Purpose
Despite great success as a targeted breast cancer therapy, trastuzumab use may be complicated by heart failure and loss of left ventricular contractile function. This review summarizes the ...risk factors, imaging, and prevention of cardiotoxicity associated with trastuzumab and other HER2-targeted therapies.
Findings
Cardiovascular disease risk factors, advanced age, and previous anthracycline treatment predispose to trastuzumab-induced cardiotoxicity (TIC), with anthracycline exposure being the most significant risk factor. Cardiac biomarkers such as troponins and pro-BNP and imaging assessments such as echocardiogram before and during trastuzumab therapy may help in early identification of TIC. Initiation of beta-adrenergic antagonists and angiotensin converting enzyme inhibitors may prevent TIC. Cardiotoxicity rates of other HER2-targeted treatments, such as pertuzumab, T-DM1, lapatinib, neratinib, tucatinib, trastuzumab deruxtecan, and margetuximab, appear to be significantly lower as reported in the pivotal trials which led to their approval.
Conclusions
Risk assessment for TIC should include cardiac imaging assessment and should incorporate prior anthracycline use, the strongest risk factor for TIC. Screening and prediction of cardiotoxicity, referral to a cardio-oncology specialist, and initiation of effective prophylactic therapy may all improve prognosis in patients receiving HER2-directed therapy. Beta blockers and ACE inhibitors appear to mitigate risk of TIC. Anthracycline-free regimens have been proven to be efficacious in early HER2-positive breast cancer and should now be considered the standard of care for early HER2-positive breast cancer. Newer HER2-directed therapies appear to have significantly lower cardiotoxicity compared to trastuzumab, but trials are needed in patients who have experienced TIC and patients with pre-existing cardiac dysfunction.
The incidence of obesity and diabetes is increasing rapidly. Optimal management is still elusive. Obesity associated with type 2 diabetes is known to cause adipose tissue inflammation, increase ...oxidative stress, and cause white fat hyperplasia and mitochondrial dysfunction. In this study, we investigated whether mitochondrial and cytosolic antioxidant-upregulated mesenchymal stem cell (MSC) delivery reduces oxidative stress and subsequently improves glucose tolerance, reduce systemic inflammation, and improves fatty liver disease in diet-induced obese (DIO) mouse models.
Antioxidant genes Sod2 (mitochondrial) and catalase (cytosolic) or null (control) were upregulated in human adipose tissue-derived MSCs using adenoviral constructs. Modified MSCs were then delivered intraperitoneally into mice that were fed a 45% or 60% high-fat diet (HFD), and animals were followed for 4 weeks.
Over 4 weeks, body weight remained stable; however, we noted a significant reduction in liver fat content by histological analysis and liver triglyceride assay. Triglyceride assay (p < 0.01) confirmed reduced liver fat accumulation in animals that received either Sod2- or Cat-MSCs. There was a lower plasma level of inflammatory marker TNFα, measured in mice that were fed either 45% or 60% HFD and received Sod2- or Cat-MSCs, indicating reduced systemic inflammation. Ucp1 mRNA was upregulated approximately 100-1000-fold for omental fat and 10-100-fold for pericardial fat compared to the Null-MSC-receiving group. Pcgc1a and Prdm16 mRNA upregulation was also noted particularly for pericardial fat. Glucose tolerance showed a positive improvement trend with a lower area under the curve (AUC) values for both Sod2- and Cat-MSCs groups in comparison to control. For mice fed with 60% HFD and that received Sod2-MSCs, glucose levels were significantly lower than control (*p < 0.05) at a time point of 60 min in the glycemic curve during glucose tolerance test.
Reduction of oxidative stress post-antioxidant-upregulated MSC delivery, intraperitoneally, reduces systemic inflammation and fat accumulation in the liver. There is evidence of an increase in browning of white adipose tissue depots with concomitant improvement of glucose tolerance in a weight-independent fashion. Antioxidant-upregulated MSC delivery may be a safe yet effective therapy for obesity and prediabetes and improves related complication such as non-alcoholic fatty liver disease.
Type 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease. CD34+ endothelial Progenitor Cells (EPCs) are responsible for endothelial repair and neo-angiogenesis and ...can be used as a cardiovascular disease risk biomarker. This study investigated whether the addition of saxagliptin, a DPP-IV inhibitor, to metformin, may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients.
In 12 week, double-blind, randomized placebo-controlled trial, 42 subjects already taking metformin 1-2 grams/day were randomized to placebo or saxagliptin 5 mg. Subjects aged 40-70 years with diabetes for < 10 years, with no known cardiovascular disease, BMI 25-39.9, HbA1C 6-9% were included. We evaluated EPCs number, function, surface markers and gene expression, in addition to arterial stiffness, blood biochemistries, resting energy expenditure, and body composition parameters. A mixed model regression to examine saxagliptin vs placebo, accounting for within-subject autocorrelation, was done with SAS (p < 0.05).
