bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of maintenance therapy in patients with diffuse large B cell lymphoma: A systematic review and meta‐analysis
Authors: Rozental Alon , Gafter‐Gvili Anat , Vidal Liat , Raanani Pia , Gurion Ronit
Published: September 2018

Randomized trials of maintenance therapy (MT) in diffuse large B cell lymphoma (DLBCL) are inconclusive regarding its effect on overall survival (OS) and disease control. We aimed to examine the efficacy and safety of MT in this meta‐analysis. Systematic review and meta‐analysis of randomized controlled trials comparing MT with observation or placebo, in patients with DLBCL, who achieved complete response (CR) or partial response (PR) after first‐line chemotherapy with or without rituximab. Primary outcome was OS. Secondary outcomes included relapse rate, disease control (defined as progression‐free survival, event‐free survival, or disease‐free survival, as reported in the original trials), and safety. Our search yielded 14 trials including 5122 patients. Median age of patients was 49 to 70 years. Six trials included rituximab as the MT; three included Interferon alfa; other trials include thalidomide, lenalidomide, cyclophosphamide and prednisone, serine threonine kinase inhibitor enzastaurin, and mTOR inhibitor everolimus. MT did not improve OS compared to observation, OR 0.91, (95% CI 0.78‐1.07). Results were the same in a subgroup analysis by the type of maintenance (rituximab vs other). MT did decreased relapse rate, RR 0.76 (95% CI 0.65‐0.89) and improved disease control, OR 0.74 (95% CI 0.65‐0.84). Disease control was significantly improved in the subgroup of studies evaluating rituximab as maintenance OR 0.61 (95% CI 0.47‐0.79) and in the subgroup of R‐CHOP induction studies OR 0.77 (95% CI 0.67‐0.88). Serious or grade III/IV adverse events including neutropenia and infections were significantly more common in the maintenance arm, RR = 1.69 (95% CI 1.29‐2.22). MT in patients with DLBCL achieving CR or PR after induction therapy did not affect OS, yet it decreased relapse rate and improved disease control at the cost of higher infection rate. Our data do not support routine administration of MT in patients with DLBCL.
Mitochondrial Function Is Compromised in Cortical Bone Osteocytes of Long-Lived Growth Hormone Receptor Null Mice
Authors: Liu Zhongbo , Solesio Maria E , Schaffler Mitchell B , Frikha-Benayed Dorra , Rosen Clifford J , Werner Haim , Kopchick John J , Pavlov Evgeny V , Abramov Andrey Y , Yakar Shoshana
Published: September 2018

Despite increased longevity and resistance to multiple stressors, growth hormone receptor null (GHRKO) mice exhibit severe skeletal impairment. The role of GHR in maintaining osteocyte mitochondrial function is unknown. We found that GHR ablation was detrimental to osteocyte mitochondrial function. In vivo multiphoton microscopy revealed significant reductions of >10% in mitochondrial membrane potential (MMP) in GHRKO osteocytes and reduced mitochondrial volumetric density. Reductions in MMP were accompanied by reductions in glucose transporter-1 levels, steady state ATP, NADH redox index, oxygen consumption rate, and mitochondrial reserve capacity in GHRKO osteocytes. Glycolytic capacity did not differ between control and GHRKO males’ osteocytes. However, osteocytes from aged female GHRKO mice exhibited reductions in glycolytic parameters, indicating impairments in glucose metabolism, which may be sex dependent. GHRKO osteocytes exhibited increased levels of cytoplasmic reactive oxygen species (ROS) (both basal and in response to high glucose), insulin-like growth factor-1 (IGF-1), and insulin. Mitochondrial ROS levels were increased and correlated with reduced glutathione in GHRKO osteocytes. Overall, the compromised osteocyte mitochondrial function and responses to metabolic insults strongly correlated with skeletal impairments, suggesting that despite increased life span of the GHRKO mice, skeletal health span is decreased. © 2018 American Society for Bone and Mineral Research.
Retracted: Upregulated microRNA‐132 rescues cardiac fibrosis and restores cardiocyte proliferation in dilated cardiomyopathy through the phosphatase and tensin homolog–mediated PI3K/Akt signal transduction pathway
Authors: Zhang Chen‐Jun , Huang Yu , Lu Ji‐De , Lin Jie , Ge Zhi‐Ru , Huang Hui
Published: September 2018

Cardiac fibrosis is known to be present in dilated cardiomyopathy (DCM) and it predicts the occurrence of sudden death and congestive heart failure. The aim of our study is to investigate the expression of microRNA‐132 (miR‐132) and its effect on cardiocyte proliferation, apoptosis, and cardiac fibrosis by binding to phosphatase and tensin homolog (PTEN) through the phosphateidylinositol 3‐kinase (PI3K)/protein kinase (Akt) signal transduction pathway in DCM rats. DCM rat models induced by doxorubicin were established and confirmed by an ultrasonic cardiogram. Epithelial cells were treated with inhibitors, activators, and small interfering RNAs to identify the mechanisms by which miR‐132 controls cardiocyte activity and cardiac fibrosis. Angiotensin II (Ang II) and aldosterone (ALD) expressions were detected by an enzyme‐linked immunosorbent assay. The relationship between PTEN and miR‐132 was verified by a dual‐luciferase reporter assay. Cell proliferation and apoptosis were tested by the MTT assay and flow cytometry. PTEN was determined to be the target gene of miR‐132. Rat models of DCM exhibited a lower level of miR‐132, PI3K, Akt, B‐cell lymphoma 2, collagen I, and collagen III, but a higher level of PTEN, Bcl‐2–associated X protein, and proliferating cell nuclear antigen as well as inflammatory response (Ang II and ALD), accompanied by declined cardiocyte proliferation and elevated apoptosis and cardiac fibrosis. Upregulated miR‐132 or silenced PTEN activated the PI3K/Akt pathway, thus facilitating cardiocyte proliferation and repressing cardiocyte apoptosis and cardiac fibrosis, as well as inflammatory responses. Downregulated miR‐132 reversed this tendency. These findings indicate that miR‐132 activates the PI3K/Akt pathway by inhibiting PTEN expression, thus facilitating cardiocyte proliferation and inhibiting apoptosis and cardiac fibrosis in DCM rats.
Combined detection of estrogen and tumor markers is an important reference factor in the diagnosis and prognosis of lung cancer
Authors: Bai Yuquan , Shen Wulin , Zhu Minglin , Zhang Li , Wei Yanhong , Tang Hexiao , Zhao Jinping
Published: September 2018

