Nickel foam-loaded Co-MOF@TiO2/MoS2 as electrode materials for dual-function devices for glucose detection and hydrogen evolution.

Dual-functional nanomaterial electrodes have the capability to satisfy the requirements for both sweat analysis and the hydrogen evolution reaction (HER), thereby enabling the integration of electrochemical sensing and hydrogen production. In this study, ZIF-67 cubes are synthesized on nickel foam (NF), while TiO2 is obtained through an annealing process. Subsequently, the ZIF-67@TiO2/MoS2 nanocomposite is fabricated on nickel foam via a hydrothermal method. This composite material exhibits exceptional photocatalytic properties and is also suitable for the detection of glucose in sweat. The glucose detection range spans from 10 nM to 10 mM with a sensitivity of 7.24 µA mM-1 cm-2 for a signal-to-noise ratio of 3 and a detection limit of 0.43 µM. Moreover, when utilized as a hydrogen evolution electrode, this material demonstrates a current density of 10 mA cm-2 at an overpotential of 118 mV, with a Tafel slope of 73 mV/dec. The synthesis process is both straightforward and economical. This research introduces a novel concept for the design of multifunctional chemical sensors.

Biliary atresia.

Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.

Open Versus Percutaneous Stabilization of Thoracolumbar Fractures: A Large Retrospective Analysis of Safety and Reoperation Rates.

BACKGROUND: Thoracolumbar fractures (TLF) requiring surgical intervention can be treated with either open or percutaneous stabilization, each with some distinct risks and benefits. There is insufficient evidence available to support one approach as superior. METHODS: Patients who underwent spinal fixation for TLF between 2008 and 2020 were reviewed. Patients with one or two levels of fracture treated with either open or percutaneous stabilization were included. Exclusion criteria were more than two levels of fracture, patients requiring corpectomy, stabilization constructs that crossed the cervicothoracic or lumbosacral junction, history of previous thoracolumbar fusion at the same level, spinal neoplasm, anterior or lateral fixation, and spinal infection. Demographic, operative, and clinical data were collected for all patients. RESULTS: 691 patients (377 open, 314 percutaneous) met the inclusion criteria. Patients in the percutaneous cohort sustained lower estimated blood loss (73 vs 334 ml; p< 0.001) and shorter length of surgery (114 vs. 151 minutes; p< 0.001). No differences were observed in the length of hospital stay or overall reoperation rates. Asymptomatic (7.0% vs 0.8%) and symptomatic (3.5% vs 0.5%) hardware removal was more common with the percutaneous cohort, while the incidence of revision surgery due to hardware failure requiring the extension of the construct (1.9% vs 5.8%) and infection (1.9% vs 6.4%) was greater in the open group. CONCLUSION: Percutaneous stabilization for TLF was associated with shorter operative time, less blood loss, lower infection rate, higher rates of elective hardware removal, and lower rates of hardware failure requiring extension of the construct compared to open stabilization.

Blue Light Compromises Bacterial ß-Lactamases Activity to Overcome ß-Lactam Resistance.

OBJECTIVE: In this study, we evaluated the effectiveness of antimicrobial blue light (aBL; 410 nm wavelength) against ß-lactamase-carrying bacteria and the effect of aBL on the activity of ß-lactamases. METHODS: Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae strains carrying ß-lactamases as well as a purified ß-lactamase enzymes were studied. ß-lactamase activity was assessed using a chromogenic cephalosporin hydrolysis assay. Additionally, we evaluated the role of porphyrins in the photoreaction, as well as protein degradation by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Finally, we investigated the bactericidal effect of combined aBL-ceftazidime exposure against a metallo-ß-lactamase expressing P. aeruginosa strain. RESULTS: Our study demonstrated that aBL effectively killed ß-lactamase-producing bacteria and reduced ß-lactamase activity. After an aBL exposure of 1.52 J/cm2, a 50% reduction in enzymatic activity was observed in P. aeruginosa. Additionally, we found a 40% decrease in the photoreaction activity of porphyrins following an aBL exposure of 64.8 J/cm2. We also revealed that aBL reduced ß-lactamase activity via protein degradation (after 136.4 J/cm2). Additionally, aBL markedly improved the bactericidal effect of ceftazidime (by >4-log10) in the metallo-ß-lactamase P. aeruginosa strain. CONCLUSION: Our results provide evidence that aBL compromises bacterial ß-lactamase activity, offering a potential approach to overcome ß-lactam resistance in bacteria.

