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Background: Glioma, the most frequent central nervous system malignancy, is often promoted by the overexpression of Fos-like antigen 1 (FOSL1). However, the regulation of FOSL1 remains unexplored. The present study aimed to investigate the regulatory mechanism of FOSL1 to identify potential therapeutic targets for glioblastoma. Methods: This study's initial investigation utilized dual-luciferase reporter gene assays and quantitative polymerase chain reaction (qPCR) assays to establish that Kruppel-like factor 14 (KLF14) inhibits the transcription of FOSL1. Subsequent immunohistochemistry and western blotting (WB) assays on glioma tissues confirmed a negative association between FOSL1 and KLF14. This study generated KLF14 knockdown cells and double knockdown cells of KLF14 and FOSL1 and further assessed cell growth through various experimental methods. The impact of KLF14 on tumor cell migration via FOSL1 was determined using qPCR and WB assays. A xenograft tumor model was utilized to verify tumor growth suppression by KLF14. Results: The present study demonstrated that KLF14 restrains FOSL1 transcription and is inversely correlated with FOSL1 in glioma tissues. KLF14 overexpression was found to counteract FOSL1's effect on cell migration and epithelial-to-mesenchymal transition in glioma cells, which coincided with decreased Snail2 and cluster of differentiation 44 (CD44) expressions. Further, KLF14 overexpression was shown to hinder tumor progression in vivo. Conclusion: This study highlights that FOSL1 is negatively regulated by KLF14 in glioblastoma and suggests that KLF14 overexpression can mitigate tumor growth by inhibiting FOSL1, thus identifying KLF14 as a novel molecular target for treating glioblastoma. Further research into the interplay and regulatory dynamics between KLF14 and FOSL1 under varying stress conditions can enhance the precision of glioblastoma treatment.

Objective: Recent studies revealed the effect of valproate (VPA) on brain structural changes in idiopathic generalized epilepsy (IGE). We aimed to investigate the volume of the entire hippocampus and subfields in patients with IGE, and explored their associations with VPA use. Methods: A total of 211 patients with IGE and 97 healthy controls (HCs) were enrolled in this study. All participants underwent T1-weighted images. Each hippocampus was segmented into seven subfields using HippUnfold. The volumes of bilateral hippocampi and each hippocampal subfield were evaluated. Spearman correlation analyses were performed to identify VPA use related abnormalities in IGE. Subgroup analyses for juvenile myoclonic epilepsy (JME), epilepsy with generalized tonic–clonic seizures alone (GTCA), and absence epilepsy (AE) were conducted. Results: The volumes of bilateral hippocampi were reduced in IGE compared with HCs. Subgroup analysis showed significant volume reductions in right hippocampus and its subfields in GTCA. Additionally, significant volume reductions were detected in bilateral hippocampal volumes and subfields in IGE patients currently taking VPA compared with HCs. A negative correlation was observed between the left CA2 volume and the age of onset. Conclusions: Our study revealed volume reductions in bilateral hippocampi in IGE, as well as in the right hippocampus and its subfields in GTCA. Abnormalities in both subfields and the whole hippocampus were associated with VPA use. These findings suggest that VPA may have more extensive neuroanatomical effects in IGE, potentially accounting for the heterogeneity observed in neuroimaging studies.

Objective: To explore the associations between dietary zinc intake and cardiovascular diseases (CVDs), including congestive heart failure (CHF), coronary heart disease (CHD), angina, heart attack, and cerebrovascular accident (CVA), this study was performed. Setting: Data from the National Health and Nutrition Examination Survey (2005–2018) were used in this study. Dietary zinc intake was stratified into quartiles. Restricted cubic splines were constructed to assess nonlinear associations and identify cut-off values based on the type of nonlinearity. Binary logistic regressions were performed using the cut-offs. Results: Positive associations were detected between the second, third, and fourth quantiles of dietary zinc intake and decreased risks of overall CVDs (Q2: OR = 0.83, 95 % CI = 0.72–0.96; Q3: OR = 0.83, 95 % CI = 0.71–0.96; Q4: OR = 0.79, 95 % CI = 0.67–0.93). The second, third, and fourth quantiles were significantly associated with decreased risks of various CVDs (all P 0.05). Restricted cubic spline regression revealed significant nonlinear trends for associations of dietary zinc intake with the risk of developing CVDs and CHF (both P for nonlinear

