The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Longitudinal studies of a B cell-derived signature of tolerance in renal transplant recipients.

Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.

The effect of chronic corticosterone on fear learning and memory depends on dose and the testing protocol.

Chronic exposure to the stress hormone corticosterone (CORT) is known to alter plasticity within hippocampal and amygdalar circuits that mediate fear learning and memory. The purpose of this experiment was to clarify the effects of chronic CORT on Pavlovian fear conditioning, which is dependent on intact hippocampal and amygdalar activity. In particular, we assessed whether the effect of chronic CORT on fear learning and memory is influenced by two factors-the dose of CORT and the order in which rats are tested for freezing to context versus tone cues. Male Long-Evans rats received low-dose CORT (5mg/kg), high-dose CORT (40mg/kg), or vehicle injections once daily for 21days. On day 22, the rats were trained in a fear-conditioning paradigm. On days 23 and 24, the rats were tested for the retrieval of fear memories to context and tone cues in a counterbalanced way-half the rats received context testing on day 23 and then tone testing on day 24 and half the rats received tone testing on day 23 followed by context testing on day 24. Our results revealed dose-dependent effects of CORT on memory retrieval: Rats injected with high-dose CORT froze significantly more than control rats to both context and tone cues regardless of what testing day these cues were presented. However, rats injected with low-dose CORT froze significantly more than control rats to tone cues only. We also found an order effect in that the effects of CORT on freezing were greater on the second day of testing, regardless of whether that testing was to context or tones cues. This order effect may be due to a lack of extinction in the CORT rats. Overall, these results suggest a relationship between stress intensity and testing conditions that should be taken into account when assessing the effect of stress on fear memories.

Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor.

Epileptic seizures negatively affect cognition. However, the mechanisms that contribute to cognitive impairments after seizures are largely unknown. Here, we examined the effects of long-term kindling (i.e., 99 stimulations) of limbic (basolateral amygdala, dorsal hippocampus) and non-limbic (caudate nucleus) brain sites on conditioned fear and hippocampal plasticity. We first showed that kindling had no effect on acquisition of a hippocampal-dependent trace fear-conditioning task but limbic kindling impaired the retrieval of these fear memories. To determine the relationship between memory and hippocampal neuronal activity, we examined the expression of Fos protein 90 min after memory retrieval (i.e., 4 days after the last kindling stimulation). We found that limbic kindling, but not non-limbic kindling, decreased Fos expression in the granule cell layer, hilus, CA3 pyramidal cell layer, and CA1 pyramidal cell layer. Next, to investigate a mechanism that could contribute to dampen hippocampal neuronal activity in limbic-kindled rats, we focused on the endogenous anticonvulsant neuropeptide Y (NPY), which is expressed in a subset of GABAergic interneurons and can prevent glutamate release through interactions with its Y2 receptor. We found that limbic kindling significantly decreased the number of NPY-immunoreactive cells in several hippocampal subfields despite minimal staining of the neurodegenerative marker Fluoro-Jade B. However, we also noted that limbic kindling enhanced NPY immunoreactivity throughout the mossy fiber pathway. In these same regions, we observed limbic kindling-induced de novo expression of the NPY Y2 receptor. These novel findings demonstrate the site-specific effects of kindling on cognition and NPY plasticity, and they provide evidence that altered hippocampal NPY after limbic seizures coincides with dampened neural activity and cognitive impairments.

Amygdala kindling disrupts trace and delay fear conditioning with parallel changes in Fos protein expression throughout the limbic brain.

