[Generational differences in overweight and obesity among Chinese adult resident].

OBJECTIVE: To analyze the generational differences in overweight/obesity prevalence and central obesity prevalence among Chinese adult residents aged 20 years and above at the same ages. METHODS: A total of 38 908 healthy adult residents aged 20 years and above from "the China Health and Nutrition Survey" in 1991, 2000, 2009, and 2018 were selected for this study. Based on age at the time of the survey, the study subjects were divided into 6 age groups(20-29, 30-39, 40-49, 50-59, 60-69, and ≥70 years old) corresponding to 9 different generations of births in 10, 20, 30, 40, 50, 60, 70, 80, and 90 generations, respectively. All analyses were stratified by sex. A chi-square test was used to compare generational differences in overweight/obesity and central obesity at similar ages in populations born in different generations. Non-parametric tests were used to compare generational differences in BMI and waist circumference. RESULTS: (1) Body mass index(BMI), overweight/obesity rate, waist circumference, and central obesity rate showed unfavorable generational differences(P<0.0001) among different generations of residents at similar ages. BMI, overweight/obesity prevalence, waist circumference, and central obesity prevalence were higher in the younger generation. Overweight/obesity and central obesity occurred at an earlier age in the younger generation. (2) Generational differences in overweight/obesity rates and central obesity rates followed gender specificity. Unfavorable generational differences(P<0.0001) occurred in overweight/obesity as well as central obesity between the two oldest generations of females, with maximum differences of 15.5% and 8.0%. Unfavorable generational differences(P<0.0001) occurred in overweight/obesity between the two adjacent generations of men and in central obesity between the two youngest generations of men, with maximum differences of 19.5% and 17.0%. CONCLUSION: The prevalence of overweight/obesity and central obesity among Chinese adults showed unfavorable generational differences. The prevalence of overweight/obesity and central obesity was higher in the younger generation. The younger generation develops overweight/obesity at an earlier age.

Using molecular characteristics to distinguish multiple primary lung cancers and intrapulmonary metastases.

Objectives: Multiple lung cancers may present as multiple primary lung cancers (MPLC) or intrapulmonary metastasis (IPM) with variations in clinical stage, treatment, and prognosis. However, the existing differentiation criteria based on histology do not fully meet the clinical needs. Next-generation sequencing (NGS) may play an important role in assisting the identification of different pathologies. Here, we extended the relevant data by combining histology and NGS to develop detailed identification criteria for MPLC and IPM. Materials and Methods: Patients with lung cancer (each patient had ≥2 tumors) were enrolled in the training (n = 22) and validation (n = 13) cohorts. Genomic profiles obtained from 450-gene-targeted NGS were analyzed, and the new criteria were developed based on our findings and pre-existing Martini & Melamed criteria and molecular benchmarks. Results: The analysis of the training cohort indicated that patients identified with MPLC had no (or <2) trunk or shared mutations. However, 98.02% of mutations were branch mutations, and 69.23% of MPLC had no common mutations. In contrast, a higher percentage of trunk (33.08%) or shared (9.02%) mutations were identified in IPM, suggesting significant differences among mutated components. Subsequently, eight MPLC and five IPM cases were identified in the validation cohort, aligning with the independent imaging and pathologic distinction. Overall, the percentage of trunk and shared mutations was higher in patients with IPM than in patients with MPLC. Based on these results and the establishment of new determination criteria for MPLC and IPM, we emphasize that the type and number of shared variants based on histologic consistency assist in identification. Conclusion: Determining genetic alterations may be an effective method for differentiating MPLC and IPM, and NGS can be used as a valuable assisting tool.

Auto-inhibition and activation of a short Argonaute-associated TIR-APAZ defense system.

Short prokaryotic Ago accounts for most prokaryotic Argonaute proteins (pAgos) and is involved in defending bacteria against invading nucleic acids. Short pAgo associated with TIR-APAZ (SPARTA) has been shown to oligomerize and deplete NAD+ upon guide-mediated target DNA recognition. However, the molecular basis of SPARTA inhibition and activation remains unknown. In this study, we determined the cryogenic electron microscopy structures of Crenotalea thermophila SPARTA in its inhibited, transient and activated states. The SPARTA monomer is auto-inhibited by its acidic tail, which occupies the guide-target binding channel. Guide-mediated target binding expels this acidic tail and triggers substantial conformational changes to expose the Ago-Ago dimerization interface. As a result, SPARTA assembles into an active tetramer, where the four TIR domains are rearranged and packed to form NADase active sites. Together with biochemical evidence, our results provide a panoramic vision explaining SPARTA auto-inhibition and activation and expand understanding of pAgo-mediated bacterial defense systems.

