Development and validation of a nomogram to predict leptomeningeal metastases in lung adenocarcinoma: Cervical lymph node metastasis is an important association factor.

BACKGROUND: The goal of this study was to create a nomogram using routine parameters to predict leptomeningeal metastases (LMs) in advanced lung adenocarcinoma (LAC) patients to prevent needless exams or lumbar punctures and to assist in accurately diagnosing LMs. METHODS: Two hundred and seventy-three patients with LMs and brain metastases were retrospectively reviewed and divided into derivation (n = 191) and validation (n = 82) cohorts using a 3:7 random allocation. All LAC patients with LMs had positive cerebrospinal fluid cytology results and brain metastases confirmed by magnetic resonance imaging. Binary logistic regression with backward stepwise selection was used to identify significant characteristics. A predictive nomogram based on the logistic model was assessed through receiver operating characteristic curves. The validation cohort and Hosmer-Lemeshow test were used for internal validation of the nomogram. RESULTS: Five clinicopathological parameters, namely, gene mutations, surgery at the primary lung cancer site, clinical symptoms of the head, N stage, and therapeutic strategy, were used as predictors of LMs. The area under the curve was 0.946 (95% CI 0.912-0.979) for the training cohort and 0.861 (95% CI 0.761-0.961) for the internal validation cohort. There was no significant difference in performance between the two cohorts (p = 0.116). In the internal validation, calibration plots revealed that the nomogram predictions were well suited to the actual outcomes. CONCLUSIONS: We created a user-friendly nomogram to predict LMs in advanced lung cancer patients, which could help guide treatment decisions and reduce unnecessary lumbar punctures.

A Facial Feature and Lip Movement Enhanced Audio-Visual Speech Separation Model.

The cocktail party problem can be more effectively addressed by leveraging the speaker's visual and audio information. This paper proposes a method to improve the audio's separation using two visual cues: facial features and lip movement. Firstly, residual connections are introduced in the audio separation module to extract detailed features. Secondly, considering the video stream contains information other than the face, which has a minimal correlation with the audio, an attention mechanism is employed in the face module to focus on crucial information. Then, the loss function considers the audio-visual similarity to take advantage of the relationship between audio and visual completely. Experimental results on the public VoxCeleb2 dataset show that the proposed model significantly enhanced SDR, PSEQ, and STOI, especially 4 dB improvements in SDR.

Efficacy and safety of endovenous microwave ablation versus laser ablation for great saphenous vein varicosis: study protocol for a multicentre, randomised controlled non-inferiority trial.

INTRODUCTION: Endovenous microwave ablation (EMA) is a relatively novel thermal ablation treatment for great saphenous vein (GSV) varicosis, and its efficacy and safety are rarely reported. This study aims to explore whether EMA can be comparable to endovenous laser ablation (EVLA), which is a widely used thermal ablation treatment in clinical practice. METHODS AND ANALYSIS: This is a multicentre, randomised controlled non-inferiority trial to compare the efficacy and safety of EMA and EVLA in patients with GSV varicosis. We will recruit 180 patients in 6 centres and randomly assign them into treatment group (EMA group) and control group (EVLA group) in a 1:1 ratio. The patients will return to the hospitals at 7 days, 3 months, 6 months and 12 months, and will be called at 1 month after the treatment for follow-up visits. The primary outcome is the occlusion rate of GSV immediately, at 6 months, and at 12 months after the treatment. The secondary outcomes are Venous Clinical Severity Score (VCSS), Aberdeen Varicose Vein Questionnaire (AVVQ) Score, operation time and instrument performance evaluation. ETHICS AND DISSEMINATION: This protocol has been approved by the Clinical Trial Ethics Committee of Beijing Hospital (2020BJYYEC-126-02), Peking Union Medical College Hospital (KS2020393), Beijing Tsinghua Changgung Hospital (No.20279-2-02), Beijing Luhe Hospital.Capital Medical University (2020-LHYW-030-01), the First Hospital of Hebei Medical University (No.2020249), and the First Affiliated Hospital of Xi'an Jiaotong University (XJTU1AF2021LSY-12). The trial results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04726124.

