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Patient pathway

Daniel S Chen, Herbert Hurwitz
Cancer immunotherapy (CIT) has transformed cancer treatment. In particular, immunotherapies targeting the programmed death ligand 1 (PD-L1)/programmed death 1 pathway have demonstrated durable clinical benefit in some patients. However, CIT combinations may create a more favorable environment in which to maximize the potential of the immune system to eliminate cancer. Here we describe 3 key mechanisms related to vascular endothelial growth factor (VEGF)-mediated immunosuppression: inhibition of dendritic cell maturation, reduction of T-cell tumor infiltration, and promotion of inhibitory cells in the tumor microenvironment; supporting data are also described...
July 2018: Cancer Journal
Annalaura Mastrangelo, Gabriel Á Martos-Moreno, Francisco J Rupérez, Julie A Chowen, Coral Barbas, Jesús Argente
OBJECTIVE: Mutations in the pregnancy-associated plasma protein A2 (PAPP-A2) gene have recently been shown to cause postnatal growth failure in two prepubertal patients from a non-consanguineous Spanish family due to the resulting decrease in IGF1 bioavailability. Although a specific pharmacological treatment of this entity is yet to be established, both children received progressive subcutaneous doses (40 to 120 μg/kg) of rhIGF1 twice daily for 2 years. The improvements in growth, hyperinsulinemia and bone mineral density have been previously reported...
August 12, 2018: Growth Hormone & IGF Research
Michael R Zile, William T Abraham, JoAnn Lindenfeld, Fred A Weaver, Faiez Zannad, Todd Graves, Tyson Rogers, Elizabeth G Galle
BACKGROUND: The Food and Drug Administration (FDA) initiated the Expedited Access Pathway (EAP) to accelerate approval of novel therapies targeting unmet needs for life-threatening conditions. EAP allows for the possibility of initial FDA approval using intermediate end points with postapproval demonstration of improved outcomes. OBJECTIVE: Describe the EAP process using the BeAT-HF trial as a case study. METHODS: BeAT-HF will examine the safety and effectiveness of baroreflex activation therapy (BAT) in heart failure patients with reduced ejection fraction using an Expedited and Extended Phase design...
July 22, 2018: American Heart Journal
Wei Zhang, Yajuan Zhai, Wenbin Wang, Min Cao, Chunjie Ma
Gastric cancer (GC) is a deadly disease with high incidence worldwide in recent years. Long noncoding RNAs (lncRNAs) were found to play imperative roles in many biological processes, such as cancer development and progression. Specifically, TP73-AS1, a novel cancer-related lncRNA, was documented to be up-regulated in several malignancies, but the clinical significance and functional role of TP73-AS1 in GC is still unknown. RT-qPCR was performed to evaluate TP73-AS1 transcription in GC tissue specimens and cell lines...
August 14, 2018: Gene
Anne M Dubin, Neal W Jorgensen, Andrew E Radbill, David J Bradley, Jennifer N Silva, Sabrina Tsao, Ronald J Kanter, Ronn E Tanel, Bhavya Trivedi, Ming-Lon Young, Andreas Pflaumer, Jorge McCormack, Stephen P Seslar
BACKGROUND: Since the onset of pediatric catheter ablation, the pediatric electrophysiology community has reported outcomes via various registries (PAPCA and the Pediatric Catheter Ablation registry (PCAR)). Most recently, a modern era pediatric and congenital ablation registry (MAP-IT) was developed for eventual incorporation into the NCDR IMPACT registry. OBJECTIVE: We aimed to describe initial findings from the MAP-IT pilot registry, and compare these findings to earlier registries...
August 14, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Xiao Tan, Zhongqiang Zhang, Hongliang Yao, Liangfang Shen
T-cell immunoglobulin domain and mucin domain-4 (Tim-4) is overexpressed in several tumors and is correlated with enhanced tumor development and metastasis. In this study, we investigated the physiological alterations and molecular events related to Tim-4 overexpression in a mouse model of colorectal cancer (CRC). In the current study, we observed that Tim-4 is upregulated in CRC tissues compared with neighboring normal tissues. In addition, statistical analysis revealed that elevated Tim-4 expression was strongly linked to distant metastasis, TNM stage and reduced overall survival duration in CRC patients...