The correlation between lung cancer tumor markers and sex differences in lung cancer remains a clinical problem that is worthy of further study. This study investigated the significance of the combined detection of 17β‐estrogen (E2) and tumor markers in the diagnosis and prognosis of lung cancer. A total of 174 patients, including 117 patients with non–small‐cell lung cancer (NSCLC) and 57 patients with benign pulmonary lesions (BPL), were enrolled. An enzyme‐linked immunosorbent assay was used to detect the expression of E2, carcinoembryonic antigen (CEA), neuron‐specific enolase (NSE), and cytokeratin 19 fragment antigen 21‐1 (CYFRA21‐1) in patients with NSCLC and BPL to analyze the correlation between E2 and CEA, NSE or CYFRA21‐1 expression, and its correlation with clinicopathological features and prognosis. The expression of tumor markers was then examined in different lung cancer cells (A549, H1795, H460, and SK‐MES‐1). The expression of tumor markers was detected by a real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) and Western blot analysis. The expressions of p‐p44/42 mitogen‐activated protein kinase (MAPK) and phospho‐AKT (p‐AKT) were detected by Western blot analysis. The expression levels of E2, CEA, NSE, and CYFRA21‐1 in patients with NSCLC were significantly higher than those in patients with BPL (
P < .05); E2 was positively correlated with tumor markers (
P < .01). Patients with a high expression of E2 and tumor markers showed a poor prognosis (
P < .05). RT‐quantitative PCR and Western blot analysis showed that the expression levels of CEA, NSE, CYFRA21‐1, p‐p44/42 MAPK, and p‐AKT in the E2 group were higher than those in the other groups (
P < .05). These studies indicate that the interaction of E2 and tumor markers can significantly improve the role of tumor markers in the diagnosis and prognosis of lung cancer.
Ivermectin inhibits the growth of glioma cells by inducing cell cycle arrest and apoptosis in vitro and in vivo
Authors: Song Dandan , Liang Hongsheng , Qu Bo , Li Yijing , Liu Jingjing , Zhang Yanan , Li Lu , Hu Li , Zhang Xiangtong , Gao Aili
Published: September 2018

Glioma, the most predominant primary malignant brain tumor, remains uncured due to the absence of effective treatments. Hence, it is imperative to develop successful therapeutic agents. This study aimed to explore the antitumor effects and mechanisms of ivermectin (IVM) in glioma cells in vitro and in vivo. The effects of IVM on cell viability, cell cycle arrest, apoptosis rate, and morphological characteristics were determined respectively by MTT assay/colony formation assay, flow cytometry, and transmission electron microscope. In addition, the expression levels of cycle‐related and apoptosis‐associated proteins were individually examined by Western blot analysis. Moreover, cell proliferation and apoptosis analyses were carried out by TUNEL, Ki‐67, cleaved caspase‐3, and cleaved caspase‐9 immunostaining assay. Our results demonstrated that IVM has a potential dosage‐dependent inhibition effect on the apoptosis rate of glioma cells. Meanwhile, the results also revealed that IVM induced apoptosis by increasing caspase‐3 and caspase‐9 activity, upregulating the expressions of p53 and Bax, downregulating Bcl‐2, activating cleaved caspase‐3 and cleaved caspase‐9, and blocking cell cycle in G0/G1 phase by downregulating levels of CDK2, CDK4, CDK6, cyclin D1, and cyclin E. These findings suggest that IVM has an inhibition effect on the proliferation of glioma cells by triggering cell cycle arrest and inducing cell apoptosis in vitro and in vivo, and probably represents promising agent for treating glioma.
Effects of miR‐503‐5p on apoptosis of human pulmonary microvascular endothelial cells in simulated microgravity
Authors: Tang Na‐Ping , Hui Tao‐Tao , Ma Jing , Mei Qi‐Bing
Published: September 2018