Human enteroviruses (EVs) represent a global public health concern due to their association with a range of serious pediatric illnesses. Despite the high morbidity and mortality exerted by EVs, no broad-spectrum antivirals are currently available. Herein, we presented evidence that doxycycline can inhibit in vitro replication of various neurotropic EVs, including enterovirus A71 (EV-A71), enterovirus D68 (EV-D68), and coxsackievirus (CV)-A6, in a dose-dependent manner. Further investigations indicated that the drug primarily acted at the post-entry stage of virus infection in vitro, with inhibitory effects reaching up to 89 % for EV-A71 when administered two hours post-infection. These findings provide valuable insights for the development of antiviral drugs against EV infections.

This study introduces “Specialis Revelio,” a sophisticated text pre-processing module aimed at enhancing the detection of disguised toxic content in online communications. Through a blend of conventional and novel pre-processing methods, this module significantly improves the accuracy of existing toxic text detection tools, addressing the challenge of content that is deliberately altered to evade standard detection methods. • Integration with Existing Systems: “Specialis Revelio” is designed to augment popular toxic text classifiers, enhancing their ability to detect and filter toxic content more effectively. • Innovative Pre-processing Methods: The module combines traditional pre-processing steps like lowercasing and stemming with advanced strategies, including the handling of adversarial examples and typo correction, to reveal concealed toxicity. • Validation through Comparative Study: Its effectiveness was validated via a comparative analysis against widely used APIs, demonstrating a marked improvement in the detection of various toxic text indicators.

ABSTRACT: Objectives: The aims of this study were to investigate the characteristics of Klebsiella pneumoniae meningitis and the impact of convergence of carbapenem resistance and hypervirulence on patient mortality.Methods: Antimicrobial resistance and virulence-related genes were investigated in 25 K. pneumoniae strains causing meningitis. Clinical data for 25 patients from February 2009 to February 2019 were evaluated. Multilocus sequence typing (MLST), serotyping, analysis of mobile genetic elements and pulsed-field gel electrophoresis (PFGE) were performed. GraphPad Prism was used for statistical analysis.Results: The mortality rate of patients with K. pneumoniae meningitis was 30.0%. Significant differences were observed between non-survivor and survivor groups regarding mechanical ventilation, peripheral deep vein catheter insertion and GCS score, but not sex, age or meningeal integrity destruction. Multidrug resistance was observed in 21 isolates. Rates of detection for each virulence gene ranged from 4.0% for wzy-K1 to 100.0% for entB. Detection rates of carbapenem-resistant K. pneumoniae (CRKP), hypervirulent K. pneumoniae (HvKP) and hypervirulent carbapenem-resistant K. pneumoniae (Hv-CRKP) were 68.0%, 68.0% and 48.0%, respectively. In total, 16 clusters and 19 clones were identified among the 25 isolates. Mortality rates differed significantly between the non-Hv-CRKP (1/11) versus Hv-CRKP groups (5/9), but were comparable in the carbapenem-susceptible K. pneumoniae versus CRKP groups and the classical K. pneumoniae versus HvKP groups.Conclusions: Klebsiella pneumoniae meningitis is associated with high mortality. Klebsiella pneumoniae-induced meningitis has highly divergent origins. Convergence of carbapenem resistance and hypervirulence leads to high mortality in patients with K. pneumoniae meningitis, which is of great clinical concern.

