David L Basi

University of Minnesota Duluth, Duluth, Minnesota, United States

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Publications (16)45.71 Total impact

  • No preview · Article · Oct 2015
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    ABSTRACT: Objective: A proteomic study was conducted to identify differentially expressed salivary proteins in "Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)" patients that could serve as potential biomarkers for BRONJ diagnosis. Materials and Methods: Whole saliva obtained from 20 BRONJ patients and 20 controls were pooled within groups according to BP exposure (for both BRONJ and control groups) and lesion size (BRONJ group only, Figure-1). The pooled samples were analyzed using iTRAQ labeled two-dimensional liquid chromatography-tandem mass spectrometry. Results: Overall, 1340 proteins were identified. Of these, biomarker candidates were selected based on p value (<0.001), change in protein expression (=>1.5-fold increase or decrease relative to the respective comparison group), and unique peptides identified (=>2). Three specific comparisons were made between BRONJ and control groups: (I) low-infusion controls versus low-infusion BRONJ; (II) high-infusion controls versus high-infusion BRONJ; and (III) high-infusion controls versus low-infusion BRONJ. Two hundred proteins were found to be differentially expressed in BRONJ cases compared to controls, including 15 proteins in comparison-I, 78 in comparison-II, and 107 in comparison-III. The differentially expressed proteins were predicted to have a role in drug metabolism and molecular transport in comparison-I; cellular movement, hematological function and immune cell trafficking in comparison-II; and dermatological diseases, developmental disorder and organismal abnormalities in comparison-III. Of all the differentially expressed proteins, we selected two proteins for further validation. Immunoassays confirmed increased expression of metalloproteinase-9 in individual saliva (p=0.048) and serum samples (p=0.05) of BRONJ patients compared to controls. Desmoplakin was undetectable in saliva. However, their levels were decreased in BRONJ serum samples compared to controls, although the difference was statistically insignificant (p=0.157). Conclusion: The molecular signatures identified by this cross-sectional study suggest that multiple pathological reactions are involved in BRONJ development. The role of MMP-9 and desmoplakin in BRONJ requires further investigation.
    No preview · Conference Paper · Mar 2013

  • No preview · Article · Oct 2012 · Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons
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    ABSTRACT: Neurobiological mechanisms of human musculoskeletal pain are poorly understood. This case-control study tested the hypothesis that biomarkers within temporomandibular muscle and joint disorders (TMJD) subjects' masseter muscles or temporomandibular joint (TMJ) synovial fluid correlate with plasma biomarker concentrations. Fifty subjects were recruited and categorized into TMJD cases (n=23) and pain-free controls (n=27) at the University of Minnesota School of Dentistry. Prior to specimen collection, pain intensity and pressure pain threshold masseter muscles and the TMJs were assessed. We collected venous blood; biopsied masseter muscle; and sampled TMJ synovial fluid on the subjects' side of maximum pain intensity. We assayed these tissues for the presence of nerve growth factor (NGF), bradykinin (BK), leukotreine B(4) (LTB(4) ) and prostaglandin E(2) (PGE(2) ), F(2) -isoprostane (F(2) I) and substance P (SP). The data was analyzed using Spearman Correlation Coefficients. We found that only plasma concentrations of bradykinin statistically correlated with synovial fluid concentrations (ρ=-0·48, P=0·005), but no association was found between pain intensities. The data suggests that biomarkers used to assess TMJD need to be acquired in a site-specific manner. We also discovered that F(2) I concentrations were associated with muscle pain intensity and muscle pressure pain threshold (PTT) (β=0·4, 95%CI: 0·03-0·8) and joint PPT (β=0·4, 95%CI: 0·07-0·8) suggesting that muscle oxidative stress is involved in myofascial pain and that F(2) -I may be a biomarker for myofascial pain.
