Size-Switchable Ru Nanoaggregates for Enhancing Phototherapy: Hyaluronidase-Triggered Disassembly to Alleviate Deep Tumor Hypoxia.

Hypoxia is a critical factor for restricting photodynamic therapy (PDT) of tumor, and it becomes increasingly severe with increasing tissue depth. Thus, the relief of deep tumor hypoxia is extremely important to improve the PDT efficacy. Herein, tumor microenvironment (TME)-responsive size-switchable hyaluronic acid-hybridized Ru nanoaggregates (HA@Ru NAs) were developed via screening reaction temperature to alleviate deep tumor hypoxia for improving the tumor-specific PDT by the artful integration multiple bioactivated chemical reactions in situ and receptor-mediated targeting (RMT). In this nanosystem, Ru NPs not only enabled HA@Ru NAs to have near infrared (NIR)-mediated photothermal/photodynamic functions, but also could catalyze endogenous H2O2 to produce O2 in situ. More importantly, hyaluronidase (HAase) overexpressed in the TME could trigger disassembly of HA@Ru NAs via the hydrolysis of HA, offering the smart size switch capability from 60 to 15 nm for enhancing tumor penetration. Moreover, the RMT characteristics of HA ensured that HA@Ru NAs could specially enter CD44-overexpressed tumor cells, enhancing tumor-specific precision of phototherapy. Taken together these distinguishing characteristics, smart HA@Ru NAs successfully realized the relief of deep tumor hypoxia to improve the tumor-specific PDT.

Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

The neuroprotective effect of near infrared light therapy in aged mice with postoperative neurocognitive disorder by upregulating IRF7.

BACKGROUND: Postoperative neurocognitive disorder (PND) is a common central nervous system complication after undergoing surgery and anesthesia especially in elderly patients, while the therapeutic options are very limited. This study was carried out to investigate the beneficial effects of transcranial near infrared light (NIRL) which was employed to the treatment of PND and propose the involved mechanisms. METHODS: The PND mice were established through left carotid artery exposure under isoflurane anesthesia and received transcranial NIRL treatment. Behavioral testing was performed to evaluate the cognitive function of PND mice after transcranial NIRL therapy. Changes in the transcriptomic profiles of prefrontal cortex (PFC) and hippocampus (HP) were identified by next generation sequencing (NGS), and the molecular mechanisms involved were examined by both in vivo mouse model and in vitro cell culture studies. RESULTS: We found that transcranial NIRL therapy effectively ameliorated learning and memory deficit induced by anesthesia and surgery in aged mice. Specifically, we identified down-regulation of interferon regulatory factor 7 (IRF7) in the brains of PND mice that was mechanistically associated with increased pro-inflammatory M1 phenotype of microglia and elevated neuroinflammatory. NIRL treatment produced protective effects through the upregulation of IRF7 expression and reversing microglial phenotypes from pro-inflammatory to neuroprotective, resulting in reduced brain damage and improved cognitive function in PND mice. CONCLUSION: Our results indicate that transcranial NIRL is an effective and safe therapy for PND via alleviating neuroinflammation, and IRF7 plays a key transcription factor in regulating the M1-to-M2 switch of microglia.

Evaluation of Long-Term Nutrition Outcomes After Duodenal Switch: A Systematic Review and Meta-Analysis.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) is the most effective and durable metabolic and bariatric surgery to achieve a target weight loss. However, many surgeons are hesitant to adopt BPD-DS due to a lack of training, technical complexity, and long-term nutrition deficiencies. This meta-analysis aimed to investigate long-term nutrition outcomes after primary BPD-DS in the management of obesity. METHODS: Cochrane, Embase, PubMed, Scopus, and Web of Science were searched for articles from their inception to February 2023 by 2 independent reviewers using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) system. The review was registered prospectively with PROSPERO (CRD42023391316). RESULTS: From 834 studies screened, 8 studies met the eligibility criteria, with a total of 3443 patients with obesity undergoing primary BPD-DS. At long-term follow-up (≥5 years), 25.4% of patients had vitamin A deficiency (95% CI: -.012, .520, I2 = 94%), and 57.3% had vitamin D deficiency (95% CI: .059, 1.086, I2 = 86%). Calcium deficiency was observed in 125 patients (22.2%, 95% CI: .061, .383, I2 = 97%), and 69.7% had an abnormal parathyroid hormone level (95% CI: .548, .847, I2 = 78%). Ferritin level was abnormal in 30 patients (29.0%, 95% CI: .099, .481, I2 = 79%). CONCLUSIONS: Despite displaying comparable nutrition-related outcomes to mid-term follow-up, our study demonstrated that BPD-DS could result in a high level of long-term nutrition deficiency after BPD-DS for selected patients. However, further randomized controlled studies with standardized supplementation regimens and improvement in compliance are necessary to evaluate and prevent long-term nutritional deficiencies after BPD-DS.

