The Bifunctional Effects of Lactoferrin (LFcinB11) in Inhibiting Neural Cell Adhesive Molecule (NCAM) Polysialylation and the Release of Neutrophil Extracellular Traps (NETs).

The expression of polysialic acid (polySia) on the neuronal cell adhesion molecule (NCAM) is called NCAM-polysialylation, which is strongly related to the migration and invasion of tumor cells and aggressive clinical status. Thus, it is important to select a proper drug to block tumor cell migration during clinical treatment. In this study, we proposed that lactoferrin (LFcinB11) may be a better candidate for inhibiting NCAM polysialylation when compared with CMP and low-molecular-weight heparin (LMWH), which were determined based on our NMR studies. Furthermore, neutrophil extracellular traps (NETs) represent the most dramatic stage in the cell death process, and the release of NETs is related to the pathogenesis of autoimmune and inflammatory disorders, with proposed involvement in glomerulonephritis, chronic lung disease, sepsis, and vascular disorders. In this study, the molecular mechanisms involved in the inhibition of NET release using LFcinB11 as an inhibitor were also determined. Based on these results, LFcinB11 is proposed as being a bifunctional inhibitor for inhibiting both NCAM polysialylation and the release of NETs.

The case of young people who use e-cigarettes infrequently: Who is this population? What becomes of them?

BACKGROUND: Emerging data indicate that many adolescents and young adults ("youth") engage in infrequent, or occasional, e-cigarette use. However, little is known about this population as they are often subsumed into the broader "any past-30-day use" category used to define youth "current use." This study aimed to focus on infrequent e-cigarette use by youth, examining its correlates and transitional outcomes. METHODS: Participants were from a prospective cohort study of youth (aged 15-24 at baseline). Among youth who had used e-cigarettes, we classified "infrequent use" as using e-cigarettes ≤5 days in the last 30 days (n=273) and "frequent use" as using e-cigarettes ≥6 days in the last 30 days (n=278). Descriptive statistics, Markov modeling, and logistic regression were utilized. RESULTS: By the 12-month follow-up, 76.8% of those using infrequently at baseline remained in the "infrequent use" category, 6.3% reported no recent use, and 16.8% had escalated to the "frequent use" category. Among the youth using infrequently at baseline, those who did (vs. did not) escalate to frequent use by follow-up had higher baseline nicotine dependence and were more likely to have family members who used tobacco. CONCLUSIONS: Infrequent e-cigarette use is extremely common, and often fairly stable, among young people. Prevention efforts must certainly attempt to reduce escalation and attend to both individual and interpersonal factors (e.g., nicotine dependence, family use). Yet prevention efforts must additionally attend to the case of continued infrequent use, given the high prevalence of people in this category and their regular exposure to e-cigarette harms.

Nicotine information disclosed online by e-cigarette brands popular with young people.

INTRODUCTION: E-cigarette use is most prevalent among adolescents and young adults - and there are often misperceptions about product risk. The purpose of this study was to determine what nicotine information is provided on e-cigarette brand websites. METHODS: Based on national and local surveys, we identified 44 e-cigarette brands commonly used in the US by adolescents and young adults. For each of these brands, their associated websites were analyzed for disclosed nicotine information. Specifically, for each brand's website, we coded whether there was information on nicotine concentration (recorded if a numerical value was provided such as '5% nicotine'), nicotine form (free-base, nicotine salts, or not stated), and nicotine type (tobacco-derived, synthetically derived, or not stated). Coding allowed for both lay (e.g. 'nic salts') as well as scientific (e.g. 'isomers') terms. RESULTS: Of the 44 brands examined, all provided basic information on nicotine concentration (e.g. '5% nicotine'). However, 23% of brands did not disclose information on nicotine form (i.e. nicotine salt vs free-base), and 66% of brands did not disclose information on nicotine type (i.e. synthetic vs tobacco-derived). CONCLUSIONS: Overall, these results suggest that the e-cigarette industry is not fully informing its consumers about the nicotine in their products. Given that nicotine form and type have implications for e-cigarette addiction potential, these findings highlight a public health concern. There is a need for more comprehensive national regulations for mandating product constituents and emissions disclosures.

Efficacy and safety of Yiqi Peiyuan granules for improving the short-term prognosis of patients with acute kidney injury: A multicenter, double-blind, placebo-controlled, randomized trial.