Recent studies have shown that microRNA (miRNAs) can play important roles in the regulation of endothelial cell (EC) function. However, the expression profile of miRNAs and their effects on the apoptosis of ECs under microgravity conditions remains unclear. In this study, the apoptosis of human pulmonary microvascular endothelial cells (HPMECs) under simulated microgravity was identified by Annexin V and propidium iodide double staining and transmission electron microscopy. miRNA microarray assay was used to screen the differentially expressed miRNAs in HPMECs under simulated microgravity, and eight differentially expressed miRNAs were identified. Specifically, miR‐503‐5p, which was found to be most significantly upregulated in both microarray and quantitative reverse‐transcription polymerase chain reaction assays, was selected for further functional investigation. Overexpression of miR‐503‐5p induced apoptosis of HPMECs under normal gravity and aggravated the negative effects of simulated microgravity on HPMECs. Furthermore, silencing of miR‐503‐5p expression effectively attenuated the negative effects of simulated microgravity on HPMECs. Further experiments showed that the mRNA and protein expression of anti‐apoptotic factor B‐cell lymphoma‐2 (Bcl‐2), which has been confirmed as a direct target of miR‐503‐5p, was inhibited by the upregulation of miR‐503‐5p and increased by the downregulation of miR‐503‐5p. Taken together, our findings demonstrate, for the first time, that miR‐503‐5p can induce apoptosis of HPMECs under simulated microgravity through, at least in part, inhibiting the expression of Bcl‐2.
Novel TGF‐β1 inhibitor antagonizes TGF‐β1‐induced epithelial‐mesenchymal transition in human A549 lung cancer cells
Authors: Jeong Ji‐Hoon , Jang Hae Jin , Kwak Sungmin , Sung Gi‐Jun , Park Seung‐Ho , Song Ji‐Hye , Kim Hyunhee , Na Younghwa , Choi Kyung‐Chul
Published: September 2018

Transforming growth factor β1 (TGF‐β1), a multifunctional cytokine, is known to promote tumor invasion and metastasis and induce epithelial‐mesenchymal transition (EMT) in various cancer cells. Inhibition of TGF‐β1 signaling is a new strategy for cancer therapy. Most cancer cells display altered or nonfunctional TGF‐β1 signaling; hence, TGF‐β1 inhibitors exert limited effects on these cells. Recent studies have suggested that developing a TGF‐β1 inhibitor from natural compounds is a key step to create novel therapeutic agents. This study aimed to develop a new anti‐TGF‐β1 therapy for cancer. We found an improved analog of chalcones, compound 67, and investigated its effects in vitro. We demonstrated the inhibitory role of compound 67 through migration and invasion assays on TGF‐β1‐induced EMT of human A549 lung cancer cells. Compound 67 inhibited TGF‐β1‐induced smad2 phosphorylation, suppressed TGF‐β1‐induced EMT markers, matrix metalloproteinase‐2 (MMP‐2) and MMP‐9, and inhibited migration and invasion of A549 cells. The study results showed that compound 67 is useful to prevent tumor growth and metastasis.
Transduction and transfection of difficult‐to‐transfect cells: Systematic attempts for the transfection of protozoa Leishmania
Authors: Keller Andrea‐Anneliese , Scheiding Berith , Breitling Reinhard , Licht Andreas , Hemmerich Peter , Lorkowski Stefan , Reissmann Siegmund
Published: September 2018

Cell‐penetrating peptides (CPPs) are used to internalize different cargoes, including DNA, into live mammalian and plant cells. Despite many cells being easily transfected with this approach, other cells are rather “difficult” or “hard to transfect,” including protist cells of the genus Leishmania. Based on our previous results in successfully internalizing proteins into
Leishmania tarentolae cells, we used single CPPs and three different DNA‐binding proteins to form protein‐like complexes with plasmids covered with CPPs. We attempted magnetofection, electroporation, and transfection using a number of commercially available detergents. While complex formation with negatively charged DNA required substantially higher amounts of CPPs than those necessary for mostly neutral proteins, the cytotoxicity of the required amounts of CPPs and auxiliaries was thoroughly studied. We found that
Leishmania cells were indeed susceptible to high concentrations of some CPPs and auxiliaries, although in a different manner compared with that for mammalian cells.

The lack of successful transfections implies the necessity to accept certain general limitations regarding DNA internalization into difficult‐to‐transfect cells. Only electroporation allowed reproducible internalization of large and rigid plasmid DNA molecules through electrically disturbed extended membrane areas, known as permeable membrane macrodomains.
Astragaloside suppresses tumor necrosis factor receptor‐associated factor 5 signaling pathway and alleviates neurodegenerative changes in retinal pigment epithelial cells induced by isoflurane
Authors: Chen Pei‐Jun , Shang An‐Quan , Wang Wei‐Wei , Yang Jian‐Ping
Published: September 2018

Epidemiological studies showed that isoflurane, a general anesthetic widely used in surgery including those for the children, is associated with impairment of neurodevelopment and neurodegenerative diseases, such as Alzheimer’s disease (AD) and age‐related macular degeneration (AMD), which are related to the accumulation of reactive oxygen species (ROS). Astragaloside (AS) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge. In this study, we used retinal pigment epithelial cells, which share plenty of features with neurodegenerative diseases such as AD and AMD to investigate the effect of AS. Cell cycle re‐entry and proapoptosis were seen in retinal pigment epithelium (RPE) cells treated with isoflurane, which was alleviated by pretreatment of AS. Further, tumor necrosis factor receptor‐associated factor 5 (TRAF5) and downstream nuclear factor‐κB (NF‐κB) were investigated to elucidate the molecular mechanism underlying protective effect of AS. RPE cells exposed to isoflurane expressed higher TRAF5 and NF‐κB than those pretreated with AS, suggesting a critical role of TRAF5 therein. In Morris water maze (MWM) assay, Sprague‐Dawley rats pretreated with AS and then exposed to isoflurane spent less time in swimming to the platform, and their TRAF5 expression was significantly lower than those received anesthesia alone. Further studies on the consequence of forced downregulation or upregulation are warranted that may employ cutting‐edge technologies such as optogenetics to overcome the difficulties in manipulating expression of TRAF5. Although the link between TRAF5 and neurodegeneration requires more in‐depth investigations, our study provide a novel hint on the pathological mechanism of isoflurane and suggest a potential target for eliminating persistent side effect of anesthesia.
Subcellular compartmentalization of glutathione peroxidase 1 allelic isoforms differentially impact parameters of energy metabolism
Authors: Aashique Md , Roy Amrita , Diamond Alan , Bera Soumen
Published: September 2018

