Project MED (Medicine, Exposure, and Development): Promoting Access to Healthcare Education for Historically Underrepresented Groups Through Community Engagement, Sustainability, and Technology.

In the U.S., disparities in the healthcare workforce have led to inadequate health outcomes in communities of historically underserved groups. To address the lack of resources and opportunities in health career education for historically underserved group students, Project MED was established. The mission is to expose high school students to the breadth of opportunities in the healthcare field and to prepare students for successful careers in healthcare. Through 3 main pillars-Learn, Lead, and Launch-Project MED has developed a robust repository of 20 workshops, recruited and trained eight mentors, and curated a database of ≥100 opportunities for over 50 students.

Effect of Combined 68Ga-PSMAHBED-CC Uptake Pattern and Multiparametric MRI Derived With Simultaneous PET/MRI in the Diagnosis of Primary Prostate Cancer: Initial Experience.

OBJECTIVE: The purpose of this study is to assess whether temporal changes in 68Ga-prostate-specific membrane antigen (PSMA)-HBED-CC uptake and multiparametric MRI parameters derived using PET/MRI can aid in characterization of benign and malignant prostate lesions. MATERIALS AND METHODS: Thirty-five men with 29 malignant and six benign prostate lesions undergoing complete clinical workup including histologic analysis were enrolled for this retrospective study. All had undergone simultaneous whole-body 68Ga-PSMAHBED-CC PET/MRI. Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) assessment was made using a 5-point scale showing the likelihood of cancer with the combination of multiparametric MRI findings. Gallium-68-PSMA uptake was recorded at two time points: early (7 minutes) and delayed (54 minutes), adopting a copy-and-paste function of the ROI defined on MR images. ROC curve analysis was performed to test the diagnostic accuracy of early versus delayed PSMA uptake (measured as maximum standardized uptake value [SUV]). A multiple-ROI analysis was done to obtain ROCs for combined PET SUV and multiparametric MRI datasets. Spearman analysis was performed to assess the correlations. RESULTS: There was a significant difference between early and delayed PSMA uptake in malignant prostatic lesions (p < 0.01), which was able to characterize prostate lesions with an AUC of 0.83 and 0.94. Combined ROC analysis of PI-RADSv2 category derived from multiparametric MRI and differential PSMA uptake in characterizing prostatic lesions improved the AUC to 0.99. CONCLUSION: Dual-phase PSMA uptake improves accuracy of classifying malignant versus benign prostate lesions and complements multiparametric MRI in the diagnosis of prostate cancer.

Improving Diagnosis of Primary Prostate Cancer With Combined 68Ga-Prostate-Specific Membrane Antigen-HBED-CC Simultaneous PET and Multiparametric MRI and Clinical Parameters.

OBJECTIVE: The current study was designed to test the diagnostic performance of 68Ga-prostate-specific membrane antigen (PSMA) PET and multiparametric MRI along with clinical parameters in the characterization of prostatic lesions. MATERIALS AND METHODS: Eighty-two men with 63 malignant and 21 benign histologically proven prostate lesions who underwent complete clinical workup were included in this retrospective study. All patients underwent simultaneous whole-body 68Ga-PSMA PET/MRI with dedicated multiparametric MRI. Prostate Imaging-Reporting and Data System (PI-RADS) version 2 assessment was used for predicting the likelihood of cancer. Uptake of 68Ga-PSMA was recorded by adopting the copy-and-paste function of ROIs defined on MR images. ROC and combined ROC analyses were performed to test the diagnostic accuracy of individual and combined parameters. Spearman analysis was used to assess the correlations. RESULTS: PSMA uptake (maximum standardized uptake value) was significantly different among tumors with Gleason scores of 7, 8, and 9, with the lowest uptake in tumors with a score of 7 and the highest uptake in tumors with a score of 9. There was a significant difference between early- and delayed-phase PSMA uptake in malignant prostatic lesions (p < 0.01). Significant correlations were observed between delayed and differential PSMA uptake and PI-RADS category (p < 0.01 and < 0.01, respectively), digital rectal examination findings (p = 0.01 and < 0.01, respectively), Gleason score (p = 0.05 and < 0.05, respectively), and prostate-specific antigen levels (p = 0.01 for both). Combined ROC analysis of prostate-specific antigen levels, digital rectal examination findings, multiparametric MRI, and differential PSMA uptake were able to characterize prostatic lesions with a mean (± SD) AUC of 0.94 ± 0.03, compared with their individual AUCs of 0.77, 0.70, 0.82, and 0.88. CONCLUSION: Gallium-68-PSMA PET combined with multiparametric MRI showed high diagnostic accuracy for prostate cancer diagnosis compared with either multiparametric MRI or PET alone or with clinical factors (e.g., digital rectal examination or prostate-specific antigen level) alone, and the combination further improves characterization of prostatic lesions.

Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics.

Inositol 1,4,5-trisphosphate receptors (IP3 Rs) regulate autophagy in normal cells and are associated with metastasis in cancer cells. In breast cancer, however, the regulation and role of IP3 Rs is not clear. To study this, we used MCF-7 breast cancer cell line and mouse model of breast cancer. Inhibiting IP3 R sub types resulted in compromised bioenergetics both in terms of glucose and mitochondrial metabolism. The siRNA mediated silencing of IP3 R or its blocking by its inhibitors Xestospongin C and 2-Amino-ethoxy diphenyl borate increased cell death and LC3II expression in MCF-7 cells as well as attenuated cellular bioenergetics. The level of Autophagy related gene, Atg5 was found to be up regulated after pharmacological as well as siRNA blocking of IP3 R. The specificity of its role in autophagy was confirmed through specific shRNA knockdown of the Atg5 along with IP3 R inhibitor. Inhibiting as well as silencing of IP3 R receptor also resulted in increase in ROS production which was abolished after pretreatment with N-acetyl cysteine. Its role in autophagy was confirmed through decrease in the levels of LC3 II after pretreatment with IP3 R inhibitor and N acetyl cysteine.Moreover, inhibiting as well as silencing IP3 R-induced cell death in MCF-7 cells was attenuated by autophagic inhibitors (Bafilomycin A1 or 3-Methyladeneine). In mice, blocking of IP3 Rs by 2-Amino-ethoxy diphenyl borate arrested tumor growth. Overall our findings indicate that IP3 R blocking resulted in autophagic cell death in breast cancer cells and provides a role of IP3 Rs in determining the breast cancer cell fate. J. Cell. Biochem. 118: 2333-2346, 2017. © 2017 Wiley Periodicals, Inc.

Reliability of 18F-FDG PET Metabolic Parameters Derived Using Simultaneous PET/MRI and Correlation With Prognostic Factors of Invasive Ductal Carcinoma: A Feasibility Study.

OBJECTIVE: The objective of our study was to correlate semiquantitative PET parameters-standardized uptake value (SUV) and total lesion glycolysis (TLG)-derived in simultaneous PET/MRI using MRI-based attenuation correction with clinical and histopathologic prognostic factors in patients with breast cancer. MATERIALS AND METHODS: Eighty-two invasive ductal carcinomas in 69 women were included in the study. All the subjects underwent whole-body (WB) PET/MRI (supine WB mode) and dedicated PET/MRI of the breast (prone breast imaging mode) for staging on a simultaneous PET/MRI system. The SUV and TLG values were calculated from 18F-FDG PET data using MRI-based attenuation correction (2-point Dixon sequence for tissue segmentation). Relationships between SUV and TLG values and clinical and histopathologic parameters (i.e., tumor size, tumor grade, Ki-67 status, and hormonal receptor expression status) were evaluated using Spearman correlation coefficient analysis. RESULTS: A significant correlation was observed between mean SUV (SUVmean) and maximum SUV (SUVmax) values derived with WB PET and regional PET of the breasts performed simultaneously with MRI (r = 0.88 and 0.89, respectively). A significant difference (p < 0.05) was observed in SUVmean, SUVmax, and TLG values between the grades and molecular subtypes of breast cancer. High SUVmean, SUVmax, and TLG values were found to correlate with larger tumor size (p < 0.01), higher proliferation index (p < 0.05), higher grade (p < 0.01), and triple-negative hormonal receptor status (p < 0.01, p < 0.05). CONCLUSION: Semiquantitative FDG parameters derived with MRI-based attenuation correction in simultaneous PET/MRI are reliable and correlate with clinicopathologic features such as grade as well as subtype and thus could be used in the prognostication of breast cancer.