BACKGROUND: Yiqi Peiyuan (YQPY) prescription, a composite prescription of traditional Chinese medicine, has been used to prevent or delay the continued deterioration of renal function after acute kidney injury (AKI) in some institutions and has shown considerable efficacy. OBJECTIVE: This is the first randomized controlled trial to assess efficacy and safety of YQPY for improving short-term prognosis in adult patients with AKI. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a prospective, double-blind, multicenter, randomized, and placebo-controlled clinical trial. A total of 144 enrolled participants were randomly allocated to two groups according to a randomization schedule. Participants, caregivers and investigators assessing the outcomes were blinded to group assignment. Patients in the YQPY group received 36 g YQPY granules twice a day for 28 days. Patients in the placebo group received a placebo in the same dose as the YQPY granules. MAIN OUTCOME MEASURES: The primary outcome was the change in the estimated glomerular filtration rate (eGFR) between baseline and after 4 and 24 weeks of treatment. The secondary outcomes were the change of serum creatinine (Scr) level between baseline and after treatment, and the incidence of endpoint events, defined as eGFR increasing by more than 25% above baseline, eGFR >75 mL/min per 1.73 m2 or the composite endpoint, which was defined as the sum of patients meeting either of the above criteria. RESULTS: Data from a total of 114 patients (59 in the YQPY group and 55 in the control group) were analyzed. The mean changes in eGFR and Scr in weeks 4 and 24 had no difference between the two groups. In further subgroup analysis (22 in the YQPY group and 31 in the control group), the mean change in eGFR after treatment for 4 weeks was 27.39 mL/min per 1.73 m2 in the YQPY group and 5.78 mL/min per 1.73 m2 in the placebo group, and the mean difference between groups was 21.61 mL/min per 1.73 m2 (P <0.001). Thirteen (59.1%) patients in the YQPY group and 5 (16.1%) in the placebo group reached the composite endpoints (P = 0.002). During the intervention, 2 and 4 severe adverse events were reported in the YQPY and placebo groups, respectively. CONCLUSION: The YQPY granules can effectively improve the renal function of patients 4 weeks after the onset of AKI, indicating that it has good efficacy for improving short-term renal outcomes in patients with AKI. The YQPY granules may be a promising therapy for adults with AKI. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100051723. Please cite this article as: Wu JJ, Zhang TY, Qi YH, Zhu MY, Fang Y, Qi CJ, et al. Efficacy and safety of Yiqi Peiyuan granules for improving the short-term prognosis of patients with acute kidney injury: a multicenter, double-blind, placebo-controlled, randomized trial. J Integr Med. 2024; Epub ahead of print.

CPT1A mediates the succinylation of SP5 which activates transcription of PDPK1 to promote the viability and glycolysis of prostate cancer cells.

Succinylation modification involves in the progression of human cancers. The present study aimed to investigate the role of CPT1A, which is a succinyltransferase in the progression of prostate cancer (PCa). CCK-8 was used to detect the cell viability. Seahorse was performed to evaluate the cell glycolysis. Luciferase assay was used to detect the transcriptional regulation. ChIP was performed to assess the binding between transcriptional factors with the promoters. Co-IP was used to assess the binding between proteins. We found that CPT1A was highly expressed in PCa tissues and cell lines. Silencing of CPT1A inhibited the viability and glycolysis of PCa cells. Mechanistically, CPT1A promoted the succinylation of SP5, which strengthened the binding between SP5 and the promoter of PDPK1. SP5 activated PDPK1 transcription and PDPK1 activated the AKT/mTOR signal pathway. These findings might provide novel targets for the diagnosis or therapy of prostate cancer.

Optimal insertion site for ultrasound-guided radial artery catheterization utilizing the dynamic needle tip positioning technique: A prospective randomized controlled study.

