Parasitic behavior and developmental morphology of Mesocomys trabalae (Hymenoptera: Eupelmidae), a promising parasitoid of the Japanese giant silkworm Caligula japonica (Lepidoptera: Saturniidae).

The egg parasitoid Mesocomys trabalae Yao, Yang, and Zhao is used as a biocontrol agent against the emerging defoliator pest Caligula japonica Moore in East Asia. It has been proven that the eggs of Antheraea pernyi Guérin-Méneville can be used as a factitious host for the mass production of M. trabalae. We examined the parasitic behavior and morphological characteristics of the developmental stages of M. trabalae reared on A. pernyi eggs. The parasitic behavior of M. trabalae encompasses 10 steps, involving searching, antennation, locating the oviposition site, drilling, probing, detecting, oviposition, host feeding, grooming, and resting, with the oviposition step further divided into 3 stages. We determined that the parasitoid released an egg during the second stage of the oviposition step, while her body remained in a relatively static state. Among all the steps in parasitic behavior, probing occupied the longest time, accounting for 26.33% of the entire parasitism process. It was followed by oviposition (15.88%), drilling (15.10%), antennation (13.09%), detecting (10.79%), host feeding (10.02%), and the remaining steps, each occupying less than 5.00% of the total time in steps. The pre-emergence of adult M. trabalae comprised of 4 stages: egg (0-1 day), larva (2-6 days), prepupa (7-11 days), pupa (12-20 days), followed by the development into an adult, and it usually took 20-22 days to develop from an egg into an adult at 25°C. This study advances our understanding of the biology of Mesocomys parasitoids and their mass-rearing for use in augmentation programs.

The beneficial effects of neutrophil elastase inhibitor on gastrointestinal dysfunction in sepsis.

To investigate the effects of neutrophil elastase inhibitor (sivelestat sodium) on gastrointestinal function in sepsis. A reanalysis of the data from previous clinical trials conducted at our center was performed. Septic patients were divided into either the sivelestat group or the non-sivelestat group. The gastrointestinal dysfunction score (GIDS), feeding intolerance (FI) incidence, serum levels of intestinal barrier function and inflammatory biomarkers were recorded. The clinical severity and outcome variables were also documented. A total of 163 septic patients were included. The proportion of patients with GIDS ≥2 in the sivelestat group was reduced relative to that in the non-sivelestat group (9.6% vs. 22.5%, p = 0.047) on the 7th day of intensive care unit (ICU) admission. The FI incidence was also remarkably reduced in the sivelestat group in contrast to that in the non-sivelestat group (21.2% vs. 37.8%, p = 0.034). Furthermore, the sivelestat group had fewer days of FI [4 (3, 4) vs. 5 (4-6), p = 0.008]. The serum levels of d-lactate (p = 0.033), intestinal fatty acid-binding protein (p = 0.005), interleukin-6 (p = 0.001), white blood cells (p = 0.007), C-reactive protein (p = 0.001), and procalcitonin (p < 0.001) of the sivelestat group were lower than those of the non-sivelestat group. The sivelestat group also demonstrated longer ICU-free days [18 (0-22) vs. 13 (0-17), p = 0.004] and ventilator-free days [22 (1-24) vs. 16 (1-19), p = 0.002] compared with the non-sivelestat group. In conclusion, sivelestat sodium administration appears to improve gastrointestinal dysfunction, mitigate dysregulated inflammation, and reduce disease severity in septic patients.

Angiotensin-converting enzyme 2 alleviates liver fibrosis through the renin-angiotensin system.

The present letter to the editor is related to the study titled 'Angiotensin-converting enzyme 2 improves liver fibrosis in mice by regulating autophagy of hepatic stellate cells'. Angiotensin-converting enzyme 2 can alleviate liver fibrosis by regulating autophagy of hepatic stellate cells and affecting the renin-angiotensin system.

Ontogenetic morphological changes of the venom apparatus in 4 eupelmid egg parasitoids.

