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With the combined effects of climate change and anthropogenic disturbance, landslide hazards have progressively increased and emerged as one of the most significant natural threats to socio-economic safety and human life. Synthetic aperture radar interferometry (InSAR) can measure subtle ground displacement and thus has immense potential for detecting active landslides. However, the operational application of InSAR for landslide detection and inventory update in wide-area is still hindered by the high labor and time costs for visual interpretation and manual editing of InSAR results. Aiming at this problem, we developed a novel method using InSAR and convolutional neural network (CNN) for automated identification of active landslides over wide areas. It first performs InSAR analysis to produce a surface displacement velocity map of the target region and then employs an improved Faster RCNN based on attended ResNet-34 and Feature Pyramid Networks (FPN) to detect active landslides from the velocity map. Taking the Guizhou province in southwest China as a case study, we processed 1168 scenes of Sentinel-1 images and 473 scenes of PALSAR-2 images to derive the surface displacement and identified 1627 active landslides, including 326 manually labeled landslides and 1301 landslides automatically detected by Faster RCNN. The improved Faster RCNN achieved good recall, precision, F1 score, and average precision (AP) at 91.49%, 91.33%, 0.914, and 0.940, respectively. Further experiments indicated that the trained Faster RCNN showed satisfactory applicability and result accuracy for different test areas and various InSAR techniques. Therefore, the proposed approach has great potential applications for building inventories of active landslides over wide areas and regularly updating the records, which is crucial for preventing landslide disasters and mitigating losses.

In this study, we analyzed the relationship between the refrigerant distribution of a multiparallel evaporator and the structural design of a distributor to address uneven distribution of gas–liquid refrigerants in multiparallel evaporators under variable operating conditions. Herein, we proposed the shunting concept of “flow pattern setting and critical distribution” and designed a theoretical model for a rectifying nozzle-type critical distributor (RNCD). We built the experimental bench of a multiparallel evaporator using an RNCD and compared the cooling time of each cold storage, the superheat of each branch pipe, the cooling capacity of each cold storage, and the pressure drop of the distributor. Further, we investigated the shunting performance of the RNCD. The experimental results showed that the evaporation temperatures were −32 °C to −24 °C when cold storage temperatures of −22 °C to −14 °C, respectively. The unevenness of superheat at the outlet of each evaporator branch pipe of the RNCD was 0.0884–0.1275, while the unevenness associated with the refrigeration capacity of each cold storage was 0.1424–0.1714. This study provides basic research information to solve the problem of uneven refrigerant distribution when considering gas–liquid two-phase flow in multiparallel evaporators under variable operating conditions.

There is an urgent demand for continuous detection and monitoring of active slopes in wide reservoir areas, as reservoir impoundments may activate unstable slopes. Although satellite time-series InSAR has been widely used in mapping active landslides, the tedious artificial interpretation of InSAR results limits the efficiency and reliability of landslides detection. We propose a set of procedures for deformation monitoring and continuous automatic landslide identification in wide reservoir areas. The local time window estimation can extract the nonlinear deformation in the time series InSAR signal, thus enhancing the deformation field. Spatial adaptive clustering enables the effective extraction of unstable slopes. The abnormal deformation trends of landslides can be updated through the continuous identification of new results and comparison with historical results. The procedure is used to continuously detect unstable slopes in the Lianghekou reservoir area before and after the impoundment. Combining the ascending and descending SAR data of Sentinel-1, 109 historically active landslides were found and 18 new landslides were activated within one year after the first water storage. The distribution and types of unstable slopes were analyzed, followed by two case studies. The first case shows the different effects of the two-stage water storage on slope deformations, indicating rising water levels' critical role in landslide activation. The second case shows the consolidation settlement of the embankment dam and the influence of water storage on slope deformation monitoring. The results demonstrate the effectiveness of the InSAR automatic landslide identification and this study provides a technical reference for similar reservoir area.

As the longest water transfer route in the world, the South-North Water Diversion Project (SNWDP) plays a key role in mitigating the serious water shortage problem in the arid north China, and thus the routine stability monitoring of this mega infrastructure becomes a critical issue to ensure continuous fresh water supply. Compared with traditional geodetic tools such as leveling and GNSS that can only measure deformation at discrete points along the canal, modern satellite Synthetic Aperture Radar Interferometry (InSAR) that can capture subtle ground deformation over wide areas is much more suitable to accomplish this challenging task. In this study, we carried out multi-scale InSAR analyses with multi-track Sentinel-1 data stacks to monitor deformation along the Middle Route canal of SNWDP. A coarse-resolution InSAR analysis was first carried out to map regional land subsidence in north China, and the result suggested that the Middle Route canal bypassed the huge subsidence funnel in the southeast part of Hebei province and exhibited overall stability. Afterwards, the results of relatively high-resolution InSAR analyses performed within the 5 km buffering zones along the entire canal revealed that a few sections were affected by significant embankment deformation or land subsidence. In particular, the high-filled canal sections are more prone to deform, such as the cases in Ye County and Jiaozuo City in Henan province. The validation of InSAR deformation measurements with synchronous leveling in Jiaozuo City indicated that a measurement accuracy of 6 mm was achieved. Another big problem identified is the severe uneven land subsidence along the Tianjin Branch Route, which may pose great threats upon the long-term safety of local water transfer operation, and must be handled properly to avoid further degradation.