BACKGROUND: The dynamic needle tip positioning technique represents an advanced version of the short-axis out-of-plane ultrasound-guided approach employed for radial artery catheterization. The study aimed to explore the most effective insertion site capable of expeditiously and accurately executing the procedure in a clinical setting. METHODS: A prospective randomized controlled study encompassed 246 elective surgery patients necessitating invasive arterial monitoring. Participants were randomly assigned to three distinct groups: Site 1 (targeting the radial styloid process), Site 2 (midway between Sites 1 and 3), and Site 3 (distal one-third of the forearm). The dynamic needle tip positioning technique was implemented across all groups. Crucial parameters, such as first-attempt success rate, time to success, overall success rate, total catheterization time, number of attempts, and complications, were meticulously documented and compared. RESULTS: The Site 2 cohort presented a significantly heightened first-attempt success rate compared to Site 1 (97.5% vs 80%, p = 0.003) and Site 3 (97.5% vs 81.25%, p = 0.006). Moreover, Site 2 displayed a reduced time to success in contrast to Site 1 (31.5 vs 38, p = 0.003) and Site 3 (31.5 vs 40, p = 0.006). Total catheterization time was significantly shorter in Site 2 compared to Site 1 (32 vs 42.5, p < 0.001) and Site 3 (32 vs 43.5, p < 0.001). Site 2 necessitated fewer attempts than Site 1 (p = 0.02) and Site 3 (p = 0.03). Male gender and puncture at Site 2 were associated with expedited time to success. Adverse events manifested more frequently in the Site 3 group compared to the Site 1 group (15% vs 3.75%, p = 0.03) and the Site 2 group (15% vs 2.5%, p = 0.01). CONCLUSIONS: The optimal insertion site for ultrasound-guided radial artery catheterization utilizing the dynamic needle tip positioning technique in adult patients is situated midway between the radial styloid process and the distal one-third of the forearm.

An Enzyme-responsive Porphyrin Metal-organic Framework Nanosystem for Targeted and Enhanced Synergistic Cancer Photo-chemo Therapy.

BACKGROUND: The clinical efficiency of photodynamic therapy (PDT) in combination with chemotherapy has proven to be a promising strategy for tumor treatment, yet is restricted by the high glutathione (GSH) concentration at the tumor site and nonspecific drug targeting. OBJECTIVE: The goal of the current research was to create a biocompatible GSH-depleting and tumor- targeting nanoparticle (denoted as DOX/CA@PCN-224@HA) for the combined photodynamic and chemo photo-chemo) therapy. METHODS: The nanoparticles were characterized by transmission electron microscopy (TEM). A UV-vis spectrophotometer was used to measure the drug loading efficiency (DE) and encapsulation efficiency (EE). The GSH-depleting ability was measured using Ellman's test. Confocal laser scan microscopy (CLSM) was used to assess the cellular uptake. MTT was adopted to evaluate the cytotoxicity of DOX/CA@PCN-224@HA against 4T1 cells. RESULTS: The altered PCN-224 showed excellent monodispersing with a dimension of approximately 193 nm ± 2 nm in length and 79 nm ± 3 nm in width. The larger and spindle grid-like structure of PCN-224 obtains better dual-drug loading ability (DOX: 20.58% ± 2.60%, CA: 21.81% ± 1.98%) compared with other spherical PCN-224 nanoparticles. The ultimate cumulative drug release rates with hyaluronidase (HAase) were 74% ± 1% (DOX) and 45% ± 2% (CA) after 72 h. DOX/CA@PCN-224@HA showed GSH-consuming capability, which could improve the PDT effect. The drug-loaded nanoparticles could accurately target 4T1 cells through biological evaluations. Moreover, the released DOX and CA display cooperative effects on 4T1 cells in vitro. DOX/CA@PCN-224@HA nanoparticles showed inhibition against 4T1 cells with an IC50 value of 2.71 µg mL-1. CONCLUSION: This nanosystem displays great potential for tumor-targeted enhanced (photo-chemo) therapy.

Demographic and Behavioral Differences Between Adolescents and Young Adults Who Use E-Cigarettes at Low and High Frequency.

BACKGROUND: Among adolescents and young adults (AYAs), "current use" of electronic cigarettes (e-cigarettes) is commonly defined as any use in the past 30 days. However, few studies have examined differences among those within this broad category. This study examined characteristics of AYAs who used e-cigarettes at a low frequency (within the last 3 months but <6 days out of the past 30 days) and those who used e-cigarettes at a high frequency (6+ days out of the past 30 days). METHODS: We conducted cross-sectional analyses among 551 Ohio AYAs (15- to 24-year-olds) who reported using an e-cigarette to vape nicotine in the past 3 months. We used descriptive statistics and logistic regression to characterize those using e-cigarettes at a low frequency and a high frequency. RESULTS: Among our sample of AYAs who reported past 3-month e-cigarette use, about half (50.8%) reported using an e-cigarette 6 or more days out of the past 30 days (ie, high frequency). In the multivariable analysis, reported nicotine dependence (Odds Ratio [OR]: 7.0, 95% CI: 4.8, 10.3) and current other tobacco product use (OR: 1.8, 95% CI: 1.1, 2.9) were associated with high-frequency e-cigarette use. CONCLUSION: Our results suggest that frequency of use is an important characteristic in understanding AYA e-cigarette use. Any use in the past 30 days may not be sensitive enough to understand dependence and tobacco-use behaviors. Further characterizing "current" e-cigarette use by frequency of use may provide meaningful information for public health professionals to better target intervention and cessation efforts to AYAs.

