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Introduction: PEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic NSCLC (mNSCLC [EGFR/ALK wild type]) with programmed cell death ligand 1 (PD-L1) tumor cell (TC) membrane expression status of 25% or higher. We report the final analysis of PEARL., Methods: Adults (N = 669) with previously untreated stage IV mNSCLC were randomized (1:1) to durvalumab 20 mg/kg every four weeks or chemotherapy every three weeks for four to six cycles. The dual primary endpoints were overall survival (OS) in the population with PD-L1 TC of 25% or higher and OS in the population at low risk of early mortality (LREM) with PD-L1 TC of 25% or higher., Results: Durvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the 25% and higher PD-L1 TC population (OS hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.71-0.99, p = 0.037; median OS 14.6 months, 95% CI: 12.2-16.9 versus 12.8 months, 95% CI: 10.1-14.7, respectively). In the 25% and higher PD-L1 TC low risk of early mortality population the OS hazard ratio for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79-1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6-17.2) versus 15.0 months (95% CI: 13.1-16.8), respectively. In the safety population, the incidence of grade 3 or 4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy)., Conclusions: Durvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and 25% and higher PD-L1 TC. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC., Competing Interests: Disclosure Dr. Lu discloses consulting fees from AstraZeneca, Hutchison, Roche, Simcere; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Roche, Hansoh, Hengrui Therapeutics; participation on a Data Safety Monitoring Board or Advisory Boards for Roche, Hengrui Therapeutics; leadership or fiduciary role in other board, society, committee or advocacy group, (unpaid) for Innovent Biologics, Inc. Dr. Wu discloses payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Roche, Hansoh, Bristol Myers Squibb, Merck, Lilly, Pfizer, Novartis, Jiangsu Hengrui Pharmaceutical, Innovent Biologics, Qilu Pharmaceuticals. Dr. Tran discloses payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer; support for attending meetings and/or travel from AstraZeneca; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Vietnam Lung Association (ViLA). Dr. Laktionov has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for AstraZeneca, Biocad, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche AG; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Biocad, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche AG. Dr. Clarke discloses participation on Advisory Boards for AstraZeneca. Drs. Song, Mann, and Shi are employees of, and own stocks in, AstraZeneca. Yinglei Liu is an employee of AstraZeneca. Dr. Wu discloses grants (paid to institution) from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Hengrui, Roche; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Pfizer, Roche, Sanofi. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Anaerobic fermentation of potato leaves and stems for organic acid synthesis, serving as food additives, faces impediments due to misconceptions about the effects of moisture stress on the acid-synthesizing microbiome. An ingenious method, avoiding interference from microbiome and nutrient integrations, was employed in the present study. Results showed that increasing the moisture level from 60 % to 75 % significantly improved lactic acid (182.64 %), acetic acid (163.55 %), propionic acid (1960.43 %), nonprotein nitrogen, free amino acid and ammonia levels but reduced pH value and water-soluble carbohydrate and hemicellulose levels. Microbiologically, the high-moisture groups enriched Lactiplantibacillus, Levilactobacillus and Enterobacter, upregulated glycolysis, nitrogen, pyruvate and propanoate metabolisms, and activated genes for acid-producing and ammonia-forming enzymes. Notably, Lactiplantibacillus and Enterobacter prevailed in glycolysis and nitrogen metabolism, respectively, and Levilactobacillus was more prominent in pyruvate and propanoate metabolism under high-moisture conditions. Collectively, a moisture level of 75 % benefited organic acid synthesis from potato waste via anaerobic fermentation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

To demonstrate the feasibility of automating UED operation and diagnosing the machine performance in real time, a two-stage machine learning (ML) model based on self-consistent start-to-end simulations has been implemented. This model will not only provide the machine parameters with adequate precision, toward the full automation of the UED instrument, but also make real-time electron beam information available as single-shot nondestructive diagnostics. Furthermore, based on a deep understanding of the root connection between the electron beam properties and the features of Bragg-diffraction patterns, we have applied the hidden symmetry as model constraints, successfully improving the accuracy of energy spread prediction by a factor of five and making the beam divergence prediction two times faster. The capability enabled by the global optimization via ML provides us with better opportunities for discoveries using near-parallel, bright, and ultrafast electron beams for single-shot imaging. It also enables directly visualizing the dynamics of defects and nanostructured materials, which is impossible using present electron-beam technologies., (© 2022. The Author(s).)

Optimization algorithms/techniques such as genetic algorithm, particle swarm optimization, and Gaussian process have been widely used in the accelerator field to tackle complex design/online optimization problems. However, connecting the algorithm with the optimization problem can be difficult, as the algorithms and the problems may be implemented in different languages, or they may require specific resources. We introduce an optimization platform named Teeport that is developed to address the above issues. This real-time communication-based platform is designed to minimize the effort of integrating the algorithms and problems. Once integrated, the users are granted a rich feature set, such as monitoring, controlling, and benchmarking. Some real-life applications of the platform are also discussed., 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 © 2021 Zhang, Huang and Song.)