Mammalian trans-editing factor ProX is able to deacylate tRNAThr mischarged with alanine.

The precise coupling of tRNAs with their cognate amino acids, known as tRNA aminoacylation, is a stringently regulated process that governs translation fidelity. To ensure fidelity, organisms deploy multiple layers of editing mechanisms to correct mischarged tRNAs. Prior investigations have unveiled the propensity of eukaryotic AlaRS to erroneously attach alanine onto tRNACys and tRNAThr featuring the G4:U69 base pair. In light of this, and given ProXp-ala's capacity in deacylating Ala-tRNAPro, we embarked on exploring whether this trans-editing factor could extend its corrective function to encompass these mischarged tRNAs. Our in vitro deacylation assays demonstrate that murine ProXp-ala (mProXp-ala) is able to efficiently hydrolyze Ala-tRNAThr, while Ala-tRNACys remains unaffected. Subsequently, we determined the first structure of eukaryotic ProXp-ala, revealing a dynamic helix α2 involved in substrate binding. By integrating molecular dynamics simulations and biochemical assays, we pinpointed the pivotal interactions between mProXp-ala and Ala-tRNA, wherein the basic regions of mProXp-ala as well as the C3-G70 plays essential role in recognition. These observations collectively provide a cogent rationale for mProXp-ala's deacylation proficiency against Ala-tRNAThr. Our findings offer valuable insights into the translation quality control within higher eukaryotic organisms, where the fidelity of translation is safeguarded by the multi-functionality of extensively documented proteins.

Generational Differences in Food Consumption among Chinese Adults of Different Ages.

Limited knowledge currently exists regarding the dynamics of generational shifts in food consumption among adult residents in China. This study aimed to investigate the generational differences in dietary status among different generations of Chinese adult residents aged 20 years and older. Survey participants from four waves (1991, 2000, 2009, and 2018) of the China Health and Nutrition Survey (CHNS) cohort were included in the study (N = 40,704), providing three-day 24 h dietary data. Participants were categorized into six age groups (20-29, 30-39, 40-49, 50-59, 60-69, and ≥70 years old), each corresponding to specific generations (Gen 10, 20, 30, 40, 50, 60, 70, 80, and 90) based on their age at the time of the survey. This study examined generational differences in the intake of cereals, animal-based foods, vegetables, fruits, dairy, energy, and the contribution of macronutrients to energy using chi-square tests and Kruskal-Wallis tests. All analyses were stratified by gender. Our findings revealed that younger generations exhibited lower daily intake of cereals, vegetables, energy, and contribution of carbohydrates to energy, compared to their older counterparts, regardless of gender. Conversely, regardless of male or female, younger generations showed higher daily consumption of animal-based foods, average fruit and dairy intake, fruit and dairy consumption rates, as well as contributions of protein and fat to energy, compared to older generations. The magnitude of generational differences in food consumption varied by age and gender. In addition, cereal and vegetable intake, energy intake, and contribution of carbohydrates to energy declined with age across all generations, while average dairy intake, fruit and dairy consumption rates, and the contribution of fat to energy tended to increase, regardless of gender. In conclusion, generational differences in food consumption were evident among different generations of Chinese adult residents, characterized by an increase in animal-based food intake and the contribution of fat to energy among generations. Attention should be directed towards addressing the eating behavior of younger generations.

