Explore the vast range of titles available.

Diagnostic histopathology is a gold standard for diagnosing hematopoietic malignancies. Pathologic diagnosis requires labor-intensive reading of a large number of tissue slides with high diagnostic accuracy equal or close to 100 percent to guide treatment options, but this requirement is difficult to meet. Although artificial intelligence (AI) helps to reduce the labor of reading pathologic slides, diagnostic accuracy has not reached a clinically usable level. Establishment of an AI model often demands big datasets and an ability to handle large variations in sample preparation and image collection. Here, we establish a highly accurate deep learning platform, consisting of multiple convolutional neural networks, to classify pathologic images by using smaller datasets. We analyze human diffuse large B-cell lymphoma (DLBCL) and non-DLBCL pathologic images from three hospitals separately using AI models, and obtain a diagnostic rate of close to 100 percent (100% for hospital A, 99.71% for hospital B and 100% for hospital C). The technical variability introduced by slide preparation and image collection reduces AI model performance in cross-hospital tests, but the 100% diagnostic accuracy is maintained after its elimination. It is now clinically practical to utilize deep learning models for diagnosis of DLBCL and ultimately other human hematopoietic malignancies. Replacing diagnostic histopathology with AI-based tools requires large training datasets and robustness to sample variability. Here, the authors present a deep learning platform with high accuracy in large diffuse B-cell lymphoma diagnosis across multiple hospitals, trained on small datasets.

Shaoguang Li and colleagues identify Alox5 as a key gene that regulates the function of leukemia stem cells but not normal hematopoietic stem cells in mice, highlighting how cancer and normal stem cells distinctly self-renew and differentiate. Targeting of cancer stem cells is believed to be essential for curative therapy of cancers, but supporting evidence is limited. Few selective target genes in cancer stem cells have been identified. Here we identify the arachidonate 5-lipoxygenase (5-LO) gene ( Alox5 ) as a critical regulator for leukemia stem cells (LSCs) in BCR-ABL–induced chronic myeloid leukemia (CML). In the absence of Alox5 , BCR-ABL failed to induce CML in mice. This Alox5 deficiency caused impairment of the function of LSCs but not normal hematopoietic stem cells (HSCs) through affecting differentiation, cell division and survival of long-term LSCs (LT-LSCs), consequently causing a depletion of LSCs and a failure of CML development. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs similarly by affecting LT-LSCs, and prolonged survival. These results demonstrate that a specific target gene can be found in cancer stem cells and its inhibition can completely inhibit the function of these stem cells.

Short pitch corrugation has been a problem for railways worldwide over one century. In this paper, a parametric investigation of fastenings is conducted to understand the corrugation formation mechanism and gain insights into corrugation mitigation. A three-dimensional finite element vehicle–track dynamic interaction model is employed, which considers the coupling between the structural dynamics and the contact mechanics, while the damage mechanism is assumed to be differential wear. Various fastening models with different configurations, boundary conditions, and parameters of stiffness and damping are built up and analysed. These models may represent different service stages of fastenings in the field. Besides, the effect of train speeds on corrugation features is studied. The results indicate: (1) Fastening parameters and modelling play an important role in corrugation formation. (2) The fastening longitudinal constraint to the rail is the major factor that determines the corrugation formation. The fastening vertical and lateral constraints influence corrugation features in terms of spatial distribution and wavelength components. (3) The strengthening of fastening constraints in the longitudinal dimension helps to mitigate corrugation. Meanwhile, the inner fastening constraint in the lateral direction is necessary for corrugation alleviation. (4) The increase in fastening longitudinal stiffness and damping can reduce the vibration amplitudes of longitudinal compression modes and thus reduce the track corrugation propensity. The simulation in this work can well explain the field corrugation in terms of the occurrence possibility and major wavelength components. It can also explain the field data with respect to the small variation between the corrugation wavelength and train speed, which is caused by frequency selection and jump between rail longitudinal compression modes.