Background: No effective approaches to target mutant Kras have yet been developed. Immunoprevention using KRAS-specific antigenic peptides to trigger T cells capable of targeting tumor cells relies heavily on lipid metabolism. To facilitate better TCR/peptide/MHC interactions that result in better cancer preventive efficacy, we combined KVax with avasimibe, a specific ACAT1 inhibitor, tested their anti-cancer efficacy in mouse lung cancer models, where Kras mutation was induced before vaccination. Methods: Control of tumor growth utilizing a multi-peptide Kras vaccine was tested in combination with avasimibe in a syngeneic lung cancer mouse model and a genetically engineered mouse model (GEMM). Activation of immune responses after administration of Kras vaccine and avasimibe was also assessed by flow cytometry, ELISpot and IHC. Findings: We found that Kras vaccine combined with avasimibe significantly decreased the presence of regulatory T cells in the tumor microenvironment and facilitated CD8+ T cell infiltration in tumor sites. Avasimibe also enhanced the efficacy of Kras vaccines target mutant Kras. Whereas the Kras vaccine significantly increased antigen-specific intracellular IFN-γ and granzyme B levels in CD8+ T cells, avasimibe significantly increased the number of tumor-infiltrating CD8+ T cells. Additionally, modulation of cholesterol metabolism was found to specifically impact in T cells, and not in cancer cells. Interpretation: Avasimibe complements the efficacy of a multi-peptide Kras vaccine in controlling lung cancer development and growth. This treatment regimen represents a novel immunoprevention approach to prevent lung cancer. Keywords: Chemoimmunoprevention, Kras, Peptide vaccine, Avasimibe, Cholesterol metabolism, T cell

Summary: Immunotherapy with monoclonal antibodies targeting immune checkpoint molecules, including programmed death-1 (PD-1), PD ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, has become prominent in the treatment of many types of cancer. However, a significant number of patients treated with immune checkpoint inhibitors (ICIs) develop immune-related adverse events (irAEs). irAEs can affect any organ system, and although most are clinically manageable, irAEs can result in mortality or long-term morbidity. Factors that can predict irAEs remain elusive. Understanding the etiology of ICI-induced irAEs and ways to limit these adverse events are needed. In this review, we provide basic science and clinical insights on the mechanisms responsible for ICI efficacy and ICI-induced irAEs. We further provide insights into approaches that may uncouple irAEs from the ability of ICIs to kill tumor cells.

Summary: Although PD-1-blocking immunotherapies demonstrate significant therapeutic promise, a subset of the patients could develop hyperprogressive disease (HPD) with accelerated tumor growth after anti-PD1 immunotherapy. To elucidate the underlying mechanisms, we compared the mutational and transcriptional landscapes between the pre- and post-therapy tumors of two patients developing HPD after anti-PD-1 immunotherapy. In post-therapy HPD tumors, somatic mutations were found in known cancer genes, including tumor suppressor genes such as TSC2 and VHL, along with transcriptional upregulation of oncogenic pathways, including IGF-1, ERK/MAPK, PI3K/AKT, and TGF-β. We found that post-therapy HPD tumors were less immunogenic than pre-therapy tumors, concurrent with an increased presence of ILC3 cells, a subset of innate lymphoid cells. We also developed a gene expression signature predictive of HPD. In summary, we identified the genomics and immune features associated with HPD, which may help identify patients at risk of adverse clinical outcome after anti-PD-1 immunotherapy. : Physiology (170590663/189723279); Immunology (186131996Physiology; Biotechnology; Cell Biology; Omics Subject Areas: Physiology (170590663/189723279, ), Immunology (186131996Physiology, Biotechnology, Cell Biology, Omics

