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Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC.

IMPORTANCE: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non−small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. OBJECTIVE: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. INTERVENTION: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. RESULTS: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. CONCLUSIONS AND RELEVANCE: The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03046316

A promising approach to prevent heat- and cold-related illnesses is the integration of zero-energy input control technology into personal thermal management (PTM) systems while reducing energy consumption. However, achieving optimal wearing comfort while maintaining subambient metabolic temperatures using thermally regulating materials without an energy supply remains challenging. In this study, we provide a simple and reliable methodology to produce a phase-changeable metafabric made of thermoplastic polyurethane and phase change capsule (PCC) particles with high moisture permeability and thermal comfort. This approach skillfully incorporates spray-formed PCC particles into a three-dimensional nanofibrous aggregate, forming a stable self-entangled network structure in a single step through simultaneous humidity-assisted electrospraying and electrospinning processes. Additionally, the metafabric demonstrates prominent water resistance and superhydrophobicity, which are attributed to the integration of PCC particles and nanofibers, resulting in the formation of a microporous/nanoporous structure resembling the surface of a lotus leaf. As a result, the phase-changeable metafabric shows an active and passive thermal control performance, with a water vapor transmittance rate of 13.1 kg m–2d–1and a phase change enthalpy of 115.05 J g–1even after 100 thermal cycles. Furthermore, it displays excellent waterproofing capability, characterized by a water contact angle of 158.7° and the ability to withstand a high hydrostatic pressure of 87 kPa. In addition, the metafabric exhibits a good mechanical performance, boasting a tensile strength of 10.5 MPa. Overall, the proposed economical metafabric is an exemplary candidate material for next-generation PTM systems.

The developments of modern surveillance technology pose great challenges to combat concealment for warfighters. Traditional camouflage suits cannot accommodate the need for camouflage stealth in complex warfare scenarios. Herein, a bidirectional diffusion-controlled in situ synthesis methodology is reported to achieve electrochromic nanofibrous membranes with mimetic chameleon skin structures (CSENs) by assembling electrochromic covalent organic frameworks on nanofibers. CSENs exhibit reversible color changes in the visible and near-infrared ranges under an applied potential with fast response times (25.8 s/26.2 s). The macro- and mesoporous structures in CSENs favored the transportation of electrolyte ions, achieving excellent color difference and coloration efficiency of 35.58 and 1053.26 cm2/C, respectively. Importantly, CSENs feature unique properties of self-standing, breathability, and flexibility, which are attributed to the micrometer pores constructed by entangled nanofibers. As a proof-of-concept study, the CSEN-based flexible electrochromic suit exhibits a dynamic camouflage function in real environments, showing promising properties as smart textiles for dynamic camouflage stealth.

Extracellular vesicles (EVs) have garnered significant attention in biomedical applications. However, the rapid, efficient, and unbiased separation of EVs from complex biological fluids remains a challenge due to their heterogeneity and low abundance in biofluids. Herein, we report a novel approach to reconfigure and modify an artificial insertion peptide for the unbiased and rapid isolation of EVs in 20 min with ∼80% recovery in neutral conditions. Moreover, the approach demonstrates exceptional anti-interference capability and achieves a high purity of EVs comparable to standard ultracentrifugation and other methods. Importantly, the isolated EVs could be directly applied for downstream protein and nucleic acid analyses, including proteomics analysis, exome sequencing analysis, as well as the detection of both epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) gene mutation in clinical plasma samples. Our approach offers great possibilities for utilizing EVs in liquid biopsy, as well as in various other biomedical applications.

RNA is an essential biomolecule that determines and regulates numerous biological process in cells. The sensitive and specific imaging of the expression level, localization and dynamic change of RNAs in living cells possesses great significance in biological and medicine. The fluorescence functional nucleic acid probes with well-designed sequences are increasingly reported to be applied for living cell imaging, ascribing to their exceptional sensitivity and designability. In this review, the importance and examples of the living cell imaging of different types of RNAs are discussed. The fluorescence imaging methods based on functional nucleic acid probes, including non-amplification and amplification methods, are detailedly introduced. Especially, the combination of different amplification methods to achieve superior imaging performance is an advanced strategy to overcome the disadvantages of single amplification methods, so these methods are also introduced in detail. Finally, the downstream applications including subcellular imaging, in-depth disease mechanism investigation and disease diagnosis are demonstrated. In general, functional nucleic acid probe is a promising tool for imaging of RNAs in living cells, and this technique is rapidly improving ascribing to the emerging advances in functional nucleic acid and microscopy technology.

