Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

Efficacy of chemotherapy containing bevacizumab in patients with metastatic colorectal cancer according to programmed cell death ligand 1

BACKGROUND Bevacizumab,an anti-vascular endothelial growth factor(VEGF)monoclonal antibody,inhibits angiogenesis and reduces tumor growth.Serum VEGF-C,lactate dehydrogenase,and inflammatory markers have been reported as predictive markers related to bevacizumab treatment.Programmed cell death ligand 1(PD-L1)could act upon VEGF receptor 2 to induce cancer cell angiogenesis and metastasis.AIM To investigate the efficacy of bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer(CRC)according to the expression of PD-L1.METHODS This analysis included CRC patients who received bevacizumab plus FOLFOX or FOLFIRI as first-line therapy between June 24,2014 and February 28,2022,at Samsung Medical Center(Seoul,South Korea).Analysis of patient data included evaluation of PD-L1 expression by the combined positive score(CPS).We analyzed the efficacy of bevacizumab according to PD-L1 expression status in patients with CRC.RESULTS A total of 124 patients was included in this analysis.Almost all patients were treated with bevacizumab plus FOLFIRI or FOLFOX as the first-line chemotherapy.While 77%of patients received FOLFOX,23%received FOLFIRI as backbone first-line chemotherapy.The numbers of patients with a PD-L1 CPS of 1 or more,5 or more,or 10 or more were 105(85%),64(52%),and 32(26%),respectively.The results showed no significant difference in progression-free survival(PFS)and overall survival(OS)with bevacizumab treatment between patients with PDL1 CPS less than 1 and those with PD-L1 CPS of 1 or more(PD-L1<1%vs PD-L1≥1%;PFS:P=0.93,OS:P=0.33),between patients with PD-L1 CPS less than 5 and of 5 or more(PD-L1<5%vs PD-L1≥5%;PFS:P=0.409,OS:P=0.746),and between patients with PD-L1 CPS less than 10 and of 10 or more(PD-L1<10%vs PD-L1≥10%;PFS:P=0.529,OS:P=0.568).CONCLUSION Chemotherapy containing bevacizumab can be considered as first-line therapy in metastatic CRC irrespective of PD-L1 expression.

Quercetin Alleviates Lipopolysaccharide-Induced Cardiac Inflammation via Inhibiting Autophagy and Programmed Cell Death

Objective The aim of this study is to explore the potential modulatory role of quercetin against Endotoxin or lipopolysaccharide(LPS)induced septic cardiac dysfunction.Methods Specific pathogen-free chicken embryos(n=120)were allocated untreated control,phosphate buffer solution(PBS)vehicle,PBS with ethanol vehicle,LPS(500 ng/egg),LPS with quercetin treatment(10,20,or 40 nmol/egg,respectively),Quercetin groups(10,20,or 40 nmol/egg).Fifteenday-old embryonated eggs were inoculated with abovementioned solutions via the allantoic cavity.At embryonic day 19,the hearts of the embryos were collected for histopathological examination,RNA extraction,real-time polymerase chain reaction,immunohistochemical investigations,and Western blotting.Results They demonstrated that the heart presented inflammatory responses after LPS induction.The LPS-induced higher mRNA expressions of inflammation-related factors(TLR4,TNFα,MYD88,NF-κB1,IFNγ,IL-1β,IL-8,IL-6,IL-10,p38,MMP3,and MMP9)were blocked by quercetin with three dosages.Quercetin significantly decreased immunopositivity to TLR4 and MMP9 in the treatment group when compared with the LPS group.Quercetin significantly decreased protein expressions of TLR4,IFNγ,MMP3,and MMP9 when compared with the LPS group.Quercetin treatment prevented LPS-induced increase in the mRNA expression of Claudin 1 and ZO-1,and significantly decreased protein expression of claudin 1 when compared with the LPS group.Quercetin significantly downregulated autophagyrelated gene expressions(PPARα,SGLT1,APOA4,AMPKα1,AMPKα2,ATG5,ATG7,Beclin-1,and LC3B)and programmed cell death(Fas,Bcl-2,CASP1,CASP12,CASP3,and RIPK1)after LPS induction.Quercetin significantly decreased immunopositivity to APOA4,AMPKα2,and LC3-II/LC3-I in the treatment group when compared with the LPS group.Quercetin significantly decreased protein expressions of AMPKα1,LC3-I,and LC3-II.Quercetin significantly decreased the protein expression to CASP1 and CASP3 by immunohistochemical investigation or Western blotting in treatment group when compared with LPS group.Conclusion Quercetin alleviates cardiac inflammation induced by LPS through modulating autophagy,programmed cell death,and myocardiocytes permeability.

