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Introduction Cells burn sugars and fatty acids to harvest free energy for living, which, however, inevitably results in the production of reactive oxygen species (ROS), the harmful derivatives of molecular [...], Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.

Introduction Various types of viruses are capable of infecting the host, causing viral persistence, latency, and host tumorigenesis, typically including liver, cervical, and nasopharyngeal cancers and some subtypes of leukemia. [...], Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-[beta] treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/ aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-[beta] signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-[beta] correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-[beta] provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.

The high-frequency excitation generated by the wheel polygon seriously affects the safety of the train. In order to explore the evolution mechanism of wheel polygonisation, a long-term prediction model of wheel circumferential wear on both sides of the wheelset is proposed. Based on a new updating strategy, the model is implemented by combining the coupled vehicle/track dynamic model and the wheel circumferential wear model. The wheel circumferential wear model is implemented by local tangential contact model FaStrip and USFD (a wear model proposed by The University of Sheffield). By analysing the measured data, five wheel circumferential states are summarised, which are employed as wheel non-circular excitations to analyse the evolution of the wheel polygons on both sides of the wheelset. The results show that the same order of the polygonal wheels on both sides of the wheelset is the main reason for the evolution of the order of polygonal wheels in integer multiples. When the circumferences of the wheels on both sides are in an asymmetric state, the wheels on both sides will interact with each other, and the final circumferences of the wheels will gradually evolve into mixed polygonal circumferences related to the initial orders. [ABSTRACT FROM AUTHOR]

The dynamical performance of vehicles on railway tracks is significantly influenced by wheel‐rail interactions, which makes the wheel‐rail force be a safety indicator of vehicle systems. Owing to the high cost of direct measurement, inversion models are widely used to measure the wheel‐rail force. This study proposes a model called the Lightweight Wheel‐Rail Force Inversion Model (LFIM) to calculate the wheel‐rail force by using vibration signals collected from the vehicle system. The model can extract the relevant features, and outperforms prevalent models. It is also resource efficient and small in size, which makes it suitable for edge computing environment. The basic LFIM yielded a correlation coefficient of 0.99 in experiments, significantly higher than the value recorded by the traditional dynamic methods. The compressed LFIM yielded a 91% reduction in floating‐point operations (FLOPs) and had an R2 score of 90%, which satisfies the demands for vehicle monitoring. By balancing accuracy and size, LFIM is a feasible model to deploy on edge devices to monitor the wheel‐rail force in real‐time and assess the safety of railway vehicles. [ABSTRACT FROM AUTHOR]

Weak immunogenicity of tumor cells is a root cause for the ultimate failure of immunosurveillance and immunotherapy. Although tumor evolution can be shaped by immunoediting toward a less immunogenic phenotype, mechanisms governing the initial immunogenicity of primordial tumor cells or original cancer stem cells remain obscure. Here, using a single tumor-repopulating cell (TRC) to form tumors in immunodeficient or immunocompetent mice, we demonstrated that immunogenic heterogeneity is an inherent trait of tumorigenic cells defined by the activation status of signal transducer and activator of transcription 1 (STAT1) protein in the absence of immune pressure. Subsequent investigation identified that the RNA binding protein cold shock domain–containing protein E1 (CSDE1) can promote STAT1 dephosphorylation by stabilizing T cell protein tyrosine phosphatase (TCPTP). A methyltransferase SET and MYN domain–containing 3 (SMYD3) was further identified to mediate H3K4 trimethylation of CSDE1 locus, which was under the regulation of mechanotransduction by cell-matrix and cell-cell contacts. Thus, owing to the differential epigenetic modification and subsequent differential expression of CSDE1, nascent tumorigenic cells may exhibit either a high or low immunogenicity. This identified SMYD3-CSDE1 pathway represents a potential prognostic marker for cancer immunotherapy effectiveness that requires further investigation. Shocking the immune system: One way tumors overcome immunosurveillance and immunotherapy is through their inherent lack of immunogenicity, however, the mechanisms underlying this are not well understood. Here, Lv et al. have utilized a single tumor-repopulating cell model in mice to demonstrate that immunogenic heterogeneity is regulated by signal transducer and activator of transcription 1 (STAT1) and cold shock domain containing protein E1 (CSDE1). CSDE1 is additionally regulated epigenetically by mechanotransduction and has the propensity to exhibit either high or low immunogenicity. Thus, CSDE1 expression could be a potential marker for cancer immunotherapy response that requires further investigation. — DH [ABSTRACT FROM AUTHOR]