GLORI for absolute quantification of transcriptome-wide m6A at single-base resolution.

N6-methyladenosine (m6A) is the most abundant posttranscriptional chemical modification in mRNA, involved in regulating various physiological and pathological processes throughout mRNA metabolism. Recently, we developed GLORI, a sequencing method that enables the production of a globally absolute-quantitative m6A map at single-base resolution. Our technique utilizes the glyoxal- and nitrite-based chemical reaction, which selectively deaminates unmethylated adenosines while leaving m6A intact. The RNA library can then be prepared using a modified library construction protocol from enhanced UV crosslinking and immunoprecipitation (eCLIP) or commercial kits. Here we provide a detailed protocol for proper RNA sample handling and provide further guidelines for the use of a tailored bioinformatics pipeline (GLORI-tools) for subsequent data analysis. Compared with current methods, this new method is both exceptionally sensitive and robust, capable of identifying ~80,000 m6A sites with 50 Gb sequencing data in mammalian cells. It also provides a quantitative readout for m6A sites at single-base resolution. We hope the technique will provide a precise and unbiased tool for investigating m6A biology across various fields. Basic expertise in molecular biology and knowledge of bioinformatics are required for the protocol. The entire procedure can be completed within a week, with the library construction process taking ~4 d.

The Association Between the License Fee Increase and the Density of Tobacco Retailers in California-A Segmented Interrupted Time-Series Analysis by Income and Race/Ethnicity.

INTRODUCTION: On May 9, 2016, the State of California passed a law to increase the licensing fee for tobacco retailers from a one-time-only fee of $100 to an annual fee of $265, effective on June 9, 2016. This study investigates the association between this fee increase and retailer densities by neighborhood income and race/ethnicity characteristics. METHODS: We obtained quarterly data on the number of active tobacco retailer licenses from 2011 to 2020 in every zip code in California from the California Department of Tax and Fee Administration. These data were then linked to zip code-level income, race/ethnicity, and population measures. We used a single-group segmented interrupted time-series analysis to assess the association between the increase in licensing fees and retailer densities by neighborhood income and race/ethnicity. RESULTS: After the implementation of the annual licensing fees, the retailer density decreased both immediately and gradually. Specifically, the retailer density dropped by 0.47 in the first quarter following the intervention. Compared to the pre-intervention time trend, the retailer density decreased quarterly by 0.05. Furthermore, the impacts of increasing licensing fees were more pronounced in low-income and the majority Black zip codes. CONCLUSIONS: Given that higher smoking prevalence is associated with greater tobacco outlet density, the licensing fee increase could be an effective policy tool to reduce tobacco use among economically disadvantaged and minority Black communities, thereby addressing tobacco-use disparities. IMPLICATIONS: This study used the single-group segmented interrupted time-series analysis to assess the association between the licensing fee increase and tobacco retailer densities by neighborhood income and race/ethnicity. We found that this licensing fee increase was associated with reduced retailer densities and the total number of active retailers right after the implementation. We further found that the annual licensing fee policy had a continuous effect in reducing tobacco retailer densities in all zip codes. The impacts of increasing licensing fees were more pronounced in low-income and majority of Black zip codes.

Systematics of deep-sea starfish order Brisingida (Echinodermata: Asteroidea), with a revised classification and assessments of morphological characters.