Pretreatment can alleviate programmed cell death in mesenchymal stem cells

In this editorial,we delved into the article titled“Cellular preconditioning and mesenchymal stem cell ferroptosis.”This groundbreaking study underscores a pivotal discovery:Ferroptosis,a type of programmed cell death,drastically reduces the viability of donor mesenchymal stem cells(MSCs)after engraftment,thereby undermining the therapeutic value of cell-based therapies.Furthermore,the article proposes that by manipulating ferroptosis mechanisms through preconditioning,we can potentially enhance the survival rate and functionality of MSCs,ultimately amplifying their therapeutic potential.Given the crucial role ferroptosis plays in shaping the therapeutic outcomes of MSCs,we deem it im-perative to further investigate the intricate interplay between programmed cell death and the therapeutic effectiveness of MSCs.

Roles of the tumor microenvironment in the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advanced GC.In recent years,with the progress in tumor immunology research,attention has shifted toward immunotherapy as a therapeutic approach for GC.Programmed cell death protein 1(PD-1)inhibitors,as novel immunosuppressive medications,have been widely utilized in the treatment of GC.However,many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy.To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy,to maximize the clinical activity of immunosuppressive drugs,and to elicit a lasting immune response,it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients.This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment,aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor+chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers

BACKGROUND The combination of programmed cell death protein-1(PD-1)inhibitor and che-motherapy is approved as a standard first-or second-line treatment in patients with advanced oesophageal or gastric cancer.However,it is unclear whether this combination is superior to chemotherapy alone.AIM To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer,gastroesophageal junction(GEJ)cancer,or oesophageal carcinoma.METHODS We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer.We employed either random or fixed models to analyze the outcomes of each clinical trial,en-compassing data on overall survival(OS),progression-free survival(PFS),objective response rate,and adverse events(AEs).RESULTS Nine phase 3 clinical trials(7016 advanced oesophageal and gastric cancer patients)met the inclusion criteria.Our meta-analysis demonstrated that the pooled PD-1 inhibitor+chemotherapy group had a significantly longer OS than the chemotherapy-alone group[hazard ratio(HR)=0.76,95%confidence interval(CI):0.71-0.81];the pooled PFS result was consistent with that of OS(HR=0.67,95%CI:0.61-0.74).The count of patients achieving an objective response in the PD-1 inhibitor+chemotherapy group surpassed that of the chemotherapy-alone group[odds ratio(OR)=1.86,95%CI:1.59-2.18].AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group,regardless of whether≥grade 3 only(OR=1.30,95%CI:1.07-1.57)or all AE grades(OR=1.88,95%CI:1.39-2.54)were examined.We performed a subgroup analysis based on the programmed death-ligand 1(PD-L1)combined positive score(CPS)and noted extended OS and PFS durations within the CPS≥1,CPS≥5,and CPS≥10 subgroups of the PD-1 inhibitor+chemotherapy group.CONCLUSION In contrast to chemotherapy alone,the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer,GEJ tumor,or oesophageal cancer.This holds true particularly for individuals with PD-L1 CPS scores of≥5 and≥10.

C-reactive protein to albumin ratio predict responses to programmed cell death-1 inhibitors in hepatocellular carcinoma patients

BACKGROUND Over the years,programmed cell death-1(PD-1)inhibitors have been routinely used for hepatocellular carcinoma(HCC)treatment and yielded improved survival outcomes.Nonetheless,significant heterogeneity surrounds the outcomes of most studies.Therefore,it is critical to search for biomarkers that predict the efficacy of PD-1 inhibitors in patients with HCC.AIM To investigate the role of the C-reactive protein to albumin ratio(CAR)in evaluating the efficacy of PD-1 inhibitors for HCC.METHODS The clinical data of 160 patients with HCC treated with PD-1 inhibitors from January 2018 to November 2022 at the First Affiliated Hospital of Guangxi Medical University were retrospectively analyzed.RESULTS The optimal cut-off value for CAR based on progression-free survival(PFS)was determined to be 1.20 using x-tile software.Cox proportional risk model was used to determine the factors affecting prognosis.Eastern Cooperative Oncology Group performance status[hazard ratio(HR)=1.754,95%confidence interval(95%CI)=1.045-2.944,P=0.033],CAR(HR=2.118,95%CI=1.057-4.243,P=0.034)and tumor number(HR=2.932,95%CI=1.246-6.897,P=0.014)were independent prognostic factors for overall survival.CAR(HR=2.730,95%CI=1.502-4.961,P=0.001),tumor number(HR=1.584,95%CI=1.003-2.500,P=0.048)and neutrophil to lymphocyte ratio(HR=1.120,95%CI=1.022-1.228,P=0.015)were independent prognostic factors for PFS.Two nomograms were constructed based on independent prognostic factors.The C-index index and calibration plots confirmed that the nomogram is a reliable risk prediction tool.The ROC curve and decision curve analysis confirmed that the nomogram has a good predictive effect as well as a net clinical benefit.CONCLUSION Overall,we reveal that the CAR is a potential predictor of short-and long-term prognosis in patients with HCC treated with PD-1 inhibitors.If further verified,CAR-based nomogram may increase the number of markers that predict individualized prognosis.

