Attach to Form 990 or Form 990-EZ.
Information about Schedule A (Form 990 or 990-EZ) and its instructions is at www.irs.gov/form990.
| (i)Name of supported organization | (ii) EIN | (iii) Type of organization (described on lines 1- 9 above or IRC section (see instructions)) | (iv) Is the organization listed in your governing document? | (v) Amount of monetary support (see instructions) | (vi) Amount of other support (see instructions) | |
|---|---|---|---|---|---|---|
| Yes | No | |||||
| Total | ||||||
Calendar year (or fiscal year beginning in) ![]() |
(a) 2010 | (b) 2011 | (c) 2012 | (d) 2013 | (e) 2014 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 1 | Gifts, grants, contributions, and membership fees received. (Do not include any "unusual grants.") .... | ||||||
| 2 | Tax revenues levied for the organization's benefit and either paid to or expended on its behalf....... | ||||||
| 3 | The value of services or facilities furnished by a governmental unit to the organization without charge.. | ||||||
| 4 | Total. Add lines 1 through 3 | ||||||
| 5 | The portion of total contributions by each person (other than a governmental unit or publicly supported organization) included on line 1 that exceeds 2% of the amount shown on line 11, column (f).. | ||||||
| 6 | Public support. Subtract line 5 from line 4. | ||||||
Calendar year
(or fiscal year beginning in) ![]() |
(a) 2010 | (b) 2011 | (c) 2012 | (d) 2013 | (e) 2014 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 7 | Amounts from line 4.. | ||||||
| 8 | Gross income from interest, dividends, payments received on securities loans, rents, royalties and income from similar sources... | ||||||
| 9 | Net income from unrelated business activities, whether or not the business is regularly carried on.. | ||||||
| 10 | Other income. Do not include gain or loss from the sale of capital assets (Explain in Part VI.).. | ||||||
| 11 | Total support Add lines 7 through 10. | ||||||
Calendar year (or fiscal year beginning in) ![]() |
(a) 2010 | (b) 2011 | (c) 2012 | (d) 2013 | (e) 2014 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 1 | Gifts, grants, contributions, and membership fees received. (Do not include any "unusual grants.") . | ||||||
| 2 | Gross receipts from admissions, merchandise sold or services performed, or facilities furnished in any activity that is related to the organization's tax-exempt purpose...... | ||||||
| 3 | Gross receipts from activities that are not an unrelated trade or business under section 513.. | ||||||
| 4 | Tax revenues levied for the organization's benefit and either paid to or expended on its behalf... | ||||||
| 5 | The value of services or facilities furnished by a governmental unit to the organization without charge.. | ||||||
| 6 | Total. Add lines 1 through 5. | ||||||
| 7a | Amounts included on lines 1, 2, and 3 received from disqualified persons... | ||||||
| b | Amounts included on lines 2 and 3 received from other than disqualified persons that exceed the greater of $5,000 or 1% of the amount on line 13 for the year. | ||||||
| c | Add lines 7a and 7b.. | ||||||
| 8 | Public support (Subtract line 7c from line 6.) | ||||||
Calendar year (or fiscal year beginning in) ![]() |
(a) 2010 | (b) 2011 | (c) 2012 | (d) 2013 | (e) 2014 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 9 | Amounts from line 6... | ||||||
| 10a | Gross income from interest, dividends, payments received on securities loans, rents, royalties and income from similar sources.. | ||||||
| b | Unrelated business taxable income (less section 511 taxes) from businesses acquired after June 30, 1975. | ||||||
| c | Add lines 10a and 10b. | ||||||
| 11 | Net income from unrelated business activities not included in line 10b, whether or not the business is regularly carried on. | ||||||
| 12 | Other income. Do not include gain or loss from the sale of capital assets (Explain in Part VI.) .. | ||||||
| 13 | Total support. (Add lines 9, 10c, 11, and 12.).. | ||||||
| Section A - Adjusted Net Income | (A) Prior Year |
(B) Current Year (optional) |
||||
| 1 | Net short-term capital gain | 1 | ||||
| 2 | Recoveries of prior-year distributions | 2 | ||||
| 3 | Other gross income (see instructions) | 3 | ||||
| 4 | Add lines 1 through 3 | 4 | ||||
| 5 | Depreciation and depletion | 5 | ||||
