In vitro gas production kinetics are influenced by grain processing, flake density, starch retrogradation, and Aspergillus oryzae fermentation extract containing α-amylase activity.

Grain processing such as particle size, flake density, or starch retrogradation can influence ruminal degradability characteristics; however, it is unclear how exogenous α-amylase supplementation interacts with different processed grains. Four experiments were conducted to compare the effects of Aspergillus oryzae fermentation extract (Amaize; Alltech Biotechnology Inc., Nicholasville, KY) supplementation on in vitro gas production kinetics of grain substrates with different processing methods that are common in the feedlot industry. In experiment 1, corn processing (dry-rolled, high-moisture, steam-flaked) and Amaize supplementation (0 or 15 U α-amylase activity/100 mL) were evaluated in a 3 × 2 factorial arrangement of treatments. The rate of gas production for dry-rolled corn was higher (P < 0.001) with Amaize supplementation. In experiment 2, flake density (296, 322, 348, 373, and 399 g/L) and starch retrogradation (storage in heat-sealed foil bags for 3 d at 23 or 55°C) were evaluated in a 5 × 2 factorial arrangement of treatments. There was a flake density × starch retrogradation interaction (P < 0.01) for the rate of gas production because the decrease in the rate of gas production with starch retrogradation was greater at lighter flake densities compared with heavier flake densities. In experiment 3, Amaize supplementation was evaluated across flake densities of nonretrograded steam-flaked corn (stored at 23°C) used in experiment 2. There was a flake density × Amaize interaction (P < 0.01) for the rate of gas production where Amaize supplementation resulted in a lower rate of gas production at lighter flake densities (296, 322, and 348 g/L) but a higher rate of gas production at heavier flake densities (373 and 399 g/L). In experiment 4, Amaize supplementation was evaluated across flake densities of retrograded steam-flaked corn (stored at 55°C) used in experiment 2. Gas production was lower after 24 h with Amaize supplementation for retrograded flakes produced to a density of 322 and 399 g/L while Amaize supplementation did not influence gas production at 24 h at other flake densities. There was a flake density × Amaize interaction for the rate of gas production because Amaize supplementation resulted in a faster (P < 0.01) rate of gas production for all flake densities except retrograded flakes produced to a density of 296 g/L. Enzymatic starch availability was positively correlated with the rate of gas production. These data demonstrate that supplementation of 15 U/100 mL of Amaize resulted in greater rates of gas production for dry-rolled corn, corn steam-flaked to heavier densities, and retrograded steam-flaked corn.

Grain processing has been used for decades to improve digestibility of finishing cattle diets, leading to improved growth and feed efficiency. Grain processing methods that result in changes in particle size, flake density, or starch retrogradation have all been shown to affect the degradability characteristics of nutrients in the rumen. Supplementation of feed additives containing exogenous enzyme activity could have the potential to improve digestibility, growth performance, and feed efficiency of livestock. However, it is unknown how supplementation of exogenous α-amylase activity influences degradability characteristics of different processed grains. The objectives of this study were to compare the effects of Aspergillus oryzae fermentation extract supplementation on in vitro gas production kinetics of grain substrates with different processing methods that are common in the feedlot industry. Enzymatic starch availability of steam-flaked corn, but not dry-rolled or high-moisture corn, was reflective of the rate of in vitro gas production. Increasing flake density and increasing starch retrogradation decreased the rate of in vitro gas production. Supplementation of A. oryzae fermentation extract resulted in increased rates of gas production for dry-rolled corn, corn steam-flaked at heavier densities, and retrograded steam-flaked corn.

Postdevelopment Performance and Validation of the Artificial Intelligence-Enhanced Electrocardiogram for Detection of Cardiac Amyloidosis.