Zoledronate and Molecular Iodine Cause Synergistic Cell Death in Triple Negative Breast Cancer through Endoplasmic Reticulum Stress.

Women consuming molecular iodine (I2) through seaweeds suffer the least from breast cancers. Zoledronate (Zol) is in clinical use for alleviation of bone pain in cancer patients. Triple negative breast cancers exhibit high mortality due to lack of neoadjuvant chemotherapy. I2 and Zol independently cause weak antiproliferative and apoptotic effect. So far, their combined effects have not been tested. We analyzed the effect of combination of I2 with Zol as a potent adjuvant therapeutic agent for triple negative breast cancer cells (MDA-MBA-231) and in the mice model of breast cancer. Cell viability, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, Western blotting, real-time PCR, flow cytometry, and other assays were performed for assessing cell death, calcium levels, and migration potential, respectively, in treated cells. The increased caspase 8, increased [Ca(2+)]c levels, and endoplasmic reticulum (ER) stress resulted in apoptosis. Real time and fluorescence-based analysis demonstrated that the combination treatment targets ER Ca(2+) homeostasis chaperons leading to apoptosis. Combination therapy reduces metalloproteinases 2 and 9, inhibits invasion/migration of cells, and prevents growth of tumor in mice. I2 + Zol combination treatment induces synergistic increase in ER-mediated apoptosis, reduces invasion/migration potential of MDA-MB-231 cells, and exhibits antiproliferative property in vivo demonstrating its potential as combination therapy.

Antiviral signaling protein MITA acts as a tumor suppressor in breast cancer by regulating NF-κB induced cell death.

Emerging evidences suggest that chronic inflammation is one of the major causes of tumorigenesis. The role of inflammation in regulation of breast cancer progression is not well established. Recently Mediator of IRF3 Activation (MITA) protein has been identified that regulates NF-κB and IFN pathways. Role of MITA in the context of inflammation and cancer progression has not been investigated. In the current report, we studied the role of MITA in the regulation of cross talk between cell death and inflammation in breast cancer cells. The expression of MITA was significantly lower on in estrogen receptor (ER) positive breast cancer cells than ER negative cells. Similarly, it was significantly down regulated in tumor tissue as compared to the normal tissue. The overexpression of MITA in MCF-7 and T47D decreases the cell proliferation and increases the cell death by activation of caspases. MITA positively regulates NF-κB transcription factor, which is essential for MITA induced cell death. The activation of NF-κB induces TNF-α production which further sensitizes MITA induced cell death by activation of death receptor pathway through capsase-8. MITA expression decreases the colony forming units and migration ability of MCF-7 cells. Thus, our finding suggests that MITA acts as a tumor suppressor which is down regulated during tumorigenesis providing survival advantage to tumor cell.

Aggression and its correlation with plasma C-reactive protein levels in patients with schizophrenia: A hospital based cross-sectional study.

Background: The correlation between plasma C-reactive protein (CRP) and aggression in schizophrenia has recently become an area of interest. As an acute phase reactant, neuro-immuno-modulatory and neurohumoral functions of CRP might have a role in understanding causation of aggression in disease and this may have implications in therapeutic intervention. Aims: To assess aggression and plasma CRP in patients with schizophrenia and to compare aggression in patients with normal and elevated CRP. Methods and Material: A hospital-based cross-sectional study was carried out over a period of one year (2019-2020). Patients of schizophrenia as per International Classification of Diseases 10 were selected. Modified Overt Aggression Scale was applied, and plasma CRP levels were estimated in the selected patients. Statistical Analysis: Mean aggression scores were compared in patients with normal and elevated CRP. And aggression scores were correlated with plasma CRP levels. Results: Mean aggression score (22.93 ± 2.80) was significantly (P < .001) higher in patients with elevated CRP. There is a positive correlation (r = 0.855, P < .001) between aggression and plasma CRP. Conclusion: Patients with elevated CRP were more aggressive compared to the patients with normal CRP.