Personalized circulating tumor DNA detection to monitor immunotherapy efficacy and predict outcome in locally advanced or metastatic non-small cell lung cancer.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) or combined with chemotherapy exhibit substantial efficacy for the treatment of advanced non-small cell lung cancer (NSCLC). However, reliable biomarkers that can monitor response to first-line ICIs ± chemotherapy remain unclear. METHODS: A total of 16 tumor tissues and 46 matched peripheral blood samples at baseline and during treatment were retrospectively collected from 19 locally advanced or metastatic NSCLC patients. The circulating tumor DNA (ctDNA) burden by tumor-informed assay was detected to monitor and predict the therapeutic response and survival of NSCLC patients treated with first-line ICIs or plus chemotherapy. RESULTS: We found that ctDNA was only positively detected in one patient by tumor-agnostic assay with a mean variant allele fraction (VAF) of 6.40%, whereas it was positively detected in three patients by tumor-informed assay with a mean VAF of 8.83%, 0.154%, and 0.176%, respectively. Tumor-informed assays could sensitively detect ctDNA in 93.75% (15/16) of patients. Trends in the level of ctDNA from baseline to first evaluation was consistent with the radiographic changes. There was a greater decrease in ctDNA after treatment compared with baseline in patients with partial response compared to patients with stable disease/progressive disease. Patients with over a 50% reduction in ctDNA had a significant progression-free survival and overall survival benefit. CONCLUSION: The tumor-informed assay was favorable for ctDNA detection, and early dynamic changes in plasma ctDNA may be a valuable biomarker for monitoring the efficacy and predicting the outcome in advanced NSCLC patients treated with first-line ICIs ± chemotherapy.

Differences in DNA damage repair gene mutations between left- and right-sided colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. Studies have shown that the DNA damage response (DDR) mutation is strongly associated with microsatellite instability (MSI) status and is an indication for patients with CRCs receiving immune checkpoint inhibitor (ICI) treatment. However, DDR mutation in microsatellite stable (MSS) CRC remains unclear. METHODS: In this study, Fisher's exact test, Student'st-test, Wilcoxon rank-sum test and Cox proportional hazards regression model were performed, and a p value of < 0.05 was considered statistically significant. RESULTS: The most common gene alterations were APC (77%), TP53 (73%), KRAS (48%), and PIK3CA (25%). The mutationfrequency of APC and TP53 in left-sided CRC was significantly higher than that for right-sided CRC, while the mutation frequency of PIK3CA, ACVR2A, FAT4, and RNF43 in right-sided CRC was significantly higher than that for left-sided CRC. DDR mutations occurred in100% of MSI CRCs and in 83.77% of MSS CRCs, with the most frequently mutated DDR genes being ARID1A (7.5%), ATM (5.7%,) and BRCA2 (2.6%). When right- and left-sided CRCs were compared, no significant difference was observed for DDR genes and pathways. A survival analysis indicated that the DDR mutation was not associated with overall survival (OS) in MSS CRCs, while left-sided patients with homologous recombination repair (HRR) pathway mutations had a significantly prolonged OS compared with right-sided CRCs. CONCLUSIONS: Here, we found that stage and grade were statistically significant independent prognostic factors in the left-sided CRC and the right-sided CRC, recommending treatment for these patients stratified by stage. For the future, utilizing DDR gene defects for expanding treatment options and improving prognosis is an issue worth exploring.

Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC.

Background: Stress is an important risk factor to induce psychiatric disorders such as depression. Phloretin (PHL), a natural dihydrochalcone compound, has been shown to exhibit anti-inflammatory and anti-oxidative effects. However, the impact of PHL on the depression and the underlying mechanism remain unclear. Methods: The animal behavior tests were used to determine the protective of PHL on the chronic mild stress (CMS)-induced depression-like behaviors. The Magnetic Resonance Imaging (MRI), electron microscopy analysis, fiber photometry, electrophysiology, and Structure Illumination Microscopy (SIM) were used to investigate the protective of PHL on the structural and functional impairments induced by CMS exposure in the mPFC. The RNA sequencing, western blot, reporter gene assay, and chromatin immunoprecipitation were adopted to investigate the mechanisms. Results: We showed that PHL efficiently prevented the CMS-induced depressive-like behaviors. Moreover, PHL not only attenuated the decrease of synapse losses but also improved the dendritic spine density and neuronal activity in the mPFC after CMS exposure. Furthermore, PHL remarkably inhibited the CMS-induced microglial activation and phagocytic activity in the mPFC. In addition, we demonstrated that PHL decreased the CMS-induced synapse losses by inhibiting the deposition of complement C3 deposition onto synapses and subsequent microglia-mediated synaptic engulfment. Finally, we revealed that PHL inhibited the NF-κB-C3 axis to display neuroprotective effects. Conclusions: Our results indicate that PHL represses the NF-κB-C3 axis and subsequent microglia-mediated synaptic engulfment to protect against CMS-induced depression in the mPFC.