Type 2 diabetes (T2D) is one of the most escalating global metabolic diseases, which is highly associated with insulin resistance (IR) and risk of combination with nonalcoholic fatty liver disease (NAFLD). Previous studies suggest that soluble klotho (sKL) could serve as a circulating hormone to mediate energy metabolism, but the detailed mechanism is poorly understood. In this study, we generated T2D models of wild-type (WT), sKL heterozygous (KL+/−), and sKL transgenic (TgKL) mice continuously fed a high-fat diet (HFD) and constructed L02 cell lines that stably overexpress sKL to investigate the effect of sKL on hepatic glucose and lipid metabolism. Surprisingly, we discovered that sKL deficiency resulted in exacerbated diabetic phenotypes and hepatic glucolipid metabolism disorders in HFD-fed KL+/− diabetic mice (KL+/− DM), whereas TgKL diabetic mice (TgKL DM) exhibited ameliorated diabetic phenotypes and decreased IR. Mechanistic studies in vitro and in vivo demonstrated that sKL could inhibit the PI3K/AKT/mTORC1 signaling to upregulate peroxisome proliferator-activated receptor α (PPARα) expression by directly interacting with type 1 insulin-like growth factor receptor (IGF1R) in HFD-fed T2D mice. Thus, sKL could improve hepatic glucolipid homeostasis to ameliorate diabetic phenotypes and lipid accumulation and may function as a potential therapeutic target for the treatment of T2D and reduce the risk of NAFLD.

Dickkopf-2 (DKK2) is an antagonist of canonical Wnt signaling, which is involved in various biological processes of development, such as epidermal appendage formation and eye development. To identify underlying effects of DKK2 during embryonic development, we generated a DKK2 homozygous knockout human embryonic stem cell (hESC) line through the CRISPR/Cas9 genome-editing technology. This cell line, which maintains normal stem cell morphology and stably expresses pluripotent markers, could provide an ideal platform for exploring the role of DKK2 in embryonic development. In addition, Zeocin selection combined with tiny clone picking might be a highly efficient way to generate gene-knockout hESC lines.

Summary: Non-oxidative propane dehydrogenation (PDH) is an attractive reaction from both an industrial and a scientific viewpoint because it allows direct large-scale production of propene and fundamental analysis of C-H activation respectively. The main challenges are related to achieving high activity, selectivity, and on-stream stability of environment-friendly and cost-efficient catalysts without non-noble metals. Here, we describe an approach for the preparation of supported ultrasmall ZnO nanoparticles (2–4 nm, ZnO NPs) for high-temperature applications. The approach consists of encapsulation of NPs into a nitrogen-doped carbon (NC) layer in situ grown from zeolitic imidazolate framework-8 on a Silicalite-1 support. The NC layer was established to control the size of ZnO NPs and to hinder their loss to a large extent at high temperatures. The designed catalysts exhibited high activity, selectivity, and on-stream stability in PDH. Propene selectivity of about 90% at 44.4% propane conversion was achieved at 600°C after nearly 6 h on stream. : Chemistry; Catalysis; Nanoparticles Subject Areas: Chemistry, Catalysis, Nanoparticles

Objectives: Brain abscess (BA) is a rare and life-threatening disease which remains to be a challenge for physicians despite recent advances in both the diagnosis and treatment strategies. Appropriate management of brain abscesses requires a combined surgical and medical approach to prevent associated life-threatening complications. In clinical practice, new diagnostic techniques, such as metagenomic next-generation sequencing (mNGS) and quantitative electroencephalogram (qEEG), can help physicians identify the causative pathogens of brain abscesses in order to provide early pathogen-targeted therapy. Clinical presentation: Here, we report a case of a 27-year-old Chinese woman with a Prevotella loescheii brain abscess into ventricular system. The diagnosis of the causative pathogen was identified by mNGS of abscess drainage fluid, leading to precise and targeted antimicrobial therapy and successful management of the abscess. We, therefor, avoided devastating consequences of the intraventricular rupture of the brain abscess. Conclusion: Appropriate management of BA requires a combination of both surgical and medical approaches. The increasing availability of molecular diagnostic techniques, such as the mNGS that is used to elucidate the microbial composition of the abscesses for definitive diagnosis, is likely to drive the future development of optimal treatment strategies for BA.