Specific genetic variations in the gene for the selenium‐containing antioxidant protein glutathione peroxidase 1 (GPX1) are associated with the risk of a variety of common diseases, including cancer, diabetes, and cardiovascular disorders. Two common variations have been focused upon, one resulting in leucine or proline at codon 198 and another resulting in 5, 6, or 7 alanine repeats were previously shown to affect the distribution of GPX1 between the cytoplasm and mitochondria. Human MCF7 cells engineered to exclusively express GPX1 with five alanine repeats at amino terminus and proline at codon 198 (A5P) and seven alanine repeats at amino terminus and leucine at codon 198 (A7L), as well as derivatives targeted to the mitochondria by the addition of a mitochondrial localization sequence (mA5P and mA7L) were used to assess the consequences of the expression of these proteins on the cellular redox state and bioenergetics. Ectopic expression of A5P and A7L reduced the levels of reactive oxygen species, and the mitochondrially targeted derivatives exhibited better activity in these assays. Bioenergetics and mitochondrial integrity were assessed by measuring mitochondrial membrane potential, oxygen consumption, adenosine triphosphate (ATP) levels, and the levels of lactate dehydrogenase. The results of these assays indicated distinctively, and sometimes opposing, patterns with regard to differences between the consequences of the expression of A5P, A7L, mA5P, and mA7L. These data provide new information on the consequences of differences in the primary structure and cellular location of GPX1 proteins and contribute to the understanding of how these effects might contribute to human disease.
Interleukin 17 is an important pathogenicity gene in pediatric sepsis
Authors: Han Yujie , Li Xiaoying , Gao Shasha , Liu Xianghong , Kang Lili , Li Xiaomei , Lang Yujie , Li Xiao , Sun Mingying , Gai Zhongtao , Yu Shenglin
Published: September 2018

Objective

Sepsis represents a complex disease with the dysregulated inflammatory response. The purpose of this study is to explore the role of interleukin 17 (IL‐17, also known as IL‐17A) in the occurrence and development of pediatric sepsis.

Methods

We established the sepsis neonatal rat model with the method of intraperitoneal injection of Escherichia coli (E coli). At each target time point, we got the blood from heart after anesthetizing animals, and the lung and liver tissues were fixed in formalin. Immunohistochemistry and enzyme‐linked immunosorbent assay assay was used to analyze the expression of IL‐17A in the lung/liver and plasma respectively. A public data set of neonatal sepsis gene microarray was used to verify our result, and explore main functions of IL‐17A in sepsis.

Results

The expression levels of IL‐17A in the plasma, lung and liver gradually increased with the extension of the experimental time in sepsis group, and were significantly higher than control group at 4 hours after injection of E coli (P < 0.01). In our study, we found the levels of IL‐17A mRNA in pediatric sepsis group were significantly higher than control group, which is consistent with the neonatal rat septicemia model. In addition, through the functional (GO) enrichment analysis, we found the genes associated with IL‐17A in pediatric sepsis are mainly enriched in the functions of immune response and cell membrane formation.

Conclusion

IL‐17A might be a potential therapeutic target for pediatric sepsis.
Therapeutic agency, in‐session behavior, and patient–therapist interaction
Authors: Huber Julia , Born Ann‐Kathrin , Claaß Christine , Ehrenthal Johannes C. , Nikendei Christoph , Schauenburg Henning , Dinger Ulrike
Published: September 2018

Objective

The aim of this study was to investigate associations between patients’ subjective agency, their observable in‐session behavior, and the patient–therapist interaction during the early phase of psychotherapy.

Methods

The sample included 52 depressed patients in psychodynamic psychotherapy. After Session 5, the patients’ agency and the quality of the therapeutic alliance were assessed. Based on session recordings, two independent observers rated the patients’ involvement, their interpersonal behavior, and the therapists’ directiveness.

Results

Higher agency was associated with stronger therapeutic alliances. Patients who indicated higher agency in their therapy participated more actively in the session and showed less hostile impact messages. Patients’ agency was not related to therapists’ directiveness.

Conclusions

Patients’ sense of agency in psychotherapy was associated with more active involvement and affiliative interaction. The findings support the idea that patients need to feel capable of acting within and having an influence on their therapy to benefit from it.
LncRNA DGCR5 represses the development of hepatocellular carcinoma by targeting the miR‐346/KLF14 axis
Authors: Wang Yu‐Gang , Liu Juan , Shi Min , Chen Fa‐Xiang
Published: September 2018

