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Tumor necrosis factor

From Wikipedia, the free encyclopedia
(Redirected from Cachectin)
"TNF" redirects here. For other uses, see TNF (disambiguation).
Not to be confused with lymphotoxin alpha.

TNF
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTNF, DIF, TNF-alpha, TNFA, TNFSF2, Tumour necrosis factor, TNF-α, tumor necrosis factor, TNLG1F, Tumor necrosis factor alpha
External IDsOMIM: 191160; MGI: 104798; HomoloGene: 496; GeneCards: TNF; OMA:TNF - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7124

21926

Ensembl

ENSMUSG00000024401

UniProt

P01375

P06804

RefSeq (mRNA)

NM_000594

NM_001278601
NM_013693

RefSeq (protein)

NP_000585

NP_001265530
NP_038721

Location (UCSC)Chr 6: 31.58 – 31.58 MbChr 17: 35.42 – 35.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha, TNFα [without a dash in between] or TNF-α [with a dash][5][6]) is a cytokine and member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain. It is the first cytokine to be described as an adipokine as secreted by adipose tissue.[7]

TNF signaling occurs through two receptors: TNFR1 and TNFR2.[8][9] TNFR1 is constitutively expressed on most cell types, whereas TNFR2 is restricted primarily to endothelial, epithelial, and subsets of immune cells.[8][9] TNFR1 signaling tends to be pro-inflammatory and apoptotic, whereas TNFR2 signaling is anti-inflammatory and promotes cell proliferation.[8][9] Suppression of TNFR1 signaling has been important for treatment of autoimmune diseases,[10] whereas TNFR2 signaling promotes wound healing.[9]

TNF-α exists as a transmembrane form (mTNF-α) and as a soluble form (sTNF-α). sTNF-α results from enzymatic cleavage of mTNF-α,[11] by a process called substrate presentation. mTNF-α is mainly found on monocytes/macrophages where it interacts with tissue receptors by cell-to-cell contact.[11] sTNF-α selectively binds to TNFR1, whereas mTNF-α binds to both TNFR1 and TNFR2.[12] TNF-α binding to TNFR1 is irreversible, whereas binding to TNFR2 is reversible.[13]

The primary role of TNF is in the regulation of immune cells. TNF, as an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, and inflammation, inhibit tumorigenesis and viral replication, and respond to sepsis via IL-1 and IL-6-producing cells. Dysregulation of TNF production has been implicated in a variety of human diseases including Alzheimer's disease,[14] cancer,[15] major depression,[16] psoriasis[17] and inflammatory bowel disease (IBD).[18] Though controversial, some studies have linked depression and IBD to increased levels of TNF.[19][20]

As an adipokine, TNF promotes insulin resistance, and is associated with obesity-induced type 2 diabetes.[7] As a cytokine, TNF is used by the immune system for cell signaling. If macrophages (certain white blood cells) detect an infection, they release TNF to alert other immune system cells as part of an inflammatory response.[7] Certain cancers can cause overproduction of TNF. TNF parallels parathyroid hormone both in causing secondary hypercalcemia and in the cancers with which excessive production is associated. Under the name tasonermin, TNF is used as an immunostimulant drug in the treatment of certain cancers. Drugs that counter the action of TNF are used in the treatment of various inflammatory diseases such as rheumatoid arthritis.