Brisingida Fisher 1928 is one of the seven currently recognised starfish orders, and one of the least known taxa as being exclusive deep-sea inhabitants. Modern deep-sea expeditions revealed their common occurrences in various deep-sea settings including seamounts, basins and hydrothermal vent peripheral, underlining the necessity of clarifying their global diversity and phylogeny. In this study, we present a comprehensive molecular phylogeny of Brisingida which encompasses the highest taxonomic diversity to date. DNA sequences (COI, 16S, 12S and 28S) were obtained from 225 specimens collected in the global ocean, identified as 58 species spanning 15 of the 17 extant genera. Phylogenetic relationship was inferred using both maximum likelihood and Bayesian inference methods, revealing polyphyletic families and genera and indicating nonnegligible bias in prior morphology-based systematics. Based on the new phylogeny, a novel classification of the order, consisting of 5 families and 17 genera, is proposed. Families Odinellidae, Brisingasteridae and Novodiniidae (sensu Clark and Mah, 2001) were resurrected to encompass the genera Odinella, Brisingaster and Novodinia. Brisingidae and Freyellidae were revised to include 11 and 3 genera, respectively. A new genus and species, two new subgenera and seven new combinations are described and a key to each genus and family is provided. Transformations of morphological traits were evaluated under the present phylogenetic hypothesis. A series of paedomorphic characters were found in many genera and species, which led to a high degree of homoplasy across phylogenetically distant groups. Our results provide new insights in the phylogeny and ontogeny of the order, and highlight the necessity to evaluate character convergence under sound phylogenetic hypothesis.

Construction of an acute myeloid leukemia prognostic model based on m6A-related efferocytosis-related genes.

Background: One of the most prevalent hematological system cancers is acute myeloid leukemia (AML). Efferocytosis-related genes (ERGs) and N6-methyladenosine (m6A) have an important significance in the progression of cancer, and the metastasis of tumors. Methods: The AML-related data were collected from The Cancer Genome Atlas (TCGA; TCGA-AML) database and Gene Expression Omnibus (GEO; GSE9476, GSE71014, and GSE13159) database. The "limma" R package and Venn diagram were adopted to identify differentially expressed ERGs (DE-ERGs). The m6A related-DE-ERGs were obtained by Spearman analysis. Subsequently, univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) were used to construct an m6A related-ERGs risk signature for AML patients. The possibility of immunotherapy for AML was explored. The pRRophetic package was adopted to calculate the IC50 of drugs for the treatment of AML. Finally, the expression of characterized genes was validated by quantitative reverse transcription-PCR (qRT-PCR). Results: Based on m6A related-DE-ERGs, a prognostic model with four characteristic genes (UCP2, DOCK1, SLC14A1, and SLC25A1) was constructed. The risk score of model was significantly associated with the immune microenvironment of AML, with four immune cell types, 14 immune checkpoints, 20 HLA family genes and, immunophenoscore (IPS) all showing differences between the high- and low-risk groups. A total of 56 drugs were predicted to differ between the two groups, of which Erlotinib, Dasatinib, BI.2536, and bortezomib have been reported to be associated with AML treatment. The qRT-PCR results showed that the expression trends of DOCK1, SLC14A1 and SLC25A1 were consistent with the bioinformatics analysis. Conclusion: In summary, 4 m6A related- ERGs were identified and the corresponding prognostic model was constructed for AML patients. This prognostic model effectively stratified the risk of AML patients.

Glutathione promotes the synergistic effects of venetoclax and azacytidine against myelodysplastic syndrome­refractory anemia by regulating the cell cycle.

Azacitidine is a DNA methyltransferase inhibitor that has been used as a singular agent for the treatment of myelodysplastic syndrome-refractory anemia with excess blast-1 and -2 (MDS-RAEB I/II). However, recurrence and overall response rates following this treatment remain unsatisfactory. The combination of azacitidine and venetoclax has been used for the clinical treatment of a variety of hematological diseases due to the synergistic killing effect of the two drugs. Venetoclax is a BCL-2 inhibitor that can inhibit mitochondrial metabolism. In addition, azacitidine has been shown to reduce the levels of myeloid cell leukemia 1 (MCL-1) in acute myeloid leukemia cells. MCL-1 is an anti-apoptotic protein and a potential source of resistance to venetoclax. However, the mechanism underlying the effects of combined venetoclax and azacitidine treatment remains to be fully elucidated. In the present study, the molecular mechanism underlying the impact of venetoclax on the efficacy of azacitidine was investigated by examining its effects on cell cycle progression. SKM-1 cell lines were treated in vitro with 0-2 µM venetoclax and 0-4 µM azacytidine. After 24, 48 and 72 h of treatment, the impact of the drugs on the cell cycle was assessed by flow cytometry. Following drug treatment, changes in cellular glutamine metabolism pathways was analyzed using western blotting (ATF4, CHOP, ASCT2, IDH2 and RB), quantitative PCR (ASCT2 and IDH2), liquid chromatography-mass spectrometry (α-KG, succinate and glutathione) and ELISA (glutamine and glutaminase). Venetoclax was found to inhibit mitochondrial activity though the alanine-serine-cysteine transporter 2 (ASCT2) pathway, which decreased glutamine uptake. Furthermore, venetoclax partially antagonized the action of azacitidine through this ASCT2 pathway, which was reversed by glutathione (GSH) treatment. These results suggest that GSH treatment can potentiate the synergistic therapeutic effects of venetoclax and azacitidine combined treatment on a myelodysplastic syndrome-refractory anemia cell line at lower concentrations.