Effect of ST36 electroacupuncture on the switch of skeletal muscle fibres in mice with sciatic nerve dissociation.

Skeletal muscle is striated muscle that moves autonomously and is innervated by peripheral nerves. Peripheral nerve injury is very common in clinical treatment. However, the commonly used treatment methods often focus on the regeneration of the injured nerve but overlook the pathological changes in the injured skeletal muscle. Acupuncture, as the main treatment for denervated skeletal muscle atrophy, is used extensively in clinical practice. In the present study, a mouse model of lower limb sciatic nerve detachment was constructed and treated with electroacupuncture Stomach 36 to observe the atrophy of lower limb skeletal muscle and changes in skeletal muscle fibre types before and after electroacupuncture Stomach 36 treatment. Mice with skeletal muscle denervation showed a decrease in the proportion of IIa muscle fibres and an increase in the proportion of IIb muscle fibres, after electroacupuncture Stomach 36. The changes were reversed by specific activators of p38 MAPK, which increased IIa myofibre ratio. The results suggest that electroacupuncture Stomach 36 can reverse the change of muscle fibre type from IIb to IIa after denervation of skeletal muscle by inhibiting p38 MAPK. The results provide an important theoretical basis for the treatment of clinical peripheral nerve injury diseases with electroacupuncture, in addition to novel insights that could facilitate the study of pathological changes of denervated skeletal muscle.

Fabry disease biomarkers in patients switched from enzyme-replacement therapy to migalastat oral chaperone therapy.

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme-replacement therapy (ERT) to migalastat. Methods: 16 Gb3 isoforms and eight lyso-Gb3 analogues were analyzed in plasma and urine by LC-MS/MS at baseline and at three different time points in naive participants and participants switching from either agalsidase α or ß to migalastat. Results: 29 adult participants were recruited internationally (seven centers). The Mainz Severity Score Index and mean biomarker levels remained stable (p ≥ 0.05) over a minimum of 12 months compared with baseline following the treatment switch. Conclusion: In this cohort of patients with Fabry disease with amenable mutations, in the short term, a switch from ERT to migalastat did not have a marked effect on the average biomarker profile.

Single Anastomosis Duodenal Switch versus Classic Duodenal Switch: Long-term Outcomes from a Prospective Comparative Cohort Study.

PURPOSE: The literature on long-term outcomes of duodenal switch (DS) compared to single anastomosis duodenal switch (SADI-S) procedures is lacking. We evaluated the long-term outcomes of SADI-S compared to those after the classic DS procedure. METHODS: This is a follow-up report from a single-institution prospective cohort study comparing long-term outcomes of SADI-S versus DS both as one- and two-stage procedures (ClinicalTrials.gov: NCT02792166). Data is depicted as count (percentage) or median (interquartile range). RESULTS: Forty-two patients underwent SADI-S, of whom 11 had it as a second-stage procedure (26%). Of 20 patients who underwent DS, twelve had it as a second-stage procedure (60%). Both groups were similar at baseline. Median follow-up times for one-stage SADI-S and DS were 57 (24) and 57 (9) months, respectively (p = 0.93). Similar BMI reductions were observed after one-stage SADI-S (16.5 kg/m2 [8.5]) and DS (18.9 kg/m2 [7.2]; p = 0.42). At median follow-up of 51 (21) and 60 (15) months after second-stage SADI-S and DS, respectively (p = 0.60), surgical procedures yielded reductions in BMI of 20.5 kg/m2 (14.0) and 24.0 kg/m2 (13.9), respectively (p = 0.52). Follow-up rates were similar for one-stage (≥ 88%; p = 0.29) and second-stage procedures (≥ 83%; p = 0.16). Similar diabetes and hypertension remissions were found (p = 0.77; P = 0.54, respectively). Despite fat-soluble vitamin deficiencies at baseline, after supplementation, they were either eliminated or less prevalent long-term after SADI-S. Daily bowel movements were also less frequent. CONCLUSIONS: Long-term weight and comorbidity outcomes after SADI-S are similar to those of DS both as one- and two-stage surgeries. SADI-S procedure may allow for similar beneficial outcomes with less burden from gastrointestinal symptoms and fat-soluble vitamin deficiencies.