Amygdala kindling is well known to increase unconditioned fear and anxiety. However, relatively little is known about whether this form of kindling causes functional changes within the neural circuitry that mediates fear learning and the retrieval of fear memories. To address this issue, we examined the effect of short- (i.e., 30 stimulations) and long-term (i.e., 99 stimulations) amygdala kindling in rats on trace and delay fear conditioning, which are aversive learning tasks that rely predominantly on the hippocampus and amygdala, respectively. After memory retrieval, we analyzed the pattern of neural activity with Fos, the protein product of the immediate early gene c-fos. We found that kindling had no effect on acquisition of the trace fear conditioning task but it did selectively impair retrieval of this fear memory. In contrast, kindling disrupted both acquisition and retrieval of fear memory in the delay fear conditioning task. We also found that kindling-induced impairments in memory retrieval were accompanied by decreased Fos expression in several subregions of the hippocampus, parahippocampus, and amygdala. Interestingly, decreased freezing in the trace conditioning task was significantly correlated with dampened Fos expression in hippocampal and parahippocampal regions whereas decreased freezing in the delay conditioning task was significantly correlated with dampened Fos expression in hippocampal, parahippocampal, and amygdaloid circuits. Overall, these results suggest that amygdala kindling promotes functional changes in brain regions involved in specific types of fear learning and memory.

Humeral fracture in arm wrestling: bone morphology as a permanent risk factor. Indications for safety measures in arm wrestling.

BACKGROUND: Arm wrestling has been recognized as a popular and potentially dangerous competition. Reports on injuries related to arm wrestling are increasing. The most important of these injuries are humeral shaft fractures. The generally accepted theory states that the shoulder joint is actively internally rotated against the opponent while the elbow is fixed in flexion resulting in enormous violent torque forces across the humeral shaft. METHODS: The reported fracture morphology seems similar so we theorized that the basis of this fracture type is the bone structure. There is no experimental model of the arm wrestling fracture other than a virtual one. We assess morphology of the humeral bone by means of the bone cutting procedures and to verify the theory that the structure of humeral bone is a basis of the arm-wrestling fracture by means of newly developed model on human bones. RESULTS: Results of the study suggest that the humeral shaft fracture morphology during arm wrestling is based on the spiral structure of the bone combined with the direction of the revolving, rotational force during the match. CONCLUSION: The safety rules of the arm-wrestling match based on results of our experimental study and the literature metaanalysis are also formulate.

Posttransplantation lymphoproliferative disorder in kidney and heart transplant recipients receiving thymoglobulin: a systematic review.

Posttransplantation lymphoproliferative disorder (PTLD) is an important complication of transplantation. Risk factors include increased overall immunosuppression exposure and inadequate antiviral prophylaxis; however, the effects of T-cell-depleting agents on PTLD are unclear. A systematic literature review was conducted to assess PTLD in clinical studies published 1999-2009 in transplant patients with ≥ 3 years follow-up who received Thymoglobulin for induction. Twenty studies were identified (12 kidney, 7 heart, and 1 liver), of which 3 were excluded for insufficient PTLD reporting. The final study group comprised 2,246 kidney and heart transplant recipients (liver study excluded) who received Thymoglobulin. At a median follow-up of 5 years, the incidence of PTLD was 0.98% (kidney, 0.93%; heart, 1.05%) among Thymoglobulin-treated patients. The cumulative Thymoglobulin dose reported in these studies was not associated with the development of PTLD (P = NS). However, incidence of PTLD was significantly lower with antiviral prophylaxis (0.63%) than without (1.87%; P = .013). Heart transplant recipients not receiving antiviral prophylaxis had the highest PTLD incidence, possibly attributable to a greater overall immunosuppressive burden. This analysis revealed that PTLD incidences in kidney and heart transplant recipients receiving Thymoglobulin were low overall and perhaps related more to concomitant anti-viral prophylaxis use.

Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients.

Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1-year, randomized, controlled, open-label, exploratory study assessed two belatacept-based regimens compared to a tacrolimus (TAC)-based, steroid-avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept-mycophenolate mofetil (MMF), belatacept-sirolimus (SRL), or TAC-MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty-nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept-MMF, belatacept-SRL and TAC-MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two-thirds of patients in the belatacept groups remained on CNI- and steroid-free regimens at 12 months and the calculated glomerular filtration rate was 8-10 mL/min higher with either belatacept regimen than with TAC-MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC-based regimen.

Brain SPECT and Neuropsychological Examination in Patients with a History of Minor Craniocerebral Trauma Nine Years after Head Injury.