History

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Discovery

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In the 1890s, William B. Coley, based on anecdotes of cancer patients being cured by sudden attacks of erysipelas, theorized that bacterial infections had a beneficial effect against tumors, particularly sarcomas. Coley was able to successfully treat cancer patients by injecting them with a mixture of bacterial toxins from heat-sterilized Streptococcus and Bacillus prodigiosus in and around the tumors, causing the tumors to hemorrhage. However, the effectiveness of this treatment was inconsistent and repeated injections caused severe side effects such as chills and fevers, causing the treatment to be discontinued.[21]

In the 1930s and 1940s, Shear et al. isolated the active tumor-hemorrhaging agent from the bacterial toxins of Escherichia coli and Serratia marcescens. They demonstrated that this agent, endotoxin, when injected into mice with sarcomas, could inhibit tumor growth or cause tumor regression.[22] However, tumor regression was highly variable, with smaller doses of endotoxin often having more potency than larger doses, or entire batches of mice being resistant to the endotoxin.[23]

In 1975, Elizabeth Carswell and Lloyd Old et al. investigated the tumor-killing properties of endotoxin by extracting serum from donor mice injected with endotoxin, and injecting the serum into recipient mice carrying transplanted sarcomas. They discovered that donor mice infected with Bacillus Calmette Guerin (BCG), upon exposure to endotoxin, produced serum that caused the tumors to hemorrhage in the recipient mice. The serum of BCG-infected donor mice did not contain residual endotoxins, leading the authors to conclude that the serum contained a separate cytotoxic factor, termed Tumor Necrosis Factor (TNF). Since BCG-infected mice had enlarged spleens due to an increased production of macrophages, the authors deduced that TNF was released by macrophages upon exposure to endotoxins.[24]

In addition to causing sarcomas to hemorrhage in vivo, TNF was also cytotoxic to L-929 cells, a transformed cell line, in vitro. Cytotoxicity to L-929 cells in vitro became the standard technique for detecting TNF. [25] TNF was cytotoxic to cancerous and transformed cell lines, but not to normal, untransformed cell lines, raising hopes that it could be used as a cancer therapy. [24]

Isolation, Sequencing, and Expression

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In August 1984, Bharat Aggarwal et al. at Genentech purified and characterized human TNF. The TNF was produced by culturing HL-60, a human cell line, with phorbol myristate acetate (PMA), a phagocyte stimulant similar to endotoxin. The TNF was purified using controlled pore glass beads, DEAE chromatography, Mono Q chromatography, and reversed-phase HPLC. TNF purified using reversed-phase HPLC was determined to have a molecular weight of 17,000 kDa by SDS-PAGE, whereas TNF purified using TSK-HPLC under nondenaturing conditions was determined to have an approximate molecular weight of 45,000 kDa, suggesting that TNF naturally exists as an oligomer. The TNF amino acid sequence was determined using Edman degradation, revealing a sequence of 157 amino acids with significant homology to the amino acid sequence of lymphotoxin. [26]

In that same month, Pennica et al, also at Genentech, sequenced the cDNA of human TNF. A cDNA library was constructed from the mRNA of HL-60 cells induced by PMA. A 42-base long DNA probe, constructed by guessing the codons of a portion of the TNF amino acid sequence, was used to screen the cDNA library. The matching cDNA was sequenced, revealing a presequence of 76 amino acids followed by the 157 amino acids of mature TNF. The authors deduced that TNF is first synthesized into a larger precursor form containing a signal peptide, before being processed and released as a smaller mature form. The authors also synthesized TNF in e coli and verified its cytotoxicity against L-929 cells in vitro and against mouse sarcomas in vivo. [27]

Physiological Effects

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In June 1981, Ian A. Clark et al. found that healthy mice infected with Plasmodium vinckei, a malaria-causing parasite, upon exposure to endotoxin, developed malaria-like symptoms such as liver damage, hypoglycemia, and blood clotting, while also releasing mediators including TNF. Uninfected mice did not release these mediators when injected with endotoxin. These results, combined with evidence of endotoxins in the serum of malaria patients, led the authors to propose that mediators such as TNF are present in acute malaria infections, and that they play a role in causing malaria symptoms. [28]

