Identification of four distinct regions of allelic imbalances on chromosome 1 by the combined comparative genomic hybridization and microsatellite analysis on hepatocellular carcinoma.

Frequent chromosome 1 abnormalities detected in human hepatocellular carcinoma have been implicated in early genetic events of liver carcinogenesis. Recurrent loss of 1p with a common deleted region 1p36-p34 has been reported from microsatellite analysis, whereas common gain of the whole chromosome q-arm was described from several comparative genomic hybridization studies. The relationships between copy number changes and allelic status however remains unclear. In this study, we have conducted a simultaneous comparative genomic hybridization and microsatellite analysis study on chromosome 1 in 31 hepatocellular carcinoma cases. Microsatellite analysis revealed frequent loss of heterozygosity on 1p at loci D1S468 (74%), D1S450 (67%), D1S2667 (65%), D1S2697 (75%), D1S199 (52%), and D1S234 (67%) corresponded to the distal 1p36 region and coincided with 12 cases (86%) that presented losses on 1p by comparative genomic hybridization analysis. Although comparative genomic hybridization indicated a common deleted region of 1p36-p35 in the current series, microsatellite analysis has refined the smallest overlapping region (SOR) to 1p36.13-p36.22. Gain of 1q as revealed by comparative genomic hybridization suggested low and high-level gains, and cases that displayed an amplicon below the heterochromatic region 1q21-q25. Common allelic imbalances of polymorphic markers D1S2635 (64%), D1S484 (67%), D1S2878 (65%), D1S196 (70%), D1S249 (64%) D1S2785 (75%), D1S2842 (73%) and D1S2836 (74%) that corresponded to the regions 1q23.1-q24.2, 1q32.1 and 1q43-q44 were detected. Three distinct regions of allelic imbalances were thus suggested on recurring 1q gain found in hepatocellular carcinoma. Furthermore, microsatellite analysis has enabled a mapping of common overrepresented regions and suggested SOR on 1q23.1-q23.3 (D1S2635-D1S2878), 1q25.1-q31.1 (D1S452-D1S238), and 1q43 (D1S2785-D1S2842). Our current study has refined chromosome 1 aberrations in hepatocellular carcinoma to four regions of allelic imbalances. The SORs delineated should provide basis for further molecular investigation in hepatocarcinogenesis on genes residing on these chromosomal regions.     

Regulation of ST2L expression on T helper (Th) type 2 cells

T1/ST2L, an IL-1 receptor homologue, is selectively expressed on murine Th2 cells and specific anti-ST2L antibodies can profoundly modulate the Th1/Th2 balance in vivo. Naive CD4+ T cells do not express ST2L but do so on activation with specific antigen in the presence of IL-4 or when stimulated with low doses of antigen in the absence of exogenously added IL-4. Similarly enhanced ST2L expression occurred after stimulation of Th2 cells with antigen or the mitogen ConA in the presence of APC. Restimulation of Th2 cells in the presence of IFN-gamma led to a decreased expression of ST2L to below basal levels. Conversely, Th2 cells cultured with IL-4 led to increased ST2L expression. The reduced expression of ST2L in response to high doses of antigen is also reversed by the neutralization of IFN-gamma. Using an ST2L promoter/luciferase reporter gene construct, we show that the distal but not proximal ST2L promoter is responsible for specific gene expression in Th2 cells. IL-4 enhances, whereas IFN-gamma suppresses ST2L expression via direct modulation of the distal promoter of the ST2L gene. These data provide a mechanistic explanation for the selective expression of ST2L on Th2 cells.     

Resistance to Leishmania major infection correlates with the induction of nitric oxide synthase in murine macrophages.

Inbred strains of mice differ considerably in their innate resistance to leishmanial infection. BALB/c mice are highly susceptible to cutaneous leishmaniasis caused by Leishmania major, whereas CBA mice are resistant. We now show that this resistance correlates with the ability of macrophages to synthesize nitric oxide (NO) following activation with interferon-gamma or tumor necrosis factor alpha. Furthermore, the larger amounts of NO generated by resistant macrophages are related to higher levels of NO synthase activity, a difference which is not attributable to the number or the affinity of the receptors for interferon-gamma on these cells. The level of NO synthesis by activated macrophages was also correlated to the resistance in a number of other inbred mouse strains tested; macrophages from the resistant B10.S, C57BL and C3H mice produced significantly higher levels of NO than the macrophages from the susceptible BALB.b and DBA/2 mice.     

