Incident dementia and long-term exposure to constituents of fine particle air pollution: A national cohort study in the United States.

Growing evidence suggests that fine particulate matter (PM2.5) likely increases the risks of dementia, yet little is known about the relative contributions of different constituents. Here, we conducted a nationwide population-based cohort study (2000 to 2017) by integrating the Medicare Chronic Conditions Warehouse database and two independently sourced datasets of high-resolution PM2.5 major chemical composition, including black carbon (BC), organic matter (OM), nitrate (NO3-), sulfate (SO42-), ammonium (NH4+), and soil dust (DUST). To investigate the impact of long-term exposure to PM2.5 constituents on incident all-cause dementia and Alzheimer's disease (AD), hazard ratios for dementia and AD were estimated using Cox proportional hazards models, and penalized splines were used to evaluate potential nonlinear concentration-response (C-R) relationships. Results using two exposure datasets consistently indicated higher rates of incident dementia and AD for an increased exposure to PM2.5 and its major constituents. An interquartile range increase in PM2.5 mass was associated with a 6 to 7% increase in dementia incidence and a 9% increase in AD incidence. For different PM2.5 constituents, associations remained significant for BC, OM, SO42-, and NH4+ for both end points (even after adjustments of other constituents), among which BC and SO42- showed the strongest associations. All constituents had largely linear C-R relationships in the low exposure range, but most tailed off at higher exposure concentrations. Our findings suggest that long-term exposure to PM2.5 is significantly associated with higher rates of incident dementia and AD and that SO42-, BC, and OM related to traffic and fossil fuel combustion might drive the observed associations.

Unraveling a Concerted Proton-Coupled Electron Transfer Pathway in Atomically Precise Gold Nanoclusters.

Metal nanoclusters (MNCs) represent a promising class of materials for catalytic carbon dioxide and proton reduction as well as dihydrogen oxidation. In such reactions, multiple proton-coupled electron transfer (PCET) processes are typically involved, and the current understanding of PCET mechanisms in MNCs has primarily focused on the sequential transfer mode. However, a concerted transfer pathway, i.e., concerted electron-proton transfer (CEPT), despite its potential for a higher catalytic rate and lower reaction barrier, still lacks comprehensive elucidation. Herein, we introduce an experimental paradigm to test the feasibility of the CEPT process in MNCs, by employing Au18(SR)14 (SR denotes thiolate ligand), Au22(SR)18, and Au25(SR)18- as model clusters. Detailed investigations indicate that the photoinduced PCET reactions in the designed system proceed via an CEPT pathway. Furthermore, the rate constants of gold nanoclusters (AuNCs) have been found to be correlated with both the size of the cluster and the flexibility of the Au-S framework. This newly identified PCET behavior in AuNCs is prominently different from that observed in semiconductor quantum dots and plasmonic metal nanoparticles. Our findings are of crucial importance for unveiling the catalytic mechanisms of quantum-confined metal nanomaterials and for the future rational design of more efficient catalysts.

Dendritic morphology of developing hippocampal neurons in Cyp11a1 null mice.

INTRODUCTION: Neurosteroids have a variety of neurological functions, such as neurite growth, neuroprotection, myelination, and neurogenesis. P450scc, encoded by CYP11A1 gene, is the cholesterol side chain cleavage enzyme that catalyzes the first and rate limiting step in the steroidogenesis. In this study, we examine the dendritic morphology in developing hippocampal neurons of Cyp11a1 null mice at P15, a critical period for synapse formation and maturation. METHODS: Knockout mice were maintained until P15 with hormone administration. The Golgi-Cox method stained CA1 and CA3 pyramidal neurons in the hippocampus to reveal dendritic morphology. RESULTS: We demonstrated that Cyp11a1 null mice usually die within 7 days after birth and thus collected brain samples at postnatal day 5 (P5) for examination. There were significant shrinkage of dendrite size and diminishment of dendritic branching in CA1 and CA3 pyramidal neurons in the hippocampus of Cyp11a1 null mice, suggesting a developmental delay. We wonder if this delay may catch up later in life. Since the age of P15 is a critical period for synapse formation and maturation, the Cyp11a1 null mice were rescued by receiving hormone administration until P15 that the dendritic morphology in the developing hippocampal neurons could be examined. The results indicated that the total dendritic length, number of dendritic branches, as well as dendritic arborization in the CA1 and CA3 pyramidal neurons are significantly decreased in P15 knockout mice when compared to the wild type. The spine densities were also significantly decreased. In addition, the western blot analysis revealed decrease PSD-95 expression levels in the knockout mice compared to the wild type at P15. CONCLUSION: These results suggested that Cyp11a1 deficiency impairs the dendritic structures in the developing hippocampal pyramidal neurons.

