bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential role of HER2‐overexpressing exosomes in countering trastuzumab‐based therapy
Authors: Ciravolo Valentina , Huber Veronica , Ghedini Gaia C. , Venturelli Elisabetta , Bianchi Francesca , Campiglio Manuela , Morelli Daniele , Villa Antonello , Mina Pamela Della , Menard Sylvie , Filipazzi Paola , Rivoltini Licia , Tagliabue Elda , Pupa Serenella M. 
Published: April 2011

AbstractExosomes are endosome‐derived nanovesicles actively released into the extracellular environment and biological fluids, both under physiological and pathological conditions, by different cell types. We characterized exosomes constitutively secreted by HER2‐overexpressing breast carcinoma cell lines and analyzed in vitro and in vivo their potential role in interfering with the therapeutic activity of the humanized antibody Trastuzumab and the dual tyrosine kinase inhibitor (TKI) Lapatinib anti‐HER2 biodrugs. We show that exosomes released by the HER2‐overexpressing tumor cell lines SKBR3 and BT474 express a full‐length HER2 molecule that is also activated, although to a lesser extent than in the originating cells. Release of these exosomes was significantly modulated by the growth factors EGF and heregulin, two of the known HER2 receptor‐activating ligands and naturally present in the surrounding tumor microenvironment. Exosomes secreted either in HER2‐positive tumor cell‐conditioned supernatants or in breast cancer patients' serum bound to Trastuzumab. Functional assays revealed that both xenogeneic and autologous HER2‐positive nanovesicles, but not HER2‐negative ones, inhibited Trastuzumab activity on SKBR3 cell proliferation. By contrast, Lapatinib activity on SKBR3 cell proliferation was unaffected by the presence of autologous exosomes. Together, these findings point to the role of HER2‐positive exosomes in modulating sensitivity to Trastuzumab, and, consequently, to HER2‐driven tumor aggressiveness. J. Cell. Physiol. 227: 658–667, 2012. © 2011 Wiley Periodicals, Inc.
Urokinase induces stromal cell‐derived factor‐1 expression in human hepatocellular carcinoma cells
Authors: Hsu Wen‐Hsiu , Chen Cheng‐Nan , Huang Hai‐I , Lai Yi‐Liang , Teng Chun‐Yuh , Kuo Wu‐Hsien 
Published: April 2011

AbstractBoth the urokinase‐type plasminogen activator (uPA) and the uPA receptor (uPAR) play important roles with regard to hepatocellular carcinoma (HCC) progression and metastasis. Notably, the stromal cell‐derived factor‐1 (SDF‐1) is an important chemokine involved in HCC pathology. However, the influence of uPA on SDF‐1 expression in human HCC cells remains unknown. We investigated the mechanisms underlying the modulation of SDF‐1 expression through uPA stimulation in human HCC SK‐Hep‐1 cells. SK‐Hep‐1 cells stimulation with uPA induced increases in the expression and secretion of SDF‐1. By using specific inhibitors and small interfering RNA, we have demonstrated that the activation of extracellular signal‐related kinase (ERK) and c‐Jun‐NH2‐terminal kinase (JNK) pathways are critical for uPA‐induced SDF‐1 expression. Transcription factor ELISA and chromatin immunoprecipitation assays suggest that uPA increase Sp1‐ and AP‐1‐DNA‐binding activities in SK‐Hep‐1 cells. Inhibition of Sp1 and AP‐1 activations by specific siRNAs blocked the uPA‐induced SDF‐1 promoter activity and expression. The effect of uPA on SK‐Hep‐1 signaling and SDF‐1 expression is mediated by uPAR. In summary, our findings serve to elucidate the uPA/uPAR downstream signaling, providing new insight into the function of uPA in HCC cells. J. Cell. Physiol. 227: 697–704, 2012. © 2011 Wiley Periodicals, Inc.
The tumor suppressor role of CTCF
Authors: Fiorentino Francesco Paolo , Giordano Antonio 
Published: April 2011