BACKGROUND: We have previously applied artificial intelligence (AI) to an electrocardiogram (ECG) to detect cardiac amyloidosis (CA). OBJECTIVES: In this validation study, the authors observe the postdevelopment performance of the AI-enhanced ECG to detect CA with respect to multiple potential confounders. METHODS: Amyloid patients diagnosed after algorithm development (June 2019-January 2022) with a 12-lead ECG were identified (n = 440) and were required to have CA. A 15:1 age- and sex-matched control group was identified (n = 6,600). Area under the receiver operating characteristic (AUC) was determined for the cohort and subgroups. RESULTS: The average age was 70.4 ± 10.3 years, 25.0% were female, and most patients were White (91.3%). In this validation, the AI-ECG for amyloidosis had an AUC of 0.84 (95% CI: 0.82-0.86) for the overall cohort and between amyloid subtypes, which is a slight decrease from the original study (AUC 0.91). White, Black, and patients of "other" races had similar algorithm performance (AUC >0.81) with a decreased performance for Hispanic patients (AUC 0.66). Algorithm performance shift over time was not observed. Low ECG voltage and infarct pattern exhibited high AUC (>0.90), while left ventricular hypertrophy and left bundle branch block demonstrated lesser performance (AUC 0.75 and 0.76, respectively). CONCLUSIONS: The AI-ECG for the detection of CA maintained an overall strong performance with respect to patient age, sex, race, and amyloid subtype. Lower performance was noted in left bundle branch block, left ventricular hypertrophy, and ethnically diverse populations emphasizing the need for subgroup-specific validation efforts.

Integrating online community support into outpatient breast cancer care: Mayo Clinic Connect online platform.

INTRODUCTION: Mayo Clinic Connect is an online community of over 100,000 members who support each other through sharing lived experience when facing and managing new diagnoses. The community is moderated by Mayo Clinic staff and volunteer patient mentors. METHODS: Mayo Clinic breast clinic patients undergoing evaluation received a binder of support resources including a brochure about Mayo Clinic Connect at visits between January and May of 2019. Surveys were distributed at subsequent visits between May and December of 2019 to assess patient awareness about the online resource, participation frequency, purpose of use, and benefits for members, as well as reasons for not joining (non-members). The primary aim was to assess patient resilience, coping, and self-management after joining the online community. RESULTS: Nine hundred surveys were distributed, and 102 participants completed surveys between May and December 2019. Forty-five percent (n = 46) had heard about Mayo Clinic Connect; 34% (n = 15) through a brochure. The remainder heard about the community from a Mayo Clinic provider (43%; n = 19) or other resources (22%, n = 10; no response n = 2). Twenty percent (n = 20) of survey participants registered as Breast Cancer group members, and most of this subgroup (55%; n = 11) reported understanding diagnosis, treatment plans, and finding peer support as reasons for joining. Seventy-five percent of Mayo Clinic Connect participants (n = 15) reported the community met or exceeded expectations. CONCLUSION: This pilot study reveals the potential positive impact of introducing an online peer support group into clinical care plans for patients coping with a new and anxiety-provoking cancer diagnosis.

Sex-specific cut-off values for soluble suppression of tumorigenicity 2 (ST2) biomarker increase its cardiovascular prognostic value in the community.

BACKGROUND: Suppression of tumorigenicity 2 (ST2) has important cardiovascular prognostic value in community patients; however, previous analyses have utilized non-sex specific cut-off values. We assessed whether sex-specific ST2 cut-off values would improve the prognostic utility of ST2 in the asymptomatic community. METHODS: A total of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of high sensitivity troponin, natriuretic peptides and ST2 were obtained in 1681 individuals. ST2, cardiac biomarkers and associated co-morbidities were evaluated by sex-specific ST2 quartile analysis. ST2 concentrations were also analysed as dichotomous variables defined as being above the sex-specific cut-off for each the outcomes of heart failure (HF), major adverse cardiac event (MACE) and mortality. RESULTS: Median ST2 concentration was 29.4 ng/mL in male subjects and 24.1 ng/mL in female subjects. Higher ST2 concentrations were associated with incident HF (p<0.001; preserved ejection fraction (EF) p<0.001, reduced EF p=0.23), MACE (p=0.003) and mortality (p<0.001) across sex-specific quartiles. Event-based, hazard ratio (HR) analysis revealed sex-specific ST2 cut-offs were significantly more predictive of incident HF, MACE and mortality compared to non-sex-specific analysis even following adjustment for cardiac co-morbidities and traditional biomarkers. CONCLUSIONS: These data suggest that sex-specific cut-offs, greater than non-sex specific cut-offs, significantly impact the prognostic value of the biomarker ST2 in the asymptomatic community cohort.Clinical SignificanceSuppression of tumorigenicity 2 (ST2) is a biomarker which has known associations with heart failure (HF), major adverse cardiac events (MACEs) and mortality in the general population.Recent data support the concept of sex-specific cut off values and individualized approaches based on sex to predict cardiovascular disease. Given the difference in pathobiology between the sexes, the fact that such approaches improve risk stratification is understandable. Thus, when sex-specific treatments are developed, this may similarly lead to improved outcomes.The use of sex-specific ST2 cut-off values significantly improved the prognostic value in predicting HF, MACE, and mortality in an asymptomatic community. This prognostication was particularly strong for HF with preserved ejection fraction and remained clinically significant following adjustment for cardiac co-morbidities and other traditional cardiac biomarkers (NTproBNP and hscTnI).