In this study, the processing parameters of a laser powder bed fusion (LPBF)-fabricated CoCrNi alloy were systematically investigated for their impact on mechanical properties, microstructure, and fracture characteristics when the relative density exceeds 99%. The maximum relative density of 99.89% was attained at a laser power of 225 W, and scan speed of 1000 mm/s, accompanied by a hardness value of 276.83 HV. However, it is important to note that the highest relative density did not correspond to the maximum σUTS. Tensile testing revealed that increasing the laser power at the same scan speeds led to a decrease in elongation. The LPBF-fabricated CoCrNi alloy exhibited enhanced defect tolerance due to its cellular microstructure, which confined ductile dimple sizes to the nanoscale and impeded crack propagation through pinning effects. At scan speeds of 1000 mm/s and energy densities below 83 J/mm³, an increased presence of unmelted powder and pores was observed. Besides, it was confirmed that the crystallographic texture displayed the strongest orientation within the sample. Theoretical calculations indicated that over 50% of the yield strength is attributed to the dislocation structure. These findings contribute to the process optimization of LPBF, providing a valuable reference for adjusting process parameters to enhance material mechanical properties, particularly when targeting relative densities above 99%.

Plasma-wall interaction (PWI) is a critical concern in tokamaks because of its significant impact on the lifetimes of plasma-facing materials (PFMs), fuel retention, and plasma performance. In 2020, the Experimental Advanced Superconducting Tokamak (EAST) PFMs were upgraded to predominantly metallic walls. Following the 2021 experimental campaign, the deposition distribution and fuel retention on the surfaces of the PFMs along both the poloidal and toroidal directions were analyzed. The poloidal tests commenced at the high-field side (HFS), proceeded to the lower divertor, then to the low-field side (LFS), and finally to the upper divertor. The toroidal tests were performed at the midplane of the HFS, beginning from port A and ending at port P. The distributions of the deposits in the poloidal and toroidal directions were clearly asymmetrical. Mo and Fe particles sputtered from the first wall and inner stainless steel (SS) components were prone to deposition in the lower divertor region, as evidenced by the fact that the elemental content in the far-SOL region of the inner divertor exhibited Mo and Fe peaks, as did both the near- and far-SOL regions of the outer divertor. In addition, quick re-deposition of W and Fe was observed, as demonstrated by the fact that their contents near the erosion sources were higher than those farther away along the toroidal first wall on the HFS. This tendency was stronger for W than for Fe. Further analysis indicated that the deposits consisted of Li, C, O, W, Mo, Fe, Cu, and Ni. The Li and Fe contents were much higher than those of other metal impurities, with peak values of 8.17 μg/mm2 and 7.78 μg/mm2, respectively. The Li content decreased along the HFS first wall from 8.17 μg/mm2 at P-2 to 1.82 μg/mm2 at P-22, and then increased to 2.72 μg/mm2 at P-32 in the divertor, while the Fe content was higher around the top side and the midplane of the HFS. The deposited Li originated from routine wall conditioning and existed primarily in the form of Li2CO3. Additionally, other metal impurities deposited on the Li2CO3 surfaces exhibited various irregular shapes, often appearing as aggregated and recrystallized small particles. Furthermore, significant deuterium (D) retention on the order of 1021 atoms/m2 was measured on all the analyzed SiC-coated graphite tiles on the HFS. The D content at location P-10 at the midplane was the highest along the poloidal direction of the HFS because it was directly facing the NBI beam.