AbstractCTCF is an evolutionary conserved and ubiquitously expressed protein that binds thousands of sites in the human genome. Ectopic expression of CTCF in various normal and tumoral human cell lines inhibits cell division and clonogenicity, with the consequence to consider CTCF a potential tumor‐suppressor factor. In this review article, we focused on the molecular mechanisms engaged by CTCF to modulate the expression of several key‐regulators of differentiation, cellular senescence, cell cycle control and progression, whose expression is frequently altered in tumors. Moreover, we discussed common features of CTCF at each tumor‐related DNA‐binding sequence, such as protein‐partners, post‐translational modifications, and distinctive epigenetic marks establishment. The investigation of the molecular mechanisms engaged by CTCF to modulate tumor‐related genes emphasizes the cell‐type dependency of its tumor suppressor role. Indeed, the ability of CTCF to bind their promoters strictly depends by cell‐type features as DNA methylation, BORIS‐binding and post‐translational modifications as PARYlation. J. Cell. Physiol. 227: 479–492, 2012. © 2011 Wiley Periodicals, Inc.
Cdk5 mediates vimentin ser56 phosphorylation during GTP‐induced secretion by neutrophils
Authors: Lee Ki‐Young , Liu Lijuan , Jin Yan , Fu Song‐bin , Rosales Jesusa L. 
Published: April 2011

AbstractSecretion by neutrophils contributes to acute inflammation following injury or infection. Vimentin has been shown to be important for secretion by neutrophils but little is known about its dynamics during secretion, which is regulated by cyclin‐dependent kinase 5 (Cdk5). In this study, we sought to examine the vimentin dynamics and its potential regulation by Cdk5 during neutrophil secretion. We show that vimentin is a Cdk5 substrate that is specifically phosphorylated at Ser56. In response to neutrophil stimulation with GTP, vimentin Ser56 was phosphorylated and colocalized with Cdk5 in the cytoplasmic compartment. Vimentin pSer56 and Cdk5 colocalization was consistent with coimmunoprecipitation from stimulated cells. Vimentin Ser56 phosphorylation occurred immediately after stimulation, and a remarkable increase in phosphorylation was noted later in the secretory process. Decreased GTP‐induced vimentin Ser56 phosphorylation and secretion resulted from inhibition of Cdk5 activity by roscovitine or olomoucine or by depletion of Cdk5 by siRNA, suggesting that GTP‐induced Cdk5‐mediated vimentin Ser56 phosphorylation may be related to GTP‐induced Cdk5‐mediated secretion by neutrophils. Indeed, inhibition of vimentin Ser56 phosphorylation led to a corresponding inhibition of GTP‐induced secretion, indicating a link between these two events. While fMLP also induced vimentin Ser56 phosphorylation, such phosphorylation was unaffected by roscovitine, which nonetheless, inhibited secretion, suggesting that Cdk5 regulates fMLP‐induced secretion via a mechanism independent of Cdk5‐mediated vimentin Ser56 phosphorylation. These findings demonstrate the distinct involvement of Cdk5 in GTP‐ and fMLP‐induced secretion by neutrophils, and support the notion that specific targeting of Cdk5 may serve to inhibit the neutrophil secretory process. J. Cell. Physiol. 227: 739–750, 2012. © 2011 Wiley Periodicals, Inc.
PAI‐1 in tissue fibrosis
Authors: Ghosh Asish K. , Vaughan Douglas E. 
Published: April 2011