Outcomes of Moderate-to-Severe Acute Kidney Injury following Left Ventricular Assist Device Implantation.

BACKGROUND: Although acute kidney injury (AKI) is a common complication following cardiac surgery, less is known about the occurrence and consequences of moderate/severe AKI following left ventricular assist device (LVAD) implantation. METHODS: All patients who had an LVAD implanted at our center from 2008 to 2016 were reviewed to determine the incidence of, and risk factors for, moderate/severe (stage 2/3) AKI and to compare postoperative complications and mortality rates between those with and those without moderate/severe AKI. RESULTS: Of 246 patients, 68 (28%) developed moderate/severe AKI. A multivariable logistic regression comprising body mass index and prior sternotomy had fair predictive ability (area under the curve = 0.71). A 1-unit increase in body mass index increased the risk of moderate/severe AKI by 7% (odds ratio = 1.07; 95% confidence interval: 1.03-1.11); a prior sternotomy increased the risk more than 3-fold (odds ratio = 3.4; 95% confidence interval: 1.84-6.43). The group of patients with moderate/severe AKI had higher rates of respiratory failure and death than the group of patients with mild/no AKI. Patients with moderate/severe AKI were at 3.2 (95% confidence interval: 1.2-8.2) times the risk of 30-day mortality compared to those without. Even after adjusting for age and Interagency Registry for Mechanically Assisted Circulatory Support profile, those with moderate/severe AKI had 1.75 (95% confidence interval: 1.03-3.0) times the risk of 1-year mortality compared to those without. DISCUSSION: Risk-stratifying patients prior to LVAD placement in regard to AKI development may be a step toward improving surgical outcomes.

Author Correction: Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Extraskeletal osteosarcoma: A large series treated at a single institution.

Purpose: This study is to present a large cohort of extraskeletal osteosarcoma (ESOS) and evaluate prognostic factors and treatment options. Methods: Medical records were reviewed retrospectively for 41 patients with extraskeletal osteosarcoma that was diagnosed by pathology, and treated at our institution between 1960 and 2016. Kaplan-Meier analysis and Cox proportional hazards regression were used to identify variables that affect survival outcomes. Results: 41 patients were identified from 952 osteosarcomas. 32 patients had non-metastatic disease. Prognostic factors were identified by univariate analysis and multi-variate analysis. Surgery (p<0.001), and surgery type (p<0.001) both were shown to significantly affect overall survival (OS). Chemotherapy and radiation therapy (RT) did not show any significant effect on OS, local recurrence, or progression free survival as a whole. However for patients who had incomplete resection with residual tumor RT improved OS (p=0.03). The survival curve for ESOS follows more closely that of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Conclusions: ESOS is a very rare tumor. Attempt to achieve wide resection is the treatment of choice. However for patients who are not able to achieve complete resection, RT may improve OS. The behavior of ESOS more closely follows that of NRSTS than osteosarcoma of the bone.

Malignant thymoma with metastasis associated with paraneoplastic myasthenia gravis.