LES modelling of flow in a simple airway model

Detailed information about the flow field pattern is highly important in accurately predicting particle deposition sites in the human airway. Flow in the upper airway during heavy breathing can have a Reynolds number as high as 9300, and therefore presents turbulent features. Although turbulence is believed to have an important effect on the airflow and other transport processes in the bronchial tree, to date both theoretical and numerical studies have predominantly assumed the flow to be laminar. In this paper, transitional/turbulent flow during inspiration is studied using a large eddy simulation (LES) in a single asymmetric bifurcation model of human upper airway. The influence of the non-laminar flow on the patterns and the particle paths is investigated in both 2D and 3D models. Throughout the investigation, comparisons with the laminar and conventional k- models for the same configuration and flow conditions are made. The LES model is also carefully validated against published experimental data in a stenotic tube model. The results demonstrate that the LES model is capable of capturing instantaneous eddy formation and flow separation in (almost) laminar, transitional and turbulent flow regimes, and hence may be used as a powerful and practical tool to provide much of the detailed flow information required for tracing the particle trajectories and particle deposition in human airways.     

鼻咽癌放疗患者T细胞亚群测定的临床分析

目的探讨鼻咽癌(NPC)分期及放疗对免疫与肿瘤复发、转移及肿瘤退缩的相关性.方法每位病人放疗前及放疗后各测定T细胞亚群指标一次.结果早、晚期鼻咽癌放疗前后T细胞亚群相比,除早期鼻咽癌CD3下降无统计学意义外,余CD3、CD4、CD4/CD8下降;CD8升高均有统计学意义,晚期鼻咽癌的改变尤为突出,有极显著统计学意义(P＜0.001).放疗后肿瘤退缩与否的T细胞亚群测定无统计学意义.放疗后肿瘤有复发或转移者CD4、CD4/CD8下降有极显著统计学意义(P＜0.001).CD8升高有统计学意义.结论T细胞亚群指标的测定,对鼻咽癌患者的免疫功能状况,放疗对免疫功能的影响,对鼻咽癌放疗后复发及转移的可能性判断均有一定的临床意义.     

Potential cancer therapy with the fragile histidine triad gene: review of the preclinical studies.

CONTEXT: The fragile histidine triad gene (FHIT) encompasses a human common fragile site, FRA3B, that is susceptible to environmental carcinogens. Deletion and inactivation of FHIT have been seen in a number of human premalignant and malignant lesions. OBJECTIVE: To review and evaluate preclinical studies of cancer therapy using the FHIT tumor suppressor gene and related studies involving Fhit protein expression. DATA SOURCES: A MEDLINE search of articles published from 1996 to June 2001 was performed; article reference lists were used to retrieve additional relevant articles. STUDY SELECTION: Immunohistochemical studies of primary tumors or relevant lesions were selected to evaluate Fhit expression in premalignant or malignant stages. Preclinical studies on antitumorigenic or therapeutic introduction of FHIT were reviewed for the effects of exogenous Fhit expression. For the immunohistochemical analyses, 26 studies were included that analyzed at least 15 cases of a single type of tumor. For precancerous lesions, 9 studies were included that analyzed at least 4 cases. For studies of FHIT introduction, 9 published studies were included. DATA EXTRACTION: Using primary data from each of the studies, we assessed the rationale and potential contribution of FHIT cancer therapy. Data was independently abstracted by 2 authors and study quality was assessed by 2 other authors. DATA SYNTHESIS: Overall, 60% (1162/1948 cases) of primary tumors showed absent or markedly reduced Fhit protein expression in cancer cells. Studies of preneoplastic lesions or early-stage cancer showed absence or marked reduction of Fhit protein expression in 0% to 93% of samples (overall, 31% [127/408 cases]). Preclinical studies using 26 cancer-derived cell lines from human lung, head and neck, esophageal, gastric, cervical, pancreatic, and kidney cancers, showed that reintroduction of FHIT resulted in inhibition of in vitro tumor cell growth or of in vivo tumorigenicity in 17 (57%) of 30 cell line experiments. Model systems for human preventive cancer therapy suggested that oral introduction of viral vector-mediated FHIT into Fhit-deficient mice may prevent carcinogen-induced tumor development in some cases. CONCLUSION: These findings show that FHIT gene therapy may potentially be clinically useful for treatment of cancer and also prevention of carcinogen-induced tumor development, suggesting a rationale for further research involving FHIT introduction.     

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.     

Assessment of the Long-Term Impact of Pancreatoduodenectomy on Health-Related Quality of Life Using the EORTC QLQ-PAN26 Module

Annals of Surgical Oncology - Long-term pancreatoduodenectomy (PD) survivors have previously reported favorable quality of life (QoL). However, there has been a paucity of studies utilizing...