T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substanti... more T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substantianigra from induced cell death. However, the role of T-cells in neurodegenerative models such as Parkinson's disease (PD) has not been fully elucidated. To examine the role of T-lymphocytes on motor behavior in the 6-hydroxydopamine (6-OHDA) unilateral striatal partial lesion PD rat model, we assessed progression of hemi-parkinsonian lesions in the substantia nigra, induced by 6-OHDA striatal injections, in athymic rats (RNU-/-, T-lymphocyte-deficient) as compared to RNU-/+ rats (phenotypically normal). Motor skills were determined by the cylinder and D-amphetamine sulfate-induced rotational behavioral tests. Cylinder behavioral test showed no significant difference between unilaterally lesioned RNU-/- and RNU-/+ rats. However both unilaterally lesioned RNU-/- and RNU-/+ rats favored the use of the limb ipsilateral to lesion. Additionally, amphetamine-induced rotational test revealed...
A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the t... more A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the temporal muscle after transection of the zygomatic arch is described. This approach allows a very low basal exposure of the middle and temporal fossa, minimizing the amount of temporal lobe retraction needed to approach intradural and extradural lesion in this location. This approach is simple, easily performed, does not require extensive skull base removal, and still offers excellent visualization of the middle fossa and of the region of the tentorial incisura.
Neural stem cells (NSCs) are capable of tracking migrating glioma cells. To exploit this tropism ... more Neural stem cells (NSCs) are capable of tracking migrating glioma cells. To exploit this tropism to generate an antitumor T-cell response, partic- ularly against disseminating tumor pockets, we inoculated intracranial glioma-bearing mice with interleukin 12 (IL-12) producing NSCs. Intra- tumoral therapy with IL-12-secreting NSCs prolonged survival compared to treatment with nonsecretory NSCs or saline. NSCs demonstrated strong tropism for disseminating
Cyr61 is a member of the CCN family of growth factors; these proteins are secreted and can act as... more Cyr61 is a member of the CCN family of growth factors; these proteins are secreted and can act as ligands of distinct integrins. We show that Cyr61 can enhance tumorigenicity of glioma cells acting through activated integrin-linked kinase (ILK) to stimulate -catenin-TCF/Lef and Akt signaling pathways. Overexpression of Cyr61 occurred in highly tumori- genic glioma cell lines and in 68%
TMEFF1 is a novel transmembrane protein, containing two follisatin domains and an epidermal growt... more TMEFF1 is a novel transmembrane protein, containing two follisatin domains and an epidermal growth factor-like region. These structural domains suggest a role for TMEFF1 in growth factor signaling. TMEFF1 fused to enhanced green fluorescent protein revealed that TMEFF1 is expressed on the cell membrane. Northern analysis of normal human tissue showed that TMEFF1 is predominantly expressed in the brain. Study
Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studie... more Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studies have shown that complex interactions of multiple factors are responsible for these hospitalizations. A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Medicare database of newly diagnosed elderly glioblastoma multiforme (GBM) patients who underwent surgical resection between 1991 and 2007. Hospitals were classified into high- or low-readmission rate cohorts using a risk-adjusted methodology. Bivariate comparisons of outcomes were conducted. Multivariate analysis evaluated differences in quality of care according to hospital readmission rates. A total of 1,273 patients underwent surgery in 338 hospitals; 523 patients were treated in 228 high-readmission hospitals and 750 in 110 low-readmission hospitals. Patient characteristics for high-versus low-readmission hospitals were compared. In a confounder-adjusted model, patients treated in hig...
OBJECT The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and the Ce... more OBJECT The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and the Centers for Medicare and Medicaid Services hospital-acquired conditions (HACs) are administrative data-based metrics. The use of these outcomes as standard performance measures has been discussed in previous studies. With the objective of determining the applicability of these events as performance metrics among patients undergoing brain tumor surgery, this study had 2 aims: 1) to evaluate the association between PSIs, HACs, and in-hospital mortality rates; and 2) to determine a correlation between hospital volume, PSIs, and HACs. METHODS Patients with brain tumors treated between 1998 and 2009 were captured in the Nationwide Inpatient Sample database. Hospitals were categorized into groups according to surgical volume. Associations between PSIs, HACs, and in-hospital mortality rates were studied. Factors associated with a PSI, HAC, and mortality were evaluated in a multivariate setting. R...
Currently, there is no gadolinium-based contrast agent available for conventional magnetic resona... more Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Aβ plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(β-l-malic acid) (PMLA) containing covalently attached gadolinium-DOTA(Gd-DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Aβ plaques and is detected by MRI. It efficiently detected Aβ plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD.