Parasitoid wasps, notably egg parasitoids of the family Eupelmidae (Hymenoptera: Chalcidoidea), a key natural enemy of insect pests, offer a sustainable approach to pest management in agriculture. This study investigated the venom apparatus's developmental dynamics across 4 species of eupelmid egg parasitoids: Anastatus. japonicus, Anastatus fulloi, Mesocomys trabalae and Mesocomys albitarsis. A comprehensive anatomical investigation revealed differences in the dimensions of the venom apparatus across different developmental stages in adult females. We found that the venom apparatus of these 4 studied species consists of a venom gland and a reservoir with an associated Dufour's gland. As the length of post-emergence increases, a significant enlargement in the venom apparatus is evident across all the studied parasitoid species. Notably, M. albitarsis consistently exhibites the shortest venom gland length, whereas that of A. fulloi is the longest among the observed species. At the high day age, the width of venom glands of the 2 Mesocomys species surpasses those of the Anastatus species; for the volume of the venom reservoir, there is a steady increase in all 4 species before the age of 6­7 days, with a decline on 8th day, especially for A. japonicus. This research provided new insights into the developmental trajectories of venom apparatus in eupelmid egg parasitoids and the potential impact of venom potency on their success.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Prognostic Significance of PD-L1 Expression in Gastric Cancer Patients with Peritoneal Metastasis.

BACKGROUND: Recently, many studies have explored the relationship between the expression of programmed death ligand 1 (PD-L1) and prognosis in gastric cancer, but there is still controversy. Additionally, few studies have specifically investigated the expression of PD-L1 in patients with peritoneal metastasis. METHODS: Immunohistochemistry was used to analyze the expression of PD-L1 in gastric cancer patients with peritoneal metastasis. The combined positive score (CPS) was calculated to evaluate the expression of PD-L1, and the clinicopathological data were analyzed to explore prognostic significance. RESULTS: In total, 147 gastric cancer patients with peritoneal metastasis were enrolled. The negative PD-L1 expression was defined as a CPS < 1, and high PD-L1 expression was defined as a CPS ≥ 10. PD-L1 expression with CPS ≥ 1 and CPS-negative was detected in 67 (45.58%) and 80 (54.42%) patients, respectively. High PD-L1 expression at PD-L1 CPS ≥ 10 was detected in 21(14.29%) patients. The median overall survival (OS) was 18.53 months in the CPS < 10 group and 27.00 months in the CPS ≥ 10 group; the OS difference between the two groups was significant (p = 0.015). Multivariate analysis demonstrated that a poor Eastern Cooperative Oncology Group performance score (ECOG PS) (p = 0.002) and severe peritoneal metastasis (p = 0.033) were significantly associated with poor survival, while palliative chemotherapy (p = 0.002) and high PD-L1 expression (p = 0.008) were independent and significantly favorable prognostic factors. CONCLUSIONS: Our study demonstrated that PD-L1 expression was widely presented in gastric cancer patients with peritoneal metastasis, while a CPS no less than 10 predicted better prognosis.

Comparison of the biology of Frankliniella intonsa and Megalurothrips usitatus on cowpea pods under natural regimes through an age-stage, two-sex life table approach.

Two thrips, Megalurothrips usitatus (Bagnall) and Frankliniella intonsa (Trybom) are major pests of cowpea in South China. To realistically compare the growth, development and reproductive characteristics of these two thrips species, we compared their age-stage, two-sex life tables on cowpea pods under summer and winter natural environmental regimes. The results showed that the total preadult period of M. usitatus was 8.09 days, which was significantly longer than that of F. intonsa (7.06 days), while the adult female longevity of M. usitatus (21.14 days) was significantly shorter than that of F. intonsa (25.77 days). Significant differences were showed in male adult longevity (10.68 days for F. intonsa and 16.95 days for M. usitatus) and the female ratio of offspring (0.67 for F. intonsa and 0.51 for M. usitatus), and the total preadult period of M. usitatus (16.20 days) was significantly longer than that of F. intonsa (13.66 days) in the winter regime. The net reproductive rate (summer: R0 = 85.62, winter: R0 = 105.22), intrinsic rate of increase (summer: r = 0.3020 day-1, winter: r = 0.2115 day-1), finite rate of increase (summer: λ = 1.3526 day-1, winter: λ = 1.2356 day-1) and gross reproduction rate (summer: GRR = 139.34, winter: GRR = 159.88) of F. intonsa were higher than those of M. usitatus (summer: R0 = 82.91, r = 0.2741, λ = 1.3155, GRR = 135.71; winter: R0 = 80.62, r = 0.1672, λ = 1.1820, GRR = 131.26), and the mean generation times (summer: T = 14.73 days, winter: T = 22.01 days) of F. intonsa were significantly shorter than those of M. usitatus (summer: T = 16.11 days, winter: T = 26.25 days). These results may contribute to a better understanding of the bioecology of different thrips species, especially the interspecific competition between two economically important cowpea thrips with the same ecological niche in a changing environment.

