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BackgroundSmall intestinal neuroendocrine tumors (SI-NETs) are the most common neoplasms of the small bowel. The majority of tumors are located in the distal ileum with a high incidence of multiple synchronous primary tumors. Even though up to 50% of SI-NET patients are diagnosed with multifocal disease, the mechanisms underlying multiple synchronous lesions remain elusive.MethodsWe performed whole genome sequencing of 75 de-identified synchronous primary tumors, 15 metastases, and corresponding normal samples from 13 patients with multifocal ileal NETs to identify recurrent somatic genomic alterations, frequently affected signaling pathways, and shared mutation signatures among multifocal SI-NETs. Additionally, we carried out chromosome mapping of the most recurrent copy-number alterations identified to determine which parental allele had been affected in each tumor and assessed the clonal relationships of the tumors within each patient.ResultsAbsence of shared somatic variation between the synchronous primary tumors within each patient was observed, indicating that these tumors develop independently. Although recurrent copy-number alterations were identified, additional chromosome mapping revealed that tumors from the same patient can gain or lose different parental alleles. In addition to the previously reported CDKN1B loss-of-function mutations, we observed potential loss-of-function gene alterations in TNRC6B, a candidate tumor suppressor gene in a small subset of ileal NETs. Furthermore, we show that multiple metastases in the same patient can originate from either one or several primary tumors.ConclusionsOur study demonstrates major genomic diversity among multifocal ileal NETs, highlighting the need to identify and remove all primary tumors, which have the potential to metastasize, and the need for optimized targeted treatments.

Ileal neuroendocrine tumors (NETs) represent the most common neoplasm of the small intestine. Although up to 50% of patients with ileal NETs are diagnosed with multifocal disease, the mechanisms by which multifocal ileal NETs arise are not yet understood. In this study, we analyzed genome-wide sequencing data to examine patterns of copy number variation in 40 synchronous primary ileal NETs derived from three patients. Chromosome (chr) 18 loss of heterozygosity (LOH) was the most frequent copy number alteration identified; however, not all primary tumors from the same patient had evidence of this LOH. Our data revealed three distinct patterns of chr18 allelic loss, indicating that primary tumors from the same patient can present different LOH patterns including retention of either parental allele. In conclusion, our results are consistent with the model that multifocal ileal NETs originate independently. In addition, they suggest that there is no specific germline allele on chr18 that is the target of somatic LOH.

This paper proposes a highly sensitive and high-resolution resonant MEMS electrostatic field sensor based on electrostatic stiffness perturbation, which uses resonant frequency as an output signal to eliminate the feedthrough interference from the driving voltage. The sensor is composed of a resonator, driving electrode, detection electrode, transition electrode, and electrostatic field sensing plate. The working principle is that when there is an electrostatic field, an induction charge will appear at the surface of the electrostatic field sensing plate and induce electrostatic stiffness on the resonator, which will cause a resonant frequency shift. The resonant frequency is used as the output signal of the microsensor. The characteristics of the electrostatic field sensor are analyzed with a theoretical model and verified by finite element simulation. A device prototype is fabricated based on the Silicon on Insulator (SOI) process and tested under vacuum conditions. The results indicate that the sensitivity of the sensor is 0.1384 Hz / (kV / m) and the resolution is better than 10 V/m. [ABSTRACT FROM AUTHOR]

This paper proposes a novel wafer-level vacuum packaged electric field microsensor (EFM) featuring a high quality factor, low driving voltage, low noise, and low power consumption. The silicon-on-insulator (SOI) conductive handle layer was innovatively used as the sensing channel to transmit the external electric field to the surface of the sensitive structure, and the vacuum packaging was realized through anodic bonding between the SOI and glass-on-silicon (GOS). The fabrication process was designed and successfully realized, featured with a simplified process and highly efficient batch manufacturing, and the final chip size was only 5 × 5 mm. A theoretical model for the packaged device was set up. The influence of key parameters in the packaging structure on the output characteristics of the microsensor was analyzed on the basis of the proposed model. Experiments were conducted on the wafer-level vacuum-packaged EFM to characterize its performance. Experimental results show that, under the condition of applying 5 V DC driving voltage, the required AC driving voltage of the sensor was only 0.05 VP, and the feedthrough was only 4.2 mV. The quality factor was higher than 5000 and was maintained with no drop in the 50-day test. The vacuum in the chamber of the sensor was about 10 Pa. A sensitivity of 0.16 mV/(kV/m) was achieved within the electrostatic field range of 0–50 kV/m. The linearity of the microsensor was 1.62%, and the uncertainty was 4.42%. [ABSTRACT FROM AUTHOR]