Genomic alteration profile and PD-L1 expression among different breast cancer subtypes in Chinese population and their correlations.

BACKGROUD: There were limitations existing in programmed cell-death ligand 1 (PD-L1) as predictive biomarkers for breast cancer (BC), hence exploring the correlation between PD-L1 levels and other biomarkers in BC may become a very useful therapeutic clinical tool. METHODS: A total of 301 Chinese patients with different BC subtypes including 47 HR+/HER2+, 185 HR+/HER2-, 38 HR-/HER2+, and 31 triple-negative breast cancer (TNBC) were enrolled in our study. Next-generation sequencing based Yuansu450 gene panel was used for genomic alteration identification and PD-L1 expression was tested using immunohistochemistry. RESULTS: The most prevalent BC-related mutations were TP53 mutations, followed by mutations in PIK3CA, ERBB2, CDK12, and GATA3 in our Chinese cohort. We found that mutations DDR2 and MYCL were only mutated in HR-/HER2+ subtype, whereas H3-3A and NRAS mutations were only occurred in HR-/HER2- subtype. The percentage of patients with PD-L1-positive expression was higher in patients with HR-/HER2- mainly due to the percentage of PD-L1-high level. Mutational frequencies of TP53, MYC, FAT4, PBRM1, PREX2 were observed to have significant differences among patients with different BC subtypes based on PD-L1 levels. Moreover, a positive correlation was observed between TMB and PD-L1 level in HR+/HER2- subtype, and showed that the proportion of patients with high PD-L1 expression was higher than that of patients with low PD-L1 expression in the HR+/HER2- and HR+/HER2+ cohorts with high Ki67 expression. CONCLUSIONS: The genomic alterations based on PD-L1 and other biomarkers of different cohorts may provide more possibilities for the treatment of BC with different subtypes.

Predicting Best-Selling New Products in a Major Promotion Campaign Through Graph Convolutional Networks.

Many e-commerce platforms, such as AliExpress, run major promotion campaigns regularly. Before such a promotion, it is important to predict potential best sellers and their respective sales volumes so that the platform can arrange their supply chains and logistics accordingly. For items with a sufficiently long sales history, accurate sales forecast can be achieved through the traditional statistical forecasting techniques. Accurately predicting the sales volume of a new item, however, is rather challenging with existing methods; time series models tend to overfit due to the very limited historical sales records of the new item, whereas models that do not utilize historical information often fail to make accurate predictions, due to the lack of strong indicators of sales volume among the item's basic attributes. This article presents the solution deployed at Alibaba in 2019, which had been used in production to prepare for its annual "Double 11" promotion event whose total sales amount exceeded U.S. $ 38 billion in a single day. The main idea of the proposed solution is to predict the sales volume of each new item through its connections with older products with sufficiently long sales history. In other words, our solution considers the cross-selling effects between different products, which has been largely neglected in previous methods. Specifically, the proposed solution first constructs an item graph, in which each new item is connected to relevant older items. Then, a novel multitask graph convolutional neural network (GCN) is trained by a multiobjective optimization-based gradient surgery technique to predict the expected sales volumes of new items. The designs of both the item graph and the GCN exploit the fact that we only need to perform accurate sales forecasts for potential best-selling items in a major promotion, which helps reduce computational overhead. Extensive experiments on both proprietary AliExpress data and a public dataset demonstrate that the proposed solution achieves consistent performance gains compared to existing methods for sales forecast.

Pathological complete remission in ALK-positive lung cancer patient after multiple lines of conversion therapy.