Anatomy, Diagnosis and Treatment 1st International Skull Base Congress, Hannover, June 1992, 1994
A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the t... more A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the temporal muscle after transection of the zygomatic arch is described. This approach allows a very low basal exposure of the middle and temporal fossa, minimizing the amount of temporal lobe retraction needed to approach intradural and extradural lesion in this location. This approach is simple, easily performed, does not require extensive skull base removal, and still offers excellent visualization of the middle fossa and of the region of the tentorial incisura.
Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a signifi... more Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy that can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise non-invasive MRI diagnostic method, we have engineered a new class of poly(β-L-malic acid) polymeric nano-imaging agents (NIA). The NIA carrying attached MRI tracer are able to pass through blood brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative "MRI virtual biopsy" method is based on nanoconjugate carrying MRI contrast agent Gadolinium-DOTA and antibodies recognizing tumor specific markers and extravasating through BBB. In newly developed double tumo...
Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of ma... more Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of malignant tumours. Diverse genetic programs regulate CSC behaviours, and CSCs from glioblastoma patients are qualitatively distinct from each other. The intrinsic connection between the presence of CSCs and malignancy is unclear. We set out to test whether tumour stem-like cells can be identified from benign tumours. Tumour sphere cultures were derived from hormone-positive and -negative pituitary adenomas. Characterisation of tumour stem-like cells in vitro was performed using self-renewal assays, stem cell-associated marker expression analysis, differentiation, and stimulated hormone production assays. The tumour-initiating capability of these tumour stem-like cells was tested in serial brain tumour transplantation experiments using SCID mice. In this study, we isolated sphere-forming, self-renewable, and multipotent stem-like cells from pituitary adenomas, which are benign tumours. We f...
Diseases involving the proximity of the internal carotid artery at the skull base require identif... more Diseases involving the proximity of the internal carotid artery at the skull base require identification of this vessel in the temporal bone to gain vascular control for any maneuver in its vicinity. This article details the technique of surgical dissection and exposure of the internal carotid artery within the skull base through a transtemporal middle cranial fossa approach. The anatomic landmarks important in utilizing this procedure include the greater superficial petrosal nerve, the mandibular branch of the trigeminal nerve, and the middle meningeal artery. With this approach, the internal carotid artery can be followed throughout the carotid canal and beyond the formen lacerun to the region of the cavernous sinus. The indications and limitations of this procedure are described and several clinical applications are provided.
In this Phase I trial, patients' peripheral blood dendritic cells were pulsed with peptides e... more In this Phase I trial, patients' peripheral blood dendritic cells were pulsed with peptides eluted from the surface of autologous glioma cells. Three biweekly intradermal vaccinations of peptide-pulsed dendritic cells were administered to seven patients with glioblastoma multiforme and two patients with anaplastic astrocytoma. Dendritic cell vaccination elicited systemic cytotoxicity in four of seven tested patients. Robust intratumoral cytotoxic and memory T-cell infiltration was detected in two of four patients who underwent reoperation after vaccination. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous peptide-pulsed dendritic cell vaccine for patients with malignant glioma.
We have identified a novel human malignancy-associated gene (MAG) expressed in various malignant ... more We have identified a novel human malignancy-associated gene (MAG) expressed in various malignant tumors including glioblastomas and hepatocellular carcinomas (HCCs) and in tumor preexisting conditions such as hepatitis C virus- and hepatitis B virus-induced liver cirrhosis. The expression of MAG was characterized using reverse transcription-PCR (RT-PCR), rapid amplification of cDNA ends PCR, RNA dot blotting, RNase protection assay, and Northern blot analysis. Rapid amplification of cDNA ends PCR yielded a 536-bp MAG fragment in HCC, macroregenerative liver nodules with dysplasia, and liver cirrhosis but not in normal liver or placenta. By RT-PCR, MAG expression was not found in 12 different normal tissues but found in 46 of 51 (90%) premalignant and malignant tissues of various sites. Embryonic liver and brain were positive for MAG expression together with tumors from the same organs, but the corresponding normal adult tissues were negative. By RNase protection assay, MAG mRNA was ...