Synergistic autophagy blockade and VDR signaling activation enhance stellate cell reprogramming in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic tumor microenvironment (TME) consisting of abundant activated pancreatic stellate cells (PSCs). PSCs play a key role in the refractory responses of PDAC to immunotherapy and chemotherapy and deactivating PSCs into quiescence through vitamin D receptor (VDR) signaling activation is a promising strategy for PDAC treatment. We observed p62 loss in PSCs hindered the deactivation efficacy of VDR ligands, and hypothesized that reversing p62 levels by inhibiting autophagy processing, which is responsible for p62 loss, could sensitize PSCs toward VDR ligands. Herein, we constructed a PSC deactivator with dual functions of VDR activation and autophagy inhibition, utilizing a pH-buffering micelle (LBM) with an inherent ability to block autophagic flux to encapsulate calcipotriol (Cal), a VDR ligand. This Cal-loaded LBM (C-LBM) could efficiently reprogram PSCs, modulate the fibrotic TME, and alter immunosuppression. In combination with PD-1 antagonists and chemotherapy, C-LBM showed superior antitumor efficacy and significantly prolonged the survival of PDAC mice. These findings suggest that synergistic autophagy blockade and VDR signaling activation are promising therapeutic approaches to reprogram PSCs and improve the PDAC response to immunotherapy.

Macropinocytic dextran facilitates KRAS-targeted delivery while reducing drug-induced tumor immunity depletion in pancreatic cancer.

Background: Pancreatic cancer comprises not only cancer cells but also a collection of cross-talking noncancerous cells within tumor. Therefore, selective delivery of cytotoxic agents towards cancer cells and limiting the collateral damage to tumor suppressive benign cells, such as effector lymphocytes in the tumor microenvironment, is of great value. Methods: Pancreatic cancer cells harbor oncogenic KRAS which induces a constitutively high level of macropinocytosis. Inspired by such uniquity, we sought to explore the targeting potential of dextran, a biomaterial presumed to be endocytosed in the macropinocytosis dependent manner. Cell entry preference, mechanism and subcellular sorting of dextran with different molecular weights were firstly examined. Triptolide (TP), a potent cytotoxin was then set as the model payload for dextran conjugation. KRAS selectivity and the therapeutic effects of dextran-conjugated TP were investigated via both in vitro cellular studies and in vivo tumor model assessment. Results: Dextran, with a specific molecular weight of 70 kDa rather than other weights, was identified as a robust KRAS-responsive intracellular delivery carrier with enhanced entry upon KRAS mutation. The 70 kDa dextran-conjugated TP (DEX-TP) displayed greater efficacy and cellular deposition efficiency towards KRAS mutant cells than KRAS wild-type cells. Treatment with DEX-TP suppressed tumor progression in KRAS mutant pancreatic cancer orthotopic mouse models with reduced toxicity and significantly extended mouse survival time. Furthermore, the conjugate attained a more favorable therapeutic outcome in the tumor immune microenvironment than the free drug, preserving the fraction of T cells and their effector cytokines. Conclusions: In summary, macropinocytic dextran was able to provide drug delivery selectivity towards KRAS mutant cancer cells and reduce tumor immunity depletion caused by the cytotoxic drug in pancreatic cancer.

Lightweight, amphipathic and fire-resistant prGO/MXene spherical beads for rapid elimination of hazardous chemicals.

Frequent leaks of hazardous chemicals have a huge impact on human lives, property and the ecological environment. Therefore, the three-dimensional functional porous materials with high absorption efficiency and special wettability for the disposal of hazardous chemical spills is an urgent demand. In this work, a series of spherical beads consisting of partially reduced graphene oxide (prGO) and MXene (Ti3C2Tx) nanosheets were constructed by hydrogen bond induced self-assembly along with freeze-drying and thermal treatment. The lightweight and amphipathic prGO/MXene spherical beads (prGMSBDs) had millimeter-level size, spherical morphology and highly porous internal structure, which were especially suitable for eliminating hazardous chemicals. Because of their excellent thermal stability and fire retardance, the prGMSBDs could be used to absorb flammable organic liquids, reducing the fire risk of the flammable hazardous chemical spills. Indeed, the prGMSBDs exhibited outstanding absorption performances for various hazardous chemicals, including organic solvents and water-based concentrated acid and alkali. Moreover, the prGMSBDs showed relatively stable absorption performance after five absorption-drying cycles. Due to meeting the requirements of both amphipathic characteristic and flame retardancy, the prGMSBDs reported in this work may offer a promising strategy for rapidly cleaning up various hazardous chemicals and open a feasible route to protecting the combustible hazardous chemical spills from fire.

Albumin-conjugated drug is irresistible by single gene mutation of endocytic system: Verification by genome-wide CRISPR-Cas9 loss-of-function screens.