NLRX1 regulates TNF-α-induced mitochondria-lysosomal crosstalk to maintain the invasive and metastatic potential of breast cancer cells.

An increased level of proinflammatory cytokines, including TNF-α in tumor microenvironment regulates the bioenergetic capacity, immune evasion and survival of cancer cells. Emerging evidences suggest that mitochondrial immune signaling proteins modulates mitochondrial bioenergetic capacity, in addition to the regulation of innate immune response. The optimal oxidative phosphorylation (OxPhos) capacity is required for the maintenance of functional lysosomes and autophagy flux. NLRX1, a mitochondrial NOD family receptor protein, regulates mitochondrial function during apoptosis and tissue injury. However, its role in regulation of mitochondrial and lysosomal function to modulate autophagy flux during inflammatory conditions is not understood. In the current study, we investigated the role of NLRX1 in modulating TNF-α induced autophagy flux and mitochondrial turnover and its implication in regulating the invasive and metastatic capability of breast cancer cells. Expression analyses of clinical breast cancer samples and meta-analysis of multiple public databases revealed that NLRX1 expression is significantly increased in basal-like and metastatic breast carcinoma as compared to non-basal-like and primary breast cancer. Depletion of NLRX1 expression in triple-negative breast cancer cells, altered the organization and activity of OxPhos complexes in presence of TNF-α. NLRX1 depletion further impaired lysosomal function and hence the turnover of damaged mitochondria through mitophagy in presence of TNF-α. Importantly, loss of NLRX1 decreased OxPhos-dependent cell proliferation and migration ability of triple-negative breast cancer cells in presence of TNF-α. These evidences suggest an essential role of NLRX1 in maintaining the crosstalk of mitochondrial metabolism and lysosomal function to regulate invasion and metastasis capability of breast cancer cells.

A Practical Approach to Optimize Scan Protocol for Simultaneous Whole-Body Positron Emission Tomography/Magnetic Resonance Imaging in Cancer Staging.

OBJECTIVE: The aim of the report is to present time efficient whole-body positron emission tomography/magnetic resonance imaging (PET/MRI) protocol evolved and tested for comprehensive evaluation of cancer patients. MATERIALS AND METHODS: Whole body as well as regional simultaneous PET and MRI was performed on Biograph mMR (Siemens, Erlangen, Germany) Simultaneous PET/MRI system in 4500 clinical cases of various cancers from 2013 to 2017 with an in-house designed imaging protocol to assess its utility. RESULTS: Using this protocol, the whole body is covered with optimized sequences (T1, T2, short tau inversion recovery, diffusion, and 3D volumetric interpolated breath-held) with PET which has been found adequate for complete metastatic workup in 30-45 min. With region-specific studies, it provides a comprehensive staging workup in an additional 10-15 min. The workflow offered additive advantages of effectively addressing incidentalomas besides being useful in terms of diagnostic utility. CONCLUSION: The proposed whole-body PET MRI imaging protocol used in a clinical setting is found acceptable and reasonably time efficient to optimally exploit the potentials of the technique in oncology.

Association of pharmacokinetic and metabolic parameters derived using simultaneous PET/MRI: Initial findings and impact on response evaluation in breast cancer.

PURPOSE: To study relationships among pharmacokinetic and 18F-fluorodeoxyglucose (18F-FDG) PET parameters obtained through simultaneous PET/MRI in breast cancer patients and evaluate their combined potential for response evaluation. METHODS: The study included 41 breast cancer patients for correlation study and 9 patients (pre and post therapy) for response evaluation. All patients underwent simultaneous PET/MRI with dedicated breast imaging. Pharmacokinetic parameters and PET parameters for tumor were derived using an in- house developed and vendor provided softwares respectively. Relationships between SUV and pharmacokinetic parameters and clinical as well as histopathologic parameters were evaluated using Spearman correlation analysis. Response to chemotherapy was derived as percentage reduction in size and in parameters post therapy. RESULTS: Significant correlations were observed between SUVmean, max, peak, TLG with Ktrans (ρ=0.446, 0.417, 0.491, 0.430; p≤0.01); with Kep(ρ=0.303, ρ=0.315, ρ=0.319; p≤0.05); and with iAUC(ρ=0.401, ρ=0.410, ρ=0.379; p≤0.05, p≤0.01). The ratio of ve/iAUC showed significant negative correlation to SUVmean, max, peak and TLG (ρ=0.420, 0.446, 0.443, 0.426; p≤0.01). Ability of SUV as well as pharmacokinetic parameters to predict response to therapy matched the RECIST criteria in 9 out of 11 lesions in 9 patients. Maximum post therapy quantitative reduction was observed in SUVpeak, TLG and Ktrans. CONCLUSION: Simultaneous PET/MRI enables illustration of close interactions between glucose metabolism and pharmacokinetic parameters in breast cancer patients and potential of their simultaneity in response assessment to therapy.