August 14, 2018: Cancer Letters
Yuehong Wang, Linying Wu, Yinan Yao, Guohua Lu, Liming Xu, Jianying Zhou
The prognosis of small cell lung cancer (SCLC) is poor despite its good initial response to chemotherapy. Polo-like kinase 1 (PLK1) is a crucial mitotic regulator that is overexpressed in many tumors, and its overexpression is associated with tumor aggressiveness and a poor prognosis. However, its role in SCLC is still poorly characterized. Based on immunohistochemistry findings, the PLK1 protein is expressed at higher levels in SCLC tumor samples than in normal lung tissue samples. The selective PLK1 inhibitor BI 6727 significantly induced the inhibition of proliferation and apoptosis in a dose-dependent manner in SCLC cell lines...
August 14, 2018: Cancer Letters
Robert Roskoski
The Ras-Raf-MEK-ERK signal transduction cascade is arguably the most important oncogenic pathway in human cancers. Ras-GTP promotes the formation of active homodimers or heterodimers of A-Raf, B-Raf, and C-Raf by an intricate process. These enzymes are protein-serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2 which, in turn, catalyze the phosphorylation and activation of ERK1 and ERK2. The latter catalyze the regulatory phosphorylation of dozens of cytosolic and nuclear proteins...
August 14, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Julius Fink, Masahito Matsumoto, Yoshifumi Tamura
Sedentary lifestyle and over-nutrition are the main causes of obesity and type 2 diabetes (T2D). However, the same causes are major triggers of hypogonadism. Many T2D patients show low testosterone levels while hypogonadal men seem to be prone to become diabetic. Testosterone plays a major role in the regulation of muscle mass, adipose tissue, inflammation and insulin sensitivity and is therefore indirectly regulating several metabolic pathways, while T2D is commonly triggered by insulin resistance, increased adipose tissue and inflammation, showing a negative correlation between testosterone levels and T2D...
August 14, 2018: Steroids
Penglong Cao, Shuai Zhao, Zhigang Sun, Nan Jiang, Yuhong Shang, Yingxin Wang, Juebin Gu, Shijun Li
A low level of breast cancer metastasis suppressor 1-like (BRMS1L) has been implicated in tumour metastasis involving breast cancer and other cancers. It remains unclear whether BRMS1L is involved in epithelial ovarian cancer (EOC) metastasis and what the molecular mechanism of BRMS1L is in suppressing EOC metastasis. In this study, we examined the mRNA expression and protein level of BRMS1L by screening EOC patients. Our results show that BRMS1L expression is downregulated in EOC patients compared to that in normal people and negatively correlated to pathological stages of EOC...
August 14, 2018: Experimental Cell Research
Aaron B Caughey, Stephen L Wood, George A Macones, Ian J Wrench, Jeffrey Huang, Mikael Norman, Karin Pettersson, William J Fawcett, Medhat M Shalabi, Amy Metcalfe, Leah Gramlich, Gregg Nelson, R Douglas Wilson
OBJECTIVE: This ERAS Guideline for intraoperative care in Cesarean Delivery (CD) will provide best practice, evidenced-based, recommendations for intra-operative care with primarily, a maternal focus. The 'focused' pathway process for scheduled and unscheduled CD, for this ERAS CD guideline will consider, from decision to operate (starting with the 30 - 60 minutes prior to skin incision) through the conduct of the surgery. METHODS: The literature search (1966-2017) used Embase and PubMed to search medical subject headings including "Cesarean Section", "Cesarean Section", "Cesarean Section Delivery" and all pre- and intra-operative ERAS® items...
August 14, 2018: American Journal of Obstetrics and Gynecology
Jong-Ho Cha, Wen-Hao Yang, Weiya Xia, Yongkun Wei, Li-Chuan Chan, Seung-Oe Lim, Chia-Wei Li, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee, Jennifer L Hsu, Hung-Ling Wang, Chu-Wei Kuo, Wei-Chao Chang, Sirwan Hadad, Colin A Purdie, Aaron M McCoy, Shirong Cai, Yizheng Tu, Jennifer K Litton, Elizabeth A Mittendorf, Stacy L Moulder, William F Symmans, Alastair M Thompson, Helen Piwnica-Worms, Chung-Hsuan Chen, Kay-Hooi Khoo, Mien-Chie Hung
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD)...
August 16, 2018: Molecular Cell
Jana R Jenquin, Leslie A Coonrod, Quinn A Silverglate, Natalie A Pellitier, Melissa A Hale, Guangbin Xia, Masayuki Nakamori, J Andrew Berglund
Myotonic dystrophy type 1 (DM1) is an autosomal dominant, CTG•CAG microsatellite expansion disease. Expanded CUG repeat RNA sequester the muscleblind-like (MBNL) family of RNA-binding proteins, thereby disrupting their normal cellular function leading to global mis-regulation of RNA processing. Previously, the small molecule furamidine was shown to reduce CUG foci and rescue mis-splicing in a DM1 HeLa cell model and rescue mis-splicing in the HSALR DM1 mouse model, but furamidine's mechanism of action was not explored...
