bluuebunny/crossref_metadata_2025 huggingface dataset:
Aqueous Extract ofAgaricus blazeiMurrill Prevents Age-Related Changes in the Myenteric Plexus of the Jejunum in Rats
Authors: Santi-Rampazzo Ana Paula de , Schoffen João Paulo Ferreira , Cirilo Carla Possani , Zapater Mariana Cristina Vicente Umada , Vicentini Fernando Augusto , Soares Andréia Assunção , Peralta Rosane Marina , Bracht Adelar , Buttow Nilza Cristina , Natali Maria Raquel Marçal
Published: April 2015

This study evaluated the effects of the supplementation with aqueous extract ofAgaricus blazeiMurrill (ABM) on biometric and blood parameters and quantitative morphology of the myenteric plexus and jejunal wall in aging Wistar rats. The animals were euthanized at 7 (C7), 12 (C12 and CA12), and 23 months of age (C23 and CA23). The CA12 and CA23 groups received a daily dose of ABM extract (26 mg/animal) via gavage, beginning at 7 months of age. A reduction in food intake was observed with aging, with increases in the Lee index, retroperitoneal fat, intestinal length, and levels of total cholesterol and total proteins. Aging led to a reduction of the total wall thickness, mucosa tunic, villus height, crypt depth, and number of goblet cells. In the myenteric plexus, aging quantitatively decreased the population of HuC/D+neuronal and S100+glial cells, with maintenance of the nNOS+nitrergic subpopulation and increase in the cell body area of these populations. Supplementation with the ABM extract preserved the myenteric plexus in old animals, in which no differences were detected in the density and cell body profile of neurons and glial cells in the CA12 and CA23 groups, compared with C7 group. The supplementation with the aqueous extract of ABM efficiently maintained myenteric plexus homeostasis, which positively influenced the physiology and prevented the death of the neurons and glial cells.
Antifibrotic Activity of Acylated and Unacylated Ghrelin
Authors: Angelino Elia , Reano Simone , Ferrara Michele , Agosti Emanuela , Graziani Andrea , Filigheddu Nicoletta
Published: April 2015

Fibrosis can affect almost all tissues and organs, it often represents the terminal stage of chronic diseases, and it is regarded as a major health issue for which efficient therapies are needed. Tissue injury, by inducing necrosis/apoptosis, triggers inflammatory response that, in turn, promotes fibroblast activation and pathological deposition of extracellular matrix. Acylated and unacylated ghrelin are the main products of the ghrelin gene. The acylated form, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Although unacylated ghrelin does not bind or activate GHSR-1a, it shares with the acylated form several biological activities. Ghrelin peptides exhibit anti-inflammatory, antioxidative, and antiapoptotic activities, suggesting that they might represent an efficient approach to prevent or reduce fibrosis. The aim of this review is to summarize the available evidence regarding the effects of acylated and unacylated ghrelin on different pathologies and experimental models in which fibrosis is a predominant characteristic.
Protective Effect ofHericium erinaceuson Alcohol Induced Hepatotoxicity in Mice
Authors: Hao Lijun , Xie Yuxi , Wu Guikai , Cheng Aibin , Liu Xiaogang , Zheng Rongjuan , Huo Hong , Zhang Junwei
Published: April 2015

We investigated the effects ofHericium erinaceus(HEM) on liver injury induced by acute alcohol administration in mice. Mice received ethanol (5 g/kg BW) by gavage every 12 hrs for a total of 3 doses. HEM (200 mg/kg BW) was gavage before ethanol administration. Subsequent serum alanine aminotransferase (ALT) level, aspartate aminotransaminase (AST) level, Maleic dialdehyde (MDA) level, hepatic total antioxidant status (TAOS), and activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were determined by ELISA and immunohistochemistry, respectively. HEM administration markedly(P<0.05)decreased serum ALT, AST, and MDA levels. The hepatic histopathological observations showed that HEM had a relatively significant role in mice model, which had alcoholic liver damage. In conclusion, we observed that HEM (200 mg/kg BW) supplementation could restrain the hepatic damage caused by acute alcohol exposure.
Construction, Expression, and Characterization of a Recombinant Immunotoxin Targeting EpCAM
Authors: Lv Minghua , Qiu Feng , Li Tingting , Sun Yuanjie , Zhang Chunmei , Zhu Ping , Qi Xiaokun , Wan Jun , Yang Kun , Zhang Kui
Published: April 2015

Epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein overexpressed in human epithelioma but with relatively low expression in normal epithelial tissues. To exploit this differential expression pattern for targeted cancer therapy, an EpCAM‐targeted immunotoxin was developed and its antitumor activity was investigated in vitro. An immunotoxin (scFv2A9‐PE or APE) was constructed by genetically fusing a truncated form (PE38KDEL) of Pseudomonas aeruginosa exotoxin with an anti‐EpCAM single‐chain variable fragment (scFv). ELISA and flow cytometry were performed to verify immunotoxin (scFv2A9‐PE or APE) antigen‐binding activity with EpCAM. Cytotoxicity was measured by MTT assay. Confocal microscopy was used to observe its cellular localization. The results of ELISA and flow cytometry revealed that the immunotoxin efficiently recognized recombinant and natural EpCAM. Its antigen‐binding activity was relatively lower than 2A9. MTT assay confirmed potent reduction in EpCAM‐positive HHCC (human hepatocellular carcinoma) cell viability (IC50 50 pM). Immunofluorescence revealed that the immunotoxin localized to endoplasmic reticulum 24 h later. In conclusion, we described the development of an EpCAM‐targeted immunotoxin with potent activity against tumor cells, which may lay the foundation for future development of therapeutic antibody for the treatment of EpCAM‐positive tumors.
The Evaluation of Plasma and Leukocytic IL‐37 Expression in Early Inflammation in Patients with Acute ST‐Segment Elevation Myocardial Infarction after PCI
Authors: Wang Xin , Cai Xiangna , Chen Lan , Xu Duanmin , Li Jilin
Published: April 2015

