Phase 1b/2 study of penpulimab (AK105), an antiprogrammed cell death-1 immunoglobulin G1 antibody, in advanced or metastatic solid tumors (AK105-204).

BACKGROUND: Penpulimab, a new-generation antiprogrammed cell death-1 immunoglobulin G1 monoclonal antibody, was engineered to optimize receptor occupancy and eliminate fragment crystallizable γ-mediated effector function. In this multicenter, phase 1b/2, multicohort study, the objective was to investigate the efficacy, safety, and immunogenicity of penpulimab in advanced solid tumors. METHODS: Patients who had unresectable, advanced solid tumors were enrolled from six centers and received 200 mg penpulimab on day 1 every 2 weeks for up to 24 months. The primary end point was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version criteria 1.1. RESULTS: Between September 2, 2019, and January 1, 2020, 65 patients were enrolled and received penpulimab. At the time of data cutoff (May 11, 2022), the median follow-up was 12.6 months (range, 1.1-28.6 months). The ORR was 12.3 (95% confidence interval [CI], 5.5%-22.8%), with three (4.6%) complete responses and five (7.7%) partial responses. Twelve patients (18.5%) achieved stable disease, resulting in a disease control rate of 30.8% (95% CI, 19.9%-43.4%). The median duration of response was not reached (95% CI, 6.70 months to not estimable). In all cohorts, the median progression-free survival was 1.74 months (95% CI, 1.41-2.69 months), and the median overall survival was 16.59 months (95% CI, 7.82-22.18 months). Grade 3 or greater treatment-related adverse events and immune-related adverse events occurred in 9.2% and 27.7% of patients, respectively. Positive antidrug antibody responses to penpulimab were observed in one patient (1.8%). CONCLUSIONS: Penpulimab showed promising antitumor activity with an acceptable safety profile, offering a potential new treatment approach for solid tumors. These findings supported the evaluation of penpulimab's durable activity and safety, as monotherapy or in combination therapy, in specific malignancies.

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

INTRODUCTION: Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. METHODS: Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). RESULTS: Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. CONCLUSIONS: The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Guiding the Formation of Metal-Organic Structures of 1,4-Diaminoanthraquinone through Surface-Based Cu Atoms.

The gradual guidance of the formation of metal-organic structures through surface-based Cu atoms for 1,4-diaminoanthraquinones (DAQs) has been studied by scanning tunneling microscopy (STM) at room temperature. On the Ag(110) surface, the transition from a hydrogen-bond network structure to metal-organic coordination structures of DAQs can be induced by introducing foreign copper atoms. Due to the weak interaction between DAQs and Ag(110), thermal treatment easily leads to the desorption of DAQs from the surface. To address this challenge, Cu(111) is selected as the substrate. Under thermal driving and in the presence of copper adatoms, the hydrogen-bond network structure of DAQs on the surface gradually undergoes a transition into a metal-coordinated structure, eventually leading to the formation of metal-organic complexes through amino dehydrogenation. It is demonstrated that the construction of a metal-organic coordination structure on metal surfaces is a result of the competition among factors such as metal atoms, functional groups of molecules, surface chemical activity, and temperature.

Ligand-Enabled C6-Selective C-H Arylation of Pyrrolo[2,3-d] Pyrimidine Derivatives with Pd Catalysts: An Approach to the Synthesis of EGFR Inhibitor AEE-788.

Herein, we report the Pd(II)-catalyzed direct C-H arylation of pyrrolo[2,3-d]pyrimidine derivatives with aryl iodides, which is enabled by bidentate pyridine-pyridine ligands. A range of aryl iodides proved to be suitable coupling partners affording the desired products in good yields with high levels of C6 selectivity. This protocol features good tolerance of reactive functional groups, mild reaction conditions, and a simple reaction system, which provides an expeditious route to an essential class of 6-arylpyrrolo[2,3-d]pyrimidines frequently found in bioactive compounds, and provides a step-economical access to the second-generation EGFR inhibitor AEE-788.

Synergistic effects of ferulic acid esterase-producing lactic acid bacteria, cellulase and xylanase on the fermentation characteristics, fibre and nitrogen components and microbial community structure of Broussonetia papyrifera during ensiling.