Identification of Factors Contributing to Methadone-Induced Daytime Sleepiness in Cancer Patients and Proposal of the Conversion Ratio from Other Opioids to Oral Methadone: A Retrospective Cohort Study.

Background: When methadone is used to treat cancer pain, the Japanese health insurance system recommends to determine the starting dose according to the equivalency conversion table based on the morphine-equivalent daily dose (MEDD) of prior opioids proposed by the National Comprehensive Cancer Network. Owing to the wide range in variability of the conversion table, methadone increases the incidence of daytime sleepiness. Objective: To identify the factors associated with daytime sleepiness and propose a conversion ratio from pretreatment MEDD to oral methadone that decreases the risk of daytime sleepiness. Design: Retrospective cohort study. Setting/Subjects: One hundred patients who started oral methadone to relieve cancer pain at Ashiya Municipal Hospital (Hyogo, Japan) from January 1, 2013, to August 31, 2022, were enrolled. Measurements: The primary endpoint, the conversion ratio from pretreatment MEDD to oral methadone without daytime sleepiness, was determined using receiver operator characteristic (ROC) curve analysis. Results: The incidence of daytime sleepiness within seven days of methadone initiation was 40.0%. The factors identified as contributing to daytime sleepiness were pretreatment MEDD (odds ratio [OR]: 0.941, 95% confidence interval [CI]: 0.916-0.966, p <0.001) and methadone dose (OR: 1.395, 95% CI: 1.178-1.652, p <0.001). The conversion ratio from pretreatment MEDD to oral methadone was 0.24, with an area under the ROC curve of 0.909 (p <0.001). Conclusions: Daytime sleepiness developed when methadone dose is high relative to pretreatment MEDD. To the best of our knowledge, this is the first study to suggest the conversion ratio from pretreatment MEDD to oral methadone without causing daytime sleepiness.

Identification of a TonB-Dependent Receptor Involved in Lanthanide Switch by the Characterization of Laboratory-Adapted Methylosinus trichosporium OB3b.

Two methanol dehydrogenases (MDHs), MxaFI and XoxF, have been characterized in methylotrophic and methanotrophic bacteria. MxaFI contains a calcium ion in its active site, whereas XoxF contains a lanthanide ion. Importantly, the expression of MxaFI and XoxF is inversely regulated by lanthanide bioavailability, i.e., the "lanthanide switch." To reveal the genetic and environmental factors affecting the lanthanide switch, we focused on two Methylosinus trichosporium OB3b mutants isolated during routine cultivation. In these mutants, MxaF was constitutively expressed, but lanthanide-dependent XoxF1 was not, even in the presence of 25 µM cerium ions, which is sufficient for XoxF expression in the wild type. Genotyping showed that both mutants harbored a loss-of-function mutation in the CQW49_RS02145 gene, which encodes a TonB-dependent receptor. Gene disruption and complementation experiments demonstrated that CQW49_RS02145 was required for XoxF1 expression in the presence of 25 µM cerium ions. Phylogenetic analysis indicated that CQW49_RS02145 was homologous to the Methylorubrum extorquens AM1 lanthanide transporter gene (lutH). These findings suggest that CQW49_RS02145 is involved in lanthanide uptake across the outer membrane. Furthermore, we demonstrated that supplementation with cerium and glycerol caused severe growth arrest in the wild type. CQW49_RS02145 underwent adaptive laboratory evolution in the presence of cerium and glycerol ions, resulting in a mutation that partially mitigated the growth arrest. This finding implies that loss-of-function mutations in CQW49_RS02145 can be attributed to residual glycerol from the frozen stock. IMPORTANCE Lanthanides are widely used in many industrial applications, including catalysts, magnets, and polishing. Recently, lanthanide-dependent metabolism was characterized in methane-utilizing bacteria. Despite the global demand for lanthanides, few studies have investigated the mechanism of lanthanide uptake by these bacteria. In this study, we identify a lanthanide transporter in Methylosinus trichosporium OB3b and indicate the potential interaction between intracellular lanthanide and glycerol. Understanding the genetic and environmental factors affecting lanthanide uptake should not only help improve the use of lanthanides for the bioconversion of methane into valuable products like methanol but also be of value for developing biomining to extract lanthanides under neutral conditions.