Objective. Acute ST‐segment elevation myocardial infarction (ASTEMI) is accompanied by increased expression of inflammation and decreased expression of anti‐inflammation. IL‐37 was found to be involved in the atherosclerosis‐related diseases and increased in acute coronary syndrome. However, the level of IL‐37 in blood plasma and leukocytes from patients with ASTEMI after percutaneous coronary intervention (PCI) has not been explored. Methods. We collected peripheral venous blood from consented patients at 12 h, 24 h, and 48 h after PCI and healthy volunteers. Plasma IL‐37, IL‐18, IL‐18‐binding protein (BP), and high sensitive C reaction protein (hs‐CRP) were quantified by ELISA and leukocytic IL‐37 and ICAM‐1 by immunoblotting. Results. Plasma IL‐37, IL‐18, and IL‐18 BP expression decreased compared to those in healthy volunteers while hs‐CRP level was high. Both leukocytic IL‐37 and ICAM‐1 were highest expressed at 12 h point but significantly decreased at 48 h point. Conclusion. These findings suggest L‐37 does not play an important role in the systematic inflammatory response but may be involved in leukocytic inflammation in ASTEMI after PCI.
The Combination of N‐Acetyl Cysteine, Alpha‐Lipoic Acid, and Bromelain Shows High Anti‐Inflammatory Properties in Novel In Vivo and In Vitro Models of Endometriosis
Authors: Agostinis C. , Zorzet S. , De Leo R. , Zauli G. , De Seta F. , Bulla R.
Published: April 2015

To evaluate the efficacy of an association of N‐acetyl cystein, alpha‐lipoic acid, and bromelain (NAC/LA/Br) in the treatment of endometriosis we set up a new in vivo murine model. We explored the anti‐inflammatory and proapoptotic effect of this combination on human endometriotic endothelial cells (EECs) and on endothelial cells isolated from normal uterus (UtMECs). We implanted fragments of human endometriotic cysts intraperitoneally into SCID mice to evaluate the efficacy of NAC/LA/Br treatment. UtMECs and EECs, untreated or treated with NAC/LA/Br, were activated with the proinflammatory stimulus TNF‐α and their response in terms of VCAM1 expression was evaluated. The proapoptotic effect of higher doses of NAC/LA/Br on UtMECs and EECs was measured with a fluorogenic substrate for activated caspases 3 and 7. The preincubation of EECs with NAC/LA/Br prior to cell stimulation with TNF‐α prevents the upregulation of the expression of the inflammatory “marker” VCAM1. Furthermore NAC/LA/Br were able to induce EEC, but not UtMEC, apoptosis. Finally, the novel mouse model allowed us to demonstrate that mice treated with NAC/LA/Br presented a lower number of cysts, smaller in size, compared to untreated mice. Our findings suggest that these dietary supplements may have potential therapeutic uses in the treatment of chronic inflammatory diseases like endometriosis.
Combined Label-Free Quantitative Proteomics and microRNA Expression Analysis of Breast Cancer Unravel Molecular Differences with Clinical Implications
Authors: Gámez-Pozo Angelo , Berges-Soria Julia , Arevalillo Jorge M. , Nanni Paolo , López-Vacas Rocío , Navarro Hilario , Grossmann Jonas , Castaneda Carlos A. , Main Paloma , Díaz-Almirón Mariana , Espinosa Enrique , Ciruelos Eva , Fresno Vara Juan Ángel
Published: April 2015

Better knowledge of the biology of breast cancer has allowed the use of new targeted therapies, leading to improved outcome. High-throughput technologies allow deepening into the molecular architecture of breast cancer, integrating different levels of information, which is important if it helps in making clinical decisions. microRNA (miRNA) and protein expression profiles were obtained from 71 estrogen receptor–positive (ER+) and 25 triple-negative breast cancer (TNBC) samples. RNA and proteins obtained from formalin-fixed, paraffin-embedded tumors were analyzed by RT-qPCR and LC/MS-MS, respectively. We applied probabilistic graphical models representing complex biologic systems as networks, confirming that ER+ and TNBC subtypes are distinct biologic entities. The integration of miRNA and protein expression data unravels molecular processes that can be related to differences in the genesis and clinical evolution of these types of breast cancer. Our results confirm that TNBC has a unique metabolic profile that may be exploited for therapeutic intervention. Cancer Res; 75(11); 2243–53. ©2015 AACR.
Grapefruit-Derived Nanovectors Use an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites
Authors: Wang Qilong , Ren Yi , Mu Jingyao , Egilmez Nejat K. , Zhuang Xiaoyin , Deng Zhongbin , Zhang Lifeng , Yan Jun , Miller Donald , Zhang Huang-Ge
Published: April 2015