Comparative Analysis of the Venom Proteins from Two Eupelmid Egg Parasitoids Anastatus japonicus and Mesocomys trabalae.

Parasitic wasps are abundant and diverse Hymenoptera insects that lay their eggs inside or on the external surface of the host and inject venom into the host to create a more favorable environment for the larvae to survive and regulate the host's immunity, metabolism, and development. But research on the composition of egg parasitoid venom is very limited. In this study, we used a combination of transcriptomic and proteomic approaches to identify the protein fractions of the venom in both eupelmid egg parasitoids, Anastatus japonicus and Mesocomys trabalae. We identified 3422 up-regulated venom gland genes (UVGs) in M. trabalae and 3709 in A. japonicus and analyzed their functions comparatively. By proteome sequencing, we identified 956 potential venom proteins in the venom pouch of M. trabalae, of which 186 were contained in UVGs simultaneously. A total of 766 proteins were detected in the venom of A. japonicus, of which 128 venom proteins were highly expressed in the venom glands. At the same time, the functional analysis of these identified venom proteins was carried out separately. We found the venom proteins in M. trabalae are well known but not in A. japonicus, which may be related to the host range. In conclusion, identifying venom proteins in both egg parasitoid species provides a database for studying the function of egg parasitoid venom and its parasitic mechanism.

Comparative demographics, population projections and egg maturation patterns of four eupelmid egg parasitoids on the factitious host Antherae pernyi.

BACKGROUND: The genera Anastatus and Mesocomys (both Hymenoptera: Eupelmidae) are important solitary egg endoparasitoids as biological control agents for lepidopterous and hemipterous pests worldwide. Here, we comparatively evaluated the demographic parameters of four important eupelmid egg parasitoids (Anastatus fulloi, A. japonicus, Mesocomys albitarsis and M. trabalae) reared on the factitious host eggs of the Chinese oak silkworm Antheraea pernyi, using age-stage two-sex life tables, their population projections as well as egg maturation patterns. RESULTS: Both the age-specific net reproductive rate (lx mx ) and reproductive value (vxj ) increased initially and then gradually decreased with increasing age in all four parasitoid species. Overall, the two Mesocomys species had higher survival rates at stable age-stage distribution, peak reproductive values, and intrinsic rates of increase than the two Anastatus species. Mesocomys albitarsis had the longest longevity, whereas A. japonicus had the longest oviposition days and mean generation time. The two Mesocomys species are thus projected to have faster population increase than the two Anastatus species. Adult females of all four parasitoid species emerged with only a few mature eggs (< 6 eggs) and most of their eggs were matured post-emergence (strict synovigeny). The estimated 90% of lifetime complement of reproduction (offspring) and realized days were 374 and 32 for A. japonicus, 337 and 22 for M. trabalae, 330 and 19 for M. albitarsis and 147 and 28 for A. fulloi. CONCLUSION: Our results indicated that the two Mesocomys species have higher control capacity than the two Anastatus species. Provision of adult food for these strictly synovigenic parasitoids would be essential to prolong their lifespan and continuously produce eggs for parasitizing their hosts for mass rearing or augmentative biological control programs. © 2023 Society of Chemical Industry.

Demography and Fitness of Anastatus japonicus Reared from Antheraea pernyi as a Biological Control Agent of Caligula japonica.