What do young people know about the nicotine in their e-cigarettes?

INTRODUCTION: In recent years, the nicotine in e-cigarettes has been available in either a 'free-base' (unprotonated) or 'nicotine salt' (protonated) form. Additionally, e-cigarette nicotine can be either 'synthetic' or 'tobacco-derived'. These dimensions of nicotine have implications for nicotine absorption, bioavailability and sensory experiences. However, it is unclear if the young people using e-cigarettes are aware of these nicotine dimensions. METHODS: Data came from a cohort of Ohio youth (aged 15-24) who reported using an e-cigarette in the past 4 months (N=271). Participants were enrolled and provided background information in 2021; their 12-month follow-up survey asked about the presence, form and type of nicotine in their usual e-cigarette. Individuals who reported that they could distinguish between tobacco-derived and synthetic nicotine were additionally asked to describe the difference. RESULTS: Of the 247 youth who reported that there was nicotine in their usual e-cigarette, 71.7% did not know whether it was free-base or nicotine salt and 75.7% did not know whether it was synthetic or tobacco-derived. Awareness was higher among youth who were using e-cigarettes at a greater frequency and quantity. The majority reported that they could not detect a difference between the experience of using synthetic vs tobacco-derived nicotine. CONCLUSIONS: These findings indicate the generally limited awareness about nicotine among youth who used e-cigarettes. Improvements in health communications and requirements for e-cigarette industry disclosures are necessary to ensure that consumers are better informed about the dimensions-and the risks-of the nicotine they are consuming.

Reconstruction of Nasal Tip Using "Seagull-shaped" Cavum Concha Cartilage Composite Scaffold.

BACKGROUND: The nasal tip plays a crucial role both esthetically and functionally. The application of nasal tip grafts is an effective method for improving nasal tip form. Ear cartilage is a common choice for nasal tip grafts, but it still presents several challenges in clinical application that need to be addressed. This study aims to address the issues associated with the use of ear cartilage in clinical rhinoplasty applications through the development of a novel septal extension graft using ear cartilage for nasal tip reconstruction. METHODS: From May 2018 to April 2022, a total of 132 cases of nasal tip reconstruction surgeries were performed using a seagull-shaped nasal septum extension graft, constructed with bilateral cavum concha cartilage. Among these cases, 25 patients had previously undergone rhinoplasty using silicone implant, 7 patients had undergone augmentation rhinoplasty using expanded polytetrafluoroethylene, whereas the rest were primary rhinoplasty cases. All patients were followed up for a period ranging from 3 months to 4 years postoperatively, with photographs taken to assess the nasal tip morphology. RESULTS: In this study, all patients exhibited good healing of the incisions made at the posterior aspect of the auricular concha, with no occurrences of hematoma and inconspicuous scarring. In 116 cases, significant improvement in nasal appearance and a realistic nasal tip form were achieved postoperatively, yielding satisfactory outcomes. Only 16 patients experienced minor issues with nasal tip morphology, which were subsequently improved through further surgical procedures. CONCLUSION: This study reports a surgical technique for nasal tip refinement using bilaterally harvested cavum concha cartilage to construct a seagull-shaped nasal septal extension graft. The procedure has achieved satisfactory outcomes, and its application is worth extending to clinical practice.

Cascade strategy for glucose oxidase-based synergistic cancer therapy using nanomaterials.