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming im... more Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming immune responses to tumor. Interleukin (IL)-23 can act directly on DC to promote immunogenic presentation of tumor peptide in vitro. Here, we evaluated the combination of bone marrow-derived DC and IL-23 on the induction of antitumor immunity in a mouse intracranial glioma model. DCs can be
Neural progenitor-like cells have been isolated from bone marrow and the cells have the ability o... more Neural progenitor-like cells have been isolated from bone marrow and the cells have the ability of tracking intracranial tumor. However, the capacity of the cells to deliver molecules for activating immune response against intracranial tumor and the identity of cellular and molecular factors that are involved in such immune responses have yet to be elucidated. Here, we isolated neural stem-like
T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substanti... more T-lymphocytes have been previously implicated in protecting dopaminergic neurons in the substantianigra from induced cell death. However, the role of T-cells in neurodegenerative models such as Parkinson's disease (PD) has not been fully elucidated. To examine the role of T-lymphocytes on motor behavior in the 6-hydroxydopamine (6-OHDA) unilateral striatal partial lesion PD rat model, we assessed progression of hemi-parkinsonian lesions in the substantia nigra, induced by 6-OHDA striatal injections, in athymic rats (RNU-/-, T-lymphocyte-deficient) as compared to RNU-/+ rats (phenotypically normal). Motor skills were determined by the cylinder and D-amphetamine sulfate-induced rotational behavioral tests. Cylinder behavioral test showed no significant difference between unilaterally lesioned RNU-/- and RNU-/+ rats. However both unilaterally lesioned RNU-/- and RNU-/+ rats favored the use of the limb ipsilateral to lesion. Additionally, amphetamine-induced rotational test revealed...
A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the t... more A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the temporal muscle after transection of the zygomatic arch is described. This approach allows a very low basal exposure of the middle and temporal fossa, minimizing the amount of temporal lobe retraction needed to approach intradural and extradural lesion in this location. This approach is simple, easily performed, does not require extensive skull base removal, and still offers excellent visualization of the middle fossa and of the region of the tentorial incisura.
Neural stem cells (NSCs) are capable of tracking migrating glioma cells. To exploit this tropism ... more Neural stem cells (NSCs) are capable of tracking migrating glioma cells. To exploit this tropism to generate an antitumor T-cell response, partic- ularly against disseminating tumor pockets, we inoculated intracranial glioma-bearing mice with interleukin 12 (IL-12) producing NSCs. Intra- tumoral therapy with IL-12-secreting NSCs prolonged survival compared to treatment with nonsecretory NSCs or saline. NSCs demonstrated strong tropism for disseminating
Cyr61 is a member of the CCN family of growth factors; these proteins are secreted and can act as... more Cyr61 is a member of the CCN family of growth factors; these proteins are secreted and can act as ligands of distinct integrins. We show that Cyr61 can enhance tumorigenicity of glioma cells acting through activated integrin-linked kinase (ILK) to stimulate -catenin-TCF/Lef and Akt signaling pathways. Overexpression of Cyr61 occurred in highly tumori- genic glioma cell lines and in 68%
TMEFF1 is a novel transmembrane protein, containing two follisatin domains and an epidermal growt... more TMEFF1 is a novel transmembrane protein, containing two follisatin domains and an epidermal growth factor-like region. These structural domains suggest a role for TMEFF1 in growth factor signaling. TMEFF1 fused to enhanced green fluorescent protein revealed that TMEFF1 is expressed on the cell membrane. Northern analysis of normal human tissue showed that TMEFF1 is predominantly expressed in the brain. Study
Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studie... more Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studies have shown that complex interactions of multiple factors are responsible for these hospitalizations. A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Medicare database of newly diagnosed elderly glioblastoma multiforme (GBM) patients who underwent surgical resection between 1991 and 2007. Hospitals were classified into high- or low-readmission rate cohorts using a risk-adjusted methodology. Bivariate comparisons of outcomes were conducted. Multivariate analysis evaluated differences in quality of care according to hospital readmission rates. A total of 1,273 patients underwent surgery in 338 hospitals; 523 patients were treated in 228 high-readmission hospitals and 750 in 110 low-readmission hospitals. Patient characteristics for high-versus low-readmission hospitals were compared. In a confounder-adjusted model, patients treated in hig...
OBJECT The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and the Ce... more OBJECT The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and the Centers for Medicare and Medicaid Services hospital-acquired conditions (HACs) are administrative data-based metrics. The use of these outcomes as standard performance measures has been discussed in previous studies. With the objective of determining the applicability of these events as performance metrics among patients undergoing brain tumor surgery, this study had 2 aims: 1) to evaluate the association between PSIs, HACs, and in-hospital mortality rates; and 2) to determine a correlation between hospital volume, PSIs, and HACs. METHODS Patients with brain tumors treated between 1998 and 2009 were captured in the Nationwide Inpatient Sample database. Hospitals were categorized into groups according to surgical volume. Associations between PSIs, HACs, and in-hospital mortality rates were studied. Factors associated with a PSI, HAC, and mortality were evaluated in a multivariate setting. R...
Currently, there is no gadolinium-based contrast agent available for conventional magnetic resona... more Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Aβ plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(β-l-malic acid) (PMLA) containing covalently attached gadolinium-DOTA(Gd-DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Aβ plaques and is detected by MRI. It efficiently detected Aβ plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD.
