In organic chemistry , xylene or xylol (from Greek ξύλον (xylon) 'wood'; IUPAC name : dimethylbenzene ) are any of three organic compounds with the formula (CH 3 ) 2 C 6 H 4 . They are derived from the substitution of two hydrogen atoms with methyl groups in a benzene ring; which hydrogens are substituted determines which of three structural isomers results. It is a colorless, flammable, slightly greasy liquid of great industrial value.
55-519: Wendy K. Wee ( Principal Financial & Accounting Officer ) Telik, Inc. was set up in 1988 and was reverse merged into privately held MabVax in May 2014. The major drug of the company was TELINTRA, an investigational agent that was in development for the treatment of myelodysplastic syndrome (MDS) and idiopathic chronic neutropenia . In 2007, a class action was filed against Telik, Inc., alleging that they made false and misleading statements about
110-409: A tear gas agent. Oxidation and ammoxidation also target the methyl groups, affording dicarboxylic acids and the dinitriles. Electrophiles attack the aromatic ring, leading to chloro- and nitroxylenes. Xylene is flammable but of modest acute toxicity, with LD 50 ranges from 200 to 5000 mg/kg for animals. Oral LD 50 for rats is 4300 mg/kg. The principal mechanism of detoxification
165-504: A FISH panel for MDS, or virtual karyotype . Xylene The mixture is referred to as both xylene and, more precisely, xylenes. Mixed xylenes refers to a mixture of the xylenes plus ethylbenzene . The four compounds have identical molecular formulas C 8 H 10 . Typically the four compounds are produced together by various catalytic reforming and pyrolysis methods. Xylenes are an important petrochemical produced by catalytic reforming and also by coal carbonisation in
220-538: A connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy (therapy associated MDS, t-MDS). MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea , or procarbazine , typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to DNA topoisomerase II inhibitors occurs after
275-752: A dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from other causes of anemia, thrombocytopenia, and leukopenia is important. MDS is diagnosed with any type of cytopenia (anemia, thrombocytopenia, or neutropenia) being present for at least 6 months, the presence of at least 10% dysplasia or blasts (immature cells) in 1 cell lineage, and MDS associated genetic changes, molecular markers or chromosomal abnormalities. A typical diagnostic investigation includes: The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis , dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts. Dysplasia can affect all three lineages seen in
330-649: A global consortium began construction of one of the world's largest xylene plants in Singapore . Xylene was first isolated and named in 1850 by the French chemist Auguste Cahours (1813–1891), having been discovered as a constituent of wood tar . Xylenes are produced by the methylation of toluene and benzene . Commercial or laboratory-grade xylene produced usually contains about 40–65% of m -xylene and up to 20% each of o -xylene , p -xylene and ethylbenzene . The ratio of isomers can be shifted to favor
385-449: A good prognosis : Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern Indicators of a poor prognosis : Advanced age; severe neutropenia or thrombocytopenia; high blast count in
440-420: A material used for endodontics (root-canal treatments). In the petroleum industry, xylene is also a frequent component of paraffin solvents, used when the tubing becomes clogged with paraffin wax. Xylene is used in the laboratory to make baths with dry ice to cool reaction vessels, and as a solvent to remove synthetic immersion oil from the microscope objective in light microscopy . In histology , xylene
495-851: A more favorable IPSS score tend to have a more favorable outcome with transplantation. Iron overload may develop in MDS as a result of repeated RBC transfusions , which are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may obviate the need for RBC transfusion, many MDS patients may not respond to these treatments, thus may develop secondary hemochromatosis due to iron overload from repeated transfusions. Patients with chronic iron overload can have iron deposits in their liver, heart, and endocrine glands. For patients requiring many transfusions, serum ferritin levels, number of transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. The goal
550-426: A more orderly DNA methylation profile in the hematopoietic stem cell nucleus , thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia . Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to
605-451: A myelodysplastic/myeloproliferative neoplasm (MDS/MPN) rather than pure myelodysplastic process. Some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan , cyclophosphamide , busulfan , and chlorambucil ) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as
SECTION 10
#1732802471773660-448: A part of a routine blood count: Patients with MDS have an overall risk of almost 30% for developing acute myelogenous leukemia . Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea , and pallor , but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Fever, weight loss and splenomegaly should point to
715-440: A shorter latency of only 1–3 years and can have a 11q23 translocation. Other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into MDS. MDS is thought to arise from mutations in the multipotent bone-marrow stem cell , but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells
770-430: A similar survival benefit to azacitidine and has a response rate as high as 43%. Decitabine is available in combination with cedazuridine as Decitabine/cedazuridine (Inqovi) is a fixed-dosed combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Lenalidomide is effective in reducing red blood cell transfusion requirement in patients with
825-462: A solvent in printing , rubber , and leather industries. It is a common component of ink, rubber , and adhesives . In thinning paints and varnishes , it can be substituted for toluene where slower drying is desired, and thus is used by conservators of art objects in solubility testing. Similarly it is a cleaning agent , e.g., for steel , silicon wafers , and integrated circuits . In dentistry, xylene can be used to dissolve gutta percha ,
880-405: A variety of alcohols. The azeotrope with water consists of 60% xylenes and boils at 94.5 °C. As with many alkylbenzene compounds, xylenes form complexes with various halocarbons . The complexes of different isomers often have dramatically different properties from each other. p -Xylene is the principal precursor to terephthalic acid and dimethyl terephthalate , both monomers used in
935-693: Is MDS that often progresses to acute myelocytic leukemia, or less commonly, chronic myelomonocytic leukemia . Transient myeloproliferative disease , renamed Transient Abnormal Myelopoiesis (TAM), is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia . The elimination of other causes of cytopenias, along with
990-636: Is a group of disorders caused by a defect, familial, or sporadic inactivating mutations , in one of the two GATA2 genes . These autosomal dominant mutations cause a reduction in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development , maintenance, and functionality of blood-forming , lymph-forming , and other tissue-forming stem cells . In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations
1045-521: Is converted to isophthalic acid derivatives, which are components of alkyd resins . Generally, two kinds of reactions occur with xylenes: those involving the methyl groups and those involving the ring C–H bonds. Being benzylic and hence weakened, the C–H bonds of the methyl groups are susceptible to free-radical reactions, including halogenation to the corresponding xylene dichlorides (bis(chloromethyl)benzenes), while mono-bromination yields xylyl bromide ,
1100-715: Is defined as: Hypoplastic MDS, MDS with fibrosis, MDS with bi-allelic TP53 inactivation, and CCUS were added to the WHO 5th ed. Another subtype called Myeloid neoplasms with germ line predisposition and organ dysfunction includes CEBPA / DDX41 / RUNX1 disorders, GATA2 deficiency and SAMD9 /9L syndromes. The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML. The IPSS scoring system can help guide therapy for patients with MDS. In those with low risk MDS (designated by an IPSS score less than 3.5), no disease specific treatment has been found to be helpful and treatment
1155-431: Is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion. Mutations in splicing factors have been found in 40–80% of people with MDS, with a higher incidence of mutations detected in people who have more ring sideroblasts . Mutations in
SECTION 20
#17328024717731210-634: Is focused on supportive care by maintaining blood counts. Erythrostimulating agents such as darbepoetin alfa or erythropoietin may be used to raise the red blood cell count. The mean duration of response to erythrostimulating agents is 8-23 months, and the response rate is about 39% (with a response defined as a 1 mg/dL rise in the hemoglobin level or a person not requiring a transfusion). Romiplostim and eltrombopag are thrombopoeitin receptor agonists which act on megakaryocytes (platelet precursor cells) to increase platelet production. They are used to increase platelet counts and have been shown to reduce
1265-402: Is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB ), then transformation to acute myelogenous leukemia (AML)
1320-927: Is oxidation to methylbenzoic acid and hydroxylation to hydroxylene. The main effect of inhaling xylene vapor is depression of the central nervous system (CNS), with symptoms such as headache, dizziness, nausea and vomiting. At an exposure of 100 ppm, one may experience nausea or a headache. At an exposure between 200 and 500 ppm, symptoms can include feeling "high", dizziness, weakness, irritability, vomiting, and slowed reaction time. The side effects of exposure to low concentrations of xylene ( < 200 ppm ) are reversible and do not cause permanent damage. Long-term exposure may lead to headaches, irritability, depression, insomnia, agitation, extreme tiredness, tremors, hearing loss, impaired concentration and short-term memory loss. A condition called chronic solvent-induced encephalopathy , commonly known as "organic-solvent syndrome" has been associated with xylene exposure. There
1375-454: Is said to have occurred. The progression of MDS to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell. Although recognition of leukemic transformation was historically important (see History ), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML, but rather from
1430-407: Is the most widely used clearing agent. Xylene is used to remove paraffin from dried microscope slides prior to staining. After staining, microscope slides are put in xylene prior to mounting with a coverslip. In one large-scale application, para-xylene is converted to terephthalic acid . The major application of ortho-xylene is as a precursor to phthalate esters , used as plasticizer . Meta-xylene
