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(12) Patent Application Publication (10) Pub. No.: US 2005/0255484A1 Walkirs Et Al

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US 2005O255484A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0255484A1 Walkirs et al. (43) Pub. Date: Nov. 17, 2005 (54) DIAGNOSTIC MARKERS OF STROKE AND (60) Provisional application No. 60/313,775, filed on Aug. CEREBRAL INJURY AND METHODS OF 20, 2001. Provisional application No. 60/334,964, USE THEREOF filed on Nov. 30, 2001. Provisional application No. 60/346,485, filed on Jan. 2, 2002. Provisional appli (75) Inventors: Gunars E. Walkirs, Escondido, CA cation No. 60/313,775, filed on Aug. 20, 2001. Pro (US); Jeffrey R. Dahlen, San Diego, visional application No. 60/334,964, filed on Nov.30, CA (US); Howard J. Kirchick, San Diego, CA (US); Kenneth F. Buechler, 2001. Provisional application No. 60/346,485, filed Rancho Santa Fe, CA (US) on Jan. 2, 2002. Correspondence Address: Publication Classification FOLEY & LARDNER P.O. BOX 80278 (51) Int. Cl." ........................... C12O 1/68; G01N 33/53; GO1N 33/567 SAN DIEGO, CA 92138-0278 (US) (52) U.S. Cl. .................................................. 435/6; 435/7.2 (73) Assignee: Biosite, Inc. (21) Appl. No.: 10/875,800 (57) ABSTRACT Filed: Jun. 23, 2004 (22) The present invention relates to methods for the diagnosis Related U.S. Application Data and evaluation of Stroke and transient ischemic attacks. A variety of markers are disclosed for assembling a panel for (63) Continuation-in-part of application No. 10/714,078, Such diagnosis and evaluation. In various aspects, the inven filed on Nov. 14, 2003, which is a continuation-in-part tion provides methods for early detection and differentiation of application No. 10/673,077, filed on Sep. 26, 2003, which is a continuation-in-part of application No. of Stroke types and transient ischemic attacks, for determin 10/371,149, filed on Feb. 20, 2003, which is a con ing the prognosis of a patient presenting with Stroke Symp tinuation-in-part of application No. PCT/US02/ toms, and identifying a patient at risk for cerebral vasos 26604, filed on Aug. 20, 2002. pasm. Invention methods provide rapid, Sensitive and Said application No. 10/371,149 is a continuation-in Specific assays to greatly increase the number of patients that part of application No. 10/225,082, filed on Aug. 20, can receive beneficial Stroke treatment and therapy, and 2002. reduce the costs associated with incorrect Stroke diagnosis. B-chimerin 2.0 15 Hem SC Normal Patent Application Publication Nov. 17, 2005 Sheet 1 of 7 US 2005/0255484A1 Fig. 1A: B-chimerin 2.0 15 Hem SC Normal Patent Application Publication Nov. 17, 2005 Sheet 2 of 7 US 2005/0255484A1 Fig. 1B: MPO Hem SC Normal Patent Application Publication Nov. 17, 2005 Sheet 3 of 7 US 2005/0255484A1 Fig. 1C: NDKA 160 Hem lsc Normal Patent Application Publication Nov. 17, 2005 Sheet 4 of 7 US 2005/0255484A1 Fig. 1D: Nogo receptor 10 Hem sc Normal Patent Application Publication Nov. 17, 2005 Sheet 5 of 7 US 2005/0255484A1 Fig. 1E: RAGE Hem SC Normal Patent Application Publication Nov. 17, 2005 Sheet 6 of 7 US 2005/0255484A1 Fig. 1F: RNA-BP Hem ISC Normal Patent Application Publication Nov. 17, 2005 Sheet 7 of 7 US 2005/0255484A1 Fig. 1G: UFDP1H Hem SC Normal US 2005/0255484 A1 Nov. 17, 2005 DIAGNOSTIC MARKERS OF STROKE AND unilateral neurologic dysfunction that extends progressively, CEREBRAL INJURY AND METHODS OF USE without producing headache or fever. Evolving Stroke may THEREOF also become a “completed Stroke,” in which Symptoms develop rapidly and are maximal within a few minutes. RELATED APPLICATIONS 0007 Hemorrhagic stroke is caused by intracerebral or 0001. This application is a continuation-in-part applica Subarachnoid hemorrhage, i.e., bleeding into brain tissue, tion of U.S. application Ser. No. 10/714,078, filed Nov. 14, following blood vessel rupture within the brain. Intracere 2003; which is a continuation-in-part