DNA-DISK: Automated end-to-end data storage via enzymatic single-nucleotide DNA synthesis and sequencing on digital microfluidics.

In the age of information explosion, the exponential growth of digital data far exceeds the capacity of current mainstream storage media. DNA is emerging as a promising alternative due to its higher storage density, longer retention time, and lower power consumption. To date, commercially mature DNA synthesis and sequencing technologies allow for writing and reading of information on DNA with customization and convenience at the research level. However, under the disconnected and nonspecialized mode, DNA data storage encounters practical challenges, including susceptibility to errors, long storage latency, resource-intensive requirements, and elevated information security risks. Herein, we introduce a platform named DNA-DISK that seamlessly streamlined DNA synthesis, storage, and sequencing on digital microfluidics coupled with a tabletop device for automated end-to-end information storage. The single-nucleotide enzymatic DNA synthesis with biocapping strategy is utilized, offering an ecofriendly and cost-effective approach for data writing. A DNA encapsulation using thermo-responsive agarose is developed for on-chip solidification, not only eliminating data clutter but also preventing DNA degradation. Pyrosequencing is employed for in situ and accurate data reading. As a proof of concept, DNA-DISK successfully stored and retrieved a musical sheet file (228 bits) with lower write-to-read latency (4.4 min of latency per bit) as well as superior automation compared to other platforms, demonstrating its potential to evolve into a DNA Hard Disk Drive in the future.

Construction of an artificial phosphoketolase pathway that efficiently catabolizes multiple carbon sources to acetyl-CoA.

The canonical glycolysis pathway is responsible for converting glucose into 2 molecules of acetyl-coenzyme A (acetyl-CoA) through a cascade of 11 biochemical reactions. Here, we have designed and constructed an artificial phosphoketolase (APK) pathway, which consists of only 3 types of biochemical reactions. The core enzyme in this pathway is phosphoketolase, while phosphatase and isomerase act as auxiliary enzymes. The APK pathway has the potential to achieve a 100% carbon yield to acetyl-CoA from any monosaccharide by integrating a one-carbon condensation reaction. We tested the APK pathway in vitro, demonstrating that it could efficiently catabolize typical C1-C6 carbohydrates to acetyl-CoA with yields ranging from 83% to 95%. Furthermore, we engineered Escherichia coli stain capable of growth utilizing APK pathway when glycerol act as a carbon source. This novel catabolic pathway holds promising route for future biomanufacturing and offering a stoichiometric production platform using multiple carbon sources.

NeoaPred: a deep-learning framework for predicting immunogenic neoantigen based on surface and structural features of peptide-human leukocyte antigen complexes.

MOTIVATION: Neoantigens, derived from somatic mutations in cancer cells, can elicit anti-tumor immune responses when presented to autologous T cells by human leukocyte antigen. Identifying immunogenic neoantigens is crucial for cancer immunotherapy development. However, the accuracy of current bioinformatic methods remains unsatisfactory. Surface and structural features of peptide-HLA class I (pHLA-I) complexes offer valuable insight into the immunogenicity of neoantigens. RESULTS: We present NeoaPred, a deep-learning framework for neoantigen prediction. NeoaPred accurately constructs pHLA-I complex structures, with 82.37% of the predicted structures showing an RMSD of < 1 Å. Using these structures, NeoaPred integrates differences in surface, structural, and atom group features between the mutant peptide and its wild-type counterpart to predict a foreignness score. This foreignness score is an effective factor for neoantigen prediction, achieving an AUROC (Area Under the Receiver Operating Characteristic Curve) of 0.81 and an AUPRC (Area Under the Precision-Recall Curve) of 0.54 in the test set, outperforming existing methods. AVAILABILITY AND IMPLEMENTATION: The source code is released under an Apache v2.0 license and is available at the GitHub repository (https://github.com/Dulab2020/NeoaPred).