Due to the substantial heterogeneity among extracellular vesicle (EV) subpopulations, single-EV analysis has the potential to elucidate the mechanisms behind EV biogenesis and shed light on the myriad functions, leading to the development of novel diagnostics and therapeutics. While many studies have been devoted to reveal between-EV variations in surface proteins and RNAs, DNA cargos (EV-DNA) have received little attention. Here, we report a hydrogel-based droplet digital multiple displacement amplification approach for the comprehensive analysis of EV-DNA at the single-EV level. Single EVs are dispersed in thousands of hydrogel droplets and lysed for DNA amplification and identification. The droplet microfluidics strategy empowers the assay with single-molecule sensitivity and capability for absolute quantification of DNA-containing EVs. In particular, our findings indicate that 5–40% EVs are associated with DNA, depending on the cell of origin. Large EVs exhibit a higher proportion of DNA-containing EVs and a more substantial presence of intraluminal DNA, compared to small EVs. These DNA-containing EVs carry multiple DNA fragments on average. Furthermore, both double-stranded DNA and single-stranded DNA were able to be detected at the single-EV level. Utilizing this method, the abundance, distribution, and biophysical properties of EV-DNA in various EV populations are evaluated. The DNA level within EVs provides insight into the status of the originating cells and offers valuable information on the outcomes of anticancer treatments. The utilization of single-EV analysis for EV-DNA holds significant promise for early cancer detection and treatment response monitoring.

The digitization of health records and growing availability of tumour DNA sequencing provide an opportunity to study the determinants of cancer outcomes with unprecedented richness. Patient data are often stored in unstructured text and siloed datasets. Here we combine natural language processing annotations1,2with structured medication, patient-reported demographic, tumour registry and tumour genomic data from 24,950 patients at Memorial Sloan Kettering Cancer Center to generate a clinicogenomic, harmonized oncologic real-world dataset (MSK-CHORD). MSK-CHORD includes data for non-small-cell lung (n= 7,809), breast (n= 5,368), colorectal (n= 5,543), prostate (n= 3,211) and pancreatic (n= 3,109) cancers and enables discovery of clinicogenomic relationships not apparent in smaller datasets. Leveraging MSK-CHORD to train machine learning models to predict overall survival, we find that models including features derived from natural language processing, such as sites of disease, outperform those based on genomic data or stage alone as tested by cross-validation and an external, multi-institution dataset. By annotating 705,241 radiology reports, MSK-CHORD also uncovers predictors of metastasis to specific organ sites, including a relationship between SETD2mutation and lower metastatic potential in immunotherapy-treated lung adenocarcinoma corroborated in independent datasets. We demonstrate the feasibility of automated annotation from unstructured notes and its utility in predicting patient outcomes. The resulting data are provided as a public resource for real-world oncologic research.

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In this work, static immersion and gravimetric methods were used to study the corrosion behavior of three common stainless steels and four Ni-based alloys in a NaCl–MgCl2–KCl mixed molten salt under vacuum atmosphere. The corrosion test was conducted at 700 °C, with a maximum exposure time of 100 h. Corrosion behavior was determined by measuring the mass loss of the sample at different time intervals and the corrosion rates at 100 h. The microstructure of the alloy was analyzed by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), atomic force microscope (AFM), and X-ray diffraction (XRD). The results showed that stainless steels were generally more severely corroded than Ni-based alloys. 304 stainless steel and In800H exhibited the worst corrosion resistance, whereas Ni-based alloy In625 had the best corrosion resistance. Fe and Cr were dissolved in the molten chloride salts and reacted with the molten chloride salts. Mo played a positive role in suppressing the corrosion of the alloys in molten chloride salts by inhibiting the outward diffusion of the elements.

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The increasing utilization of X-rays has generated a growing need for efficient shielding materials. However, the existing Pb-based materials suffer from a narrow X-ray absorbing range, high weight, and rigidity. Inspired by the natural leaf, which can efficiently absorb light through chlorophyll and carotenoids in confined cells, we engineer ultralight and superelastic nanofibrous Bi2O3/Gd2O3meta-aerogels (BGAs) with X-ray nanotrap arrays by manipulating the 3D confined assembly of 1D Bi2O3and Gd2O3nanofibers. The BGAs can synergistically absorb X-ray photons from complementary energy ranges into the nanotraps and induce cyclic collisions with Bi2O3and Gd2O3nanofibers, maximizing the effective X-ray attenuation. The meta-aerogel exhibits the integrated performance of efficient X-ray shielding efficiency (60–83%, 16–90 keV), ultralow density (10 mg cm–3), and superelasticity. The production of these meta-aerogels presents an avenue for the development of next-generation X-ray protective materials and the resolution of X-ray imaging systems.