application of U.S. bral and Subarachnoid hemorrhage are Subsets of a broader application Ser. No. 10/673,077, filed Sep. 26, 2003; which category of hemorrhage referred to as intracranial hemor is a continuation-in-part of U.S. application Ser. No. 10/371, rhage. Intracerebral hemorrhage is typically due to chronic 149, filed Feb. 20, 2003; which is a continuation-in-part hypertension, and a resulting rupture of an arteriosclerotic application of U.S. application Ser. No. 10/225,082, filed vessel. Stroke-associated Symptom(s) of intracerebral hem Aug. 20, 2002, and International Application No. PCT/ orrhage are abrupt, with the onset of headache and Steadily US02/26604, filed Aug. 20, 2002; each of which claims the increasing neurological deficits. Nausea, vomiting, delirium, benefit of U.S. Provisional Application Nos. 60/313,775, Seizures and loSS of consciousness are additional common filed Aug. 20, 2001, 60/334,964 filed Nov. 30, 2001, and Stroke-associated Symptoms. 60/346,485, filed Jan. 2, 2002; the contents of each of which 0008. In contrast, most Subarachnoid hemorrhage is are hereby incorporated herein in their entirety, including all caused by head trauma or aneurysm rupture which is accom tables, figures, and claims. panied by high pressure blood release which also causes direct cellular trauma. Prior to rupture, aneurysms may be FIELD OF THE INVENTION asymptomatic, or occasionally associated with tension or 0002 The present invention relates to the identification migraine headaches. However, headache typically becomes and use of diagnostic markers for Stroke and cerebral injury. acute and Severe upon rupture, and may be accompanied by In a various aspects, the invention relates to methods for the varying degrees of neurological deficit, vomiting, dizziness, early detection and differentiation of Stroke and transient and altered pulse and respiratory rates. ischemic attacks and the identification of individuals at risk 0009 Transient ischemic attacks (TIAS) have a sudden for delayed neurological deficits upon presentation with onset and brief duration, typically 2-30 minutes. Most TIAS Stroke Symptoms. are due to emboli from atherosclerotic plaques, often origi nating in the arteries of the neck, and can result from brief BACKGROUND OF THE INVENTION interruptions of blood flow. The symptoms of TIAS are identical to those of Stroke, but are only transient. Concomi 0003. The following discussion of the background of the tant with underlying risk factors, patients experiencing TIAS invention is merely provided to aid the reader in understand are at a markedly increased risk for Stroke. ing the invention and is not admitted to describe or constitute prior art to the present invention. 0010. The foregoing can be viewed as a manifestation of “brain ischemia. For example, the long-standing definition 0004 Stroke is a manifestation of vascular injury to the of TIAS has been based on the assumption that TIAS are brain which is commonly Secondary to atherosclerosis or asSociated with complete resolution of brain ischemia occur hypertension, and is the third leading cause of death (and the ring rapidly enough to cause only transient Symptoms. In Second most common cause of neurologic disability) in the contrast, ischemic Stroke was thought to cause permanent United States. Stroke can be categorized into two broad injury to brain tissues. The Similarity of these acute clinical types, “ischemic Stroke' and "hemorrhagic Stroke.” Addi syndromes made it difficult to differentiate them; they were tionally, a patient may experience transient ischemic attacks, distinguished on the basis of an arbitrary criterion for the which are in turn a high risk factor for the future develop duration of Symptoms. But the development of Symptoms of ment of a more Severe episode. acute cerebral ischemia constitutes a medical emergency. 