ß-Hydroxybutyrate enhances astrocyte glutamate uptake through EAAT1 expression regulation.

ß-Hydroxybutyrate (BHB) has been reported to exert neuroprotective functions and is considered a promising treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's. Numerous studies have revealed BHB's multifaceted roles, including anti-senescence, anti-oxidative, and anti-inflammatory activities. However, the underlying mechanisms warrant further investigation. Astrocytes, the most abundant glial cells in the central nervous system, play a pivotal role in the development and progression of neurodegenerative diseases. While BHB is known to alter neuronal metabolism and function, its effects on astrocytes remain poorly understood. In this study, we conducted transcriptome sequencing analysis to identify differentially expressed genes induced by BHB in astrocytes and found that the gene Solute carrier family 1 member 3 (Slc1a3), encoding the glutamate transporter EAAT1, was significantly upregulated by BHB treatment. Cellular and animal-based experiments confirmed an increase in EAAT1 protein expression in primary astrocytes and the hippocampus of mice treated with BHB. This upregulation may be due to the activation of the Ca2+/CAMKII pathway by BHB. Furthermore, BHB improved astrocytes' glutamate uptake and partially restored neuronal viability impaired by glutamate-induced excitotoxicity when astrocytes were functionalized. Our results suggest that BHB may alleviate neuronal damage caused by excessive glutamate by enhancing the glutamate absorption and uptake capacity of astrocytes. This study proposes a novel mechanism for the neuroprotective effects of BHB and reinforces its beneficial impact on the central nervous system (CNS).

Cataract-causing Y204X mutation of crystallin protein CRYßB1 promotes its C-terminal degradation and higher-order oligomerization.

Crystallin proteins are a class of main structural proteins of the vertebrate eye lens, and their solubility and stability directly determine transparency and refractive power of the lens. Mutation in genes that encode these crystallin proteins is the most common cause for congenital cataracts. Despite extensive studies, the pathogenic and molecular mechanisms that effect congenital cataracts remain unclear. In this study, we identified a novel mutation in CRYBB1 from a congenital cataract family, and demonstrated that this mutation led to an early termination of mRNA translation, resulting in a 49-residue C-terminally truncated CRYßB1 protein. We show this mutant is susceptible to proteolysis, which allowed us to determine a 1.2-Å resolution crystal structure of CRYßB1 without the entire C-terminal domain. In this crystal lattice, we observed that two N-terminal domain monomers form a dimer that structurally resembles the WT monomer, but with different surface characteristics. Biochemical analyses and cell-based data also suggested that this mutant is significantly more liable to aggregate and degrade compared to WT CRYßB1. Taken together, our results provide an insight into the mechanism regarding how a mutant crystalin contributes to the development of congenital cataract possibly through alteration of inter-protein interactions that result in protein aggregation.

Small Molecule-Induced Post-Translational Acetylation of Catalytic Lysine of Kinases in Mammalian Cells.

Reversible lysine acetylation is an important post-translational modification (PTM). This process in cells is typically carried out enzymatically by lysine acetyltransferases and deacetylases. The catalytic lysine in the human kinome is highly conserved and ligandable. Small-molecule strategies that enable post-translational acetylation of the catalytic lysine on kinases in a target-selective manner therefore provide tremendous potential in kinase biology. Herein, we report the first small molecule-induced chemical strategy capable of global acetylation of the catalytic lysine on kinases from mammalian cells. By surveying various lysine-acetylating agents installed on a promiscuous kinase-binding scaffold, Ac4 was identified and shown to effectively acetylate the catalytic lysine of >100 different protein kinases from live Jurkat/K562 cells. In order to demonstrate that this strategy was capable of target-selective and reversible chemical acetylation of protein kinases, we further developed six acetylating compounds on the basis of VX-680 (a noncovalent inhibitor of AURKA). Among them, Ac13/Ac14, while displaying excellent in vitro potency and sustained cellular activity against AURKA, showed robust acetylation of its catalytic lysine (K162) in a target-selective manner, leading to irreversible inhibition of endogenous kinase activity. The reversibility of this chemical acetylation was confirmed on Ac14-treated recombinant AURKA protein, followed by deacetylation with SIRT3 (a lysine deacetylase). Finally, the reversible Ac13-induced acetylation of endogenous AURKA was demonstrated in SIRT3-transfected HCT116 cells. By disclosing the first cell-active acetylating compounds capable of both global and target-selective post-translational acetylation of the catalytic lysine on kinases, our strategy could provide a useful chemical tool in kinase biology and drug discovery.

Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells.

BACKGROUND: Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. METHODS: Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. RESULTS: Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. CONCLUSION: ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.

High-Throughput Screening for Oligonucleotide Detection by ADE-OPI-MS.

Oligonucleotides represent a class of shorter DNA or RNA nucleic acid polymers extensively applied in the biomedical field. Despite progress in detecting and analyzing oligonucleotides, high-throughput analysis of the samples remains challenging. In this work, a high-throughput analysis method for oligonucleotide analysis was developed based on acoustic droplet ejection-open port interface-mass spectrometry (ADE-OPI-MS) technology. This approach was applied to determine the enzymatic activity of terminal deoxynucleotide transferase (TdT) for DNA synthesis, with a rate of 3 s/sample, which enhanced single-sample analysis efficiency approximately 60-fold over the previous gel analysis. After testing approximately 10,000 TdT mutants, we obtained three new variants with higher catalytic activities. Finally, by integrating these mutants, the catalytic activity of TdT was improved about 4 times compared to the starting mutant. Our results successfully established a high-throughput screening method for oligonucleotide analysis, which not only provides a foundation to engineer highly efficient TdT for ab initio synthesis of DNA but also paves the way for the potential application of oligonucleotide analysis in biomedical fields.

Dynamics Playing a Key Role in the Covalent Binding of Inhibitors to Focal Adhesion Kinase.

Covalent kinase inhibitors (CKIs) have recently garnered considerable attention, yet the rational design of CKIs continues to pose a great challenge. In the discovery of CKIs targeting focal adhesion kinase (FAK), it has been observed that the chemical structure of the linkers plays a key role in achieving covalent targeting of FAK. However, the mechanism behind the observation remains elusive. In this work, we employ a comprehensive suite of advanced computational methods to investigate the mechanism of CKIs covalently targeting FAK. We reveal that the linker of an inhibitor influences the contacts between the warhead and residue(s) and the residence time in active conformation, thereby dictating the inhibitor's capability to bind covalently to FAK. This study reflects the complexity of CKI design and underscores the importance of considering the dynamic interactions and residence times for the successful development of covalent drugs.

Demethylase FTO inhibits the occurrence and development of triple-negative breast cancer by blocking m 6A-dependent miR-17-5p maturation-induced ZBTB4 depletion.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer, and its mechanisms of occurrence and development remain unclear. In this study, we aim to investigate the role and molecular mechanisms of the demethylase FTO (fat mass and obesity-associated protein) in TNBC. Through analysis of public databases, we identify that FTO may regulate the maturation of miR-17-5p and subsequently influence the expression of zinc finger and BTB domain-containing protein 4 (ZBTB4), thereby affecting the occurrence and progression of TNBC. We screen for relevant miRNAs and mRNAs from the GEO and TCGA databases and find that the FTO gene may play a crucial role in TNBC. In vitro cell experiments demonstrate that overexpression of FTO can suppress the proliferation, migration, and invasion ability of TNBC cells and can regulate the maturation of miR-17-5p through an m 6A-dependent mechanism. Furthermore, we establish a xenograft nude mouse model and collect clinical samples to further confirm the role and impact of the FTO/miR-17-5p/ZBTB4 regulatory axis in TNBC. Our findings unveil the potential role of FTO and its underlying molecular mechanisms in TNBC, providing new perspectives and strategies for the research and treatment of TNBC.