Selaginella doederleinii Hieron has been traditionally used as a folk antitumor herbal medicine in China. In this paper, the phytochemical components of the total biflavonoids extract from S. doederleinii were studied by using high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-QTOF MS/MS) in negative ion mode, and their in vitro and in vivo anticancer effects were evaluated. Four types of biflavonoids from S. doederleinii, including IC3′–IIC8′′, IC3′–IIC6′′, IC3′–IIC3′′′, and C–O linked biflavonoids were examined originally using QTOF MS/MS. The fragmentation behavior of IC3′–IIC3′′′ linked biflavonoids was reported for the first time. A total of twenty biflavonoids were identified or tentatively characterized and eight biflavonoids were found from S. doederleinii for the first time. Furthermore, the 3-(4,5-Dimethyl-2-thizolyl)-2,5-diphenyltertazolium bromide (MTT) assay and xenograft model of mouse lewis lung cancer(LLC) in male C57BL/6 mice revealed favorable anticancer properties of the total biflavonoids extracts from S. doederleinii. The results of this work could provide useful knowledge for the identification of biflavonoids in herbal samples and further insights into the chemopreventive function of this plant.

A three-dimensional (3D) finite element (FE) dynamic frictional rolling contact model is presented for the study of short pitch corrugation that considers direct and instantaneous coupling between the contact mechanics and the structural dynamics in a vehicle-track system. In this study, we examine the system responses in terms of vibration modes, contact forces and the resulting wear with smooth rail and corrugated rail with progressively increasing amplitude to infer the conditions for consistent corrugation initiation and growth. Wear is assumed to be the damage mechanism, and short pitch corrugation is modeled using wavelengths from field observations of a Dutch railway. The contribution of this paper is a global perspective of the consistency conditions that govern the evolution of short pitch corrugation. The main insights are as follows: (1) the longitudinal vibration modes are probably dominant for short pitch corrugation initiation; (2) during short pitch corrugation evolution, the interaction and consistency between longitudinal and vertical modes should determine the development of short pitch corrugation, and once a certain severity is reached, vertical modes become dominant; and (3) in the case simulated in this paper, corrugation does not grow probably due to not only the different resulting main frequencies of the vertical and longitudinal contact forces, but also the inconsistency between the frequencies of the vertical and longitudinal vibration modes and the resulting wear. It is inferred that in the continuous process of initiation and growth of the corrugation, there should be a consistency between them, and this could be done by the control of certain track parameters.

Although skeletal progenitors provide a reservoir for bone-forming osteoblasts, the major energy source for their osteogenesis remains unclear. Here, we demonstrate a requirement for mitochondrial oxidative phosphorylation in the osteogenic commitment and differentiation of skeletal progenitors. Deletion of Evolutionarily Conserved Signaling Intermediate in Toll pathways (ECSIT) in skeletal progenitors hinders bone formation and regeneration, resulting in skeletal deformity, defects in the bone marrow niche and spontaneous fractures followed by persistent nonunion. Upon skeletal fracture, Ecsit-deficient skeletal progenitors migrate to adjacent skeletal muscle causing muscle atrophy. These phenotypes are intrinsic to ECSIT function in skeletal progenitors, as little skeletal abnormalities were observed in mice lacking Ecsit in committed osteoprogenitors or mature osteoblasts. Mechanistically, Ecsit deletion in skeletal progenitors impairs mitochondrial complex assembly and mitochondrial oxidative phosphorylation and elevates glycolysis. ECSIT-associated skeletal phenotypes were reversed by in vivo reconstitution with wild-type ECSIT expression, but not a mutant displaying defective mitochondrial localization. Collectively, these findings identify mitochondrial oxidative phosphorylation as the prominent energy-driving force for osteogenesis of skeletal progenitors, governing musculoskeletal integrity. Skeletal progenitors provide a reservoir for bone-forming osteoblasts. However, the major energy source for their osteogenesis remains unresolved. Here, the authors demonstrate that ESCIT-mediated regulation of mitochondrial metabolism is required for osteogenesis.