Inflammation is a hallmark of cancer. Activated immune cells are intrinsically capable of homing to inflammatory sites. Using three inflammatory-driven disease mouse models, we show that grapefruit-derived nanovectors (GNV) coated with inflammatory-related receptor enriched membranes of activated leukocytes (IGNVs) are enhanced for homing to inflammatory tumor tissues. Blocking LFA-1 or CXCR1 and CXCR2 on the IGNVs significantly inhibits IGNV homing to the inflammatory tissue. The therapeutic potential of IGNVs was further demonstrated by enhancing the chemotherapeutic effect as shown by inhibition of tumor growth in two tumor models and inhibiting the inflammatory effects of dextran sulfate sodium-induced mouse colitis. The fact that IGNVs are capable of homing to inflammatory tissue and that chemokines are overexpressed in diseased human tissue provides the rationale for using IGNVs to more directly deliver therapeutic agents to inflammatory tumor sites and the rationale for the use of IGNVs as treatment for certain cancers in personalized medicine. Cancer Res; 75(12); 2520–9. ©2015 AACR.
Daurinol Enhances the Efficacy of Radiotherapy in Lung Cancer via Suppression of Aurora Kinase A/B Expression
Authors: Woo Jong Kyu , Kang Ju-Hee , Shin DongYun , Park Seong-Hyeok , Kang Kyungsu , Nho Chu Won , Seong Je Kyung , Lee Sang-Jin , Oh Seung Hyun
Published: April 2015

The aurora kinases constitute one family of serine/threonine kinases whose activity is essential for mitotic progression. The aurora kinases are frequently upregulated in human cancers and are associated with sensitivity to chemotherapy in certain ones. In the present study, we investigated whether aurora kinases could be a target to overcome radioresistance or enhance the radiosensitivity of lung cancer. For that purpose, we determined the therapeutic potential of daurinol, an investigational topoisomerase inhibitor, alone and in combination with radiation, by observing its effect on aurora kinases. Daurinol decreased cell viability and proliferation in human colon and lung cancer cells. Gene expression in daurinol-treated human colon cancer cells was evaluated using RNA microarray. The mRNA expression of 18 genes involved in the mitotic spindle check point, including aurora kinase A (AURKA) and aurora kinase B (AURKB), was decreased in daurinol-treated human colon cancer cells as compared with vehicle-treated cells. As expected, radiation increased expression levels of AURKA and AURKB. This increase was effectively attenuated by siRNAs against AURKA and AURKB, which suppressed cell growth and increased apoptosis under radiation. Furthermore, the expression of AURKA and AURKB was suppressed by daurinol in the presence or absence of radiation in colon and lung cancer cells. Daurinol alone or in combination with radiation decreased lung cancer growth in xenograft mouse models. Our data clearly confirm the antitumor and radiosensitizing activity of daurinol in human lung cancer cells through the inhibition of AURKA and AURKB. Mol Cancer Ther; 14(7); 1693–704. ©2015 AACR.
INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor
Authors: Kofuji Satoshi , Kimura Hirotaka , Nakanishi Hiroki , Nanjo Hiroshi , Takasuga Shunsuke , Liu Hui , Eguchi Satoshi , Nakamura Ryotaro , Itoh Reietsu , Ueno Noriko , Asanuma Ken , Huang Mingguo , Koizumi Atsushi , Habuchi Tomonori , Yamazaki Masakazu , Suzuki Akira , Sasaki Junko , Sasaki Takehiko
Published: April 2015

Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P3. In vivo, neither inactivation of Inpp4b (Inpp4bΔ/Δ) nor heterozygous deletion of Pten (Pten+/−) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P3 phosphatase activity of INPP4B can function as a “back-up” mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers.

Significance: Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bona fide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P3. Cancer Discov; 5(7); 730–9. ©2015 AACR.

See related commentary by Vo and Fruman, p. 697.

See related article by Chew et al., p. 740.

This article is highlighted in the In This Issue feature, p. 681
Primary Bone Lymphoma: A Clinical Analysis of 17 Patients in a Single Institution
Authors: Hayase Eiko , Kurosawa Mitsutoshi , Suzuki Hiroaki , Kasahara Kohei , Yamakawa Tomohiro , Yonezumi Masakatsu , Suzuki Sachiko , Teshima Takanori
Published: April 2015

Primary bone lymphoma (PBL) comprises less than 1% of all malignant lymphomas. Because few studies of PBL have been conducted in Japan, the characteristics of Japanese patients with PBL have not been fully elucidated. We retrospectively analyzed 17 patients diagnosed with PBL at our institution between 2001 and 2011. Median patient age was 60 years. Eleven patients had diffuse large B-cell lymphoma and 2 patients had T-cell lymphoma histology. The spine was the most frequently involved site at the time of presentation. There were 11 patients with stage IV disease and 11 patients with high or high-intermediate risk according to the International Prognostic Index (IPI). Thirteen patients achieved complete response (CR) after initial treatment. At a median follow-up of 31 months, the 3-year overall survival (OS) and progression free survival were 63.5 and 49.9%, respectively. Localized disease, low or low-intermediate IPI, and CR after initial treatment were associated with a good outcome in patients with PBL and significantly associated with a better OS. Spine involvement and T/NK-cell phenotype are more frequent in Japanese than in Caucasian patients with PBL.
Long-Term Outcome of Endoscopic Radiofrequency Ablation for Ingrowth Thyroglossal Duct Cyst
Authors: Fang Lian , Shan Jing , Zhang Tian-Yu
Published: April 2015

Aims: To evaluate the effectiveness and safety of endoscopic radiofrequency (RF) ablation to treat ingrowth thyroglossal duct cysts (TGDCs). Methods: Between September 2008 and October 2013, 9 patients with ingrowth TGDCs underwent endoscopic RF ablation at our hospital. Their operative time, blood loss, time until recovery of normal diet, postoperative hospitalization time, and recurrence were retrospectively analyzed. Results: In the study, 8 patients underwent an RF procedure of less than 60 min. All patients resumed a normal diet within 48 h after the operation. The operative blood loss was <10 ml in 2 patients, and between 10 and 20 ml in 7 patients. The postoperative pain value was 2 (n = 2) and 3 or 4 (n = 7). Seven patients were discharged home on postoperative day 2 or 3, and 2 patients on postoperative day 4. The postoperative follow-up period was from 14 to 32 months. Only 1 patient suffered recurrence and underwent a modified Sistrunk procedure as a remedy. All patients reported complete resolution of the symptoms in their last follow-up. Conclusions: Endoscopic RF ablation can be considered the preferred choice for treating ingrowth TGDCs because of minimal morbidity and rapid postoperative recovery. However, for lesions involving complicated branches, the modified Sistrunk procedure may be necessary.
Cribriform Adenocarcinoma of the Tongue and Minor Salivary Gland: Transoral Robotic Surgical Resection
Authors: Worrall Douglas M. , Brant Jason A. , Chai Raymond L. , Weinstein Gregory S.
Published: April 2015