Anti-Inflammatory and Immunomodulatory Effects of 0.1 Sub-Terahertz Irradiation in Collagen-Induced Arthritis Mice.

The primary emphasis of photoimmunology is the impact of nonionizing radiation on the immune system. With the development of terahertz (THz) and sub-terahertz (sub-THz) technology, the biological effects of this emerging nonionizing radiation, particularly its influence on immune function, remain insufficiently explored but are progressively attracting attention. Here, we demonstrated that 0.1 sub-THz radiation can modulate the immune system and alleviate symptoms of arthritis in collagen-induced arthritis (CIA) mice through a nonthermal manner. The application of 0.1 sub-THz irradiation led to a decrease in proinflammatory factors within the joints and serum, reducing the levels of blood immune cells and the quantity of splenic CD4+ T cells. Notably, 0.1 sub-THz irradiation restored depleted Treg cells in CIA mice and re-established the Th17/Treg equilibrium. These findings suggested that sub-THz irradiation plays a crucial role in systemic immunoregulation. Further exploration of its immune modulation mechanisms revealed the anti-inflammatory properties of 0.1 sub-THz on LPS-stimulated skin keratinocytes. Through the reduction in NF-κB signaling and NLRP3 inflammasome activation, 0.1 sub-THz irradiation effectively decreased the production of inflammatory factors and immune-active substances, including IL-1ß and PGE2, in HaCaT cells. Consequently, 0.1 sub-THz irradiation mitigated the inflammatory response and contributed to the maintenance of immune tolerance in CIA mice. This research provided significant new evidence supporting the systemic impacts of 0.1 sub-THz radiation, particularly on the immune system. It also enhanced the field of photoimmunology and offered valuable insights into the potential biomedical applications of 0.1 sub-THz radiation for treating autoimmune diseases.

Randomized, Single-Blind, Comparative Study of Remimazolam Besylate vs Propofol for Facial Plastic Surgery.

BACKGROUND: Use of local anesthesia and conscious sedation with a combination of a sedative and anesthetic drug during a surgical procedure is an approach designed to avoid intubation, which produces fewer adverse events compared to general anesthesia. In the present study, a comparison was made between the efficacy and safety of remimazolam besylate and propofol for facial plastic surgery. OBJECTIVES: The objective was to evaluate the clinical efficacy, comfort, and incidence of adverse events of remimazolam compared with propofol combined with alfentanil in outpatient facial plastic surgery. METHODS: In this randomized, single-blind, single-center, comparative study, facial plastic surgery patients were randomly divided into remimazolam-alfentanil (n = 50) and propofol-alfentanil (n = 50) groups for sedation and analgesia. The primary endpoint was the incidence of hypoxemia, while secondary endpoints included efficacy and safety evaluations. RESULTS: There were no significant differences regarding the surgical procedure, sedation and induction times, pain and comfort scores, muscle strength recovery, heart rate, respiratory rate, and blood pressure, but the dosage of alfentanil administered to the remimazolam group (387.5 µg) was lower than that for the propofol group (600 µg). The incidence of hypoxemia (P = .046) and towing of the mandibular (P = .028), as well as wake-up (P = .027) and injection pain (P = .008), were significantly higher in the propofol group than the remimazolam group. CONCLUSIONS: Remimazolam and propofol had similar efficacies for sedation and analgesia during facial plastic surgery, but especially the incidence of respiratory depression was significantly lower in patients given remimazolam.

Therapeutic Drug Monitoring of Perampanel in Children With Refractory Epilepsy: Focus on Influencing Factors on the Free-Perampanel Concentration.