Monascus spp. are commonly used for a wide variety of applications in the food and pharmaceutical industries. In previous studies, the knock-out of mrflbA (a putative regulator of the G protein α subunit) in M. ruber led to autolysis of the mycelia, decreased pigmentation and lowered mycotoxin production. Therefore, we aimed to obtain a comprehensive overview of the underlying mechanism of mrflbA deletion at the proteome level. A two-dimensional gel electrophoresis analysis of mycelial proteins indicated that the abundance of 178 proteins was altered in the ΔmrflbA strain, 33 of which were identified with high confidence. The identified proteins are involved in a range of activities, including carbohydrate and amino acid metabolism, hyphal development and the oxidative stress response, protein modification, and the regulation of cell signaling. Consistent with these findings, the activity of antioxidative enzymes and chitinase was elevated in the supernatant of the ΔmrflbA strain. Furthermore, deletion of mrflbA resulted in the transcriptional reduction of secondary metabolites (pigment and mycotoxin). In short, the mutant phenotypes induced by the deletion of mrflbA were consistent with changes in the expression levels of associated proteins, providing direct evidence of the regulatory functions mediated by mrflbA in M. ruber. [ABSTRACT FROM AUTHOR]

One of the major concerns in the development of three-dimensional (3D) electric field sensors (EFSs) is their susceptibility to cross-axis coupling interference. The output signal for each sensing axis of a 3D EFS is often coupled by electric field components from the two other orthogonal sensing axes. In this paper, a one-dimensional (1D) electric field sensor chip (EFSC) with low cross-axis coupling interference is presented. It is designed to be symmetrical, forming a pair of in-plane symmetrically-located sensing structures. Using a difference circuit, the 1D EFSC is capable of sensing parallel electric fields along symmetrical structures and eliminating cross-axis coupling interference, which is contrast to previously reported 1D EFSCs designed for perpendicular electric field component measurement. Thus, a 3D EFS with low cross-axis coupling interference can be realized using three proposed 1D EFSCs. This 3D EFS has the advantages of low cross-axis coupling interference, small size, and high integration. The testing and calibration systems of the proposed 3D EFS were developed. Experimental results show that in the range of 0–120 kV/m, cross-axis sensitivities are within 5.48%, and the total measurement errors of this 3D EFS are within 6.16%. [ABSTRACT FROM AUTHOR]

This paper proposes a high sensitivity electric field microsensor (EFM) based on torsional resonance. The proposed microsensor adopts torsional shutter, which is composed of shielding electrodes and torsional beams. The movable shielding electrodes and the fixed sensing electrodes are fabricated on the same plane and interdigitally arranged. Push-pull electrostatic actuation method is employed to excite the torsional shutter. Simulation results proved that the torsional shutter has higher efficiency of charge induction. The optimization of structure parameters was conducted to improve its efficiency of charge induction further. A micromachining fabrication process was developed to fabricate the EFM. Experiments were conducted to characterize the EFM. A good linearity of 0.15% was achieved within an electrostatic field range of 0-50 kV/m, and the uncertainty was below 0.38% in the three roundtrip measurements. A high sensitivity of 4.82 mV/(kV/m) was achieved with the trans-resistance of 100 MO, which is improved by at least one order of magnitude compared with previously reported EFMs. The efficiency of charge induction for this microsensor reached 48.19 pA/(kV/m). [ABSTRACT FROM AUTHOR]