| 6 | Portion of operating expenses paid or incurred for production or collection of gross income or for management, conservation, or maintenance of property held for production of income (see instructions) | 6 | ||||
| 7 | Other expenses (see instructions) | 7 | ||||
| 8 | Adjusted Net Income (subtract lines 5, 6 and 7 from line 4) | 8 | ||||
| Section B - Minimum Asset Amount | (A) Prior Year |
(B) Current Year (optional) |
||||
| 1 | Aggregate fair market value of all non-exempt-use assets (see instructions for short tax year or assets held for part of year): | 1 | ||||
| a | Average monthly value of securities | 1a | ||||
| b | Average monthly cash balances | 1b | ||||
| c | Fair market value of other non-exempt-use assets | 1c | ||||
| d | Total (add lines 1a, 1b, and 1c) | 1d | ||||
| e | Discount claimed for blockage or other factors (explain in detail in Part VI): | |||||
| 2 | Acquisition indebtedness applicable to non-exempt use assets | 2 | ||||
| 3 | Subtract line 2 from line 1d | 3 | ||||
| 4 | Cash deemed held for exempt use. Enter 1-1/2% of line 3 (for greater amount, see instructions). | 4 | ||||
| 5 | Net value of non-exempt-use assets (subtract line 4 from line 3) | 5 | ||||
| 6 | Multiply line 5 by .035 | 6 | ||||
| 7 | Recoveries of prior-year distributions | 7 | ||||
| 8 | Minimum Asset Amount (add line 7 to line 6) | 8 | ||||
| Section C - Distributable Amount | Current Year | |||||
| 1 | Adjusted net income for prior year (from Section A, line 8, Column A) | 1 | ||||
| 2 | Enter 85% of line 1 | 2 | ||||
| 3 | Minimum asset amount for prior year (from Section B, line 8, Column A) | 3 | ||||
| 4 | Enter greater of line 2 or line 3 | 4 | ||||
| 5 | Income tax imposed in prior year | 5 | ||||
| 6 | Distributable Amount. Subtract line 5 from line 4, unless subject to emergency temporary reduction (see instructions) | 6 | ||||
| 7 | Check here if the current year is the organization's first as a non-functionally-integrated Type III supporting organization (see instructions) | |||||
| Section D - Distributions | Current Year | |
|---|---|---|
| 1 Amounts paid to supported organizations to accomplish exempt purposes | ||
|
2
Amounts paid to perform activity that directly furthers exempt purposes of supported organizations, in excess of income from activity |
||
| 3 Administrative expenses paid to accomplish exempt purposes of supported organizations | ||
| 4 Amounts paid to acquire exempt-use assets | ||
| 5 Qualified set-aside amounts (prior IRS approval required) | ||
| 6 Other distributions (describe in Part VI). See instructions | ||
| 7Total annual distributions. Add lines 1 through 6. | ||
|
8
Distributions to attentive supported organizations to which the organization is responsive (provide details in Part VI). See instructions |
||
| 9 Distributable amount for 2014 from Section C, line 6 | ||
| 10 Line 8 amount divided by Line 9 amount | ||
| Section E - Distribution Allocations (see instructions) |
(i) Excess Distributions |
(ii) Underdistributions Pre-2014 |
(iii) Distributable Amount for 2014 |
|
|---|---|---|---|---|
|
1
Distributable amount for 2014 from Section C, line 6 |
||||
|
2
Underdistributions, if any, for years prior to 2014 (reasonable cause required--see instructions) |
||||
| 3 Excess distributions carryover, if any, to 2014: | ||||
| a From 2009.......X | ||||
| b From 2010.......X | ||||
| c From 2011.......X | ||||
| d From 2012.......X | ||||
| e From 2013....... | ||||
| fTotal of lines 3a through e | ||||
| g Applied to underdistributions of prior years | ||||
| h Applied to 2014 distributable amount | ||||
|
i
Carryover from 2009 not applied (see instructions) |
||||
| j Remainder. Subtract lines 3g, 3h, and 3i from 3f. | ||||
| 4Distributions for 2014 from Section D, line 7: | ||||
| $ | ||||
| a Applied to underdistributions of prior years | ||||
| b Applied to 2014 distributable amount | ||||
| c Remainder. Subtract lines 4a and 4b from 4. | ||||
|
5
Remaining underdistributions for years prior to 2014, if any. Subtract lines 3g and 4a from line 2 (if amount greater than zero, see instructions) |
||||
|
6
Remaining underdistributions for 2014. Subtract lines 3h and 4b from line 1 (if amount greater than zero, see instructions) |
||||
|
7 Excess distributions carryover to 2015. Add lines 3j and 4c. |
||||
| 8 Breakdown of line 7: | ||||
| a From 2010.......X | ||||