The oxidation resistance of Mg–Zn–Zr (ZK60) alloys with the addition of minor rare-earth element (RE) oxides (CeO2, La2O3) was investigated in 420 °C in air and pure O2 environments. It was revealed that the oxidation behavior of ZK60, ZK60-La2O3 and ZK60-CeO2 is different. In comparison to typical intergranular oxidation in ZK60 alloy, owing to diverse phase transformations between La and Mg, the La–Mg phase is continuously distributed in the grain boundaries, and furthermore, a dense and protective layer consisting La–Mg intermetallic phase is coated on the surface, which can effectively inhibit the oxidation of the Mg substrate, exhibiting excellent oxidation resistance. However, the presence of discontinuously distributed Ce-rich phases at the grain boundaries and the chain reaction during high-temperature exposure are the reasons for the deterioration of the oxidation resistance in ZK60-CeO2. It is anticipated that our findings will inspire the development of next-generation low-cost and excellent high-temperature performance Mg alloys.

Emissivity and absorptivity are important parameters in overhead power line conductors that depend on the conductor surface condition, so their values change as the conductors age. They have an important effect on their thermal behavior, so it is important to know their value when designing dynamic line rating (DLR) strategies. DLR methods are becoming increasingly important, especially in areas with congested power lines, as they allow the full capacity of the lines to be utilized by dynamically determining their maximum allowable currents without exceeding the safe temperature limits of the conductors, thus ensuring that they operate within safe limits. However, measuring emissivity and absorptivity is non-trivial and requires complex tests that cannot be performed in the field. Using simulations based on a realistic thermoelectric model and experimental tests performed on three types of transmission line conductors in a high-current laboratory, this paper shows the importance and effect of emissivity on conductor temperature. It also presents a method for measuring the emissivity value based on adjusting the emissivity and absorptivity values in the thermoelectric model to match the experimental values. The results presented show that aged conductors allow an increase in the maximum current carrying capacity compared to new conductors in the order of 5–14 %, depending on the conductor type considered and the operating conditions.

The microstructure evolution of near β-Ti alloys with initially lamellar and equiaxed microstructures subjected to dynamic loading was investigated. Results showed that during high strain rate compression, shear failure is more likely to occur in equiaxed microstructure. Owing to temperature rise and stress concentration, the lamellar α phase in adiabatic shear band (ASB) zone was recrystallized and re-melted, while the equiaxed α phase transformed in strip-shaped following the propagating direction of adiabatic shear band. During high strain rate loading, the twinning transfer was observed between β matrix and α phase, which demonstrates that twinning is the dominant deformation mode to accommodate plastic deformation.

To study material erosion and deposition during different wall conditioning processes in the Experimental Advanced Superconducting Tokamak (EAST), two newly developed quartz crystal microbalances (QMBs) at the mid-plane of port C (C-QMB) and port J (J-QMB) with the same radial radius were used for in-situ and real-time measurements during the 2021 autumn experimental campaign. It was found that the material deposition was mainly influenced by the location of the antenna and the power of the ion cyclotron range of frequency (ICRF), rather than the location of the gas inlet, during the wall cleaning with helium plasma and siliconization assisted with ICRF plasma. The higher energy and density of plasma could result in higher deposition rates near the antenna. While, during lithium (Li) coating, the material deposition was greatly influenced by the location of the Li oven due to the deposition of unionized Li atoms. The ICRF power influenced the material deposition behavior far away from the Li ovens. Besides, a stronger effect on impurity suppression was observed with a more uniform deposition trend of Li coating. This necessitates further study on the influence of factors such as the location of the Li oven and ICRF antenna, the temperature of ovens, and ICRF power on the homogeneity of wall conditioning.

This report does some work on big data analysis of EV loads and extends automatic generation control (AGC) to automatic active power control (APC) by combining the current operating conditions of the grid and the spatial and temporal distribution characteristics of the adjustable capacity of EV loads. One year of user data from three EV charging stations provided by Chongqing is processed, cleaned, and clustered to analyze several typical EV load behaviors and the assessment of their adjustable characteristics. The data processing methods and the comparison of the K-means algorithm, the direct clustering, and the hierarchical clustering algorithm DPC clustering algorithm are also shown for this example.