    Full-text · Article · Jan 2012 · Journal of Oral Rehabilitation
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    ABSTRACT: The use of nitrogen-containing bisphosphonates (n-bis) is associated with necrosis of the jaws, also known as bisphosphonate-related osteonecrosis of the jaws (BRONJ); however, the pathophysiology is unknown. Matrix metalloproteinase-9 (MMP-9) expression is essential for normal bone healing and is also required for angiogenesis. N-bis alters MMP-9 expression in vitro and in vivo; therefore, we hypothesized that n-bis alters MMP-9 expression during oral wound healing after tooth extraction. A total accumulated dose of 2.25 mg/kg (n = 20) of Zoledronic acid (ZA) Zometa or saline (control, n = 20) was administered to Sprague-Dawley male rats. Next, both groups had maxillary molar teeth extracted. Rats were sacrificed at postoperative day 1, 3, 7, or 21. Western blotting or multiplex ELISA was used to evaluate proteins of interest. Real-time polymerase chain reaction was used to assess the relative quantities of target gene mRNA. MMP-9 enzymatic activity was assessed by zymography. The ZA group showed a statistically significant reduction in bone mineralization rate 21 days after tooth extraction compared with the control group (Student t test, P = .005). Moreover, ZA-treated animals showed a statistically significant increase in MMP-9-specific mRNA at postoperative days 3 (P = .003), 7 (P < .0001), and 21 (P < .0001) and protein on postoperative days 3 (P = .005) and 7 (P < .0001). MMP-9 enzymatic activity was also increased in ZA-treated rats compared with control animals (Student t test, P = .014). We also evaluated the extraction sockets for the presence of tissue inhibitor of MMP-1 (TIMP1), which is an inhibitor of MMP-9 enzymatic activity. TIMP1-specific mRNA and protein were not significantly altered by ZA treatment at the times tested (P > .05). Receptor of NF-κB ligand (RANKL) is known to regulate the expression of MMP-9; we therefore assessed the RANKL expression in our experimental oral wound-healing model. The ZA-treated animals had significantly increased RANKL mRNA at postoperative days 3 (P = .02) and 21 (P = .004), while the protein expression was significantly increased at postoperative days 1 (P < .0001), 7 (P = .02), and 21 (P = .03) compared with the control group. ZA reduced bone mineralization within tooth extraction sockets, suggesting aberrant bone healing. ZA increases the amount and enzymatic activity of MMP-9, while apparently not altering the amount of TIMP1 within extraction sockets. RANKL is increased in ZA-treated rats, which suggests that increased MMP-9 expression is due, in part, to augmented RANKL expression.
    No preview · Article · Jul 2011 · Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons
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    ABSTRACT: To evaluate the frequency, risk factors, and clinical presentation of bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ). We performed a retrospective analysis of 576 patients with cancer treated with intravenous pamidronate and/or zoledronate between January, 2003 and December, 2007 at the University of Minnesota Masonic Cancer Center and Park Nicollet Institute. Eighteen of 576 identified patients (3.1%) developed BRONJ including 8 of 190 patients (4.2%) with breast cancer, 6 of 83 patients (7.2%) with multiple myeloma, 2 of 84 patients (2.4%) with prostate cancer, 1 of 76 patients (1.3%) with lung cancer, 1 of 52 patients (1.9%) with renal cell carcinoma, and in none of the 73 patients with other malignancies. Ten patients (59%) developed BRONJ after tooth extraction, whereas 7 (41%) developed it spontaneously (missing data for 1 patient). The mean number of BP infusions (38.1 ± 19.06 infusions vs. 10.5 ± 12.81 infusions; P<0.001) and duration of BP treatment (44.3 ± 24.34 mo vs. 14.6 ± 18.09 mo; P<0.001) were significantly higher in patients with BRONJ compared with patients without BRONJ. Multivariate Cox proportional hazards regression analysis showed that diabetes [hazard ratio (HR)=3.40; 95% confidence interval (CI), 1.14-10.11; P=0.028], hypothyroidism (HR=3.59; 95% CI, 1.31-9.83; P=0.013), smoking (HR=3.44; 95% CI, 1.28-9.26; P=0.015), and higher number of zoledronate infusions (HR=1.07; 95% CI, 1.03-1.11; P=0.001) significantly increased the risk of developing BRONJ. Increased cumulative doses and long-term BP treatment are the most important risk factors for BRONJ development. Type of BP, diabetes, hypothyroidism, smoking, and prior dental extractions may play a role in BRONJ development.