| b From 2011.......X | ||||
| c From 2012.......X | ||||
| d From 2013....... | ||||
| e From 2014....... | ||||
| Facts And Circumstances Test |
|---|
| Return Reference | Explanation |
|---|
| Software ID: | |
| Software Version: |
Attach to Form 990 or 990-EZ.
Information about Schedule O (Form 990 or 990-EZ) and its instructions is at| Return Reference | Explanation |
|---|---|
| FORM 990, PART VI, SECTION A, LINE 2 | VARI, VAI, VAEI, AND VAIGS SHARE COMMON MANAGEMENT. DAVID VAN ANDEL, DR. JANA HALL, TIMOTHY MYERS AND DAVID WHITESCARVER ARE ALSO OFFICERS OF VAI, AND DAVID VAN ANDEL, TIMOTHY MYERS AND DAVID WHITESCARVER ARE OFFICERS OF VAEI AND VAIGS. |
| FORM 990, PART VI, SECTION A, LINE 7A | THE TRUSTEES OF VAN ANDEL INSTITUTE HAVE THE AUTHORITY TO ELECT ONE OR MORE MEMBERS OF VARI'S GOVERNING BODY. |
| FORM 990, PART VI, SECTION B, LINE 11 | FOLLOWING COMPLETION OF THE FINANCIAL STATEMENT AUDIT, THE FORM 990 IS PREPARED AND REVIEWED BY MANAGEMENT. IT IS THEN CIRCULATED TO THE FULL BOARD FOR REVIEW AND FINAL APPROVAL PRIOR TO FILING WITH THE IRS. |
| FORM 990, PART VI, SECTION B, LINE 12C | VARI HAS WRITTEN CONFLICT OF INTEREST ("COI") POLICIES AND PROCEDURES (ADMINISTERED BY VAN ANDEL INSTITUTE) WHICH ADMINISTER AND ENFORCE A PROCESS TO IDENTIFY, EVALUATE, AND MANAGE POTENTIAL CONFLICTS OF INTEREST. THESE POLICIES HAVE BEEN BOARD APPROVED. VAI ADMINISTERS THE COI POLICIES AND PROCEDURES THROUGH TWO COMMITTEES: THE CONFLICTS COMMITTEE ("CC") AND THE INSTITUTIONAL COI COMMITTEE ("ICOIC"). THE COI POLICIES AND PROCEDURES APPLY TO AND SERVE AS A GUIDE FOR EVERYONE IN THE ORGANIZATION. THEY 1) PROVIDE A USEFUL RESOURCE WHEN DEVELOPING ACTIVITIES OR RELATIONSHIPS WITH OUTSIDE ENTITIES OR PERSONS, AND 2) ESTABLISH COMMITTEES TO REVIEW AND MANAGE POTENTIAL CONFLICTS OF INTEREST AS THEY MAY ARISE. THE CC, CHAIRED BY THE CHIEF LEGAL OFFICER, REQUIRES ANNUAL AND UPDATED DISCLOSURES BY COVERED PERSONS AND REVIEWS AND APPROVES MANAGEMENT PLANS. THE INSTITUTIONAL COI POLICIES AND PROCEDURES SERVE AS A GUIDE FOR MEMBERS OF THE BOARDS OF TRUSTEES AND SENIOR EXECUTIVES. IN THE EVENT A POTENTIAL COI ARISES AT THE BOARD OR SENIOR EXECUTIVE LEVEL, THE ICOIC MEETS TO REVIEW AND DECIDE HOW TO MANAGE SUCH POTENTIAL CONFLICTS OF INTEREST IN ACCORDANCE WITH THE COI POLICIES AND PROCEDURES. |
| FORM 990, PART VI, SECTION B, LINE 15 | COMPARABILITY DATA FROM EXPERT THIRD PARTY IS OBTAINED AND REVIEWED BY THE INDEPENDENT, JOINT COMPENSATION COMMITTEE OF VAN ANDEL RESEARCH INSTITUTE AND RELATED ORGANIZATIONS TO DETERMINE APPROPRIATE COMPENSATION FOR THE CEO, EXECUTIVE MANAGEMENT OFFICIALS, OFFICERS, AND KEY EMPLOYEES, ON BEHALF OF VAN ANDEL RESEARCH INSTITUTE. |
| FORM 990, PART VI, SECTION C, LINE 19 | THE CONFLICT OF INTEREST POLICY AND FINANCIAL STATEMENTS ARE AVAILABLE TO THE PUBLIC UPON REQUEST. |
| FORM 990, PART XI, LINE 9: | LOSS ON INTEREST RATE SWAP -7,760,074. |
| FORM 990, PART III, LINE 2 | VAN ANDEL RESEARCH INSTITUTE (VARI) IS DEDICATED TO DETERMINING THE EPIGENETIC, GENETIC, MOLECULAR, AND CELLULAR ORIGINS OF CANCER, PARKINSON'S DISEASE, AND OTHER ILLNESSES AND TO TRANSLATING THOSE FINDINGS INTO EFFECTIVE THERAPIES. THE INSTITUTE'S SCIENTISTS WORK IN ON-SITE LABORATORIES AND PARTICIPATE IN COLLABORATIONS THAT SPAN THE GLOBE. WITH EPIGENETICS AS ITS COMMON THREAD, THE INSTITUTE IS ORGANIZED INTO THE CENTER FOR CANCER AND CELL BIOLOGY, THE CENTER FOR EPIGENETICS, AND THE CENTER FOR NEURODEGENERATIVE SCIENCE. THE CORE TECHNOLOGIES AND SERVICES GROUP PROVIDES A VIVARIUM, A BIOREPOSITORY, AND VALUABLE ON-SITE CAPABILITIES IN IMAGING, PATHOLOGY, BIOINFORMATICS, GENOMICS AND FLOW CYTOMETRY. RESEARCH BY VARI SCIENTISTS IS PUBLISHED IN MAJOR PEER-REVIEWED JOURNALS, INCLUDING, IN 2015, SCIENCE, NATURE, CELL, CELL RESEARCH, NEW ENGLAND JOURNAL OF MEDICINE, CIRCULATION RESEARCH, EXPERIMENTAL CELL RESEARCH, JOURNAL OF TRANSLATION MEDICINE, EXPERIMENTAL NEUROLOGY, GENOME BIOLOGY, GENOME RESEARCH, AMERICAN JOURNAL OF CANCER RESEARCH, AMERICAN JOURNAL OF SURGICAL PATHOLOGY, ANALYTICAL CHEMISTRY, BONE RESEARCH, CANCER RESEARCH, INTERNATIONAL JOURNAL OF CANCER, INTERNATIONAL JOURNAL OF ONCOLOGY, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF BONE AND MINERAL RESEARCH, JOURNAL OF MEDICINAL CHEMISTRY, JOURNAL OF PARKINSON'S DISEASE, MOLECULAR CELL, NEUROBIOLOGY OF DISEASE, PLOS ONE, AND PSYCHONEUROENDOCRINOLOGY. |