In this study, the probability integral method, Synthetic Aperture Radar Interferometry (InSAR), and the Okada dislocation model were collaboratively used to analyze deformation in the Alhada Pb-Zn mine. The predicted deformation values of the subsidence centers in three subsidence areas were 107 mm, 120 mm, and 83 mm, respectively, as predicted using the probability integral method. The coherent scatterer InSAR technique was used to analyze the time-series deformation of the mining area, and the same subsidence center locations and similar deformation values were observed. The Okada dislocation model was used to invert the optimal parameters of the underground-mining ore body causing the surface subsidence, indicating that the surface subsidence is mainly caused by the mining of ore bodies in the 888 and 848 middle sections. We further simulated ground deformation using the multi-source Okada model. The results showed that the predicted and modeled deformations are highly correlated with the observed deformation. Through the analysis and comparison of the InSAR results, it was concluded that the three subsidence areas do not threaten the stability of the main buildings in the mining area. Using theoretical, observational, and modeling methods, the development and evolution of the subsidence area in mines can be established, which could provide basic data for subsidence control work and guarantee mine production safety. [ABSTRACT FROM AUTHOR]

A long-term tracking test was performed on a newly designed high-speed train with the nominal speed of 250 km/h. The wheel roughness and structural vibration were both recorded during two re-profiling cycles. The 3rd order polygonal wear was observed in the early stage. The vibration of the axlebox can be aggravated even at lower speed when the passing frequency of polygonal wear approaches the P2 resonance frequency. Subsequently, the 22nd–25th and 14th–15th order developed. The trend analysis suggests that the development of high-order polygonal wear is exponential-like. Moreover, a localised decline is explored during the development progress due to the change of route, which indicates the polygonal wear can be suppressed by reducing the proportion of constant-speed operation. It is also found that the acceleration amplitude of 550–650 Hz shows the most remarkable rise with the mileage, following the 300–400 Hz. However, there is a slight difference of characteristic frequency between the initially dominant peak and the finally developed order. The high-frequency vibration induced by high-order polygonal wear can be noticed on the entire vehicle, and it transmits between the adjacent wheels through the rail. [ABSTRACT FROM AUTHOR]

Aims. Metformin is an oral antidiabetic agent that has been widely prescribed for the treatment of type II diabetes. In recent years, anticancer properties of metformin have been revealed for numerous human malignancies. However, there are few indications available regarding the feasibility and safety of these studies in an advanced extrahepatic cholangiocarcinoma (EHCC) population. This study is aimed at evaluating the feasibility, safety, and value of metformin use and survival in patients with advanced EHCC. Methods. All patients with advanced EHCC observed at Fuyang People's Hospital between January 2015 and November 2020 were included in the study. Case data, clinical information, and imaging results were abstracted from the self-administered questionnaire and electronic medical record. All patients were divided into study subjects and control subjects, and the study subjects were given metformin, 0.5 g, three times a day, while control subjects were without metformin. The metformin use and survival time of the subjects were asked by telephone, out-patient, or door-to-door visit, after they left the hospital. Results. One hundred and thirty-three study cases and 589 controls were included in the analysis. This study showed that metformin use cannot improve the overall survival rate of patients with advanced EHCC ([95% CI]: -17.05-0.375, t = − 1.889 , P value = 0.061), but the survival time of patients with drainage treatment from control group (n = 496) was significantly shorter than that of patients with drainage treatment from the study group (n = 113), and the difference was statistically significant (z = − 2.230 , P value = 0.026). There were significant differences between metformin used before or after the diagnosis of advanced EHCC (OR[95% CI], 3.432[2.617-4.502]; P value = 0.001) in survival time. And there was significant difference between the duration of metformin use and survival prognosis (OR[95% CI], 2.967[1.383-6.368]; P = 0.005). Conclusion. Metformin can improve the survival of advanced EHCC patients who underwent drainage treatment, especially for metformin use after diagnosis of advanced EHCC and long duration of metformin. [ABSTRACT FROM AUTHOR]