Resample method is used to do geometric correction on remotely sensed image. However, geometric correction can lead to decrease of spectral information quality. The research to maintain the spectral information has been the focus in the remote sensing domain. The quality of the images is evaluated and analyzed in the view of the quality assessment of image application. By comparing the results at different spatial resolution, the quality of the aerial images is evaluated objectively. The image application quality evaluation is carried out in three aspects: statistical feature, texture feature and energy feature. The result showed that the evaluation of aerial images can accurately reflect mulfi-scale effect of resampling information loss. [ABSTRACT FROM AUTHOR]

Electrostatic voltage is a vital parameter in industrial production lines, for reducing electrostatic discharge harms and improving yields. Due to such drawbacks as package shielding and low resolution, previously reported electric field microsensors are still not applicable for industrial static monitoring uses. In this paper, we introduce a newly designed microsensor package structure, which enhances the field strength inside the package cavity remarkably. This magnification effect was studied and optimized by both theoretical calculation and ANSYS simulation. By means of the digital synthesizer and digital coherent demodulation method, the compact signal processing circuit for the packaged microsensor was also developed. The meter prototype was calibrated above a charged metal plate, and the electric field resolution was 5 V/m, while the measuring error was less than 3 V, from −1 kV to 1 kV in a 2 cm distance. The meter was also installed into a production line and showed good consistency with, and better resolution than, a traditional vibratory capacitance sensor. [ABSTRACT FROM AUTHOR]

This paper proposes an electric field microsensor (EFM) with mutual shielding electrodes. Based on the charge-induction principle, the EFM consists of fixed electrodes and piezoelectric-driving vertically-movable electrodes. All the fixed electrodes and movable electrodes work as both sensing electrodes and shielding electrodes. In other words, all the fixed and movable electrodes are sensing electrodes, and they are mutually shielding electrodes simultaneously. The movable electrodes are driven to periodically modulate the electric field distribution at themselves and the fixed electrodes, and the induced currents from both movable and fixed electrodes are generated simultaneously. The electrode structure adopts an interdigital structure, and the EFM has been simulated by finite element methods. Simulation results show that, since the sensing area of this EFM is doubled, the variation of induced charge is twice, and therefore the output signal of the sensor is increased. The piezoelectric material, lead zirconate titanate (PZT), is prepared by the sol–gel method, and the microsensor chip is fabricated. [ABSTRACT FROM AUTHOR]

As one of the most important active remote sensing technologies, synthetic aperture radar (SAR) provides advanced advantages of all-day, all-weather, and strong penetration capabilities. Due to its unique electromagnetic spectrum and imaging mechanism, the dimensions of remote sensing data have been considerably expanded. Important for fundamental research in microwave remote sensing, SAR image classification has been proven to have great value in many remote sensing applications. Many widely used SAR image classification algorithms rely on the combination of hand-designed features and machine learning classifiers, which still experience many issues that remain to be resolved and overcome, including optimized feature representation, the fuzzy confusion of speckle noise, the widespread applicability, and so on. To mitigate some of the issues and to improve the pattern recognition of high-resolution SAR images, a ConvCRF model combined with superpixel boundary constraint is developed. The proposed algorithm can successfully combine the local and global advantages of fully connected conditional random fields and deep models. An optimizing strategy using a superpixel boundary constraint in the inference iterations more efficiently preserves structure details. The experimental results demonstrate that the proposed method provides competitive advantages over other widely used models. In the land cover classification experiments using the MSTAR, E-SAR and GF-3 datasets, the overall accuracy of our proposed method achieves 90.18 ± 0.37, 91.63 ± 0.27, and 90.91 ± 0.31, respectively. Regarding the issues of SAR image classification, a novel integrated learning containing local and global image features can bring practical implications. [ABSTRACT FROM AUTHOR]

