Synthesis of α-ketoamides via oxidative amidation of diazo compounds with O-benzoyl hydroxylamines as nitrogen source and the oxidant.

A simple, efficient method has been described for the construction of an array of α-ketoamides from readily available O-benzoyl hydroxylamines and diazo compounds as starting materials. There was a combined use of CuI as a catalyst and H2O as the oxygen source. The investigation reveals that the O-benzoyl hydroxylamines serve a dual role as both an amine source and the oxidant in this mechanism, thereby obviating the need for additional oxidants in the transformation process. This methodology could give a wider range of products in good to excellent yields for most substrates, and thus, we provide a new idea for the synthesis of α-ketoamides.

Acid/Base-Steered Cascade Cyclization: An Efficient One-Pot Access to Diverse Isobenzofuranone and Isoindolobenzoxazinone Derivatives.

We herein report the acid/base-steered two distinct reaction pathways of 2-acylbenzoic acids with isatoic anhydrides. In the presence of Na2CO3, the cascade process consists of the cyclization of 2-acetylbenzoic acid and nucleophilic ring-opening reaction of isatoic anhydride to furnish isobenzofuranone derivatives with high efficiency. However, p-toluenesulfonic acid can promote the product isobenzofuranones to undergo sequential intramolecular rearrangment, nucleophilic addition and cyclization reaction to produce diverse isoindolobenzoxazinones in good yields. The synthetic utility of this method was further demonstrated by the gram-scale preparation of the desired products and the facile transformations of the resulting products.

Copper-Catalyzed Difluoroalkylation Reaction.

This review describes recent advances in copper-catalyzed difluoroalkylation reactions. The RCF2 radical is generally proposed in the mechanism of these reactions. At present, various types of copper-catalyzed difluoroalkylation reactions have been realized. According to their characteristics, we classify these difluoroalkylation reactions into three types.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

BACKGROUND: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. MATERIALS AND METHODS: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. RESULTS: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. CONCLUSION: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. IMPLICATIONS FOR PRACTICE: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

Diagnostic efficacy of anti-SARS-CoV-2 IgG/IgM test for COVID-19: A meta-analysis.

The serological testing of anti-SARS-CoV-2 immunoglobulin G (IgG) and/or IgM is widely used in the diagnosis of COVID-19. However, its diagnostic efficacy remains unclear. In this study, we searched for diagnostic studies from the Web of Science, PubMed, Embase, CNKI, and Wanfang databases to calculate the pooled diagnostic accuracy measures using bivariate random-effects model meta-analysis. As a result, 22 from a total of 1613 articles, including 2282 patients with SARS-CoV-2 and 1485 healthy persons or patients without SARS-CoV-2, were selected for a meta-analysis. Pooled sensitivity, specificity, and area under curve of the summary receiver operator curve (SROC) were: (a) 0.85 (95% confidence interval [CI]: 0.79-0.90), 0.99 (95% CI: 0.98-1.00), and 0.99 (95% CI: 0.97-0.99) for anti-SARS-CoV-2 IgG and (b) 0.74 (95% CI: 0.65-0.81), 0.99 (95% CI: 0.97-1.00), and 0.95 (95% CI: 0.93-0.97) for IgM. A subgroup analysis among detection methods indicated the sensitivity of IgG and IgM using enzyme-linked immunosorbent assay were slightly lower than those using gold immunochromatography assay (GICA) and chemiluminescence immunoassay (P > .05). These results showed that the detection of anti-SARS-CoV-2 IgG and IgM had high diagnostic efficiency to assist the diagnosis of SARS-CoV-2 infection. And, GICA might be used as the preferred method for its accuracy and simplicity.

Laboratory findings of COVID-19: a systematic review and meta-analysis.