Inside the cracked kernel: establishing the molecular basis of AMG510 and MRTX849 in destabilising KRASG12C mutant switch I and II in cancer treatment.

The Kirsten rat sarcoma oncoprotein (KRAS) has been punctuated by drug development failures for decades due to frequent mutations that occur mostly at codon 12 and the seemingly intractable targeting of the protein. However, with advances in covalent targeting, the oncoprotein is being expunged from the 'undruggable' list of proteins. This feat has seen some covalent drugs at different stages of clinical trials. The advancement of AMG510 and MRTX849 as inhibitors of cysteine mutated KRAS (KRASG12C) to phase-III clinical trials informed the biased selection of AMG510 and MRTX849 for this study. Despite this advance, the molecular and atomistic modus operandi of these drugs is yet to come to light. In this study, we employed computational tools to unravel the atomistic interactions and subsequent conformational effects of AMG510 and MRTX849 on the mutant KRASG12C. It was revealed that AMG510 and MRTX849 complexes presented similar total free binding energies, (ΔGbind), of -88.15 ± 5.96 kcal/mol and -88.71 ± 7.70 kcal/mol, respectively. Gly10, Lys16, Thr58, Gly60, Glu62, Glu63, Arg68, Asp69, Met72, His95, Tyr96, Gln99, Arg102 and Val103 interacted prominently with AMG510 and MRTX849. These residues interacted with the pharmacophoric moieties of AMG510 and MRTX849 via hydrogen bonds with decreasing bond lengths at various stages of the simulation. These interactions together with pi-pi stacking, pi-sigma and pi-alkyl interactions induced unfolding of switch I whiles compacting switch II, which could interrupt the binding of effector proteins to these interfaces. These insights present useful atomistic perspectives into the success of AMG510 and MRTX849 which could guide the design of more selective and potent KRAS inhibitors.Communicated by Ramaswamy H. Sarma.

Treatment Patterns for Targeted Therapies, Non-Targeted Therapies, and Drug Holidays in Patients with Psoriasis.

INTRODUCTION: We aimed to evaluate US treatment patterns and, more specifically, switch patterns among patients with psoriasis (PsO) who initiated treatment with targeted therapy (TT) and subsequently switched to another therapy. METHODS: This retrospective study used IBM® MarketScan® Commercial and Medicare Databases (1/1/2006-3/31/2020) to evaluate treatment patterns in biologic- and apremilast-naive patients with PsO. TT included apremilast, adalimumab, etanercept, infliximab, ustekinumab, or other biologics (certolizumab pegol, secukinumab, brodalumab, ixekizumab, guselkumab, or tildrakizumab). Adults with ≥ 1 prescription for a TT, ≥ 2 PsO claims separated by ≥ 1 day on or before the index date (date of first TT prescription), and continuous medical and pharmacy enrollment for 1 year before and 2 years after the index date were eligible. Non-targeted therapy (NTT) was defined as non-targeted oral systemic treatment, topical treatment, phototherapy, or no treatment. Kaplan-Meier (KM) analysis was used to estimate time to reinitiation of TT (24-month continuous enrollment post-index was not required). RESULTS: A total of 11,526 patients with PsO were included; mean [standard deviation (SD)] age and Charlson Comorbidity Index score were 48.3 (12.8) years and 0.9 (1.43), respectively. During the follow-up, 69.2% of the patients were treated with NTT. Median time to first NTT, for those who received NTT, was 205 days (longest: adalimumab, 252 days). Among patients who switched to NTT after initiating treatment with TT, 52.6% reinitiated treatment with TT (least common: apremilast, 45.6%), with a median time to reinitiation of 106 days (longest: other biologics, 136 days). For all patients on NTT, the probability of reinitiating any TT was 60.7% at 24 months. CONCLUSIONS: PsO treatment is often cyclical in nature. Patients frequently experience drug holidays or transition back to TT after using NTT. The consideration of real-world treatment patterns in future economic models may provide new insights into the clinical effectiveness and value of PsO treatments.