Introduction: Traditional therapeutic approaches for the treatment of advanced non-small-cell lung cancer (NSCLC) are based on chemotherapy. However, the discovery and understanding of oncogenic driver alterations has led to the development of targeted therapies that have substantially improved patient outcomes. Still, to date, there have been no reports of patients with advanced anaplastic lymphoma kinase (ALK)-positive lung cancer achieving clinical complete response (cCR) in the systemic lesion and pathological complete remission (pCR) in primary lung lesion after multiple lines of conversion therapy. Methods: In this case, a 55-year-old man was diagnosed with ALK-positive, stage IV lung adenocarcinoma using immunohistochemistry and next generation sequencing (NGS) tests. Results: Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, were used respectively as first-line, second-line, and third-line therapy. The patient received treatment with crizotinib and achieved partial response (PR), but 5 months later the efficacy was evaluated as progressive disease (PD). Ceritinib was used as the second-line treatment, but the disease progressed 6 months later. Alectinib was used as the third-line treatment, but the efficacy was evaluated as PD. From April 2019 to November 2019, the patient received 4 cycles of induction chemotherapy with pemetrexed/carboplatin/bevacizumab and then switched to pemetrexed/bevacizumab as the fourth-line treatment, and received the fifth line treatment, cetuximab/paclitaxel liposome/nedaplatin, for 1 cycle, but the disease still progressed. Then the patient received the sixth line of treatment, camrelizumab/lorlatinib, for 9 antitumor cycles, resulting in PR. The patient underwent surgery followed by maintenance treatment with lorlatinib and achieved cCR. To our knowledge, this is the first documented case of cCR in a patient with ALK-positive advanced lung adenocarcinoma treated with multiple lines of therapy followed by surgical treatment. Discussion: This case reveals the possible survival benefit of immunotherapy after multiple line treatment in ALK-positive advanced lung adenocarcinoma, indicating that it is possible find new therapeutic targets based on NGS molecular detection and provide precise therapeutic strategies for clinical practice when drug resistance or progression occurs in cancer therapy.

Genomic and clinicopathological features of lung adenocarcinomas with micropapillary component.

Background: Lung adenocarcinoma (LA) with a micropapillary component (LAMPC) is a histological subtype of lung cancer that has received increasing attention due to its correlation with poor prognosis, and its tendency to recur and metastasize. At present, comprehensive genomic profiles and clinicopathological features for LAMPC remain unclear and require further investigation. Methods: From September 2009 to October 2020, a total of 465 LAMPC patients were recruited and divided into four groups according to MPC proportions, and the correlations between varying proportions of MPCs and clinicopathological characteristics were analyzed. Twenty-nine (29) LAMPC patients and 89 LA patients without MPC (non-MPC) that had undergone NGS testing were selected for further study The comprehensively analyze genomic variations and the difference between LAMPC and MPC were determined. In addition, Gene alterations of LAMPC between Chinese and Western populations were also compared using cBioPortal data. Results: A higher proportion of MPCs, associated with higher tumor stage, pleural invasion, and vascular tumor thrombus formation, was determined in LA patients. Compared to non-MPC patients, LAMPC patients were determined to have a lower frequency of single nucleotide variants and a higher frequency of insertion-deletion mutations. Mutations in TP53, CTNNB1, and SMAD4, and ALK rearrangements/fusions were significantly more frequent in LAMPC patients. ERBB2 mutations were only detected in non-MPC patients. Gene mutations in the Wnt pathway were significantly more common in LAMPC patients as compared to non-MPC patients. ALK fusions were more prevalent in younger patients. Patients with KRAS or LBP1B mutations had significantly larger tumor diameters than patients with wild-type KRAS or LBP1B. Patients with KRAS mutations were more likely to develop vascular tumor thrombus. Using the cBioPortal public database, we determined that mutations in EGFR were significantly higher in Chinese patients than in a Memorial Sloan Kettering Cancer Center (MSKCC) Western cohort. ALK fusions were exclusively detected in the Chinese cohort, while mutations in KEAP1 and NOTCH4 were only detected in the MSKCC cohort. Our analysis of signaling pathways revealed that Wnt pathway gene mutations were significantly higher in the Chinese cohort. Conclusion: LA patients with higher proportions of MPCs were determined to have a higher tumor stage, pleural invasion, and vascular tumor thrombosis formation. We comprehensively analyzed the genomic mutation characteristics of LAMPC patients and identified multiple, novel MPC-related gene alterations and pathway changes. Our data provide further understanding of the nature of the LAMPC and potential drug-targeted gene alterations, which may lead to new therapeutic strategies.

Comprehensive analyses of genomic features and mutational signatures in adenosquamous carcinoma of the lung.