BACKGROUND: This study aimed to assess the effect of perampanel dose, age, sex, and antiseizure medication cotherapy on steady-state free-perampanel concentration in children with refractory epilepsy, as well as the relationship between inflammation and the pharmacokinetics of perampanel. METHODS: This prospective study in China included 87 children with refractory epilepsy treated with adjunctive perampanel therapy. Free and total perampanel concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Free-perampanel concentration was compared among patients with various potential influencing factors. RESULTS: A total of 87 pediatric patients (44 female children) aged 2-14 years were enrolled. The mean free-perampanel concentration and free concentration-to-dose (CD) ratio in plasma were 5.7 ± 2.7 ng/mL (16.3 ± 7.7 nmol/L) and 45.3 ± 21.0 (ng/mL)/(mg/kg) [129.6 ± 60.1 (nmol/L)/(mg/kg)], respectively. The protein binding of perampanel in plasma was 97.98%. A linear relationship was observed between perampanel dose and free concentration in plasma, and a positive relationship was found between the total and free-perampanel concentrations. Concomitant use of oxcarbazepine reduced the free CD ratio by 37%. Concomitant use of valproic acid increased the free CD ratio by 52%. Five patients had a plasma high-sensitivity C-reactive protein (Hs-CRP) level of >5.0 mg/L (Hs-CRP positive). The total and free CD ratios of perampanel were increased in patients with inflammation. Two patients with inflammation developed adverse events, which disappeared as the Hs-CRP level returned to normal, and neither required perampanel dose reduction. Age and sex did not influence the free-perampanel concentration. CONCLUSIONS: This study found complex drug interactions between perampanel and other concomitant antiseizure medications, providing valuable information to enable clinicians to apply perampanel in the future reasonably. In addition, it may be important to quantify both the total and free concentrations of perampanel to assess complex pharmacokinetic interactions.

7295 elderly hospitalized patients with catheter-associated urinary tract infection: a case-control study.

BACKGROUND: Catheter-associated urinary tract infection (CAUTI) ranks second among nosocomial infections in elderly patients after lung infections. Improper treatment can lead to death. This study analysed the risk factors, pathogen distribution, clinical characteristics and outcomes of CAUTI in elderly inpatients with a large sample size to provide evidence for clinical prevention and control. METHODS: Based on the HIS and LIS, a case‒control study was conducted on all hospitalized patients with indwelling urinary catheters ≥ 60 years old from January 1, 2019, to December 31, 2022, and the patients were divided into the CAUTI group and the non-CAUTI group. RESULTS: CAUTI occurred in 182 of 7295 patients, and the infection rate was 3.4/per 1000 catheter days. Urine pH ≥ 6.5, moderate dependence or severe dependence in the classification of self-care ability, age ≥ 74 years, male sex, hospitalization ≥ 14 days, indwelling urinary catheter ≥ 10 days, diabetes and malnutrition were independent risk factors for CAUTI (P < 0.05). A total of 276 strains of pathogenic bacteria were detected in urine samples of 182 CAUTI patients at different times during hospitalization. The main pathogens were gram-negative bacteria (n = 132, 47.83%), followed by gram-positive bacteria (n = 91, 32.97%) and fungi (n = 53, 19.20%). Fever, abnormal procalcitonin, positive urinary nitrite and abnormal urination function were the clinical characteristics of elderly CAUTI patients (P < 0.001). Once CAUTI occurred in elderly patients, the hospitalization days were increased by 18 days, the total hospitalization cost increased by ¥18,000, and discharge all-cause mortality increased by 2.314 times (P<0.001). CONCLUSION: The situation of CAUTI in the elderly is not optimistic, it is easy to have a one-person multi-pathogen infection, and the proportion of fungi infection is not low. Urine pH ≥ 6.5, moderate or severe dependence on others and malnutrition were rare risk factors for elderly CAUTI in previous studies. Our study analysed the clinical characteristics of CAUTI in the elderly through a large sample size, which provided a reliable basis for its diagnosis and identified the adverse outcome of CAUTI.

Spectral Characteristics and Functional Responses of Phospholipid Bilayers in the Terahertz Band.

