Unconventional superconductivity in chiral molecule-TaS2 hybrid superlattices.

Chiral superconductors, a unique class of unconventional superconductors in which the complex superconducting order parameter winds clockwise or anticlockwise in the momentum space1, represent a topologically non-trivial system with intrinsic time-reversal symmetry breaking (TRSB) and direct implications for topological quantum computing2,3. Intrinsic chiral superconductors are extremely rare, with only a few arguable examples, including UTe2, UPt3 and Sr2RuO4 (refs. 4-7). It has been suggested that chiral superconductivity may exist in non-centrosymmetric superconductors8,9, although such non-centrosymmetry is uncommon in typical solid-state superconductors. Alternatively, chiral molecules with neither mirror nor inversion symmetry have been widely investigated. We suggest that an incorporation of chiral molecules into conventional superconductor lattices could introduce non-centrosymmetry and help realize chiral superconductivity10. Here we explore unconventional superconductivity in chiral molecule intercalated TaS2 hybrid superlattices. Our studies reveal an exceptionally large in-plane upper critical field Bc2,|| well beyond the Pauli paramagnetic limit, a robust π-phase shift in Little-Parks measurements and a field-free superconducting diode effect (SDE). These experimental signatures of unconventional superconductivity suggest that the intriguing interplay between crystalline atomic layers and the self-assembled chiral molecular layers may lead to exotic topological materials. Our study highlights that the hybrid superlattices could lay a versatile path to artificial quantum materials by combining a vast library of layered crystals of rich physical properties with the nearly infinite variations of molecules of designable structural motifs and functional groups11.

AMPK Attenuation of ß-Adrenergic Receptor-Induced Cardiac Injury via Phosphorylation of ß-Arrestin-1-ser330.

BACKGROUND: ß-adrenergic receptor (ß-AR) overactivation is a major pathological cue associated with cardiac injury and diseases. AMPK (AMP-activated protein kinase), a conserved energy sensor, regulates energy metabolism and is cardioprotective. However, whether AMPK exerts cardioprotective effects via regulating the signaling pathway downstream of ß-AR remains unclear. METHODS: Using immunoprecipitation, mass spectrometry, site-specific mutation, in vitro kinase assay, and in vivo animal studies, we determined whether AMPK phosphorylates ß-arrestin-1 at serine (Ser) 330. Wild-type mice and mice with site-specific mutagenesis (S330A knock-in [KI]/S330D KI) were subcutaneously injected with the ß-AR agonist isoproterenol (5 mg/kg) to evaluate the causality between ß-adrenergic insult and ß-arrestin-1 Ser330 phosphorylation. Cardiac transcriptomics was used to identify changes in gene expression from ß-arrestin-1-S330A/S330D mutation and ß-adrenergic insult. RESULTS: Metformin could decrease cAMP/PKA (protein kinase A) signaling induced by isoproterenol. AMPK bound to ß-arrestin-1 and phosphorylated Ser330 with the highest phosphorylated mass spectrometry score. AMPK activation promoted ß-arrestin-1 Ser330 phosphorylation in vitro and in vivo. Neonatal mouse cardiomyocytes overexpressing ß-arrestin-1-S330D (active form) inhibited the ß-AR/cAMP/PKA axis by increasing PDE (phosphodiesterase) 4 expression and activity. Cardiac transcriptomics revealed that the differentially expressed genes between isoproterenol-treated S330A KI and S330D KI mice were mainly involved in immune processes and inflammatory response. ß-arrestin-1 Ser330 phosphorylation inhibited isoproterenol-induced reactive oxygen species production and NLRP3 (NOD-like receptor protein 3) inflammasome activation in neonatal mouse cardiomyocytes. In S330D KI mice, the ß-AR-activated cAMP/PKA pathways were attenuated, leading to repressed inflammasome activation, reduced expression of proinflammatory cytokines, and mitigated macrophage infiltration. Compared with S330A KI mice, S330D KI mice showed diminished cardiac fibrosis and improved cardiac function upon isoproterenol exposure. However, the cardiac protection exerted by AMPK was abolished in S330A KI mice. CONCLUSIONS: AMPK phosphorylation of ß-arrestin-1 Ser330 potentiated PDE4 expression and activity, thereby inhibiting ß-AR/cAMP/PKA activation. Subsequently, ß-arrestin-1 Ser330 phosphorylation blocks ß-AR-induced cardiac inflammasome activation and remodeling.