Although there was no significant increase in CD34+ cell number, CD31+ cells percentage increased. Saxagliptin increased migration (in response to SDF1α) with a trend of higher colony formation count. MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells, indicating a functional improvement. Gene expression analysis showed an upregulation in CD34+ cells for antioxidant SOD1 (p < 0.05) and a downregulation in CD34- cells for IL-6 (p < 0.01). For arterial stiffness, both augmentation index and systolic blood pressure measures went down in saxagliptin subjects (p < 0.05).
Saxagliptin, in combination with metformin, can help improve endothelial dysfunction in early diabetes before macrovascular complications appear. Trial registration Trial is registered under clinicaltrials.gov, NCT02024477.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular diseases (CVD) and vascular health. Peripheral blood-derived CD34+ progenitor cells have been used as biomarker for CVD ...risk and may play a similar role in OSA and CVD risk assessment. Although there are some controversial results in the literature, OSA patients may have a reduction in the number and function of CD34+ cells. The damages promoted by OSA in CD34+ cells may lead to an increase in endothelial oxidative stress and endothelial inflammation which may lead to a reduced endothelial repair capacity. In this study, we explored the effect of continuous positive airway pressure (CPAP) on peripheral blood-derived CD34+ cells and arterial stiffness (another predictor of endothelial health and CVD risk) in OSA patients.
Nine overweight and obese subjects without prediabetes or diabetes were recruited. Eight out of nine subjects had moderate to severe degree of OSA. CD34+ cells were isolated from peripheral blood. Number and function of these cells were monitored before and after 3 months of treatment with CPAP. No significant changes were observed in the number of CD34+ cells, CFU-Hill's colony formation unit (CFU) count or migratory response to the chemotactic factor SDF-1a after CPAP use. However, CXCR4 mRNA expression significantly increased by 2.2-fold indicating that CPAP may have a positive effect on SDF1a receptor (CXCR4), thereby improving migration of CD34+ cells mediated by SDF1a after the 3 month period. Interestingly, in clinical arena our results showed a reduction of pulse wave velocity (an established parameter of arterial stiffness) following CPAP therapy.
Our findings suggest that 3-month CPAP intervention does not show statistical significant increase in CD34+ cell number and function, in mostly moderate to severe OSA subjects; however, it did demonstrate a positive trend. CPAP therapy, did help improve arterial stiffness parameter.
Background: Mesenchymal stromal cells (MSCs) can home-in to inflamed fat depots to deliver antioxidants locally and help reduce oxidative stress, inflammation and improve NAFLD in high-fat diet (HFD) ...induced obese (DIO) diabetic mice.
Methods: Antioxidants Sod2 (mitochondrial), Catalase (cytosolic) or Null (control) genes were upregulated individually, or in combination in adipose-derived MSCs. Modified MSCs were examined in-vitro in presence of adipogenic media to mimic DIO milieu. Next, modified MSCs were delivered intraperitoneally (IP) in mice that received 45% or 60% HFD for 8 to16 weeks.
Results: In-vitro, we noted reduced MSC lipid droplets with SOD2, Catalase and combination compared to Null. Inflammatory marker IL6 mRNA, was down-regulated in SOD2, Cat and combination MSCs vs. Null-MSCs. In-vivo, n=4, Glucose tolerance test (GTT) improved with SOD2 MSC delivery in (p=0.07) at week-4. Plasma inflammatory marker TNFa, was reduced in both SOD2 and Catalase MSC groups (p<0.05) vs. Null-MSCs group. Analysis of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (∼1000 and 100-fold, respectively) and PGC1A mRNA was upregulated. Increased Ucp1 was confirmed by staining. There was a reduction in liver fat content by histology and liver triglyceride assay (p<0.05). Outcome measures of SOD2+Catalase combination MSC delivery in-vivo is pending.
Conclusion: Upregulation of SOD2 plus Catalase, in-vitro, reduced inflammation in adipogenic media more so than individual gene upregulation. In-vivo, delivery of Sod2 and Catalase upregulated individually in MSCs, reduced inflammation and improved GTT with concomitant increased browning of white fat and reduced liver fat. Our results indicate that antioxidant upregulated modified MSC delivery IP, to target inflamed fat depots helps reduce oxidative stress and inflammation and can be an efficient tool for treating obesity, diabetes and NAFLD.
Disclosure
C.C. Domingues: None. N. Kundu: None. Y. Kropotova: None. S. Sen: None.
Funding
Clinical and Translational Science Institute at Children's National
Background: Mesenchymal stromal cells (MSCs) are multipotent cells that can home-in to the sites of inflammation. Therefore, antioxidant-upregulated MSCs delivered intra-peritoneally can home-in to ...local inflamed fat pockets which may reduce inflammation and improve glucose tolerance in diet-induced obese and diabetic mouse model.
Methods: GFP-containing adenoviral constructs were used to upregulate antioxidants Sod2 (mitochondrial) and Catalase (cytosolic) in human adipose-derived MSCs. Modified MSCs were delivered (IP) into mice subjected to 45% and 60% high-fat diet for 8-16 weeks.