Albumin-conjugated drugs attain KRAS mutant cancer targeting through KRAS-enhanced macropinocytosis and intensified lysosomal degradation due to reduced neonatal Fc receptor (FcRn) expression. The cytosolic delivery of active payloads relies on endocytosis and subsequent intracellular processing of albumin delivery vehicles, wherein complex regulatory mechanisms and molecular machineries are closely involved. Despite the obvious merit of KRAS targeting, could such an endocytic process involving extra molecular regulators also bring about extra vulnerabilities to albumin-conjugated drugs, particularly, unexpected drug resistance? To assess such risks, here we performed an unbiased drug resistance mechanism comparison in pancreatic cancer, between free triptolide (TP, a potent cytotoxin) and albumin-conjugated TP, using genome-wide CRISPR-Cas9 loss-of-function screens. GTF2H5, a subunit of GTF2H transcription factor complex, was the only hit identified regardless of forms of TP treatment. With drug efficacy tests on GTF2H5 knockout clones, we further concluded that GTF2H5 deficiency conferred drug resistance primarily due to the pharmacological mechanism of action (MoA) of TP. In addition, molecules previously considered to be able to affect endocytosis and intracellular processing were not enriched during the screening with albumin-conjugated TP. With the aid of genome-wide CRISPR-Cas9 loss-of-function screens, we conclude that the pharmacological resistance of the active payload, rather than any potential loss-of-function mutations in endocytic molecular machineries, is the solely crucial drug resistance mechanism of albumin-conjugated drugs.

KRAS-enhanced macropinocytosis and reduced FcRn-mediated recycling sensitize pancreatic cancer to albumin-conjugated drugs.

Pancreatic ductal adenocarcinoma (PDAC) is a dominantly (~95%) KRAS-mutant cancer that has extremely poor prognosis, in part this is due to its strong intrinsic resistance towards almost all therapeutic agents. PDAC relies heavily on KRAS-transformed metabolism, including enhanced macropinocytosis and catabolism of extracellular albumin, to maintain its proliferation and progression. However, it has yet to be validated that whether such transformed metabolism could be exploited for the drug delivery to open therapeutic windows of cytotoxic agents in KRAS-mutant PDAC. In this study, we attempt to answer this question by focusing on the impact of two critical regulators of albumin catabolism, KRAS and the neonatal Fc receptor (FcRn), on the sensitivity of PDAC to doxorubicin (DOX, a model cytotoxic agent) and albumin-conjugated doxorubicin (DOX-ALB). Using cell lines and cell-derived xenografts with different KRAS genotypes and FcRn levels, we demonstrated that KRAS-enhanced macropinocytosis and reduced FcRn expression sensitize PDAC to DOX-ALB but not free DOX. In both in vitro and in vivo comparsion, the DOX-ALB demonstrated ~10 times enlarged therapeutic window compared with free DOX, in PDAC with KRAS mutation and reduced FcRn level, two events appear to occur simultaneously in the investigated PDAC. In summary, we conclude that albumin conjugation is an exploitable drug delivery strategy that significantly opens the therapeutic windows of otherwise undevelopable anti-cancer agents for KRAS-mutant PDAC therapy, and creates a new landscape for clinical evaluation and future translation of such compounds.

A Fast and On-Machine Measuring System Using the Laser Displacement Sensor for the Contour Parameters of the Drill Pipe Thread.

The inconvenient loading and unloading of a long and heavy drill pipe gives rise to the difficulty in measuring the contour parameters of its threads at both ends. To solve this problem, in this paper we take the SCK230 drill pipe thread-repairing machine tool as a carrier to design and achieve a fast and on-machine measuring system based on a laser probe. This system drives a laser displacement sensor to acquire the contour data of a certain axial section of the thread by using the servo function of a CNC machine tool. To correct the sensor's measurement errors caused by the measuring point inclination angle, an inclination error model is built to compensate data in real time. To better suppress random error interference and ensure real contour information, a new wavelet threshold function is proposed to process data through the wavelet threshold denoising. Discrete data after denoising is segmented according to the geometrical characteristics of the drill pipe thread, and the regression model of the contour data in each section is fitted by using the method of weighted total least squares (WTLS). Then, the thread parameters are calculated in real time to judge the processing quality. Inclination error experiments show that the proposed compensation model is accurate and effective, and it can improve the data acquisition accuracy of a sensor. Simulation results indicate that the improved threshold function is of better continuity and self-adaptability, which makes sure that denoising effects are guaranteed, and, meanwhile, the complete elimination of real data distorted in random errors is avoided. Additionally, NC50 thread-testing experiments show that the proposed on-machine measuring system can complete the measurement of a 25 mm thread in 7.8 s, with a measurement accuracy of ±8 µm and repeatability limit ≤ 4 µm (high repeatability), and hence the accuracy and efficiency of measurement are both improved.