Co-culture of RhoA-overexpressed microtia chondrocytes and adipose-derived stem cells in the construction of tissue-engineered ear-shaped cartilage.

Microtia is a congenital auricle dysplasia with a high incidence and tissue engineering technology provides a promising strategy to reconstruct auricles. We previously described that the engineered cartilage constructed from microtia chondrocytes exhibited inferior levels of biochemical and biomechanical properties, which was proposed to be resulted of the decreased migration ability of microtia chondrocytes. In the current study, we found that Rho GTPase members were deficient in microtia chondrocytes. By overexpressing RhoA, Rac1, and CDC42, respectively, we further demonstrated that RhoA took great responsibility for the decreased migration ability of microtia chondrocytes. Moreover, we constructed PGA/PLA scaffold-based cartilages to verify the chondrogenic ability of RhoA overexpressed microtia chondrocytes, and the results showed that overexpressing RhoA was of limited help in improving the quality of microtia chondrocyte engineered cartilage. However, coculture of adipose-derived stem cells (ADSCs) significantly improved the biochemical and biomechanical properties of engineered cartilage. Especially, coculture of RhoA overexpressed microtia chondrocytes and ADSCs produced an excellent effect on the wet weight, cartilage-specific extracellular matrix, and biomechanical property of engineered cartilage. Furthermore, we presented that coculture of RhoA overexpressed microtia chondrocytes and ADSCs combined with human ear-shaped PGA/PLA scaffold and titanium alloy stent fabricated by CAD/CAM and 3D printing technology effectively constructed and maintained auricle structure in vivo. Collectively, our results provide evidence for the essential role of RhoA in microtia chondrocytes and a developed strategy for the construction of patient-specific tissue-engineered auricular cartilage.

SiX2 (X = S, Se) Nanowire Gate-All-Around MOSFETs for Sub-5 nm Applications.

The gate-all-around (GAA) field-effect transistor (FET) holds great potential to support next-generation integrated circuits. Nanowires such as carbon nanotubes (CNTs) are one important category of channel materials in GAA FETs. Based on first-principles investigations, we propose that SiX2 (X = S, Se) nanowires are promising channel materials that can significantly elevate the performance of GAA FETs. The sub-5 nm SiX2 (X = S, Se) nanowire GAA FETs exhibit excellent ballistic transport properties that meet the requirements of the 2013 International Technology Roadmap for Semiconductors (ITRS). Compared to CNTs, they are also advantageous or at least comparable in terms of gate controllability, device dimensions, etc. Importantly, SiSe2 GAA FETs show superb gate controllability due to the ultralow minimum subthreshold swing (SSmin) that breaks "Boltzmann's tyranny". Moreover, the energy-delay product (EDP) of SiX2 GAA FETs is significantly lower than that of the CNT FETs. These features make SiX2 nanowires ideal channel material in the sub-5 nm GAA FET devices.

Single-Molecule Discrimination of Saccharides Using Carbon Nitride Nanopores.

Structural complexity brings a huge challenge to the analysis of sugar chains. As a single-molecule sensor, nanopores have the potential to provide fingerprint information on saccharides. Traditionally, direct single-molecule saccharide detection with nanopores is hampered by their small size and weak affinity. Here, a carbon nitride nanopore device is developed to discern two types of trisaccharide molecules (LeApN and SLeCpN) with minor structural differences. The resolution of LeApN and SLeCpN in the mixture reaches 0.98, which has never been achieved in solid-state nanopores so far. Monosaccharide (GlcNAcpN) and disaccharide (LacNAcpN) can also be discriminated using this system, indicating that the versatile carbon nitride nanopores possess a monosaccharide-level resolution. This study demonstrates that the carbon nitride nanopores have the potential for conducting structure analysis on single-molecule saccharides.