1H NMR Metabolomics Reveals Association of High Expression of Inositol 1, 4, 5 Trisphosphate Receptor and Metabolites in Breast Cancer Patients.

1H NMR is used to detect alterations in metabolites and their linkage to metabolic processes in a number of pathological conditions including breast cancer. Inositol 1, 4, 5 trisphosphate (IP3R) receptor is an intracellular calcium channel known to regulate metabolism and cellular bioenergetics. Its expression is up regulated in a number of cancers. However, its linkage to metabolism in disease conditions has not been evaluated. This study was designed to determine the association if any, of these metabolites with altered expression of IP3R in breast cancer. We used 1H NMR to identify metabolites in the serum of breast cancer patients (n = 27) and performed Real-time Polymerase Chain Reaction analysis for quantifying the expression of IP3R type 3 and type 2 in tissues from breast cancer patients (n = 40). Principal Component Analysis (PCA) and Partial Least Square-Discriminant Analysis (PLS-DA) clearly distinguished patients with high/low IP3R expression from healthy subjects. The present study revealed high expression of IP3R type 2 and type 3 in human breast tumor tissue compared to adjacent non-tumorous tissue. Moreover, patients with ≥ 2-fold increase in IP3R (high IP3R group) had significantly higher concentration of metabolic intermediates compared to those with < 2-fold increase in IP3R (low IP3R group). We observed an increase in lipoprotein content and the levels of metabolites like lactate, lysine and alanine and a decrease in the levels of pyruvate and glucose in serum of high IP3R group patients when compared to those in healthy subjects. Receiver operating characteristic (ROC) curve analysis was performed to show the clinical utility of metabolites. In addition to the human studies, functional relevance of IP3Rs in causing metabolic disruption was observed in MCF-7 and MDA MB-231 cells. Results from our studies bring forth the importance of metabolic (or metabolomics) profiling of serum by 1H NMR in conjunction with tissue expression studies for characterizing breast cancer patients. The results from this study provide new insights into relationship of breast cancer metabolites with IP3R.

Role of pharmacokinetic parameters derived with high temporal resolution DCE MRI using simultaneous PET/MRI system in breast cancer: A feasibility study.

PURPOSE: To evaluate the reliability of pharmacokinetic parameters like Ktrans, Kep and ve derived through DCE MRI breast protocol using 3T Simultaneous PET/MRI (3Tesla Positron Emission Tomography/Magnetic Resonance Imaging) system in distinguishing benign and malignant lesions. MATERIALS AND METHODS: High temporal resolution DCE (Dynamic Contrast Enhancement) MRI performed as routine breast MRI for diagnosis or as a part of PET/MRI for cancer staging using a 3T simultaneous PET/MRI system in 98 women having 109 breast lesions were analyzed for calculation of pharmacokinetic parameters (Ktrans, ve, and Kep) at 60s time point using an in-house developed computation scheme. RESULTS: Receiver operating characteristic (ROC) curve analysis revealed a cut off value for Ktrans, Kep, ve as 0.50, 2.59, 0.15 respectively which reliably distinguished benign and malignant breast lesions. Data analysis revealed an overall accuracy of 94.50%, 79.82% and 87.16% for Ktrans, Kep, ve respectively. Introduction of native T1 normalization with an externally placed phantom showed a higher accuracy (94.50%) than without native T1 normalization (93.50%) with an increase in specificity of 87% vs 84%. CONCLUSION: Overall the results indicate that reliable measurement of pharmacokinetic parameters with reduced acquisition time is feasible in a 3TMRI embedded PET/MRI system with reasonable accuracy and application may be extended to exploit the potential of simultaneous PET/MRI in further work on breast cancer.

hsa-miR-4485 regulates mitochondrial functions and inhibits the tumorigenicity of breast cancer cells.