BACKGROUND: The high fibre content of whole plants of Broussonetia papyrifera limits its efficient utilization. Ferulic acid esterase (FAE), in combination with xylanase, can effectively cleave the lignin-carbohydrate complex, promoting the function of cellulase. However, little is known about the impact of these additives on silage. To effectively utilize natural woody plant resources, FAE-producing Lactiplantibacillus plantarum RO395, xylanase (XY) and cellulase (CE) were used to investigate the dynamic fermentation characteristics, fibre and nitrogen components and microbial community structure during B. papyrifera ensiling. RESULTS: Broussonetia papyrifera was either not treated (CK) or treated with FAE-producing lactic acid bacteria (LP), CE, XY, LP + CE, LP + XY or LP + CE + XY for 3, 7, 15, 30 or 60 days, respectively. In comparison with those in the CK treatment, the L. plantarum and enzyme treatments (LP + CE, LP + XY and LP + XY + CE), especially the LP + XY + CE treatment, significantly increased the lactic acid concentration and decreased the pH and the contents of acid detergent insoluble protein and NH3 -N (P < 0.05). Enzyme addition improved the degradation efficiency of lignocellulose, and a synergistic effect was observed after enzyme treatment in combination with LP; in addition, the lowest acid detergent fibre, neutral detergent fibre, hemicellulose and cellulose contents were detected after the LP + CE + XY treatment (P < 0.05). Moreover, CE, XY and LP additions significantly improved the microbial community structure, increased the relative abundance of Lactiplantibacillus and Firmicutes, and effectively inhibited undesirable bacterial (Enterobacter) growth during ensiling. CONCLUSION: FAE-producing L. plantarum and the two tested enzymes exhibited synergistic effects on improving the quality of silage, which indicates that this combination can serve as an efficient method for improved B. papyrifera silage utilization. © 2023 Society of Chemical Industry.

Female labour participation and infant mortality in Nigeria: implication for the sustainable development goal 3.

Over the time, link between female labour participation and infant mortality has become a subject of debate among scholars and policymakers in developing countries. This subject becomes more critical for a country like Nigeria where there is a persistent challenge to attain minimal global infant mortality rates by 2030, and where over 47% of female working population is unemployed. Against this background, this study utilizes fully modified ordinary least squares to estimate the relationship between female labour participation and infant mortality in Nigeria. The results show that at least 98 children per 1,000 births died in Nigeria between 1990 and 2020. Similarly, over 47% of female working population is currently unemployed in Nigeria. Female labour participation and infant mortality possess a significant negative relationship. Consequently, participation of women in the labour market has a significant effect in reducing infant mortality in Nigeria. In the same vein, female employment contributed to the reduction of infant mortality, though not substantial in nature. As such, the Nigerian policymakers should create a conducive environment that will facilitate participation of more women in the Nigerian labour market so that there will be further reduction of infant mortality in order to achieve the SDG 3.

Au fil du temps, le lien entre la participation des femmes au travail et la mortalité infantile est devenu un sujet de débat parmi les universitaires et les décideurs politiques des pays en développement. Ce sujet devient plus critique pour un pays comme le Nigeria, où il est toujours difficile d'atteindre des taux de mortalité infantile mondiaux minimaux d'ici 2030 et où plus de 47 % de la population active féminine est au chômage. Dans ce contexte, cette étude utilise les moindres carrés ordinaires entièrement modifiés pour estimer la relation entre la participation des femmes au travail et la mortalité infantile au Nigéria. Les résultats montrent qu'au moins 98 enfants pour 1 000 naissances sont morts au Nigeria entre 1990 et 2020. De même, plus de 47 % de la population active féminine est actuellement au chômage au Nigeria. La participation des femmes au travail et la mortalité infantile entretiennent une relation négative significative. Par conséquent, la participation des femmes au marché du travail a un effet significatif sur la réduction de la mortalité infantile au Nigéria. Dans le même ordre d'idées, l'emploi des femmes a contribué à la réduction de la mortalité infantile, même si elle n'est pas substantielle. En tant que tel, les décideurs politiques nigérians devraient créer un environnement propice qui facilitera la participation d'un plus grand nombre de femmes au marché du travail nigérian afin de réduire davantage la mortalité infantile afin d'atteindre l'ODD 3.