In 1985, Kevin J. Tracy, Ian Milsark, and Anthony Cerami found that mice immunized from TNF via TNF antiserum were resistant to the lethal effects of endotoxin, indicating that TNF is one of the mediators of endotoxin lethality. [29] In 1986, this was confirmed by Kevin J. Tracy and Bruce Beutler, when they demonstrated that mice injected with TNF exhibited common symptoms of endotoxin poisoning, such as hypotension, metabolic acidosis, hemoconcentration, and death. [30]

In 1991, Michael Goodman demonstrated that mice injected with TNF released increased levels of tyrosine and 3-methyl-L-histidine in their skeletal muscles, indicating that TNF induces muscle breakdown. [31] In 1996, Stefferl et al. demonstrated that mice injected with mouse TNF develop fevers, definitively demonstrating that TNF is a pyrogen. Previous studies showed inconclusive results due to the use of human TNF, rather than mouse TNF, on mice. [32]

The observation that TNF induces wasting and endotoxic shock led to rethinking about its potential role as a cancer therapy. [25]

Identification with Cachectin

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In September 1981, Masanobu Kawakami and Anthony Cerami investigated the tendency of bacteria endotoxins to induce hypertriglyceridemia, caused by a deficiency of lipoprotein lipase (LPL), when administered to animals. They extracted serum from donor mice injected with endotoxin and injected the serum into recipient mice. They discovered that endotoxin-resistant recipient mice had decreased LPL activity after receiving the serum of endotoxin-treated mice, even though their LPL activities were not markedly reduced when injected with endotoxin directly. The authors also discovered that exudate cells, consisting mostly of macrophages, when incubated with endotoxins, produced a medium that lowered LPL activity when injected into mice. The authors deduced that hypertriglyceridemia was caused by a mediating factor, termed cachectin, secreted by exudate cells in response to endotoxins. [33]

In 1985, Beutler et al. demonstrated that mouse cachectin has similar cytotoxicity against L-929 cells as TNF, as well as a near identical N-terminal amino acid sequence to human TNF, indicating that cachectin and TNF were the same protein. Since cachectin (now TNF) is known to suppress the biosynthesis of a specific protein, lipoprotein lipase, the authors deduced that TNF's cytotoxic mechanism operated in a similar way. [34]

Name Changes

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In 1968, lymphotoxin, a cytotoxin secreted by lymphocytes, was discovered. Both TNF and lymphotoxin were detected based on their ability to kill L-929 cells, were able to bind to the two known TNF receptors, TNFRI and TNFRII, and shared significant genetic and amino acid homology. The similarities between TNF and lymphotoxin led to the unofficial renaming of TNF to TNF-α and lymphotoxin to TNF-β, with the published rationale being that they are detected with the same in vitro assays. [25]

In 1993, lymphotoxin, which is not a transmembrane protein, was discovered to be present on the cell membrane by forming a complex with a separate transmembrane glycoprotein, termed lymphotoxin-β. [35] Lymphotoxin was also discovered to play a critical role in the development of lymphoid organs, distinguishing its biological function from TNF. As a result of these developments, TNF-β was renamed to lymphotoxin-α, and TNF-α was renamed back to TNF. [25]

Gene

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The human TNF gene was cloned in 1985.[36] It maps to chromosome 6p21.3, spans about 3 kilobases and contains 4 exons. The last exon shares similarity with lymphotoxin alpha (LTA, once named as TNF-β).[37] The three prime untranslated region (3'-UTR) of TNF contains an AU-rich element (ARE).

Structure

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TNF is primarily produced as a 233-amino acid-long type II transmembrane protein arranged in stable homotrimers.[38][39] From this membrane-integrated form the soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage by the metalloprotease TNF alpha converting enzyme (TACE, also called ADAM17).[40] The soluble 51 kDa trimeric sTNF tends to dissociate at concentrations below the nanomolar range, thereby losing its bioactivity. The secreted form of human TNF takes on a triangular pyramid shape, and weighs around 17-kDa. Both the secreted and the membrane bound forms are biologically active, although the specific functions of each is controversial. But, both forms do have overlapping and distinct biological activities.[41]

The common house mouse TNF and human TNF are structurally different.[42] The 17-kilodalton (kDa) TNF protomers (185-amino acid-long) are composed of two antiparallel β-pleated sheets with antiparallel β-strands, forming a 'jelly roll' β-structure, typical for the TNF family, but also found in viral capsid proteins.