| FORM 990, PART III, LINE 4A | LINE 4A - PROGRAM SERVICE ACTIVITY #1 CENTER FOR CANCER AND CELL BIOLOGY THE CENTER FOR CANCER AND CELL BIOLOGY, DIRECTED BY BART WILLIAMS, PH.D., COMPRISES 14 LABORATORIES ENGAGED IN BASIC RESEARCH IN MOLECULAR AND STRUCTURAL BIOLOGY AND IN TRANSLATIONAL RESEARCH ON CANCERS, THE TUMOR MICROENVIRONMENT, AND SKELETAL DISEASES. THE CENTER WELCOMED PATRICK GROHAR, M.D., PH.D., AS AN ASSOCIATE PROFESSOR IN JULY 2015. INVESTIGATORS WITHIN THE CENTER IN 2015 RECEIVED NEW R01 AND R21 AWARDS FROM THE NATIONAL INSTITUTES OF HEALTH, AND A RENEWAL AWARD FROM THE BREAST CANCER RESEARCH FOUNDATION. ALSO, A NEW RESEARCH CONTRACT WITH A PHARMACEUTICAL FIRM WAS SIGNED. VAN ANDEL RESEARCH INSTITUTE'S PATHWAY OF HOPE INITIATIVE PROGRESSED IN 2015 UNDER THE DIRECTION OF ASSOCIATE PROFESSOR JEFFREY MACKEIGAN, PH.D. TSC CAUSES NON-CANCEROUS TUMORS IN MAJOR ORGANS, AND PATIENTS AFFLICTED WITH DISEASE OFTEN SUFFER FROM EPILEPSY, LEARNING DISABILITIES, AND OTHER COMPLICATIONS. THE PATHWAY OF HOPE INITIATIVE INVOLVES TSC INVESTIGATORS FROM ACROSS THE UNITED STATES, WITH FUNDING FROM THE MICHIGAN STRATEGIC FUND, BLUE CROSS BLUE SHIELD OF MICHIGAN, GREAT LAKES SCRIP, ROCKFORD CONSTRUCTION, COLLIERS INTERNATIONAL, TEAM HANNAH TSC, AND INDIVIDUAL DONORS. THE TSC RESEARCH TEAM HAS SCREENED FOR GENES NEVER BEFORE LINKED TO TSC AND IS INVESTIGATING SEVERAL THAT ARE INTRIGUING. THE MACKEIGAN LAB PUBLISHED A COMPARISON OF TWO DRUGS, EVEROLIMUS AND SIROLIMUS, AND THE CLINICAL TRIAL OUTCOMES FOR MANAGING TSC USING THESE DRUGS (MACKEIGAN AND KRUEGER, NEURO-ONCOLOGY 17(12): 1550-1559). STUDIES OF THREE-DIMENSIONAL MOLECULAR STRUCTURES AND THEIR PHYSICAL INTERACTIONS HAVE BEEN PROCEEDING ON SEVERAL FRONTS IN 2015. G PROTEIN-COUPLED RECEPTORS FORM A LARGE, COMPLEX GROUP OF MOLECULAR RECEPTORS IN HUMANS, AND MANY IMPORTANT QUESTIONS ABOUT THEM REMAIN. ONE MAJOR QUESTION WAS ANSWERED WITH THE SOLUTION OF THE RHODOPSIN-ARRESTIN STRUCTURE BY THE XU AND MELCHER LABS, WHICH PROVIDES A BASIS FOR UNDERSTANDING GPCR-MEDIATED, ARRESTIN-BIASED SIGNALING. THE COMPLEX IS RESPONSIBLE FOR REGULATING VITAL PHYSIOLOGICAL FUNCTIONS AND SERVES AS A MAJOR PHARMACOLOGICAL DRUG TARGET. THE NEW FINDINGS PROVIDE SCIENTISTS WITH A ROADMAP FOR SELECTIVELY TARGETING CELLULAR PATHWAYS, WHICH MAY LEAD TO MORE-EFFECTIVE DRUGS WITH FEWER SIDE EFFECTS FOR DISEASES SUCH AS CANCER, HEART DISEASE, AND NEURODEGENERATIVE DISORDERS. THIS PROJECT ALSO EMPLOYED CUTTING-EDGE X-RAY LASER TECHNOLOGY TO SOLVE THE STRUCTURE OF THESE COMPLEX MOLECULES (KANG ET AL., NATURE 523(7562): 561-567). ANOTHER STUDY FROM THESE LABS UNCOVERED THE MECHANISM OF ALLOSTERIC REGULATION OF AMP-ACTIVATED PROTEIN KINASE; THIS ENZYME IS A PROMISING TARGET FOR TREATING DIABETES, OBESITY, AND CANCER (LI ET AL., CELL RESEARCH 25(1): 50-66). STRUCTURAL STUDIES OF PLANT MOLECULES HAVE ALSO ADVANCED. STRINGOLACTONES ARE PLANT HORMONES THAT PROMOTE ROOT SYMBIOSIS WITH NITROGEN-FIXING BACTERIA SUCH AS RHIZOBIUM. VARI LABS HAVE MODELED THE INTERACTION OF STRINGOLACTONE WITH THE DWARF3 PROTEIN, REVEALING THE MECHANISM OF RECEPTOR RECOGNITION AND SIGNALING, WHICH IS A STEP TOWARD IMPROVING THE CRUCIAL MYCORRHIZAL AND RHIZOBIUM SYMBIOSIS OF AGRICULTURAL PLANTS (ZHAO ET AL., CELL RESEARCH 25(11): 1219-1236). ANOTHER STUDY SHOWED PRONOUNCED CONFORMATION CHANGES IN THE MYC3 PROTEIN IN ARABIDOPSIS, IDENTIFYING THE DYNAMIC MECHANISM BY WHICH THE SIGNALING PATHWAY OF THE CRUCIAL PLANT HORMONE JASMONATE IS REPRESSED OR ACTIVATED (ZHANG ET AL., NATURE 525(7568): 269-273). JASMONATE SIGNALING REGULATES A VARIETY OF PLANT PROCESSES, INCLUDING SEED GERMINATION, ROOT GROWTH, FLOWERING, AND PHOTOSYNTHESIS. UNDERSTANDING INTERACTIONS BETWEEN THESE PLANT PROTEINS NOT ONLY HAS IMPLICATIONS FOR GLOBAL CROP PRODUCTION, BUT ALSO OFFERS INSIGHTS INTO MOLECULAR MECHANISMS THAT MAY PLAY A ROLE IN HUMAN DISEASES. MICRO-RNAS ARE AN INCREASINGLY INTERESTING AND RELEVANT AREA OF RESEARCH IN HEALTH AND DISEASE. THE SEMPERE LAB REPORTED A LARGE PROGNOSTIC STUDY OF BLADDER CANCER THAT IDENTIFIED THE MICRO-RNA MIR-34A AS A POTENTIAL BIOMARKER AND/OR THERAPEUTIC TARGET FOR THIS DISEASE (ANDREW ET AL., INTERNATIONAL JOURNAL OF CANCER 137(5): 1158-1166). ANOTHER STUDY PUBLISHED IN 2015 WAS A CRITICAL ANALYSIS OF THE POTENTIAL OF MICRO-RNAS AS BIOMARKERS