Nanomaterial-based cancer therapy faces significant limitations due to the complex nature of the tumor microenvironment (TME). Starvation therapy is an emerging therapeutic approach that targets tumor cell metabolism using glucose oxidase (GOx). Importantly, it can provide a material or environmental foundation for other diverse therapeutic methods by manipulating the properties of the TME, such as acidity, hydrogen peroxide (H2O2) levels, and hypoxia degree. In recent years, this cascade strategy has been extensively applied in nanoplatforms for ongoing synergetic therapy and still holds undeniable potential. However, only a few review articles comprehensively elucidate the rational designs of nanoplatforms for synergetic therapeutic regimens revolving around the conception of the cascade strategy. Therefore, this review focuses on innovative cascade strategies for GOx-based synergetic therapy from representative paradigms to state-of-the-art reports to provide an instructive, comprehensive, and insightful reference for readers. Thereafter, we discuss the remaining challenges and offer a critical perspective on the further advancement of GOx-facilitated cancer treatment toward clinical translation.

Identification of dual STRN-NTRK2 rearrangements in a high grade sarcoma, with good clinical response to first-line larotrectinib therapy.

BACKGROUND: Among the three NTRK genes, NTRK2 possesses a tremendous structural complexity and involves tumorigenesis of several types of tumors. To date, only STRN and RBPMS are identified in the fusion with NTRK2 in adult soft tissue tumors. More recently, the highly selective Trk tyrosine kinases inhibitors, including larotrectinib and entrectinib, have shown significant efficacy for treating tumors harboring NTRK fusions and were approved by FDA. CASE PRESENTATION: We report a case of sarcoma in a 35-year-old female harboring two STRN-NTRK2 gene fusions, with a good clinical response to first-line larotrectinib treatment. Core biopsy of the 16.5 cm gluteal mass showed a high-grade mesenchymal neoplasm with features reminiscent of a solitary fibrous tumor, but negative for STAT6. In-house next-generation sequencing gene fusion panel showed two in-frame STRN-NTRK2 fusions, which contain the same 5' partner sequence (exon 1-3) of STRN, and the 3' fusion partner starting from either the exon 15 or the exon 16 of NTRK2. Due to the large size and location of the tumor, first-line neoadjuvant therapy with larotrectinib was initiated. The patient has an excellent clinical response with an 83% tumor size reduction by imaging. The tumor was subsequently completely resected. After 130 days, larotrectinib was reinitiated for lung metastasis (up to 7 cm), and a complete resolution was achieved. When compared with NTRK1 and NTRK3, NTRK2 fusions are the least common. Of note, the only other report in the literature on NRTK2 fusion-positive sarcoma also showed solitary fibrous tumor (SFT)-like morphology, and the patient responded well to larotrectinib as the second line adjuvant therapy. CONCLUSIONS: In conclusion, the identification of NTRK2 fusions in patients with soft tissue tumors could significantly improve the clinical outcome through selective NTRK inhibitor therapy, especially in the first-line setting. Prompt RNA-based NGS testing at initial diagnosis may benefit these patients. Our case is among the first few in the literature on NTRK2 fusion sarcoma with first-line larotrectinib therapy in the primary and metastatic setting, with good clinical response and minimal side effects.

The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC.

PURPOSE: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617. EXPERIMENTAL DESIGN: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression models were used. All statistical tests were two sided, and a P value <0.05 was considered significant. RESULTS: A total of 17.1% (56/328) of patients had the KRAS-variant, and overall survival rates were similar between KRAS-variant and non-variant patients. However, there was a time-dependent effect of cetuximab seen only in KRAS-variant patients-while the hazard of death was higher in cetuximab-treated patients within year 1 [HR = 3.37, 95% confidence interval (CI): 1.13-10.10, P = 0.030], death was lower from year 1 to 4 (HR = 0.33, 95% CI: 0.11-0.97, P = 0.043). In contrast, in non-variant patients, the addition of cetuximab significantly increased local failure (HR = 1.59, 95% CI: 1.11-2.28, P = 0.012). CONCLUSIONS/DISCUSSION: Although an overall survival advantage was not achieved in KRAS-variant patients, there is potential impact of cetuximab for this genetic subset of patients. In contrast, cetuximab seems to harm non-variant patients. These findings further support the importance of genetic patient selection in trials studying the addition of systemic agents to radiotherapy. SIGNIFICANCE: The KRAS-variant is the first functional, inherited miRNA-disrupting variant identified in cancer. Our findings support that cetuximab has a potentially beneficial impact on KRAS-variant patients treated with radiation. The work confirms prior evidence that KRAS-variant patients are a subgroup who are especially sensitive to radiation. These findings further support the potential of this class of variants to enable true treatment personalization, considering the equally important endpoints of response and toxicity.