August 17, 2018: ACS Chemical Biology
Jinglan Jin, Hongqin Xu, Ruihong Wu, Junqi Niu, Shibo Li
PURPOSE: We aimed to study the aberrant DNA methylation profile associated with hepatitis B virus (HBV) infection and to identify key genes and pathways associated with the HBV infection stage. METHODS: A total of 54 antiviral treatment-naive HBV-infected patients and 6 healthy controls were included. Genome-wide methylated DNA immunoprecipitation analysis was performed, as previously described, after which the chip data were preprocessed. Subsequently, Cytoscape software was used for the construction of a protein-protein interaction network, and Database for Annotation, Visualization, and Integrated Discovery software was used to conduct functional enrichment analysis...
August 17, 2018: Journal of Medical Virology
Pedro Isaacsson Velho, Michael A Carducci
Despite the heterogeneity of prostate cancer (PCa), androgen stimulation is fundamental to its development, growth and lethality. Therefore, the blockade of androgen receptor (AR) signaling is critical to controlling the disease, even after progression with castrate levels of androgens. Areas covered: We review the current understanding of new ways to block the AR, using novel antiandrogen inhibitors, which act on different parts of the AR signaling pathway in PCa. We also review new approaches, such as the use of poly (ADP-ribose) polymerase (PARP) inhibitors, targeting both the AR and the DNA repair pathway, potentially adding synergy and improving efficacy and the combination of AR inhibitors and immunotherapy...
August 17, 2018: Expert Opinion on Investigational Drugs
Seunggu J Han, Ramin A Morshed, Irene Troncon, Kesshi M Jordan, Roland G Henry, Shawn L Hervey-Jumper, Mitchel S Berger
OBJECTIVE Herein, the authors report their experience with intraoperative stimulation mapping to locate the descending subcortical motor pathways in patients undergoing surgery for hemispheric gliomas within or adjacent to the rolandic cortex, with particular description of the morbidity and functional outcomes associated with this technique. METHODS This is a retrospective analysis of patients who, in the period between 1997 and 2016, had undergone resection of hemispheric perirolandic gliomas within or adjacent to descending motor pathways...
August 17, 2018: Journal of Neurosurgery
Xiaoli Mi, Gabriel Griffin, Winston Lee, Sanjay Patel, Robert Ohgami, Chi Young Ok, Sa Wang, Julia T Geyer, Wenbin Xiao, Mikhail Roshal, Jacqueline S Garcia, Lewis B Silverman, Stephen E Sallan, Jon C Aster, Marian H Harris, Olga K Weinberg
The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified 9 cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data...
August 16, 2018: American Journal of Hematology
Nicholas D J Strzalkowski, Aaron D Chau, Liu Shi Gan, Zelma H T Kiss
The cerebellum is implicated in the pathophysiology of numerous movement disorders, which makes it an attractive target for noninvasive neurostimulation. Continuous theta burst stimulation (cTBS) can induce long lasting plastic changes in human brain; however, the efficacy of different simulation protocols has not been investigated at the cerebellum. Here, we compare a traditional 50-Hz and a modified 30-Hz cTBS protocols at modulating cerebellar activity in healthy subjects. Seventeen healthy adults participated in two testing sessions where they received either 50-Hz (cTBS50 ) or 30-Hz (cTBS30 ) cerebellar cTBS...
August 16, 2018: Cerebellum
Bingjie Zhang, Yida Pan, Lei Xu, Dehua Tang, Robert Gregory Dorfman, Qian Zhou, Yuyao Yin, Yang Li, Lixing Zhou, Shimin Zhao, Xiaoping Zou, Lei Wang, Mingming Zhang
OBJECTIVE: Many studies have confirmed the glucose-lowering effect of berberine in type 2 diabetes patients. Although the mechanism of action of berberine involves the improvement of insulin sensitivity, its hypoglycemic mechanism remains elusive. Here we show a new mechanism by which berberine antagonizes glucagon signaling and find that SIRT3 is involved in the hypoglycemic effect of berberine. METHODS: Gene knockout and overexpression were used to assess the inhibitory effect of berberine on SIRT3...
August 16, 2018: Endocrine
Bruno Lima Giacobbo, Janine Doorduin, Hans C Klein, Rudi A J O Dierckx, Elke Bromberg, Erik F J de Vries
Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways...
August 17, 2018: Molecular Neurobiology
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