Anatomy, Diagnosis and Treatment 1st International Skull Base Congress, Hannover, June 1992, 1994
A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the t... more A simple transzygomatic approach to the middle fossa centered on the inferior retraction of the temporal muscle after transection of the zygomatic arch is described. This approach allows a very low basal exposure of the middle and temporal fossa, minimizing the amount of temporal lobe retraction needed to approach intradural and extradural lesion in this location. This approach is simple, easily performed, does not require extensive skull base removal, and still offers excellent visualization of the middle fossa and of the region of the tentorial incisura.
Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a signifi... more Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy that can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. To develop a more precise non-invasive MRI diagnostic method, we have engineered a new class of poly(β-L-malic acid) polymeric nano-imaging agents (NIA). The NIA carrying attached MRI tracer are able to pass through blood brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative "MRI virtual biopsy" method is based on nanoconjugate carrying MRI contrast agent Gadolinium-DOTA and antibodies recognizing tumor specific markers and extravasating through BBB. In newly developed double tumo...
Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of ma... more Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of malignant tumours. Diverse genetic programs regulate CSC behaviours, and CSCs from glioblastoma patients are qualitatively distinct from each other. The intrinsic connection between the presence of CSCs and malignancy is unclear. We set out to test whether tumour stem-like cells can be identified from benign tumours. Tumour sphere cultures were derived from hormone-positive and -negative pituitary adenomas. Characterisation of tumour stem-like cells in vitro was performed using self-renewal assays, stem cell-associated marker expression analysis, differentiation, and stimulated hormone production assays. The tumour-initiating capability of these tumour stem-like cells was tested in serial brain tumour transplantation experiments using SCID mice. In this study, we isolated sphere-forming, self-renewable, and multipotent stem-like cells from pituitary adenomas, which are benign tumours. We f...
Diseases involving the proximity of the internal carotid artery at the skull base require identif... more Diseases involving the proximity of the internal carotid artery at the skull base require identification of this vessel in the temporal bone to gain vascular control for any maneuver in its vicinity. This article details the technique of surgical dissection and exposure of the internal carotid artery within the skull base through a transtemporal middle cranial fossa approach. The anatomic landmarks important in utilizing this procedure include the greater superficial petrosal nerve, the mandibular branch of the trigeminal nerve, and the middle meningeal artery. With this approach, the internal carotid artery can be followed throughout the carotid canal and beyond the formen lacerun to the region of the cavernous sinus. The indications and limitations of this procedure are described and several clinical applications are provided.
In this Phase I trial, patients' peripheral blood dendritic cells were pulsed with peptides e... more In this Phase I trial, patients' peripheral blood dendritic cells were pulsed with peptides eluted from the surface of autologous glioma cells. Three biweekly intradermal vaccinations of peptide-pulsed dendritic cells were administered to seven patients with glioblastoma multiforme and two patients with anaplastic astrocytoma. Dendritic cell vaccination elicited systemic cytotoxicity in four of seven tested patients. Robust intratumoral cytotoxic and memory T-cell infiltration was detected in two of four patients who underwent reoperation after vaccination. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous peptide-pulsed dendritic cell vaccine for patients with malignant glioma.
We have identified a novel human malignancy-associated gene (MAG) expressed in various malignant ... more We have identified a novel human malignancy-associated gene (MAG) expressed in various malignant tumors including glioblastomas and hepatocellular carcinomas (HCCs) and in tumor preexisting conditions such as hepatitis C virus- and hepatitis B virus-induced liver cirrhosis. The expression of MAG was characterized using reverse transcription-PCR (RT-PCR), rapid amplification of cDNA ends PCR, RNA dot blotting, RNase protection assay, and Northern blot analysis. Rapid amplification of cDNA ends PCR yielded a 536-bp MAG fragment in HCC, macroregenerative liver nodules with dysplasia, and liver cirrhosis but not in normal liver or placenta. By RT-PCR, MAG expression was not found in 12 different normal tissues but found in 46 of 51 (90%) premalignant and malignant tissues of various sites. Embryonic liver and brain were positive for MAG expression together with tumors from the same organs, but the corresponding normal adult tissues were negative. By RNase protection assay, MAG mRNA was ...
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming im... more Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming immune responses to tumor. Interleukin (IL)-23 can act directly on DC to promote immunogenic presentation of tumor peptide in vitro. Here, we evaluated the combination of bone marrow-derived DC and IL-23 on the induction of antitumor immunity in a mouse intracranial glioma model. DCs can be
Neural progenitor-like cells have been isolated from bone marrow and the cells have the ability o... more Neural progenitor-like cells have been isolated from bone marrow and the cells have the ability of tracking intracranial tumor. However, the capacity of the cells to deliver molecules for activating immune response against intracranial tumor and the identity of cellular and molecular factors that are involved in such immune responses have yet to be elucidated. Here, we isolated neural stem-like
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Papers by Keith Black