AbstractFibrosis is defined as a fibroproliferative or abnormal fibroblast activation‐related disease. Deregulation of wound healing leads to hyperactivation of fibroblasts and excessive accumulation of extracellular matrix (ECM) proteins in the wound area, the pathological manifestation of fibrosis. The accumulation of excessive levels of collagen in the ECM depends on two factors: an increased rate of collagen synthesis and or decreased rate of collagen degradation by cellular proteolytic activities. The urokinase/tissue type plasminogen activator (uPA/tPA) and plasmin play significant roles in the cellular proteolytic degradation of ECM proteins and the maintenance of tissue homeostasis. The activities of uPA/tPA/plasmin and plasmin‐dependent MMPs rely mostly on the activity of a potent inhibitor of uPA/tPA, plasminogen activator inhibitor‐1 (PAI‐1). Under normal physiologic conditions, PAI‐1 controls the activities of uPA/tPA/plasmin/MMP proteolytic activities and thus maintains the tissue homeostasis. During wound healing, elevated levels of PAI‐1 inhibit uPA/tPA/plasmin and plasmin‐dependent MMP activities, and, thus, help expedite wound healing. In contrast to this scenario, under pathologic conditions, excessive PAI‐1 contributes to excessive accumulation of collagen and other ECM protein in the wound area, and thus preserves scarring. While the level of PAI‐1 is significantly elevated in fibrotic tissues, lack of PAI‐1 protects different organs from fibrosis in response to injury‐related profibrotic signals. Thus, PAI‐1 is implicated in the pathology of fibrosis in different organs including the heart, lung, kidney, liver, and skin. Paradoxically, PAI‐1 deficiency promotes spontaneous cardiac‐selective fibrosis. In this review, we discuss the significance of PAI‐1 in the pathogenesis of fibrosis in multiple organs. J. Cell. Physiol. 227: 493–507, 2012. © 2011 Wiley Periodicals, Inc.
Regulation of endothelial barrier function by TGF‐β type I receptor ALK5: Potential role of contractile mechanisms and heat shock protein 90
Authors: Antonov Alexander S. , Antonova Galina N. , Fujii Makiko , ten Dijke Peter , Handa Vaishali , Catravas John D. , Verin Alexander D. 
Published: April 2011

AbstractMultifunctional cytokine transforming growth factor‐beta (TGF‐β1) plays a critical role in the pathogenesis of acute lung inflammation by controlling endothelial monolayer permeability. TGF‐β1 regulates endothelial cell (EC) functions via two distinct receptors, activin receptor‐like kinase 1 (ALK1) and activin receptor‐like kinase 5 (ALK5). The precise roles of ALK1 and ALK5 in the regulation of TGF‐β1‐induced lung endothelium dysfunction remain mostly unknown. We now report that adenoviral infection with constitutively active ALK5 (caALK5), but not caALK1, induces EC retraction and that this receptor predominantly controls EC permeability. We demonstrate that ubiquitinated ALK5 and phosphorylated heat shock protein 27 (phospho‐Hsp27) specifically accumulate in the cytoskeleton fraction, which parallels with microtubule collapse, cortical actin disassembly and increased EC permeability. We have found that ALK1 and ALK5 interact with heat shock protein 90 (Hsp90). Moreover, the Hsp90 inhibitor radicicol (RA) prevents accumulation of ubiquitinated caALK5 and phospho‐Hsp27 in the cytoskeletal fraction and restore the decreased EC permeability induced by caALK5. We hypothesize that specific translocation of ubiquitinated ALK5 receptor into the cytoskeleton compartment due to its lack of degradation is the mechanism that causes the divergence of caALK1 and caALK5 signaling. J. Cell. Physiol. 227: 759–771, 2012. © 2011 Wiley Periodicals, Inc.
Biological AFM: where we come from – where we are – where we may go
Authors: Casuso Ignacio , Rico Felix , Scheuring Simon 
Published: April 2011

AbstractBiological atomic force microscopy (AFM) is a fast growing and advancing field. This review's objective is to overview the state of the art and to retrace achievements of biological AFM as presented by past and present research, and wishes to give a (subjective) outlook where AFM may go in the upcoming years. The following areas of interest are discussed: High‐resolution imaging, cell imaging, single molecule force spectroscopy, cell mechanical measurements, combined AFM instrumentation, and AFM instrumentation. Of all these topics, particular representative examples are shown, each of them standing for a variety of achievements by many research groups. Copyright © 2011 John Wiley & Sons, Ltd.
Outcomes of hepatic resection for huge hepatocellular carcinoma (≥10 cm in diameter)
Authors: Yamashita Yo‐ichi , Taketomi Akinobu , Shirabe Ken , Aishima Shinichi , Tsuijita Eiji , Morita Kazutoyo , Kayashima Hiroto , Maehara Yoshihiko 
Published: April 2011

