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Targeting therapy

Marco Possanzini, Carlo Greco
The treatment of metastatic breast cancer is largely focused on systemic therapy. However, over the past decades, there has been growing interest in the use of metastasis-directed therapy in selected cases presenting with an oligometastatic phenotype, i.e. low disease burden with a more indolent biology. Identification of the oligometastatic breast cancer population has, so far, proven elusive. Stereotactic radiotherapy offers an effective, non-invasive approach to ablate metastatic disease both in the brain and in extra-cranial settings...
June 28, 2018: Breast: Official Journal of the European Society of Mastology
Yunjian Zhang, Shuizhen Zhou, Yuanfeng Zhou, Lifei Yu, Linmei Zhang, Yi Wang
OBJECTIVE: The aim of this study was to investigate the characteristics and composition of intestinal microbiota in children with refractory epilepsy after ketogenic diet (KD) therapy and to explore the bacterial biomarkers related to clinical efficacy. METHODS: We prospectively analyzed 20 patients (14 males, 6 females) treated with KD. Clinical efficacy, electroencephalogram (EEG) changes, and laboratory tests were evaluated, and fecal specimens were obtained prior to and 6 months after therapy...
June 28, 2018: Epilepsy Research
Jiahuan Zou, Mengwei Zhuang, Xiaopeng Yu, Na Li, Rudi Mao, Zhida Wang, Jianing Wang, Xiaoyan Wang, Huaiyu Zhou, Lining Zhang, Yongyu Shi
The effectiveness of immunotherapy targeting the immune checkpoint PD-L1/PD-1 pathway highlights importance of elucidating the regulatory mechanisms of PD-L1 expression in cancer cells. Previous studies demonstrate that oncogene MYC up-regulates PD-L1 expression in lymphomas. In the present study, we investigated the regulatory role of MYC in the PD-L1 expression induced by IFN-γ in HCC cells. Unexpectedly, knockdown of MYC expression using siRNA assay increased the inducible expression of PD-L1 both at mRNA and protein levels...
July 5, 2018: Molecular Immunology
M Moteabbed, A Trofimov, F H Khan, Y Wang, G C Sharp, A L Zietman, J A Efstathiou, H-M Lu
PURPOSE: Hypofractionated radiotherapy of prostate cancer is gaining clinical acceptance given its potential increase in therapeutic ratio and evidence for noninferiority and lack of added late toxicities compared to conventional fractionation. However, concerns have been raised that smaller number of fractions might lead to larger dosimetric influence by interfractional motion. We aim to compare the effect of these variations on hypofractionated pencil beam scanning (PBS) proton therapy and volumetric modulated arc therapy (VMAT) for localized prostate cancer...
July 14, 2018: Medical Physics
Tiago Cardoso, Andrew Adler, Bengt Mattsson, Deirdre B Hoban, Sara Nolbrant, Jenny Nelander Wahlestedt, Agnete Kirkeby, Shane Grealish, Anders Björklund, Malin Parmar
Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are a promising unlimited source of cells for cell replacement therapy in Parkinson´s disease (PD). A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non-human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, VM patterned hESC-derived progenitors were grafted into the midbrain of 6-hydroxydopamine-lesioned rats, and analyzed at 6, 18 and 24 weeks for a time-course evaluation of specificity and extent of graft-derived fiber outgrowth as well as potential for functional recovery...
July 14, 2018: Journal of Comparative Neurology
Hsiang-Ju Chen, Rui-Lan Huang, Phui-Ly Liew, Po-Hsuan Su, Lin-Yu Chen, Yu-Chun Weng, Cheng-Chang Chang, Yu-Chi Wang, Michael Wing-Yan Chan, Hung-Cheng Lai
Ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy. Prevailing evidences suggest that drug resistance and recurrence of ovarian HGSC are caused by the presence of cancer stem cells. Therefore, targeting cancer stems is appealing, however, all attempts to date, have failed. To circumvent this limit, we analyzed differential transcriptomes at early differentiation of ovarian HGSC stem cells and identified the developmental transcription factor GATA3 as highly expressed in stem, compared to progenitor cells...