The Coronavirus Disease (COVID-19) pandemic first broke out in December 2019 in Wuhan, China, and has now spread worldwide. Laboratory findings have been only partially described in some observational studies. To date, more comprehensive systematic reviews of laboratory findings on COVID-19 are missing. We performed a systematic review with a meta-analysis to assess laboratory findings in patients with COVID-19. Observational studies from three databases were selected. We calculated pooled proportions and 95% confidence interval (95% CI) using the random-effects model meta-analysis. A total of 1106 articles were identified from PubMed, Web of Science, CNKI (China), and other sources. After screening, 28 and 7 studies were selected for a systematic review and a meta-analysis, respectively. Of the 4,663 patients included, the most prevalent laboratory finding was increased C-reactive protein (CRP; 73.6%, 95% CI 65.0-81.3%), followed by decreased albumin (62.9%, 95% CI 28.3-91.2%), increased erythrocyte sedimentation rate (61.2%, 95% CI 41.3-81.0%), decreased eosinophils (58.4%, 95% CI 46.5-69.8%), increased interleukin-6 (53.1%, 95% CI 36.0-70.0%), lymphopenia (47.9%, 95% CI 41.6-54.9%), and increased lactate dehydrogenase (LDH; 46.2%, 95% CI 37.9-54.7%). A meta-analysis of seven studies with 1905 patients showed that increased CRP (OR 3.0, 95% CI: 2.1-4.4), lymphopenia (OR 4.5, 95% CI: 3.3-6.0), and increased LDH (OR 6.7, 95% CI: 2.4-18.9) were significantly associated with severity. These results demonstrated that more attention is warranted when interpreting laboratory findings in patients with COVID-19. Patients with elevated CRP levels, lymphopenia, or elevated LDH require proper management and, if necessary, transfer to the intensive care unit.

Overexpression of dedicator of cytokinesis 2 correlates with good prognosis in colorectal cancer associated with more prominent CD8+ lymphocytes infiltration: a colorectal cancer analysis.

Recently, dedicator of cytokinesis 2 (DOCK2) has been reportedly exhibited high mutation prevalence in the Asian colorectal cancer (CRC) cohort. However, the expression pattern of DOCK2 and its clinical significance in CRC were still unknown. To characterize the role of DOCK2, a tissue microarray (TMA) containing 481 archived paraffin-embedded CRC specimens was performed by immunohistochemistry. Among which, 54 primary CRC tissues showed high expression of DOCK2 protein, while others were negative. Moreover, DOCK2 expression was positively associated with invasion depth (P < .001) and tumor size (P = .016). Significantly, Kaplan-Meier survival analysis revealed that patients with higher DOCK2 expression had a longer overall survival time (P = .017). Furthermore, univariate and multivariate Cox regression analysis confirmed that DOCK2 is an independent prognostic marker in CRC (P = .049,; HR, 0.519; 95% CI, 0.270 to 0.997). In addition, we observed a strong correlation between the infiltration of CD8+ T lymphocytes and DOCK2 expression (P = .0119). Our findings demonstrated that overexpressed DOCK2 might involve in recruiting CD8+ T lymphocytes and serve as a novel prognostic indicator and indicated a potential therapeutic strategy by restoring DOCK2 for CRC.

Low serum gastrin associated with ER+ breast cancer development via inactivation of CCKBR/ERK/P65 signaling.

BACKGROUND: Gastrin is an important gastrointestinal hormone produced primarily by G-cells in the antrum of the stomach. It normally regulates gastric acid secretion and is implicated in a number of human disease states, but how its function affects breast cancer (BC) development is not documented. The current study investigated the suppressive effects of gastrin on BC and its underlying mechanisms. METHODS: Serum levels of gastrin were measured by enzyme-linked immunosorbent assay (ELISA) and correlation between gastrin level and development of BC was analyzed by chi-square test. Inhibitory effects of gastrin on BC were investigated by CCK-8 assay and nude mice models. Expressions of CCKBR/ERK/P65 in BC patients were determined through immunohistochemistry (IHC) and Western blot. Survival analysis was performed using the log-rank test. RESULTS: The results indicated that the serum level of gastrin in BC patients was lower compared with normal control. Cellular and molecular experiments indicated that reduction of gastrin is associated with inactivation of cholecystokinin B receptor (CCKBR)/ERK/P65 signaling in BC cells which is corresponding to molecular type of estrogen receptor (ER) positive BC. Furthermore, we found that low expression of gastrin/CCKBR/ERK /P65 was correlated to worse prognosis in BC patients. Gastrin or ERK/P65 activators inhibited ER+ BC through CCKBR-mediated activation of ERK/P65. Moreover, combination treatment with gastrin and tamoxifen more efficiently inhibited ER+ BC than tamoxifen alone. CONCLUSIONS: We concluded that low serum gastrin is related to increased risk of ER+ BC development. The results also established that CCKBR/ERK/P65 signaling function is generally tumor suppressive in ER+ BC, indicating therapies should focus on restoring, not inhibiting, CCKBR/ERK/P65 pathway activity.