Gasdermin E as troublemaker: Cytokine release syndrome (CRS) is a complication associated with chimeric antigen receptor (CAR) T cell therapy in cancer patients. The mechanisms that trigger CRS are not clear, but Liu et al. describe a role for the pore-forming protein gasdermin E (GSDME) during tumor cell pyroptosis, which contributes to CRS. CAR T cells release granzyme B, which activates caspase 3 and cleaves GSDME in target tumor cells and causes pyroptosis. Pyroptosis by GSDME leads to activation of caspase 1 and GSDMD in macrophages, which is critical for triggering CRS. Elevated levels of GSDME in cancer patients positively correlated to CRS severity. In addition, the ability of CAR T cells to induce pyroptosis is associated with the levels of perforin and granzyme B released. Cytokine release syndrome (CRS) counteracts the effectiveness of chimeric antigen receptor (CAR) T cell therapy in cancer patients, but the mechanism underlying CRS remains unclear. Here, we show that tumor cell pyroptosis triggers CRS during CAR T cell therapy. We find that CAR T cells rapidly activate caspase 3 in target cells through release of granzyme B. The latter cleaves gasdermin E (GSDME), a pore-forming protein highly expressed in B leukemic and other target cells, which results in extensive pyroptosis. Consequently, pyroptosis-released factors activate caspase 1 for GSDMD cleavage in macrophages, which results in the release of cytokines and subsequent CRS. Knocking out GSDME, depleting macrophages, or inhibiting caspase 1 eliminates CRS occurrence in mouse models. In patients, GSDME and lactate dehydrogenase levels are correlated with the severity of CRS. Notably, we find that the quantity of perforin/granzyme B used by CAR T cells rather than existing CD8+ T cells is critical for CAR T cells to induce target cell pyroptosis. [ABSTRACT FROM AUTHOR]

Identification of mechanisms that program early effector T cells to either terminal effector T (T eff ) or memory T (T m ) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early T eff cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8 + T eff cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8 + T cells up-regulate HIF-1α to compete with AhR for HIF-1β, leading to the loss of AhR activity in HIF-1α high short-lived effector cells, but sustained in HIF-1α low memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8 + MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how T eff cells are regulated to differentiate into memory cells., Competing Interests: Competing interests statement:The authors declare no competing interest.

The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.

Solid tumor cells live in a highly dynamic mechanical microenvironment. How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma. Here, we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells. Mechanistically, integrin β8 was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein (YAP). YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), allowing MAFG to transactivate the stemness genes NANOG , SOX2 , and NESTIN . Inactivation also restored β8 expression, thereby forming a closed mechanical loop. Importantly, MAFG expression is correlated with worse prognosis. Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation, which has therapeutic implications for exploring innovative strategies to attack malignancies., (Copyright © 2023 Jiadi Lv et al.)