Long non‐coding RNAs (lncRNAs) are a class of regulatory noncoding RNAs. Emerging evidence highlights the critical roles of lncRNAs in the progression of hepatocellular carcinoma (HCC). Although many lncRNAs have been identified in the development of HCC, the association between DiGeorge syndrome critical region gene 5 (DGCR5) and HCC remains unclear. In the current study, we focused on the biological role of DGCR5 in HCC. We observed that DGCR5 was decreased in HCC cells, including SMCC7721, Hep3B, HepG2, MHCC‐97L, MHCC‐97H, and SNU449 hepatocellular carcinoma cells, compared with the normal human liver cell line THLE‐3 normal human liver cells. In addition, DGCR5 overexpression could repress HCC cell growth, migration, and invasion considerably. Increasing studies have indicated the interactions between lncRNAs and microRNAs. MicroRNAs are endogenous small noncoding RNAs and they can play important roles in tumorigenesis. MicroRNA 346 (miR‐346) has been demonstrated in various human cancer types, including HCC. MiR‐346 was found to be increased in HCC cells and DGCR5 can act as a sponge of miR‐346 to modulate the progression of HCC. The binding correlation between DGCR5 and miR‐346 was validated in our research. Subsequently, Krüppel‐like factor 14 (KLF14) was predicted as a downstream target of miR‐346 and miR‐346 can induce the development of HCC by inhibiting KLF14. Finally, we proved that DGCR5 can rescue the inhibited levels of KLF14 repressed by miR‐346 mimics in MHCC‐97H and Hep3B cells. Taken together, it was indicated in our study that DGCR5 can restrain the progression of HCC through sponging miR‐346 and modulating KLF14 in vitro.
Regulatory role of microRNA‐320a in the proliferation, migration, invasion, and apoptosis of trophoblasts and endothelial cells by targeting estrogen‐related receptor γ
Authors: Liu Rong‐Hua , Meng Qin , Shi Yan‐Ping , Xu Huai‐Sheng
Published: September 2018

Recently, microRNAs (miRNAs) have been demonstrated to participate in many physiological and biological processes, especially by acting as circulating biomarkers or modulators in cell differentiation. Therefore, the aim of the current study was to clarify whether microRNA‐320a (miR‐320a) regulates the proliferation, migration, invasion, and apoptosis of trophoblasts and endothelial cells. In this study, miR‐320a mimics and inhibitors were transfected into HTR.8/SVneo cells and human umbilical vein endothelial cells (HUVECs) using liposomes. Subsequently, the expression of miR‐320a and estrogen‐related receptor γ (ERRγ) mRNA was detected by a reverse transcription quantitative polymerase chain reaction, whereas the protein expression of ERRγ, vascular endothelial growth factor (VEGF), angiogenin 1 (Ang‐1), human 3beta‐hydroxysteroid dehydrogenase type 1 (HSD3B1), and human chorionic gonadotropin (HCG) was detected by western blot analysis. Furthermore, the proliferation, invasion/migration, and apoptosis of cells were analyzed by the cell counting kit‐8 assay, transwell assay, and flow cytometry, respectively. The results showed that overexpression of miR‐320a decreased the optical density (OD) values and the proliferation rate of HTR.8/SVneo cells and HUVECs, while inhibiting the expression of VEGF, Ang‐1, HSD3B1, and HCG in these cells. Furthermore, miR‐320a reduced the ability of cell invasion and migration, while increasing the rate of cell apoptosis. After cotransfecting the cells with miR‐320a and ERRγ small (or short) interfering RNA (siRNA), the decreased ERRγ expression led to inhibited proliferation, migration, and invasion, but increased apoptosis of HTR.8/SVneo cells and HUVECs. Our results further revealed that miR‐320a induced the apoptosis of trophoblasts and endothelial cells while inhibiting their proliferation, migration, and invasion by decreasing the expression of ERRγ and by indirectly suppressing the expression of VEGF, Ang‐1, HSD3B1, and HCG.
Surgical trauma‐induced CCL18 promotes recruitment of regulatory T cells and colon cancer progression
Authors: Sun Zhirong , Du Chunchun , Xu Pingbo , Miao Changhong
Published: September 2018

Background: Surgical stress has been suggested to facilitate colon cancer growth and metastasis. However, the precise mechanisms by which surgical trauma promotes colon cancer progression remain poorly understood.

Methods: To unravel the mechanisms underlying surgery‐induced colon cancer progression, a syngenic transplantation tumor model was established with CT26 cells, and the effect of laparotomy on tumor progression was investigated. Especially, the expression of several chemokines was assessed, and their roles in recruiting CD4+ CD25+ regulatory T cells (Tregs) after surgery were analyzed.

Results: Tregs population was significantly increased in the tumor tissue and peripheral blood of tumor‐bearing mice after laparotomy. C‐C motif chemokine ligand 18 (CCL18) expression was significantly upregulated after laparotomy in tumor tissue and the peritoneal cavity of tumor‐bearing mice, and it was positively correlated with the recruitment of Tregs. Functionally, CCL18 knockdown significantly reduces tumor growth and angiogenesis compared with control. Through analysis of Tregs, we found an upregulated proportion of Tregs in tumor tissue, peritoneal cavity, and peripheral blood after laparotomy, but this enhancement was blocked after CCL18 knockdown. In patients with colon cancer, a higher Tregs proportion is positively correlated to more advanced clinical TNM stages and shorter survival. Furthermore, a positive correlation was found between the serum CCL18 level and the Treg proportion in clinical samples.

Conclusion: Surgical trauma contributes to colon cancer progression by increasing CCL18 expression and hence promotes Treg recruitment, which leads to an immunosuppressive environment.
Antimicrobial effects of mesenchymal stem cells primed by modified LPS on bacterial clearance in sepsis
Authors: Saeedi Pardis , Halabian Raheleh , Fooladi Abbas Ali Imani
Published: September 2018

Background and Objectives

Mesenchymal stem cells (MSCs)‐based regenerative therapy is now considered as an alternative approach to revive infectious diseases, including sepsis. Nevertheless, the efficiency of MSC application is limited by the poor survival rate of engrafted MSCs. Hence, preconditioning was established as a strategy to increase the cells’ efficiency.