Different Doses of Clazosentan for Aneurismal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials.

Clazosentan therapy has been found to be effective in reducing the incidence of vasospasm after aneurismal subarachnoid hemorrhage (aSAH). The objective of this meta-analysis was to determine whether different doses of clazosentan treatment significantly reduced the incidence of delayed ischemic neurological deficits (DINDs) and new cerebral infarction (NCI). We systematically searched PubMed, Embase, Cochrane library and Medline from inception until October, 2015. All randomized controlled trials related to the functions of clazosentan in aSAH were included. Analyses were performed following the method guideline of Cochrane Back Review Group. Four randomized placebo-controlled trials met eligibility criteria and enrolled a total of 2159 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk, 0.49 and 95% CI, 0.33-0.73) and NCI (relative risk, 0.42 and 95% CI, 0.25-0.71) in patients treated with a high dose of clazosentan (15 mg/h) after aSAH. In addition, a high dose of clazosentan (15 mg/h) had no more effect on the incidence of adverse events than that of a low dose (1-5 mg/h). The results of the present meta-analysis show that a high dose of clazosentan significantly reduced the incidence of the vasospasm-related DINDs and NCI. Further study is required to fully understand the potential usefulness of clazosentan in patients with aSAH.

Distinct mechanisms mediate naive and memory CD8 T-cell tolerance.

Peripheral tolerance to developmentally regulated antigens is necessary to sustain tissue homeostasis. We have now devised an inducible and reversible system that allows interrogation of T-cell tolerance induction in endogenous naïve and memory CD8 T cells. Our data show that peripheral CD8 T-cell tolerance can be preserved through two distinct mechanisms, antigen addiction leading to anergy for naïve T cells and ignorance for memory T cells. Induction of antigen in dendritic cells resulted in substantial expansion and maintenance of endogenous antigen-specific CD8 T cells. The self-reactive cells initially exhibited effector activity but eventually became unresponsive. Upon antigen removal, the antigen-specific population waned, resulting in development of a self-specific memory subset that recalled to subsequent challenge. In striking contrast to naïve CD8 T cells, preexisting antigen-specific memory CD8 T cells failed to expand after antigen induction and essentially ignored the antigen despite widespread expression by dendritic cells. The inclusion of inflammatory signals partially overcame memory CD8 T-cell ignorance of self-antigen. Thus, peripheral CD8 T-cell tolerance for naïve CD8 T cells depended on the continuous presence of antigen, whereas memory CD8 T cells were prohibited from autoreactivity in the absence of inflammation.

Hypervalent iodine: a powerful electrophile for asymmetric α-functionalization of carbonyl compounds.

Environmentally friendly hypervalent iodine reagents are unusually effective promoters of asymmetric α-functionalization of carbonyl compounds. By using hypervalent iodine reagents, various substituents can be introduced into the α-position of carbonyl compounds. In the present review, we briefly survey the asymmetric α-functionalization of carbonyl compound reactions catalyzed by these hypervalent iodine reagents.

Brain tumor segmentation based on the U-NET+⁣+ network with efficientnet encoder.

BACKGROUND: Brain tumor is a highly destructive, aggressive, and fatal disease. The presence of brain tumors can disrupt the brain's ability to control body movements, consciousness, sensations, thoughts, speech, and memory. Brain tumors are often accompanied by symptoms like epilepsy, headaches, and sensory loss, leading to varying degrees of cognitive impairment in affected patients. OBJECTIVE: The study goal is to develop an effective method to detect and segment brain tumor with high accurancy. METHODS: This paper proposes a novel U-Net+⁣+ network using EfficientNet as the encoder to segment brain tumors based on MRI images. We adjust the original U-Net+⁣+ model by removing the dense skip connections between sub-networks to simplify computational complexity and improve model efficiency, while the connections of feature maps at the same resolution level are retained to bridge the semantic gap. RESULTS: The proposed segmentation model is trained and tested on Kaggle's LGG brain tumor dataset, which obtains a satisfying performance with a Dice coefficient of 0.9180. CONCLUSION: This paper conducts research on brain tumor segmentation, using the U-Net+⁣+ network with EfficientNet as an encoder to segment brain tumors based on MRI images. We adjust the original U-Net+⁣+ model to simplify calculations and maintains rich semantic spatial features at the same time. Multiple loss functions are compared in this study and their effectiveness are discussed. The experimental results shows the model achieves a high segmention result with Dice coefficient of 0.9180.

