Clinical and pathological significance of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression in high grade serous ovarian cancer

We investigated programmed cell death 1 (PD-1) / programmed cell death ligand 1 (PD-L1) expression in high grade serous ovarian cancer (HGSOC) and its relationship to tumor infiltrating lymphocytes (TIL) and prognosis. Formalin fixed paraffin embedded (FFPE) samples of 94 HGSOC cases were included in the study. Immunohistochemical analysis (CD3, CD4, CD8, PD-1 and PD-L1) was performed. Samples were analyzed for expression of immune proteins in the peritumoral stromal and intratumoral areas, scored, and expression was correlated with overall survival, stage, and age. PD-L1 staining ratio with a score greater than 0 was found to have lower survival. There were two positive staining patterns, patchy/diffuse and patchy/focal patterns, in 24 (25.5%) cases. Considering the threshold value ≥5%, we demonstrated that the PD-L1 positive cancer cell membrane immunoreactivity rate and patchy/diffuse PD-L1 expression were 9.6% (n = 9). There was statistically significant relationship between high PD-1 scores and PD-L1 cases of ≥ 5%. A statistically significant difference was found between PD-L1 staining and survival in patients with a threshold ≥ 5%. However an appropriate rate for treatment was determined in 9.6% cases. There was a statistically significant correlation between PD-1 positive TIL score and intratumoral CD3, peritumoral stromal CD3, intratumoral CD4 and intratumoral CD8 positive cells. Survival was lower in cases with higher PD-L1 positive stromal TIL score.     

Understanding the function of the tumor microenvironment,and compounds from marine organisms for breast cancer therapy

The pathology and physiology of breast cancer(BC),including metastasis,and drug resistance,is driven by multiple signaling pathways in the tumor microenvironment(TME),which hamper antitumor immunity.Recently,long non-coding RNAs have been reported to mediate pathophysiological developments such as metastasis as well as immune suppression within the TME.Given the complex biology of BC,novel personalized therapeutic strategies that address its diverse pathophysiologies are needed to improve clinical outcomes.In this review,we describe the advances in the biology of breast neoplasia,including cellular and molecular biology,heterogeneity,and TME.We review the role of novel molecules such as long non-coding RNAs in the pathophysiology of BC.Finally,we provide an up-to-date overview of anticancer compounds extracted from marine microorganisms,crustaceans,and fishes and their synergistic effects in combination with other anticancer drugs.Marine compounds are a new discipline of research in BC and offer a wide range of anti-cancer effects that could be harnessed to target the various pathways involved in BC development,thus assisting current therapeutic regimens.     

Management of Hyperuricemia with Rasburicase Review

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5–10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non‐recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost‐effective option in the management of hyperuricemia.     

Lipopolysaccharide neutralization by a novel peptide derived from phosvitin

Lipopolysaccharide (LPS), also known as endotoxin, is the primary trigger of sepsis, which is associated with high mortality in patients. No therapeutic agents are currently efficacious enough to protect patients from sepsis characterized by LPS-mediated tissue damage and organ failure. Previously, a phosvitin-derived peptide, Pt5, which consists of the C-terminal 55 residues of zebrafish phosvitin, has been shown to function as an antibacterial agent. In this study, we have generated six mutants by site-directed mutagenesis based on the sequence of Pt5, and found that one of the six mutants, Pt5e, showed the strongest bactericidal activities against Escherichia coli and Staphylococcus aureus. We then demonstrated that Pt5e was able to bind to LPS and lipoteichoic acid (LTA). More importantly, we showed that Pt5e significantly inhibited LPS-induced tumor-necrosis factor (TNF)-α and interleukin (IL)-1β release from murine RAW264.7 cells and considerably reduced serum TNF-α and IL-1β levels in mice. Additionally, Pt5e protected the liver from damage by LPS, and remarkably promoted the survival rate of the endotoxemia mice. Furthermore, Pt5e displayed no cytotoxicity to murine RAW264.7 macrophages and no hemolytic activity toward human red blood cells. These data together indicate that Pt5e is an endotoxin-neutralizing agent with a therapeutic potential in clinical treatment of LPS-induced sepsis.     

The PPARα agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism

Obesity is associated with an increased risk for malignant lymphoma development. We used Bcr/Abl transformed B cells to determine the impact of aggressive lymphoma formation on systemic lipid mobilization and turnover. In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro. Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased. These findings suggest that B-cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator-activated receptor α (PPARα) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARα in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.     

Quantitative Multispectral Analysis Following Fluorescent Tissue Transplant for Visualization of Cell Origins,Types, and Interactions

With the desire to understand the contributions of multiple cellular elements to the development of a complex tissue; such as the numerous cell types that participate in regenerating tissue, tumor formation, or vasculogenesis, we devised a multi-colored cellular transplant model of tumor development in which cell populations originate from different fluorescently colored reporter gene mice and are transplanted, engrafted or injected in and around a developing tumor. These colored cells are then recruited and incorporated into the tumor stroma. In order to quantitatively assess bone marrow derived tumor stromal cells, we transplanted GFP expressing transgenic whole bone marrow into lethally irradiated RFP expressing mice as approved by IACUC. 0ovarian tumors that were orthotopically injected into the transplanted mice were excised 6-8 weeks post engraftment and analyzed for bone marrow marker of origin (GFP) as well as antibody markers to detect tumor associated stroma using multispectral imaging techniques. We then adapted a methodology we call MIMicc- Multispectral Interrogation of Multiplexed cellular compositions, using multispectral unmixing of fluoroprobes to quantitatively assess which labeled cell came from which starting populations (based on original reporter gene labels), and as our ability to unmix 4, 5, 6 or more spectra per slide increases, we''ve added additional immunohistochemistry associated with cell lineages or differentiation to increase precision. Utilizing software to detect co-localized multiplexed-fluorescent signals, tumor stromal populations can be traced, enumerated and characterized based on marker staining.¹     