July 14, 2018: International Journal of Cancer. Journal International du Cancer
Isaac Nardi, Theresa Reno, Xinwei Yun, Terra Sztain, Jami Wang, Huifang Dai, Li Zheng, Jae Kim, Dan Raz
In the last decade, it has become clear that epigenetic changes act together with genetic mutations to promote virtually every stage of tumorigenesis and cancer progression. This knowledge has triggered searches for "epigenetic drugs" that can be developed into new cancer therapies. Here we report that triptolide reduced lung cancer incidence from 70% to 10% in a Fen1 E160D transgenic mouse model and effectively inhibited cancer growth and metastasis in A549 and H460 mouse xenografts. We found that triptolide induced lung cancer cell apoptosis that was associated with global epigenetic changes to histone 3 (H3)...
July 14, 2018: International Journal of Cancer. Journal International du Cancer
Michele Ghidini, Jens C Hahne, Melissa Frizziero, Gianluca Tomasello, Francesco Trevisani, Andrea Lampis, Rodolfo Passalacqua, Nicola Valeri
Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer...
July 13, 2018: Targeted Oncology
Marion Ferreira, Eric Pichon, Delphine Carmier, Emilie Bouquet, Cécile Pageot, Theodora Bejan-Angoulvant, Marion Campana, Emmanuelle Vermes, Sylvain Marchand-Adam
Immunotherapy medications that target programmed death 1 protein (PD-1) and programmed death-ligand 1 (PD-L1), such as nivolumab, pembrolizumab, and atezolizumab, are currently used in the first- or second-line treatment of non-small cell lung cancers, among other indications. However, these agents are associated with immune-related side effects, the most common of which are endocrinopathies, colitis, hepatitis, and interstitial pneumonitis. In contrast, coronary toxicities are rarely reported and remain poorly understood...
July 13, 2018: Targeted Oncology
Angelo Antonini, Bianca Nitu
Development of motor fluctuations and dyskinesia characterizes the transition from early to advanced Parkinson disease stage. Current therapeutic strategies to manage motor complications aim at increasing the number of levodopa administrations and extending its benefit by the association of enzyme blockers and dopamine agonists. However, as disease progresses, mobility becomes progressively dependent on levodopa absorption and its plasma bioavailability, resulting in loss of independence, worse quality of life and increased caregiver burden...
July 13, 2018: Journal of Neural Transmission
Anna Juncadella, Konstantinos Papamichael, Byron P Vaughn, Adam S Cheifetz
BACKGROUND: A treat-to-target therapeutic approach is emerging as the new standard of care for treating inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). AIMS: We aimed to investigate the association of serum adalimumab concentrations during maintenance therapy with biochemical, endoscopic, and histologic remission in IBD. METHODS: This retrospective multicenter study included consecutive IBD patients on adalimumab maintenance therapy who had a C-reactive protein (CRP) within 1 week and/or endoscopic evaluation within 12 weeks of therapeutic drug monitoring between July 2013 and December 2016...
July 13, 2018: Digestive Diseases and Sciences
Alexia Kagiava, Kleopas A Kleopa
Gene delivery to the peripheral nervous system for therapeutic applications remains technically challenging but could eventually have a significant impact on the development of innovative treatments not only for inherited but also for acquired peripheral neuropathies. Here we describe the method for lumbar intrathecal injection of viral vectors in experimental mice. This gene delivery route provides widespread and stable over time Schwann cell-targeted or ubiquitous gene expression in the peripheral nervous system...
2018: Methods in Molecular Biology
Carla de Castro Sant' Anna, Alberto Gomes Ferreira Junior, Paulo Soares, Fabricio Tuji, Eric Paschoal, Luiz Cláudio Chaves, Rommel Rodriguez Burbano
Cancer is a genetic disease characterized by uncontrolled cell growth and metastasis. Cancer can have a number of causes, such the activation of oncogenes, the inactivation of tumor-suppressing genes, mutagenesis provoked by external factors, and epigenetic modifications. The development of diagnostic tools and treatments using a molecular biological approach permits the use of sensitive, low-cost, noninvasive tests for cancer patients. Biomarkers can be used to provide rapid, personalized oncology, in particular the molecular diagnosis of chronic myeloid leukemia, and gastric, colon, and breast cancers...