Cell signaling

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TNF can bind two receptors, TNFR1 (TNF receptor type 1; CD120a; p55/60) and TNFR2 (TNF receptor type 2; CD120b; p75/80). TNFR1 is 55-kDa and TNFR2 is 75-kDa.[43] TNFR1 is expressed in most tissues, and can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, whereas TNFR2 is found typically in cells of the immune system, and responds to the membrane-bound form of the TNF homotrimer. As most information regarding TNF signaling is derived from TNFR1, the role of TNFR2 is likely underestimated. At least partly because TNFR2 has no intracellular death domain, it shows neuroprotective properties.[44]

Signaling pathway of TNFR1. Dashed grey lines represent multiple steps.

Upon contact with their ligand, TNF receptors also form trimers, their tips fitting into the grooves formed between TNF monomers. This binding causes a conformational change to occur in the receptor, leading to the dissociation of the inhibitory protein SODD from the intracellular death domain. This dissociation enables the adaptor protein TRADD to bind to the death domain, serving as a platform for subsequent protein binding. Following TRADD binding, three pathways can be initiated.[45][46]

  • Activation of NF-κB: TRADD recruits TRAF2 and RIP. TRAF2 in turn recruits the multicomponent protein kinase IKK, enabling the serine-threonine kinase RIP to activate it. An inhibitory protein, IκBα, that normally binds to NF-κB and inhibits its translocation, is phosphorylated by IKK and subsequently degraded, releasing NF-κB. NF-κB is a heterodimeric transcription factor that translocates to the nucleus and mediates the transcription of a vast array of proteins involved in cell survival and proliferation, inflammatory response, and anti-apoptotic factors.
  • Activation of the MAPK pathways: Of the three major MAPK cascades, TNF induces a strong activation of the stress-related JNK group, evokes moderate response of the p38-MAPK, and is responsible for minimal activation of the classical ERKs. TRAF2/Rac activates the JNK-inducing upstream kinases of MLK2/MLK3,[47] TAK1, MEKK1 and ASK1 (either directly or through GCKs and Trx, respectively). SRC- Vav- Rac axis activates MLK2/MLK3 and these kinases phosphorylate MKK7, which then activates JNK. JNK translocates to the nucleus and activates transcription factors such as c-Jun and ATF2. The JNK pathway is involved in cell differentiation, proliferation, and is generally pro-apoptotic.
  • Induction of death signaling: Like all death-domain-containing members of the TNFR superfamily, TNFR1 is involved in death signaling.[48] However, TNF-induced cell death plays only a minor role compared to its overwhelming functions in the inflammatory process. Its death-inducing capability is weak compared to other family members (such as Fas), and often masked by the anti-apoptotic effects of NF-κB. Nevertheless, TRADD binds FADD, which then recruits the cysteine protease caspase-8. A high concentration of caspase-8 induces its autoproteolytic activation and subsequent cleaving of effector caspases, leading to cell apoptosis.

The myriad and often-conflicting effects mediated by the above pathways indicate the existence of extensive cross-talk. For instance, NF-κB enhances the transcription of C-FLIP, Bcl-2, and cIAP1 / cIAP2, inhibitory proteins that interfere with death signaling. On the other hand, activated caspases cleave several components of the NF-κB pathway, including RIP, IKK, and the subunits of NF-κB itself. Other factors, such as cell type, concurrent stimulation of other cytokines, or the amount of reactive oxygen species (ROS) can shift the balance in favor of one pathway or another.[citation needed] Such complicated signaling ensures that, whenever TNF is released, various cells with vastly diverse functions and conditions can all respond appropriately to inflammation.[citation needed] Both protein molecules tumor necrosis factor alpha and keratin 17 appear to be related in case of oral submucous fibrosis[49]