Adenosquamous carcinoma (ASC) of the lung is a relatively rare tumor with strong aggressiveness and poor prognosis. The analysis of mutational signatures is becoming routine in cancer genomics and has implications for pathogenesis, classification, and prognosis. However, the distribution of mutational signatures in ASC patients has not been evaluated. In this study, we sought to reveal the landscape of genomic mutations and mutational signatures in ASC. Next-generation sequencing (NGS) technology was used to retrieve genomic information for 124 ASC patients. TP53 and EGFR were the most prevalent somatic mutations observed, and were present in 66.9% and 54.8% of patients, respectively. CDKN2A (21%), TERT (21%), and LRP1B (18.5%) mutations were also observed. An analysis of gene fusion/rearrangement characteristics revealed a total of 64 gene fusions. The highest frequency of variants was determined for ALK fusions, with six ALK-EML4 classical and two intergenic ALK fusions, followed by three CD74-ROS1 fusions and one ROS1-SYN3 fusion. EGFR 19del (45.6%), and EGFR L858R (38.2%) and its amplification (29.4%) were the top three EGFR mutations. We extracted mutational signatures from NGS data and then performed a statistical analysis in order to search for genomic and clinical features that could be linked to mutation signatures. Amongst signatures cataloged at COSMIC, the most prevalent, high-frequency base changes were for C > T; and the five most frequent signatures, from highest to lowest, were 2, 3, 1, 30, and 13. Signatures 1 and 6 were determined to be associated with age and tumor stage, respectively, and Signatures 22 and 30 were significantly related to smoking. We additionally evaluated the correlation between tumor mutational burden (TMB) and genomic variations. We found that mutations ARID2, BRCA1, and KEAP1 were associated with high TMB. The homologous recombination repair (HRR) pathway-related gene mutation displayed a slightly higher TMB than those without mutations. Our study is the first to report comprehensive genomic features and mutational signatures in Chinese ASC patients. Results obtained from our study will help the scientific community better understand signature-related mutational processes in ASC.

Genomic Features of Organ-Specific Metastases in Lung Adenocarcinoma.

Background: The genomic features of cancer cells may confer the metastatic ability of lung adenocarcinoma (LUAD) to metastasize to specific organs. We aimed to identify the differences in genomic alterations between patients with primary LUAD with and without metastases and to elucidate the metastatic biology that may help developing biomarker-directed therapies for advanced or metastatic disease. Methods: A retrospective cohort of 497 patients with LUAD including 388 primary tumors (PR), 53 bone metastases (MT-bone), 30 liver metastases (MT-liver), and 26 brain metastases (MT-brain) was tested for genomic alterations by a next-generation sequencing assay. Results: The EGFR, TP53, TERT, LRP1B, CDKN2A, ERBB2, ALK, and KMT2C genes had a high frequency of mutations, and the mutations were shared by PR and metastases groups. TP53 and EGFR were the most common mutated genes. In comparison with PR, KRAS, STK11, ATM, NPM1, and ROS1 were significantly mutated in MT-brain, and TP53, MYC, RSPO2, CDKN2a, and CDKN2B were significantly mutated in MT-liver. The frequencies of TP53, CDKN2A, MTAP, PRKCI, and APC mutations were higher in MT-bone than that in PR. The ERBB, phosphoinositide-3-kinase/protein kinase B (PI3K-AKT), cell cycle, Fibroblast growth factor (FGF), and homologous recombination deficiency signaling pathways were affected in both PR and metastases, and there is higher frequency of mutations in metastases. Moreover, the co-mutations in patients with PR and metastasis were respectively analyzed. In addition, the programmed death ligand 1 (PD-L1) level was obviously related to tumor stage and tumor metastases, and the tumor mutational burden was correlated to clinicopathological features including age, gender, pathological stages, and tumor metastases. FGFR1, KAT6A, MYC, RAD21, TP53, and DAXX were also dramatically correlated to the tumor mutational burden. Conclusion: Metastases are the most devastating stage of tumors and the main cause of cancer-related deaths. Our results provided a clinically relevant view of the tumor-intrinsic mutational landscape of patients with metastatic LUAD.

Case Report: Durable partial response to icotinib plus crizotinib in a lung adenocarcinoma patient with double uncommon EGFR G719D/L861Q mutations and an acquired novel CUX1-MET fusion.