Insights into the Rearrangement of the Molecular Assembly Structure of 6-Aminonicotinic Acid in Its Hydrated Environment.

Water, as a ubiquitous and essential component of life, is known to have a significant impact on the structure and function of organic molecules. In this study, we investigate the role of water in the phase transition of organic molecular assembly structures by scanning tunneling microscopy at room temperature. The results show that the -O-H···O hydrogen induced by water molecules can lead to a significant structural transition in the molecular assembly, specifically through selective weakening of -C-H···O between 6-aminonicotinic acid and the formation of new -O-H···O bonds between 6-aminonicotinic acid and water molecules. Subsequent thermal treatment of these molecular assembly structures reveals that the formation of -N-H···O hydrogen bonds induced by water molecules has created a different pathway for the phase transition of the molecular assembly structure. This knowledge has important implications for the design of organic molecules with specific nanostructures that can be controlled through hydration.

Association between adult food insecurity and self-reported asthma in the United States: NHANES 2003-2018.

OBJECTIVE: Asthma is a chronic disease of the lungs. The development of asthma is related to various risk factors. Food insecurity is a critical social determinant of health, although there is little information on the association between adult food insecurity and asthma. The purpose of this study is to explore the potential correlation in US adults. METHODS: The study population data were extracted from NHANES 2003-2018. Food insecurity was measured using the USDA FSSM and categorized as full, marginal, low, or very low food security. The assessment of self-reported asthma was determined by self-report questionnaires. The self-reported positive outcomes were that participants had asthma and a history of asthma attacks and asthma-related ER visits in the past year. We developed two multivariate logistic regression models. Stratified analyses were performed by gender and age. RESULTS: A total of 38,077 participants were considered in our final analysis. Compared to participants with FFS, the ORs (95% CIs) for asthma were 1.16 (1.00-1.33), 1.42 (1.23-1.64), and 1.56 (1.34-1.80) for participants with MFS, LFS, and VLFS, respectively (Model II). Additionally, after full adjustment, individuals with VLFS had 49% greater risks of asthma attacks (OR = 1.49; 95% CI 1.13-1.97). The ORs (95% CIs) for asthma-related ER visits were 1.59 (1.14-2.23) and 1.98 (1.36-2.87) for participants with LFS and VLFS, respectively (Model II). The positive correlations remained robust when stratified by gender and age. CONCLUSION: Our research showed that food insecurity among US adults was associated with asthma, asthma attacks, and asthma-related ER visits.

First report of brown rot caused by Monilia mumecola on Chinese plum (Prunus salicina) in Fujian, China.