July 13, 2018: Clinical and Experimental Medicine
Sunisa Chirakul, Michael H Norris, Sirawit Pagdepanichkit, Nawarat Somprasong, Linnell B Randall, James F Shirley, Bradley R Borlee, Olga Lomovskaya, Apichai Tuanyok, Herbert P Schweizer
Therapy of Burkholderia pseudomallei acute infections is largely limited to a few β-lactam antibiotics such as ceftazidime or meropenem. Although relatively rare, resistance emergence during therapy leads to treatment failures with high mortality rates. In the absence of acquired external resistance determinants in B. pseudomallei emergence of β-lactam resistance is invariably caused by mutational modification of genomically encoded factors. These include the deletion of the ceftazidime target penicillin-binding protein 3 or amino acid changes in the Class A PenA β-lactamase that expand its substrate spectrum, as well as penA gene duplication and amplification or its overexpression via transcriptional up-regulation...
July 13, 2018: Scientific Reports
Francesco Di Virgilio, Alba Clara Sarti, Simonetta Falzoni, Elena De Marchi, Elena Adinolfi
Modulation of the biochemical composition of the tumour microenvironment is a new frontier of cancer therapy. Several immunosuppressive mechanisms operate in the milieu of most tumours, a condition that makes antitumour immunity ineffective. One of the most potent immunosuppressive factors is adenosine, which is generated in the tumour microenvironment owing to degradation of extracellular ATP. Accruing evidence over the past few years shows that ATP is one of the major biochemical constituents of the tumour microenvironment, where it acts at P2 purinergic receptors expressed on both tumour and host cells...
July 13, 2018: Nature Reviews. Cancer
Tamar L Ben-Shaanan, Maya Schiller, Hilla Azulay-Debby, Ben Korin, Nadia Boshnak, Tamar Koren, Maria Krot, Jivan Shakya, Michal A Rahat, Fahed Hakim, Asya Rolls
Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow...
July 13, 2018: Nature Communications
Xiaojing Zhang, Yin Peng, Yong Huang, Shiqi Deng, Xianling Feng, Gangqiang Hou, Huijuan Lin, Jian Wang, Ruibin Yan, Yanqiu Zhao, Xinmin Fan, Stephen J Meltzer, Song Li, Zhe Jin
Less than a century ago, gastric cancer (GC) was the most common cancer throughout the world. Despite advances in surgical, chemotherapeutic, and radiotherapeutic treatment, GC remains the number 3 cancer killer worldwide. This fact highlights the need for better diagnostic biomarkers and more effective therapeutic targets. RAB11-FIP2, a member of the Rab11 family of interacting proteins, exhibits potential tumor suppressor function. However, involvement of RAB11-FIP2 in gastric carcinogenesis is yet to be elucidated...
July 13, 2018: Cell Death & Disease
Jianzong Li, Yue Huang, Miaomiao Wu, Chuanfang Wu, Xin Li, Jinku Bao
Anaplastic lymphoma kinase (ALK) is considered as a validated molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the effectiveness of molecularly targeted therapies using ALK inhibitors is almost universally limited by drug resistance. Drug resistance to molecularly targeted therapies has now become a major obstacle to effective cancer treatment and personalized medicine. It is of particular importance to provide an improved understanding on the mechanisms of resistance of ALK inhibitors, thus rational new therapeutic strategies can be developed to combat resistance...
July 13, 2018: Scientific Reports
Mathew S Eapen, Anudeep Kota, Howard Vindin, Kielan D McAlinden, Dia Xenaki, Brian G Oliver, Deepak A Deshpande, Sukhwinder Singh Sohal, Pawan Sharma
Increased airway smooth muscle (ASM) mass is observed in COPD which is correlated with disease severity and negatively impact lung function. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase  activated by various stress stimuli, including reactive oxygen species, tumor necrosis factor-α, and lipopolysaccharide and is known to regulate cell proliferation...
July 13, 2018: Clinical Science (1979-)
Benjamin L Franc, Timothy P Copeland, Robert Thombley, Miran Park, Ben Marafino, Mitzi L Dean, W John Boscardin, Hope S Rugo, David Seidenwurm, Bhupinder Sharma, Stephen R Johnston, R Adams Dudley
Background: The objective of this study was to examine the presence and magnitude of US geographic variation in use rates of both recommended and high-cost imaging in young patients with early-stage breast cancer during the 18 month period after surgical treatment of their primary tumor. Methods: Using the Truven Health MarketScan Commercial Database, a descriptive analysis was conducted of geographic variation in annual rates of dedicated breast imaging and high-cost body imaging of 36,045 women aged 18 to 64 years treated with surgery for invasive unilateral breast cancer between 2010 and 2012...
July 2018: Journal of the National Comprehensive Cancer Network: JNCCN
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