Focal perfusion deficits disclosed by single photon emission computerized tomography (SPECT) show more diffuse brain dysfunction than computed tomography (CT) examinations in case of head trauma. The aim of the study was to evaluate SPECT as an enhancing and complementary diagnostic method in patients after minor craniocerebral trauma (mCCT) and establish a possible correlation between clinical symptoms and disturbances of cerebral blood flow (CBF). SPECT examination and neuropsychological assessment was performed in seven patients about nine years after head injury, scoring 13-15 points on the Glasgow COMA SCALE and without evidence of structural brain damage. Neuropsychological assessment addressed global cognitive status, verbal and visual memory, working memory, object and space perception, executive function, self-assessment of memory, mood and health-related complaints. A direct relationship was shown between mCCT and the observed CBF disorders, and between the CBF disorders and cognitive dysfunction. Because of its sensitivity, SPECT, should be regarded as a method complementary to CT in mCCT.

Diffuse Axonal Injury: a Brief Review and Examples of the Use of Neurofunctional Imaging (Tc-99m HMPAO SPECT) in Diagnosis and Follow-up.

Diffuse axonal injury (DAI) is a growing problem nowadays as its social and economic costs amount to millions of dollars. DAI is now thought to be the predominant mechanism of injury in almost half the cases of traumatic brain injury connected with loss of consciousness. Computed tomography and magnetic resonance imaging are substantial techniques to diagnose DAI but they have their limitations. Neuropsychological tests used in follow-up disclose persistent disabilities in patients with total regression of CT and MRI changes. In those situations SPECT is appropriate as it shows lesions not disclosed by other imaging techniques. This article describes two cases in which usefulness of SPECT has been proved. A brief review of DAI has been included.

Organ donation and utilization, 1995-2004: entering the collaborative era.

Continued progress in organ donation will help enable transplantation to alleviate the increasing incidence of end-stage organ disease. This article discusses the implementation and effect of the federally initiated Organ Donation Breakthrough Collaborative; it then reviews organ donation data, living and deceased, from 1995 to 2004. It is the first annual report of the Scientific Registry of Transplant Recipients to include national data following initiation of the collaborative in 2003. Prior to that, annual growth in deceased donation was 2%-4%; in 2004, after initiation of the collaborative, deceased donation increased 11%. Identification and dissemination of best practices for organ donation have emphasized new strategies for improved consent, including revised approaches to minority participation, timing of requests and team design. The number of organs recovered from donation after cardiac death (DCD) grew from 64 in 1995 to 391 in 2004. While efforts are ongoing to develop methodologies for identifying expanded criteria donors (ECD) for organs other than kidney, it is clear DCD and ECD raise questions regarding cost and recovery. The number of living donor organs increased from 3493 in 1995 to 7002 in 2004; data show trends toward more living unrelated donors and those providing non-directed donations.

Report of a National Conference on Donation after cardiac death.

A national conference on organ donation after cardiac death (DCD) was convened to expand the practice of DCD in the continuum of quality end-of-life care. This national conference affirmed the ethical propriety of DCD as not violating the dead donor rule. Further, by new developments not previously reported, the conference resolved controversy regarding the period of circulatory cessation that determines death and allows administration of pre-recovery pharmacologic agents, it established conditions of DCD eligibility, it presented current data regarding the successful transplantation of organs from DCD, it proposed a new framework of data reporting regarding ischemic events, it made specific recommendations to agencies and organizations to remove barriers to DCD, it brought guidance regarding organ allocation and the process of informed consent and it set an action plan to address media issues. When a consensual decision is made to withdraw life support by the attending physician and patient or by the attending physician and a family member or surrogate (particularly in an intensive care unit), a routine opportunity for DCD should be available to honor the deceased donor's wishes in every donor service area (DSA) of the United States.

Early brain spect in patients after minor craniocerebral trauma.