Background/Aims: Cribriform adenocarcinoma of the tongue and minor salivary gland (CATMSG) is a rare, locally invasive, and poorly recognized tumor, typically occurring on the base of the tongue. This case report describes the previously unreported use of transoral robotic surgery (TORS) for the local resection of CATMSG in a novel location, the palatine tonsil, and leverages follow-up information to compare TORS to conventional surgical approaches. Methods: We performed transoral radical tonsillectomy, limited pharyngectomy, and base-of-tongue resection with staged left selective neck dissection. Results: Tumor pathology revealed an infiltrating salivary gland carcinoma with perineural invasion and a histologically similar adenocarcinoma in 1 of 64 left neck lymph nodes. TORS was performed with no perioperative complications, and the patient was subsequently discharge on postoperative day 3 with a Dobhoff tube. Postoperatively, the Dobhoff tube was removed at 1 month, the patient was advanced to soft foods by mouth at 2 months, and 3-month positron emission tomography-computed tomography scan showed no evidence of distant metastases and evolving postsurgical changes in the left tonsillectomy bed. Conclusions: This case report highlights the use of TORS resection with minimal acute and long-term morbidity compared to conventional approaches for the resection of this rare, locally invasive salivary gland carcinoma in the palatine tonsil.
Incidence and Risk Factors for Urolithiasis in Patients with Crohn's Disease
Authors: Kim Min Jung , Woo Sook-young , Kim Eun Ran , Hong Sung Noh , Chang Dong Kyung , Rhee Poong-Lyul , Kim Jae J. , Rhee Jong Chul , Kim Young-Ho
Published: April 2015

Background: The incidence of urinary tract calculi is thought to be higher in patients with inflammatory bowel disease (IBD) than that in the general population. However, few data are available about urolithiasis in patients with Crohn's disease (CD). We investigated the incidence of urolithiasis and the risk factors for urolithiasis in patients with CD. Methods: We examined the records of 387 patients with CD followed at Samsung Medical Center from July 2011 to June 2013. Evidence for the presence of calculi was obtained from radiologic findings (plain films, ultrasonography, or computed tomography), urinary colic symptoms, or a treatment history of urolithiasis after diagnosis of CD. Demographic variables, phenotype, concurrent medications, and previous CD-related surgery were analyzed. Results: Urinary tract calculi were found in 18 (4.7%) patients, which developed after the CD diagnosis. The incidence of urolithiasis in CD was 706 per 100,000 patient-years. Cox models with a time-dependent covariate showed that azathioprine (AZA)/6-mercaptopurine (6-MP) treatment (hazard ratio = 0.963; 95% CI: 0.931, 0.996; p = 0.030) was negatively associated with urolithiasis. Conclusions: The annual incidence rate of urolithiasis in patients with CD was 0.7%. AZA/6-MP therapy was associated with a low risk of urolithiasis in these patients.
The Association of CARD8 rs2043211 Polymorphism with Preeclampsia in the Chinese Han Population
Authors: Wang Xuefeng , Liu Mengchun , Liu Zhen , Niu Zhaoyuan , Liu Shiguo
Published: April 2015

Objective: The purpose of our study was to investigate the association between polymorphism of rs2043211 in CARD8 and susceptibility to preeclampsia (PE) in the Chinese Han population. Methods: 261 PE patients and 451 controls were genotyped for rs2043211 with the method of TaqMan allele discrimination assays. Clinical data were collected to perform genotype-phenotype analysis. Results: Our study suggested that the rs2043211 variant was associated with the development of PE in the Chinese Han population. The genotypic and allelic frequencies differed significantly between the two groups (χ2 = 8.198, p = 0.017 by genotype; χ2 = 6.741, p = 0.009 by allele). The T allele was the risk allele for predisposition to PE (OR = 1.331, 95% CI 1.072-1.652). Conclusion: The polymorphism of rs2043211 in CARD8 may be a relevant host susceptibility factor for the development of PE in the Chinese Han population.
Induction of Functional Hepatocyte-Like Cells by Overexpression of FOXA3 and HNF4α in Rat Bone Marrow Mesenchymal Stem Cells
Authors: Dai Keqiang , Chen Ran , Ding Yi , Niu Zhipeng , Fan Jinyu , Xu Cunshuan
Published: April 2015