Early Metabolomic and Immunologic Biomarkers as Prognostic Indicators for COVID-19.

This prospective study in Hong Kong aimed at identifying prognostic metabolomic and immunologic biomarkers for Coronavirus Disease 2019 (COVID-19). We examined 327 patients, mean age 55 (19-89) years, in whom 33.6% were infected with Omicron and 66.4% were infected with earlier variants. The effect size of disease severity on metabolome outweighed others including age, gender, peak C-reactive protein (CRP), vitamin D and peak viral levels. Sixty-five metabolites demonstrated strong associations and the majority (54, 83.1%) were downregulated in severe disease (z score: -3.30 to -8.61). Ten cytokines/chemokines demonstrated strong associations (p < 0.001), and all were upregulated in severe disease. Multiple pairs of metabolomic/immunologic biomarkers showed significant correlations. Fourteen metabolites had the area under the receiver operating characteristic curve (AUC) > 0.8, suggesting a high predictive value. Three metabolites carried high sensitivity for severe disease: triglycerides in medium high-density lipoprotein (MHDL) (sensitivity: 0.94), free cholesterol-to-total lipids ratio in very small very-low-density lipoprotein (VLDL) (0.93), cholesteryl esters-to-total lipids ratio in chylomicrons and extremely large VLDL (0.92);whereas metabolites with the highest specificity were creatinine (specificity: 0.94), phospholipids in large VLDL (0.94) and triglycerides-to-total lipids ratio in large VLDL (0.93). Five cytokines/chemokines, namely, interleukin (IL)-6, IL-18, IL-10, macrophage inflammatory protein (MIP)-1b and tumour necrosis factor (TNF)-a, had AUC > 0.8. In conclusion, we demonstrated a tight interaction and prognostic potential of metabolomic and immunologic biomarkers enabling an outcome-based patient stratification.

Guidelines for management of actual or suspected inadvertent intra-arterial injection of sclerosants.

BACKGROUND: Inadvertent intra-arterial injection of sclerosants is an uncommon adverse event of both ultrasound-guided and direct vision sclerotherapy. This complication can result in significant tissue or limb loss and significant long-term morbidity. OBJECTIVES: To provide recommendations for diagnosis and immediate management of an unintentional intra-arterial injection of sclerosing agents. METHODS: An international and multidisciplinary expert panel representing the endorsing societies and relevant specialities reviewed the published biomedical, scientific and legal literature and developed the consensus-based recommendations. RESULTS: Actual and suspected cases of an intra-arterial sclerosant injection should be immediately transferred to a facility with a vascular/interventional unit. Digital Subtraction Angiography (DSA) is the key investigation to confirm the diagnosis and help select the appropriate intra-arterial therapy for tissue ischaemia. Emergency endovascular intervention will be required to manage the risk of major limb ischaemia. This includes intra-arterial administration of vasodilators to reduce vasospasm, and anticoagulants and thrombolytic agents to mitigate thrombosis. Mechanical thrombectomy, other endovascular interventions and even open surgery may be required. Lumbar sympathetic block may be considered but has a high risk of bleeding. Systemic anti-inflammatory agents, anticoagulants, and platelet inhibitors and modifiers would complement the intra-arterial endovascular procedures. For risk of minor ischaemia, systemic oral anti-inflammatory agents, anticoagulants, vasodilators and antiplatelet treatments are recommended. CONCLUSION: Inadvertent intra-arterial injection is an adverse event of both ultrasound-guided and direct vision sclerotherapy. Medical practitioners performing sclerotherapy must ensure completion of a course of formal training (specialty or subspecialty training, or equivalent recognition) in the management of venous and lymphatic disorders (phlebology), and be personally proficient in the use of duplex ultrasound in vascular (both arterial and venous) applications, to diagnose and provide image guidance to venous procedure. Expertise in diagnosis and immediate management of an intra-arterial injection is essential for all practitioners performing sclerotherapy.