Multimodal abnormalities of brain structures in adolescents and young adults with major depressive disorder: An activation likelihood estimation meta-analysis.

BACKGROUND: Major depressive disorder (MDD) in adolescents and young adults contributes significantly to global morbidity, with inconsistent findings on brain structural changes from structural magnetic resonance imaging studies. Activation likelihood estimation (ALE) offers a method to synthesize these diverse findings and identify consistent brain anomalies. AIM: To identify consistent brain structural changes in adolescents and young adults with MDD using ALE meta-analysis. METHODS: We performed a comprehensive literature search in PubMed, Web of Science, Embase, and Chinese National Knowledge Infrastructure databases for neuroimaging studies on MDD among adolescents and young adults published up to November 19, 2023. Two independent researchers performed the study selection, quality assessment, and data extraction. The ALE technique was employed to synthesize findings on localized brain function anomalies in MDD patients, which was supplemented by sensitivity analyses. RESULTS: Twenty-two studies comprising fourteen diffusion tensor imaging (DTI) studies and eight voxel-based morphometry (VBM) studies, and involving 451 MDD patients and 465 healthy controls (HCs) for DTI and 664 MDD patients and 946 HCs for VBM, were included. DTI-based ALE demonstrated significant reductions in fractional anisotropy (FA) values in the right caudate head, right insula, and right lentiform nucleus putamen in adolescents and young adults with MDD compared to HCs, with no regions exhibiting increased FA values. VBM-based ALE did not demonstrate significant alterations in gray matter volume. Sensitivity analyses highlighted consistent findings in the right caudate head (11 of 14 analyses), right insula (10 of 14 analyses), and right lentiform nucleus putamen (11 of 14 analyses). CONCLUSION: Structural alterations in the right caudate head, right insula, and right lentiform nucleus putamen in young MDD patients may contribute to its recurrent nature, offering insights for targeted therapies.

Neoadjuvant chemotherapy for gastric cancer: a meta-analysis of randomized, controlled trials.

BACKGROUND AND AIM: Although the effect of neoadjuvant chemotherapy in gastric cancer has been extensively studied, the data of survival benefit are still controversial. The purpose of this work was to assess the effectiveness of neoadjuvant chemotherapy followed by surgery in patients with gastric cancer. METHODS: We searched systematically electronic through the databases of PUBMED, EMBASE, China Biological Medicine, and China National Knowledge Infrastructure Whole Article for studies published from 1975. Two reviewers independently evaluated the relevant reports and searched manually reference from these reports for additional trials. Outcomes assessed by meta-analysis included overall survival rate, progression-free survival rate, R0 resection rate, downstaging effect, postoperative complications, and perioperative mortality. RESULTS: Six randomized, controlled trials with 781 patients were included in the meta-analysis. Odds ratio (95% confidence interval; P-value), expressed as neoadjuvant chemotherapy and surgery versus surgery alone, was 1.16 (0.85-1.58; P = 0.36) for overall survival, 1.24 (0.78-1.96; P = 0.36) for R0 resection, 1.25 (0.75-2.09; P = 0.39) for postoperative complications, and 3.60 (0.59-22.45; P = 0.17) for perioperative mortality. CONCLUSIONS: Compared with surgery alone, neoadjuvant chemotherapy followed by surgery was not associated with a higher rate of overall survival or complete resection (R0 resection). It does not increase treatment-related morbidity and mortality. This meta-analysis did not demonstrate a survival benefit for the combination of neoadjuvant chemotherapy and surgery.

Large negative differential resistance and rectifying behaviors in isolated thiophene nanowire devices.

