Biologically Targeted Agents in Head and Neck Cancers
John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford in Head & Neck Surgery Plastic Surgery, 2018
As discussed earlier, there is an increasing understanding of the molecular pathways leading to malignant transformation in normal cells. DNA damage, which is an inevitable consequence of cellular metabolism and proliferation, can also be caused by exogenous agents including ionizing and non-ionizing irradiation and environmental chemical toxins. Clinical and medical oncologists exploit these agents, in the form of radiotherapy and chemotherapy, to inflict DNA damage on cancer cells. However, cancers frequently have a deranged DNA damage response and, as discussed earlier, this leads to a state of genomic instability that can drive the evolution of more aggressive cellular clones within the tumour. Importantly, the loss of key components of the DNA damage response may also constitute a cancer-specific molecular ‘Achilles’ heel’ that is vulnerable to therapeutic exploitation with a new generation of targeted radiosensitizing agents.59 Development of radiosensitizers designed to target the DNA damage response (DDR) will require very careful clinical trial design, because of the potential risks of unwanted and unacceptable normal tissue toxicity arising from damage to normal cells.57, 59
The Physics of Proton Biology *
Harald Paganetti in Proton Therapy Physics, 2018
Not all normal tissue complications can be parameterized with cell kill parameters such as (α/β)x. For instance, it has been shown that the proton RBE for asymptomatic radiographic changes in lung CT is significantly higher than 1.1 [75]. Thus, while for tumors the RBE for cell death might be relevant, other endpoints are presumably more relevant for most normal tissue complications. Organ-specific effects of interest are early effects such as erythema and late effects such as lung fibrosis, brain necrosis, or spinal cord injury. It is unclear to what extent the RBE for cell survival is a predictive surrogate for OAR RBE. Surviving cells with unrepaired or misrepaired damage can transmit changes to descendent cells, and malignant transformation can thus be initiated by gene mutation. For instance, no relation has been found between fibroblast radiosensitivity and the development of late normal tissue effects such as fibrosis [76,77]. The relationship between clinically observed late effects and DNA repair capacity has been discussed by Bentzen [78].
Malignant Neoplasms of the Colon
Philip H. Gordon, Santhat Nivatvongs, Lee E. Smith, Scott Thorn Barrows, Carla Gunn, Gregory Blew, David Ehlert, Craig Kiefer, Kim Martens in Neoplasms of the Colon, Rectum, and Anus, 2007
The sequence of nucleotides within cellular chromosomes is reproduced faithfully and is passed down from generation to generation during cell division. A “normal” rate of mutation is estimated to be one mistake in every 10 billion base pairs copied. To correct replication errors, a repair mechanism is dependent on genes called mismatch repair genes. Malignant transformation appears to result from the accumulation of mutations within genes that are critical to cell growth and differentiation caused either by an increase in the mutational rate or because the DNA repair process is compromised. A carcinoma is the end result of four to 12 genetic changes that convey a growth advantage to the mutated cells. During the initiation phase, there is an increase in the mutational rate of DNA. Mutations in some genes become incorporated into an individual’s genome and are passed from generation to generation. These “germline mutations” may occur in genes related to carcinoma and, as a result, cause hereditary carcinoma. Other mutations, termed “somatic,” cause a sporadic carcinoma. Knudson (37) proposed that inherited carcinomas arise in individuals with germline mutations of one allele of a recessively acting carcinoma gene, after which only one additional somatic alteration is needed to inactivate the gene and initiate carcinogenesis. Sporadic carcinomas require two somatic mutations (or allelic loss).
Insights into apoptotic proteins in chemotherapy: quantification techniques and informing therapy choice
Published in Expert Review of Proteomics, 2018
Apoptosis is a process of programmed cell death that normally occurs during development or processes such as aging and to maintain cell population in tissues [1]. Hence, reduced apoptosis or its resistance plays an essential role in carcinogenesis [2]. Malignant transformation of cells involves gross alterations in protein expression. The qualitative and quantitative measurement of these alterations may be used for improved cancer diagnosis and treatment monitoring. The proteome is the entire set of proteins that are produced or modified by an organism or system under distinct conditions. Variations in the proteome can either be posttranslational modifications such as phosphorylation or ubiquitination, or distinct proteins are produced under distinct settings, e.g. carcinogenesis [3].
Pathogenicity and virulence of human T lymphotropic virus type-1 (HTLV-1) in oncogenesis: adult T-cell leukemia/lymphoma (ATLL)
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Sanaz Ahmadi Ghezeldasht, David J. Blackbourn, Arman Mosavat, Seyed Abdolrahim Rezaee
Many factors, such as viral and cellular factors, can act as cell transformation agents. For example, in the case of HTLV-1 BCL-xL, BAD expressions were up-regulated [176], but BIM gene expression was down-regulated in the ATLL cells to suppress apoptosis [177]. In our high-throughput studies, BCL2A1 [87] and BCL2L11 (BIM) genes were up-regulated and down-regulated [178], respectively. In the early stage of the infected cell transformation, apoptosis is inhibited by constitutive production of Bcl-xL, induced by Tax, and leads to leukemia promotion [179,180]. High throughput and gene expression studies in our laboratory had very controversial results in the up-regulation or down-regulation [85,89] of BIM in infected cancerous cells. However, Mühleisen et al. showed that Tax expressing cells became resistant to cell death by suppressing the expression of pro-apoptotic BH3-only proteins, BIM, and BID [181]. Overall, it can be suggested that the BIM expression, as an element of the intrinsic apoptosis pathway, does not have a pivotal role in ATLL cell transformation.
Human mesenchymal stem cell therapy in the management of luminal and perianal fistulizing Crohn’s disease – review of pathomechanism and existing clinical data
Published in Expert Opinion on Biological Therapy, 2018
Renáta Bor, Anna Fábián, Klaudia Farkas, Tamás Molnár, Zoltán Szepes
Serious adverse event related with MSC therapy has not been published so far. A meta-analysis of randomized controlled trials did not detect an association between acute infusional toxicity, organ system complications, infection, death, or malignancy; however, significant association was found between MSCs and transient fever [54]. In addition, despite the theoretical risk of malignant transformation, cancer formation related with cell therapy has not been reported [55]. Predominantly, mild clinical symptoms have occurred, which – apart from the fever – did not show any difference between the control and therapeutic groups. The most frequent adverse events after local administration of MSCs were proctalgia, diarrhea, and peri-anal inflammation (increase of C-reactive protein, anal abscess, etc.) which did not require hospitalization [44,48,52,53]. Intravenous administration of MSCs is associated with nonspecific systemic symptoms such as fever, headache, nausea, fatigue, anorexia, or dizziness [32,34,56].
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