Non-small cell lung cancer (NSCLC) patients harboring MET exon 14 skipping or high MET amplification display a high rate of response to MET inhibitors. However, MET fusions in NSCLC have rarely been revealed. In this report, a 63-year-old woman with lung adenocarcinoma (LADC), harboring EGFR exon 18 G719D and exon 21 L861Q mutations, received first-generation, EGFR-tyrosine kinase inhibitor (TKI) icotinib therapy. Next generation sequencing (NGS) results only displayed an EGFR T790M point mutation following icotinib resistance. Thus, the patient was treated with osimertinib and achieved a stable disease (SD). However, disease progressed after 15 months and a novel MET fusion (CUX1 exon14-MET exon15) in addition to EGFR G719D/L861Q mutations were simultaneously detected in a tissue biopsy sample. After more than nine months, the patient subsequently achieved a PR with the combination of icotinib and crizotinib. To our knowledge, this is the first case of LADC patient displaying the presence of EGFR double uncommon mutations and an acquired novel CUX1-MET fusion that has benefited from icotinib plus crizotinib treatment. Following nine months of PR with icotinib plus crizotinib, the patient, until the time of publication, is exhibiting stable disease. The results suggest that the CUX1-MET fusion may be sensitive to crizotinib, although previous reports indicated that some MET fusion cases did not respond to crizotinib. Given this disparity, distinguishing MET fusion partners when crizotinib is used in LADC treatment is also very important.

Wheat leaf area index prediction using data fusion based on high-resolution unmanned aerial vehicle imagery.

BACKGROUND: Leaf Area Index (LAI) is half of the amount of leaf area per unit horizontal ground surface area. Consequently, accurate vegetation extraction in remote sensing imagery is critical for LAI estimation. However, most studies do not fully exploit the advantages of Unmanned Aerial Vehicle (UAV) imagery with high spatial resolution, such as not removing the background (soil and shadow, etc.). Furthermore, the advancement of multi-sensor synchronous observation and integration technology allows for the simultaneous collection of canopy spectral, structural, and thermal data, making it possible for data fusion. METHODS: To investigate the potential of high-resolution UAV imagery combined with multi-sensor data fusion in LAI estimation. High-resolution UAV imagery was obtained with a multi-sensor integrated MicaSense Altum camera to extract the wheat canopy's spectral, structural, and thermal features. After removing the soil background, all features were fused, and LAI was estimated using Random Forest and Support Vector Machine Regression. RESULTS: The results show that: (1) the soil background reduced the accuracy of the LAI prediction of wheat, and soil background could be effectively removed by taking advantage of high-resolution UAV imagery. After removing the soil background, the LAI prediction accuracy improved significantly, R2 raised by about 0.27, and RMSE fell by about 0.476. (2) The fusion of multi-sensor synchronous observation data could achieve better accuracy (R2 = 0.815 and RMSE = 1.023), compared with using only one data; (3) A simple LAI prediction method could be found, that is, after selecting a few features by machine learning, high prediction accuracy can be obtained only by simple multiple linear regression (R2 = 0.679 and RMSE = 1.231), providing inspiration for rapid and efficient LAI prediction of wheat. CONCLUSIONS: The method of this study can be transferred to other sites with more extensive areas or similar agriculture structures, which will facilitate agricultural production and management.

Water leak control for the oil-producing wells using Downhole Water Sink Technology.

Casing or tubing leaks cause unwanted water production from oil-producing wells. Many chemical and mechanic water control technologies can be used to solve this problem, including squeezing chemical shutoff fluids into the targeted zone or using plugs, cement, packers, patches to block the leakage. Although those methods are field-proven to be effective, the mechanical solutions may require well logs to detect the water entry point in the well. Chemical methods may present environment risks. In this study, an alternative method, Downhole Water Sink, is proposed to solve the problem of unwanted water production from a casing or tubing leak. The effectiveness of this method to control water production in a well with casing or tubing leaks is tested using the Hele-Shaw experimental model. The results show that this method can control unwanted water production via dynamic control of the pressure drawdown in the reservoir. From a technical standpoint, the advantage of this technology is that it eliminates the need to run logs to locate the water entry point and does not require chemical injection into the formation. From an environmental standpoint, this technology has the circular economy elements. Because the produced water in this technology contains little or no oil, it can be reused for reinjection into the reservoir for water flooding or pressure maintenance purposes. Therefore, a production-reinjection process to recycle the produced water is established to reduce the pollution caused by discharging the wastewater into the environment.