A colorimetric sensing strategy based on chitosan-stabilized platinum nanoparticles for quick detection of α-glucosidase activity and inhibitor screening.

α-Glucosidase (α-Glu) is implicated in the progression and pathogenesis of type II diabetes (T2D). In this study, we developed a rapid colorimetric technique using platinum nanoparticles stabilized by chitosan (Ch-PtNPs) to detect α-Glu activity and its inhibitor. The Ch-PtNPs facilitate the conversion of 3,3',5,5'-tetramethylbenzidine (TMB) into oxidized TMB (oxTMB) in the presence of dissolved O2. The catalytic hydrolysis of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) by α-Glu produces ascorbic acid (AA), which reduces oxTMB to TMB, leading to the fading of the blue color. However, the presence of α-Glu inhibitors (AGIs) hinders the generation of AA, allowing Ch-PtNPs to re-oxidize colorless TMB back to blue oxTMB. This unique phenomenon enables the colorimetric detection of α-Glu activity and AGIs. The linear range for α-Glu was found to be 0.1-1.0 U mL-1 and the detection limit was 0.026 U mL-1. Additionally, the half-maximal inhibition value (IC50) for acarbose, an α-Glu inhibitor, was calculated to be 0.4769 mM. Excitingly, this sensing platform successfully detected α-Glu activity in human serum samples and effectively screened AGIs. These promising findings highlight the potential application of the proposed strategy in clinical diabetes diagnosis and drug discovery.

Fano resonance in molecular junctions of spin crossover complexes.

In this paper, we introduce a novel molecular switch paradigm that integrates spin crossover complexes with the Fano resonance effect. Specifically, by performing density-functional theory calculations, the feasibility of achieving Fano resonance using spin crossover complexes is demonstrated in our designed molecular junctions using the complex {Fe[H2B(pz)2]2[Bp(bipy)]} [pz = 1-pyrazolyl, Bp(bipy) = bis(phenylethynyl)(2,2'-bipyridine)]. It is further revealed that the Fano resonance, particularly the Fano dip, is most prominent in the junction with cobalt tips among all the schemes, together with the spin-filtering effect. Most importantly, this junction of cobalt tips is able to exhibit three distinct conductance states, which are controlled by the modulation of Fano resonance due to the spin-state transition of the complex and the applied gate voltage. Such a molecular switch paradigm holds potential for applications in logic gates, memory units, sensors, thermoelectrics, and beyond.

Effect of different screen brightness and devices on online visual acuity test.

PURPOSE: This study aimed to study the difference in test results of online visual acuity (VA) test under different devices and screen brightness conditions and to compare online VA test with Early Treatment Diabetic Retinopathy Study (ETDRS). METHODS: Healthy volunteers with the best corrected VA of 0.0 LogMAR or higher were recruited. VAs under ETDRS were tested first, and then online VA test (the Stanford Acuity Test, StAT) visual acuities using iPad Air2 and Microsoft Surface pro4 under 50% and 100% screen brightness were performed. The VA results and the testing times were compared between different devices and screen brightness conditions. RESULTS: A total of 101 eyes were included in this study. The VA results measured by the StAT were better than those of ETDRS. The VA results measured at 100% screen brightness were better than those of 50% brightness (mean difference, 0.013 logMAR at most, less than 1 letter); the VA results measured by iPad Air2 were better than those of Surface pro4 (mean difference, -0.009 logMAR at most, less than 1 letter). Significantly less time was spent on VA testing under StAT than that under ETDRS. CONCLUSION: The impact of screen brightness and the device on the VA results generated by online VA tests was clinically insignificant. In addition, online VA tests are found to be reliable and more time efficient than ETDRS.