Tanshinone IIA (Tan IIA) is an important characteristic component and active ingredient in Salvia miltiorrhiza , and its various aspects of research are constantly being updated to explore its potential application. In this paper, we review the recent progress on pharmacological activities and the therapeutic mechanisms of Tan IIA according to literature during the years 2015–2021. Tan IIA shows multiple pharmacological effects, including anticarcinogenic, cardiovascular, nervous, respiratory, urinary, digestive, and motor systems activities. Tan IIA modulates multi-targets referring to Nrf2, AMPK, GSK-3β, EGFR, CD36, HO-1, NOX4, Beclin-1, TLR4, TNF-α, STAT3, Caspase-3, and bcl-2 proteins and multi-pathways including NF-κB, SIRT1/PGC1α, MAPK, SREBP-2/Pcsk9, Wnt, PI3K/Akt/mTOR pathways, TGF-β/Smad and Hippo/YAP pathways, etc., which directly or indirectly influence disease course. Further, with the reported targets, the potential effects and possible mechanisms of Tan IIA against diseases were predicted by bioinformatic analysis. This paper provides new insights into the therapeutic effects and mechanisms of Tan IIA against diseases.

Cancer stem cells play a critical role in disease initiation and insensitivity to chemotherapy in numerous hematologic malignancies and some solid tumors, and these stem cells need to be eradicated to achieve a cure. Key to successful targeting of cancer stem cells is to identify and functionally test critical target genes and to fully understand their associated molecular network in these stem cells. Human chronic myeloid leukemia (CML) is well accepted as one of the typical types of hematopoietic malignancies that are derived from leukemia stem cells (LSCs), serving as an excellent model disease for understanding the biology of LSCs and developing effective, selective, and curative strategies through targeting LSCs. Here, we discuss LSCs in CML with a focus on identification of unique biological features of these stem cells to emphasize the feasibility and significance of specific targeting of LSCs while sparing normal stem cell counterparts in leukemia therapy. Stem Cells Translational Medicine 2019;8:768&774 BCR‐ABL changes activities of some signaling pathways independently of its kinase activity. Inhibition of BCR‐ABL kinase activity by tyrosine kinase inhibitors (TKIs) alters numerous signaling pathways in a leukemia stem cell (LSC) of chronic myeloid leukemia (CML), including JAK/STAT and PI3K/AKT. However, some signaling pathways activated by BCR‐ABL are not changed, including Alox5, Alox15, stearoyl‐CoA desaturase 1, and B lymphocyte kinase, providing an explanation for TKI resistance of LSCs in CML.

Background The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC). Results In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts. Conclusion This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.

Background: In recent years, the impact of bacterial biofilms on traumatic wounds and the means to combat them have become a major research topic in the field of medicine. The eradication of biofilms formed by bacterial infections in wounds has always been a huge challenge. Herein, we developed a hydrogel with the active ingredient berberine hydrochloride liposomes to disrupt the biofilm and thereby accelerate the healing of infected wounds in mice. Methods: We determined the ability of berberine hydrochloride liposomes to eradicate the biofilm by means of studies such as crystalline violet staining, measuring the inhibition circle, and dilution coating plate method. Encouraged by the in vitro efficacy, we chose to coat the berberine hydrochloride liposomes on the Poloxamer range of in-situ thermosensitive hydrogels to allow fuller contact with the wound surface and sustained efficacy. Eventually, relevant pathological and immunological analyses were carried out on wound tissue from mice treated for 14 days. Results: The final results show that the number of wound tissue biofilms decreases abruptly after treatment and that the various inflammatory factors in them are significantly reduced within a short period. In the meantime, the number of collagen fibers in the treated wound tissue, as well as the proteins involved in healing in the wound tissue, showed significant differences compared to the model group. Conclusion: From the results, we found that berberine liposome gel can accelerate wound healing in Staphylococcus aureus infections by inhibiting the inflammatory response and promoting re-epithelialization as well as vascular regeneration. Our work exemplifies the efficacy of liposomal isolation of toxins. This innovative antimicrobial strategy opens up new perspectives for tackling drug resistance and fighting wound infections.