1485-571: Is to maintain ferritin levels to < 1000 µg/L . Currently, two iron chelators are available in the US, deferoxamine for intravenous use and deferasirox for oral use. A third chelating agent is available, deferiprone , but it has limited utility in MDS patients because of a major side effect of neutropenia. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy has been shown. Iron overload not only leads to organ damage, but also induces genomic instability and modifies
1540-577: Is variable, with about 30% of patients progressing to refractory AML. Low risk MDS (which is associated with favorable genetic variants, decreased myeloblastic cells [less than 5% blasts], less severe anemia, thrombocytopenia, or neutropenia or lower International Prognostic Scoring System scores) is associated with a life expectancy of 3–10 years. Whereas high risk MDS is associated with a life expectancy of less than 3 years. Stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly. Indicators of
1595-458: Is very little information available that isolates xylene from other solvent exposures in the examination of these effects. Hearing disorders have been also linked to xylene exposure, both from studies with experimental animals, as well as clinical studies. Xylene is also a skin irritant and strips the skin of its oils, making it more permeable to other chemicals. The use of impervious gloves and masks, along with respirators where appropriate,
1650-1009: The Company’s business and prospects during the Class Period. Myelodysplastic syndrome A myelodysplastic syndrome ( MDS ) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue , shortness of breath , bleeding disorders , anemia , or frequent infections . Some types may develop into acute myeloid leukemia . Risk factors include previous chemotherapy or radiation therapy , exposure to certain chemicals such as tobacco smoke , pesticides , and benzene , and exposure to heavy metals such as mercury or lead . Problems with blood cell formation result in some combination of low red blood cell , platelet , and white blood cell counts. Some types of MDS cause an increase in
1705-466: The WHO 5th edition and International Consensus Classification (ICC) systems are both actively in use. The list of dysplastic syndromes under the 2008 WHO system included the following: Includes the subset Thrombocytosis (MDS/MPN-T) myelodysplastic/myeloproliferative disorder Revised to MDS with IB1 and MDS with IB2. (Increased Blasts) MDS may present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to
Telik - Misplaced Pages Continue
1760-399: The accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS. Hematopoietic stem cell aging is thought to be associated with the accrual of multiple genetic and epigenetic aberrations leading to the suggestion that MDS is, in part, related to an inability to adequately cope with DNA damage . An emerging perspective is that
1815-431: The bone marrow (20–29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section; completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern Karyotype prognostic factors: Cytogenetic abnormalities can be detected by conventional cytogenetics,
1870-423: The bone marrow. The best way to diagnose dysplasia is by morphology and special stains ( PAS ) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by: On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors , which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to
1925-470: The center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles . This morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. Also, topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia ( RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands . In
1980-401: The chromosome 5q deletion subtype ( 5q- syndrome ) of MDS and the median duration of response is greater than 2 years. Luspatercept is a TGFβ ligand that acts to decrease SMAD2 and SMAD3 signaling involved in erythropoeisis and may be used in MDS with anemia that is not responsive to erythrocyte stimulating agents or mild MDS with ring sideroblasts. Luspatercept was shown to decrease
2035-591: The cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion , MDS patients rarely experience injury from severe anemia. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to iron overload . The recognition of epigenetic changes in DNA structure in MDS has explained
2090-584: The deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, lenalidomide , a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome , and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients
2145-636: The dropping of the atomic bombs in Hiroshima and Nagasaki during World War II). Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia . GATA2 deficiency and SAMD9 /9L syndromes each account for about 15% of MDS cases in children. MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation , benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving
2200-433: The genes encoding for isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) occur in 10–20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state. GATA2 deficiency
2255-424: The hematopoietic niche, favoring progression to acute leukemia. Chelation therapy should be considered to decrease iron overload in selected MDS patients. Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction), it is associated with a rare risk of kidney failure or liver failure. Due to these risks, close monitoring is required. The outlook in MDS
Telik - Misplaced Pages Continue
