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Gene Therapy for Cancer Treatment
Published in Yashwant V. Pathak, Gene Delivery Systems, 2022
Manish P. Patel, Mansi S. Shah, Mansi N. Athalye, Jayvadan K. Patel
Some pharmaceutical companies have developed several medications, such as Novartis-LBH589, cIAP1 and cIAP2, which inhibit the Bcl-2 protein, thus promoting apoptosis and tumor regression, prevent or delay tumor resistance and prolong remission following gene therapy [Amer 2014]. Notably, clinical trials for the treatment of cervical dysplasia (high-grade squamous intraepithelial lesions) caused by human papilloma virus with the DNA vaccine VGX-3100 are in advanced stages (phase III, NCT03185013) [Ginn et al. 2017]. Most commonly, HSV thymidine-kinase has been used to convert the non-toxic pro-drug ganciclovir into the cytotoxic triphosphate ganciclovir [Ginn et al. 2017]. Therapies that are targeting CD19, an antigen present in most B-cell malignancies but absent in normal tissues other than the B-cell lineage, are at the forefront of CAR-based technology. A turning point occurred when the positive outcomes from three CAR therapy trials were published in 2010 and 2011. These studies showed unprecedented antitumor activity in patients with B-cell lymphoma, chronic lymphocytic leukemia (NCT01029366, NCT00466531) or B-cell acute lymphoblastic leukemia. This success concluded with the recent USFDA and EMA approval of two CAR T-cell therapies targeting CD19-expressing B cells.
Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The understanding of cancer pathogenesis has significantly improved in the recent past which has led to new therapeutic concepts such as targeted agents designed to inhibit molecular pathways that are crucial for tumor growth, or immunotherapeutic approaches (Vanneman and Dranoff, 2012; Gotwals et al., 2017; Banchereau and Palucka, 2018) including immune checkpoint inhibitors (Dine et al., 2017). Another recent example is Yescarta, a chimeric antigen receptor (CAR) T cell therapy, approved as the second gene therapy by the FDA for treating diffuse large B-cell lymphoma (DLBCL, the most common type of non-Hodgkin lymphoma; FDA, 2018c); Yescarta has received the orphan drug status (see next section). This has led to an improved survival of patients suffering from certain types of cancer and finds expression, too, in a trend towards an increased share of oncologic drugs as part of the number of drugs approved per year as shown in the following figure (see also Centerwatch, 2018).
Opportunities and challenges in radiomics and radiogenomics
Published in Ruijiang Li, Lei Xing, Sandy Napel, Daniel L. Rubin, Radiomics and Radiogenomics, 2019
Ruijiang Li, Yan Wu, Michael Gensheimer, Masoud Badiei Khuzani, Lei Xing
Beyond radiogenomics association studies, one important emerging direction is to leverage the complementary power of imaging and molecular data and integrate them into a unifying model to further improve prediction accuracy of clinical outcomes. This is particularly relevant for improving the value of imaging for precision medicine. Cottereau et al.51 showed that combination of molecular profile and metabolic tumor volume at FDG-PET imaging improved patient stratification for progression-free and overall survival in diffuse large B-cell lymphoma. Grossmann et al.38 combined gene expression and CT radiomic signatures to enhance the accuracy of survival prediction in lung cancer. Cui et al.52 showed that integrating O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation status and volume of the high-risk subregion at multiparametric MRI improved survival stratification in glioblastoma. Recently, Lee et al. developed a CT image-based prognostic signature and validated it in an external cohort of patients with stage I NSCLC.53 Further, it was shown that a composite imaging and genomic signature improved prognostic accuracy upon either one used alone. While still preliminary, these studies provide the initial evidence that image-based biomarkers can provide additional information beyond molecular analysis alone and integrating both will provide more accurate assessment of prognosis and outcomes for individual patients.