Mitochondrial dysfunction and programmed cell death in osteosarcoma

Osteosarcoma is the most prevalent primarymalignant bone tumor,primarily affecting adolescents aged 15–25 years.It is characterized by a high recurrence rate,poor prognosis,and lack of important biomarkers.Significant mitochondrial dysfunction in osteosarcoma cells has been widely reported by recent studies.Dysfunctional mitochondria occupy an important position in cellularmetabolic reprogramming,immune microenvironment regulation,and programmed cell death.Therefore,targeting mitochondrial dysfunction may represent a new mechanism to overcome therapeutic barriers in the treatment of osteosarcoma and provides crucial target molecules for further development of targeted therapies and immunotherapies.The present article summarizes the recent reports of mitochondrial dysfunction in osteosarcoma and links it to various programmed cell death mechanisms,aiming to provide the basis for further clinical practice.

Research progress regarding programmed cell death 1/programmed cell death ligand 1 inhibitors combined with targeted therapy for treating hepatocellular carcinoma

In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is considered to be an effective treatment for advanced HCC.Immune checkpoint inhibitors targeting programmed cell death 1(PD-1)/programmed cell death ligand 1(PDL1)are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC.However,treating advanced HCC is still a great challenge,and the need for new treatments remains urgent.This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.

Ultrastructural Features of Nucleus Degradation During Programmed Cell Death of Starchy Endosperm Cells in Rice

Ultrastructural features of nucleus degradation during programmed cell death (PCD) of starchy endosperm cells in rice ( Oryza sativa L.) were observed using transmission electron microscopy. Several distinct morphological features of PCD have been found in the developing starchy endosperm cells, e.g. nucleus deformation, chromatin condensation, nuclear envelope disruption, and nuclear matrix leakage. DNA ladder displayed a smear of large DNA fragments from nucleus and evident bands of small DNA fragments (140-180 bp) from both nucleus and cytoplasm. In contrast with the rapid nucleus degradation, cell organelles in cytoplasm, such as rough endoplasmic reticulum, amyloplast, and mitochondrion, maintained their metabolic functions for a longer time. Seed reserves were continually synthesized and accumulated in the starchy endosperm cells despite the nucleus degradation during the PCD process. These results suggest that starchy endosperm cells remain active during reserve material synthesis and accumulation in the PCD process. The specific relationships between nucleus and cytoplasm in the developing endosperm cells and the morphological changes of nucleus in the endosperm PCD process were also discussed.

Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment

BACKGROUND Comprehensive genomic analysis has shown that small bowel adenocarcinoma(SBA)has different genomic profiles from gastric and colorectal cancers.Hence,it is essential to establish chemotherapeutic regimens based on SBA characteristics.The expression of programmed cell death-ligand 1(PD-L1)and programmed cell death-ligand 2(PD-L2)in SBA is not fully understood.Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes(TILs);therefore,the status of TILs in the tumor microenvironment(TME)may influence their efficacy.The ratio of FoxP3+to CD8+T cells has been reported to be useful in predicting the prognosis of digestive system cancers.AIM To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues.METHODS We performed immunohistochemical analysis for PD-L1,PD-L2,CD8,FoxP3,and DNA mismatch repair(MMR)proteins using formalin-fixed,paraffin-embedded tissues from 50 patients diagnosed with primary SBA.The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells throughout the tumor center and invasive margins,and finally evaluated using the combined positive score(CPS).We assessed CD8+and FoxP3+T cells in the intratumoral and tumor-surrounding stroma.Subsequently,we calculated and summed the ratio of FoxP3 to CD8+T cell counts.Immune-related cell densities were graded as low or high.Immunohistochemical results were compared with clinicopathological factors and patient prognosis.The distribution of cancer-specific survival(CSS)was estimated using the Kaplan–Meier method,and the log-rank test was used to test for significant differences in CSS.A Cox proportional hazard model was also used to assess the effect of tumor variables on CSS.RESULTS PD-L1 expression was positive in 34%in tumor cells(T-PD-L1)and 54%in tumor-infiltrating immune cells(I-PDL1)of the cases examined.T-PD-L2 was positive in 34%and I-PD-L2 was positive in 42%of the cases.PD-L1 CPS≥10 and PD-L2 CPS≥10 were observed in 50%and 56%of the cases,respectively.Deficient MMR(dMMR)was 14%of the cases.T-PD-L1,I-PD-L1 and PD-L1 CPS≥10 were all significantly associated with dMMR(P=0.037,P=0.009,and P=0.005,respectively).T-PD-L1,I-PD-L1,and PD-L1 CPS≥10 were all associated with deeper depth of invasion(P=0.001,P=0.024,and P=0.002,respectively).I-PD-L2 expression and PD-L2 CPS≥10 were significantly higher in the differentiated histological type(P=0.015 and P=0.030,respectively).The I-PD-L1 and IPD-L2 levels were significantly associated with better CSS(P=0.037 and P=0.015,respectively).CD8-high was significantly associated with less lymph node metastasis(P=0.047),less distant metastasis(P=0.024),less peritoneal dissemination(P=0.034),and earlier TNM stage(P=0.047).The CD8-high group had better prognosis than the CD8-low group(P=0.018).FoxP3 expression was not associated with any clinicopathological factors or prognosis.We found that patients with PD-L2 CPS≥10 tended to have worse prognosis in the FoxP3/CD8-low group(P=0.088).CONCLUSION The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status.Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.

Morphological Changes in Nucellar Cells Undergoing Programmed Cell Death (PCD) During Pollen Chamber Formation in Ginkgo biloba

Programmed cell death (PCD) of the nucellar cells at the micropylar end is involved in pollen chamber morphogenesis in Ginkgo biloba L. A development-course observation of the morphological changes in the nucellar cells undergoing PCD to form pollen chamber was performed. During the PCD, the nucellar cells degraded their cellular components through an orderly progression. Through the vactiolation, the cytosol was engulfed by the enlarging vacuole, leaving out various organelles, which remained morphologically integrated. As the vacuolation continued, the vacuole collapsed with the breakage of the tonoplast and the cytosol disappeared completely. Organelles were subsequently destroyed. Ultimately, nucellar cells digested away all of their cytoplasm, leaving with cell walls. They became collapsed as the nucellus developed. Intracellular membranes were strikingly changed, playing a role in leading to cell death. Some of these noticeable changes were the appearance of multivesicular body, multicycle-like membranes, membrane-bounded bodies containing some organelles, tonoplast rupture and numerous vesicles. The dehiscence of the apical epidermis, resulting in the opening, appeared to have followed two different pathways with one involving a specific epidermal cell autolysis and the other by detachment from middle lamella of two neighboring epidermal cells without cell autolysis. The specific epidermal cells had been dead prior to the dehiscence of the apical epidermis, which marked the sites of the dehiscence followed. In view of the changes in the cellular morphology, a process of nucellar cell PCD in the course of the pollen chamber formation was demonstrated.

The clinical association of programmed cell death protein 4(PDCD4) with solid tumors and its prognostic significance:a meta-analysis

Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.

Reduced Expression of Programmed Cell Death 5 Protein in Tissue of Human Prostate Cancer

Objective To investigate the expression of programmed cell death 5 （PDCD5） in tissues of normal human prostate （NP）, benign prostatic hyperplasia （BPH）, and prostate cancer （PCa） in order to assess the clinical role of PDCD5 in PCa. Methods PDCD5 expression was determined by EnVision immunohistochemical staining in forma-lin-fixed and paraffin-embedded specimens obtained from 12 subjects with NP, 22 with BPH, and 22 with PCa. In addition, PCa cases were classified as low/middle-risk （Gleason sumS7） and high-risk （Gleason sum〉7） on the basis of Gleason grade. Positive expression rates and intensity of PDCD5 protein were observed under light microscope and analyzed with computer imaging technique. Expression of PDCD5 was compared among different prostatic tissues. Results The expression of PDCD5 was significantly lower in tissue of PCa than in tissues of NP and BPH （P〈0.01）. However, there was no significant difference in PDCD5 expression between tissues of NP and BPH. In addition, the expression of PDCD5 was further downregulated with the increase of Gleason sum in PCa. Conclusions By downregulating apoptosis, low PDCD5 expression may play an important role in the occurrence and development of PCa. PDCD5 is supposed to have a potential clinical value to be a new predictor of progression and target of gene therapy in PCa.