IN BREAST CANCER MANAGEMENT (GRAVEEL ET AL., BREAST CANCER: TARGETS AND THERAPY 7: 59-79). YET ANOTHER STUDY PROVIDED NOVEL INSIGHT INTO POTENTIAL NEW THERAPEUTIC APPROACHES FOR TRIPLE-NEGATIVE BREAST CANCER, A PARTICULARLY DIFFICULT TO TREAT AND AGGRESSIVE FORM OF THE DISEASE (SAMENI ET AL., CLIN CANCER RES., IN PRESS). VARI ALSO TOOK PART IN ESTABLISHING A UNIFORM NAMING SYSTEM FOR MICRO-RNA GENES AND HELPED ESTABLISH A NEW OPEN-ACCESS DATABASE, MIRGENEDB, ON MICRO-RNAS (FROMM ET AL., ANNUAL REVIEW OF GENETICS 49: 213-242). PROGRESS CONTINUES IN OUR STUDIES OF PANCREATIC CANCER. WORK DONE IN THE HAAB LAB SHOWED THAT SIALYL-LEWIS X PROTEIN INCREASES IN PANCREATIC CANCERS THAT ARE NEGATIVE FOR THE TRADITIONAL MARKER, THE CA19-9 PROTEIN. THIS MAY HELP IN DIFFERENTIATING AMONG SUBGROUPS OF PATIENTS WITH PANCREATIC TUMORS SO THAT THE MOST EFFECTIVE TREATMENT CAN BE PROVIDED (TANG ET AL., MOLECULAR AND CELLULAR PROTEOMICS 14(5): 1323-1333). A SECOND STUDY SHOWED THAT A SUBSET OF PANCREATIC CANCERS HAS AN INCREASE IN CELL-SURFACE GLYCANS CONTAINING A 3'-FUCOSE SUGAR COMPONENT, WHICH MAY COMPLEMENT OTHER BIOMARKERS AND ALLOW IMPROVED DETECTION OF PANCREATIC CANCERS (SINGH ET AL., JOURNAL OF PROTEOME RESEARCH 14(6): 2594-2605). VARI RESEARCHERS HAVE DEVELOPED A KIDNEY-SPECIFIC MOUSE MODEL OF BIRT-HOGG-DUBE SYNDROME TUMORIGENESIS BY KNOCKING OUT THE FLCN GENE IN THE KIDNEY'S PROXIMAL TUBULES. THIS MODEL AVOIDS MANY PROBLEMS THAT NORMALLY OCCUR IN GENETIC KNOCK-OUTS AND ACCURATELY MODELS HUMAN BIRT-HOGG-DUBE SYNDROME (CHEN ET AL., KIDNEY INTERNATIONAL 88(5): 1057-1069). A PROJECT EXPLORING THE WNT/BETA-CATENIN PATHWAY AND THE HEPSIN PATHWAY IN PROSTATE CANCER FOUND THAT THE ACTIVITY OF BOTH IS INCREASED, AND THUS THEY COULD BECOME TARGETS OF CHEMOTHERAPY (VALKENBURG ET AL., THE PROSTATE 75(14): 1579-1585). A STUDY OF MELANOMA XENOGRAFT MODELS TREATED WITH THE DRUG VEMURAFENIB FOUND SEVERAL MECHANISMS BY WHICH THE CANCER CELLS BECAME RESISTANT TO THERAPY. HOWEVER, WHEN VEMURAFENIB WAS COMBINED WITH AN INHIBITOR OF THE MEK PROTEIN, THE TUMORS WERE ERADICATED (MONSMA ET AL., AMERICAN JOURNAL OF CANCER RESEARCH 5(4): 1507-1518). IN CLINICALLY RELATED RESEARCH, A STUDY OF HUMAN OSTEOSARCOMA (BONE CANCER) FOUND THAT THERE WERE SPECIFIC CHANGES IN GENE EXPRESSION IN CELLS THAT WERE HIGHLY RESISTANT TO CHEMOTHERAPY. SUCH CELLS ARE SENSITIVE TO TARGETED EPIGENETIC THERAPIES, AND TARGETING THOSE CHANGES MAY BE A VALUABLE THERAPEUTIC STRATEGY (FOLEY ET AL., JOURNAL OF TRANSLATIONAL MEDICINE 13: 110). A STUDY OF TISSUES FROM TWO INDIVIDUALS SUFFERING FROM OCULOECTODERMAL SYNDROME IDENTIFIED TWO MUTATIONS OF THE KRAS GENE. THE LOW FREQUENCIES OF THE MUTATIONS IN THE PATIENTS SUGGEST THAT THE DISEASE IS A MOSAIC RAS-RELATED DISORDER (PEACOCK ET AL., AMERICAN JOURNAL OF MEDICAL GENETICS A 167(7): 1429-1435). RESEARCH ON THE METABOLISM OF BOTH NORMAL AND PATHOLOGICAL BONE TISSUES HAS CONTINUED IN 2015. A STUDY OF THE WNTLESS PROTEIN, WHICH IS REQUIRED FOR THE SECRETION OF ALL WNT MOLECULES, FOUND THAT WNTLESS REGULATES THE FORMATION OF CARTILAGE AND BONE AND IS ACTIVE IN AFFECTING EMBRYONIC BONE DEVELOPMENT (ZHONG ET AL., DEVELOPMENTAL DYNAMICS 244(10): 1347-1355). IN A STUDY OF BONE HEALING, RADIOACTIVE TECHNETIUM-METHYLENE DIPHOSPHONATE ([99M]TC-MDP) WAS USED TO IMAGE THE HEALING PROCESS. THE UPTAKE OF THIS RADIOTRACER CORRESPONDED TO THE LOCATIONS OF OSTEOBLAST GENERATION IN HEALING OF BONES AND TO OSTEOBLAST CELL MATURATION IN CELL CULTURE (ZHONG ET AL., BONE RESEARCH 3: 15013). ANOTHER VARI STUDY PRODUCED THE FIRST REPORT OF THE FUNCTION OF THE CD82 TRANSMEMBRANE PROTEIN IN BLOOD PLATELETS. CD82 WAS FOUND TO FUNCTION IN MODULATING CLOT RETRACTION, INTEGRIN ALPHAIIB-BETA3 EXPRESSION, CELL ADHESION, AND TYROSINE KINASE SIGNALING (UCHTMANN ET AL., EXPERIMENTAL CELL RESEARCH 339(2): 261-269). IN CULTURES OF PROSTATE CANCER CELLS, CYTOPLASMIC ANDROGEN RECEPTOR, WHEN ACTED ON BY ANDROGEN, RAPIDLY STIMULATED THE SRC TYROSINE KINASE ENZYME. CANCER CELL INVASIVE BEHAVIOR IS STIMULATED BY A RAPID BUT SUSTAINED INCREASE IN SRC ACTIVITY (ZARIF ET AL., ONCOTARGET 6(9): 6862-6876). |