Brown rot caused by Monilinia spp. (anamorph Monilia) is a common disease in stone fruits worldwide, but the species in different hosts or regions may vary. Monilia mumecola is a recently identified species, only reported in some regions. Although the pathogen has been found on plum in Yunnan, Hubei, and Zhejiang provinces, and Chongqing municipality in China (Yin et al. 2015), it has not been reported in southeast coast of China. In May 2022, brown rot with grey spores on fruit was observed in a plum orchard with 15% disease incidence in Sanming City, Fujian Province, located in southeast coast of China. Four single-spored isolates were obtained from germinating conidia on the water agar for further investigation. The colonies on potato dextrose agar (PDA) were initially white, gradually turned gray to brown, with lobbed margins and rare sporulation. Average mycelial growth rate ranged from 0.74 to 1.08 cm/day at 25 oC. Conidia were lemon-shaped or subglobose, hyaline, with an average size of 17.64 to 19.35×11.14 to 14.44 µm (n=30). Each isolate produced one to three or four germ tubes. Such characteristics are similar to M. mumecola (Yin et al. 2015). To confirm the identity of the isolates, genomic DNA was extracted and species-specific primers of Hu et al. (2011) were used to amplify the 712 bp sequence. In addition, the ITS region, partial genes of glyceraldehyde-3- phosphate dehydrogenase (GAPDH) and beta-tubulin (TUB2) were also amplified using primers sets ITS1/ITS4 (Glass and Donaldson 1995), Mon-G3pdhF/Mon-G3pdhR and Mon-TubF1/ Mon-TubR1, respectively (Hu et al. 2011). Sequences obtained for those three regions were 478, 762 and 1527 bp, respectively. Each region of all four isolates was identical, so one sequence for each region was submitted to GenBank with accession numbers OQ207672, OQ225251 and OQ225252, respectively, which had 100% identity with M. mumecola HQ908786 (ITS), HQ908784 (GAPDH), and HQ908775 (TUB2) using BLAST analysis in NCBI database, respectively. Pathogenicity was conducted with mycelium plugs from the edge of 7-day-old colony on three mature 'Angeleno' plums fruit (Prunus salicina) creating nine inoculations with three wounds per fruit, and each wound was 5 mm in diameter and 2 mm in depth. The same amount fruit and wounds inoculated with PDA plugs without fungi were used as a control. Brown rot symptoms were observed on all inoculated plums 4 days post-inoculation under room temperature with 100% humidity, whereas control plums remained symptomless. Fungal colonies re-isolated from the lesions showed the same morphological features as the original isolate , thus fulfilling Koch's postulates. To our knowledge, this is the first report of M. mumecola on plum in Fujian Province of China. The findings in this studies have important management implications for local plum growers because more than one Monilia species have been reported, where only M. fructicola was present in this region.

Penpulimab, an anti-PD1 IgG1 antibody in the treatment of advanced or metastatic upper gastrointestinal cancers.

BACKGROUND: The safety and anti-tumor activity of penpulimab in patients with advanced upper gastrointestinal (UGI) cancers were evaluated in this study. METHODS: Patients with advanced UGI cancers naive to immune checkpoint inhibitors were enrolled in two trials of penpulimab. In the Phase Ia/Ib trial in Australia, patients received penpulimab intravenous infusion of 1, 3 and 10 mg/kg every 2 weeks in dose-escalation phase and 200 mg every 2 weeks in dose-expansion phase. In the phase Ib/II trial conducted in China, patients received 200 mg penpulimab every 2 weeks. Primary endpoints were safety and tolerability for the phase Ia/Ib trial and the objective response rate for the phase Ib/II trial. The safety and efficacy of penpulimab in patients with UGI cancers in these two trials were evaluated. RESULTS: A total of 67 patients with UGI cancers from Australia and China were enrolled in these two trials and had received penpulimab with a median of 6 (1-64) doses. 44.8% of patients experienced at least one treatment-related adverse event (TRAE), and 7.5% of patients experienced a grade ≥3 TRAE. Among 60 patients evaluable for response, the confirmed objective response rates ranged between 11.1 and 26.3% across cohorts for pancreatic cancer, cholangiocarcinoma, gastric or Gastroesophageal junction carcinoma (Gastric/GEJ), and hepatocellular carcinoma. 11/13 (85.0%) responders had ongoing responses at data cutoff date. CONCLUSIONS: Penpulimab monotherapy demonstrated an acceptable safety and encouraged anti-tumor activity in patients with advanced UGI cancers. Further exploration in a large cohort of patients is warranted. TRIAL REGISTRATION: Phase Ia/Ib trial in Australia (NCT03352531) and phase Ib/II trial in China (NCT04172506).

Leaf trait association in relation to herbivore defense, drought resistance, and economics in a tropical invasive plant.