In animal models TNF selectively kills autoreactive T cells.[50]

There is also evidence that TNF-α signaling triggers downstream epigenetic modifications that result in lasting enhancement of pro-inflammatory responses in cells.[51][52][53][54]

Enzyme regulation

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This protein may use the morpheein model of allosteric regulation.[55]

Clinical significance

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TNF was thought to be produced primarily by macrophages,[56] but it is produced also by a broad variety of cell types including lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neurons.[57][unreliable medical source?] Large amounts of TNF are released in response to lipopolysaccharide, other bacterial products, and interleukin-1 (IL-1). In the skin, mast cells appear to be the predominant source of pre-formed TNF, which can be released upon inflammatory stimulus (e.g., LPS).[58]

It has a number of actions on various organ systems, generally together with IL-1 and interleukin-6 (IL-6):

A local increase in concentration of TNF will cause the cardinal signs of Inflammation to occur: heat, swelling, redness, pain and loss of function.

Whereas high concentrations of TNF induce shock-like symptoms, the prolonged exposure to low concentrations of TNF can result in cachexia, a wasting syndrome. This can be found, for example, in cancer patients.

Said et al. showed that TNF causes an IL-10-dependent inhibition of CD4 T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.[60]

The research of Pedersen et al. indicates that TNF increase in response to sepsis is inhibited by the exercise-induced production of myokines. To study whether acute exercise induces a true anti-inflammatory response, a model of 'low grade inflammation' was established in which a low dose of E. coli endotoxin was administered to healthy volunteers, who had been randomised to either rest or exercise prior to endotoxin administration. In resting subjects, endotoxin induced a 2- to 3-fold increase in circulating levels of TNF. In contrast, when the subjects performed 3 hours of ergometer cycling and received the endotoxin bolus at 2.5 h, the TNF response was totally blunted.[61] This study provides some evidence that acute exercise may inhibit TNF production.[62]

In the brain TNF can protect against excitotoxicity.[44] TNF strengthens synapses.[8] TNF in neurons promotes their survival, whereas TNF in macrophages and microglia results in neurotoxins that induce apoptosis.[44]

TNF-α and IL-6 concentrations are elevated in obesity.[63][64][65] Use of monoclonal antibodies against TNF-α is associated with increases rather than decreases in obesity, indicating that inflammation is the result, rather than the cause, of obesity.[65] TNF and IL-6 are the most prominent cytokines predicting COVID-19 severity and death.[7]

TNFα in Liver Fibrosis

TNFα mediates the inflammation that activates resident Hepatic Stellate Cells (HSCs) into the fibrogenic myofibroblasts that are largely responsible for liver fibrosis. However, whereas TNF receptor 1 knock-out mice demonstrate reduced fibrosis, TNFα can also suppress collagen α1(I) gene expression in fibroblasts in vitro, raising questions in regard to the complexity of its role in liver fibrosis.[66]

While TNFα treatment suppresses collagen α1 gene expression, apoptosis, and proliferation in activated HSCs in vitro, an activity that should ameliorate fibrosis, it has also been shown to inhibit apoptosis in activated HSCs, an activity which should, in principle, induce fibrosis.[67] Specifically, TNFα produced by hepatic macrophages is known to support the survival of HSCs, the source of hepatic myofibroblasts.[68] TNFα is therefore believed to promote liver fibrosis through its pro-survival effect, despite its pleiotropic effects on HSCs.[69]

Yet another way TNFα contributes to the worsening of liver fibrosis is by stimulating the production of TGF-β by hepatocytes and TIMP1 by hepatocytes and HSCs.[70]