Function of flavonoids on different types of programmed cell death and its mechanism:a review

Cell death in the living system plays a vital role in maintaining the homeostasis and balancing the cell count in the body.Programmed cell death(PCD)is a crucial component of several development and defense mechanisms.PCD is also important in terms of aging which avoids the accumulation of cellular damage by maintaining cell division.Depending on the execution of cell death and its role in destruction,PCD is categorized into several subtypes.The major different forms of PCD in animals are apoptosis,autophagy and necrosis,which can be distinct in morphological terms.More intense investigations of cell death have given close insight showing other important types of cellular destruction and their pivotal roles in treating disease conditions like cancer.Flavonoids have been acquired a great interest for disease therapies and chemoprevention through activation of several PCD mechanisms.The significant potential of natural flavonoids in the induction of distinct signaling cascades is being a massive approach for targeting uncontrolled cell growth.For these reasons,understanding PCD mechanisms is a promising approach for the interventions in treating cancer.Thus,it is intriguing that understanding the different forms of PCD mechanism induced by flavonoids with more accurate descriptions on the biochemical and cellular processes are gaining more significance in cancer research.Here,we provide a brief overview on the different types of PCD and aim to discuss the functional role of flavonoids in promoting different types of cell death as well as an extensive brief review on their mechanism of action has been highlighted.

Floret-specific differences in gene expression and support for the hypothesis that tapetal degeneration of Zea mays L. occurs via programmed cell death

The maize （Zea mays） spikelet consists of two florets, each of which contains three developmentally synchronized anthers. Morphologically, the anthers in the upper and lower florets proceed through apparently similar developmental programs. To test for global differences in gene expression and to identify genes that are coordinately regulated during maize anther development, RNA samples isolated from upper and lower floret anthers at six developmental stages were hybridized to cDNA microarrays. Approximately 9% of the tested genes exhibited statistically significant differences in expression between anthers in the upper and lower florets. This finding indicates that several basic biological processes are differentially regulated between upper and lower floret anthers, including metabolism, protein synthesis and signal transduction. Genes that are coordinately regulated across anther development were identified via cluster analysis. Analysis of these results identified stage-specific, early in development, late in development and bi-phasic expression profiles. Quantitative RT-PCR analysis revealed that four genes whose homologs in other plant species are involved in programmed cell death are up-regulated just prior to the time the tapetum begins to visibly degenerate （i.e., the mid-microspore stage）. This finding supports the hypothesis that developmentally normal tapetal degeneration occurs via programmed cell death.

Nitric Oxide Content in Wheat Leaves and Its Relation to Programmed Cell Death of Main Stem and Tillers Under Different Nitrogen Levels

Nitric oxide （NO） is a key signaling molecule in different physiological processes of plants, including programmed cell death （PCD）. PCD of tillers plays an important role in surviving which are major components of grain yield. PCD was triggered in wheat leaves of main stem and tillers by NO content under different nitrogen treatments. In wheat, NO could be synthesized endogenously by nitrate reductase （NR）. As an inducible enzyme, NR activity was closely related to substrate concentration. Therefore, different nitrogen levels would change NR activity and NO production. The objective of this study was to determine the effects of NR activity, NO production, and the correlation between them on different tillers growth, development, senescence, and kernel protein content under different nitrogen levels. Field-experiments were conducted in 2009-2011 growing seasons, using two wheat cultivars with different spike-types. Results showed that for main stem and primary tillers, NR activity and NO content reached high level at heading stage, while for secondary tiller, the level of NR activity was low, but NO content was high in the present research. The NO synthesis depending on NR activity in wheat leaves was significant in the early growing stage, but the NO synthesis weakened with the progress of growing period. NO was related to the senescence of wheat leaves, but PCD was more sensitive to marked changes of NO content than NO content itself. N application had marked influence on the aging process of primary tiller, while had little influence on that of main stem and secondary tiller. Moreover, N fertilizer application could increase spike rate and protein content of primary tiller by N fertilizer application.