Fine classification of vegetation types has always been the focus and difficulty in the application field of remote sensing. Unmanned Aerial Vehicle (UAV) sensors and platforms have become important data sources in various application fields due to their high spatial resolution and flexibility. Especially, UAV hyperspectral images can play a significant role in the fine classification of vegetation types. However, it is not clear how the ultrahigh resolution UAV hyperspectral images react in the fine classification of vegetation types in highly fragmented planting areas, and how the spatial resolution variation of UAV images will affect the classification accuracy. Based on UAV hyperspectral images obtained from a commercial hyperspectral imaging sensor (S185) onboard a UAV platform, this paper examines the impact of spatial resolution on the classification of vegetation types in highly fragmented planting areas in southern China by aggregating 0.025 m hyperspectral image to relatively coarse spatial resolutions (0.05, 0.1, 0.25, 0.5, 1, 2.5 m). The object-based image analysis (OBIA) method was used and the effects of several segmentation scale parameters and different number of features were discussed. Finally, the classification accuracies from 84.3% to 91.3% were obtained successfully for multi-scale images. The results show that with the decrease of spatial resolution, the classification accuracies show a stable and slight fluctuation and then gradually decrease since the 0.5 m spatial resolution. The best classification accuracy does not occur in the original image, but at an intermediate level of resolution. The study also proves that the appropriate feature parameters vary at different scales. With the decrease of spatial resolution, the importance of vegetation index features has increased, and that of textural features shows an opposite trend; the appropriate segmentation scale has gradually decreased, and the appropriate number of features is 30 to 40. Therefore, it is of vital importance to select appropriate feature parameters for images in different scales so as to ensure the accuracy of classification. [ABSTRACT FROM AUTHOR]

The scope of this research lies in the combination of pre-trained Convolutional Neural Networks (CNNs) and Quantum Convolutional Neural Networks (QCNN) in application to Remote Sensing Image Scene Classification(RSISC). Deep learning (RL) is improving by leaps and bounds pretrained CNNs in Remote Sensing Image (RSI) analysis, and pre-trained CNNs have shown remarkable performance in remote sensing image scene classification (RSISC). Nonetheless, CNNs training require massive, annotated data as samples. When labeled samples are not sufficient, the most common solution is using pre-trained CNNs with a great deal of natural image datasets (e.g., ImageNet). However, these pre-trained CNNs require a large quantity of labelled data for training, which is often not feasible in RSISC, especially when the target RSIs have different imaging mechanisms from RGB natural images. In this paper, we proposed an improved hybrid classical-quantum transfer learning CNNs composed of classical and quantum elements to classify open-source RSI dataset. The classical part of the model is made up of a ResNet network which extracts useful features from RSI datasets. To further refine the network performance, a tensor quantum circuit is subsequently employed by tuning parameters on near-term quantum processors. We tested our models on the open-source RSI dataset. In our comparative study, we have concluded that the hybrid classical-quantum transferring CNN has achieved better performance than other pre-trained CNNs based RSISC methods with small training samples. Moreover, it has been proven that the proposed algorithm improves the classification accuracy while greatly decreasing the amount of model parameters and the sum of training data.

Lung cancer is a disease with remarkable heterogeneity. A deep understanding of the tumor microenvironment (TME) offers potential therapeutic strategies against this malignant disease. More and more attention has been paid to the roles of macrophages in the TME. This article briefly summarizes the origin of macrophages, the mutual regulation between anti-tumoral immunity and pro-tumoral statuses derived from macrophage polarization, and the therapeutic opportunities targeting alternately activated macrophages (AAM)-type macrophage polarization. Among them, cellular components including T cells, as well as acellular components represented by IL-4 and IL-13 are key regulators driving the polarization of AAM macrophages. Novel treatments targeting macrophage-associated mechanisms are mainly divided into small molecule inhibitors, monoclonal antibodies, and other therapies to re-acclimate AMM macrophages. Finally, we paid special attention to an immunosuppressive subgroup of macrophages with T cell immunoglobulin and mucin domain-3 (TIM-3) expression. Based on cellular interactions with cancer cells, TIM3+ macrophages facilitate the proliferation and progression of cancer cells, yet this process exposes targets blocking the ligand-receptor recognition. To sum up, this is a systematic review on the mechanism of tumor-associated macrophages (TAM) polarization, therapeutic strategies and the biological functions of Tim-3 positive macrophages that aims to provide new insights into the pathogenesis and treatment of lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Wu, Wang, Ma, Zhang and Xue.)