Japanese giant silkworm (JGS), Caligula japonica Moore, is an emerging defoliator pest of forest and fruit trees in East Asia, causing severe economic losses. To develop a cost-effective biological control program against JGS, we used eggs of the Chinese oak silkworm (COS) Antheraea pernyi Guérin-Méneville as an alternative host to rear the most dominant JGS egg parasitoid Anastatus japonicus Ashmead. We compared the demographic parameters and total parasitism (killing) rates of A. japonicus parasitizing JGS and COS eggs using an age-stage, two-sex life table method. The results showed that A. japonicus performed differently on these two different hosts. Anastatus japonicus reared from COS eggs had a higher fecundity (369.7 eggs per female) and a longer oviposition period (35.9 days) on the COS than JGS eggs (180.9 eggs; 24.0 days). Consequently, A. japonicus parasitizing COS eggs had a higher intrinsic rate of increase (r = 0.1466 d-1), finite rate of increase (λ = 1.1579 d-1) and net reproductive rate (R0 = 284.9 offspring) than those parasitizing JGS eggs (r = 0.1419 d-1, λ = 1.1525 d-1, R0 = 150.0 offspring). The total net parasitism rate (the number of parasitized hosts in which the parasitoids successfully developed) of A. japonicus parasitizing COS eggs was 284.9, significantly higher than that of A. japonicus parasitizing JGS eggs (150.0), while the net non-effective parasitism rate (the number of parasitized hosts in which the parasitoids failed to develop) of the former (0.0) was significantly lower than that of the latter (9.6). These results suggest that A. japonicus can be efficiently reared on the alternative (or factitious) COS eggs, and the reared parasitoids have a high biological control potential against the target JGS.

Chinese oak silkworm Antherae pernyi egg, a suitable factitious host for rearing eupelmid egg parasitoids.

BACKGROUND: Eupelmid egg parasitoids in the genera Anastatus and Mesocomys are important biological control agents for lepidopterous and hemipterous pests worldwide. The egg of Chinese oak silkworm Antheraea pernyi has been widely used for mass rearing of Trichogramma parasitoids. This study evaluated the suitability and optimal use methods of A. pernyi egg as a factitious host for the rearing of six eupelmid egg parasitoids (Anastatus fulloi, Anastatus gansuensis, Anastatus japonicus, Anastatus meilingensis, Mesocomys albitarsis and Mesocomys trabalae). Each parasitoid was tested for its oviposition preference and offspring performance on various differently treated host eggs (extracted from virgin moths or laid naturally by virgin or mated moths, and washed or unwashed prior to the use) in both no-choice and choice tests. RESULTS: All treated A. pernyi eggs were readily parasitized by the six parasitoids. In general, A. gansuensis and M. trabalae preferred washed over unwashed eggs regardless of the fertilization status of host eggs, A. fulloi and A. meilingensis parasitized more unfertilized than fertilized host eggs, and A. japonicus and M. albitarsis did not show a preference among differently treated host eggs. Host egg treatment did not significantly affect offspring fitness (development time, survival, sex ratio and body size) nor reproductive potential of developed adult females for each parasitoid species, except for M. albitarsis (whose females contained more eggs when reared from unfertilized than fertilized host eggs). CONCLUSION: Results suggest that manually extracted, unfertilized and washed A. pernyi eggs are most suitable for mass rearing of these eupelmid egg parasitoids in biological control programs.

The genomic architecture of EBV and infected gastric tissue from precursor lesions to carcinoma.

BACKGROUND: Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) present unique molecular signatures, but the tumorigenesis of EBVaGCs and the role EBV plays during this process remain poorly understood. METHODS: We applied whole-exome sequencing, EBV genome sequencing, and whole-genome bisulfite sequencing to multiple samples (n = 123) derived from the same patients (n = 25), which covered saliva samples and different histological stages from morphologically normal epithelial tissues to dysplasia and EBVaGCs. We compared the genomic landscape between EBVaGCs and their precursor lesions and traced the clonal evolution for each patient. We also analyzed genome sequences of EBV from samples of different histological types. Finally, the key molecular events promoting the tumor evolution were demonstrated by MTT, IC50, and colony formation assay in vitro experiments and in vivo xenograft experiments. RESULTS: Our analysis revealed increasing mutational burden and EBV load from normal tissues and low-grade dysplasia (LD) to high-grade dysplasia (HD) and EBVaGCs, and oncogenic amplifications occurred late in EBVaGCs. Interestingly, within each patient, EBVaGCs and HDs were monoclonal and harbored single-strain-originated EBV, but saliva or normal tissues/LDs had different EBV strains from that in EBVaGCs. Compared with precursor lesions, tumor cells showed incremental methylation in promotor regions, whereas EBV presented consistent hypermethylation. Dominant alterations targeting the PI3K-Akt and Wnt pathways were found in EBV-infected cells. The combinational inhibition of these two pathways in EBV-positive tumor cells confirmed their synergistic function. CONCLUSIONS: We portrayed the (epi) genomic evolution process of EBVaGCs, revealed the extensive genomic diversity of EBV between tumors and normal tissue sites, and demonstrated the synergistic activation of the PI3K and Wnt pathways in EBVaGCs, offering a new potential treatment strategy for this disease.