Understanding the vibrational information encoded within the terahertz (THz) spectrum of biomolecules is critical for guiding the exploration of its functional responses to specific THz radiation wavelengths. This study investigated several important phospholipid components of biological membranes-distearoyl phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylcholine (DPPC), sphingosine phosphorylcholine (SPH), and lecithin bilayer-using THz time-domain spectroscopy. We observed similar spectral patterns for DPPC, SPH, and the lecithin bilayer, all of which contain the choline group as the hydrophilic head. Notably, the spectrum of DSPE, which has an ethanolamine head group, was different. Interestingly, density functional theory calculations confirmed that the absorption peak common to DSPE and DPPC at approximately 3.0 THz originated from a collective vibration of their similar hydrophobic tails. Accordingly, the cell membrane fluidity of RAW264.7 macrophages with irradiation at 3.1 THz was significantly enhanced, leading to improved phagocytosis. Our results highlight the importance of the spectral characteristics of the phospholipid bilayers when studying their functional responses in the THz band and suggest that irradiation at 3.1 THz is a potential non-invasive strategy to increase the fluidity of phospholipid bilayers for biomedical applications such as immune activation or drug administration.

Integrative Proteome Analysis Revels 3-Hydroxybutyrate Exerts Neuroprotective Effect by Influencing Chromatin Bivalency.

3-hydroxybutyrate (3OHB) has been proved to act as a neuroprotective molecule in multiple neurodegenerative diseases. Here, we employed a quantitative proteomics approach to assess the changes of the global protein expression pattern of neural cells upon 3OHB administration. In combination with a disease-related, protein-protein interaction network we pinpointed a hub marker, histone lysine 27 trimethylation, which is one of the key epigenetic markers in multiple neurodegenerative diseases. Integrative analysis of transcriptomic and epigenomic datasets highlighted the involvement of bivalent transcription factors in 3OHB-mediated disease protection and its alteration of neuronal development processes. Transcriptomic profiling revealed that 3OHB impaired the fate decision process of neural precursor cells by repressing differentiation and promoting proliferation. Our study provides a new mechanism of 3OHB's neuroprotective effect, in which chromatin bivalency is sensitive to 3OHB alteration and drives its neuroprotective function both in neurodegenerative diseases and in neural development processes.

LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.

With the wide clinical use of the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth-generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS-106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell-free assay, LS-106 potently inhibited the kinase activities of EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S with IC50 values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS-106 exhibited comparable kinase inhibitory effect to osimertinib on EGFRL858R/T790M and wild-type EGFR. Results from cellular experiments demonstrated that LS-106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR19del/T790M/C797S or EGFRL858R/T790M/C797S , and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR19del/T790M/C797S (named PC-9-OR cells) using the CRISPR/Cas9 system and found that LS-106 markedly suppressed the activation of EGFR19del/T790M/C797S and the proliferation of PC-9-OR cells. Moreover, cells harboring EGFR19del/T790M/C797S underwent remarkable apoptosis upon LS-106 treatment. In vivo experiments further demonstrated that oral administration of LS-106 caused significant tumor regression in a PC-9-OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS-106 as a novel fourth-generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S-triple-mutant tumor models.

Treatment of pyogenic granuloma in children with a 595 nm pulsed dye laser: A retrospective study of 212 patients.