Liver regeneration has always been of great therapeutic interest, particularly to generate hepatocytes from other types of cells including adult stem cells and induced pluripotent stem cells. In this study, it was found that overexpression of both FOXA3 and HNF4α can convert rat bone marrow mesenchymal stem cells (BMSCs) to functional hepatocyte-like cells (HLCs). The results show that these HLCs had the typical hepatocyte morphology with unique hepatocyte markers such as ALB, G6P, KRT18, TAT, TTR, KRT19 and AFP. Simultaneously, they also exhibited hepatic functions such as glycogen storage, indocyanine green absorption, and cytoplasmic accumulation of neutral triglycerides and lipids. In addition to that, these functions could be maintained in the process of cell culture, thus suggesting that FOXA3 and HNF4α are powerful transcription factors for inducing rat BMSCs to differentiate into functional HLCs, and this study will provide a novel method to generate HLCs.
Efficacy and Safety of Sublingual Immunotherapy for Two Seasons in Patients with Japanese Cedar Pollinosis
Authors: Okamoto Yoshitaka , Okubo Kimihiro , Yonekura Syuji , Hashiguchi Kazuhiro , Goto Minoru , Otsuka Takashi , Murata Tadayuki , Nakao Yuji , Kanazawa Chigiri , Nagakura Hitoshi , Okawa Toru , Nakano Koichi , Hisamitsu Minako , Kaneko Shinya , Konno Akiyoshi
Published: April 2015

Background: Japanese cedar (JC) pollinosis is the most common seasonal allergic rhinitis in Japan. Standardized JC pollen extract is available for subcutaneous immunotherapy, but this treatment is limited by potentially serious side effects. The aim of this double-blind, randomized comparative study was to evaluate the efficacy and safety of standardized JC pollen extract in a new oral formulation (CEDARTOLEN®, Torii Pharmaceutical Co., Ltd., Tokyo, Japan) for sublingual immunotherapy (SLIT) for JC pollinosis. Methods: A total of 531 subjects with JC pollinosis were randomized into 2 groups at a ratio of 1:1 to receive daily sublingual administration of standardized JC pollen extract with a maintenance dose of 2,000 Japanese allergy units (JAU) or placebo for 2 consecutive pollen seasons. The efficacy was evaluated using the total nasal symptom and medication score (TNSMS) as the primary end point. Secondary end points included the total ocular symptom and medication score (TOSMS) and scores for individual symptoms and medication. Results: The TNSMS was significantly lower (p < 0.0001) in the SLIT group than in the placebo group in the peak symptom period by 18 and 30% in the first and second seasons, respectively. All secondary end points were also significantly lower in the SLIT group in both seasons. No systemic anaphylaxis occurred. Conclusions: SLIT with daily administration of standardized JC pollen extract was effective for improving nasal and ocular symptoms of JC pollinosis and reducing the use of relief medication. The JC pollen extract was well tolerated with only local adverse events.
Prognostic Factors in Patients Receiving Neoadjuvant 5-Fluorouracil plus Cisplatin for Advanced Esophageal Cancer (JCOG9907)
Authors: Yokota Tomoya , Ando Nobutoshi , Igaki Hiroyasu , Shinoda Masayuki , Kato Ken , Mizusawa Junki , Katayama Hiroshi , Nakamura Kenichi , Fukuda Haruhiko , Kitagawa Yuko
Published: April 2015

Objective: Neoadjuvant chemotherapy with 5-fluorouracil plus cisplatin and subsequent esophagectomy with two- to three-field lymphadenectomy is a standard treatment for patients with clinical stage II/III squamous cell carcinoma (SCC) of the esophagus. This study investigates the prognostic factors for patients who received neoadjuvant chemotherapy. Methods: Of 164 patients assigned to receive neoadjuvant chemotherapy in the JCOG9907 trial, multivariate analyses were performed for 159 and 149 patients to evaluate the preoperative and the combined preoperative and postoperative prognostic factors, respectively. Results: The multivariate analyses using preoperative factors showed that clinical stage T3 [vs. cT1-2; hazard ratio (HR) 3.60, p = 0.0007] and serum albumin (Alb) <4.0 g/dl (vs. ≥4.0 g/dl; HR 2.29, p = 0.0005) were associated with a poor prognosis. Four independent prognostic factors were identified by multivariate analysis of both preoperative and postoperative factors: pathological curability B (pB; R0 with stage IV or pD < pN) or pC [microscopic or macroscopic residual tumor (R1/R2)] [vs. pA (R0); HR 1.93, p = 0.015], pathological stage N1 (vs. pN0; HR 3.86, p = 0.0012), cT3 (vs. cT1-2; HR 2.80, p = 0.0073), and serum Alb <4.0 g/dl (vs. ≥4.0 g/dl; HR 2.03, p = 0.0069). Conclusions: Preoperative cT stage, Alb, and postoperative pathological findings are independent prognostic factors for patients undergoing neoadjuvant chemotherapy for advanced thoracic esophageal SCC. This analysis may aid in stratification according to individual patient risk.
Experimental Evaluation of Tracheo-Amniotic Shunting for Induced Congenital High Airway Obstruction in a Sheep Model
Authors: DeKoninck Philip , Endo Masayuki , Deprest Jan A. , De Catte Luc
Published: April 2015

Objective: To evaluate the feasibility of tracheo-amniotic shunting in a sheep model for congenital high airway obstruction syndrome. Material and Methods: High airway obstruction was induced around day 95 (term = 145 days) in 10 lamb fetuses by tracheal clipping. Five days later, ultrasound-guided tracheoamniotic shunting was done using either the Harrison double-pigtail bladder stent (HS) or a double-basket device (BS). Caesarean section (CS) was done around day 110. At each time point, the cardiothoracic index (CTI) was measured. Lung-to-body weight ratio (LBWR) was calculated at fetal necropsy. The primary endpoint was successful shunting defined as anatomically correct placement and functional airway decompression; the secondary endpoint was survival until CS. Results: Two sheep aborted 3 fetuses after tracheal occlusion. Overall, the median CTI at CS was significantly smaller compared to baseline [0.52 (interquartile range, IQR: 0.52-0.54) vs. 0.58 (IQR: 0.54-0.63); p = 0.01]. In the HS group (n = 4), none of the shunts were correctly positioned. In the BS group (n = 3), there was 1 correct shunt placement; however, this fetus was stillborn. Median LBWR suggested pulmonary overgrowth [0.10 (IQR: 0.08-0.11)]. Conclusion: In our hands, using this model with a long and mobile neck and relative oligohydramnios, tracheoamniotic shunting for airway obstruction has a high failure rate. If further pursued, alternative techniques or different models should be considered.
Iatrogenic Congenital Diaphragmatic Hernia following Prenatal Pleuroamniotic Shunting
Authors: Thomas Joseph T. , Petersen Scott , Hurrion Elizabeth , Gray Peter H. , Bourke Christoper , Kumar Sailesh , Gardener Glenn
Published: April 2015