We describe a patient who initially presented with a mixed thymic tumor and developed myasthenia gravis 8 years following thymectomy with recurrence of metastatic disease. Metastasis to the pleura, mediastinum, and cervical spine was identified with a positron emission tomography scan when this patient presented with recurring pneumonias and atrial fibrillation. The presentation and diagnosis were clouded by multiple courses of prednisone and chemotherapy for respiratory complications and metastatic disease, respectively. Classical myasthenia gravis symptoms emerged when his prednisone was tapered. The delayed presentation of paraneoplastic disease and the rare metastatic site make this case particularly unusual.

Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells.

Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed on tumor cells that suppresses the T cell-mediated immune response. Therapies targeting the PD-L1 pathway promote anti-tumor immunity and have shown promising results in some types of cancers. However, the functional and therapeutic roles of PD-L1 in osteosarcoma remain largely unknown. In this study, we found that PD-L1 protein was expressed in osteosarcoma cell lines and tissue microarray of patient tumors. Tissue microarray immunohistochemistry analysis showed that the overall and five-year survival rates of patients with high levels of PD-L1 expression were significantly shorter than patients with low levels. High levels of PD-L1 expression were also associated with metastasis in osteosarcoma patients. Furthermore, we applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system to target PD-L1 gene at the DNA level in osteosarcoma cell lines. We found that the expression of PD-L1 could be efficiently disrupted by CRISPR/Cas9 system and PD-L1 knockdown increased drug sensitivities for doxorubicin and paclitaxel. These results suggest that PD-L1 is an independent prognostic factor in osteosarcoma and that PD-L1 knockout by CRISPR/Cas9 may be a therapeutic approach for the treatment of osteosarcoma.

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11.

Osteosarcoma is the most common bone cancer in children and adolescents. Previously, we have found that cyclin-dependent kinase 11 (CDK11) signaling was essential for osteosarcoma cell growth and survival. Subsequently, CDK11 siRNA gene targeting, expression profiling, and network reconstruction of differentially expressed genes were performed between CDK11 knock down and wild type osteosarcoma cells. Reconstructed network of the differentially expressed genes pointed to the AR as key to CDK11 signaling in osteosarcoma. CDK11 increased transcriptional activation of AR gene in osteosarcoma cell lines. AR protein was highly expressed in various osteosarcoma cell lines and patient tumor tissues. Tissue microarray analysis showed that the disease-free survival rate for patients with high-expression of AR was significantly shorter than for patients with low-expression of AR. In addition, AR gene expression knockdown via siRNA greatly inhibited cell growth and viability. Similar results were found in osteosarcoma cells treated with AR inhibitor. These findings suggest that CDK11 is involved in the regulation of AR pathway and AR can be a potential novel prognostic marker and therapeutic target for osteosarcoma treatment.

miR-15b modulates multidrug resistance in human osteosarcoma in vitro and in vivo.

The development of multidrug resistance (MDR) in cancer cells to chemotherapy drugs continues to be a major clinical problem. MicroRNAs (miRNA, miR) play an important role in regulating tumour cell growth and survival; however, the role of miRs in the development of drug resistance in osteosarcoma cells is largely uncharacterized. We sought to identify and characterize human miRs that act as key regulators of MDR in osteosarcoma. We utilized a miR microarray to screen for differentially expressed miRs in osteosarcoma MDR cell lines. We determined the mechanisms of the deregulation of expression of miR-15b in osteosarcoma MDR cell lines, and its association with clinically obtained tumour samples was examined in tissue microarray (TMA). The significance of miR-15b in reversing drug resistance was evaluated in a mouse xenograft model of MDR osteosarcoma. We identified miR-15b as being significantly (P < 0.01) downregulated in KHOSMR and U-2OSMR cell lines as compared with their parental cell lines. We found that Wee1 is a target gene of miR-15b and observed that transfection with miR-15b inhibits Wee1 expression and partially reverses MDR in osteosarcoma cell lines. Systemic in vivo administration of miR-15b mimics sensitizes resistant cells to doxorubicin and induces cell death in MDR models of osteosarcoma. Clinically, reduced miR-15b expression was associated with poor patient survival. Osteosarcoma patients with low miR-15b expression levels had significantly shorter survival times than patients with high expression levels of miR-15b. These results collectively indicate that MDR in osteosarcoma is associated with downregulation of miR-15b, and miR-15b reconstitution can reverse chemotherapy resistance in osteosarcoma.