BACKGROUND: Pyogenic granuloma (PG) is a common vascular neoplasm in children. Data on 595 nm pulsed dye lasers for the treatment of PG in children remain scarce. OBJECTIVE: To summarize the clinical characteristics and to evaluate the effectiveness and safety of the 595 nm pulsed dye laser for the treatment of PG in children. STUDY DESIGN: Retrospective case series. METHODS: A retrospective study was performed on 212 patients treated for PG with a 595 nm pulsed dye laser. SPSS version 19.0 was used for statistical analysis. RESULTS: Among all 212 patients treated, 208 showed complete resolution of the lesion, and 4 dropped out after one treatment due to bleeding. A single treatment was sufficient in 139 (66.8%) patients, while two or three treatments were sufficient in 69 (33.2%) patients. Male patients responded better than female patients (χ2 = 7.603, p =0.006). Lesions in the nonorbital region responded better than those in the orbital region (χ2 = 7.445, p =0.006). The size of the lesion affected the effectiveness, and lesions with smaller diameters (t = -5.776, p <0.01) and heights (t = -10.368, p <0.01) showed better results. COMPLICATIONS AND SIDE EFFECTS: Twelve patients (5.8%) were reported to have local complications and side effects, including edematous erythema, slight bleeding, hyperpigmentation, and hypopigmentation. The edematous erythema and slight bleeding disappeared gradually after several days. The localized pigment changes usually resolved spontaneously and disappeared completely after 6 months. CONCLUSIONS: Our experience confirmed the efficacy and safety of the 595 nm pulsed dye laser for the treatment of PG in children.

Maternal diabetes induces autism-like behavior by hyperglycemia-mediated persistent oxidative stress and suppression of superoxide dismutase 2.

Epidemiological studies show that maternal diabetes is associated with an increased risk of autism spectrum disorders (ASDs), although the detailed mechanisms remain unclear. The present study aims to investigate the potential effect of maternal diabetes on autism-like behavior in offspring. The results of in vitro study showed that transient hyperglycemia induces persistent reactive oxygen species (ROS) generation with suppressed superoxide dismutase 2 (SOD2) expression. Additionally, we found that SOD2 suppression is due to oxidative stress-mediated histone methylation and the subsequent dissociation of early growth response 1 (Egr1) on the SOD2 promoter. Furthermore, in vivo rat experiments showed that maternal diabetes induces SOD2 suppression in the amygdala, resulting in autism-like behavior in offspring. SOD2 overexpression restores, while SOD2 knockdown mimics, this effect, indicating that oxidative stress and SOD2 expression play important roles in maternal diabetes-induced autism-like behavior in offspring, while prenatal and postnatal treatment using antioxidants permeable to the blood-brain barrier partly ameliorated this effect. We conclude that maternal diabetes induces autism-like behavior through hyperglycemia-mediated persistent oxidative stress and SOD2 suppression. Here we report a potential mechanism for maternal diabetes-induced ASD.

Platelet Distribution Width: A Significant Predictor of Poor Outcome After Mechanical Thrombectomy.

OBJECTIVES: Elevated platelet distribution width (PDW) is a recognized marker of platelet activity. Herein, we investigated the association between admission PDW values and clinical outcome at 3 months in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy (MT). MATERIALS AND METHODS: We retrospectively collected consecutive patients diagnosed with AIS following MT from two stroke centers. PDW was measured on admission. Subjects were divided into two groups according to the clinical outcome using the modified Rankin Scale at 3 months. Multiple regression analyses and receiver operating characteristic (ROC) curves were performed to determine the associations between admission PDW values, clinical parameters, and functional outcome. RESULTS: A total of 162 subjects were enrolled. Patients in the poor outcome group had a significantly higher percentage of PDW >16.0 fL compared with the good outcome group (57.3% vs. 26.9%, P < 0.001). After adjusting for a range of confounding factors, multiple regression analysis showed that PDW >16.0 fL was an independent predictor of poor outcome at 3 months (odds ratio 4.572, 95% confidence interval 1.896-11.026, P = 0.001). ROC curve analysis revealed that PDW >16.0 fL predicted poor outcome with 57.3% sensitivity and 73.1% specificity (the area under the ROC curve 0.637, 95% confidence interval 0.558-0.711, P = 0.004). CONCLUSIONS: Elevated PDW is an independent predictor of poor functional outcome in patients with anterior circulation AIS undergoing MT at 3 months.