We report a case of an iatrogenic congenital diaphragmatic hernia (CDH) following left pleuroamniotic shunting at 20 weeks gestation for severe left pleural effusion. The infant developed respiratory difficulty after birth and was diagnosed with left CDH on imaging with the intraoperative findings confirming the hernia to be at an unusual site and likely secondary to the shunting.
Switch to Aflibercept in the Treatment of Neovascular AMD: One-Year Results in Clinical Practice
Authors: Pinheiro-Costa João , Costa José M. , Beato João N. , Freitas-da-Costa Paulo , Brandão Elisete , Falcão Manuel S. , Falcão-Reis Fernando , Carneiro Ângela M.
Published: April 2015

Purpose: To report the clinical outcomes of intravitreal aflibercept therapy in eyes with refractory and recurrent neovascular age-related macular degeneration (AMD) switched from intravitreal bevacizumab or ranibizumab. Methods: This is a retrospective review of eyes with neovascular AMD switched to intravitreal aflibercept with at least 1 year of follow-up after the switch. All patients had had a minimum of 3 injections of bevacizumab or ranibizumab before the switch. Aflibercept was used in patients considered refractory to bevacizumab (group 1) and in recurrent patients on therapy with ranibizumab due to an institutional policy decision (group 2). Changes in best-corrected visual acuity, fluid on optical coherence tomography (OCT), central retinal thickness (CRT) and the frequency of injections were compared. Results: Eighty-five eyes of 69 patients were analyzed, 39 eyes in group 1 and 46 in group 2. The mean follow-up time was 31.6 months prior to the switch and 14.7 months on treatment with aflibercept. One year after the switch, there was a nonsignificant mean decrease of 2 letters in visual acuity in both groups (group 1: from 58.2 to 55.8 letters, p = 0.086; group 2: from 56.4 to 54.5 letters, p = 0.168), but the mean number of injections per month was significantly lower (from 0.76 to 0.57, p < 0.001). With the switch, 90.6% of the patients showed anatomic improvement with a reduction of fluid on OCT, and both groups presented significant improvement in CRT (group 1: 65.3 µm, p = 0.051; group 2: 91.0 µm, p < 0.001). Conclusion: Aflibercept appears to be a valuable tool for the management of patients with poor responses to other anti-vascular endothelial growth factor drugs. These patients could have anatomic improvement, and the injection intervals could be extended.
VPS13D Gene Variant Is Associated with Altered IL-6 Production and Mortality in Septic Shock
Authors: Nakada Taka-aki , Boyd John H. , Russell James A. , Aguirre-Hernández Rosalía , Wilkinson Mark D. , Thair Simone A. , Nakada Emiri , McConechy Melissa K. , Fjell Christopher D. , Walley Keith R.
Published: April 2015

Background: Genetic variations contribute to septic shock mortality. To discover a novel locus, we performed in vitro genome-wide association studies (GWAS) and further tested the result in a cohort of septic shock patients. Methods: Two in vitro GWAS using a quantitative trait locus analysis of stimulated IL-6 production in lymphoblastoid cells from 60 individuals of European ancestry were performed. VPS13D rs6685273 was genotyped in European ancestry patients (n = 498). The VPS13D gene was silenced in vitro. Results: Two GWAS using lymphoblastoid cells identified the locus of VPS13D rs6685273 that was significant in the same direction in both GWAS. The VPS13D rs6685273 C allele was associated with increased IL-6 production. Patients with septic shock who had the VPS13D rs6685273 CC genotype had an increased 28-day mortality (p = 0.023) and more organ failure (p < 0.05) compared to the CT/TT genotypes. VPS13D in vitro gene silencing in the HeLa cell line increased IL-6 production. Furthermore, the rs6685273 genotype was associated with differential VPS13D splice variant expression. Conclusions: The VPS13D rs6685273 C allele was associated with increased IL-6 production in vitro. The patients with the VPS13D rs6685273 CC genotype had increased 28-day mortality and increased organ failure. VPS13D appears to regulate IL-6 production.
Molecular Delineation of Partial Trisomy 14q and Partial Trisomy 12p in a Patient with Dysmorphic Features, Heart Defect and Developmental Delay
Authors: Bose Divya , Krishnamurthy Venkatesh , Venkatesh K.S. , Aiyaz Mohamed , Shetty Mitesh , Rao Sudha N. , Kutty A.V.M.
Published: April 2015

This study describes a molecular analysis of partial trisomy 14q and partial trisomy 12p in a 5-year-old male child presenting with dysmorphic features, congenital heart disease and global developmental delay. Chromosomal analysis of the patient with GTG bands revealed a 47,XY,+der(14)t(12;14)(p13;q22)mat karyotype; the mother's karyotype was 46,XX,t(12;14)(p13;q22). Further, oligonucleotide array- CGH studies revealed an amplification of 32.3 Mb in the 14q11.1q22.1 region, substantiating partial trisomy 14q and additionally displaying an amplification of ∼1 Mb in the 12p13.3pter region for partial trisomy 12p. This is the first study to demonstrate a novel association of partial trisomies of 14q and 12p due to a 3:1 segregation of a maternal balanced translocation involving chromosomes 12 and 14. Gene ontology studies indicated 5 potential candidate genes in the amplified regions for the observed congenital anomalies.
Genetics and Epigenetics of Diabetic Nephropathy
Authors: Liu Ruijie , Lee Kyung , He John Cijiang
Published: April 2015