Unveiling the Anomalous Hall Response of the Magnetic Structure Changes in the Epitaxial MnBi2Te4 Films.

Recently discovered as an intrinsic antiferromagnetic topological insulator, MnBi2Te4 has attracted tremendous research interest, as it provides an ideal platform to explore the interplay between topological and magnetic orders. MnBi2Te4 displays distinct exotic topological phases that are inextricably linked to the different magnetic structures of the material. In this study, we conducted electrical transport measurements and systematically investigated the anomalous Hall response of epitaxial MnBi2Te4 films when subjected to an external magnetic field sweep, revealing the different magnetic structures stemming from the interplay of applied fields and the material's intrinsic antiferromagnetic (AFM) ordering. Our results demonstrate that the nonsquare anomalous Hall loop is a consequence of the distinct reversal processes within individual septuple layers. These findings shed light on the intricate magnetic structures in MnBi2Te4 and related materials, offering insights into understanding their transport properties and facilitating the implementation of AFM topological electronics.

Antioxidant peptides, the guardian of life from oxidative stress.

Reactive oxygen species (ROS) are produced during oxidative metabolism in aerobic organisms. Under normal conditions, ROS production and elimination are in a relatively balanced state. However, under internal or external environmental stress, such as high glucose levels or UV radiation, ROS production can increase significantly, leading to oxidative stress. Excess ROS production not only damages biomolecules but is also closely associated with the pathogenesis of many diseases, such as skin photoaging, diabetes, and cancer. Antioxidant peptides (AOPs) are naturally occurring or artificially designed peptides that can reduce the levels of ROS and other pro-oxidants, thus showing great potential in the treatment of oxidative stress-related diseases. In this review, we discussed ROS production and its role in inducing oxidative stress-related diseases in humans. Additionally, we discussed the sources, mechanism of action, and evaluation methods of AOPs and provided directions for future studies on AOPs.

Tunneling-Driven Marcus-Inverted Triplet Energy Transfer in a Two-Dimensional Perovskite.

Quantum tunneling, a phenomenon that allows particles to pass through potential barriers, can play a critical role in energy transfer processes. Here, we demonstrate that the proper design of organic-inorganic interfaces in two-dimensional (2D) hybrid perovskites allows for efficient triplet energy transfer (TET), where quantum tunneling of the excitons is the key driving force. By employing temperature-dependent and time-resolved photoluminescence and pump-probe spectroscopy techniques, we establish that triplet excitons can transfer from the inorganic lead-iodide sublattices to the pyrene ligands with rapid and weakly temperature-dependent characteristic times of approximately 50 ps. The energy transfer rates obtained based on the Marcus theory and first-principles calculations show good agreement with the experiments, indicating that the efficient tunneling of triplet excitons within the Marcus-inverted regime is facilitated by high-frequency molecular vibrations. These findings offer valuable insights into how one can effectively manipulate the energy landscape in 2D hybrid perovskites for energy transfer and the creation of diverse excitonic states.

Exceptionally High-glum Circularly Polarized Lasers Empowered by Strong 2D-Chiroptical Response in a Host-Guest Supramolecular Microcrystal.

Circularly polarized (CP) lasers hold tremendous potential for advancing spin information communication and display technologies. Organic materials are emerging candidates for high-performance CP lasers because of their abundant chiral structures and excellent gain characteristics. However, their dissymmetry factor (glum) in CP emission is typically low due to the weak chiral light matter interactions. Here, we presented an effective approach to significantly amplifying glum by leveraging the intrinsic 2D-chiroptical response of an anisotropic organic supramolecular crystal. The organic complex microcrystal was designed to exhibit large 2D-chiroptical activities through strong coupling interactions between their remarkable linear birefringence (LB) and high degree of fluorescence linear polarization. Such 2D-chiroptical response can be further enhanced by the stimulated emission resulted from an increased degree of linear polarization, yielding a nearly pure CP laser with an exceptionally high glum of up to 1.78. Moreover, exploiting the extreme susceptibility of LB to temperature, we demonstrate a prototype of temperature-controlled chiroptical switches. These findings offer valuable insights for harnessing organic crystals to facilitate the development of high-performance CP lasers and other chiroptical devices.