The modulation of mitochondrial functions is important for maintaining cellular homeostasis. Mitochondria essentially depend on the import of RNAs and proteins encoded by the nuclear genome. MicroRNAs encoded in the nucleus can translocate to mitochondria and target the genome, affecting mitochondrial function. Here, we analyzed the role of miR-4485 in the regulation of mitochondrial functions. We showed that miR-4485 translocated to mitochondria where its levels varied in response to different stress conditions. A direct binding of miR-4485 to mitochondrial 16S rRNA was demonstrated. MiR-4485 regulated the processing of pre-rRNA at the 16S rRNA-ND1 junction and the translation of downstream transcripts. MiR-4485 modulated mitochondrial complex I activity, the production of ATP, ROS levels, caspase-3/7 activation, and apoptosis. Transfection of a miR-4485 mimic downregulated the expression of regulatory glycolytic pathway genes and reduced the clonogenic ability of breast cancer cells. Ectopic expression of miR-4485 in MDA-MB-231 breast carcinoma cells decreased the tumorigenicity in a nude mouse xenograft model. Furthermore, levels of both precursor and mature miR-4485 are decreased in tumor tissue of breast cancer patients. We conclude that the mitochondria-targeted miR-4485 may act as a tumor suppressor in breast carcinoma cells by negatively regulating mitochondrial RNA processing and mitochondrial functions.

Phytochemicals for breast cancer therapy: current status and future implications.

Breast cancer is one of the most common malignancies among women, representing nearly 30% of newly diagnosed cancers every year. Till date, various therapeutic interventions, including surgery, chemotherapy, hormonal therapy, and radiotherapy are available and are known to cause a significant decline in the overall mortality rate. However, therapeutic resistance, recurrence and lack of treatment in metastasis are the major challenges that need to be addressed. Increasing evidence suggests the presence of cancer stem cells (CSCs) in heterogeneous population of breast tumors capable of selfrenewal and differentiation and is considered to be responsible for drug resistance and recurrence. Therefore, compound that can target both differentiated cancer cells, as well as CSCs, may provide a better treatment strategy. Due to safe nature of dietary agents and health products, investigators are introducing them into clinical trials in place of chemotherapeutic agents.This current review focuses on phytochemicals, mainly flavonoids that are in use for breast cancer therapy in preclinical phase. As phytochemicals have several advantages in breast cancer and cancer stem cells, new synthetic series for breast cancer therapy from analogues of most potent natural molecule can be developed via rational drug design approach.

QSAR guided semi-synthesis and in-vitro validation of anticancer activity in ursolic acid derivatives.

As a part of our anticancer drug discovery programme, QSAR models were developed for the prediction of anticancer activities of ursolic acid derivatives against the human hepatocellular carcinoma HepG2, breast carcinoma MDA-MB-231 and the human ductal breast epithelial T47D cancer cell lines followed by wet lab semi-synthesis of virtually active derivatives, their in-vitro biological evaluation and apoptosis. The development of QSAR models was carried out by forward stepwise multiple linear regression method using a leave-one-out approach. Virtually active derivatives were semi synthesized, spectroscopically characterized and then in-vitro tested against human cancer cell lines. Active derivatives were checked via DNA fragmentation assay. The results exhibited regression coefficients (r(2)) and the cross-validation regression coefficients (rCV(2)) for the human HepG2, MDA-MB-231 and T47D cancer cell lines as .95 and .90; .92 and .87; .89 and .83 respectively showing the prediction accuracy of the models against biological activities. Computational molecular modeling is a valid modern approach, widely used in the identification of potential drug leads. The most active virtual derivatives of UA were semi- synthesized and their in-vitro and ex-vivo evaluation showed similar results with the predicted one, validating our QSAR models. Out of several active derivatives, the three UA2, UA7 and UA10 were potentially active against the above human cancer cell lines. These findings may be of immense importance in the anticancer drug development of an inexpensive and widely available natural product, ursolic acid.