Background: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) in the USA and worldwide, contributing to significant morbidity and mortality in diabetic patients. A genetic factor for the development of DN is strongly implicated, as only one third of diabetic patients eventually develop kidney disease. Growing evidence also supports an important role of epigenetic modifications in DN. Summary: Multiple studies have been performed to identify risk genes and loci associated with DN. So far, only several genes and loci have been identified, none of which showed a strong association with DN. Therefore, a better study design with a larger sample size to identify rare variants and a clinically defined patient population to identify genes and loci associated with progressive DN are still needed. In addition to genetic factors, epigenetic modifications, such as DNA methylation, histone modifications and microRNAs, also play a major role in the pathogenesis of DN through a second layer of gene regulation. Although a major progress has been made in this field, epigenetic studies in DN are still in the early phase and have been limited mostly due to the heterogeneity of kidney tissue samples with multiple cells. However, rapid development of high-throughput genome-wide techniques will help us to better identify genetic variants and epigenetic changes in DN. Key Message: Understanding of genetic and epigenetic changes in DN is needed for the development of new biomarkers and better drug targets against DN. Summarized in this review are important recent findings on genetic and epigenetic studies in the field of DN.
Genetic Analysis of Leukocyte Type-I Interferon Production and Risk of Coronary Artery Disease
Authors: Nelson Christopher P. , Schunkert Heribert , Samani Nilesh J. , Erridge Clett
Published: April 2015

Objective—

Patients with systemic lupus erythematosus are genetically predisposed to enhanced production of the type-I interferon IFN-α and are also at elevated risk of developing atherosclerosis compared with healthy subjects. We aimed to test whether genetic predisposition to increased type-I IFN production affects risk of coronary artery disease.

Approach and Results—

Using a list of 11 single nucleotide polymorphisms from the results of genome-wide association studies for systemic lupus erythematosus, which we hypothesised would be enriched in variants that regulate type-I IFN production, we identified a genetic risk score based on 3 single nucleotide polymorphisms (rs10516487, rs3131379 and rs7574865), which correlated significantly with production of IFN-α by human peripheral leukocytes stimulated with CpG-oligonucleotide (n=60,
P
=1.50×10
−5
). These single nucleotide polymorphisms explained 27.8% of variation in the CpG-oligonucleotide-induced IFN-α response and were also associated with Toll-like receptor-7/8– and Toll-like receptor-9–dependent IFN-α and IFN-β responses, but were not associated with inflammatory cytokine production in response to Toll-like receptor-4 stimulation or risk of coronary artery disease in 22 233 cases and 64 762 controls (odds ratio 1.00, 95% CI 0.98–1.02) using Mendelian randomization–based analyses. Coronary artery disease risk was also not associated with the full panel of 11 systemic lupus erythematosus single nucleotide polymorphisms or loci responsible for the monogenic type-I interferonopathies Aicardi-Goutières syndrome and Spondyloenchondrodysplasia with immune dysregulation.

Conclusions—

The results argue against the potential utility of drugs targeting type-I IFN production for coronary artery disease. The use of genetic variants that modify leukocyte signaling pathways, rather than circulating biomarkers, as instruments in Mendelian randomization analyses may be useful for studies investigating causality of other candidate pathways of atherogenesis.
Skin Autofluorescence as a Measure of Advanced Glycation End Products Deposition Predicts 5-Year Amputation in Patients With Peripheral Artery Disease
Authors: de Vos Lisanne C. , Boersema Jeltje , Mulder Douwe J. , Smit Andries J. , Zeebregts Clark J. , Lefrandt Joop D.
Published: April 2015

Objective—

Patients with peripheral artery disease are at risk for critical limb ischemia and amputation. Accumulation of advanced glycation end products is increased and predictive for coronary and cerebrovascular events in several high cardiovascular risk groups. We hypothesized that accumulation of tissue advanced glycation end products, measured by skin autofluorescence (SAF), predicts amputation in patients with peripheral artery disease.

Approach and Results—

Between October 2007 and June 2008, 252 patients with peripheral artery disease were included at the outpatient clinic. During a 5-year follow-up, 22 (9%) had an amputation because of critical limb ischemia. Competing risks regression analysis showed a subproportional hazard ratio of 3.05 (95% confidence interval [CI], 1.87–4.96);
P
<0.0001 for amputation per unit incease of SAF. After correction for diabetes mellitus and Fontaine stage, subproportional hazard ratio was 2.72 (95% CI, 1.38–5.39);
P
=0.004. In patients with Fontaine stage I and II only (n=215), SAF was the only predictor for amputation, subproportional hazard ratio 4.05 (95% CI, 2.09–7.83);
P
<0.0001. Fontaine stage multiplied by SAF resulted in a significant increase of the area under the curve for prediction of amputation when compared with Fontaine stage only: area under the curve increased from 0.74 (95% CI, 0.63–0.86) to 0.83 (95% CI, 0.74–0.92);
P
=0.003.

