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Chronic inflammation is initiated by immune disruptors\u2010induced progressive changes in physiology and function of susceptible host tissues that lead to increased immune suppression and multistep disease processes including carcinogenesis. The interrelated multiple hypotheses that are presented for the first time in this article are extension of author's earlier series of \u2018accidental\u2019 discoveries on the role of inflammation in developmental stages of immune dysfunction toward tumorigenesis and angiogenesis. Detailed analyses of data on chronic diseases suggest that nearly all age\u2010associated illnesses, generally categorized as \u2018mild\u2019 (e.g., increased allergies), \u2018moderate\u2019 (e.g., hypertension, colitis, gastritis, pancreatitis, emphysema) or \u2018severe\u2019 (e.g., accelerated neurodegenerative and autoimmune diseases or site\u2010specific cancers and metastasis) are variations of hypersensitivity responses of tissues that are manifested as different diseases in immune\u2010responsive or immune\u2010privileged tissues. Continuous release\/presence of low level histamine (subclinical) in circulation could contribute to sustained oxidative stress and induction of \u2018mild\u2019 or \u2018moderate\u2019 or \u2018severe\u2019 (immune tsunami) immune disorders in susceptible tissues. Site\u2010specific cancers are proposed to be \u2018severe\u2019 (irreversible) forms of cumulative delayed hypersensitivity responses that would induce immunological chaos in favor of tissue growth in target tissues. Shared or special features of growth from fetus development into adulthood and aging processes and carcinogenesis are briefly compared with regard to energy requirements of highly complex function of Yin and Yang. Features of Yang (growth\u2010promoting) arm of acute inflammation during fetus and cancer growth will be compared for consuming low energy from glycolysis (Warburg effect). Growth of fetus and cancer cells under hypoxic conditions and impaired mitochondrial energy requirements of tissues including metabolism of essential branched amino acids (e.g., val, leu, isoleu) will be compared for proposing a working model for future systematic research on cancer biology, prevention and therapy. Presentation of a working model provides insightful clues into bioenergetics that are required for fetus growth (absence of external threat and lack of high energy\u2010demands of Yin events and parasite\u2010like survival in host), normal growth in adulthood (balance in Yin and Yang processes) or disease processes and carcinogenesis (loss of balance in Yin\u2013Yang). Future studies require focusing on dynamics and promotion of natural\/inherent balance between Yin (tumoricidal) and Yang (tumorigenic) of effective immunity that develop after birth. Lawless growth of cancerous cells and loss of cell contact inhibition could partially be due to impaired mitochondria (mitophagy) that influence metabolism of branched chain amino acids for biosynthesis of structural proteins. The author invites interested scientists with diverse expertise to provide comments, confirm, dispute and question and\/or expand and collaborate on many components of the proposed working model with the goal to better understand cancer biology for future designs of cost\u2010effective research and clinical trials and prevention of cancer. Initial events during oxidative stress\u2010induced damages to DNA\/RNA repair mechanisms and inappropriate expression of inflammatory mediators are potentially correctable, preventable or druggable, if future studies were to focus on systematic understanding of early altered immune response dynamics toward multistep chronic diseases and carcinogenesis.<\/jats:p>","DOI":"10.1186\/s40169-016-0108-3","type":"journal-article","created":{"date-parts":[[2016,8,23]],"date-time":"2016-08-23T14:41:19Z","timestamp":1471963279000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Is cancer a severe delayed hypersensitivity reaction and histamine a blueprint?"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-2742","authenticated-orcid":false,"given":"Mahin","family":"Khatami","sequence":"first","affiliation":[{"name":"National Cancer Institute (NCI) the National Institutes of Health (NIH) Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,8,23]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/PSY.0b013e31817b9371"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61460-4"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/56.5.B198"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-009-9059-2"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers6010297"},{"key":"e_1_2_13_7_1","unstructured":"KhatamiM(2016) In:Cancer research and therapy: scam of century\u2013promote immunity [Yin\u2010Yang]. 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