A prospective study made 57 measurements of cerebral blood flow (CBF) by Single Photon Emission Computed Tomography (SPECT) in post-traumatic patients. The aim of the investigation was to evaluate CBF in patients after minor craniocerebral trauma (mCCT) to ascertain the clinicotopographic correlation of the CBF changes, and to study SPECT in comparison with computed tomography (CT) findings. In addition, evaluation of the usefulness of SPECT for forensic medicine, assessment of secondary brain injury by SPECT and the predictive value of hypofrontalism were performed. A direct correlation was shown between mCCT and the observed CBF disorders, and between the CBF disorders and clinical symptoms as well as better SPECT sensitivity in comparison with CT. The usefulness of SPECT for forensic medicine purposes was also shown. Secondary brain injuries were disclose and the predictive value of hypofrontalism was confirmed. No correlation between GCS and CBF changes was found.

New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.

OBJECTIVE: To determine the relative tolerability and efficacy of two newer antiepileptic drugs, lamotrigine (LTG) and gabapentin (GBP), as compared to carbamazepine (CBZ) in older patients with epilepsy. METHODS: This was an 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 mg/day. The primary outcome measure was retention in trial for 12 months. RESULTS: Mean age was 72 years. The most common etiology was cerebral infarction. Patients had multiple medical conditions and took an average of seven comedications. Mean plasma levels at 6 weeks were as follows: GBP 8.67 +/- 4.83 microg/mL, LTG 2.87 +/- 1.60 microg/mL, CBZ 6.79 +/- 2.92 microg/mL. They remained stable throughout the trial. Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% (p = 0.0002). Significant paired comparisons: LTG vs CBZ: p < 0.0001; GBP vs CBZ: p = 0.008. Terminations for adverse events: LTG 12.1%, GBP 21.6%, CBZ 31% (p = 0.001). Significant paired comparisons: LTG vs CBZ: p < 0.0001; LTG vs GBP: p = 0.015. There were no significant differences in seizure free rate at 12 months. CONCLUSIONS: The main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.

Livers transplanted from donors after cardiac death occurring in the ICU or the operating room have excellent outcomes.

BACKGROUND: Increasing donor hospital cooperation with donation after cardiac death (DCD) requires the organ procurement organization (OPO) to use current withdrawal of life support (WLS) protocols. Hospital ICU nurses/physicians are comfortable performing the emotionally draining procedure of WLS in the ICU while OPOs are reluctant to accept these donors due to increased warm ischemia (WI). In our area, several hospitals will only allow WLS to occur in the ICU. This study compares liver outcomes from DCD donors where death occurred in the ICU (DCDICU) vs the OR (DCDOR). METHODS: From March 2003 to June 2004, 34 DCD donors were recovered by our OPO. WLS occurred in the ICU for 26 donors (76%) and in the OR for 8 donors (24%). Thirteen of 26 DCDICU and 5 of 8 DCDOR livers were transplanted. Donor demographics, warm ischemic time, cold ischemic time, distance shipped, and recipient functions were analyzed. RESULTS: Eighteen livers were transplanted both locally and at distant transplant centers. Results are outlined in the . CONCLUSIONS: Although DCDICU donors averaged approximately 4 minutes longer WI than DCDOR donors, short-term results for both groups were equivalent. These findings support using DCDICU livers. DCDICU donors have the potential to significantly improve donor hospital cooperation.

Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Design and implementation of microarray gene expression markup language (MAGE-ML).

BACKGROUND: Meaningful exchange of microarray data is currently difficult because it is rare that published data provide sufficient information depth or are even in the same format from one publication to another. Only when data can be easily exchanged will the entire biological community be able to derive the full benefit from such microarray studies. RESULTS: To this end we have developed three key ingredients towards standardizing the storage and exchange of microarray data. First, we have created a minimal information for the annotation of a microarray experiment (MIAME)-compliant conceptualization of microarray experiments modeled using the unified modeling language (UML) named MAGE-OM (microarray gene expression object model). Second, we have translated MAGE-OM into an XML-based data format, MAGE-ML, to facilitate the exchange of data. Third, some of us are now using MAGE (or its progenitors) in data production settings. Finally, we have developed a freely available software tool kit (MAGE-STK) that eases the integration of MAGE-ML into end users' systems. CONCLUSIONS: MAGE will help microarray data producers and users to exchange information by providing a common platform for data exchange, and MAGE-STK will make the adoption of MAGE easier.

Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.

The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.