To harness the full potential of the ultrafast electron diffraction (UED) and microscopy (UEM), we must know accurately the electron beam properties, such as emittance, energy spread, spatial-pointing jitter, and shot-to-shot energy fluctuation. Owing to the inherent fluctuations in UED/UEM instruments, obtaining such detailed knowledge requires real-time characterization of the beam properties for each electron bunch. While diagnostics of these properties exist, they are often invasive, and many of them cannot operate at a high repetition rate. Here, we present a technique to overcome such limitations. Employing a machine learning (ML) strategy, we can accurately predict electron beam properties for every shot using only parameters that are easily recorded at high repetition rate by the detector while the experiments are ongoing, by training a model on a small set of fully diagnosed bunches. Applying ML as real-time noninvasive diagnostics could enable some new capabilities, e.g., online optimization of the long-term stability and fine single-shot quality of the electron beam, filtering the events and making online corrections of the data for time-resolved UED, otherwise impossible. This opens the possibility of fully realizing the potential of high repetition rate UED and UEM for life science and condensed matter physics applications.

Doxorubicin (DOX) is a highly efficient chemotherapeutic drug limited by its cardiotoxicity. Galectin-3 (Gal-3) overexpression is associated with several cardiovascular diseases. In this study, the in vivo models of DOX-treated rats and the in vitro model of DOX-treated H9C2 cells were used. DOX induced cardiac injury and dysfunction accompanied with the upregulation of Gal-3 at the end of the experiment, while inhibition of Gal-3 with modified citrus pectin (MCP) exhibited a dramatic improvement in cardiac function of the DOX-treated rats, as manifested by increased left ventricular systolic pressure and ±d p /d t max and decreased left ventricular end-diastolic pressure. The plasma levels of myocardial injury markers such as lactate dehydrogenase, creatine kinase, creatine kinase-MB, and cardiac troponin I were decreased after MCP treatment. In parallel, MCP attenuated myocardial tissue markers of oxidative stress such as hydrogen peroxide and malondialdehyde restored the activities of superoxide dismutase, catalase, and glutathione peroxidase and upregulated antioxidant peroxiredoxin-4 (Prx-4). To further verify the role of Prx-4, it was downregulated by siRNA-mediated knockdown in H9C2 cells. MCP could not reverse DOX-induced oxidative stress in Prx-4-knock-down cells. In conclusion, Gal-3 mediated DOX-induced cardiotoxicity and Gal-3 inhibition attenuated DOX-induced cardiac dysfunction by upregulating the expression of Prx-4 to reduce myocardial oxidative stress.

Purpose: Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world., Methods: EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography., Results: EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases)., Conclusions: EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.

Purpose: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation among fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods. Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH ( N = 206) and whole-exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61-0.80 defines substantial agreement) or R 2 statistics., Results: EGFR mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with EGFR amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification., Conclusions: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches., (©2019 American Association for Cancer Research.)

Background: c-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity., Method: We generated and tested a bivalent anti-c-Met monoclonal antibody ABT-700 in vitro for binding potency and antagonistic activity and in vivo for antitumor efficacy in human tumor xenografts. Human cancer cell lines and gastric cancer tissue microarrays were examined for MET amplification by fluorescence in situ hybridization (FISH)., Results: ABT-700 exhibits a distinctive ability to block both HGF-independent constitutive c-Met signaling and HGF-dependent activation of c-Met. Cancer cells addicted to the constitutively activated c-Met signaling driven by MET amplification undergo apoptosis upon exposure to ABT-700. ABT-700 induces tumor regression and tumor growth delay in preclinical tumor models of gastric and lung cancers harboring amplified MET. ABT-700 in combination with chemotherapeutics also shows additive antitumor effect. Amplification of MET in human cancer tissues can be identified by FISH., Conclusions: The preclinical attributes of ABT-700 in blocking c-Met signaling, inducing apoptosis and suppressing tumor growth in cancers with amplified MET provide rationale for examining its potential clinical utility for the treatment of cancers harboring MET amplification.