The tremendous menace of the COVID-19 pandemic has underscored the urgency for antipathogen masks to stop the transmission of airborne infectious diseases. Most prevailing antipathogen masks manifest a slower sterilization rate that lags behind the pathogen momentum traversing the masks, thereby engendering an elevated susceptibility to infection. Here we tailor nanofibrous meta-aerogel electric traps, 3D-assembled from self-knotted carbon nanotube networks in an all rigid nanofibrous skeleton. This superior configuration revolves around the creation of numerous “dielectrophoretic–aerodynamic grippers”, which are capable of directional manipulation of microbes toward the region of the lethal intensive electric field. Based on this, we present a disinfection unit comprising a pair of aerogel electrodes that demonstrate a rapid killing rate (>99.99% biocidal efficacy within 0.016 s) and long-term durability (12 h of continuous operation). Additionally, a microbutton lithium cell is employed as a power supply to fabricate an antipathogen face mask with this disinfection unit, which exhibits superior pathogen inactivation efficacy compared to commercial masks. This scalable biocidal protective equipment holds great potential for use in emergency medical services.

Intestinal failure-associated liver disease (IFALD) is a common hepatobiliary complication resulting from long-term parenteral nutrition (PN) in patients with intestinal failure. The spectrum of IFALD ranges from cholestasis, steatosis, portal fibrosis, to cirrhosis. Development of IFALD is a multifactorial process, in which gut dysbiosis plays a critical role in its initiation and progression in conjunction with increased intestinal permeability, activation of hepatic immune responses, and administration of lipid emulsion. Gut microbiota manipulation including pre/probiotics, fecal microbiota transplantation, and antibiotics has been studied in IFALD with varying success. In this review, we summarize current knowledge on the taxonomic and functional changes of gut microbiota in preclinical and clinical studies of IFALD. We also review the function of microbial metabolites and associated signalings in the context of IFALD. By providing microbiota-targeted interventions aiming to optimize PN-induced liver injury, our review provides perspectives for future basic and translational investigations in the field.

Objective: To investigate comorbidities among hospitalized patients with dementia. Method: Data were extracted from the discharge records in our hospital. Comorbidities based on ICD-10 were selected from the Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI). The distributions of these comorbidities were described in dementia inpatients and age- and sex-matched nondementia controls, as well as in inpatients with Alzheimer’s disease and vascular dementia. A logistic regression model was applied to identify dementia-specific morbid conditions. Results: A total of 3355 patients with dementia were included, with a majority of 1503 (44.8%) having Alzheimer's disease, 395 (11.8%) with vascular dementia, and 441 (13.1%) with mixed dementia. The mean number of comorbidities was 3.8 in dementia patients (vs. 2.9 in controls). The most prevalent comorbidities in inpatients with dementia compared with those without dementia were cerebral vascular disease (73.0% vs. 35.9%), hypertension (62.8% vs. 56.2%), and peripheral vascular disease (53.7% vs. 31.2%). Comorbidities associated with dementia included epilepsy (OR 4.8, 95% CI 3.5–6.8), cerebral vascular disease (OR 4.1, 95% CI 3.7–4.5), depression (OR 4.0, 95% CI 3.2–5.0), uncomplicated diabetes (OR 1.5, 95% CI 1.4–1.7), peripheral vascular disease (OR 1.8, 95% CI 1.6–2.0), rheumatoid arthritis collagen vascular disease (OR 1.7, 95% CI 1.3–2.3), and anemia (OR 1.2, 95% CI 1.04–1.3). Some comorbidities suggested a protective effect against dementia. They were hypertension (OR 0.8, 95% CI 0.7–0.9), COPD (OR 0.6, 95% CI 0.5–0.6), and solid tumor without metastasis (OR 0.4, 95% CI 0.3–0.4). Vascular dementia has more cardiovascular and cerebrovascular comorbidities than Alzheimer's disease. Conclusion: Patients with dementia coexisted with more comorbidities than those without dementia. Comorbidities (esp. cardio-cerebral vascular risks) in patients with vascular dementia were more than those in patients with AD. Specifically, vascular and circulatory diseases, epilepsy, diabetes and depression increased the risk of dementia.