Costs of revision operations for distal junctional kyphosis following thoracic posterior spinal fusion for adolescent idiopathic scoliosis.

PURPOSE: To assess direct costs and risks associated with revision operations for distal junctional kyphosis/failure (DJK) following thoracic posterior spinal instrumented fusions (TPSF) for adolescent idiopathic scoliosis (AIS). METHODS: Children who underwent TPSF for AIS by a single surgeon (2014-2020) were reviewed. Inclusion criteria were minimum follow-up of 2 years, thoracolumbar posterior instrumented fusion with a lower instrumented vertebra (LIV) cranial to L2. Patients who developed DJK requiring revision operations were identified and compared with those who did not develop DJK. RESULTS: Seventy-nine children were included for analysis. Of these, 6.3% developed DJK. Average time to revision was 20.8 ± 16.2 months. Comparing index operations, children who developed DJK had significantly greater BMIs, significantly lower thoracic kyphosis postoperatively, greater post-operative lumbar Cobb angles, and significantly more LIVs cranial to the sagittal stable vertebrae (SSV), despite having statistically similar pre-operative coronal and sagittal alignment parameters and operative details compared with non-DJK patients. Revision operations for DJK, when compared with index operations, involved significantly fewer levels, longer operative times, greater blood loss, and longer hospital lengths of stay. These factors resulted in significantly greater direct costs for revision operations for DJK ($76,883 v. $46,595; p < 0.01). CONCLUSIONS: In this single-center experience, risk factors for development of DJK were greater BMI, lower post-operative thoracic kyphosis, and LIV cranial to SSV. As revision operations for DJK were significantly more costly than index operations, all efforts should be aimed at strategies to prevent DJK in the AIS population.

Does obesity and varying body mass index affect the clinical outcomes and safety of biportal endoscopic lumbar decompression? A comparative cohort study.

BACKGROUND: Endoscopic spine surgery has recently grown in popularity due to the potential benefits of reduced pain and faster recovery time as compared to open surgery. Biportal spinal endoscopy has been successfully applied to lumbar disc herniations and lumbar spinal stenosis. Obesity is associated with increased risk of complications in spine surgery. Few prior studies have investigated the impact of obesity and associated medical comorbidities with biportal spinal endoscopy. METHODS: This study was a prospectively collected, retrospectively analyzed comparative cohort design. Patients were divided into cohorts of normal body weight (Bone Mass Index (BMI)18.0-24.9), overweight (BMI 25.0-29.9) and obese (BMI > 30.0) as defined by the World Health Organization (WHO). Patients underwent biportal spinal endoscopy by a single surgeon at a single institution for treatment of lumbar disc herniations and lumbar spinal stenosis. Demographic data, surgical complications, and patient-reported outcomes were analyzed. Statistics were calculated amongst treatment groups using analysis of variance and chi square where appropriate. Statistical significance was determined as p < 0.05. RESULTS: Eighty-four patients were followed. 26 (30.1%) were normal BMI, 35 (41.7%) were overweight and 23 (27.4%) were obese. Patients with increasing BMI had correspondingly greater American Society of Anesthesiologist (ASA) scores. There were no significant differences in VAS Back, VAS Leg, and ODI scores, or postoperative complications among the cohorts. There were no cases of surgical site infections in the cohort. All cohorts demonstrated significant improvement up to 1 year postoperatively. CONCLUSIONS: This study demonstrates that obesity is not a risk factor for increased perioperative complications with biportal spinal endoscopy and has similar clinical outcomes and safety profile as compared to patients with normal BMI. Biportal spinal endoscopy is a promising alternative to traditional techniques to treat common lumbar pathology.

Avoiding Pitfalls in Adult Spinal Deformity.

To avoid the high rate of complications associated with the surgical management of adult spinal deformity, it is important to recognize and avoid three major pitfalls. The first is patient selection and determining which cases are appropriately indicated. The second is optimizing modifiable medical issues that can lead to a poor outcome, such as smoking, vitamin D deficiency, nutritional status, and poor bone quality. The third is optimizing surgical factors such as defining clinically appropriate, patient-specific target alignment goals as well as using techniques to avoid proximal junctional kyphosis and proximal junctional failure. It is important to describe these three key pitfalls that are commonly seen in the treatment of patients with adult spinal deformity and to describe methods to avoid them.