Psoriasis is a chronic inflammatory skin disease that affects 3.0% of adults or an estimated 7.56 million Americans. The most common type of psoriasis is called plaque psoriasis because of its appearance with red patches and silvery scales on the skin. A major concern of medical providers is that not all patients continue their treatment as prescribed. Many patients discontinue, switch, and often restart treatment. To develop effective psoriasis treatment plans for shared decision-making among medical providers and patients, it is important to look at how treatments are used in the real world. This can be done by conducting studies using insurance claims data from healthcare insurance providers. In this study, we evaluated treatment patterns and, more specifically, patterns in changes of treatment in US patients who began their psoriasis treatment with a targeted therapy (biologics or apremilast) and then changed to another therapy. We found that patients often took drug holidays (days with no treatment) and returned back to using a targeted therapy after using a non-targeted therapy (e.g., other oral therapy, topical treatment, phototherapy, or no treatment). Findings from this real-world study may support future studies on the clinical effectiveness and value of current and future treatments for psoriasis­especially within these targeted to non-targeted transitions.

A High-Power 3P3T Cross Antenna Switch with Low Harmonic Distortion and Enhanced Isolation Using T-Type Pull-Down Path for Cellular Mobile Devices.

This paper presents a radio frequency (RF) triple pole triple throw 3P3T cross antenna switch for cellular mobile devices. The negative biasing scheme was applied to improve the power-handling capability and linearity of the switch by increasing the maximum tolerable voltage drop across the drain and source and reverse biasing the parasitic junction diodes. To avoid signal reflection through the antenna in off-state, all the antenna ports were equipped with 50-ohm termination to provide the pull-down path. Considering the simultaneous operation of antenna ports in different switch cases, the presented T-type pull-down path demonstrated improvement of isolation by over 15 dB. Using stacked switches, the 3P3T handled the input power level of over 35 dBm. The chip was manufactured in 65 nm complementary metal oxide semiconductor (CMOS) silicon on insulator (SOI) technology with a die size of 790 × 730 µm. The proposed structure achieved insertion loss, isolation, and voltage standing wave ratio (VSWR) of less than -0.9 dB, -40 dB, and 1.6, respectively, when the input signal was 3.8 GHz. The measured results prove the implemented switch shows the second and third harmonic distortion performances of less than -60 dBm when the input power level and frequency are 25 dBm and 3.8 GHz, respectively.

Rapid screening of neuraminidase inhibitors with the benzoic acid skeleton from Paeonia suffruticosa Andrews by solid-phase extraction with an enzyme activity switch combined with mass spectrometry analysis.

It is meaningful for drug discovery to discover lead compounds with specific skeletons from medicinal herbs. Screening bioactive compounds with specific skeletons by a simple and rapid strategy is still a challenging task. Solid-phase extraction (SPE) is a simple and time-saving technique in the laboratory and is often used in the concentration of natural products. It is attractive to apply the SPE in the screening of bioactive compounds with specific skeletons. To achieve this goal, SPE with an enzyme activity (EA) switch combined with mass spectrometry analysis was first proposed. The screening of benzoic acid-derived neuraminidase (NA) inhibitors from the root cortex of Paeonia suffruticosa Andrews (CPSA) was used as an example. The NA and crude extract of CPSA were incubated to form a sample solution. Subsequently, the sample was separated, detected, and collected by the SPE with an EA switch. When the detected values reduced significantly, the EA switch was triggered, and the collection was stopped. The collected eluents were treated for LC-MS/MS analysis. Finally, combining diagnostic ions and mass spectrometry data, two benzoic acid NA inhibitors were successfully screened from CPSA. In this study, the separation, detection, and collection were performed on one instrument system. Compared with the traditional isolation strategy, this strategy with the simpler operation and higher experimental efficiency could be an effective tool for the rapid screening of lead compounds with specific skeletons.