It should furthermore be noted that CCR9+ macrophages, which play an essential role in the pathogenesis of liver fibrosis, are TNFα-dependent. When TNFα is attenuated using an anti-TNFα antibody, hepatic HSCs are not activated by CCR9+ macrophages.[71]

TNFα in NAFLD

TNFα has a dual role in the development of NAFLD. Firstly, it is released among other pro-inflammatory cytokines, such as IL-6 and IL-1β, in response to the increased signaling from NF-κB during steatosis. TNFα then participates in the recruitment of Kuppfer cells, which increase inflammation and lead to the development of NASH.[72]

Secondly, the binding of TNFα to TNFα receptor 1 (TNFR1) facilitates insulin resistance, a known contributor to NAFLD progression, by suppressing insulin signaling.[73] Following the binding of TNF-α to TNFR1, intracellular c-JUN N terminal kinase (JNK) and IkB kinase (IKK) signals are activated, and the phosphorylation of JNK (p-JNK) and IKK1/1KK2 further attenuate insulin receptor substrate 1 (IRS-1). The phosphorylation of IRS-1 leads to the suppression of insulin signaling and, subsequently, to insulin resistance.[74] Indeed, a study has demonstrated that blocking TNFR1 protected Wistar rats from diet-induced obesity and insulin resistance.[74]

TNFR1 inhibition has been suggested as a possible therapy for NAFLD. A high-fat diet (HFD) mouse model of NAFLD has been used to demonstrate that the use of an anti-TNFR1-antibody can reduce liver steatosis and triglyceride content, as well as the activation of downstream target genes of lipogenesis. Insulin resistance likewise improved in these mice as a result of the reduced activation of MAP kinase MKK7 and its downstream target JNK.[75]

It is additionally thought that TNFα increases the production of MCP-1 (monocyte chemoattractant protein-1). MCP-1 is known to be overexpressed in obesity and is believed to be responsible for the recruitment of macrophages into adipose tissue and contribute to insulin resistance.[76] The production of MCP-1 increases in primary hepatocytes exposed to TNFα; TNF-α stimulates Mcp1 gene transcription by activating the Akt/PKB pathway.[77]

The dual role of TNFα in the development of NAFLD is counteracted by the anti-inflammatory action of adiponectin, whose production is impaired in metabolic syndrome.[70]

TNFα is, therefore, thought to play a deleterious role in the progression of NAFLD to NASH and cirrhosis.

Pharmacology

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Main article: TNF inhibitor

TNF promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma. These disorders are sometimes treated by using a TNF inhibitor. This inhibition can be achieved with a monoclonal antibody such as infliximab (Remicade) binding directly to TNF, adalimumab (Humira), certolizumab pegol (Cimzia) or with a decoy circulating receptor fusion protein such as etanercept (Enbrel) which binds to TNF with greater affinity than the TNFR.[78]

On the other hand, some patients treated with TNF inhibitors develop an aggravation of their disease or new onset of autoimmunity. TNF seems to have an immunosuppressive facet as well. One explanation for a possible mechanism is this observation that TNF has a positive effect on regulatory T cells (Tregs), due to its binding to the tumor necrosis factor receptor 2 (TNFR2).[79]

Anti-TNF therapy has shown only modest effects in cancer therapy. Treatment of renal cell carcinoma with infliximab resulted in prolonged disease stabilization in certain patients. Etanercept was tested for treating patients with breast cancer and ovarian cancer showing prolonged disease stabilization in certain patients via downregulation of IL-6 and CCL2. On the other hand, adding infliximab or etanercept to gemcitabine for treating patients with advanced pancreatic cancer was not associated with differences in efficacy when compared with placebo.[80]

Interactions

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TNF has been shown to interact with TNFRSF1A.[81][82]

Nomenclature

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Because LTα is no longer referred to as TNFβ,[83] TNFα, as the previous gene symbol, is now simply called TNF, as shown in HGNC (HUGO Gene Nomenclature Committee) database.

References

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