Studies on the Programmed Cell Death in Rice During Starchy Endosperm Development

Morphological variations of the nucleus in starchy endosperm cell were observed by theelectron-transmisson microscope during endosperm development in rice. Along with thedevelopment of the starchy endosperm, the nuclei of the cells showed chromatin condensation,the typical feature of programmed cell death (PCD). The nuclei also showed nucleusdeformation, disruption of nuclear envelope, nucleoplasm leaking into the cytoplasm andnucleus disintegration resulting in nuclear residue formation. From the nucleus deformationto the nucleus disintegration, the morphological changes of the nucleus were orderlyprogressive. This indicated that the cell death of starchy endosperm in rice wasprogrammed cell death. Evans Blue staining observation showed that the cell death wasinitially detected in the central part of starchy endosperm in rice, then expandedoutward. The activities of superoxide dismutase (SOD) and catalase (CAT) in rice starchyendosperm both descended continuously as development progressed. The analysis of DNA ofrice starchy endosperm did not show the presence of DNA laddering. The above resultsshowed that the cell death of starchy endosperm in rice was a special form of PCD.

Hepatoma cells up-regulate expression of programmed cell death-1 on T cells

AIM： To investigate the effect of hepatoma cells on up-regulation of programmed cell death-1 （PD-1）, and the function of PD-1 on T cells. METHODS： HepG2 or HepG2.2.1.5 cells were cocultured with a lymphoma cell line-Jurkat cells. PD-1 expression was detected by flow cytometry. IL：2, INF-γ and IL-10 in culture supernatant were detected by enzyme-linked immunosorbent assay （ELISA）. Cytotoxic action of T cells was determined by MIF reduction assay-direct mononuclear cell cytotoxicity assay. RESULTS： The PD-1 expression on Jurkat cells increased by 16.17% ± 2.5% and 17.43% ± 2.2% after HepG2 or HepG2.2.1.5 cells were co-cultured for 48 h. The levels of IL-2, INF-γ and IL-10 in the culture supernatant were 202.9 ＋ 53.0 pg/mL, 88.6 ± 4.6 pg/mL and 63.7± 13.4 pg/mL respectively, which were significantly higher than those （102.9 ± 53 pg/mL, 39.3 ± 4.2 pg/mL, and 34.6 =E13.7 pg/mL） in the control group （P 〈 0.05）. The OD value for MTT assay in the blocking group （0.29 ± 0.06） was significantly higher than that （0.19 ± 0.09） in the control group （P 〈 0.05）. CONCLUSION： PD-1 expression on Jurkat cells is upregulated by hepatoma cells, cytokines and cytotoxic action are elevated after PD-1/PD-L1 is blocked.

The prognostic value of programmed cell death ligand 1expression in non-Hodgkin lymphoma:a meta-analysis

Objective: Although the prognostic value of programmed cell death-ligand 1(PD-L1) expression in non-Hodgkin lymphoma(NHL) has been evaluated in many studies, the results remain controversial. To investigate the prognostic role of PD-L1 expression and the association between PD-L1 expression and clinicopathological features of NHL, we performed a meta-analysis.Methods: The Pub Med, EMBASE, and Cochrane Library databases were searched up to November 30, 2017. The hazard ratio(HR), 95% confidence interval(CI), and odds ratios(OR) with 95% CIs were combined to evaluate the association of PD-L1 expression with overall survival(OS) and clinicopathological features. Review manager 5.3 and STATA 12.0 were used in this meta-analysis.Results: A total of 2,005 patients across nine studies were enrolled in our meta-analysis, and the pooled results showed that high PD-L1 expression was associated with a poor prognosis(HR=2.04, 95% CI: 1.18–3.54, P=0.01). In the subgroup analysis according to histology types, pooled results demonstrated that an increased PD-L1 expression was an unfavorable prognostic factor for diffuse large B-cell lymphoma(HR=1.92, 95% CI: 1.06–3.48, P=0.03) but not for natural killer/T-cell lymphoma(HR=2.41, 95%CI: 0.47–12.22, P=0.29). Pooled ORs indicated that PD-L1 expression was higher in NHL with international prognostic indices of≥3. However, PD-L1 expression had no correlation with gender, age, disease stage, lactate dehydrogenase level, B symptoms, and germinal center B-cell-like lymphoma.Conclusions: High PD-L1 expression was a poor prognostic biomarker in patients with NHL. Because of our limited sample size,high-quality studies with larger sample sizes are needed to validate our results.