Effects of permissive hypocaloric vs standard enteral feeding on gastrointestinal function and outcomes in sepsis.

BACKGROUND: Intestinal mucosal barrier injury and gastrointestinal dysfunction are important causes of sepsis. However, few studies have investigated the effects of enteral underfeeding on gastrointestinal function in sepsis. Moreover, no consensus on goal enteral caloric intake has been reached in sepsis. AIM: To investigate the effects of different goal caloric requirements of enteral nutrition on the gastrointestinal function and outcomes in the acute phase of sepsis. METHODS: Patients were randomly assigned to receive 30% (defined as group A), 60% (group B), or 100% (group C) of goal caloric requirements of enteral nutrition in this prospective pilot clinical trial. The acute gastrointestinal injury (AGI) grades, incidence of feeding intolerance (FI), daily caloric intake, nutritional and inflammatory markers, and biomarkers of mucosal barrier function were collected during the first 7 d of enteral feeding. The clinical severity and outcome variables were also recorded. RESULTS: A total of 54 septic patients were enrolled. The days to goal calorie of group C (2.55 ± 0.82) were significantly longer than those of group A (3.50 ± 1.51; P = 0.046) or B (4.85 ± 1.68; P < 0.001). The FI incidence of group C (16.5%) was higher than that of group A (5.0%) or B (8.7%) (P = 0.009). No difference in the incidence of FI symptoms was found between groups A and B. The serum levels of barrier function biomarkers of group B were significantly lower than those of group A (P < 0.05) on the 7th day of feeding. The prealbumin and IL-6 levels of group A were lower than those of group B (P < 0.05) on the 7th day of feeding. No significant differences in the clinical outcome variables or 28-d mortality were found among the three groups. CONCLUSION: Early moderate enteral underfeeding (60% of goal requirements) could improve the intestinal barrier function and nutritional and inflammatory status without increasing the incidence of FI symptoms in sepsis. However, further large-scale prospective clinical trials and animal studies are required to test our findings. Moreover, the effects of different protein intake on gastrointestinal function and outcomes should also be investigated in future work.

Parasitism and Suitability of Aprostocetus brevipedicellus on Chinese Oak Silkworm, Antheraea pernyi, a Dominant Factitious Host.

Aprostocetus brevipedicellus, a eulophid gregarious egg parasitoid of lepidopterous pests, is a potential biological control agent for the control of many forest pests. A dominant factitious host, Antheraea pernyi, has been widely used for mass rearing several parasitoids in China. However, whether A. pernyi eggs are suitable for A. brevipedicellus rearing remains unclear. Here we evaluated A. brevipedicellus parasitism and fitness of their offspring on A. pernyi eggs with five different treatments, including manually-extracted, unfertilized and washed eggs (MUW), naturally-laid, unfertilized and washed eggs (NUW), naturally-laid, unfertilized, and unwashed (NUUW) eggs, naturally-laid, fertilized and washed eggs (NFW), and naturally-laid, fertilized and unwashed eggs (NFUW). The results showed that A. brevipedicellus could parasitize host eggs in all treatments but significantly preferred MUW eggs to other treatments. Moreover, A. brevipedicellus preferred unfertilized eggs to fertilized eggs and parasitized more washed eggs than unwashed. The pre-emergence time of parasitoid offspring emerging from fertilized eggs was shorter than that from unfertilized eggs. More parasitoid offspring emerged from unwashed eggs than that from washed eggs. The offspring emergence rate was high (>95%) and also female-biased (>85%) among all egg treatments. The egg load of female parasitoid offspring emerging from MUW and NUW eggs was 30-60% higher than the remaining treatments. Overall, MUW eggs of A. pernyi are the most suitable for the mass production of A. brevipedicellus.