Methods

MSCs were preconditioned with 1 μg/ml of three different lipopolysaccharides (LPSs) of
Pseudomonas (Pse‐LPS),
Acinetobacter (Ac‐LPS), and
Acinetobacter inactivated lipid A by PagL (Ac‐LPS‐PagL). Then, preconditioned MSCs were exposed to oxidative stress and serum deprivation followed by evaluation of the antibacterial activity, survival, and apoptosis of MSCs. Then, the murine sepsis model treated with 100 μl phosphate‐buffered saline (control group, sepsis group), 100 μl of 1 × 10
6 wild MSCs (MSC group), and three remained groups received 100 μl of 1 × 10
6 LPS‐preconditioned MSCs (Pse‐LPS‐MSCs group: LPS purified from
Pseudomonas, or Ac‐LPS‐MSCs group: LPS purified from
Acinetobacter, and Ac‐PagL‐LPS‐MSCs group: detoxified LPS Pagl).

Results

After 4 days, LPS‐preconditioned MSC transplantation modulated the immune response and reduced inflammation in septic mice. Apoptosis of Pse‐LPS/Ac‐LPS‐preconditioned‐MSCs was obviously reduced in vitro, and the survival rate of engrafted mice was evidently elevated in Pse‐LPS‐MSCs and Ac‐LPS‐MSCs groups compared with other three groups.

Conclusion

LPS preconditioning provides an innovative strategy for evolving functional and biological properties of MSCs and ameliorates the survival rate of the mouse model of sepsis after MSC transplantation, protects cells from apoptosis and organ damages, and evaluates therapeutic properties, including immunemodulatory.
Effect of glucocorticoids on androgen biosynthesis in the testes of the toad Rhinella arenarum (Amphibia, Anura)
Authors: Czuchlej Silvia Cristina , Volonteri María Clara , Regueira Eleonora , Ceballos Nora Raquel
Published: September 2018

In rat Leydig cells, glucocorticoids (GCs) inhibit testosterone production through the interaction with the glucocorticoid receptor (GR). However, the sensitivity of those cells to GCs is regulated by the enzyme 11β‐hydroxysteroid dehydrogenase Type 1 (11β‐HSD1). In the testes of the toad Rhinella arenarum, the presence of an 11β‐HSD similar to type 2 and a cytosolic GR has also been described. However, there is a lack of information regarding the effects of GCs on amphibian testicular steroidogenesis. In this study, the effects of corticosterone on androgen production, and the activity of two steroidogenic enzymes in toad testes were reported. Corticosterone inhibits androgen production via the GR because the GR antagonist RU486 prevents corticosterone‐induced inhibition of testosterone. Corticosterone also reduced the activity of the cytochrome P450 17‐hydroxylase, C17,20‐lyase (Cyp450
c17) without affecting the 3β‐hydroxysteroid dehydrogenase/isomerase activity. This effect on Cyp450
c17 was likewise inhibited by RU486. On the other hand, corticosterone had no effect on the amount of steroidogenic acute regulator protein. These results suggest that GCs inhibit steroidogenesis in toad testes by reducing of Cyp450
c17 activity via a GR‐mediated mechanism.
Development of sensitive ddPCR assays to reliably quantify the proviral DNA reservoir in all common circulating HIV subtypes and recombinant forms
Authors: Bosman Kobus J , Wensing Annemarie MJ , Pijning Aster E , van Snippenberg Wilco J , van Ham Petra M , de Jong Dorien MC , Hoepelman Andy IM , Nijhuis Monique
Published: September 2018

Introduction

The latent reservoir is the main barrier on the road to HIV cure, and clinical approaches towards eradication are often evaluated by their effect on proviral DNA. To ensure inclusiveness and representativeness in HIV cure studies, proviral DNA quantification assays that are able to detect all common circulating HIV clades are urgently needed. Here, three HIV DNA assays targeting three different genomic regions were evaluated for their sensitivity and subtype‐tolerance using digital PCR.

Methods

A subtype‐B‐specific assay targeting gag (GAG) and two assays targeting conserved sequences in ltr and pol (LTR and JO) were assessed for their sensitivity and subtype‐tolerance in digital PCR (Bio‐Rad QX200), using a panel of serially diluted subtype reference plasmids as well as a panel of clinical isolates. Both panels represent subtypes A, B, C, D, F, G and circulating recombinant forms (CRFs) AE and AG, which together are responsible for 94% of HIV infections worldwide.

Results

HIV subtype was observed to greatly affect HIV DNA quantification results. Robust regression analysis of the serially diluted plasmid panel showed that the GAG assay was only able to linearly quantify subtype B, D and G isolates (4/13 reference plasmids, average R2 = 0.99), whereas LTR and JO were able to quantify all tested isolates (13/13 reference plasmids, respective average R2 = 0.99 and 0.98). In the clinical isolates panel, isolates were considered detectable if all replicates produced a positive result. The GAG assay could detect HIV DNA in four out of five subtype B and one out of two subtype D isolates, whereas the LTR and JO assays detected HIV DNA in all twenty‐nine tested isolates. LTR and JO results were found to be equally precise but more precise than GAG.