Inhibitory potentials of phytocompounds from Ocimum gratissimum against anti-apoptotic BCL-2 proteins associated with cancer: an integrated computational study
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Gideon A. Gyebi, Oludare M. Ogunyemi, Ibrahim M. Ibrahim, Saheed O. Afolabi, Rotimi J. Ojo, Uju D.I. Ejike, Joseph O. Adebayo
The members of the anti-apoptotic B cell lymphoma 2 (BCL- 2) protein family play key regulatory roles in cellular apoptosis. Deregulation of the normal apoptotic process in the cell, driven by the members of the BCL-2 proteins, is a fundamental element in carcinogenesis [1]. The Bcl-2 proteins are reportedly overexpressed in about half of all human cancers which reveals the involvement of the anti-apoptotic members in carcinogenesis (Yip and Reed 2008). The four BH (BH1, BH2, BH3 and BH4) conserved domains, which were identified from nuclear magnetic resonance (NMR) investigation in 2001 [2], are critical for the signaling functions of these proteins. The BH1-BH3 domain forms a hydrophobic groove, while the BH4 stabilizes the entire structure. The BH3 domain which resides superficially on the anti-apoptotic proteins plays a central role as it accommodates pro-apoptotic partners (Bax/Bak) [3]. On account of this structural built up, substances that interact with the critical amino acid residues in this groove serve as promising inhibitors that may interfere with anti-apoptotic BCL-2 proteins; and thereby promote apoptosis in cancer cells [4]. In this direction, navitoclax [5] and ABT-199 [6] and other drugable compounds have been developed through combinatorial technique and are under way through clinical trials for treatment of cancers [7]. Thus, targeting the BCL- 2 proteins, which are known to perform pivotal functions in the regulation of apoptosis, have been explored toward developing anticancer drugs.
Inflammatory and immunological changes caused by noise exposure: A systematic review
Published in Journal of Environmental Science and Health, Part C, 2022
Amirreza Abouee-Mehrizi, Yahya Rasoulzadeh, Tohid Kazemi, Mehran Mesgari-Abbasi
Yang et al (2004) indicated that the prevalence of positive anti-heat shock protein 70 antibodies (anti-Hsp70) in persons with high-frequency hearing loss (P < 0.05), and the prevalence of positive anti-Hsp60 in persons with low-frequency hearing loss was significantly increased (P < 0.01) at the Dongfeng Motor Corporation in Shiyan, Hubei in China.60 Increased immunoglobulin G (IgG) and immunoglobulin M (IgM) levels until noon and then decreased until evening were reported in the people exposed to noise at 96 dB at the Van Ferit Melen (VFM) airport in Turkey.38 Increased level of interleukin 12 (IL-12) and decreased level of natural killer T (NKT) cells were presented in old people with available audiometric testing data, inflammatory markers data and covariates data in Hertfordshire (UK).61 Increased risk for B-cell lymphoma was indicated in the Danish people between 30 and 84 years old exposed to noise above 65 dB with a primary diagnosis of non-Hodgkin lymphoma (NHL).62 Moreover, enhanced white blood cell (WBC) count, neutrophil count, IL-6, and C-reactive protein (CRP) levels were reported after hearing loss through road traffic noise in female subjects in South Korea (Table 1).63
Cadmium induces cytotoxicity in normal mouse renal MM55.K cells
Published in International Journal of Environmental Health Research, 2022
Ho Jeong Lee, Ju Hong Lee, Seon Min Lee, Na Hyun Kim, Yeon Gyu Moon, Tae Kil Tak, Moonjung Hyun, Jeong Doo Heo
Apoptosis, the process of programmed cell death, is defined by morphological change such as cytoplasmic shrinking, extensive plasma membrane blebbing, and formation of nuclear condensation. Apoptosis proceeds through two main pathways, the caspase-dependent and caspase-independent pathways. Caspases, a family of cysteine-dependent aspartate-directed proteases, play critical roles in the initiation and execution of apoptosis. In addition, mitochondrial proteins, such as B-cell lymphoma (Bcl)-2 family proteins are important for apoptosis regulation. These proteins could be either pro-apoptotic, such as Bcl-2 associated X protein (Bax) and Bcl-2 homologous antagonist/killer, or antiapoptotic, such as Bcl-extra large (Bcl-xL) (Hatok and Racay 2016). Furthermore, the AKT signaling pathway and mitogen-activated protein kinases (MAPKs) such as extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (p38 MAPKs) regulate cell survival, proliferation, and apoptosis (Wada and Penninger 2004).