    No preview · Article · Mar 2011 · American journal of clinical oncology
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    ABSTRACT: Objective: To evaluate the frequency, risk factors and clinical presentation of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in cancer patients treated with intravenous bisphosphonate (BP). Patients and Methods: We performed a retrospective analysis of 576 patients treated with pamidronate and/or zoledronate between January 2003 and December 2007 at the University of Minnesota Masonic Cancer Center and Park Nicollet Institute. Results: Eighteen of 576 identified patients (3.1%) developed BRONJ including 8 of 190 (4.2%)patients with breast cancer, 6 of 83 (7.2%) patients with multiple myeloma, 2 of 84(2.4%) patients with prostate cancer, 1 of 76 (1.3%) patients with lung cancer, 1 of 52(1.9%) patients with renal cell carcinoma and in none of the 73 patients with other malignancies. Ten patients (55%) developed BRONJ following tooth extraction, while 7 (39%) developed it spontaneously. The mean number of BP infusions (38.119.06 vs 10.512.81, p<0.0001) and duration of BP treatment (months, 44.324.34 vs 14.618.09,p<0.0001) was significantly higher in BRONJ patients compared to patients without BRONJ. Multivariate Cox proportional hazards regression analysis revealed that diabetes(HR=3.40; 95% CI=1.11-10.11; p=0.028), hypothyroidism (HR=3.59; 95% CI=1.31-9.83; p=0.013), smoking (HR=3.44; 95% CI=1.28-9.26; p=0.015), and higher number ofzoledronate infusions (HR=1.07; 95% CI=1.03-1.11; p=0.001) significantly increased therisk of developing BRONJ. Conclusion: Increased cumulative doses and long-term intravenous BP treatment are the most important risk factors for BRONJ development. Type of BP, diabetes, hypothyroidism, smoking and prior dental extractions may play a role in BRONJ development. 4-2010
    No preview · Conference Paper · Mar 2011
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    ABSTRACT: The goal of this study was to test the contributing role of increasing glucose uptake in vascular smooth muscle cells (VSMCs) in vascular complications and disease. A murine genetic model was established in which glucose trasporter 1 (GLUT1), the non-insulin-dependent glucose transporter protein, was overexpressed in smooth muscle using the sm22α promoter. Overexpression of GLUT1 in smooth muscle led to significant increases in glucose uptake (n=3, P<0.0001) as measured using radiolabeled 2-deoxyglucose. Fasting blood glucose, insulin, and nonesterified fatty acids were unchanged. Contractility in aortic ring segments was decreased in sm22α-GLUT1 mice (n=10, P<0.04). In response to vascular injury, sm22α-GLUT1 mice exhibited a proinflammatory phenotype, including a significant increase in the percentage of neutrophils in the lesion (n=4, P<0.04) and an increase in monocyte chemoattractant protein-1 (MCP-1) immunofluorescence. Circulating haptoglobin and glutathione/total glutathione were significantly higher in the sm22α-GLUT1 mice postinjury compared with controls (n=4, P<0.05), suggesting increased flux through the pentose phosphate pathway. sm22α-GLUT1 mice exhibited significant medial hypertrophy following injury that was associated with a significant increase in the percentage of VSMCs in the media staining positive for nuclear phosphoSMAD2/3 (n=4, P<0.003). In summary, these findings suggest that increased glucose uptake in VSMCs impairs vascular contractility and accelerates a proinflammatory, neutrophil-rich lesion in response to injury, as well as medial hypertrophy, which is associated with enhanced transforming growth factor-β activity.
    Full-text · Article · Jan 2011 · Arteriosclerosis Thrombosis and Vascular Biology
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    ABSTRACT: Adaptive changes to oxygen availability are critical for cell survival and tissue homeostasis. Prolonged oxygen deprivation due to reduced blood flow to cardiac or peripheral tissues can lead to myocardial infarction and peripheral vascular disease, respectively. Mammalian cells respond to hypoxia by modulating oxygen-sensing transducers that stabilize the transcription factor hypoxia-inducible factor 1α (HIF-1α), which transactivates genes governing angiogenesis and metabolic pathways. Oxygen-dependent changes in HIF-1α levels are regulated by proline hydroxylation and proteasomal degradation. Here we provide evidence for what we believe is a novel mechanism regulating HIF-1α levels in isolated human ECs during hypoxia. Hypoxia differentially increased microRNA-424 (miR-424) levels in ECs. miR-424 targeted cullin 2 (CUL2), a scaffolding protein critical to the assembly of the ubiquitin ligase system, thereby stabilizing HIF-α isoforms. Hypoxia-induced miR-424 was regulated by PU.1-dependent transactivation. PU.1 levels were increased in hypoxic endothelium by RUNX-1 and C/EBPα. Furthermore, miR-424 promoted angiogenesis in vitro and in mice, which was blocked by a specific morpholino. The rodent homolog of human miR-424, mu-miR-322, was significantly upregulated in parallel with HIF-1α in experimental models of ischemia. These results suggest that miR-322/424 plays an important physiological role in post-ischemic vascular remodeling and angiogenesis.