Role of cancer-associated fibroblasts in colorectal cancer and their potential as therapeutic targets.

Cancer-associated fibroblasts (CAFs) are mesenchymal cells in the tumor microenvironment (TME). CAFs are the most abundant cellular components in the TME of solid tumors. They affect the progression and course of chemotherapy and radiotherapy in various types of tumors including colorectal cancer (CRC). CAFs can promote tumor proliferation, invasion, and metastasis; protect tumor cells from immune surveillance; and resist tumor cell apoptosis caused by chemotherapy, resulting in drug resistance to chemotherapy. In recent years, researchers have become increasingly interested CAF functions and have conducted extensive research. However, compared to other types of malignancies, our understanding of the interaction between CRC cells and CAFs remains limited. Therefore, we searched the relevant literature published in the past 10 years, and reviewed the origin, biological characteristics, heterogeneity, role in the TME, and potential therapeutic targets of CAFs, to aid future research on CAFs and tumors.

Growth-promoting effect of antimicrobial peptide Scy-hepc on mariculture large yellow croaker Larimichthys crocea and the underlying mechanism.

With the antibiotics prohibition in feedstuffs worldwide, antimicrobial peptides (AMPs) are considered a more promising substitute for antibiotics to be used as feed additives, and positive results have been reported in livestock feeding studies. However, whether dietary supplementation of AMPs could promote the growth of mariculture animals such as fish and the underlying mechanism has not been elucidated yet. In the study, a recombinant AMP product of Scy-hepc was used as a dietary supplement (10 mg/kg) to feed mariculture juvenile large yellow croaker (Larimichthys crocea) with an average initial body weight (BW) of 52.9 g for 150 days. During the feeding trial, the fish fed with Scy-hepc showed a significant growth-promoting performance. Especially at 60 days after feeding, fish fed with Scy-hepc weighed approximately 23% more than the control group. It was further confirmed that the growth-related signaling pathways such as the GH-Jak2-STAT5-IGF1 growth axis, the PI3K-Akt and Erk/MAPK pathways were all activated in the liver after Scy-hepc feeding. Furthermore, a second repeated feeding trial was scheduled for 30 days using much smaller juvenile L. crocea with an average initial BW of 6.3 g, and similar positive results were observed. Further investigation revealed that the downstream effectors of the PI3K-Akt pathway, such as p70S6K and 4EBP1, were significantly phosphorylated, suggesting that Scy-hepc feeding might promote translation initiation and protein synthesis processes in the liver. Taken together, as an effector of innate immunity, AMP Scy-hepc played a role in promoting the growth of L. crocea and the underlying mechanism was associated with the activation of the GH-Jak2-STAT5-IGF1 axis, as well as the PI3K-Akt and Erk/MAPK signaling pathways.

National Cohort Study of Long-Term Exposure to PM2.5 Components and Mortality in Medicare American Older Adults.

There is increasing evidence linking long-term fine particulate matter (PM2.5) exposure to negative health effects. However, the relative influence of each component of PM2.5 on health risk is poorly understood. In a cohort study in the contiguous United States between 2000 and 2017, we examined the effect of long-term exposure to PM2.5 main components and all-cause mortality in older adults who had to be at least 65 years old and enrolled in Medicare. We estimated the yearly mean concentrations of six key PM2.5 compounds, including black carbon (BC), organic matter (OM), soil dust (DUST), nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+), using two independently sourced well-validated prediction models. We applied Cox proportional hazard models to evaluate the hazard ratios for mortality and penalized splines for assessing potential nonlinear concentration-response associations. Results suggested that increased exposure to PM2.5 mass and its six main constituents were significantly linked to elevated all-cause mortality. All components showed linear concentration-response relationships in the low exposure concentration ranges. Our research indicates that long-term exposure to PM2.5 mass and its essential compounds are strongly connected to increased mortality risk. Reductions of fossil fuel burning may yield significant air quality and public health benefit.

Bipolar spin-filtering and giant magnetoresistance effect in spin-semiconducting zigzag graphene nanoribbons.