Production of natural chitin film from pupal shell of moth: Fabrication of plasmonic surfaces for SERS-based sensing applications.

Commercially available types of chitin or chitin isolate are usually in powder form and are nanofibrous in microstructure. However, the surface characteristics of natural chitin in the body of insects are currently understudied. Herein, natural chitin film was successfully produced from bio-waste of insect pupae of the Japanese giant silkworm. Two different surface morphologies of the chitin film were observed. We report for the first time a micropapillary surface structure of chitin which was observed on the dorsal side of the film. To further potential of the micropapillary structured natural chitin in sensing applications, we develop a protocol for generating a nanoscopic film of Ag using thermal evaporation. The Ag-deposited natural chitin films exhibited surface-enhanced Raman scattering (SERS) activity to an extent depending on the structure of the film. In conclusion, materials science has been expanded by addition of a natural, three-dimensional chitin film with utilizable properties.

Smoking status-based efficacy difference in anti-PD-1/PD-L1 immunotherapy: a systematic review and meta-analysis.

Aim: This study aimed to evaluate the relationship between smoking status and efficacy of PD-1/PD-L1 inhibitors compared with conventional agents. Materials & methods: We reviewed Phase II/III trials of PD-1/PD-L1 inhibitors that reported hazard ratio (HR) in current/former and never smoking patients. Results: 15 qualifying trials comprising 9073 patients were eligible in this study. Compared with conventional agents, PD-1/PD-L1 inhibitors correlated with prolonged progression-free survival (HR: 0.73; 0.58-0.92) and overall survival (HR: 0.75; 0.71-0.80) in current/former smoker patients but not in never-smoker patients (HR: 1.15 and 0.86 for progression-free survival and overall survival, respectively; both p > 0.05) irrespective of cancer type, target of experimental agents and treatment strategy. Conclusion: There exit smoking status-based efficacy difference in anti-PD-1/PD-L1 immunotherapy.

Disease-free survival as a surrogate endpoint for overall survival in adjuvant trials of pancreatic cancer: a meta-analysis of 20 randomized controlled trials.

BACKGROUND: We aimed to assess whether disease-free survival (DFS) could serve as a reliable surrogate endpoint for overall survival (OS) in adjuvant trials of pancreatic cancer. METHODS: We systematically reviewed adjuvant randomized trials for non-metastatic pancreatic cancer after curative resection that reported a hazard ratio (HR) for DFS and OS. We assessed the correlation between treatment effect (HR) on DFS and OS, weighted by sample size or precision of hazard ratio estimate, assuming fixed and random effects, and calculated the surrogate threshold effect (STE). We also performed sensitivity analyses and a leave-one-out cross validation approach to evaluate the robustness of our findings. RESULTS: After screening 450 relevant articles, we identified a total of 20 qualifying trails comprising 5170 patients for quantitative analysis. We noted a strong correlation between the treatment effects for DFS and OS, with coefficient of determination of 0.82 in the random effect model, 0.82 in the fixed effect model, and 0.80 in the sample size weighting; the robustness of this finding was further verified by the leave-one-out cross-validation approach. Sensitivity analyses with restriction to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy strengthened the correlation (0.75 to 0.88) between DFS and OS. The STE was 0.96 for DFS. CONCLUSIONS: Therefore, DFS could be regarded as a surrogate endpoint for OS in adjuvant trials of pancreatic cancer. In future similar adjuvant trials, a hazard ratio for DFS of 0.96 or less would predict a treatment impact on OS.

Downregulation of PSCA promotes gastric cancer proliferation and is related to poor prognosis.