A high-resolution cone beam computed tomography (HRCBCT) reconstruction framework for CBCT-guided online adaptive therapy.

BACKGROUND: Kilo-voltage cone-beam computed tomography (CBCT) is a prevalent modality used for adaptive radiotherapy (ART) due to its compatibility with linear accelerators and ability to provide online imaging. However, the widely-used Feldkamp-Davis-Kress (FDK) reconstruction algorithm has several limitations, including potential streak aliasing artifacts and elevated noise levels. Iterative reconstruction (IR) techniques, such as total variation (TV) minimization, dictionary-based methods, and prior information-based methods, have emerged as viable solutions to address these limitations and improve the quality and applicability of CBCT in ART. PURPOSE: One of the primary challenges in IR-based techniques is finding the right balance between minimizing image noise and preserving image resolution. To overcome this challenge, we have developed a new reconstruction technique called high-resolution CBCT (HRCBCT) that specifically focuses on improving image resolution while reducing noise levels. METHODS: The HRCBCT reconstruction technique builds upon the conventional IR approach, incorporating three components: the data fidelity term, the resolution preservation term, and the regularization term. The data fidelity term ensures alignment between reconstructed values and measured projection data, while the resolution preservation term exploits the high resolution of the initial Feldkamp-Davis-Kress (FDK) algorithm. The regularization term mitigates noise during the IR process. To enhance convergence and resolution at each iterative stage, we applied Iterative Filtered Backprojection (IFBP) to the data fidelity minimization process. RESULTS: We evaluated the performance of the proposed HRCBCT algorithm using data from two physical phantoms and one head and neck patient. The HRCBCT algorithm outperformed all four different algorithms; FDK, Iterative Filtered Back Projection (IFBP), Compressed Sensing based Iterative Reconstruction (CSIR), and Prior Image Constrained Compressed Sensing (PICCS) methods in terms of resolution and noise reduction for all data sets. Line profiles across three line pairs of resolution revealed that the HRCBCT algorithm delivered the highest distinguishable line pairs compared to the other algorithms. Similarly, the Modulation Transfer Function (MTF) measurements, obtained from the tungsten wire insert on the CatPhan 600 physical phantom, showed a significant improvement with HRCBCT over traditional algorithms. CONCLUSION: The proposed HRCBCT algorithm offers a promising solution for enhancing CBCT image quality in adaptive radiotherapy settings. By addressing the challenges inherent in traditional IR methods, the algorithm delivers high-definition CBCT images with improved resolution and reduced noise throughout each iterative step. Implementing the HR CBCT algorithm could significantly impact the accuracy of treatment planning during online adaptive therapy.

Severe bradycardia induced by postoperative nausea and vomiting: A case report.

INTRODUCTION: Postoperative nausea and vomiting is a common complication for patients after anesthesia and surgery, which may result in increased parasympathetic activity, such as diaphoresis, pallor, or bradycardia. However, few cases of fatal bradycardia induced by postoperative nausea and vomiting have been reported before. Clinicians generally attribute bradycardia to certain anesthetics, instead of postoperative nausea or vomiting. PATIENT CONCERNS: A fifty-year-old female with a history of well-controlled hypertension underwent elective radical mastectomy. When recovering from anesthesia in the post-anesthesia care unit, the patient experienced severe bradycardia accompanied by hypotension and unconsciousness, shortly after nausea and vomiting. INTERVENTIONS: The patient received cardiopulmonary resuscitation immediately. OUTCOMES: Five minutes later, She recovered sinus rhythm and her vital sings tended to be stable. Three hours later, blood tests showed the N-terminal pro-B-type natriuretic peptide 127 pg/mL and cardiac troponin I 0.44 ng/mL, which peaked to 2.65 ng/mL 10 hours after the emergency. Electrocardiography revealed sinus rhythm, ST-segment depression in the inferior and anterior lateral leads, QTc prolongation, and left ventricular high voltage. Her serum cTnI continued to decline to 0.27 ng/mL on the 3rd day after surgery. She was discharged from the hospital on the fifth day and had no sequelae. CONCLUSION: Although postoperative nausea and vomiting occurs frequently, it should be kept in mind as a potential cause to blame for severe bradycardia or even life-threatening situations.