PREMISE: Exploring how functional traits vary and covary is important to understand plant responses to environmental change. However, we have limited understanding of the ways multiple functional traits vary and covary within invasive species. METHODS: We measured 12 leaf traits of an invasive plant Chromolaena odorata, associated with plant or leaf economics, herbivore defense, and drought resistance on 10 introduced populations from Asia and 12 native populations from South and Central America, selected across a broad range of climatic conditions, and grown in a common garden. RESULTS: Species' range and climatic conditions influenced leaf traits, but trait variation across climate space differed between the introduced and native ranges. Traits that confer defense against herbivores and drought resistance were associated with economic strategy, but the patterns differed by range. Plants from introduced populations that were at the fast-return end of the spectrum (high photosynthetic capacity) had high physical defense traits (high trichome density), whereas plants from native populations that were at the fast-return end of the spectrum had high drought escape traits (early leaf senescence and high percentage of withered shoots). CONCLUSIONS: Our results indicate that invasive plants can rapidly adapt to novel environmental conditions. Chromolaena odorata showed multiple different functional trait covariation patterns and clines in the native and introduced ranges. Our results emphasize that interaction between multiple traits or functions should be considered when investigating the adaptive evolution of invasive plants.

Prevalence of H6Y mutation in ß-tubulin causing thiophanate-methyl resistant in Monilinia fructicola from Fujian, China.

Brown rot disease broke out in stone fruit orchards of Fujian, China in 2019, despite pre-harvest application of methyl benzimidazole carbamate (MBC). To determine the reason, a total of 44 Monilinia fructicola strains were collected from nectarine, plum and peach fruits in this study, among which 79.5% strains were resistant to thiophanate-methyl, indicated by discriminatory dose of 5 µg/mL. The resistance of these strains was confirmed by treating detached peach fruit with label rates of formulated thiophanate-methyl which only completely inhibit infection of the sensitive strains, but not the resistant strains. Further analysis of the mechanism of MBC resistance revealed that all resistant strains carry a H6Y mutation in ß-tubulin protein Tub2, which was only reported previously in the M. fructicola strains from California, USA, and do not display obvious fitness penalties, as no significant defects in mycelial growth rate, sporulation, conidia germination, aggressiveness on detached peach fruit and temperature sensitivity was detected. In addition, we found that diethofencarb, the agent for managing MBC-resistance strains, was unable to inhibit growth of the H6Y strains. Taken together, our study, for the first time, identified a mutation form of H6Y in the ß-tubulin protein of M. fructicola in China, rendering the strains wide resistance to thiophanate-methyl. This mechanism of M. fructicola gaining resistance to MBC fungicides needs to be fully considered, when designing management strategies to control brown rot disease in stone fruit orchards.

First Report of Black Dot Caused by Colletotrichum coccodes on Potato in the Tibet Autonomous Region of China.

Potato black dot causing by Colletotrichum coccodes is a common disease in potato throughout the world, infecting underground stems, tubers, roots and foliage. Potato is becoming the third main food crop produced on ~16,000 ha annually in the Tibet Autonomous Region of China, situated on the world's highest plateau. However, the disease causing by C. coccodes has not been reported in this region. During the disease survey in the Bailang County of Tibet in August, 2020, some potato plants cv. "JiZhang 12" with chlorosis and wilting of foliage were observed. The incidence of affected plants was 20%. Necrotic lesions were also observed on the basal stems of the affected plants. Three affected plants were collected for pathogen isolation and three isolates were obtained for further investigation. The colonies on potato dextrose agar (PDA) were initially white, turning gradually black with age and producing abundant black sclerotia. Conidia were cylindrical, hyaline, aseptate, guttulate, with average size of 13.80 to 18.55×4.94 to 5.35 µm for the three isolates in which 30 conidia each were measured. Such characteristics are similar to C. coccodes (Lees and Hilton, 2003). Mycelial growth rate was 0.69 to 0.74 cm/day at 25 oC over the three isolates. The three isolates were confirmed to be C. coccodes by species-specific PCR using primer set of Cc1NF1/Cc2NR1 producing 350 bp amplicons in the internal transcribed spacer (ITS) region according to Cullen et al. (2002). The Cc1NF1/Cc2NR1 sequences were identical for three isolates, therefore one sequence from isolate BL_JZ_J1 was submitted to the GenBank with accession number OM368349. Additional genes were also sequencing including the actin (ACT), chitin synthase l (CHS1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and another larger ITS region were also amplified from genomic DNA using primers sets ACT512F/ACT783R, CHS-79F/CHS-354R (Carbone and Kohn 1999), GDF1/GDR1 (Templeton et al. 1992) and ITS1/ITS4 (Glass and Donaldson 1995), respectively. Sequences obtained for those four regions were 216 bp, 218bp, 235bp and 576 bp, respectively. Each region in the three isolates were also identical, therefore one sequence for each region was submitted to the GenBank with accession number of OM417059, OM417060, OM417061, and OM349570, respectively, which had 100% similarity with C. coccodes of MN336525 (ACT), KU821274 (CHS1), KU821397 (GAPDH) and KU821175 (ITS), respectively. Phylogenetic analyses based on the concatenated sequences of those four loci showed that the BL_JZ_J1 was close to C. coccodes, a reference isolate of CPOS1 with the accession numbers of GQ856787 (ACT), GQ856723 (CHS1), GQ856744 (GAPDH) and GQ485588 (ITS) (Yang et al. 2009). Pathogenicity was confirmed by inoculating a conidia suspension (100 µl of 105 conidia/ml) on three stems of 6-week-old potato plant cv. 'Favorita' with an artificial wound generated by sterile toothpick for each isolate. An equal volume of sterile water was injected on the wound of three stems as a noninoculated control. Brownish necrotic lesions were observed on all inoculated stems 3 days post-inoculation under natural conditions, whereas control stems remained symptomless. Reisolation of the fungus from all inoculated symptomatic plants confirmed Koch's Postulates. To our knowledge, this is the first report of C. coccodes in potato in Tibet Autonomous Region of China. The finding of black dot in this region has important management implications for the growers since the pathogen can survive for long periods in the field both on potato debris and in soil.