To explore targeted treatment options in patients with non-small-cell lung cancer (NSCLC) with rare genetic mutations in the context of a patient-centric clinical trial, we initiated, in parallel, a phase 2 adaptive umbrella trial consisting of a criteria-fulfilled (CF) cohort and a compassionate use (CU) cohort under expanded eligibility criteria, and a prospective real-world study (RWS). Here, we present efficacy and safety data from 48 patients with treatment-naive, advanced HER2-mutant NSCLC treated with the pan-HER receptor tyrosine kinase inhibitor pyrotinib (CF and CU cohorts) or physician’s therapy of choice (RWS cohort). In the phase 2 trial CF cohort (n= 28), the primary endpoint was reached with an objective response rate of 35.7% after pyrotinib treatment. Secondary endpoints included disease control rate (89.3%), median progression-free survival (PFS) (7.3 months), median overall survival (OS) (14.3 months) and toxicity, which was acceptable, with grade 3 or 4 treatment-related adverse events occurring in three patients (10.7%). The phase 2 trial CU cohort (n= 12) showed an objective response rate of 16.7%, disease control rate of 83.4%, median PFS of 4.7 months and median OS of 14.2 months after pyrotinib treatment. The RWS cohort (n= 8) had no responses to physician’s therapy of choice, while median PFS and OS were 3.0 and 12.2 months, respectively. Phase 2 umbrella trial, clinicaltrials.gov identifier: NCT03574402. RWS, clinicaltrials.gov identifier: NCT03605602.

In this work, four new cyclodepsipeptides, fusarihexins C–E (1–3) and enniatin Q (4), four new cyclopentane derivatives, fusarilins A–D (5–8), together with eight known compounds (9–16), were isolated from cultures of the endophytic fungus Fusariumsp. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR spectroscopic data. The absolute configurations were determined using Marfey’s method, a modified Mosher’s method, single-crystal X-ray diffraction analysis, and ECD analysis. The antitumor activities of the isolated compounds in vitro were evaluated. Cyclodepsipeptides displayed cytotoxicities against the Huh-7, MRMT-1, and HepG-2 cell lines. Compounds 4, 9, 10, and 12with IC50values of 1.0–9.1 μM exhibited the most potent cytotoxicities against the three cell lines as compared to the positive control-5-fluorouracil. Compounds 1–3and 11exhibited moderate cytotoxic activities (IC50values of 10.7–20.1 μM).

The widespread use of X-rays has prompted a surge in demand for effective and wearable shielding materials. However, the Pb-containing materials currently used to shield X-rays are commonly bulky, hard, and biotoxic, severely limiting their applications in wearable scenarios. Inspired by the nacre, we report on ultralight, superelastic, and nontoxic X-ray shielding nanofibrous aerogels with microarch-engineered brick/mortar structure by combining polyurethane/Bi2O3nanofibers (brick) and Gd2O3nanosheets (mortar). The synergistic attenuation effect toward X-rays from the reflection of microarches and absorption of Bi/Gd elements significantly enhances the shielding efficiency of aerogels, and microarches/robust nanofibrous networks endow the materials with superelasticity. The resultant materials exhibit integrated properties of superior X-ray shielding efficiency (91–100%), ultralow density (52 mg cm–3), large stretchability of 800% reversible elongation, and high water vapor permeability (8.8 kg m–2day–1). The fabrication of such novel aerogels paves the way for developing next-generation effective and wearable X-ray shielding materials.

Imaging of tumor-associated microRNAs (miRNAs) can provide abundant information for cancer diagnosis, whereas the occurrence of trace amounts of miRNAs in normal cells inevitably causes an undesired false-positive signal in the discrimination of cancer cells during miRNA imaging. In this study, we propose a dual-locked (D-locked) platform consisting of the enzyme/miRNA-D-locked DNAzyme sensor and the honeycomb MnO2nanosponge (hMNS) nanocarrier for highly specific cancer cell imaging. For a proof-of-concept demonstration, apurinic/apyrimidinic endonuclease 1 (APE1) and miR-21 were chosen as key models. The hMNS nanocarrier can efficiently release the D-locked DNAzyme sensor in living cells due to the decomposition of hMNS by glutathione, which can also supply Mn2+for DNAzyme cleavage. Ascribing to the smart design of the D-locked DNAzyme sensor, the fluorescence signal can only be generated by the synergistic response of APE1 and miR-21 that are overexpressed in cancer cells. Compared with the miRNA single-locked DNAzyme sensor and the small-molecule (ATP)/miRNA D-locked DNAzyme sensor, the proposed enzyme (APE1)/miRNA D-locked DNAzyme sensor exhibited 2.6-fold and 2.4-fold higher discrimination ratio (Fcancer/Fnormal) for cancer cell discrimination, respectively. Owing to the superior performance, the D-locked strategy can selectively generate a fluorescence signal in cancer cells, facilitating accurate discrimination of cancer both in vitroand in vivo. Furthermore, this D-locked platform is easily adaptable toward other target molecules by redesigning the DNA sequences. The outstanding performance and expansibility of this D-locked platform holds promising prospects for cancer diagnosis and related biomedical applications.