Summary: We synthesized a mitochondria-targeted honokiol (Mito-HNK) that facilitates its mitochondrial accumulation; this dramatically increases its potency and efficacy against highly metastatic lung cancer lines in vitro, and in orthotopic lung tumor xenografts and brain metastases in vivo. Mito-HNK is >100-fold more potent than HNK in inhibiting cell proliferation, inhibiting mitochondrial complex ǀ, stimulating reactive oxygen species generation, oxidizing mitochondrial peroxiredoxin-3, and suppressing the phosphorylation of mitoSTAT3. Within lung cancer brain metastases in mice, Mito-HNK induced the mediators of cell death and decreased the pathways that support invasion and proliferation. In contrast, in the non-malignant stroma, Mito-HNK suppressed pathways that support metastatic lesions, including those involved in inflammation and angiogenesis. Mito-HNK showed no toxicity and targets the metabolic vulnerabilities of primary and metastatic lung cancers. Its pronounced anti-invasive and anti-metastatic effects in the brain are particularly intriguing given the paucity of treatment options for such patients either alone or in combination with standard chemotherapeutics. : Natural Product Chemistry; Immunology; Medicinal and Aromatic Plants Subject Areas: Natural Product Chemistry, Immunology, Medicinal and Aromatic Plants

Effective chemoprevention of lung cancer in high-risk patients through the administration of pharmacologic or nutritional agents is urgently needed. Aerosol inhalation can deliver chemopreventive agents directly to the respiratory tract to inhibit the tumorigenic process. In this study, polyphenon E (PolyE) and (-)epigallocatechin-3-gal late (EGCG) were administered by aerosol delivery to A/J mice beginning 2 weeks after carcinogen treatment and continuing daily by inhalation throughout the remainder of the study (20 weeks). PolyE decreased tumor load by ∼ 59%. However, EGCG, both at the same dose and at a higher dose, failed to inhibit lung carcinogenesis. These results indicate that aerosol delivery of PolyE, but not EGCG, may be a useful chemopreventive protocol in subjects at high risk for lung cancer.

The objective of this investigation was to determine the efficacy of several novel agents in preventing lung tumorigenesis in mice. We evaluated polyphenon E, red ginseng, and rapamycin in A/J mice treated with the tobacco-specific carcinogen benzo(a)pyrene for their ability to inhibit pulmonary adenoma formation and growth. We found that treatment with polyphenon E exhibited a significant reduction on both tumor multiplicity and tumor load (tumor multiplicity × tumor volume) in a dose-dependent fashion. Polyphenon E (2% wt/wt) in the diet reduced tumor multiplicity by 46% and tumor load by 94%. This result provided key evidence in support of a phase II clinical chemoprevention trial of lung cancer. Administration of red ginseng in drinking water decreased tumor multiplicity by 36% and tumor load by 70%. The mammalian target of rapamycin inhibitor rapamycin showed significant efficacy against lung tumor growth in the tumor progression protocol and reduced tumor load by 84%. The results of these investigations demonstrate that polyphenon E, red ginseng, and rapamycin significantly inhibit pulmonary adenoma formation and growth in A/J mice.

We evaluated deguelin and silibinin in A/J mice treated with the tobacco-specific carcinogen benzo(a)pyrene (BP) for their ability to inhibit pulmonary adenoma formation and growth. Animals were treated with either deguelin (5.0 or 10.0 mg/kg body weight, by gavage) or silibinin at doses of 0.05% and 0.1% in the diet, approximately 10 days before a single intraperitoneal dose of BP. We found that oral administration of deguelin reduced tumor multiplicity by 56% and tumor load by 78%, whereas silibinin treatment at doses of 0.05% and 0.1% in the diet did not show any significant efficacy on either tumor multiplicity or tumor load. The result indicates that deguelin significantly inhibits pulmonary adenoma formation and growth in A/J mice. Finding new and effective agents that can prevent lung cancer is urgently needed because cancer of the lungs remains the principal cause of cancer deaths in the United States and because effective chemoprevention of this cancer type remains elusive. Thus, deguelin appears to be a promising new preventive agent for lung cancer and may be considered for further studies in other animal models and in clinical trials.

A variety of genetic alterations and gene expression changes are involved in the pathogenesis of bladder tumor. To explore these changes, oligonucleotide array analysis was performed on RNA obtained from carcinogen-induced mouse bladder tumors and normal mouse bladder epithelia using Affymetrix (Santa Clara, CA) MGU74Av2 GeneChips. Analysis yielded 1164 known genes that were changed in the tumors. Certain of the upregulated genes included EGFR-Ras signaling genes, transcription factors, cell cycle-related genes, and intracellular signaling cascade genes. However, downregulated genes include mitogen-activated protein kinases, cell cycle checkpoint genes, Rab subfamily genes, Rho subfamily genes, and SH2 and SH3 domains-related genes. These genes are involved in a broad range of different pathways including control of cell proliferation, differentiation, cell cycle, signal transduction, and apoptosis. Using the pathway visualization tool GenMAPP, we found that several genes, including TbR-l, STAT1, Smad1, Smad2, Jun, NFκB, and so on, in the TGF-β signaling pathway and p115 RhoGEF, RhoGDl3, MEKK4A/MEKK4B, P13KA, and JNK in the G13 signaling pathway were differentially expressed in the tumors. In summary, we have determined the expression profiles of genes differentially expressed during mouse bladder tumorigenesis. Our results suggest that activation of the EGFR-Ras pathway, uncontrolled cell cycle, aberrant transcription factors, and G13 and TGF-β pathways are involved, and the cross-talk between these pathways seems to play important roles in mouse bladder tumorigenesis.