Case report: Long-term clinical benefit of pyrotinib therapy following trastuzumab resistance in HER2-amplification recurrent mucinous ovarian carcinoma.

Advanced or recurrent mucinous carcinoma of the ovary minimally responds to current cytotoxic treatments and has a poor prognosis. Despite multimodal treatment with chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. Anti-HER2 therapy has been demonstrated to be an effective strategy for the treatment of HER2-positive breast cancer. However, the role of anti-HER2 therapy in ovarian cancer remains largely unknown. Here, we report the case of a young woman with FIGO Stage IIIc recurrent mucinous ovarian carcinoma (MOC) who developed trastuzumab resistance and disease progression following cross-treatment with trastuzumab combined with pertuzumab. HER2 amplification was discovered using next-generation sequencing (NGS). The patient then received bevacizumab, and pyrotinib (an irreversible HER2 antagonist) plus capecitabine treatment, and achieved a long-term clinical benefit for 22 months. Pyrotinib combined with bevacizumab is a potential treatment for MOC patients who are heavily pretreated and harbor a HER2 amplification. Our case may provide valuable treatment information for patients with advanced or recurrent MOC.

Case Report: Complete Response of Primary Massive Hepatocellular Carcinoma to Anti-Programmed Death Ligand-1 Antibody Following Progression on Anti-Programmed Death-1 Antibody.

Hepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs due to chronic liver disease, and it has a high mortality rate and limited treatment options. Immune checkpoint inhibitors have been successfully introduced and used in cancer therapy, among which inhibitors of programmed death ligand-1 (PD-L1) and its receptor programmed death-1 (PD-1) are commonly administered for HCC as combination therapy, including combined anti-angiogenic and immunotherapy combination therapy. We report a case of a primary massive HCC patient with portal hepatic vein tumor thrombus who had a good response to atezolizumab in combination with bevacizumab, following progression of disease on combined immunotherapy with pembrolizumab and lenvatinib. This case demonstrates for the first time that an HCC patient who is resistant to anti-PD-1 antibody immunotherapy can benefit from anti-PD-L1 antibody immunotherapy, providing a potentially promising strategy for the treatment of HCC.

Zinc oxide nanoparticle-triggered oxidative stress and autophagy activation in human tenon fibroblasts.

Glaucoma is a leading cause of irreversible blindness worldwide due to elevated intraocular pressure, and filtering surgery can efficiently control intraocular pressure of glaucoma patients. However, failure of filtering surgery commonly results from scarring formation at the surgical site, in which fibroblast proliferation plays an essential role in the scarring process. Our previous study has demonstrated that zinc oxide (ZnO) nanoparticles could efficiently inhibit human tenon fibroblasts (HTFs) proliferation. The present study aimed to explore the underlying mechanism involved in oxidative stress and autophagy signaling in zinc oxide (ZnO) nanoparticles-induced inhibition of HTFs proliferation. In this study, we investigated the effect of ZnO nanoparticles on HTFs proliferation, mitochondrial function, ATP production and nuclear morphology. Moreover, we also explored the interactions between ZnO nanoparticles and HTFs, investigated the influence of ZnO nanoparticles on the autophagosome formation, the expression of autophagy-related 5 (Atg5), Atg12 and Becn1 (Beclin 1), and the level of light chain 3 (LC3). The results suggested that ZnO nanoparticles can efficiently inhibit HTFs proliferation, disrupt the mitochondrial function, attenuate the adenosine triphosphate (ATP) generation, and damage the nuclear morphology of HTFs. Exposure of HTFs to ZnO nanoparticles can also induce the shifted peak, elevate the expression of Atg5, Atg12 and Becn1, enhance the autophagosome formation, and promote the LC3 expression, and thus activate autophagy signaling. Overall, ZnO nanoparticles can apparently trigger oxidative stress and activate autophagy signaling in HTFs, and thus inhibit HTFs proliferation and mediate HTFs apoptosis.