    Full-text · Article · Oct 2010 · The Journal of clinical investigation
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    ABSTRACT: Nitrogen-containing bisphosphonates (BIS) are potent inhibitors of bone resorption and are used in the treatment of a number of medical conditions, including multiple myeloma, breast cancer and osteoporosis. Recent experimental evidence demonstrates that BIS also affect endothelial cell functions and angiogenesis; however, the molecular mechanism(s) are unclear. Vascular endothelial growth factor (VEGF) is a potent pro-angiogenic signal for endothelial cells. BIS inhibit VEGF responses in endothelial cells. The VEGF receptor-2 (VEGFR2) is the main signaling receptor for VEGF in endothelial cells. We hypothesized that altered VEGFR2 expression in BIS-treated endothelial cells may account for these attenuated responses to VEGF. The affect of the BIS zoledronic acid (ZOL) was investigated in human umbilical vein endothelial cells using confocal microscopy, Western blotting, real-time PCR and flow cytometry. VEGFR2 accumulated within the ZOL-treated endothelial cells (p=0.0002), though not on the cell surface (p>0.05). ZOL did not induce VEGFR2-specific mRNA (p>0.05). ZOL inhibited endothelial cell chemotaxis towards VEGF (p=0.001). VEGF stimulation significantly reduced the amount of VEGFR2 in the endothelial cells (p=0.01). This response to VEGF was reduced by ZOL (p>0.05). The effects of ZOL on endothelial cell migration, VEGFR2 protein expression and response to VEGF were attenuated by geranylgeranyl pyrophosphate. Two- and one-way ANOVAs with Tukey or Dunnett's multiple comparison adjustments were used. The data suggest that ZOL induces aberrant VEGFR2 accumulation. This is not likely due to the induction of mRNA transcription, but rather to the disruption of the mevalonate pathway.
    No preview · Article · May 2010 · Molecular Medicine Reports
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    ABSTRACT: Heparan sulfate proteoglycans are abundant molecules in the extracellular matrix and at the cell surface. Heparan sulfate chains are composed of groups of disaccharides whose side chains are modified through a series of enzymatic reactions. Deletion of these enzymes alters heparan sulfate fine structure and leads to changes in cell proliferation and tissue development. The role of heparan sulfate modification has not been explored in the vessel wall. The goal of this study was to test the hypothesis that altering heparan sulfate fine structure would impact vascular smooth muscle cell (VSMC) proliferation, vessel structure, and remodeling in response to injury. A heparan sulfate modifying enzyme, N-deacetylase N-sulfotransferase1 (Ndst1) was deleted in smooth muscle resulting in decreased N- and 2-O sulfation of the heparan sulfate chains. Smooth muscle specific deletion of Ndst1 led to a decrease in proliferating VSMCs and the circumference of the femoral artery in neonatal and adult mice. In response to vascular injury, mice lacking Ndst1 exhibited a significant reduction in lesion formation. Taken together, these data provide new evidence that modification of heparan sulfate fine structure through deletion of Ndst1 is sufficient to decrease VSMC proliferation and alter vascular remodeling.
    Full-text · Article · Mar 2010 · Journal of Molecular and Cellular Cardiology
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    ABSTRACT: To report the clinical features, risk factors, management, and treatment outcomes of nitrogen-containing bisphosphonate (n-BIS)-related osteonecrosis of the jaw (BRONJ). Patients with suspected BRONJ were referred to the School of Dentistry for evaluation and treatment. A total of 26 patients (9 men and 17 women, mean age 64 years) were diagnosed with BRONJ. Of the 26 patients, 23 had received n-BIS therapy for cancer and 3 for osteoporosis. BRONJ lesions were noted more frequently in the mandible and in the posterior sextants. Of the 26 patients, 16 had developed BRONJ after dentoalveolar procedures, and 10 had developed it spontaneously. The mean interval to development of BRONJ was shorter in the patients with cancer receiving intravenous n-BIS than in the patients with osteoporosis receiving oral n-BIS (37.1 versus 77.7 months, P = .02). Using the American Association of Oral and Maxillofacial Surgeons staging system, 2 patients were diagnosed with stage I lesions, 19 with stage II, and 5 with stage III lesions. The initial management of BRONJ was nonsurgical, with debridement performed at subsequent visits, if needed. The BRONJ lesions healed completely in 4 patients, healed partially in 8, remained stable in 7, and progressed in 7. The spontaneous lesions responded favorably to BRONJ management compared with lesions that developed after dentoalveolar procedures (P = .01). No significant difference was found in response to BRONJ management between patients who had continued or discontinued n-BIS therapy after the BRONJ diagnosis (P = .54). Long-term n-BIS therapy and recent dental procedures are consistent findings in patients with BRONJ. Spontaneous BRONJ lesions respond favorably to current BRONJ treatment strategies.