Spintronics is one of the main topics in condensed matter physics, in which half-metallicity and giant magnetoresistance are two important objects to achieve. In this work, we study the spin dependent transport properties of zigzag graphene nanoribbons (ZGNR) with asymmetric edge hydrogenation and different magnetic configurations using the non-equilibrium Green's function method combined with density functional calculations. Our results show that when the magnetic configurations of the electrodes change from parallel to antiparallel, the currents in the tunnel junction change substantially, resulting in a high conductance state and a low conductance state, with the tunnel magnetoresistance (TMR) ratio larger than 1 × 105% achieved. In addition, in the parallel magnetic configurations, an ideal bipolar spin filtering effect is observed, making it flexible to switch the spin polarity of current by reversing the bias direction. All these features originate from the spin semiconducting behavior of the asymmetrically hydrogenated ZGNRs. The findings suggest that asymmetric edge hydrogenation provides an important way to construct multi-functional spintronic devices with ZGNRs.

Lipoxin A4 and its analog attenuate high fat diet-induced atherosclerosis via Keap1/Nrf2 pathway.

Excessive oxidative stress and decreased antioxidant capacity of macrophages are initial factors which cause macrophages to transform to foam cells, which represents a key event in the progression of atherosclerosis (AS). BML-111, the analog of lipoxin A4 (LXA4) strongly attenuated high fat (HF) diet-induced atherosclerosis by activating NF-E2 related factor 2 (Nrf2). However, the effect was not through a specific LXA4 receptor (formyl peptide receptor 2, FPR2). BML-111 also strongly inhibited HF diet-induced promotion of MDA level, increased HDL level and decreased IL-1, MCP-1, IL-6, VCAM, ICAM and TNF-α level in aorta. In the in vitro experiments, LXA4 inhibited THP-1 cells to transform to foam cells via Nrf2 pathway. Our findings demonstrated that LXA4 and its analog prevented AS induced by HF diet in SD rats, under which the possible mechanism is through Keap1/Nrf2 pathway.

Multifunctional organic nanomaterials with ultra-high photothermal conversion efficiency for photothermal therapy and inhibition of cancer metastasis.

Photothermal therapy (PTT) has gained extensive interest in tumor treatments due to its non-invasive and low-toxic nature. However, the currently available photothermal agents (PTAs) mostly show unsatisfactory photothermal conversion efficiency (PCE). Besides, as a local cancer treatment modality, PTT fails to inhibit metastasis of tumors. To address these issues, in this study, two aza-boron-dipyrromethene (aza-BODIPY)-based organic photothermal agents (OPTAs), Fc-aza-BODIPY and TPA-aza-BODIPY, were rationally coined by introducing two strong electron-donating ferrocene (Fc) moieties and two triphenylamine (TPA) rotors, which could boost intramolecular photo-induced electron transfer (PET) and molecular rotation respectively, thereby improving the PCE of aza-BODIPY dyes. After encapsulation of hydrophobic Fc-aza-BODIPY (or TPA-aza-BODIPY) and quercetin with biodegradable PLGA and DSPE-mPEG2000, the resulting nanoparticles (FAQ NPs and TAQ NPs) showed excellent optical properties with PCE of ∼72.0% and ∼79.7% and specific tumor accumulations through enhanced permeability and retention (EPR) effects. Consequently, these two NPs possessed prominent antitumor effects under 880 nm laser irradiation. Moreover, both FAQ NPs and TAQ NPs loaded with quercetin could inhibit tumor metastasis efficiently. These two multifunctional nanomaterials integrating OPTAs and anti-metastasis agents constructed a cooperative treatment program, which may provide a potential opportunity for future clinical cancer treatment.

Perioperative Outcomes of Open Anterior Vertebral Body Tethering and Instrumented Posterior Spinal Fusion for Skeletally Immature Patients With Idiopathic Scoliosis.