Results: Glucose tolerance was improved at week 4 in the antioxidant upregulated MSC-receiving groups with concomitant reduction in hyperplasia in omental fat. A reduction in plasma levels of TNFa, an well-known inflammatory marker, was found for all treated animal groups in comparison to control (null-MSCs). RT-PCR analysis of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (∼1000-fold and 10-100-fold, respectively) which was confirmed by Ucp1-staining and concomitant increases in down-stream genes such as Pgc1a and Prdm16 mRNA expression. Remarkably, the treatment showed a significant reduction in liver fat content (by histology) and triglyceride content measurement.
Conclusion: Delivery of Sod2 and Catalase upregulated MSCs improved glycemic control by reducing systemic inflammation, promotes browning of white adipose tissue and reverses hepatic lipid accumulation. These results indicate that antioxidant upregulated MSCs can help to improve glucose homeostasis, adipocyte energetics and hepatic lipid metabolism. Modified MSC therapy can be a promising therapy for type 2 diabetes, obesity and fatty liver disease.
Disclosure
C.C. Domingues: None. N. Kundu: None. Y. Kropotova: None. N. Ahmadi: None. S. Sen: None.
e23508
Background: Bone sarcomas account for about 5% of cancers in adolescents and young adults (AYA). Outcomes in this population are consistently inferior than children. It is poorly understood ...whether this is related to the tumor biology or the therapeutic approach. In addition, regimens used in AYAs are heterogeneous due to poor tolerance of pediatric regimens and lack of clinical trials specific to this population. We sought to study the therapeutic regimes and outcomes of AYA bone sarcoma patients (pts) to understand the optimal therapeutic approach better. Methods: From our institutional database, we extracted data of pts with the diagnosis of “osteosarcoma” (OS) and “Ewing sarcoma” (ES) in the AYA (15-39 yo) population from 2011-21. We included only pts with efficacy documented to different regimens. Descriptive statistics were used for patient demographics, presentation, regimens, and outcomes (Table). Objective response rate (ORR) was defined as the number of patients achieving a partial or complete response. Relapse rate (RR) was calculated for the pts that progressed after undergoing definitive curative intent treatment. Survival comparison between groups was made using the Kaplan Meier method and Log Rank Test. We used Fisher's exact test to compare differences in ORR between treatment groups. Results: We identified 30 ES and 44 OS pts. For both ES and OS, Kaplan Meier survival analysis showed no difference in presentation adjusted overall survival between treatment groups; ( x
2
.351, p .55) for ES and ( x
2
1.94 p .378) for OS. Importantly, in OS, ORR difference between Adria/IVCis and Adria/IACis was statistically significant ( p .0188). Conclusions: Our study shows the heterogeneity in first-line treatment strategies for AYA pts with bone sarcomas. For ES, response rates for VAC/IE and VAI were similar. In the OS cohort, we found ORR for Adria/IACis was 81% which was statistically different to pts receiving Adria/IVCis (ORR 30%). However, we saw relapses in 43% of pts treated with Adria/IACis. This indicates that the intra-arterial approach could be helpful for limb preservation but suggests the need for intense adjuvant chemotherapy to prevent relapses. There were no statistically significant differences in the survival outcomes of AYA bone sarcoma pts treated with pediatric versus adult regimens.Table: see text
IntroductionMesenchymal stromal cells (MSCs) are multipotent cells and capable of homing to sites of inflammation. Antioxidant-upregulated MSCs when delivered intra-peritoneally (IP) can potentially ...reach fat pockets and reduce fat inflammation and improve glucose tolerance in a high-fat diet (HFD) induced obese diabetic mouse model.MethodsGFP-containing adenoviral constructs were used to upregulate Sod2 and Catalase in human adipose-derived MSCs. Null transduced MSC was our control. Modified MSCs were delivered (IP) into mice fed 60% or 45% HFD for 8-16 weeks. MSC homing was tracked in-vivo by a laser imaging system.ResultsGlucose tolerance was improved at week 4 in the Sod2- and Cat-MSC-receiving groups vs Null with AUC as 47565, 48301, 57763, respectively. A reduction in omental fat cell size was also noted (50-60% reduction vs control). An increased level of Sod2 was detected by western blot in omental fat of 45% HFD treated group (Sod2/loading control band ratios were 0.67 and 1.25 for Null vs Sod2). A statistical significant reduction (1.5-2-fold) in plasma TNFa was noted for all treated groups vs control. qRT-PCR of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (~1000-fold and 10-100-fold, respectively) which was confirmed by Ucp1-staining and concomitant increases in genes associated with browning, such as Ppargc1a and Prdm16 mRNA expression. In vitro data also confirmed upregulation of PPARGC1a in Sod2-MSCs exposed to a hyperglycemic condition. Liver histology showed a significant reduction in liver fat content for treated groups. Liver triglyceride content was reduced by approx. 60%.ConclusionDelivery of Sod2- and Cat-MSCs improved glycemic control by reducing systemic inflammation. There was concomitant browning of white fat and hepatic lipid accumulation was reduced. Therefore, antioxidant upregulated MSCs help to improve glucose homeostasis, improve the browning process in white fat and treats fatty liver disease. This approach can be a novel therapeutic strategy for diabetes, obesity and complication such as fatty liver disease.
PDF