How Generalizable Are Findings from a Community-Based Prospective Cohort Study? Extending Estimates from the Adult Changes in Thought Study to Its Source Population.

Background: The Adult Changes in Thought (ACT) study is a cohort of Kaiser Permanente Washington members ages 65+ that began in 1994. Objective: We wanted to know how well ACT participants represented all older adults in the region, and how well ACT findings on eye disease and its relationship with Alzheimer's disease generalized to all older adults in the Seattle Metropolitan Region. Methods: We used participation weights derived from pooling ACT and Behavioral Risk Factor Surveillance System (BRFSS) data to estimate prevalences of common eye diseases and their associations with Alzheimer's disease incidence. Cox proportional hazards models accounted for age, education, smoking, sex, and APOE genotype. Confidence intervals for weighted analyses were bootstrapped to account for error in estimating the weights. Results: ACT participants were fairly similar to older adults in the region. The largest differences were more self-reported current cholesterol medication use in BRFSS and higher proportions with low education in ACT. Incorporating the weights had little impact on prevalence estimates for age-related macular degeneration or glaucoma. Weighted estimates were slightly higher for diabetic retinopathy (weighted 5.7% (95% Confidence Interval 4.3, 7.1); unweighted 4.1% (3.6, 4.6)) and cataract history (weighted 51.8% (49.6, 54.3); unweighted 48.6% (47.3, 49.9)). The weighted hazard ratio for recent diabetic retinopathy diagnosis and Alzheimer's disease was 1.84 (0.34, 4.29), versus 1.32 (0.87, 2.00) in unweighted ACT. Conclusions: Most, but not all, associations were similar after participation weighting. Even in community-based cohorts, extending inferences to broader populations may benefit from evaluation with participation weights.

Cerebrospinal venous obstruction and breast cancer: A pilot study.

METHODS: The venous drainage of the breasts is described and the cerebrospinal venous systems (CSVS) of six patients with treated breast cancer were assessed using duplex ultrasound to measure venous blood volume flows in the neck veins. RESULTS: All six patients with breast cancer showed evidence of cerebrospinal venous obstruction (CSVO). Further, all six demonstrated collateral flow in the erect position in the internal jugular vein on the same side as the diagnosed breast cancer. CONCLUSION: There is an indication for a well-designed case-control study using the duplex ultrasound neck vein examination, comparing patients treated for breast cancer with healthy women.

Outcomes of Human Leukocyte Antigen-Matched Related Donor and Haploidentical Allogeneic Hematopoietic Cell Transplantation Recipients by Immune Profiles of Recipients and Donors.

Haploidentical (Haplo) allogeneic HCTs (alloHCT) have been used more frequently over the last decade as survival is similar to HLA-matched related donor (MRD) alloHCTs. We aimed to identify donor and recipient immune signatures before alloHCT that are associated with clinically meaningful outcomes in MRD vs Haplo alloHCT recipients. This retrospective cohort study of 165 MRD (n = 132) and Haplo (n = 33) alloHCT recipients and their related donors between 2007-2019 with paired peripheral blood samples immunophenotyped for T-cell, B-cell, NK cell and dendritic cell (DC) subsets. Immune cells were quantified before alloHCT in donors and recipients; calculations of immune cell ratios were classified as high, intermediate, and low and analyzed with alloHCT outcomes. Haplo donors were younger than MRD donors (median: 35 vs 51 years), whereas Haplo recipients were older than MRD recipients (median: 68 vs 54 years), were more likely to have a Karnofsky Performance Score ≤ 70 (76% vs 57%), 3+ comorbidities (54% vs 47%), and were in complete remission prior to alloHCT (58% vs 42%). In MRD alloHCT, a lower ratio of CD4+ to CD8+ effector memory cells in the donor was associated with lower 4-yr overall survival (OS; 25% vs 61%; P = .009), lower 4-yr progression free survival (PFS; 25% vs 58%; P = .014) and higher incidence of 1-yr transplant-related mortality (TRM; 39% vs 7%; P = .009) in recipients. A higher ratio of CD8+ effector memory to total NK cells measured in MRD recipients was associated with a higher incidence of grade II-IV aGvHD (63% vs 37%; P = .004) but was not statistically significant for III-IV aGvHD (23% vs 12%). In Haplo alloHCT, a lower ratio of total T-regulatory to CD4+ central memory cells in the donor was associated with lower 4-yr PFS (22% vs 60%; P = .0091). A higher ratio of CD4+ effector memory to CD8+ effector memory cells measured in Haplo recipients pre-alloHCT was associated with lower 4-yr OS (25% vs 88%; P = .0039). In both MRD and Haplo recipients, a higher ratio of CD4+ naïve to CD4+ central memory cells was associated with a higher incidence of grade II-IV aGvHD (64% vs 38%; P = .04). Evaluation of pre-alloHCT immune signatures of the donor and recipient may influence clinically meaningful patient outcomes in both MRD and Haplo transplants.

Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis.

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. MATERIALS AND METHODS: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. RESULTS: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036). CONCLUSION: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.

Genome divergence and reproductive incompatibility among populations of Ganaspis near brasiliensis.

During the last decade, the spotted wing drosophila, Drosophila suzukii, has spread from eastern Asia to the Americas, Europe, and Africa. This fly attacks many species of cultivated and wild fruits with soft, thin skins, where its serrated ovipositor allows it to lay eggs in undamaged fruit. Parasitoids from the native range of D. suzukii may provide sustainable management of this polyphagous pest. Among these parasitoids, host-specificity testing has revealed a lineage of Ganaspis near brasiliensis, referred to in this paper as G1, that appears to be a cryptic species more host-specific to D. suzukii than other parasitoids. Differentiation among cryptic species is critical for introduction and subsequent evaluation of their impact on D. suzukii. Here, we present results on divergence in genomic sequences and architecture and reproductive isolation between lineages of Ganaspis near brasiliensis that appear to be cryptic species. We studied five populations, two from China, two from Japan, and one from Canada, identified as the G1 vs G3 lineages based on differences in cytochrome oxidase l sequences. We assembled and annotated the genomes of these populations and analyzed divergences in sequence and genome architecture between them. We also report results from crosses to test reproductive compatibility between the G3 lineage from China and the G1 lineage from Japan. The combined results on sequence divergence, differences in genome architectures, ortholog divergence, reproductive incompatibility, differences in host ranges and microhabitat preferences, and differences in morphology show that these lineages are different species. Thus, the decision to evaluate the lineages separately and only import and introduce the more host-specific lineage to North America and Europe was appropriate.

Minimal Residual Disease Status in Multiple Myeloma 1 Year After Autologous Hematopoietic Cell Transplantation and Lenalidomide Maintenance Are Associated With Long-Term Overall Survival.

PURPOSE: Prognostic Immunophenotyping in Myeloma Response (PRIMeR) is an ancillary study of minimal residual disease (MRD) assessment for multiple myeloma by next-generation multiparameter flow cytometry (MFC). Patients were enrolled on a three-arm randomized control trial (Blood and Marrow Transplants Clinical Trials Network 0702 Stem Cell Transplant for Myeloma in Combination of Novel Agents [STaMINA]; ClinicalTrials.gov identifier: NCT01109004). METHODS: Four hundred and thirty-five patients consented to the MRD panel, which included 10 monoclonal antibodies measured via six-color MFC. MRD was measured at baseline/preautologous hematopoietic cell transplant (BL/preAutoHCT), premaintenance (PM), and 1 year (Y1) after AutoHCT with a sensitivity of 10-5 to 10-6. The primary objective was to assess MRD-negative (MRDneg) at 1 year after AutoHCT and progression-free survival and overall survival (PFS/OS). RESULTS: Similar to the STaMINA results, at a median follow-up of 70 months, there was no significant difference in PFS/OS by treatment arm in the PRIMeR patients. MRDneg at all three time points was associated with significantly improved PFS, and MRDneg at Y1 had significantly longer OS. Multivariate analysis of PFS, adjusting for disease risk and treatment arm, demonstrated hazard ratios (HRs) in MRD-positive patients compared with MRDneg patients at BL, PM, and Y1 of 1.55 (P = .0074), 1.83 (P = .0007), and 3.61 (P < .0001), respectively. Corresponding HRs for OS were 1.19 (P = .48), 0.88 (P = .68), and 3.36 (P < .001). Patients with sustained MRDneg or who converted to MRDneg by Y1 had similar PFS/OS. CONCLUSION: To our knowledge, this first, prospective US cooperative group, multicenter study demonstrates that MRDneg at Y1 after AutoHCT with lenalidomide maintenance is prognostic for improved 6-year PFS and OS. Serial MRD measurements may direct trials to test how further therapy may improve long-term PFS and OS.