Chemical Constituents from a Soil‐Derived Actinomycete,Actinomadura miaoliensis BCRC 16873, and Their Inhibitory Activities on Lipopolysaccharide‐Induced Tumor Necrosis Factor Production

An investigation on the secondary metabolites from the BuOH extract of the fermentation broth of the thermotolerant polyester‐degrading actinomycete Actinomadura miaoliensis BCRC 16873 was carried out. One previously undescribed α‐pyrone (=pyran‐2‐one) derivative, designated as miaolienone ( 1 ), and a new butanolide, miaolinolide ( 2 ), together with 13 known compounds, 3 – 15 , were obtained. Their structures were established on the basis of extensive 1D‐ and 2D‐NMR analyses in combination with HR‐MS experiments. In addition, the isolated compounds 1 – 15 were evaluated for the inhibitory effects of the isolates on the production of tumor necrosis factor (TNF‐α) induced by lipopolysaccharide (LPS). Among the isolates, 1 and 2 significantly inhibited TNF‐α production in U937 cells in vitro, and the IC₅₀ values were 0.59 and 0.76 μM , respectively. Compounds 3 – 5 displayed moderate inhibitory activities on LPS‐induced TNF‐α production.     

Chemopreventive and Antioxidant Activity of the Chamazulene‐Rich Essential Oil Obtained from Artemisia arborescens L. Growing on the Isle of La Maddalena,Sardinia, Italy

The essential oils of Artemisia arborescens growing in Sardinia (Italy), collected during three plant growth stages, i.e., from the vegetative stage to post‐blooming time, were characterized. Moreover, the in vitro antiproliferative and antioxidant activities of the oil isolated from aerial parts collected in February were evaluated. The essential oils belonged to the β‐thujone/chamazulene chemotype, notably with the highest amount of chamazulene (ca. 52%) ever detected up to now in the genus Artemisia and, in general, in essential oils. Quantitative variations in the oil composition were observed as the plant passes from the vegetative to the blooming stage. The oil was tested for its potential tumor cell growth‐inhibitory effect on T98G, MDA‐MB 435S, A375, and HCT116 human cell lines, using the MTT (=3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide) assay. The highest activity was observed on A375 and HCT116 cell lines, with IC₅₀ values of 14 μg/ml. Moreover, the in vitro antioxidant and free radical‐scavenging assays revealed the oil to be an effective scavenger of the ABTS radical cation, with an activity comparable to that of Trolox^®. These results support the use of A. arborescens oil for the treatment of inflamed skin conditions. Finally, the composition of the polar fraction of the A. arborescens aerial parts was also examined, and the main component detected was 5‐O‐caffeoylquinic acid, which was identified for the first time in this plant.     

口腔癌中肿瘤出芽与VEGF—C表达及淋巴结转移的相关关系

目的：通过检测肿瘤出芽、淋巴结转移以及血管内皮生长因子-C（VEGF—C）表达水平,分析口腔癌中肿瘤出芽与VEGF—C表达及淋巴结转移的相关关系,为临床治疗提供理论参考。方法：选取2009年1月-2013年1月4年间在我院接受诊治且资料完整63例口腔癌患者作为研究对象,观察肿瘤出芽、VEGF-C表达和淋巴结转移情况,分析相互之间的相关关系。结果：本次纳入研究的患者中,检出肿瘤出芽患者40例,所占比例为63．5％,VEGF—C表达阳性患者39例,阳性率率为61．9％,淋巴结转移患者40例,转移率为63．5％;肿瘤出芽与淋巴结转移的符合率为84．1％,肿瘤出芽与VEGF—C的表达符合率为79．4％,VEGF-C的表达与淋巴结转移发生的符合率为76．2％。肿瘤出芽与淋巴结转移呈正相关,经Spear相关分析,r=0．932,P〈0．05,与VEGF-C的表达也呈正相关,经Spear相关分析,r=0．897,P〈0．05。结论：肿瘤出芽与VEGF—C的表达水平和淋巴结转移均呈正相关关系,可用于预测判断口腔癌淋巴结转移情况。     

腹会阴直肠癌柱状切除术经改良后治疗低位直肠癌的30例临床效果分析

摘要目的：探讨分析改良后的腹会阴直肠癌柱状切除术治疗低位直肠癌,降低局部复发率的临床效果。方法：回顾性分析2010年1月至2012年6月入住我院并采用改进后的腹会阴直肠癌柱状切除术（CAPR）治疗低位直肠癌的患者30例,男性20例,女性10例,年龄为57＋3．8岁,肿瘤分期为T3-T4。结果：采用改进的CAPR能切除更多远端直肠周围组织;切除标本呈柱状;30例均无术中肠穿孔;会阴切口均Ⅰ期愈合;1例发生会阴血清肿;30倒均无盆底会阴疝形成;术后30例直肠环周切缘均无癌残留;术后平均随访2．1±3．1个月,均无局部复发。结论：经改进的腹会阴直肠癌柱状切除术不仅降低了手术的操作难度,扩大了直肠周围的切除范围,降低了术中直肠穿孔率和环周切缘阳性率,从而降低术后局部复发率,该术式值得在临床上进一步推广。