A multi-energy plant combines renewable energy generation equipment, a charging station and a charging station with storage. This paper discusses integrated power systems that make full use of existing substations and support the construction of data centers, energy storage, 5g base stations, photovoltaic power plants, wind farms, gas turbines, etc., to create an advanced integrated energy system that enables the integration and sharing of resources and increases energy efficiency. The simulation results confirm that the integrated power plant system plays an important role in increasing the share of renewable energy production. Self-generation and control can in principle achieve 100% solar electricity consumption, and energy storage devices play a key role in renewable energy consumption.

This paper reviews the state-of-the-art in offshore oil and energy system design, develops a prototype hybrid marine renewable energy system and discusses an artificial intelligence algorithm to optimize the structure. A control strategy for the coordination of hybrid energy in an interconnected gas grid is developed. Numerical example results show that the optimization of the coordinated control strategy can provide a better balance between economy and reliability.

With the increasing installed capacity of new energy generation, the randomness and volatility of new energy generation has seriously affected the stable operation of the grid. And the traditional generation side dispatching method can no longer meet the demand of the grid to maintain stable operation, which greatly affects the consumption of new energy. In order to improve the rate of new energy consumption and economic efficiency, this paper proposed a regional active distribution network economic evaluation index that takes construction costs, operating costs, and new energy subsidies into account. What is more, the paper summarized the physical constraints of each equipment in the regional active distribution network. Combining the economic evaluation index and the physical constraints, the paper raised a regional active distribution network planning and scheduling model based on robust optimization. Finally, the regional active distribution network planning model based on robust optimization is validated in terms of the new energy consumption rate and the economic benefits by optimizing the examples of load-based regional active distribution network.

Because of the energy supply of the offshore oil platforms mainly relies on the supply of gas turbine, the development of renewable energy will become a rich energy supply for offshore oil platforms and a reliable way to improve the stability of the grid of the platforms. This paper developed the simulation model of offshore oil gas turbine platform power grid, simulated the hybrid power grid structure, the energy storage of frequency regulation, high wind power penetration rate, wind power and gas turbine power frequency stability and fault treatment. The method of increasing renewable energy penetration rate was proposed, and the hybrid energy coordinated control strategy of offshore oil platform was also carried out. Based on the weakly connected distributed offshore oil platform power grid project, this paper studied the influence of wind power and turbine power penetration rate on the power grid, in order to explore, determine and verify the limit of high wind power penetration rate under the condition of “large generation machine and small grid”. The simulation experiment of high wind power penetration rate under the condition of different load conditions and different wind speed limits were discussed, on the basis of research the influence degree of the stability of power grid frequency of low wind power swings, as well as to the wind power is given priority to with gas turbine mainly in both cases the advantages and disadvantages of the grid system, and attempt to put forward the corresponding switch control strategy.

The load of the offshore oil platform is mostly pump unit, Asynchronous motor with cage rotor has simple structure, reliable operation, and inexpensive. But it has a huge shortcoming of its low efficiency. When the output power is constant, improving efficiency is to decrease loss of the motor. This paper discusses some methods of energy saving and low consumption of the pump unit to improve the efficiency. Direct drive pump can completely eliminate transmission loss, eliminate bearing of centrifugal pump impeller pump, reduce friction, and thus reduce mechanical loss. The rotor copper loss and stator copper loss will be reduced by using copper squirrel cage and multi-wound motor, so the efficiency of the motor will be improved. If all the pump unit of the offshore oil platform is turned into this low consumption motor, it will save a lot of energy and greatly improve the efficiency of the load. Today, motors are widely found in various devices and their analysis involves the coupling of multiple physical fields. One of the most serious problems for some large motors is the heating problem, which generates various losses during motor operation, and these losses are eventually converted into thermal energy and emitted in the form of heat. The operating temperature of the motor has a great influence on the insulating material of the motor. Afterwards, a method of thermal-electromagnetic coupling simulation of the motor is carried out with a pump unit in the offshore oil platform as an example, and the magnetic line distribution, magnetic field density distribution cloud diagram and water pump temperature distribution of the motor are obtained, which are the basis of the electromagnetic design of the water pump and the design of the heat dissipation system.