Efficacy and safety of sintilimab in combination with chemotherapy in previously untreated advanced or metastatic nonsquamous or squamous NSCLC: two cohorts of an open-label, phase 1b study.

Combining chemotherapy with immunotherapy improves the therapeutic outcome for first-line (1L) patients with advance nonsmall-cell lung cancer (NSCLC). Two cohorts of a phase 1b study (NCT02937116) aimed to evaluate the safety and efficacy of sintilimab, a PD-1 inhibitor, plus chemotherapy in 1L patients with nonsquamous and squamous NSCLC (nsqNSCLC/sqNSCLC); and to identify potential biomarkers for treatment response. Treatment-naïve patients with nsqNSCLC were enrolled and intravenously given sintilimab (200 mg), pemetrexed (500 mg/m2), and cisplatin (75 mg/m2), every 3 weeks (Q3W) for 4 cycles in cohort D. Treatment-naïve patients with sqNSCLC were enrolled and intravenously given sintilimab (200 mg), gemcitabine (1250 mg/m2), and cisplatin (75 mg/m2), Q3W, for 6 cycles in cohort E. The primary objective was to evaluate the safety and efficacy of the treatment. The additional objective was to explore biomarkers for the treatment efficacy. Twenty-one patients with nsqNSCLC, and 20 patients with sqNSCLC were enrolled in cohort D and cohort E, respectively. By the data cutoff (April 17, 2019), 8 (38.1%) patients in cohort D and 17 (85.0%) patients in cohort E experienced grade 3-4 adverse events. The median follow-up duration was 16.4 months (14.8-23.0) in cohort D and 15.9 months (11.7-17.7) in cohort E. The objective response rate was 68.4% (95% CI 43.4%, 87.4%) in cohort D and 64.7% (95% CI 38.3%, 85.8%) in cohort E. Neither PD-L1 expression nor tumor mutation burden value was significantly associated with an improved treatment response. Sintilimab plus chemotherapy exhibited manageable toxicity and an encouraging antitumor activity in patients with nsqNSCLC and sqNSCLC.

Larotinib in patients with advanced and previously treated esophageal squamous cell carcinoma with epidermal growth factor receptor overexpression or amplification: an open-label, multicenter phase 1b study.

BACKGROUND: Larotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend an appropriate dose for its further study. METHODS: Patients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8 weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC). RESULTS: 81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI 4.9-10.2) months and 3.4 (95% CI 2.4-3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs. CONCLUSIONS: Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression. TRIAL REGISTRATION: This trial was retrospectively registered on 25/03/2019, NCT03888092. https://clinicaltrials.gov/ct2/show/NCT03888092 .