Conclusions—

Skin autofluorescence, as a measure of tissue advanced glycation end products deposition, predicts amputation in patients with peripheral artery disease during a 5-year follow-up, independent from the presence of diabetes mellitus and Fontaine stage. Even at lower Fontaine stage (I or II), SAF is a strong predictor of amputation. The multiplication of Fontaine stage by SAF results in a good prediction model of amputation.
HIF-1α and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages
Authors: Tawakol Ahmed , Singh Parmanand , Mojena Marina , Pimentel-Santillana María , Emami Hamed , MacNabb Megan , Rudd James H.F. , Narula Jagat , Enriquez José A. , Través Paqui G. , Fernández-Velasco María , Bartrons Ramón , Martín-Sanz Paloma , Fayad Zahi A. , Tejedor Alberto , Boscá Lisardo
Published: April 2015

Objective—

Although it is accepted that macrophage glycolysis is upregulated under hypoxic conditions, it is not known whether this is linked to a similar increase in macrophage proinflammatory activation and whether specific energy demands regulate cell viability in the atheromatous plaque.

Approach and Results—

We studied the interplay between macrophage energy metabolism, polarization, and viability in the context of atherosclerosis. Cultured human and murine macrophages and an in vivo murine model of atherosclerosis were used to evaluate the mechanisms underlying metabolic and inflammatory activity of macrophages in the different atherosclerotic conditions analyzed. We observed that macrophage energetics and inflammatory activation are closely and linearly related, resulting in dynamic calibration of glycolysis to keep pace with inflammatory activity. In addition, we show that macrophage glycolysis and proinflammatory activation mainly depend on hypoxia-inducible factor and on its impact on glucose uptake, and on the expression of hexokinase II and ubiquitous 6-phosphofructo-2-kinase. As a consequence, hypoxia potentiates inflammation and glycolysis mainly via these pathways. Moreover, when macrophages’ ability to increase glycolysis through 6-phosphofructo-2-kinase is experimentally attenuated, cell viability is reduced if subjected to proinflammatory or hypoxic conditions, but unaffected under control conditions. In addition to this, granulocyte-macrophage colony-stimulating factor enhances anerobic glycolysis while exerting a mild proinflammatory activation.

Conclusions—

These findings, in human and murine cells and in an animal model, show that hypoxia potentiates macrophage glycolytic flux in concert with a proportional upregulation of proinflammatory activity, in a manner that is dependent on both hypoxia-inducible factor -1α and 6-phosphofructo-2-kinase.
The Arab East and the Bedouin Component in Modern History: Emerging Perspectives on the Arid Lands as a Social Space
Authors: Büssow Johann , Franz Kurt , Leder Stefan
Published: April 2015

In this paper we argue that historians of the eastern Arab lands (Ar.al-mashriq al-ʿarabī) should turn their attention to the Bedouins for two main reasons. First, the societies in the Arab East cannot be adequately understood without a full evaluation of their Bedouin component, especially outside urban areas. Second, studying the Bedouins can open new perspectives on important debates in Middle Eastern historiography. The paper further contends that the arid lands of the Arab East still need to be explored as a historical region with its own distinct patterns of regional connectivity and political organisation. Finally, we highlight environmental history and the study of emic categories as promising avenues for future research on this region.
Bedouin Petitions from Late Ottoman Palestine: Evaluating the Effects of Sedentarization
Authors: Ben-Bassat Yuval
Published: April 2015

This article examines petitions sent to Istanbul at the end of the nineteenth century by Bedouin groups from thekazas (subdistricts) of Jaffa and Gaza, on Palestine’s central and southern coast. The Bedouins’ use of the petition process shows that many of them, especially those who had gone through a process of sedentarization, played according to the rules prevailing among the urban and rural populations in their vicinity. Their petitions also demonstrate vividly the extent to which they were involved in city politics and social life. Bedouins confidently put forward claims to landownership based on their own legal interpretation of their rights and, at times, even adopted the dominant discourse on good governance.
The ʿAmārāt, their Sheikh, and the Colonial State: Patronage and Politics in a Partitioned Middle East
Authors: Fletcher Robert S.G.
Published: April 2015

How did the era of colonial divide-and-rule in the Arab East—the creation of the new mandates of Great Britain and France—appear to the Bedouin communities who lived through it? This article examines this important period of change from the perspective of a prominent Bedouin sheikh, Fahd Ibn Hadhdhāl of the ʿAmārāt (ʿAnaza). Moving between the southern and western frontiers of Iraq, the ʿAmārāt have seldom been the focus of historical enquiry, but their attempts to navigate the disturbed interwar landscape offer a window onto the changing prospects for Bedouin groups across the Arab East. Building on a close reading of colonial sources, the article reveals how important social, economic, and political dynamics of Bedouin life persisted to shape relations within the new mandates, as the ʿAmārāt, their sheikh, and the young colonial state all jostled for influence and authority.
Nasab as Idiom and Discourse
Authors: Leder Stefan
Published: April 2015

Contemporary Bedouin-related publications about tribal groups reveal a persistent interest in lineages. This article places this phenomenon within the larger framework of Bedouin self-representation and explores the nature and specific uses of the complex and polysemic notion ofnasabin treatises and speech. The ambiguity resulting from a tension between the pragmatic context of local articulation and circumstantial (re-)definition and the ideological significance, purportedly unchangeable and defined character and moral value ofnasabis reflected in historical and modern discourses as well as in pervasive references to tribal groups as being defined bynasab. The particular concomitance of practical and ideological aspects is the reason for the lasting impact of this notion, as its structure allows for the negotiation of both political issues and individual and collective identities. The publications considered here, mostly from Syria, Jordan, and Iraq, vary between an affirmative stance that often seeks to define prestigious lineages and an attempt to balance the obvious uncertainties of the data with an interest in establishing the identity of tribal groups and narratives referring to descent. As Bedouin lore puts it, the concept of belonging defined by origins in terms of agnatic descent (nasab) is challenged, and sometimes superseded, by the affinity established through locality and cohabitation.