Summary: The molecular landscape and pathogenesis of focal nodular hyperplasia (FNH) have yet to be elucidated. We performed multi-omics approaches on FNH and paired normal liver tissues from 22 patients, followed by multi-level bioinformatic analyses and experimental validations. Generally, FNH had low mutation burden with low variant allele frequencies, and the mutation frequency significantly correlated with proliferation rate. Although no recurrently deleterious genomic events were found, some putative tumor suppressors or oncogenes were involved. Mutational signatures indicated potential impaired mismatch function and possible poison contact. Integrated analyses unveiled a group of FNH specific endothelial cells that uniquely expressed SOST and probably had strong interaction with fibroblasts through PDGFB/PDGFRB pathway to promote fibrosis. Notably, in one atypical FNH (patient No.11) with pronounced copy number variations, we observed a unique immune module. Most FNH are benign, but molecularly atypical FNH still exist; endothelial cell derived PDGFB probably promotes the fibrogenic process in FNH.

Summary: Terahertz (THz) frequency occupies a large portion of the electromagnetic spectrum that is between the infrared and microwave regions. Recent advances in THz application have stimulated interests regarding the biological effects within this frequency range. In the current study, we report that irradiation with a single-frequency THz laser on mice cortical neuron cultures increases excitatory synaptic transmission and neuronal firing activities. Microarray assay reveals gene expression dynamics after THz exposure, which is consistent with morphology and electrophysiology results. Besides, certain schedule of THz irradiation inhibits the proliferation of oligodendrocyte precursor cells (OPCs) and promotes OPC differentiation. Of note, the myelination process is enhanced after THz exposure. In summary, our observations suggest that THz irradiation can modulate the functions of different neuronal cells, with different sensitivity to THz. These results provide important understanding of the mechanisms that govern THz interactions with nervous systems and suggest THz wave as a new strategy for neuromodulation.

High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cell-intrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site.

Background: Mortality in cancer patients is directly attributable to the ability of cancer cells to metastasize to distant sites from the primary tumor. This migration of tumor cells begins with a remodeling of the local tumor microenvironment, including changes to the extracellular matrix and the recruitment of stromal cells, both of which facilitate invasion of tumor cells into the bloodstream. In breast cancer, it has been proposed that the alignment of collagen fibers surrounding tumor epithelial cells can serve as a quantitative image-based biomarker for survival of invasive ductal carcinoma patients. Specific types of collagen alignment have been identified for their prognostic value and now these tumor associated collagen signatures (TACS) are central to several clinical specimen imaging trials. Here, we implement the semi-automated acquisition and analysis of this TACS candidate biomarker and demonstrate a protocol that will allow consistent scoring to be performed throughout large patient cohorts. Methods: Using large field of view high resolution microscopy techniques, image processing and supervised learning methods, we are able to quantify and score features of collagen fiber alignment with respect to adjacent tumor-stromal boundaries. Results: Our semi-automated technique produced scores that have statistically significant correlation with scores generated by a panel of three human observers. In addition, our system generated classification scores that accurately predicted survival in a cohort of 196 breast cancer patients. Feature rank analysis reveals that TACS positive fibers are more well-aligned with each other, are of generally lower density, and terminate within or near groups of epithelial cells at larger angles of interaction. Conclusion: These results demonstrate the utility of a supervised learning protocol for streamlining the analysis of collagen alignment with respect to tumor stromal boundaries.