AbstractBackgroundThe object of the current study was to review the outcomes of hepatic resection for hepatocellular carcinoma (HCC) ≥ 10 cm.MethodsBetween 1995 and 2007, fifty‐three patients with HCC ≥ 10 cm underwent hepatic resection, and clinical data were compared to those of patients with non‐surgical treatment (n = 12). Surgical results for HCC ≥ 10 cm were compared to those of patients with HCC < 10 cm (n = 412). The independent poor prognostic factors of the patients with HCC ≥ 10 cm were identified.ResultsOverall survival was significantly better in patients with hepatic resection for HCC ≥ 10 cm than in those with non‐surgical treatment (P < 0.01). Survival rates of patients with hepatic resection for HCC ≥ 10 cm were 35% at 5 years. Morbidity and mortality rate were statistically equal. The independent poor prognostic factors of patients with hepatic resection for HCC ≥ 10 cm were revealed: T4 status, macroscopic tumor thrombus in portal vein (VP+), and the use of intra‐operative transfusion.ConclusionHepatic resections for HCC ≥ 10 cm are safe and efficacious. Minimizing intra‐operative blood loss and the establishment of an effective systemic treatment for patients with HCC ≥ 10 cm in T4 appear to be critical. J. Surg. Oncol. 2011; 104:292–298. © 2011 Wiley‐Liss, Inc.
Unresectable peritoneal carcinomatosis from colorectal cancer: A single center experience
Authors: Hompes Daphne , Boot Henk , van Tinteren Harm , Verwaal Victor 
Published: April 2011

AbstractBackground and objectivesFor unresectable peritoneal carcinomatosis (PC) median overall survival (OS) is 5–6 months. This article analyzes patients with PC from colorectal cancer (CRC) uneligible for debulking and hyperthermic intra‐peritoneal chemotherapy, describing patient‐ and tumor‐related factors possibly affecting survival.Patients and MethodsFrom 2005 to 2009, 43 patients presented with unresectable PC from CRC: male/female ratio was 29/14, median age was 57.1 years (range 34.8–76.8). “Unresectability” was defined as: six to seven abdominal regions affected by PC, involvement of mesentery or small bowel in the PC, presence of liver metastases, retroperitoneal lymph nodes, vascular invasion, and/or neural invasion.ResultsMedian time interval between diagnosis of the primary tumor and diagnosis of PC was 7.2 months (range 0.0–102.3). Primary tumors were right‐sided in >50% and had been previously resected in >58%, 74.4% of PC occurred synchronously. Ascites was present at primary diagnosis in 37.2%. In 70% of cases, six to seven abdominal regions were affected and in 58.1% PC involved small bowel/mesentery. Systemic disease was present in 16.3%. In 18.6% of patients, a palliative diversion or ostomy was constructed.Median OS was 6.3 months (range 0.4–33.1). Thirty‐one patients (72.1%) received palliative chemotherapy. Median OS was 9.3 months (range 0.9–33.1) with versus 3.1 months (range 0.4–6.5) without chemotherapy (P = 0.000), with less favorable patient and tumor characteristics in the latter group. No other factors clearly influenced OS.ConclusionPalliative chemotherapy results in better OS, but this is probably attributable to factors influencing the patient's general condition. J. Surg. Oncol. 2011; 104: 269–273. © 2011 Wiley‐Liss, Inc.
Class II radical hysterectomy for stage I–IIA cervix cancer: Prognostic factors associated to recurrence and survival in a northeast Brazil experience
Authors: Bezerra Artur Lício Rocha , Martins Mário Rino , Bezerra Simone Maria Muniz da Silva , Figueiroa José Natal , Batista Thales Paulo 
Published: April 2011