Background: Dysregulation of prostate stem cell antigen (PSCA) has been implicated in human cancers. Studies have reported that PSCA expression is generally high in prostate cancer, which correlates with a worse survival. PSCA is also highly expressed in bladder, ovarian, and pancreatic cancers. However, PSCA is expressed at low levels in gastric, gallbladder and oesophageal cancers. At present, the clinical significance, expression pattern and biological function of PSCA in gastric cancer (GC) are still unclear. Methods: Previously, we used cDNA microarray as a screening tool to compare GC tissues with its matched normal gastric mucosa tissues (MNGT), and obtained the differentially expressed genes of the two tissue types. PSCA is one of the genes significantly down-regulated in GC tissues. In this study, we detected the expression of PSCA in GC tissues and MNGT by western-blot experiment and immunohistochemical staining (IHC). Then the relationship between the expression pattern of PSCA and the clinicopathological characteristics and survival in GC was analyzed. In order to further study the function of PSCA in GC, lentivirus was used to construct stable cell lines with knockdown and overexpression of PSCA gene. We used AGS and MKN45 cell lines for plasmid transfection. Colony formation assay, MTS and nude mice xenograft model were performed to investigate the effect of PSCA in GC. Results: Western-blot and IHC assays demonstrated that the expression of PSCA in GC tissues was significantly lower than that in the MNGT. PSCA expression in GC tissues was high in 252 (57.5%) and low in 186 (42.5%) of 438 patients. PSCA expression for MNGT was high in 273 (62.3%) and low in 165 (37.7%) of 438 patients. PSCA expression was significantly associated with T classification (P=0.024), N classification (P=0.018) and TNM stage (P=0.019) using χ2 test. The relationship between PSCA expression level and patient survival was analysed using Kaplan-Meier analysis and the log-rank test. Low levels of PSCA expression were significantly associated with a poorer OS than high expression levels of PSCA (P=0.011). In the COX regression analysis of OS, all 9 variables in the univariate analysis were significantly correlated with OS (P<0.05), while the variables found to be independently correlated with OS in the multivariate analysis were PSCA expression (P=0.036), age (P<0.001), gender (P=0.007), and TNM stage (P<0.001), respectively. Univariate and multivariate analyses showed that PSCA was an independent prognostic factor for OS in GC. In vitro MTS cell proliferation experiment and clonal formation experiment and in vivo nude mouse subcutaneous tumorigenesis experiment all proved that knockdown of PSCA gene can improve the proliferation ability of GC cells, while in vitro experiment proved that overexpression of PSCA can reduce the proliferation ability of GC cells.It was found that knockdown of PSCA gene can improve the proliferation ability of GC cells both in vitro and in vivo, while overexpression of PSCA can reduce the proliferation ability of GC cells in vitro. Conclusion: Our study showed that the expression of PSCA gene was decreased in GC, which was related to more advanced pathological stages. And the expression level of PSCA in GC was an independent good prognostic factor. PSCA gene had the function of inhibiting GC proliferation.

The Value of PD-L1 Expression in Predicting the Efficacy of Anti-PD-1 or Anti-PD-L1 Therapy in Patients with Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVES: Recent trials have shown an overall survival (OS) benefit in 10-40% advanced cancer patients treated with programmed cell death 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors. Here, we aimed to evaluate the relationship between PD-L1 expression and the therapeutic efficacy of PD-1 or PD-L1 inhibitors in patients with cancer with recurrent or metastatic disease, compared with control treatments. METHODS: We systematically searched Medline (PubMed), Embase, and Cochrane Library databases up to Jan 2019 and pooled the treatment effects (hazard ratio or relative ratio) of PD-1/PD-L1 inhibitors in patients with different PD-L1 expression. RESULTS: Overall, twenty-four qualifying trials with over 14,860 subjects were eligible in this study. Compared with conventional agents, anti-PD/PD-L1 drugs significantly reduced the risk of death (hazard ratio 0.72, 95% CI 0.66 to 0.78), irrespective of the tumor type. Additionally, when PD-L1 expression ≥1% was defined as positive, anti-PD-1/PD-L1 monotherapy correlated with prolonged overall survival in patients with nonsmall cell lung cancer (NSCLC) (0.72, 0.61 to 0.86) and other cancer types (0.66, 0.57 to 0.76) patients with PD-L1 positive, rather than those with PD-L1 negative (hazard ratio for NSCLC and other cancer types: 0.84 and 0.87, respectively; all P > 0.05). The subgroup analyses to experimental agents, PD-1/PD-L1 inhibitors, PD-L1 antibody clone, and type of IHC scoring method validated the robustness of these findings. However, anti-PD-1/PD-L1 combination therapies can reduce the risk of death for patients with different cancer types, regardless of PD-L1 expression (P < 0.05 for all PD-L1 expression status). CONCLUSIONS: We recommend PD-L1 expression as a predictive biomarker in patient selection for anti-PD-1/PD-L1 monotherapy, but not for combination therapies.