Comparison of transforaminal and posterior lumbar interbody fusion outcomes in patients receiving a novel allograft versus rhBMP-2: a radiographic and patient-reported outcomes analysis.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been demonstrated to achieve the highest rates of arthrodesis in multilevel lumbar fusion but is also associated with possible perioperative morbidity. A novel allograft (OSTEOAMP) is a differentiated allograft that retains growth factors supporting bone healing. The authors sought to compare the clinical and radiographic outcomes of rhBMP-2 and the novel allograft in lumbar interbody arthrodesis to determine if the latter may be a safer and equally effective alternative to rhBMP-2 for single- and multilevel posterior or transforaminal lumbar interbody fusion (PLIF or TLIF). METHODS: Patients who underwent single- or multilevel TLIF or PLIF using either OSTEOAMP or rhBMP-2 at the authors' institution over a 2-year period were prospectively followed for 12 months. Healthcare utilization, safety measures, patient satisfaction, physical disability (measured on the Oswestry Disability Index [ODI]), back and leg pain (on the numeric rating scale [NRS]), quality of life (on the EQ-5D scale), and return to work (RTW) were prospectively recorded. For purposes of this study, this consecutive series was retrospectively analyzed and pseudarthrosis rates were assessed at 2 years of follow-up. All patients (100%) had both 12-month patient-reported outcome follow-up and 24-month clinical and radiographic follow-up. RESULTS: One thousand one hundred fifty-four patients (654 treated with OSTEOAMP, 500 with rhBMP-2) were prospectively enrolled in the institutional registry. After propensity score matching, there were no significant baseline differences between 330 novel allograft and 330 rhBMP-2 cases. Perioperative morbidity and 90-day hospital readmission (3.3% vs 2.4%, p = 0.485) did not significantly differ between the novel allograft and the rhBMP-2 cases. At the 2-year follow-up, symptomatic pseudarthrosis requiring revision surgery occurred in 8 patients (2.4%) with OSTEOAMP and 6 patients (1.8%) with rhBMP-2 (p = 0.589). The overall fusion rate at 2 years was similar between groups (p = 0.213). Both groups showed significant and equivalent improvement in patient-reported outcome measures (PROMs) from baseline to 12-month follow-up, with no significant difference in 1-year mean NRS leg pain score (2.5 vs 2.7), ODI (25 vs 26), quality-adjusted life years (0.73 vs 0.73), satisfaction (83% vs 80%), or RTW (6.6 vs 7 weeks). CONCLUSIONS: In the authors' institutional experience, OSTEOAMP is a clinically viable substitute for rhBMP-2 for single- and multilevel lumbar fusion. This novel allograft provides clinically effective arthrodesis and improvements in PROMs comparable to rhBMP-2 with a similar safety profile. Additional indications and outcome assessment in longitudinal studies are needed to further characterize this allogeneic graft.

T Cell Exhaustion Markers in Multiple Myeloma Patients are Lower After Physical Activity Intervention.