Conclusions

The results demonstrate the need for a careful validation of proviral reservoir quantification assays prior to investigations into non‐B subtype reservoirs. The LTR and JO assays can sensitively and reliably quantify HIV DNA in a panel that represents the worldwide most prevalent subtypes and CRFs (A, B, C, D, AE, F, G and AG), justifying their application in future trials aimed at global HIV cure.
Diversity and environmental adaptation of phagocytic cell metabolism
Authors: Davies Luke C , Rice Christopher M , McVicar Daniel W , Weiss Jonathan M
Published: September 2018

Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation—key components of innate immunity and response to infection. This diverse group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils—heterogeneous cell populations possessing cell and tissue-specific functions of which cellular metabolism comprises a critical underpinning. Core functions of phagocytic cells are diverse and sensitive to alterations in environmental- and tissue-specific nutrients and growth factors. As phagocytic cells adapt to these extracellular cues, cellular processes are altered and may contribute to pathogenesis. The considerable degree of functional heterogeneity among monocyte, neutrophil, and other phagocytic cell populations necessitates diverse metabolism. As we review our current understanding of metabolism in phagocytic cells, gaps are focused on to highlight the need for additional studies that hopefully enable improved cell-based strategies for counteracting cancer and other diseases.

Review on the recent advances and current understanding of how phagocytic cells adapt to meet niche-specific metabolic demands.
Prognostic role of inflammatory biomarkers in HIV‐infected patients with a first diagnosis of hepatocellular carcinoma: A single‐center study
Authors: Quiros‐Roldan Eugenia , Properzi Martina , Amadasi Silvia , Raffetti Elena , Ferraresi Alice , Biasi Luciano , Focà Emanuele , Castelli Francesco
Published: September 2018

Objectives

To assess hepatocellular carcinoma (HCC) survival and to investigate the prognostic role of immunonutritional biomarkers, as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI), in a cohort of human immunodeficiency virus (HIV)‐infected patients.

Methods

All HIV‐positive patients diagnosed with HCC at our Department from January 2000 to December 2013 were included. The outcomes were overall survival (OS), recurrence‐free survival (RFS), and liver‐related death (LRD). To examine the role of inflammatory biomarkers on the outcomes, univariate and multivariable Cox regression models were used. Receiver operating characteristic (ROC) curves were implemented to evaluate the prediction role of NLR, PLR, and PNI.

Results

A total of 40 patients (90% males) with a mean age of 48.3 years (SD = 5.6) were recruited. NLR ≥ 2.9 was associated with all causes mortality, as well as, PLR ≥ 126. NLR and PLR were predictors of OS, RFS, and LRD, while PNI did not emerge as a prognostic marker. According to the multivariate analysis, no HCC treatment was the only risk factor associated with risk of death. The areas under the ROC curves were 68.3 (95% confidence interval [CI], 54.5‐82.1) for PLR and 66.3 (95% CI, 54.3‐78.2) for NLR at 3 years; similar results were found at 5 years of follow‐up.

Conclusions

Although, if examined singularly, NLR and PLR are prognostic factors for HCC recurrence and survival in HIV‐infected patients, at the multivariate analysis, “no HCC treatment” remains the only independent risk factor associated with fatal outcome.
Phase Transitions of Branched Fatty‐Acid Calcium Salt/Water Systems
Authors: Yamamoto Yoshiaki , Kakehashi Rie , Aramaki Kenji , Nonomura Yoshimune
Published: September 2018

Calcium (Ca) salts of fatty acids are powder materials, which exhibit lubricant, hydrophobic, and bactericidal properties. These physical and biological properties depend on the chemical structure of the alkyl chain of the fatty acids. In this study, the phase behavior of iso‐stearic acid Ca salt/water binary systems was studied, and the effect of the branched structure in the alkyl chain was analyzed. Herein, calcium chloride is added to the iso‐stearic acid aqueous solution. The state of the binary systems changed with the molar ratio (R) of [Ca2+]/[iso‐stearic acid]. Precipitation occurred when R was more than 0.05, whereas the mixture changed from a micelle phase (Wm) to an oil phase (O) through a liquid crystalline phase (LC) when R was less than 0.01. The polarized microscopy images and small‐angle X‐ray scattering profiles showed that the LC is in a lamellar liquid crystalline state. In addition, we evaluated the crystal structure of the precipitated material. These results showed that the iso‐stearic acid Ca salt was in the amorphous state. In contrast, the n‐stearic acid Ca salt formed only the Wm and gel phases. These findings suggest that the branched structure of fatty acids induces loose intermolecular packing of liquid crystalline structures.
Transcriptomic analysis dissects the mechanistic insight into the Daphnia clonal variation in tolerance to toxic Microcystis
Authors: Lyu Kai , Gu Lei , Wang Hui , Zhu Xuexia , Zhang Lu , Sun Yunfei , Huang Yuan , Yang Zhou
Published: September 2018