High-Dose Proton Beam-Based Radiation Therapy in the Management of Extracranial Chondrosarcomas.

PURPOSE: Radiation therapy (RT) improves local tumor control in axial chondrosarcomas (CS). It is, however, often difficult to safely deliver the high doses (range, 70.2-77.4 Gy) required for achieving a high likelihood of local control, especially in the spine, using photons. This, however, can be achieved with proton beam therapy (PBT) due to its unique physical characteristics. The main goal of our study is to evaluate the outcomes of CS patients treated with passive scattered PBT. MATERIALS AND METHODS: Forty-four patients (N = 44) were identified who received PBT as part of their treatment from 1990 to 2012. A retrospective review of their medical and RT treatment records was conducted. Multivariate analyses were performed to identify patient- and tumor-related factors predicting for improved local control and overall survival. RESULTS: Median age was 45.5 years and 55% were female. Median tumor size was 13 cm. Most common anatomical location was the spine (80%). Median follow-up was 29.1 months. Median external beam RT dose was 70.2 Gy relative biological effectiveness (RBE) at 1.8 Gy (RBE) per fraction typically administered using a combination of photon RT + PBT (77%) or PBT alone (23%). Local control was 76% and 57%, and overall survival was 90% and 68% at 2 and 5 years, respectively. Toxicity was acceptable, with the most frequent being wound complications (16%). On multivariate analyses, grade III tumors were significantly associated with decreased local control (P = 0.019), while female sex (P = 0.037) and grade III tumors (P = 0.005) were associated with a poorer overall survival. CONCLUSIONS: High-dose proton-based RT in combination with surgery resulted in local tumor control in most of these high-risk CS patients. Female sex was predictive for decreased survival, while higher tumor grade (grade III) was predictive of decreased local control and survival. Proton beam therapy is an attractive treatment modality for these challenging tumors.

Clinical outcomes for patients after surgery and radiation therapy for mesenchymal chondrosarcomas.

INTRODUCTION: We report the outcome of 23 patients with mesenchymal chondrosarcomas treated with surgery and radiation therapy +/- chemotherapy. The intent of the project was to review the impact of patient and treatment variables on treatment outcome, in particular with regard to extent of surgery and radiation dose. PATIENTS AND METHODS: Twenty-three patients with mesenchymal chondrosarcomas were treated with surgery and radiation therapy (min. dose 44 Gy; max. dose 78 Gy; median dose 60 Gy; mean dose 61 Gy). RESULTS: The median survival for the entire cohort of patients was 21.65 years (95% confidence interval ± 4.25). The 5- and 10-year OS was 78.6%. Median disease-free survival for the 23 patients was 7.2 years. Disease-free survival (DFS) at 3 and 5 years was 70.7% and 57.8%, respectively. The local control rate at 5 and 10 years was 89.5% (95%CI 64.1-97.3%). Only three patients experienced local failure, three patients had regional failure, and eight developed distant metastases. CONCLUSIONS: In this cohort of patients local tumor control was high when using a combination of surgery and radiation. There was not a clear relationship between radiation dose and local tumor control. J. Surg. Oncol. 2016;114:982-986. © 2016 Wiley Periodicals, Inc.

Preoperative radiation therapy combined with radical surgical resection is associated with a lower rate of local recurrence when treating unifocal, primary retroperitoneal liposarcoma.

BACKGROUND AND OBJECTIVES: Local recurrence (LR) is the primary cause of death in patients with retroperitoneal liposarcoma (RP-LPS). The purpose of this study was to evaluate if the addition of preoperative radiation therapy (XRT) to radical resection for RP-LPS at a single institution was associated with improved LR. METHODS: This retrospective analysis included patients with unifocal, primary RP-LPS who underwent complete R0/R1 resection at a single institution between 1991 and 2013. Multiple patient, tumor, and surgeon characteristics were tested to evaluate their association to LR (recurrence in the retroperitoneal space). We used competing risk hazards regression to evaluate the effect of preoperative XRT on the probability of LR. RESULTS: There were 41 patients with liposarcoma histology whose tumors included entirely well-differentiated (N = 13), de-differentiated components (n = 26), myxoid (n = 1), and NOS (n = 1). Preoperative XRT was significantly associated with a lower probability of LR (HR 0.11, 95%CI 0.01-0.91, P = 0.04) and a higher 5-year local recurrence-free survival (95.6%, 95%CI 72.4-99.4%, vs. 75.0%, 95%CI 40.8-91.2%; P = 0.0213), but not with 5-year distant recurrence-free survival or disease-specific survival. CONCLUSIONS: Preoperative XRT combined with complete R0/R1 resection for unifocal, primary RP-LPS was associated with improved LR and it should be considered in the multimodality treatment of RP-LPS. J. Surg. Oncol. 2016;114:814-820. © 2016 2016 Wiley Periodicals, Inc.