We design isolated molecular nanowires composed of thiophene oligomers sandwiched between two one-dimensional gold electrodes. Electronic transport through the molecular junctions with two interface geometries is studied by performing the first principles calculations based on density functional theory and nonequilibrium Green's function. The current-voltage (I-V) curves of the molecular wires display an unexpected negative differential resistance and rectifying behaviors along with the oscillation effects, different from other theoretical and experimental studies about the analogous thiophene devices. The significant difference is attributed to the design of the one-dimensional gold electrodes with large enough vacuum layer in transverse direction in order to suppress the interaction between wires. Such transport behaviors indicate that the thiophene molecular device would be an important candidate in future molecular electronics.

Threshold dynamics of a stochastic general SIRS epidemic model with migration.

In this study, a stochastic SIRS epidemic model that features constant immigration and general incidence rate is investigated. Our findings show that the dynamical behaviors of the stochastic system can be predicted using the stochastic threshold $ R_0^S $. If $ R_0^S < 1 $, the disease will become extinct with certainty, given additional conditions. Conversely, if $ R_0^S > 1 $, the disease has the potential to persist. Moreover, the necessary conditions for the existence of the stationary distribution of positive solution in the event of disease persistence is determined. Our theoretical findings are validated through numerical simulations.

Comprehensive Mutation Profiling of Colorectal Cancer Patients With Lung or Liver Metastasis by Targeted Next-Generation Sequencing.

OBJECTIVES: Primary tumor tissue is often analyzed to search for predictive biomarkers and DNA-guided personalized therapies, but there is an incomplete understanding of the discrepancies in the genomic profiles between primary tumors and metastases, such as liver and lung metastases. METHODS: We performed in-depth targeted next-generation sequencing of 520 key cancer-associated genes for 47 matched primary and metastatic tumor samples which were retrospectively collected. RESULTS: A total of 699 mutations were detected in the 47 samples. The coincidence rate of primary tumors and metastases was 51.8% (n = 362), and compared to patients with liver metastases, patients with lung metastases had a significantly greater coincidence rate (P = .021). The number of specific mutations for the primary tumors and liver and lung metastases was 186 (26.6%), 122 (17.5%), and 29 (4.1%), respectively. Analysis of a patient with all three occurrences, including a primary tumor, liver metastasis, and lung metastasis, indicated a possible polyclonal seeding mechanism for liver metastases. Remarkably, multiple samples from patients with primary and metastatic tumors supported a mechanism of synchronous parallel dissemination from primary tumors to metastatic tumors that were not mediated through pre-metastatic tumors. We also found that the PI3K-Akt signaling pathway significantly altered lung metastases compared to matched primary tumors (P = .001). In addition, patients with mutations in CTCF, PIK3CA, or TP53 and LRP1B, AURKA, FGFR1, ATRX, DNMT3B, or GNAS had larger primary tumor sizes and metastases, especially patients with both LRP1B and AURKA mutations. Interestingly, CRC patients with TP53-disruptive mutations were more likely to have liver metastases (P = .016). CONCLUSION: In this study, we demonstrate significant differences in the genomic landscapes of colorectal cancer patients based on the site of metastasis. Notably, we observe a larger genomic variation between primary tumors and liver metastasis compared to primary tumors and lung metastasis. These findings can be used for tailoring treatments based on the specific metastatic site.

Trends in antineoplastic drug use, cost and prescribing patterns among patients with lung cancer in nine major cities of China, 2016-2020: a retrospective observational study based on inpatient and outpatient hospital data.

OBJECTIVES: It is unclear whether the use of antineoplastic drugs for patients with lung cancer in China has changed after the implementation of the national drug price negotiation in 2016 and continual update of clinical guidelines. This study aims to evaluate the trends in antineoplastic drug use, cost and prescribing patterns among patients with lung cancer in major cities of China. DESIGN: We conducted a retrospective observational study using data from January 2016 to December 2020. SETTING: This study used prescription records based on inpatient and outpatient hospital data from 97 hospitals in 9 major cities of China. PARTICIPANTS: A total of 218 325 antineoplastic drug prescriptions in patients with lung cancer were retrospectively collected from the Hospital Prescription Analysis Cooperative Project during the study period. OUTCOME MEASURES: Trends in antineoplastic drug use, cost and prescribing patterns among patients with lung cancer. RESULTS: The yearly antineoplastic prescriptions increased by 85.6% from 28 594 in 2016 to 53 063 in 2020 (Z=1.71, p=0.086). Significant increases were seen in the prescriptions for protein kinase inhibitors (PKIs) and monoclonal antibodies (mAbs), whereas significant decreases were observed in antimetabolites, plant alkaloids and platinum compounds. The yearly cost increased progressively by 145.0% from ¥113.6 million in 2016 to ¥278.3 million in 2020 (Z=2.20, p=0.027). The top three anticancer drug classes in terms of total cost were PKIs, antimetabolites and mAbs. In prescribing patterns of antineoplastic agents for lung cancer, monotherapy, and triple or more drug combinations gradually increased, while dual combinations decreased significantly from 30.8% to 19.6%. CONCLUSIONS: Prescription practices among patients with lung cancer in China underwent major changes during the study period. The observed trends can aid in understanding the present medication use status of patients with lung cancer in China and provide information for future drug management.