Copper is an essential microelement for the body and a necessary coregulator for enzymatic reactions, yet an unbalanced copper level promotes reactive oxidation and cytotoxicity, which ultimately induces cell death. Several small molecules targeting copper-induced cell death have been investigated, yet few showed promising therapeutic effects in clinical trials. In March 2022, Science first introduced the concept and mechanisms of cuproptosis, suggesting that copper-induced cell death targets the tricarboxylic acid (TCA) cycle via protein lipoylation. Does this novel form of cell death take part in tumorigenesis or tumor progression? Is cuproptosis related to clinical outcomes of diseases? Is there a cuproptosis-related panel for clinical practice in cancer treatment? Herein, based on 942 samples of lung adenocarcinoma (LUAD), we analyzed on gene set level the existence and predictive value of cuproptosis in disease diagnosis and treatment. We screened out and identified the "cupLA" panel which indicates the risk of LUAD occurrence, clinicopathological features of LUAD patients, and could guide clinicians to refine LUAD subtypes and make treatment choices., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Wang, Ma, Zhang and Xue.)

Cyclin-dependent kinase 4 (CDK4) and CDK6 are key cell-cycle regulators that are frequently dysregulated in human malignancies. CDK4/6 inhibitors are clinically approved for the treatment of hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, but improved specificity and reduced toxicity might expand their use to other indications. Through analysis of publicly available genome-wide loss-of-function data combined with single and dual-targeting CRISPR assays, we found differential cell proliferation vulnerability of cell lines to either CDK4 deletion alone, CDK6 deletion alone, combined CDK4/CDK6 deletion, or neither. CDK6 expression was the best single predictor of CDK4 (negatively correlated) and CDK6 (positively correlated) dependencies in the cancer cell lines, with adenocarcinoma cell lines being more sensitive to CDK4 deletion and hematologic and squamous cancer cell lines being more sensitive to CDK6 deletion. RB-E2F signaling was confirmed as a main downstream node of CDK4/6 in these experiments as shown by the survival effects of RB1 deletion. Finally, we show in a subset of cancer cell lines not dependent on CDK4/6 that CDK2-CCNE1 is an important alternative dependency for cell proliferation. Together, our comprehensive data exploration and functional experiments delineate the landscape of pan-cancer CDK4/6 gene dependencies and define unique cancer cell populations that might be sensitive to CDK4-selective or CDK6-selective inhibitors., Significance: This study provides functional genomic insight toward understanding the scenarios in which cancer cells are differentially sensitive to CDK4 or CDK6 inhibition and their implications in current treatment strategies., (©2022 American Association for Cancer Research.)

Objective: Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition., Design: We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer., Results: We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC., Conclusion: These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer., Competing Interests: Competing interests: AB receives research funding from Bayer, Merck and Novartis and is a consultant to Earli, and HelixNano and a cofounder of Signet Therapeutics. K-KW is a founder and equity holder of G1 Therapeutics, and he has consulting/sponsored research agreements with MedImmune, Takeda, TargImmune, BMS, AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono and Array., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells., Experimental Design: We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development., Results: The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells., Conclusions: Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy., (©2021 American Association for Cancer Research.)

Vitamin D has potent anticancer properties, especially against gastrointestinal cancers. Group-specific component (GC), a key member of vitamin D pathway proteins, could bind to and transport vitamin D to target organs. As a polymorphic protein, two common coding single nucleotide polymorphisms (SNP) [Glu416Asp (rs7041) and Thr420Lys (rs4588)] were identified in its gene. These SNPs have been associated to circulating vitamin D levels and several cancer risks in different populations. However, there is no report on their role in gastrointestinal cancer development among Chinese to date. Therefore, we examined the association between these variants and risk of gastrointestinal cancers in a case-control cohort including 964 patients with four gastrointestinal cancers (hepatocellular carcinoma, esophageal cancer, gastric cancer and colorectal cancer) and 1187 controls. Odds ratios and 95% confidence intervals were estimated by logistic regression. We found that GC Thr420Lys polymorphism has significant impact on the risk of developing gastrointestinal cancers, especially colorectal cancer. Additionally, subjects who carrying GC Asp(416)-Lys(420) haplotype, which contains the at-risk 420Lys allele, also showed significantly increased risk to develop gastrointestinal cancers. In conclusion, our study demonstrated that common genetic variants and haplo-types in GC may influence individual susceptibility to gastrointestinal cancers in Chinese population.