Cyanobacteria have become more prevalent than other phytoplankton in freshwater assemblages during summer. In such conditions, cyanobacterial traits may reduce zooplankton fitness and the energy flow efficiency from primary producers to aquatic herbivores. Cladocerans, as the dominant zooplankton grazers in freshwater ecosystems, exhibit clonal variation in their tolerance to cyanobacteria with an increasing gradient in eutrophication history. Hitherto, research on the full modes of action (MoAs) of Daphnia clonal differences in tolerance to toxic Microcystis still remains in its infancy. We conducted fitness and transcriptome analyses on two Daphnia clones, clone TH09 and TH14. A significant decline in body growth rate was detected in the sensitive clone TH09 compared with the tolerant clone TH14 at the presence of toxic Microcystis. Furthermore, transcriptional analysis indicated that major MoAs such as glutathione metabolism, protein processing in endoplasmic reticulum, amino sugar/nucleotide sugar metabolism, and arachidonic acid metabolism were linked to the tolerance fitness in Daphnia similoides. These results provided mechanistic insights into the pathways of genetic and biological processes involved in cyanobacteria tolerance in the Daphnia clonal variation, and propose that the genetic architecture of this fitness‐related trait would be helpful to clarify how zooplankton clones adapt to harmful algal blooms.
THE EXPERT REVOLUTION
Authors: Palmer Kelly , Blake David
Published: September 2018

Many managers and leaders, Palmer and Blake believe, have an outdated conception of organizational learning. They remind them that they “already have lots of experts in [their] workforce.” They point to research from their own company, Degreed, and elsewhere about how employees learn not just from an organization's learning management system, but from “employees' self‐directed learning from all of the free, informal content that is available.” A learning analytics model is described that allows companies to analyze data about how people are learning at four different levels: industry, company, organizational/team, and individual. It boils down to this: “Companies need to know if they have people with the skills that will take them into the future.”
Counterion Effect of Amine Salts on Ring‐Opening Polymerization of 1,3‐Benzoxazines
Authors: Akkus Buket , Kiskan Baris , Yagci Yusuf
Published: September 2018

The effect of nucleophilicity of counterions of amine HX salts as catalysts on the ring‐opening polymerization (ROP) of 1,3‐benzoxazines is investigated. The significant reduction observed for the ROP temperature is related to the nucleophilicity of counterions and found to show a general trend as I− > Br− > Cl−, as studied by differential scanning calorimetry and Fourier transform infrared spectroscopy. Moreover, the latent character of the amine salts is also demonstrated by tracking the benzoxazine–amine salt mixtures using 1H NMR spectroscopy. The spectral analysis gives evidences for the dormant nature of the amine HX salts toward benzoxazine at room temperature in solvent. Besides, thermal stabilities of the cured benzoxazine monomers with and without catalysts are investigated by thermogravimetric analysis.
The clinical features, underlying immunology, and treatment of autoantibody‐mediated movement disorders
Authors: Damato Valentina , Balint Bettina , Kienzler Anne‐Kathrin , Irani Sarosh R.
Published: September 2018

An increasing number of movement disorders are associated with autoantibodies. Many of these autoantibodies target the extracellular domain of neuronal surface proteins and associate with highly specific phenotypes, suggesting they have pathogenic potential. Below, we describe the phenotypes associated with some of these commoner autoantibody‐mediated movement disorders, and outline increasingly well‐established mechanisms of autoantibody pathogenicity which include antigen downregulation and complement fixation. Despite these advances, and the increasingly robust evidence for improved clinical outcomes with early escalation of immunotherapies, the underlying cellular immunology of these conditions has received little attention. Therefore, here, we outline the likely roles of T cells and B cells in the generation of autoantibodies, and reflect on how these may guide both current immunotherapy regimes and our future understanding of precision medicine in the field. In addition, we summarise potential mechanisms by which these peripherally‐driven immune responses may reach the central nervous system. We integrate this with the immunologically‐relevant clinical observations of preceding infections, tumours and human leucocyte antigen‐associations to provide an overview of the therapeutically‐relevant underlying adaptive immunology in the autoantibody‐mediated movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Transurethral ultrasound therapy of the prostate in the presence of calcifications: A simulation study
Authors: Suomi Visa , Treeby Bradley , Jaros Jiri , Makela Pietari , Anttinen Mikael , Saunavaara Jani , Sainio Teija , Kiviniemi Aida , Blanco Roberto
Published: September 2018

Purpose

Transurethral ultrasound therapy is an investigational treatment modality which could potentially be used for the localized treatment of prostate cancer. One of the limiting factors of this therapy is prostatic calcifications. These attenuate and reflect ultrasound and thus reduce the efficacy of the heating. The aim of this study is to investigate how prostatic calcifications affect therapeutic efficacy, and to identify the best sonication strategy when calcifications are present.

Methods

Realistic computational models were used on clinical patient data in order to simulate different therapeutic situations with naturally occurring calcifications as well as artificial calcifications of different sizes (1–10 mm) and distances (5–15 mm). Furthermore, different sonication strategies were tested in order to deliver therapy to the untreated tissue regions behind the calcifications.

Results

The presence of calcifications in front of the ultrasound field was found to increase the peak pressure by 100% on average while the maximum temperature only rose by 9% during a 20‐s sonication. Losses in ultrasound energy were due to the relatively large acoustic impedance mismatch between the prostate tissue and the calcifications (1.63 vs 3.20 MRayl) and high attenuation coefficient (0.78 vs 2.64 dB/MHz1.1/cm), which together left untreated tissue regions behind the calcifications. In addition, elevated temperatures were seen in the region between the transducer and the calcifications. Lower sonication frequencies (1–4 MHz) were not able to penetrate through the calcifications effectively, but longer sonication durations (20–60 s) with selective transducer elements were effective in treating the tissue regions behind the calcifications.

Conclusions

Prostatic calcifications limit the reach of therapeutic ultrasound treatment due to reflections and attenuation. The tissue regions behind the calcifications can possibly be treated using longer sonication durations combined with proper transducer element selection. However, caution should be taken with calcifications located close to sensitive organs such as the urethra, bladder neck, or rectal wall.