The molecular mechanisms of the development of teratocarcinomas from stem cells are largely unknown. To determine which genes are associated with the transformation of these cells, we have performed oligonucleotide microarray analysis, using Affymetrix U74A GeneChips, on both cell cultures and tumors in nude mice. We identified 68 genes that significantly differed in expression between the ES cell culture and the teratocarcinoma cell line, SCC-PSA1, and 51 genes with statistically different expression patterns between the ES cell tumors and the teratocarcinomas (P < .00005). We found that there were 20 genes that had common expression patterns in both groups. We also examined the role of the transition from in vitro to in vivo by comparing ES cell culture to ES cell tumor, and teratocarcinoma cell line to teratocarcinomas. We identified 22 genes that were upregulated in the ES cell tumors and 42 that had a decreased expression in the tumor (P

In the present studies, we investigated the correlation between RASSF1A promoter methylation status and Kras2 mutations in 65 primary non small cell lung cancer (NSCLC) including 33 adenocarcinomas, 12 large cell carcinomas, and 20 squamous cell carcinomas. Mutational analysis of Kras2 showed: 30% (10 of 33) of adenocarcinomas, 25% (3 of 12) of large cell carcinomas, and only 5% (1 of 20) of squamous cell carcinomas contained activated Kras2 mutation at codon 12 or 13. RASSF1A promoter region CpG island methylation was detected in adenocarcinomas (55%), large cell carcinomas (25%), and squamous cell carcinomas (25%). Interestingly, combined RASSF1A methylation and Kras2 mutation data show that only ~7% adenocarcinomas/large cell carcinomas exhibited both KRASSF1A promoter methylation and Kras2 mutation, whereas 24% adenocarcinomas, 50% large cell carcinomas, and 70% squamous cell carcinomas showed neither Kras2 mutation nor RASSF1A promoter methylation. These results showed that the majority of the primary NSCLCs with Kras2 mutations lack RASSF1A inactivation, and both RASSF1A inactivation and Kras2 mutation events occur frequently in adenocarcinomas and large cell carcinomas. Our results indicate a trend of inverse relationship between Kras2 activation and RASSF1A promoter methylation in the majority of human lung adenocarcinomas and large cell carcinomas.

Because of similarities in histopathology and tumor progression stages between mouse and human lung adenocarcinomas, the mouse lung tumor model with lung adenomas as the endpoint has been used extensively to evaluate the efficacy of putative lung cancer chemopreventive agents. In this study, a competitive cDNA library screening (CCLS) was employed to determine changes in the expression of mRNA in chemically induced lung adenomas compared with paired normal lung tissues. A total of 2555 clones having altered expression in tumors were observed following competitive hybridization between normal lung and lung adenomas after primary screening of over 160,000 clones from a mouse lung cDNA library. Among the 755 clones confirmed by dot blot hybridization, 240 clones were underexpressed, whereas 515 clones were overexpressed in tumors. Sixty-five clones with the most frequently altered expression in six individual tumors were confirmed by semiquantitative RT-PCR. When examining the 58 known genes, 39 clones had increased expression and 19 had decreased expression, whereas the 7 novel genes showed overexpression. A high percentage (>60%) of overexpressed or underexpressed genes was observed in at least two or three of the lesions. Reproducibly overexpressed genes included ERK-1, JAK-1, surfactant proteins A, B, and C, NFAT1, α-1 protease inhibitor, helix-loop-helix ubiquitous kinase (CHUK), α-adaptin, α-1 PI2, thioether S-methyltransferase, and CYP2C40. Reproducibly underexpressed genes included paroxanase, ALDH II, CC10, von Ebner salivary gland protein, and α- and β-globin. In addition, CCLS identified several novel genes or genes not previously associated with lung carcinogenesis, including a hypothetical protein (FLJ11240) and a guanine nucleotide exchange factor homologue. This study shows the efficacy of this methodology for identifying genes with altered expression. These genes may prove to be helpful in our understanding of the genetic basis of lung carcinogenesis and in developing biomarkers for lung cancer chemoprevention studies in mice.