0005 Ischemic stroke encompasses thrombotic, embolic, 0011 Concepts of brain ischemia and the temporal cor lacunar and hypoperfusion types of Strokes. Thrombi are relation with clinical events have changed considerably on occlusions of arteries created in Situ within the brain, while the basis of Studies using computed tomography (CT), emboli are occlusions caused by material from a distant magnetic resonance imaging (MRI), positron-emission Source, Such as the heart and major vessels, often dislodged tomography, and other imaging techniques. However, deter due to myocardial infarct or atrial fibrillation. Less fre mining the immediate cause of Verebral ischemia and dif quently, thrombi may also result from vascular inflammation ferentiating ischemic from hemorrhagic Stroke is difficult. due to disorderS Such as meningitis. Thrombi or emboli can CT Scans can detect parenchymal bleeding greater than 1 cm result from atherosclerosis or other disorders, for example, and 95% of all Subarachnoid hemorrhages. CT scan often arteritis, and lead to physical obstruction of arterial blood cannot detect ischemic Strokes until 6 hours from onset, Supply to the brain. Lacunar Stroke refers to an infarct within depending on the infarct size. MRI may be more effective non-cortical regions of the brain. Hypoperfusion embodies than CT Scan in early detection of ischemic Stroke, but it is diffuise injury caused by non-localized cerebral ischemia, less accurate at differentiating ischemic from hemorrhagic typically caused by myocardial infarction and arrhythmia. Stroke, and is not widely available. An electrocardiogram 0006 The onset of ischemic stroke is often abrupt, and (ECG) can be used in certain circumstances to identify a can become an "evolving Stroke’ manifested by neurologic cardiac cause of Stroke. Angiography is a definitive test to deficits that worsen over a 24-48 hour period. In evolving identify Stenosis or occlusion of large and Small cranial Stroke, "stroke-associated Symptom(s)” commonly include blood vessels, and can locate the cause of Subarachnoid US 2005/0255484 A1 Nov. 17, 2005 hemorrhages, define aneurysms, and detect cerebral vasos interest can be measured. In certain embodiments, these pasm. It is, however, an invasive procedure that is also markers can be compared to a level that is associated with limited by cost and availability.
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    Supplementary Materials

    Supplementary material. S1. Images from automatic imaging reader Cytation™ 1. A, A’, A’’ present the same field of view. Cells migrating from the upper compartment of the inserts are stained with DID (red color), Cell nuclei are stained with DAPI (blue color). A’ and A’’ demonstrate the method of analysis (A’ – nuclei numbering, A’’ – migrating cells numbering), scale bar – 300 µm. ASC BM-MSC Y BM-MSC A mean SEM mean SEM mean SEM CXCL6 2.240 0.727 4.158 0.677 2.149 1.816 CXCL16 4.277 0.248 0.763 0.405 1.130 0.346 CXCL12 -2.855 0.483 -4.528 0.226 -3.616 0.318 SMAD3 -0.511 0.191 -1.522 0.188 -1.332 0.215 TGFB2 3.742 0.533 1.238 0.210 0.990 0.568 COL14A 1.532 0.357 -0.397 0.736 -1.522 0.469 MHX 1.397 0.414 1.145 0.412 0.642 0.613 SCX 2.984 0.301 2.062 0.320 2.031 0.249 RUNX2 3.290 0.359 2.319 0.388 2.546 0.529 PPRAG 1.720 0.303 2.926 0.423 2.912 0.215 Supplementary material S3. The table provides the mean Δct and SEM values for all genes and all groups analyzed in this study (n=8 in each group). Supplementary material S2. The table provides the list of genes which displayed significantly different expression between hASCs and hBM-MSCs A based on microarray nr Exp p-value Exp Fold Change ID Symbol Entrez Gene Name 1 2.84E-05 16.896 16960355 TM4SF1 transmembrane 4 L six family member 1 2 9.10E-09 12.238 16684080 IFI6 interferon alpha inducible protein 6 3 3.93E-08 11.851 16667702 VCAM1 vascular cell adhesion molecule 1 4 1.54E-05 9.944 16840113 CXCL16 C-X-C motif chemokine ligand 16 5 2.01E-06 9.123 16852463 RAB27B RAB27B, member RAS oncogene
  • Supplementary Table 2

    Supplementary Table 2

    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942