BACKGROUND: Correcting adolescent idiopathic scoliosis (AIS) without fusion can be achieved with anterior vertebral body tethering (AVBT). However, little is known about the perioperative outcomes, pain control, and clinical outcomes in patients undergoing AVBT compared with instrumented posterior spinal fusion (IPSF). METHODS: In this retrospective cohort study, we compared pediatric patients with AIS who underwent either AVBT or IPSF. Inclusion criteria were based on the AVBT group, which included primary thoracic idiopathic scoliosis, Risser ≤1, curve magnitude 40 to 70 degrees, age 9 to 15, no prior spine surgery, index surgery between 2014 and 2019, and minimum 2-year follow-up. Patient demographics, perioperative metrics, pain visual analog scale scores, opiate morphine equivalent usage, cost data, and radiographic outcomes were compared. RESULTS: We identified 23 patients who underwent AVBT and 24 matched patients in the IPSF group based on inclusion criteria. Patients undergoing AVBT and PSF were similar in age (12±1 y vs. 13±1 y, P =0.132) and average follow-up time (3.8±1.6 y vs. 3.3±1.4 y, P =0.210). There were 23 female patients (87%) in the AVBT group and 24 female (92%) patients in the IPSF group. Intraoperatively, estimated blood loss (498±290 vs. 120±47 mL, P <0.001) and procedure duration (419±95 vs. 331±83 min, P =0.001) was significantly greater in the IPSF group compared with AVBT. Length of stay was lower in the AVBT group compared with PSF (4±1 vs. 5±2 d, P =0.04). PSF patients had significantly greater total postoperative opiate morphine equivalent use compared with AVBT (2.2±1.9 vs. 5.6±3.4 mg/kg, P <0.001). Overall direct costs following PSF and AVBT were similar ($47,655+$12,028 vs. $50,891±$24,531, P =0.58). Preoperative radiographic parameters were similar between both the groups, with a major thoracic curve at 51±10 degrees for AVBT and 54±9 degrees for IPSF ( P =0.214). At the most recent follow-up, IPSF patients had greater curve reduction to a mean major thoracic curve of 11±7 degrees (79%) compared with 19±10 degrees (63%) in AVBT patients ( P =0.002). Nine patients (39%) required revision surgery following AVBT compared with 4 patients(17%) following IPSF ( P =0.09). CONCLUSIONS: In a select cohort of patients, AVBT offers decreased surgical time, blood loss, length of stay, and postoperative opiate usage compared with IPSF. Although IPSF resulted in greater deformity correction at 2-year follow-up, the majority of patients who underwent AVBT had ≤35 major curves and avoided fusion. There is optimism for AVBT as a treatment option for select AIS patients, but long-term complications are still being understood, and the risk for revision surgeries remains high. LEVEL OF EVIDENCE: Level III.

Deep Learning-Based Sensor Array: 3D Fluorescence Spectra of Gold Nanoclusters for Qualitative and Quantitative Analysis of Vitamin B6 Derivatives.

Vitamin B6 derivatives (VB6Ds) are of great importance for all living organisms to complete their physiological processes. However, their excess in the body can cause serious problems. What is more, the qualitative and quantitative analysis of different VB6Ds may present significant challenges due to the high similarity of their chemical structures. Also, the transfer of deep learning model from one task to a similar task needs to be present more in the fluorescence-based biosensor. Therefore, to address these problems, two deep learning models based on the intrinsic fingerprint of 3D fluorescence spectra have been developed to identify five VB6Ds. The accuracy ranges of a deep neural network (DNN) and a convolutional neural network (CNN) were 94.44-97.77% and 97.77-100%, respectively. After that, the developed models were transferred for quantitative analysis of the selected VB6Ds at a broad concentration range (1-100 µM). The determination coefficient (R2) values of the test set for DNN and CNN were 93.28 and 97.01%, respectively, which also represents the outperformance of CNN over DNN. Therefore, our approach opens new avenues for qualitative and quantitative sensing of small molecules, which will enrich fields related to deep learning, analytical chemistry, and especially sensor array chemistry.

Feature Selection Assists BLSTM for the Ultrasensitive Detection of Bioflavonoids in Different Biological Matrices Based on the 3D Fluorescence Spectra of Gold Nanoclusters.