Backgrounds: Proficient-mismatch-repair or microsatellite stability (pMMR/MSS) colorectal cancer (CRC) has limited efficacy for immune checkpoint blockade (ICB) therapy and its underlying mechanism remains unclear. Guanylate binding protein 2 (GBP2) is a member of the GTPase family and is crucial to host immunity against pathogens. However, the correlations between GBP2 and immunosurveillance and immunotherapy for pMMR/MSS CRC have not been reported., Methods: Unsupervised clustering was employed to classify immune class and non-immune class in 1424 pMMR/MSS patients from six independent public datasets. This binary classification was validated using immune cells or response related signatures. The correlation between GBP2 and immune microenvironment was explored using well-established biological algorithms, multiplex immunohistochemistry (mIHC), in vitro and in vivo experiments., Results: We classified 1424 pMMR/MSS CRC patients into two classes, 'immune' and 'non-immune', and GBP2 was identified as a gene of interest. We found that lower GBP2 expression was correlated with poor prognosis and metastasis. GBP2 expression was also upregulated in the immune class and highly associated with interferon-γ (IFN-γ) signaling pathway and CD8 +T cell infiltration using gene set enrichment analysis, gene ontology analysis, single-cell sequencing and mIHC. Moreover, reduced GBP2 expression inhibited the antigen processing and presentation machinery and CXCL10/11 expression in MSS CRC cells on IFN-γ stimulation. A Transwell assay revealed that deletion of GBP2 in murine MSS CRC cells reduced CD8 +T cell migration. Mechanistically, GBP2 promoted signal transducer and transcription activator 1 (STAT1) phosphorylation by competing with SHP1 for binding to STAT1 in MSS CRC cells. Finally, an unsupervised subclass mapping (SubMap) algorithm showed that pMMR/MSS patients with high GBP2 expression may correlate with a favorable response to anti-PD-1 therapy. We further confirmed that GBP2 knockout reduced CD8 +T cell infiltration and blunted the efficacy of PD-1 blockade in tumor-bearing mice., Conclusions: Our study reveals that pMMR/MSS CRC is immunogenically heterogeneous and that GBP2 is a promising target for combinatorial therapy with ICB., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Hypoxia is known to be commonly present in breast tumor microenvironments. Stem-like cells that repopulate breast tumors, termed tumor-repopulating cells (TRC), thrive under hypoxic conditions, but the underlying mechanism remains unclear. Here, we show that hypoxia promotes the growth of breast TRCs through metabolic reprogramming. Hypoxia mobilized transcription factors HIF1α and FoxO1 and induced epigenetic reprogramming to upregulate cytosolic phosphoenolpyruvate carboxykinase (PCK1), a key enzyme that initiates gluconeogenesis. PCK1 subsequently triggered retrograde carbon flow from gluconeogenesis to glycogenesis, glycogenolysis, and the pentose phosphate pathway. The resultant NADPH facilitated reduced glutathione production, leading to a moderate increase of reactive oxygen species that stimulated hypoxic breast TRC growth. Notably, this metabolic mechanism was absent in differentiated breast tumor cells. Targeting PCK1 synergized with paclitaxel to reduce the growth of triple-negative breast cancer (TNBC). These findings uncover an altered glycogen metabolic program in breast cancer, providing potential metabolic strategies to target hypoxic breast TRCs and TNBC. SIGNIFICANCE: Hypoxic breast cancer cells trigger self-growth through PCK1-mediated glycogen metabolism reprogramming that leads to NADPH production to maintain a moderate ROS level., (©2021 American Association for Cancer Research.)

Biomechanics is a fundamental feature of a cell. However, the manner by which actomysin tension affects tumor immune evasion remains unclear. Here we show that although cytotoxic T lymphocytes (CTL) can effectively destroy stiff differentiated tumor cells, they fail to kill soft tumor-repopulating cells (TRC). TRC softness prevented membrane pore formation caused by CTL-released perforin. Perforin interacting with nonmuscle myosin heavy-chain 9 transmitted forces to less F-actins in soft TRC, thus generating an inadequate contractile force for perforin pore formation. Stiffening TRC allowed perforin the ability to drill through the membrane, leading to CTL-mediated killing of TRC. Importantly, overcoming mechanical softness in human TRC also enhanced TRC cell death caused by human CTL, potentiating a mechanics-based immunotherapeutic strategy. These findings reveal a mechanics-mediated tumor immune evasion, thus potentially providing an alternative approach for tumor immunotherapy. SIGNIFICANCE: Tumor-repopulating cells evade CD8 + cytolytic T-cell killing through a mechanical softness mechanism, underlying the impediment of perforin pore formation at the immune synapse site., (©2020 American Association for Cancer Research.)

Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here, we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2. Tet2 epigenetically activated cell-cycle-inhibiting genes p21 and p27 to induce dormancy, but also caused downregulation of integrin β3 to maintain dormancy. This stiffness-mediated dormancy was recapitulated in mouse models for both murine and primary human melanoma TRCs. These data identify an epigenetic program directed by mechanics, which drives highly tumorigenic TRCs to enter dormancy in a stiff mechanical environment. Significance: A mechanics-directed epigenetic program enables tumor-repopulating cells to enter dormancy in a stiff mechanical environment. Cancer Res; 78(14); 3926-37. ©2018 AACR ., (©2018 American Association for Cancer Research.)

In the originally published version of this Article, images in Fig. 5n were inadvertently replaced with duplicates of images in Fig. 5o during the production process. This has now been corrected in both the PDF and HTML versions of the Article.

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca 2+ release via the lysosomal Ca 2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca 2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.