| FORM 990, PART III, LINE 4B | LINE 4B - PROGRAM SERVICE ACTIVITY #2 CENTER FOR EPIGENETICS THE CENTER, ESTABLISHED IN 2014 AND DIRECTED BY PETER JONES, PH.D., D.SC., COMPRISES EIGHT LABORATORIES STUDYING EPIGENETICS AND EPIGENOMICS AND THE ROLE OF EPIGENETIC DYSFUNCTION IN CANCER AND NEURODEGENERATIVE DISEASE, CARDIOVASCULAR DISEASE, AND VIRAL TRANSCRIPTION. TWO NEW FACULTY WERE RECRUITED TO THE CENTER IN 2015: DR. SCOTT ROTHBART WAS APPOINTED AS AN ASSISTANT PROFESSOR AND DR. STEPHEN BAYLIN OF JOHNS HOPKINS UNIVERSITY ACCEPTED A PART-TIME APPOINTMENT AS A PROFESSOR. IN 2015, CENTER RESEARCHERS RECEIVED A NEW NIH GRANT AWARD, AS WELL AS A MAJOR AWARD FROM THE MICHIGAN ECONOMIC DEVELOPMENT CORPORATION. THE VARI-SU2C EPIGENETICS DREAM TEAM, LED BY PETER JONES AND STEPHEN BAYLIN, CONTINUED ITS WORK IN 2015, WITH THE AIMS OF DEVELOPING NEW COMBINATION THERAPIES TO COMBAT CANCER AND MOVING PROMISING THERAPIES TO CLINICAL TRIALS. THE TEAM FOCUSES ON EPIGENETIC MECHANISMS IN CELLS, WHICH HELP CONTROL WHETHER GENES ARE TURNED ON OR OFF WITHOUT CHANGING THE DNA SEQUENCE ITSELF. A PRINCIPAL WAY THIS IS DONE IS BY THE ADDITION OR REMOVAL OF METHYL GROUPS TO THE DNA MOLECULES (DNA METHYLATION/DEMETHYLATION). CENTER FACULTY, AS PART OF THE CANCER GENOME ATLAS RESEARCH NETWORK, CONTRIBUTED TO COMPREHENSIVE STUDIES CHARACTERIZING DIFFUSE LOWER-GRADE GLIOMAS AND PRIMARY PROSTATE CANCERS (CANCER GENOME ATLAS RESEARCH NETWORK, NEW ENGLAND JOURNAL OF MEDICINE 372(26): 2481-2498; CANCER GENOME ATLAS RESEARCH NETWORK, CELL, 163(4): 1011-1025), AS WELL AS TO A STUDY OF INVASIVE LOBULAR BREAST CANCER (CIRIELLO ET AL., CELL 163(2): 506-519). THIS WORK WILL HELP LAY THE FOUNDATION FOR IMPROVING CANCER PREVENTION, EARLY DETECTION, AND TREATMENT. ANOTHER PROJECT MADE USE OF ELMER, A SOFTWARE TOOL THAT USES DNA METHYLATION TO IDENTIFY ENHANCERS OF DNA TRANSCRIPTION. THE RESEARCHERS IDENTIFIED NETWORKS REGULATED BY KNOWN CANCER DRIVERS AND NOVEL NETWORKS THAT HAVE PROGNOSTIC POTENTIAL (YAO ET AL., GENOME BIOLOGY 16: 105). AN ASSAY CALLED MIRA FOR ANALYZING DNA METHYLATION HAS BEEN DEVELOPED AND COMBINED WITH NEXT-GENERATION SEQUENCING. THE ASSAY IS RELIABLE, COST-EFFECTIVE, AND NOT LIMITED BY PRIMER OR PROBE DESIGN (JUNG ET AL., EPIGENOMICS 7(5): 695-706). USING THIS ASSAY, DNA METHYLATION IN METASTATIC MELANOMA CELLS AND IN NORMAL MELANOCYTES WAS CHARACTERIZED. A SERIES OF METHYLATION PEAKS FOUND TO BE PRESENT IN ALL MELANOMA SAMPLES MAY BE EFFECTIVE BIOMARKERS OF THE DISEASE (JIN ET AL., GENOMICS 106(6): 322-330). A VECTOR-BASED APPROACH TO GENE RANKING WAS DEVELOPED THAT INCORPORATES TEMPORAL DISTANCE, SIGNAL INTENSITY, AND VARIANCE INTO A SINGLE SCORE. THIS METHOD IDENTIFIED AN AGE-DEPENDENT DECREASE IN THE EXPRESSION OF GENES INVOLVED IN TRANSLATION AND RIBOSOME FUNCTION (JUNG ET AL., NUCLEIC ACIDS RESEARCH 43(15): E100). A STUDY OF ENDOCRINE-DISRUPTING CHEMICALS FOUND THAT THEY EXERT DIRECT EPIGENETIC EFFECTS IN EXPOSED FETAL GERM CELLS, ALTERING DNA METHYLATION AND TRANSCRIPTION. HOWEVER, THOSE CHANGES ARE CORRECTED BY REPROGRAMMING EVENTS IN THE NEXT GENERATION, SO THE EFFECTS ARE NOT PASSED ON TO LATER GENERATIONS (IQBAL ET AL., GENOME BIOLOGY 16: 59). THE NUCLEOSOME OCCUPANCY AND METHYLATION SEQUENCING (NOME-SEQ) METHOD WAS USED TO COMPARE THESE TWO DNA CHARACTERISTICS IN NORMAL AND CANCER CELL LINES OF THE BREAST AND PROSTATE. THIS STUDY PROVIDES CELL LINE PROFILES, A BIOINFORMATIC PIPELINE, AND TOOLS THAT WILL BE USEFUL TO SCIENTISTS IN THE FIELD IN FUTURE STUDIES (STATHAM ET AL., GENOMICS DATA 3: 94-96). IN A SEPARATE RESEARCH PROJECT, A HIGH-RESOLUTION ANALYSIS OF THE CHROMATIN STRUCTURE OF HCT116 COLON CANCER CELLS AND DNA-METHYLATION-DEFICIENT DERIVATIVE CELLS WAS CARRIED OUT USING THE NOME-SEQ ASSAY. IT SHOWED A NUANCED AND CONTEXT-DEPENDENT ROLE OF METHYLATION IN THE FUNCTIONAL ORGANIZATION OF CANCER CELL EPIGENOMES (LAY ET AL., GENOME RESEARCH 25(4): 467-477). IN A STUDY OF COLORECTAL CANCER-INITIATING CELLS (CICS), LOW-DOSE 5-AZA-CDR, WHICH INHIBITS THE PLACEMENT OF METHYL GROUPS ON DNA, CAUSED CELLS TO RESPOND AS THEY DO TO A VIRAL INFECTION, WITH THE INDUCTION OF DSRNAS AND ACTIVATION OF THE MDA5/MAVS RNA RECOGNITION PATHWAY, THUS TRICKING CANCER CELLS INTO DYING. THE STUDY DENOTES A MAJOR SHIFT IN THE UNDERSTANDING OF ANTI-TUMOR MECHANISMS, IDENTIFYING THE MDA5/MAVS/IRF7 PATHWAY AS A POTENTIALLY DRUGGABLE TARGET AGAINST CICS (ROULOIS ET AL., CELL 162(5): 961-973). A COMPLEMENTARY STUDY WITH SIMILAR FINDINGS, COAUTHORED BY DR. STEPHEN BAYLIN, WHO HOLDS A JOINT APPOINTMENT AT VARI AND AT JOHNS HOPKINS