Quantitative proteomics profiling reveals the inhibition of trastuzumab antitumor efficacy by phosphorylated RPS6 in gastric carcinoma.

BACKGROUND: The anti-HER2 antibody trastuzumab is a standard treatment for gastric carcinoma with HER2 overexpression, but not all patients benefit from treatment with HER2-targeted therapies due to intrinsic and acquired resistance. Thus, more precise predictors for selecting patients to receive trastuzumab therapy are urgently needed. METHODS: We applied mass spectrometry-based proteomic analysis to 38 HER2-positive gastric tumor biopsies from 19 patients pretreated with trastuzumab (responders n = 10; nonresponders, n = 9) to identify factors that may influence innate sensitivity or resistance to trastuzumab therapy and validated the results in tumor cells and patient samples. RESULTS: Statistical analyses revealed significantly lower phosphorylated ribosomal S6 (p-RPS6) levels in responders than nonresponders, and this downregulation was associated with a durable response and better overall survival after anti-HER2 therapy. High p-RPS6 levels could trigger AKT/mTOR/RPS6 signaling and inhibit trastuzumab antitumor efficacy in nonresponders. We demonstrated that RPS6 phosphorylation inhibitors in combination with trastuzumab effectively suppressed HER2-positive GC cell survival through the inhibition of the AKT/mTOR/RPS6 axis. CONCLUSIONS: Our findings provide for the first time a detailed proteomics profile of current protein alterations in patients before anti-HER2 therapy and present a novel and optimal predictor for the response to trastuzumab treatment. HER2-positive GC patients with low expression of p-RPS6 are more likely to benefit from trastuzumab therapy than those with high expression. However, those with high expression of p-RPS6 may benefit from trastuzumab in combination with RPS6 phosphorylation inhibitors.

Phylogeny and Genetic Divergence among Sorghum Mosaic Virus Isolates Infecting Sugarcane.

Sorghum mosaic virus (SrMV, the genus Potyvirus of the family Potyviridae) is a causal agent of common mosaic in sugarcane and poses a threat to the global sugar industry. In this study, a total of 901 sugarcane leaf samples with mosaic symptom were collected from eight provinces in China and were detected via RT-PCR using a primer pair specific to the SrMV coat protein (CP). These leaf samples included 839 samples from modern cultivars (Saccharum spp. hybrids) and 62 samples from chewing cane (S. officinarum). Among these, 632 out of 901 (70.1%) samples were tested positive for SrMV. The incidences of SrMV infection were 72.3% and 40.3% in modern cultivars and chewing cane, respectively. Phylogenetic analysis showed that all tested SrMV isolates were clustered into three clades consisting of six phylogenetic groups based on 306 CP sequences (this study = 265 and GenBank database = 41). A total of 10 SrMV isolates from South America (the United States and Argentina) along with 106 isolates from China were clustered in group D, while the remaining 190 SrMV isolates from Asia (China and Vietnam) were dispersed in five groups. The SrMV isolates in group F were limited to Yunnan province in China, and those in group A were spread over eight provinces. A significant genetic heterogeneity was elucidated in the nucleotide sequence identities of all SrMV CPs, ranging from 69.0% to 100%. A potential recombination event was postulated among SrMV isolates based on CP sequences. All tested SrMV CPs underwent dominant negative selection. Geographical isolation (South America vs. Asia) and host types (modern cultivars vs. chewing cane) are important factors promoting the genetic differentiation of SrMV populations. Overall, this study contributes to the global understanding of the genetic evolution of SrMV and provides a valuable resource for the epidemiology and management of the mosaic in sugarcane.