Evaluation of P-glycoprotein (Pgp) expression in human osteosarcoma by high-throughput tissue microarray.

Survival of osteosarcoma patients is currently limited by the development of metastases and multidrug resistance (MDR). A well-established cause of MDR involves overexpression of P-glycoprotein (Pgp) in tumor cells. However, some discrepancies still exist as to the clinical significance of Pgp in osteosarcoma. We sought to elucidate further whether the Pgp expression correlated with clinical behavior in a series of patients with osteosarcoma via high-throughput tissue microarray (TMA) analysis. Immunohistochemical analysis of Pgp expression in a TMA of 114 specimens with a retrospective review of 70 osteosarcoma patients admitted to the Massachusetts General Hospital (MGH) was performed. High Pgp expression was correlated with metastasis development and poor response to pre-operative chemotherapy in osteosarcoma patients. Eighteen of the fifty-seven patients initially admitted with primary osteosarcoma showed high Pgp expression. Among these 18 patients with high Pgp expression, 13 of 18 (72%) patients eventually developed metastases. There was no significant clinical relevance between Pgp expression and osteosarcoma survival. These results support that high expression of Pgp is important, but cannot be assigned as, an individual predictor in the development of human osteosarcoma. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1606-1612, 2016.

Prognostic factors in alveolar soft part sarcoma: A SEER analysis.

OBJECTIVES: We reviewed the clinical characteristics and outcomes of patients treated for alveolar soft part sarcoma (ASPS) and analyzed the effect of surgery for patients presenting with and without metastatic disease (DM). METHODS: The SEER Registry was queried for patients with ASPS from 1973-2012. The Kaplan-Meier estimate and Cox proportional hazards were used to analyze survival outcomes and risk variables. RESULTS: Among 251 patients, 43% had DM and 67% locoregional disease (LR) on presentation. The 5-year overall survival (OS) for all patients was 56% (82% and 27% for LR and DM, respectively). Multivariate analysis identified older age (hazard ratio [HR] = 1.03 per year, P < 0.001), tumor size >10 cm (HR = 2.76, P = 0.013), DM at diagnosis (HR = 3.79, P < 0.001), and truncal primary site (HR = 1.63, P = 0.035) as independent factors predicting worse OS. For LR patients, surgery plus radiotherapy (RT) resulted in better OS compared to surgery alone P = 0.014. For DM patients, primary site surgery significantly improved survival (P < 0.001). CONCLUSION: ASPS presents with high metastasis rate but has a relatively indolent clinical course and a favorable prognosis with prolonged survival. Aggressive treatment using adjuvant RT with surgery is indicated in patients with LR disease and surgery is indicated in patients presenting with DM. J. Surg. Oncol. 2016;113:581-586. © 2016 Wiley Periodicals, Inc.

NVP-TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P-glycoprotein (PGP1) function.

BACKGROUND AND PURPOSE: Increased expression of P-glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients. EXPERIMENTAL APPROACH: In an effort to search for new chemical entities targeting PGP1-associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies. KEY RESULTS: After screening 500+ kinase inhibitors, we identified NVP-TAE684 as the most effective MDR reversing agent. NVP-TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET-743 or mitoxantrone. NVP-TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1-overexpressing cell lines. NVP-TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors. CONCLUSIONS AND IMPLICATIONS: The application of NVP-TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1-mediated MDR in human cancer and may ultimately benefit cancer patients.