UNIVERSITY, WAS PUBLISHED IN THE SAME JOURNAL ISSUE (CHIAPPINELLI ET AL., CELL 162(5): 961-973). THESE TWO STUDIES WERE INCLUDED AMONG THE DISCOVERIES HIGHLIGHTED AS TOP BIOMEDICAL ADVANCES OF 2015 BY NATURE MEDICINE. A PROJECT ON CELL GENERATION AND CELL TURNOVER IN THE HUMAN HEART PUBLISHED IN 2015 FOUND THAT THE TOTAL NUMBER OF HEART CELLS IS ESTABLISHED JUST AFTER BIRTH, BUT HEART CELLS ARE CONTINUALLY GENERATED THROUGHOUT LIFE TO REPLACE CELLS THAT DIE. UNDERSTANDING HOW THIS REGENERATION OF CELLS OCCURS WOULD LAY THE FOUNDATION FOR HARNESSING THIS CAPABILITY TO HELP DAMAGED HEARTS HEAL. (BERGMANN ET AL., CELL 161(7): 1566-1575). USING SINGLE-CELL EXPRESSION PROFILING, ANOTHER STUDY FOUND THAT A COMBINATION OF N-CADHERIN PLUS THE INTEGRINS ALPHA-1, ALPHA-5, AND ALPHA-6 ALLOWS THE ISOLATION OF REGENERATION-COMPETENT MURINE CARDIOMYOCYTES. OTHER SUBTYPES OF HEART CELLS COULD ALSO BE ISOLATED (TARNAWSKI ET AL., PLOS ONE 10(8): E0135880). THIS STUDY WAS ALSO INCLUDED IN NATURE MEDICINE'S LIST OF TOP ADVANCES OF 2015. THE HISTONE ANTIBODY SPECIFICITY DATABASE IS AN ONLINE AND EXPANDING RESOURCE CATALOGING THE BEHAVIOR OF WIDELY USED, COMMERCIALLY AVAILABLE HISTONE ANTIBODIES BY PEPTIDE MICROARRAY. THIS RECENTLY ANNOUNCED DATABASE HAS AN INTERACTIVE WEB PORTAL AND PROVIDES A VALUABLE RESOURCE FOR RESEARCHERS WHO USE THESE ANTIBODIES AS DETECTION REAGENTS (ROTHBART ET AL., MOLECULAR CELL 59(3): 502-511). |
| FORM 990, PART III, LINE 4C | LINE 4C - PROGRAM SERVICE ACTIVITY #3 CENTER FOR NEURODEGENERATIVE SCIENCE THE CENTER FOR NEURODEGENERATIVE SCIENCE WAS ESTABLISHED IN 2011 UNDER PATRIK BRUNDIN, M.D., PH.D., WHO IS ALSO ASSOCIATE DIRECTOR OF VARI. THE CENTER CURRENTLY HAS SIX LABORATORIES STUDYING PARKINSON'S DISEASE, AGING, PRIONS, AND THE RELATIONSHIP BETWEEN DEPRESSION, SUICIDE, AND BRAIN INFLAMMATION. ONE NEW FACULTY MEMBER, GARHARD COETZEE, PH.D., JOINED THE CENTER IN 2015. CENTER RESEARCHERS IN 2015 RECEIVED NEW R13 AND R01 AWARDS THE NATIONAL INSTITUTES OF HEALTH, A NEW AWARD FROM THE CURE PARKINSON'S TRUST, AND A POSTDOCTORAL FELLOWSHIP GRANT FROM THE AMERICAN PARKINSON DISEASE ASSOCIATION. TWO NEW RESEARCH CONTRACTS WERE SIGNED WITH PRIVATE FIRMS. VARI CONTINUES THE LINKED CLINICAL TRIALS INITIATIVE BEGUN IN 2014 WITH THE CURE PARKINSON'S TRUST, A UK-BASED RESEARCH CHARITY, TO IDENTIFY NEW TREATMENTS FOR PARKINSON'S DISEASE. THE COLLABORATION FOCUSES ON REPOSITIONING MEDICATIONS APPROVED TO TREAT OTHER DISEASES THAT ALSO HAVE PROMISE FOR TREATING PARKINSON'S DISEASE. THE LCT INITIATIVE COULD SIGNIFICANTLY REDUCE THE TIME AND COST OF MOVING NEW PARKINSON'S TREATMENTS FROM THE LAB TO CLINICAL USE. OUR STUDIES OF PARKINSON'S DISEASE INCLUDE A PROJECT ON THE ENGRAILED GENE. POLYMORPHISMS IN THE HUMAN ENGRAILED1 (EN1) GENE ARE ASSOCIATED WITH SPORADIC PARKINSON'S DISEASE. THE RESEARCH HAS FOUND EARLY TERMINAL DEFECTS IN THE DOPAMINERGIC NIGROSTRIATAL PATHWAY IN EN1+/- MICE. SUCH HETEROZYGOUS MICE SHOULD BE USEFUL IN UNCOVERING NEW KEYS TO PD PATHOGENESIS (NORDSTROM ET AL., NEUROBIOLOGY OF DISEASE 73(1): 70-82). ANOTHER STUDY HAS DEVELOPED A MODEL CELL CULTURE SYSTEM FOR MONITORING THE TRANSFER OF THE PROTEIN ALPHA-SYNUCLEIN BETWEEN CELLS. THIS PROVIDES RESEARCHERS WITH A TOOL FOR IDENTIFYING GENETIC MODIFIERS OR SMALL MOLECULES THAT CAN INHIBIT SUCH TRANSFER (REYES ET AL., NEUROBIOLOGY OF DISEASE 77: 266-275). A THIRD PROJECT STUDIED HOW SMALL VESICLES CALLED EXOSOMES CAN ACCELERATE THE AGGREGATION OF ALPHA-SYNUCLEIN PROTEIN. THE RESULTS SHOWED THAT EXOSOMES PROVIDE A CATALYTIC ENVIRONMENT FOR ACCELERATING THE AGGREGATION OF ALPHA-SYNUCLEIN AND THAT THE GANGLIOSIDE LIPIDS GM1 AND GM3 ARE IMPORTANT IN THE PROCESS (GREY ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 290(5): 2969-2982). A STUDY OF QUINONE-PROTEIN ADDUCTS IN THE SUBSTANTIA NIGRA FOUND THAT THE ENZYMATIC ACTIVITY OF TWO DEHYDROGENASE ENZYMES, LDH AND MDH, CAN BE COMPROMISED BY MODIFICATION OF THE QUINONE. THIS RESULT SUGGESTS THAT IMPAIRMENT OF ENERGY METABOLISM IS IMPORTANT IN THE VULNERABILITY OF AGED DOPAMINERGIC NEURONS TO PARKINSON'S DISEASE (YU ET AL., EXPERIMENTAL NEUROLOGY 271: 13-24). THE PARK9 GENE CAN PROTECT AGAINST ALPHA-SYNUCLEIN-INDUCED TOXICITY IN CELLULAR AND INVERTEBRATE MODELS OF PD, AND IT IS EXPRESSED AT A MODESTLY INCREASED LEVEL IN THE CINGULATE CORTEX OF PARKINSON'S DISEASE