AbstractBackgroundThe main aim of this study was describe the author's experience with class II radical hysterectomy and pelvic lymphadenectomy to treat stage I–IIA cervix cancer and reexamine some prognostic factors associated with disease recurrence and patient survival in this data from northeast Brazil.MethodsA cross‐sectional study was carried out on patients treated at our Centers from January 2001 to December 2008. Statistical analyses were performed using conventional methods.ResultsEighty‐eight patients were selected to analysis. Over the 7.3‐year follow‐up, 80 (91%) patients were alive and 8 (9%) disease recurrences were observed. Overall 1‐, 2‐, and 5‐year patients survival was 96.5%, 95.3%, and 84%, respectively. Recurrence was associated to tumor size ≥1 cm (P = 0.021) and compromised vaginal margin (P = 0.020). Lower survivals were associated to tumor size ≥1 cm (P = 0.038), compromised vaginal margin (P < 0.001), and lymph node metastasis (P = 0.024). Postoperative complications (n = 11) included wound infection (5.7%), partial wound dehiscence (3.4%), and bladder atony (3.4%).ConclusionsClass II radical hysterectomy has provided appropriated disease control of cervix cancer with low morbidity in our experience. Furthermore, tumor size and compromised vaginal margin were significantly associated to recurrence. These factors and lymph node metastasis were also associated to lower 5‐year survival according to our analysis. J. Surg. Oncol. 2011; 104:255–259. © 2011 Wiley‐Liss, Inc.
Origin and maintenance of the intestinal cancer stem cell
Authors: Davies Emma J. , Marsh Victoria , Clarke Alan R. 
Published: April 2011

AbstractColorectal cancer is one of the most common cancers in the western world and its incidence is steadily increasing. Understanding the basic biology of both the normal intestine and of intestinal tumorigenesis is vital for developing appropriate and effective cancer therapies. However, relatively little is known about the normal intestinal stem cell or the hypothetical intestinal cancer stem cell, and there is much debate surrounding these areas. This review briefly describes our current understanding of the properties of both the intestinal stem cell and the intestinal cancer stem cell. We also discuss recent theories regarding the origin of the intestinal cancer stem cell, and the signals required for its maintenance and proliferation. Finally, we place the relevance of cancer stem cell research into context by discussing potential clinical applications of targeting the intestinal cancer stem cell. © 2011 Wiley‐Liss, Inc.
Proteasomal non‐catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas
Authors: Matsuyama Yasushi , Suzuki Motoshi , Arima Chinatsu , Huang Qin Miao , Tomida Shuta , Takeuchi Toshiyuki , Sugiyama Ryoji , Itoh Yasutomo , Yatabe Yasushi , Goto Hidemi , Takahashi Takashi 
Published: April 2011

AbstractWe previously identified PSMD2, a subunit of the 19S regulatory complex of proteasomes, as a constituent of a signature associated with the acquisition of metastatic phenotype and poor prognosis in lung cancers. In the present study, we found that knockdown of PSMD2 decreased proteasome activity, and induced growth inhibition and apoptosis in lung cancer cell lines. These effects of siRNA‐mediated PSMD2 inhibition were associated with changes in the balance between phosphorylated AKT and p38, as well as with induction of p21. In addition, patients with higher PSMD2 expression had poorer prognosis and a small fraction of lung cancer specimens carried increased copies of PSMD2. Notably, our findings clearly illustrate that lung adenocarcinomas can be divided into two groups; those with and without general upregulation of proteasome pathway genes including PSMD2. This general upregulation was significantly more prevalent in the non‐terminal respiratory unit (non‐TRU)‐type, a recently proposed genetically and clinicopathologically relevant expression profile‐defined classification of adenocarcinomas (P < 0.001 by Fisher's exact test). Patients with adenocarcinomas with general upregulation had significantly shorter survival after potentially curative resection (P = 0.0001 by log‐rank test) independent of disease stage, as shown by multivariate Cox regression analysis. Our results suggest that PSMD2 may be a good molecular target candidate and that other co‐regulated proteasome pathway genes and/or their common regulator(s) might also be potential targets, warranting future study including elucidation of the underlying common regulatory mechanism. © 2011 Wiley‐Liss, Inc.
Mechanistic basis for the chemopreventive effects of black raspberries at a late stage of rat esophageal carcinogenesis
Authors: Wang Li‐Shu , Dombkowski Alan A. , Seguin Claire , Rocha Claudia , Cukovic Daniela , Mukundan Anju , Henry Cassandra , Stoner Gary D. 
Published: April 2011