    No preview · Article · Oct 2009 · Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons
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    ABSTRACT: Redox factor-1 (Ref-1) is a multifunctional protein that regulates redox, DNA repair, and the response to cell stress. We previously demonstrated that Ref-1(+/-) mice exhibit a significantly reduced Ref-1 mRNA and protein levels within the vasculature, which are associated with increased oxidative stress. The goal of this study was to test the hypothesis that partial loss of Ref-1 altered the cellular response to vascular injury. Fourteen days after femoral artery wire injury, we found that vessel intima-to-media ratio was significantly reduced in Ref-1(+/-) mice compared with that in wild-type mice (P < 0.01). Bromodeoxyuridine labeling and transferase-mediated dUTP nick-end labeling staining at 14 days did not differ in the Ref-1(+/-) mice. In vitro studies found no significant changes in either serum-induced proliferation or baseline apoptosis in Ref-1(+/-) vascular smooth muscle cells. Exposure to Fas ligand; however, did result in increased susceptibility of Ref-1(+/-) vascular smooth muscle cells to apoptosis (P < 0.001). Ref-1(+/-) mice exhibited an increase in circulating baseline levels of IL-10, IL-1alpha, and VEGF compared with those in wild-type mice but a marked impairment in these pathways in response to injury. In sum, loss of a single allele of Ref-1 is sufficient to reduce intimal lesion formation and to alter circulating cytokine and growth factor expression.
    Full-text · Article · Feb 2007 · AJP Heart and Circulatory Physiology
  • Anh D Le · David L Basi · A Omar Abubaker

    No preview · Article · Nov 2005 · Journal of Oral and Maxillofacial Surgery
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    ABSTRACT: The aim of this project was to test the hypothesis that redox factor 1 (Ref-1) was a critical upstream determinant of NF-kappaB-dependent survival signaling pathways in the vessel wall. Aortas from hemizygous transgenic mice harboring a single allele of Ref-1 exhibited a significant loss in NF-kappaB DNA binding activity. The NF-kappaB-dependent survival gene A20 was significantly downregulated in aortas of hemizygous Ref-1 mice, whereas IAP-2 was unchanged. Overexpression of A20 rescued cells from tumor necrosis factor (TNF)-induced apoptosis, suggesting that the loss of A20 in Ref-1 hemizygotes may be a rate-determining step in endothelial cell fate. Deletion of the previously defined redox-sensitive or the AP endonuclease domains of Ref-1 significantly decreased NF-kappaB transcriptional activation and endothelial cell survival. Furthermore, TNF-induced apoptosis was significantly potentiated in endothelial cells after delivery of Morpholino antisense oligodeoxynucleotides targeted to Ref-1. Loss of the redox-sensitive domain blocked the ability of Ref-1 to reduce p50; however, loss of the endonuclease domain did not effect p50 reduction, suggesting alternative mechanisms of action of Ref-1 on NF-kappaB activity. These findings establish a role for Ref-1 as an upstream determinant of NF-kappaB and A20-dependent signaling and endothelial survival in the vessel wall.
    Full-text · Article · Jan 2005 · Arteriosclerosis Thrombosis and Vascular Biology
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    David L. Basi · Neeta Adhikari

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Publication Stats

349 Citations
45.71 Total Impact Points


  • 2005-2013
    • University of Minnesota Duluth
      • Medical School
      Duluth, Minnesota, United States
  • 2009-2012
    • University of Minnesota Twin Cities
      • • School of Dentistry
      • • Division of Oral and Maxillofacial Surgery
      Minneapolis, Minnesota, United States