LncRNA NEAT1 aggravates lipopolysaccharide-induced acute lung injury by regulating the miR-98-5p/TLR4 axis.

Although long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) was reported to be associated with acute lung injury (ALI), its specific mechanism has not been well studied. Mouse and cell ALI models were constructed by lipopolysaccharide (LPS). Cell viability was evaluated by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide assay. Cell death was evaluated by lactate dehydrogenase release (LDH) detection kit and flow cytometry. The levels of cytokines in lung tissues lysates were detected by quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The expression of apoptosis-related markers was detected by Western blot. The relationship between NEAT1, miR-98-5p, and toll-like receptor 4 (TLR4) was determined by bioinformatics prediction, luciferase reporter assay, and RNA immunoprecipitation (RIP) assay. Rescue experiments were performed to determine the role of NEAT1/miR-98-5p/TLR4 in ALI. NEAT1 was significantly upregulated during ALI both in vitro and in vivo. NEAT1 knockdown efficiently attenuated LPS-induced ALI and reduced LPS-induced elevation of cytokines both in vitro and in vivo. NEAT1 negatively regulated miR-98-5p by directly sponging it, and TLR4 was a target of miR-98-5p. MiR-98-5p inhibition or TLR4 overexpression could obviously attenuate the protective effects of NEAT1 knockdown in LPS-treated A549 cells. Our study demonstrated that NEAT1 knockdown alleviated LPS-induced ALI by targeting the miR-98-5p/TLR4 axis.

Clinical and histopathological features of pulmonary sclerosing pneumocytoma with dense spindle stromal cells and lymph node metastasis.

AIMS: To determine the clinicopathological features of pulmonary sclerosing pneumocytoma (PSP) with spindle cells and in cases with positive detection of PSP cells in the lymph nodes. METHODS AND RESULTS: This article report the clinical, histological and immunohistochemical features of PSP with dense spindle stromal cells in five patients (including one case with lymph node metastasis) and PSP accompanied by positive nodes in two patients out of 239 cases diagnosed at our institution between 2007 and 2019. The literature on PSP was also reviewed in detail. Six patients were female, and one (with a positive node) was male; their average age was 53 years. Thoracic imaging revealed solid tumours with clear borders and a uniform texture in six patients, but one patient had a lobulated tumour with uneven densities. All tumours were unifocal, and they had an average size of 31 mm. Tumours from five cases were mainly composed of solid regions of diffuse spindle cells rather than polygonal cells. Immunohistochemical staining demonstrated that thyroid transcription factor-1, vimentin, epithelial membrane antigen (weak) and oestrogen receptor (partial) were expressed in spindle cells. The average follow-up time was 31 months. Two of the 234 PSP cases for which adequate data were available had positive nodes (metastasis rate: 0.8%), and one of the five patients with PSP with spindle cells showed lymph node metastasis (metastasis rate: 20%). In addition, stromal cells were found to be predominant at metastatic sites. CONCLUSIONS: Spindle cells are present among the stromal cells of PSP, and not all of them are round cells. PSP patients with spindle cells or male patients may be more prone to metastasis than others.

Safety and efficacy of sintilimab combined with oxaliplatin/capecitabine as first-line treatment in patients with locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma in a phase Ib clinical trial.