PURPOSE: There is compelling evidence that CD4+ and CD8+T cells are dysfunctional in multiple myeloma, compromising their ability to control disease progression. Pre-clinical models suggest that exercise represents a non-pharmacologic means to reduce immune exhaustion, but no studies to date have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in multiple myeloma patients. PATIENTS AND METHODS: The current study includes 24 multiple myeloma patients who participated in a six-month physical activity intervention, consisting of supervised strength training (n = 12) and unsupervised home-based walking arms (n = 12). Comprehensive flow cytometry was utilized to assess the frequency of CD4+ and CD8+T cells and subpopulations expressing the markers of exhaustion PD-1, TIGIT, TIM3 and/or LAG3. Ratios of exhausted to non-exhausted cell populations, and percentages of exhausted to total populations of the same lineage, were calculated for the baseline and final timepoints. RESULTS: Eighteen of 20 exhaustion measures were lower at the end of the intervention than at baseline, and several were significantly or borderline significantly reduced in the entire sample or in one of the arms. The entire sample saw improvements in the ratios of CD4+ TIGIT+ to non-exhausted CD4+ (0.7 [0.6] to 0.6 [0.4], P = .04) and CD8+ PD1+ to non-exhausted CD8+ (1.8 [2.6] to 1.5 [2.0], P = .06), and in total exhausted CD8+ as a percent of total CD8+ (72.9 [21.9] to 68.3 [19.6], P < .01). CONCLUSIONS: This pilot study suggests that physical activity induces changes in MM patients' immune systems, potentially rendering a less exhausted T cell state.

Comparative analysis of the spatial distribution of brain metastases across several primary cancers using machine learning and deep learning models.

OBJECTIVE: Brain metastases (BM) are associated with poor prognosis and increased mortality rates, making them a significant clinical challenge. Studying BMs can aid in improving early detection and monitoring. Systematic comparisons of anatomical distributions of BM from different primary cancers, however, remain largely unavailable. METHODS: To test the hypothesis that anatomical BM distributions differ based on primary cancer type, we analyze the spatial coordinates of BMs for five different primary cancer types along principal component (PC) axes. The dataset includes 3949 intracranial metastases, labeled by primary cancer types and with six features. We employ PC coordinates to highlight the distinctions between various cancer types. We utilized different Machine Learning (ML) algorithms (RF, SVM, TabNet DL) models to establish the relationship between primary cancer diagnosis, spatial coordinates of BMs, age, and target volume. RESULTS: Our findings revealed that PC1 aligns most with the Y axis, followed by the Z axis, and has minimal correlation with the X axis. Based on PC1 versus PC2 plots, we identified notable differences in anatomical spreading patterns between Breast and Lung cancer, as well as Breast and Renal cancer. In contrast, Renal and Lung cancer, as well as Lung and Melanoma, showed similar patterns. Our ML and DL results demonstrated high accuracy in distinguishing BM distribution for different primary cancers, with the SVM algorithm achieving 97% accuracy using a polynomial kernel and TabNet achieving 96%. The RF algorithm ranked PC1 as the most important discriminating feature. CONCLUSIONS: In summary, our results support accurate multiclass ML classification regarding brain metastases distribution.

Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION.

BACKGROUND: Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4). We report outcomes in Asian patients from VISION (Cohort A + C) (cut-off: November 20, 2022). METHODS: Patients with advanced METex14 skipping NSCLC, detected by liquid or tissue biopsy, received tepotinib 500 mg (450 mg active moiety) once daily. PRIMARY ENDPOINT: objective response (RECIST 1.1) by independent review. Secondary endpoints included: DOR, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: Across treatment lines in 106 Asian patients (39.6% female, 43.4% smoking history, 79.2% adenocarcinoma, 47.2% treatment-naive), ORR was 56.6% (95% CI: 46.6, 66.2), mDOR 18.5 months (10.4, ne), mPFS 13.8 months (10.8, 22.0), and mOS 25.5 months (19.3, 36.4). Consistent efficacy observed, regardless of baseline characteristics. HRQoL remained stable during treatment. Treatment-related adverse events (TRAEs) occurred in 95.3% of patients (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%). CONCLUSIONS: Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC. CLINICAL TRIAL REGISTRATION: NCT02864992.

High-sensitivity dual U-shaped PCF-SPR refractive index sensor for the detection of gas and liquid analytes.