Metabolic Switch Under Glucose Deprivation Leading to Discovery of NR2F1 as a Stimulus of Osteoblast Differentiation.

Poor survival of grafted cells is the major impediment of successful cell-based therapies for bone regeneration. Implanted cells undergo rapid death in an ischemic environment largely because of hypoxia and metabolic stress from glucose deficiency. Understanding the intracellular metabolic processes and finding genes that can improve cell survival in these inhospitable conditions are necessary to enhance the success of cell therapies. Thus, the purpose of this study was to investigate changes of metabolic profile in glucose-deprived human bone marrow stromal/stem cells (hBMSCs) through metabolomics analysis and discover genes that could promote cell survival and osteogenic differentiation in a glucose-deprived microenvironment. Metabolomics analysis was performed to determine metabolic changes in a glucose stress metabolic model. In the absence of glucose, expression levels of all metabolites involved in glycolysis were significantly decreased than those in a glucose-supplemented state. In glucose-deprived osteogenic differentiation, reliance on tricarboxylic acid cycle (TCA)-predicted oxidative phosphorylation instead of glycolysis as the main mechanism for energy production in osteogenic induction. By comparing differentially expressed genes between glucose-deprived and glucose-supplemented hBMSCs, NR2F1 (Nuclear Receptor Subfamily 2 Group F Member 1) gene was discovered to be associated with enhanced survival and osteogenic differentiation in cells under metabolic stress. Small, interfering RNA (siRNA) for NR2F1 reduced cell viability and osteogenic differentiation of hBMSCs under glucose-supplemented conditions whereas NR2F1 overexpression enhanced osteogenic differentiation and cell survival of hBMSCs in glucose-deprived osteogenic conditions via the protein kinase B (AKT)/extracellular signal-regulated kinase (ERK) pathway. NR2F1-transfected hBMSCs significantly enhanced new bone formation in a critical size long-bone defect of rats compared with control vector-transfected hBMSCs. In conclusion, the results of this study provide an understanding of the metabolic profile of implanted cells in an ischemic microenvironment and demonstrate that NR2F1 treatment may overcome this deprivation by enhancing AKT and ERK regulation. These findings can be utilized in regenerative medicine for bone regeneration. © 2022 American Society for Bone and Mineral Research (ASBMR).

A regenerable and reducing false-positive fluorescent switch for detection of ß-amyloid 1-42 oligomers.

The conventional fluorescence analysis methods for disease identification are vulnerable to the restriction with false-positive. Here, a fluorescent switch with high efficiency and regeneration by the black phosphorus (BP) nanosheets-regulated was developed to overcome false-positive issue in the assay of ß-amyloid1-42 oligomers (Aß) process. The Aß was rapidly recognized using the fluorescent emitter-nitrogen-doped carbon nanodots (N-CDs) under the regulation of BP nanosheets, while the N-CDs alone cannot recognize Aß without the introduction of BP. The fluorescence analysis methods exhibited a wide sensing range of 0.25-15.0 ng/mL and a low detection limit of 83 pg/mL for Aß analysis, which was superior to the reported fluorescence analysis method. Further, BP nanosheets were recycled, demonstrating the fluorescent switch with highly efficient, stable, and regenerable. This provides a new idea for developing high-efficiency and high-precision fluorescence detection platform.

Recent therapeutic advances in urothelial carcinoma: A paradigm shift in disease management.

Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the administration of platinum-based chemotherapy followed by observation. Despite moderate to high response rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic developments including the paradigm shift of first-line maintenance therapy with avelumab after response or stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease.