BACKGROUND: Sintilimab blocks the interaction between programmed death-1 (PD-1) and its ligands. The safety and efficacy of sintilimab combined with oxaliplatin/capecitabine (CapeOx) as first-line treatment were evaluated in patients with gastric (G)/gastroesophageal junction (GEJ) adenocarcinoma in a phase Ib clinical trial. METHODS: Patients with locally advanced or metastatic G/GEJ adenocarcinoma without previous systemic treatment were enrolled as one cohort of a multi-cohort study. Sintilimab was administered at a dose of 200 mg intravenously (IV) in combination with CapeOx (1000 mg/m2 capecitabine orally, bid, D1-14 and 130 mg/m2 oxaliplatin IV, D1) every 21 days for up to 6 cycles. After combination treatment, patients continued to receive sintilimab (200 mg) at 3 weekly intervals as maintenance therapy until progressive disease (PD), unacceptable toxicity, withdrawal of informed consent, or for up to 24 months. Adverse events (AEs) were monitored to assess safety in terms of their frequency, intensity and causality. The efficacy endpoints included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Tumor mutation burden (TMB) was evaluated for its association with clinical response. RESULTS: A total of 20 patients were enrolled and received sintilimab plus CapeOx. All patients reported treatment-related AEs (TRAEs). Grade 3-4 TRAEs were found in 11 (55.0%) patients. Seventeen patients obtained partial response and the ORR was 85.0% (95% CI: 62.1-96.8%). Three (15.0%) had stable disease and DCR was 100.0% (95% CI: 83.2-100.0%). As data cutoff of May 1, 2019, the median follow-up was 7.8 months. The median PFS was 7.5 months (95% CI: 6.2-9.4) and median OS had not been reached. The OS rates at 6 months and 12 months were 100.0 and 68.0%. No association was observed between TMB and efficacy. CONCLUSIONS: Sintilimab combined with CapeOx as first-line treatment demonstrated acceptable safety and promising efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02937116 . Registered 8 October 2016.

Founder effects, post-introduction evolution and phenotypic plasticity contribute to invasion success of a genetically impoverished invader.

Multiple mechanisms may act synergistically to promote success of invasive plants. Here, we tested the roles of three non-mutually exclusive mechanisms-founder effects, post-introduction evolution and phenotypic plasticity-in promoting invasion of Chromolaena odorata. We performed a common garden experiment to investigate phenotypic diversification and phenotypic plasticity of the genetically impoverished invader in response to two rainfall treatments (ambient and 50% rainfall). We used ancestor-descendant comparisons to determine post-introduction evolution and the QST-FST approach to estimate past selection on phenotypic traits. We found that eight traits differed significantly between plants from the invasive versus native ranges, for two of which founder effects can be inferred and for six of which post-introduction evolution can be inferred. The invader experienced strong diversifying selection in the invasive range and showed clinal variations in six traits along water and/or temperature gradients. These clinal variations are likely attributed to post-introduction evolution rather than multiple introductions of pre-adapted genotypes, as most of the clinal variations were absent or in opposite directions from those for native populations. Compared with populations, rainfall treatments explained only small proportions of total variations in all studied traits for plants from both ranges, highlighting the importance of heritable phenotypic differentiation. In addition, phenotypic plasticity was similar for plants from both ranges although neutral genetic diversity was much lower for plants from the invasive range. Our results showed that founder effects, post-introduction evolution and phenotypic plasticity may function synergistically in promoting invasion success of C. odorata.

Retracted: miR-145 modulates epithelial-mesenchymal transition and invasion by targeting ZEB2 in non-small cell lung cancer cell lines.

Lung cancer is the leading cause of cancer-related deaths worldwide. Epithelial-mesenchymal transition (EMT) is a major event that drives cancer progression. Here we aim to investigate the role of microRNA, miR-145, in regulating EMT of the highly invasive non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction analysis indicated that miR-145 was downregulated in cancer tissue compared with that in adjacent normal tissue. NSCLC cell lines, namely H1299, PC7, and SPCA-1, also demonstrated miR-145 downregulation, which is correlated well with their invasive ability, assessed by the Matrigel invasion assay. miR-145 overexpression resulted in downregulation of N-cadherin, and downregulation of vimentin and E-cadherin, suggesting a decreased EMT activity. TargetScan analysis predicted that a binding site exists between miR-145 and an oncogene, ZEB2, which was verified using the dual-luciferase assay. Alteration of miR-145 expression also induced inverse effects on ZEB2 expression, and a negative correlation exists between ZEB2 and miR-145 in human tissues. ZEB2 and miR-145 also exerted antagonizing effects on the invasion of NSCLC cells. Therefore, miR-145 is an important molecule in NSCLC that regulates cancer EMT through targeting ZEB2.