Rapid and on-site qualitative and quantitative analysis of small molecules (including bioflavonoids) in biofluids are of great importance in biomedical applications. Herein, we have developed two deep learning models based on the 3D fluorescence spectra of gold nanoclusters as a single probe for rapid qualitative and quantitative analysis of eight bioflavonoids in serum. The results proved the efficiency and stability of the random forest-bidirectional long short-term memory (RF-BLSTM) model, which was used only with the most important features after deleting the unimportant features that might hinder the performance of the model in identifying the selected bioflavonoids in serum at very low concentrations. The optimized model achieves excellent overall accuracy (98-100%) in the qualitative analysis of the selected bioflavonoids. Next, the optimized model was transferred to quantify the selected bioflavonoids in serum at nanoscale concentrations. The transferred model achieved excellent accuracy, and the overall determination coefficient (R2) value range was 99-100%. Furthermore, the optimized model achieved excellent accuracies in other applications, including multiplex detection in serum and model applicability in urine. Also, LOD in serum at nanoscale concentration was considered. Therefore, this approach opens the window for qualitative and quantitative analysis of small molecules in biofluids at nanoscale concentrations, which may help in the rapid inclusion of sensor arrays in biomedical and other applications.

m6A-immune-related lncRNA prognostic signature for predicting immune landscape and prognosis of bladder cancer.

BACKGROUND: N6-methyladenosine (m6A) related long noncoding RNAs (lncRNAs) may have prognostic value in bladder cancer for their key role in tumorigenesis and innate immunity. METHODS: Bladder cancer transcriptome data and the corresponding clinical data were acquired from the Cancer Genome Atlas (TCGA) database. The m6A-immune-related lncRNAs were identified using univariate Cox regression analysis and Pearson correlation analysis. A risk model was established using least absolute shrinkage and selection operator (LASSO) Cox regression analyses, and analyzed using nomogram, time-dependent receiver operating characteristics (ROC) and Kaplan-Meier survival analysis. The differences in infiltration scores, clinical features, and sensitivity to Talazoparib of various immune cells between low- and high-risk groups were investigated. RESULTS: Totally 618 m6A-immune-related lncRNAs and 490 immune-related lncRNAs were identified from TCGA, and 47 lncRNAs of their intersection demonstrated prognostic values. A risk model with 11 lncRNAs was established by Lasso Cox regression, and can predict the prognosis of bladder cancer patients as demonstrated by time-dependent ROC and Kaplan-Meier analysis. Significant correlations were determined between risk score and tumor malignancy or immune cell infiltration. Meanwhile, significant differences were observed in tumor mutation burden and stemness-score between the low-risk group and high-risk group. Moreover, high-risk group patients were more responsive to Talazoparib. CONCLUSIONS: An m6A-immune-related lncRNA risk model was established in this study, which can be applied to predict prognosis, immune landscape and chemotherapeutic response in bladder cancer.

Enzyme-Activated Multifunctional Prodrug Combining Site-Specific Chemotherapy with Light-Triggered Photodynamic Therapy.

Combination treatments are more effective than conventional monotherapy in combating cancer. Herein, a multifunctional prodrug BDP-L-CPT was rationally engineered and prepared by the conjugation of a boron dipyrromethene (BDP)-based photosensitizer (PS) to the active site of the chemotherapeutic drug camptothecin (CPT) via a phenyl benzoate group. After modification, the cytotoxicity of CPT was locked. Moreover, the fluorescence emission at 430 nm from the CPT component in the prodrug was substantially inhibited through the intramolecular fluorescence resonance energy transfer process. The phenyl benzoate linker in BDP-L-CPT could be selectively cleaved by exogenous carboxylesterase in phosphate-buffered saline solution and endogenous carboxylesterase overexpressed in cancer cells, which was followed by self-immolation to release free CPT. The drug release process could be monitored by the turn-on of CPT fluorescence in solution and cells. Owing to the combination of site-specific chemotherapy with light-driven photodynamic therapy, the IC50 values of the prodrug BDP-L-CPT against HepG2 human hepatocellular carcinoma and HeLa human cervical carcinoma cells were lower than those of the controls, BDP-COOH and CPT. The combined antitumor effects of the prodrug BDP-L-CPT were also observed in the mice bearing H22 tumors. Furthermore, BDP-L-CPT had a more prolonged blood circulation time in mice than CPT, which is beneficial to persistent therapy. This study may provide a promising strategy for a selective combination cancer treatment by conjugating a prodrug to a PS.