Interfacial-Assembly-Induced In Situ Transformation from Aligned 1D Nanowires to Quasi-2D Nanofilms.

As the dimensionality of materials generally affects their characteristics, thin films composed of low-dimensional nanomaterials, such as nanowires (NWs) or nanoplates, are of great importance in modern engineering. Among various bottom-up film fabrication strategies, interfacial assembly of nanoscale building blocks holds great promise in constructing large-scale aligned thin films, leading to emergent or enhanced collective properties compared to individual building blocks. As for 1D nanostructures, the interfacial self-assembly causes the morphology orientation, effectively achieving anisotropic electrical, thermal, and optical conduction. However, issues such as defects between each nanoscale building block, crystal orientation, and homogeneity constrain the application of ordered films. The precise control of transdimensional synthesis and the formation mechanism from 1D to 2D are rarely reported. To meet this gap, we introduce an interfacial-assembly-induced interfacial synthesis strategy and successfully synthesize quasi-2D nanofilms via the oriented attachment of 1D NWs on the liquid interface. Theoretical sampling and simulation show that NWs on the liquid interface maintain their lowest interaction energy for the ordered crystal plane (110) orientation and then rearrange and attach to the quasi-2D nanofilm. This quasi-2D nanofilm shows enhanced electric conductivity and unique optical properties compared with its corresponding 1D geometry materials. Uncovering these growth pathways of the 1D-to-2D transition provides opportunities for future material design and synthesis at the interface.

Identification of a Notch transcriptomic signature for breast cancer.

BACKGROUND: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would be warranted, for example to monitor the effects of future Notch-targeting therapies and to learn whether altered Notch signalling is an off-target effect of current breast cancer therapies. In this report, we have established such a classifier. METHODS: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated or reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by γ-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent datasets. RESULTS: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2), and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. CONCLUSIONS: The 20-gene transcriptional signature will be a valuable tool to evaluate the response of future Notch-targeting therapies for breast cancer, to learn about potential effects on Notch signalling from conventional breast cancer therapies and to better stratify patients for therapy considerations.

Systemic treatment options for non-small cell lung cancer after failure of previous immune checkpoint inhibitors: a bayesian network meta-analysis based on randomized controlled trials.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have brought survival benefits to non-small cell lung cancer (NSCLC), disease progression still occurs, and there is no consensus on the treatment options for these patients. We designed a network meta-analysis (NMA) to evaluate systemic treatment options for NSCLC after failure of ICIs. METHODS: PubMed, Embase, Web of Science and Cochrane Library databases were searched, then literature screening was followed by NMA. We included all Phase II and III randomized controlled trials (RCTs). Progression-free survival (PFS) and overall survival (OS) used hazard ratio (HR) for evaluation. Objective response rate (ORR) and adverse events (AEs) used odds ratio (OR) and relative risk (RR) effect sizes, respectively. R software was applied to compare the Bayesian NMA results. RESULTS: We finally included 6 studies. 1322 patients received ICI plus Chemotherapy (ICI + Chemo), ICI plus Anti-angiogenic monoclonal antibody (ICI + Antiangio-Ab), ICI plus Tyrosine kinase inhibitor (ICI + TKI), Tyrosine kinase inhibitor plus Chemotherapy (TKI + Chemo), Standard of Care (SOC), Chemotherapy (Chemo). TKI + Chemo is associated with longer PFS, higher ORR (surface under cumulative ranking curve [SUCRA], 99.7%, 88.2%), ICI + TKI achieved the longest OS (SUCRA, 82.7%). ICI + Antiangio-Ab was granted the highest safety rating for adverse events (AEs) of any grade, AEs greater than or equal to grade 3 and AEs of any grade leading to discontinuation of treatment (SUCRA, 95%, 82%, 93%). CONCLUSIONS: For NSCLC after failure of ICIs, TKI + Chemo was associated with longer PFS and higher ORR, while ICI + TKI was associated with the longest OS. In terms of safety, ICI + Antiangio-Ab was the highest.