A dual U-shaped photonic crystal fiber (PCF) biochemical sensor based on surface plasmon resonance (SPR) is designed for the simultaneous detection of gas and liquid analytes, and the properties are analyzed by the full vector finite element method (FEM). SPR is excited by placing gold nanowires on the inner surface of the U-shaped device. In this technique, the traditional metal deposition process can be replaced, subsequently reducing the difficulty and complexity of actual production and improving the phase matching between the basic mode and plasmonic modes. To improve the detection properties, the structural parameters of the sensor including the air hole diameter, spacing, gold nanowire diameter, and polishing depth are optimized, and to better evaluate and analyze the sensing properties, the wavelength and amplitude modulation inquiry method is adopted. The results show that the maximum wavelength sensitivity (WS), amplitude sensitivity (AS), minimum resolution (R), and optimal FOM are 35,000 nm/RIU, 438.08R I U -1, 2.86×10-6 R I U, and 165.16R I U -1, respectively. In addition, the sensor can detect analyte RIs between 1.00 and 1.36 for gas and liquid analytes simultaneously. Owing to the simple structure, low cost, and ambient-condition monitoring, the sensor has large potential in a myriad of applications including sewage treatment, food safety, humoral regulation, environmental and biological monitoring, and medical diagnosis.

The effect of charge and albumin on cellular uptake of supramolecular polymer nanostructures.

Intracellular delivery of functional biomolecules by using supramolecular polymer nanostructures has gained significant interest. Here, various charged supramolecular ureido-pyrimidinone (UPy)-aggregates were designed and formulated via a simple "mix-and-match" method. The cellular internalization of these UPy-aggregates in the presence or absence of serum proteins by phagocytic and non-phagocytic cells, i.e., THP-1 derived macrophages and immortalized human kidney cells (HK-2 cells), was systematically investigated. In the presence of serum proteins the UPy-aggregates were taken up by both types of cells irrespective of the charge properties of the UPy-aggregates, and the UPy-aggregates co-localized with mitochondria of the cells. In the absence of serum proteins only cationic UPy-aggregates could be effectively internalized by THP-1 derived macrophages, and the internalized UPy-aggregates either co-localized with mitochondria or displayed as vesicular structures. While the cationic UPy-aggregates were hardly internalized by HK-2 cells and could only bind to the membrane of HK-2 cells. With adding and increasing the amount of serum albumin in the cell culture medium, the cationic UPy-aggregates were gradually taken up by HK-2 cells without anchoring on the cell membranes. It is proposed that the serum albumin regulates the cellular internalization of UPy-aggregates. These results provide fundamental insights for the fabrication of supramolecular polymer nanostructures for intracellular delivery of therapeutics.

Integrative analysis reveals associations between oral microbiota dysbiosis and host genetic and epigenetic aberrations in oral cavity squamous cell carcinoma.

Dysbiosis of the human oral microbiota has been reported to be associated with oral cavity squamous cell carcinoma (OSCC) while the host-microbiota interactions with respect to the potential impact of pathogenic bacteria on host genomic and epigenomic abnormalities remain poorly studied. In this study, the mucosal bacterial community, host genome-wide transcriptome and DNA CpG methylation were simultaneously profiled in tumors and their adjacent normal tissues of OSCC patients. Significant enrichment in the relative abundance of seven bacteria species (Fusobacterium nucleatum, Treponema medium, Peptostreptococcus stomatis, Gemella morbillorum, Catonella morbi, Peptoanaerobacter yurli and Peptococcus simiae) were observed in OSCC tumor microenvironment. These tumor-enriched bacteria formed 254 positive correlations with 206 up-regulated host genes, mainly involving signaling pathways related to cell adhesion, migration and proliferation. Integrative analysis of bacteria-transcriptome and bacteria-methylation correlations identified at least 20 dysregulated host genes with inverted CpG methylation in their promoter regions associated with enrichment of bacterial pathogens, implying a potential of pathogenic bacteria to regulate gene expression, in part, through epigenetic alterations. An in vitro model further confirmed that Fusobacterium nucleatum might contribute to cellular invasion via crosstalk with E-cadherin/ß-catenin signaling, TNFα/NF-κB pathway and extracellular matrix remodeling by up-regulating SNAI2 gene, a key transcription factor of epithelial-mesenchymal transition (EMT). Our work using multi-omics approaches explored complex host-microbiota interactions and provided important insights into genetic and functional basis in OSCC tumorigenesis, which may serve as a precursor for hypothesis-driven study to better understand the causational relationship of pathogenic bacteria in this deadly cancer.