Electrogenetics: Bridging synthetic biology and electronics to remotely control the behavior of mammalian designer cells.

Electrogenetics, the combination of electronics and genetics, is an emerging field of mammalian synthetic biology in which electrostimulation is used to remotely program user-designed genetic elements within designer cells to generate desired outputs. Here, we describe recent advances in electro-induced therapeutic gene expression and therapeutic protein secretion in engineered mammalian cells. We also review available tools and strategies to engineer electro-sensitive therapeutic designer cells that are able to sense electrical pulses and produce appropriate clinically relevant outputs in response. We highlight current limitations facing mammalian electrogenetics and suggest potential future directions for research.

Simple and simultaneous quantification of cyanide, ethanol, and 1-propanol in blood by headspace GC-MS/NPD with Deans switch dual detector system.

Cyanide is a powerful and rapidly acting poison. In Japan, cyanide poisoning is rare, and regular cyanide testing can be costly and time consuming. In contrast, alcohol analysis is routinely performed in most forensic laboratories. In this study, we attempted to develop a method for the simultaneous quantification of cyanide and alcohols in blood using headspace gas chromatography (HS-GC). As nitrogen-phosphorus detection (NPD) is more sensitive to hydrogen cyanide than mass spectrometry (MS), a Deans switch was used to switch the detectors during a single run. The separation provided by three analytical columns, PoraBOND Q, CP-Sil 5 CB, and HP-INNOWax, was investigated, and PoraBOND Q was selected. The use of HS-GC-MS/NPD with a Deans switch enabled the simple and simultaneous quantification of cyanide, ethanol, and 1-propanol. Eighteen other volatile compounds were detected in the SIM/scan mode of the MS.

Supramolecular Core-Shell Nanoassemblies with Tumor Microenvironment-Triggered Size and Structure Switch for Improved Photothermal Therapy.

Photothermal therapy (PTT) is demonstrated to be an effective methodology for cancer treatment. However, the relatively low photothermal conversion efficiency, limited tumor accumulation, and penetration still remain to be challenging issues that hinder the clinical application of PTT. Herein, the core-shell hierarchical nanostructures induced by host-guest interaction between water-soluble pillar[5]arene (WP5) and polyethylene glycol-modified aniline tetramer (TAPEG) are constructed. The pH-responsive performance endows the core-shell nanostructures with size switchable property, with an average diameter of 200 nm in the neutral pH and 60 nm in the acidic microenvironment, which facilitates not only tumor accumulation but also tumor penetration. Moreover, the structure switch of WP5⊃TAPEG under acidic microenvironment and the dual mechanism regulated extending of п conjugate, inclusion in the hydrophobic cavity of WP5 and the dense distribution in the core-shell structured assemblies, dramatically enhance the absorption in the near-infrared-II region and, further, the photothermal conversion efficiency (60.2%). The as-designed intelligent nanoplatform is demonstrated for improved antitumor efficacy via PTT.

Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling.

SCOPE: T cell activation requires a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to rapidly provide substrates for biosynthesis. An individual's zinc status plays an important role in balancing the activation of T cells and is required for a proper function of immune cells. Furthermore, zinc plays an important role during effector T cell polarization to T helper cell subsets or regulatory T cells, with effector T cells relying on glycolysis and regulatory T cells on oxidative phosphorylation. Therefore, the study aims to analyze if zinc also impacts on T cell activation on the level of intracellular metabolism. METHODS AND RESULTS: Mixed lymphocyte culture and anti-CD3/CD28 stimulation is used as in vitro models for T cell activation to investigate the effect of zinc supplementation and deprivation on metabolic switching. Promoted glucose uptake, insulin receptor expression, and signaling in both zinc conditions are observed, whereas key metabolic enzymes are stimulated mainly by zinc deprivation. Alterations in cytokine production suggest an immune-activating effect of zinc deprivation and a balancing effect of zinc supplementation. CONCLUSION: The results suggest a supportive effect of both zinc supplementation and deprivation on the metabolic switch during T cell activation, adding another level of immune regulation by zinc.