AbstractThe present study used a postinitiation protocol to investigate molecular mechanisms by which black raspberries (BRBs) influence the late stages of N‐nitrosomethylbenzylamine (NMBA)‐induced esophageal tumorigenesis in rats. F344 rats were injected with NMBA and then fed either control diet or a diet containing 5% BRB powder. Control rats were injected with DMSO/water (20:80), the vehicle for NMBA. Esophagi from control, NMBA‐ and NMBA + BRB‐treated rats were collected at 35 wk for histopathological, molecular, and immunohistochemical analyses. Treatment with 5% BRBs reduced the number of dysplastic lesions and the number and size of esophageal papillomas in NMBA‐treated rats. When compared to esophagi from control rats, NMBA treatment led to the differential expression of 4807 genes in preneoplastic esophagus (PE) and 17 846 genes in esophageal papillomas. Dietary BRBs modulated 626 of the 4807 differentially expressed genes in PE and 625 of the 17 846 differentially expressed genes in esophageal papillomas towards normal levels of expression. In both PE and in papillomas, BRBs modulated the mRNA expression of genes associated with carbohydrate and lipid metabolism, cell proliferation and death, and inflammation. In these same tissues, BRBs modulated the expression of proteins associated with proliferation, apoptosis, inflammation, angiogenesis, and both cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Interestingly, matrix metalloproteinases involved in tissue invasion and metastasis, and proteins associated with cell–cell adhesion, were also modulated by BRBs. This is the first report of the effects of berries on the expression of genes associated with the late stages of rat esophageal carcinogenesis. © 2011 Wiley‐Liss, Inc.
Ultraviolet B radiation activates NF‐κB and induces iNOS expression in HR‐1 hairless mouse skin: Role of IκB kinase‐β
Authors: Chang Eun‐Jin , Kundu Joydeb Kumar , Liu Lijia , Shin Jun‐Wan , Surh Young‐Joon 
Published: April 2011

AbstractExposure to ultraviolet B (UVB) radiation is known to cause inflammatory tissue damage and skin cancer. One of the molecular links between inflammation and cancer is the eukaryotic transcription factor nuclear factor‐kappaB (NF‐κB), which is known to regulate expression of various pro‐inflammatory genes including inducible nitric oxide synthase (iNOS). The present study was aimed at elucidating the molecular mechanisms underlying UVB‐induced NF‐κB activation and iNOS expression in hairless mouse skin. Irradiation of male HR‐1 hairless mouse skin with UVB (5 kJ/m2) resulted in increased degradation of IκBα, nuclear translocation of p65 and p50, and the DNA binding of NF‐κB. Exposure to UVB radiation induced the phosphorylation and the catalytic activity of an upstream kinase IκB kinase‐β (IKKβ). Pharmacological inhibition of IKKβ attenuated UVB‐induced NF‐κB activation in mouse skin. Irradiation of mouse skin with UVB also increased phosphorylation of extracellular signal‐regulated kinase (ERK) and p38 mitogen‐activated protein (MAP) kinase. Pretreatment with SC‐514, a specific inhibitor of IKKβ, attenuated UVB‐induced phosphorylation of ERK and p38 MAP kinase. A kinetic study showed that UVB significantly increased the expression of iNOS in mouse skin at 6 h postirradiation, which was abrogated by pretreatment with SC‐514. In conclusion, the upstream kinase IKKβ is involved in UVB‐induced activation of MAP kinases and NF‐κB, and expression of iNOS in mouse skin. © 2011 Wiley‐Liss, Inc.