2310-489: The highly valued p -xylene via the patented UOP- Isomar process or by transalkylation of xylene with itself or trimethylbenzene. These conversions are catalyzed by zeolites . ZSM-5 is used to facilitate some isomerization reactions leading to mass production of modern plastics. The physical properties of the isomers of xylene differ slightly. The melting point ranges from −47.87 °C (−54.17 °F) ( m -xylene) to 13.26 °C (55.87 °F) ( p -xylene)—as usual,
2365-479: The late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, 2016, and 2022, the WHO developed new classification schemes that incorporated genetic findings (5q-) alongside morphology of the cells in the peripheral blood and bone marrow. As of 2024,
2420-436: The making of red blood cells , and antibiotics . Drug therapy may include the medications lenalidomide , antithymocyte globulin , and azacitidine . Some people can be cured by chemotherapy followed by a stem-cell transplant from a donor. About seven per 100,000 people are affected by MDS; about four per 100,000 people newly acquire the condition each year. The typical age of onset is 70 years. The prognosis depends on
2475-454: The manufacture of coke fuel . They also occur in crude oil in concentrations of about 0.5–1%, depending on the source. Small quantities occur in gasoline and aircraft fuels . Xylenes are produced mainly as part of the BTX aromatics ( benzene , toluene , and xylenes) extracted from the product of catalytic reforming known as reformate . Several million tons are produced annually. In 2011,
2530-631: The need for platelet transfusions. However, the two drugs increase the risk of progression to AML, so they are not used in MDS with excess blasts. For those with high risk MDS (characterized by an IPSS score greater than 3.5), the hypomethylating agent azacitidine showed increased survival compared to standard care (supportive care, cytarabine or chemotherapy) and is considered the standard of care. Azacitidine had increased survival (24 months vs 15 months) and higher rates of partial or complete therapeutic response (29% vs 12%) as compared to conventional care. The hypomethylating agent decitabine has shown
2585-471: The need for transfusions and this effect lasted for a median of 30.6 weeks. HLA -matched allogeneic stem cell transplantation , particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy. The success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having
2640-906: The para isomer's melting point is much higher because it packs more readily in the crystal structure. The boiling point for each isomer is around 140 °C (284 °F). The density of each isomer is around 0.87 g/mL (7.3 lb/US gal; 8.7 lb/imp gal) and thus is less dense than water . The odor of xylene is detectable at concentrations as low as 0.08 to 3.7 ppm (parts of xylene per million parts of air) and can be tasted in water at 0.53 to 1.8 ppm. P210 , P233 , P240 , P241 , P242 , P243 , P261 , P264 , P271 , P273 , P280 , P301+P310 , P302+P352 , P303+P361+P353 , P304+P312 , P304+P340 , P305+P351+P338 , P312 , P321 , P322 , P331 , P332+P313 , P337+P313 , P362 , P363 , P370+P378 , P403+P233 , P403+P235 , P405 , P501 Xylenes form azeotropes with water and
2695-439: The petroleum industry have a slightly higher risk of contracting the disease than the general population. Xylene and benzene exposures have been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to
2750-431: The production of polyethylene terephthalate (PET) plastic bottles and polyester clothing. 98% of p -xylene production, and half of all xylenes produced is consumed in this manner. o -Xylene is an important precursor to phthalic anhydride . The demand for isophthalic acid is relatively modest, so m -xylene is rarely sought (and hence the utility of its conversion to the o - and p -isomers). Xylenes are used as
2805-402: The production of immature blood cells (called blasts ), in the bone marrow or blood . The different types of MDS are identified based on the specific characteristics of the changes in the blood cells and bone marrow. Treatments may include supportive care , drug therapy, and hematopoietic stem cell transplantation . Supportive care may include blood transfusions , medications to increase
SECTION 50
#17328024717732860-418: The single lineage. This is called MDS-Low Blasts in the WHO 5th ed. Patients with MDS occasionally present with leukocytosis or thrombocytosis instead of the usual cytopenia. This may represent overlap syndromes with myeloproliferative neoplasms. Most cases of unclassifiable MDS from the 2008 WHO version would be considered Clonal Cytopenias of Undetermined Significance (CCUS) by the WHO 5th ed. CCUS
2915-502: The success of two (namely the hypomethylating agents 5-azacytidine and decitabine ) of three (the third is lenalidomide ) commercially available medications approved by the U.S. Food and Drug Administration to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating
2970-486: The type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The average survival time following diagnosis is 2.5 years. MDS was first recognized in the early 1900s; it came to be called myelodysplastic syndrome in 1976. Signs and symptoms are nonspecific and generally related to the blood cytopenias: Many individuals are asymptomatic, and blood cytopenia or other problems are identified as
3025-534: The underlying mechanism of MDS could be a defect in one or more pathways that are involved in repairing damaged DNA . In MDS an increased frequency of chromosomal breaks indicates defects in DNA repair processes. Also elevated levels of 8-oxoguanine were found in the DNA of a significant proportion of MDS patients, indicating that the base excision repair pathway that is involved in handling oxidative DNA damages may be defective in these cases. Since at least 1974,
#772227