Disulfidptosis-related long non-coding RNA signature predicts the prognosis, tumor microenvironment, immunotherapy, and antitumor drug options in colon adenocarcinoma.

This study aims to investigate the role and prognostic significance of long non-coding RNAs (lncRNAs) associated with disulfidptosis in colon adenocarcinoma (COAD). The TCGA database's clinical data and transcriptome profiles were employed. Analysis of previous studies identified 10 disulfidptosis-related genes (DRGs). We used these genes to construct a signature that could independently and accurately predict the prognosis of patients with COAD. The Kaplan-Meier (K-M) curve analysis showed that the lower-risk group had a better prognosis. With the help of multivariate Cox regression analysis, the risk score produced from the patient's signature might independently predict the outcomes. Utilizing a nomogram, the receiver operating characteristic (ROC) curve, and principal component analysis (PCA), the signature's predictive ability was also confirmed. It's interesting to note that immunotherapy, especially PD-1 immune checkpoint suppression, was more likely to benefit low-risk patients. The IC50 levels for certain anticancer agents were lower in the high-risk group. Finally, qRT-PCR analyses in colon cancer cell lines revealed elevated levels of lncRNAs CASC9, ZEB1-AS1, ATP2A1-AS1, SNHG7, AL683813.1, and AP003555.1, and reduced levels of FAM160A1-DT and AC112220.2, compared to normal cell lines. This signature offers insights into prognosis, tumor microenvironment, and options for immunotherapy and antitumor drugs in patients with COAD.

Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Lighting Up Nucleolus To Report Mitochondria Damage Using a Mitochondria-to-Nucleolus Migration Probe.

Visualization of the mitochondrial state is crucial for tracking cell life processes and diagnosing disease, while fluorescent probes that can accurately assess mitochondrial status are currently scarce. Herein, a fluorescent probe named "SYN" was designed and prepared, which can target mitochondria via the mitochondrial membrane potential. Upon pathology or external stimulation, SYN can be released from the mitochondria and accumulate in the nucleolus to monitor the status of mitochondria. During this process, the brightness of the nucleolus can then serve as an indicator of mitochondrial damage. SYN has demonstrated excellent photostability in live cells as well as an extremely inert fluorescence response to bioactive molecules and the physiological pH environment of live cells. Spectroscopic titration and molecular docking studies have revealed that SYN can be lit up in nucleoli due to the high viscosity of the nucleus and the strong electrostatic interaction with the phosphate backbone of RNA. This probe is expected to be an exceptional tool based on its excellent imaging properties for tracking mitochondrial state in live cells.

Real-Time Monitoring of mtDNA Aggregation and Mitophagy Induced by a Fluorescent Platinum Complex in Living Cells.

Mitochondrial DNA (mtDNA) is pivotal for mitochondrial morphology and function. Upon mtDNA damage, mitochondria undergo quality control mechanisms, including fusion, fission, and mitophagy. Real-time monitoring of mtDNA enables a deeper understanding of its effect on mitochondrial function and morphology. Controllable induction and real-time tracking of mtDNA dynamics and behavior are of paramount significance for studying mitochondrial function and morphology, facilitating a deeper understanding of mitochondria-related diseases. In this work, a fluorescent platinum complex was designed and developed that not only induces mitochondrial DNA (mtDNA) aggregation but also triggers mitochondrial autophagy (mitophagy) through the MDV pathway for damaged mtDNA clearance in living cells. Additionally, this complex allows for the real-time monitoring of these processes. This complex may serve as a valuable tool for studying mitochondrial microautophagy and holds promise for broader applications in cellular imaging and disease research.