PATIENTS. HOWEVER, IN A RODENT MODEL, RESEARCH SHOWED A LACK OF PARK9-MEDIATED PROTECTION AGAINST ALPHA-SYNUCLEIN-INDUCED NEUROTOXICITY (DANIEL ET AL., NEUROBIOLOGY OF DISEASE 73(1): 229-243). THE LRRK2 PROTEIN CARRYING THE G2019S MUTATION PRODUCES NEUROTOXICITY IN THE BRAIN STRIATUM. A FURTHER MUTATION TO THE LRRK2 GENE THAT INACTIVATES THE PROTEIN'S KINASE ACTIVITY ELIMINATED THE TOXIC EFFECTS, SUGGESTING THAT KINASE INHIBITORS MAY HAVE POTENTIAL AS A THERAPEUTIC APPROACH TO PARKINSON'S DISEASE (TSIKA ET AL., NEUROBIOLOGY OF DISEASE 77: 49-61). ANOTHER VARI PROJECT STUDIED THE PATHOGENIC PROPERTIES OF SYNTHETICALLY GENERATED PRION (REC-PRION). THE REC-PRION HAS A TITRATABLE INFECTIVITY AND CAN CAUSE PRION DISEASE VIA ROUTES OTHER THAN DIRECT INTRACEREBRAL CHALLENGE. THE REC-PRION DISEASE IS PATHOGENICALLY AND PATHOLOGICALLY IDENTICAL TO NATURALLY OCCURRING, CONTAGIOUS, TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (WANG ET AL., PLOS PATHOGENS 11(7): E1004958). BECAUSE AGING IS THE GREATEST RISK FACTOR FOR THE DEVELOPMENT OF PARKINSON'S DISEASE (PD), CHANGES DURING THE AGING PROCESS MAY MAKE CELLS SUSCEPTIBLE TO DISEASE-CAUSING MUTATIONS THAT ARE TOLERATED AT YOUNGER AGES. IN A C. ELEGANS WORM MODEL, THE DAF-2 MUTATION INCREASED THE LIFE SPAN OF WORMS BEARING PD-RELATED MUTATIONS AND RESCUED THE DEGENERATION OF DOPAMINE NEURONS. THIS STUDY SUGGESTS THAT SLOWING THE AGING PROCESS MAY BE AN EFFECTIVE TREATMENT FOR PD (COOPER ET AL., NPJ PARKINSON'S DISEASE 1: 15022). ANOTHER STUDY IN C. ELEGANS SHOWED THAT THE LOCATION OF REACTIVE OXYGEN SPECIES (ROS) CAUSES DIFFERENT EFFECTS ON THE ORGANISM'S LIFE SPAN. HIGHER LEVELS OF ROS IN MITOCHONDRIA INCREASE LIFE SPAN, WHILE HIGHER LEVELS IN THE CYTOPLASM DECREASE IT. THIS KNOWLEDGE MAY EVENTUALLY BE USED TO PROMOTE LONGEVITY, AS WELL AS TO UNDERSTAND THE ROLE OF ROS IN AGE-RELATED CONDITIONS SUCH AS PARKINSON'S DISEASE (SCHAAR ET AL., PLOS GENETICS 11(2): E1004972). VARI PUBLISHED SEVERAL REPORTS ON DEPRESSION, SUICIDAL BEHAVIOR, AND BRAIN INFLAMMATION IN 2015 THAT MAY PROVIDE NEW THERAPEUTIC APPROACHES FOR MANAGING SUICIDAL BEHAVIOR. ONE STUDY SUGGESTS THAT THE MACROPHAGE MIGRATION INHIBITORY PROTEIN IS INVOLVED IN DEPRESSIVE-LIKE SYMPTOMS, POSSIBLY THROUGH INTERFERON-GAMMA EFFECTS ON DOPAMINE METABOLISM. THE EFFECTS MAY BE SEX-SPECIFIC (BAY-RICHTER ET AL., JOURNAL OF NEUROINFLAMMATION 12: 163). ANOTHER STUDY FOUND THAT AGGRESSION AND IMPULSIVITY ARE ASSOCIATED WITH LATENT INFECTION BY TOXOPLASMA GONDII PARASITES AND THAT THERE ARE GENDER- AND AGE-SPECIFIC DIFFERENCES IN THESE TRAITS. SUBSEQUENT STUDIES OF THE TRAITS MAY PROVIDE ADVANCES IN PROGNOSIS AND THERAPY FOR INFECTED INDIVIDUALS (COOK ET AL., JOURNAL OF PSYCHIATRIC RESEARCH 60: 87-94) BASED ON A COMPREHENSIVE LITERATURE REVIEW, THE EFFECTS OF BRAIN INFLAMMATION ON SUICIDAL BEHAVIOR MAY BE IN PART MEDIATED BY KYNURENINE PATHWAY COMPONENTS (BRUNDIN ET AL., ACTA PSYCHIATRICA SCANDINAVICA 132(3): 192-203). A SEPARATE STUDY FOUND DYSREGULATION OF KYNURENINE METABOLISM IN DEPRESSED AND SUICIDAL PATIENTS. HIGHER CONCENTRATIONS OF INFLAMMATORY CYTOKINES IN THE CEREBROSPINAL FLUID WERE ASSOCIATED WITH MORE-SEVERE SYMPTOMS. THE GLUTAMATE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR MAY BE A TARGET FOR DEVELOPING NOVEL THERAPIES (BAY-RICHTER ET AL., BRAIN, BEHAVIOR, AND IMMUNITY 43: 110-117). A THIRD STUDY FOUND THAT MAJOR DEPRESSIVE DISORDER WAS NOT ASSOCIATED WITH HIGHER PLASMA LEVELS OF KYNURENINE PATHWAY MARKERS IN PATIENTS RECEIVING CYTOKINE THERAPY FOR DEPRESSION, SUGGESTING A DIFFERENT MECHANISM FROM THAT OF INTERFERON-INDUCED DEPRESSION (DAHL ET AL., PSYCHONEUROENDOCRINOLOGY 56: 12-22). |
| FORM 990, PART IX, COLUMN D | FUNDRAISING EXPENSES AT VARI WERE INCURRED TO SUPPORT THE MISSION OF THE RESEARCH INSTITUTE THROUGH DONOR SOLICITATION, GRANT SOLICITATION AND EXTRAMURAL PROPOSAL PREPARATION. |
| FORM 990, PART X, LINE 33 | VARI NET ASSETS ARE CONSIDERED ON A CONSOLIDATED BASIS WITH VAN ANDEL INSTITUTE (VAI), VAN ANDEL EDUCATION INSTITUTE (VAEI), AND RELATED PARTIES. ON A CONSOLIDATED BASIS, NET ASSETS ARE $1,312,631,000 PER AUDITED FINANCIAL STATEMENTS. THE NEGATIVE NET ASSET BALANCE AT VARI IS DUE TO VAI FUNDING EXPENSES ON A CASH BASIS AND THE UNREALIZED LOSS RECORDED IN ASSOCIATION WITH THE INTEREST RATE SWAP. |
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