralization of osteoblasts directly in vitro but reduced bone turnover in vivo. p-IKKα/ß and p-NFκB p65 levels were increased in BMMs of mice after differentiation into osteoclasts but were significantly decreased by Bnd. CONCLUSION: The proinflammatory cytokines and chemokines CCL2, CCL7 and CCR2 were correlated with PMOP. Bnd attenuated the increases in CCL2 and CCL7 levels to affect osteoporosis in OVX mice via the NFκB signaling pathway. Thus, Bnd may be useful as a new therapeutic for the prevention of PMOP.

Identification of the Regulators of Epidermis Development under Drought- and Salt-Stressed Conditions by Single-Cell RNA-Seq.

As sessile organisms, plants constantly face challenges from the external environment. In order to meet these challenges and survive, plants have evolved a set of sophisticated adaptation strategies, including changes in leaf morphology and epidermal cell development. These developmental patterns are regulated by both light and hormonal signaling pathways. However, our mechanistic understanding of the role of these signaling pathways in regulating plant response to environmental stress is still very limited. By applying single-cell RNA-Seq, we determined the expression pattern of PHYTOCHROME INTERACTING FACTOR (PIF) 1, PIF3, PIF4, and PIF5 genes in leaf epidermal pavement cells (PCs) and guard cells (GCs). PCs and GCs are very sensitive to environmental stress, and our previous research suggests that these PIFs may be involved in regulating the development of PCs, GCs, and leaf morphology under environmental stress. Growth analysis showed that pif1/3/4/5 quadruple mutant maintained tolerance to drought and salt stress, and the length to width ratio of leaves and petiole length under normal growth conditions were similar to those of wild-type (WT) plants under drought and salt treatment. Analysis of the developmental patterns of PCs and GCs, and whole leaf morphology, further confirmed that these PIFs may be involved in mediating the development of epidermal cells under drought and salt stress, likely by regulating the expression of MUTE and TOO MANY MOUTHS (TMM) genes. These results provide new insights into the molecular mechanism of plant adaptation to adverse growth environments.

Thiazolidinedione-Based Structure Modification of Celastrol Provides Thiazolidinedione-Conjugated Derivatives as Potent Agents against Non-Small-Cell Lung Cancer Cells through a Mitochondria-Mediated Apoptotic Pathway.

In order to improve the potential of celastrol against non-small-cell lung cancer cells, the privileged structure, thiazolidinedione, was introduced into its C-20 carboxylic group with acetylpiperazine as a linker, and the thiazolidinedione-conjugated compounds 10a-10t were prepared. The target compounds were evaluated for their cytotoxic activities against the A549 cell line, and the results showed that most of the compounds 10a-10t displayed improved potency over celastrol, and compound 10b exhibited significant activity against the A549 cell line, with an IC50 value of 0.08 µM, which was 13.8-fold more potent than celastrol (IC50 = 1.10 µM). The mechanistic studies suggested that 10b could induce A549 cell apoptosis, as evidenced by Hoechst 33342 staining and annexin V-FITC/propidium iodide dual staining assays. Western blot analysis suggested that compound 10b could upregulate Bax expression, downregulate Bcl-2 expression, and activate the mitochondria-mediated apoptotic pathway. Furthermore, compound 10b could effectively inhibit tumor growth when tested in an A549 cell xenograft mouse model. Collectively, compound 10b is worthy of further investigation to support the discovery of effective agents against non-small-cell lung cancer.

Chinese quality control indices for standardized diagnosis and treatment of gastric cancer (2022 edition).

Gastric cancer is one of the most common malignancies of the digestive system, and the number of deaths continues to increase. The standardized management of the diagnosis and treatment of gastric cancer is challenging due to the great differences in the diagnosis and treatment of gastric cancer in different regions. The Gastric Cancer Expert Committee of the National Cancer Quality Control Center (NCQCC) identified a lack of authoritative quality control standards as an opportunity to utilize its multidisciplinary membership to improve the standardized diagnosis and treatment of gastric cancer. The Gastric Cancer Expert Committee of the NCQCC aims to promote quality control and national standardization, uniformity, and normalization of gastric cancer diagnosis and treatment, which ultimately improved the survival rate and quality of life of gastric cancer patients. A panel of experts with gastrointestinal cancer surgery, gastrointestinal cancer medicine, medical imaging, pathology and radiotherapy were drawn together and determined the quality control standards for the standardized diagnosis and treatment of gastric cancer. The authors then utilized a modified Delphi approach to generate consensus recommendations.

Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial.

OBJECTIVES: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA). STUDY DESIGN: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy. RESULTS: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. CONCLUSIONS: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.