Background: Cervical dysplasia and tumorigenesis have been linked with numerous chromosomal aberrations. The goal of this study was to evaluate 35 genomic regions associated with cervical disease and to select those which were found to have the highest frequency of aberration for use as probes in fluorescent in-situ hybridization., Methods: The frequency of gains and losses using fluorescence in-situ hybridization were assessed in these 35 regions on 30 paraffin-embedded cervical biopsy specimens. Based on this assessment, 6 candidate fluorescently labeled probes (8q24, Xp22, 20q13, 3p14, 3q26, CEP15) were selected for additional testing on a set of 106 cervical biopsy specimens diagnosed as Normal, CIN1, CIN2, CIN3, and SCC. The data were analyzed on the basis of signal mean, % change of signal mean between histological categories, and % positivity., Results: The study revealed that the chromosomal regions with the highest frequency of copy number gains and highest combined sensitivity and specificity in high-grade cervical disease were 8q24 and 3q26. The cytological application of these two probes was then evaluated on 118 ThinPrep samples diagnosed as Normal, ASCUS, LSIL, HSIL and Cancer to determine utility as a tool for less invasive screening. Using gains of either 8q24 or 3q26 as a positivity criterion yielded specificity (Normal +LSIL+ASCUS) of 81.0% and sensitivity (HSIL+Cancer) of 92.3% based on a threshold of 4 positive cells., Conclusions: The application of a FISH assay comprised of chromosomal probes 8q24 and 3q26 to cervical cytology specimens confirms the positive correlation between increasing dysplasia and copy gains and shows promise as a marker in cervical disease progression.

Chromosomal abnormalities are frequent in most cervical cancers. Amplifications of both the 3q26 (TERC) and 8q24 (MYC) loci have been shown to be prevalent in both high-grade lesions and invasive cervical carcinoma. Most of these studies have looked at either the histological sample or at the entire cytological population of cells. We have developed a Papanicolaou (Pap) destaining method that allows for the accurate analysis of individual cells that were previously identified by cytopathology as dysplastic. The application of fluorescence in situ hybridization (FISH) was then implemented to determine the chromosomal status of the dysplastic cells in the samples and correlate the two events. Chromosomal abnormality is over a thousand times more frequent in dysplastic cells compared with their morphologically normal counterparts., ((c) 2009 Wiley-Liss, Inc.)

The goal of this study was to compare how accumulation of chromosomal aberrations in human papillomavirus (HPV)-infected cells correlates with the severity of cervical dysplastic lesions. We assessed the frequency of genomic alterations for 35 different loci in a pilot biopsy study and selected two loci (3q26 and 8q24) with the highest frequency of copy number gains found in high-grade dysplasia and cancer. These probes were labeled with gold and red fluorophores and combined with HPV biotin-labeled probes for subsequent detection using a tyramide signal amplification system with a green fluorophore. Cells that were both HPV positive and chromosomally abnormal were designated as "double-positive cells." Cervical cytology specimens from 235 patients were used for this blinded study. The average number of double-positive cells increased from two cells in patients with a cytological interpretation of atypical squamous cells of undetermined significance to 22 cells in low-grade squamous intraepithelial lesion and 99 cells in high-grade squamous intraepithelial lesion, reflecting an accumulation of chromosomal abnormality with disease progression. Using a cutoff of four or more double-positive cells as the criterion for the presence of a cervical intraepithelial neoplasia 2 or 3 lesion, we demonstrated that low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion cytology specimens with underlying cervical intraepithelial neoplasia 2/3 histology showed positive test results in more than 80% of cases. Correlation of 3q26 and 8q24 aneusomy with concurrent HPV infection may thus serve as a biomarker of genetic instability in HPV-infected cells.

Background: Testing for human papillomavirus (HPV) is used in the triage of women with a cervical cytology of atypical squamous cells of undetermined significance (ASCUS). A fluorescent in situ hybridization assay was developed for the detection of HPV using the catalyzed receptor deposition technique (HPV-CARD). In this study, the utility of this assay was tested for the detection of HPV in liquid-based cervical cytology specimens., Methods: A total of 195 liquid-based cytology specimens were analyzed using the HPV-CARD assay. The results from the assay were compared with HPV polymerase chain reaction (PCR) and typing results. The number of HPV-infected cells and the staining pattern was correlated with the cytology classification., Results: A 91% concordance between HPV-CARD and PCR was observed for the detection of high-risk HPV viruses. A 78% concordance was observed for specimens that were negative for HPV. In ASCUS, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL) categories, the average number of HPV-positive cells per slide was 19 cells, 127 cells, and 450 cells, respectively. The number of cells with a punctate staining, suggestive of HPV integration, was 21% in ASCUS, 34% in LSIL, and 46% in HSIL specimens., Conclusions: The results of the current study indicate positive correlations between the severity of the disease and the increased overall quantity of HPV-positive epithelial cells in cervical cytology specimens and accumulation of cells with punctate staining suggestive of integrated HPV. In summary, the developed HPV-CARD assay was found to provide novel information regarding the proportion and staining pattern of HPV-infected epithelial cells in different cytologic categories of cervical specimens.