Long-Chain Fluorescent Probe for Straightforward and Nondestructive Staining Mitochondria in Fixed Cells and Tissues.

Normally, small-molecule fluorescent probes dependent on the mitochondrial membrane potential (MMP) are invalid for fixed cells and tissues, which limits their clinical applications when the fixation of pathological specimens is imperative. Given that mitochondrial morphology is closely associated with disease, we developed a long-chain mitochondrial probe for fixed cells and tissues, DMPQ-12, by installing a C12-alkyl chain into the quinoline moiety. In fixed cells stained with DMPQ-12, filament mitochondria and folded cristae were observed with confocal and structural illumination microscopy, respectively. In titration test with three major phospholipids, DMPQ-12 exhibited a stronger binding force to mitochondria-exclusive cardiolipin, revealing its targeting mechanism. Moreover, mitochondrial morphological changes in the three lesion models were clearly visualized in fixed cells. Finally, by DMPQ-12, three kinds of mitochondria with different morphologies were observed in situ in fixed muscle tissues. This work breaks the conventional concept that organic fluorescent probes only stain mitochondria with normal membrane potentials and opens new avenues for comprehensive mitochondrial investigations in research and clinical settings.

The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial.

BACKGROUND: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown. METHODS: In the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated. RESULTS: No association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis. CONCLUSION: sTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02568839. Registered on 6 October 2015.

Deep Learning Assessment of Small Renal Masses at Contrast-enhanced Multiphase CT.

Background Accurate characterization of suspicious small renal masses is crucial for optimized management. Deep learning (DL) algorithms may assist with this effort. Purpose To develop and validate a DL algorithm for identifying benign small renal masses at contrast-enhanced multiphase CT. Materials and Methods Surgically resected renal masses measuring 3 cm or less in diameter at contrast-enhanced CT were included. The DL algorithm was developed by using retrospective data from one hospital between 2009 and 2021, with patients randomly allocated in a training and internal test set ratio of 8:2. Between 2013 and 2021, external testing was performed on data from five independent hospitals. A prospective test set was obtained between 2021 and 2022 from one hospital. Algorithm performance was evaluated by using the area under the receiver operating characteristic curve (AUC) and compared with the results of seven clinicians using the DeLong test. Results A total of 1703 patients (mean age, 56 years ± 12 [SD]; 619 female) with a single renal mass per patient were evaluated. The retrospective data set included 1063 lesions (874 in training set, 189 internal test set); the multicenter external test set included 537 lesions (12.3%, 66 benign) with 89 subcentimeter (≤1 cm) lesions (16.6%); and the prospective test set included 103 lesions (13.6%, 14 benign) with 20 (19.4%) subcentimeter lesions. The DL algorithm performance was comparable with that of urological radiologists: for the external test set, AUC was 0.80 (95% CI: 0.75, 0.85) versus 0.84 (95% CI: 0.78, 0.88) (P = .61); for the prospective test set, AUC was 0.87 (95% CI: 0.79, 0.93) versus 0.92 (95% CI: 0.86, 0.96) (P = .70). For subcentimeter lesions in the external test set, the algorithm and urological radiologists had similar AUC of 0.74 (95% CI: 0.63, 0.83) and 0.81 (95% CI: 0.68, 0.92) (P = .78), respectively. Conclusion The multiphase CT-based DL algorithm showed comparable performance with that of radiologists for identifying benign small renal masses, including lesions of 1 cm or less. Published under a CC BY 4.0 license. Supplemental material is available for this article.

Monocytes release cystatin F dimer to associate with Aß and aggravate amyloid pathology and cognitive deficits in Alzheimer's disease.

BACKGROUND: Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aß) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aß clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aß by monocytes in AD remains unclear. METHODS: Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aß by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aß. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. RESULTS: Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aß deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aß by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aß to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aß. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. CONCLUSIONS: Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aß metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.