Research Spotlight

Ravindranathan, P., D. Pasham, U. Balaji, J. Cardenas, J. Gu, S. Toden and A. Goel (2018). “Mechanistic insights into anticancer properties of oligomeric proanthocyanidins from grape seeds in colorectal cancer.” Carcinogenesis. Apr 19. [Epub ahead of print].

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Although the anticancer properties of oligomeric proanthocyanidins (OPCs) from grape seeds have been well recognized, the molecular mechanisms by which they exert anticancer effects are poorly understood. In this study, through comprehensive RNA-sequencing-based gene expression profiling in multiple colorectal cancer cell lines, we for the first time illuminate the genome-wide effects of OPCs from grape seeds in colorectal cancer. Our data revealed that OPCs affect several key cancer-associated genes. In particular, genes involved in cell cycle and DNA replication were most significantly and consistently altered by OPCs across multiple cell lines. Intriguingly, our in vivo experiments showed that OPCs were significantly more potent at decreasing xenograft tumor growth compared with the unfractionated grape seed extract (GSE) that includes the larger polymers of proanthocyanidins. These findings were further confirmed in colorectal cancer patient-derived organoids, wherein OPCs more potently inhibited the formation of organoids compared with GSE. Furthermore, we validated alteration of cell cycle and DNA replication-associated genes in cancer cell lines, mice xenografts as well as patient-derived organoids. Overall, this study provides an unbiased and comprehensive look at the mechanisms by which OPCs exert anticancer properties in colorectal cancer.

Ravi, Y., S. K. Lella, L. A. Copeland, K. Zolfaghari, K. Grady, S. Emani and C. B. Sai-Sudhakar (2018). “Does recipient work status pre-transplant affect post-heart transplant survival? A United Network for Organ Sharing database review.” J Heart Lung Transplant 37(5): 604-610.

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BACKGROUND: Recipient-related factors, such as education level and type of health insurance, are known to affect heart transplantation outcomes. Pre-operative employment status has shown an association with survival in abdominal organ transplant patients. We sought to evaluate the effect of work status of heart transplant (HTx) recipients at the time of listing and at the time of transplantation on short- and long-term survival. METHODS: We evaluated the United Network for Organ Sharing (UNOS) registry for all adult HTx recipients from 2001 to 2014. Recipients were grouped based on their work status at listing and at heart transplantation. Kaplan-Meier estimates illustrated 30-day, 1-year, 5-year, and 10-year survival comparing working with non-working groups. The Cox proportional hazards regression model was applied to adjust for covariates that could potentially confound the post-transplantation survival analysis. RESULTS: Working at listing for HTx was not significantly associated with 30-day and 1-year survival. However, 5- and 10-year mortality were 14.5% working vs 19.8% not working (p < 0.0001) and 16% working vs 26% not working (p < 0.0001), respectively. Working at HTx appeared to be associated with a survival benefit at every time interval, with a trend toward improved survival at 30 days and 1 year and a significant association at 5 and 10 years. Kaplan-Meier analysis demonstrated a 5% and 10% decrease in 5- and 10-year mortality, respectively, for the working group compared with the group not working at transplantation. The Cox proportional hazards regression model showed that working at listing and working at transplantation were each associated with decreased mortality (hazard ratio [HR] = 0.8, 95% confidence interval [CI] 0.71 to 0.91; and HR = 0.76, 95% CI 0.65 to 0.89, respectively). CONCLUSIONS: This study is the first analysis of UNOS STAR data on recipient work status pre-HTx demonstrating: (1) an improvement in post-transplant survival for working HTx candidates; and (2) an association between working pre-HTx and longer post-HTx survival. Given that work status before HTx may be a modifiable risk factor for better outcomes after HTx, we strongly recommend that UNOS consider these important findings for moving forward this patient-centered research on work status. Working at listing and working at HTx are associated with long-term survival benefits. The association may be reciprocal, where working identifies less ill patients and also improves well-being. Consideration should be given to giving additional weight to work status during organ allocation. Work status may also be a modifiable factor associated with better post-HTx outcomes.

Panda, S. K., V. Facchinetti, E. Voynova, S. Hanabuchi, J. L. Karnell, R. N. Hanna, R. Kolbeck, M. A. Sanjuan, R. Ettinger and Y. J. Liu (2018). “Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models.” J Clin Invest 128(5): 1873-1887.

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Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.

Packer, M., B. Claggett, M. P. Lefkowitz, J. J. V. McMurray, J. L. Rouleau, S. D. Solomon and M. R. Zile (2018). “Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial.” Lancet Diabetes Endocrinol. Apr 13. [Epub ahead of print].

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BACKGROUND: Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of neprilysin inhibition on the course of renal function in patients with type 2 diabetes. METHODS: In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. FINDINGS: eGFR decreased by 1.1 mL/min per 1.73 m(2) per year (95% CI 1.0-1.2) in patients without diabetes, but by 2.0 mL/min per 1.73 m(2) per year (1.9-2.1) in those with diabetes (p<0.0001). Compared with patients treated with enalapril, those treated with sacubitril/valsartan had a slower rate of decline in eGFR (-1.3 vs -1.8 mL/min per 1.73 m(2) per year; p<0.0001), and the magnitude of the benefit was larger in patients with versus those without diabetes (difference 0.6 mL/min per 1.73 m(2) per year [95% CI 0.4-0.8] in patients with vs 0.3 mL/min per 1.73 m(2) per year [0.2-0.5] in those without diabetes; pinteraction=0.038). The greater effect of neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA1c. The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0.41). INTERPRETATION: In patients in whom the renin-angiotensin system is already maximally blocked, the addition of neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. FUNDING: Novartis.

Packer, M. (2018). “Why is the use of digitalis withering? Another reason that we need medical heart failure specialists.” Eur J Heart Fail 20(5): 851-852.

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The evolution of the use of digoxin in heart failure provides additional evidence that the treatment of chronic heart failure may have become too complex for most practitioners who are tasked with the long‐term management of patients with this disease. Optimal treatment now requires the expert orchestration of as many as seven different classes of drugs, together with the appropriate application of different devices. Neither primary care physicians nor cardiologists generally have the time, experience, motivation or supporting infrastructure to tackle the complexities of this progressively disabling and lethal disorder. As a result, the typical patient with heart failure is prescribed low doses of a diuretic, an inhibitor of the renin–angiotensin system, and (if they are fortunate) a β‐blocker. Most patients do not receive target doses of these drugs nor are they offered therapy with a mineralocorticoid receptor antagonist, a neprilysin inhibitor or digoxin. When digitalis – a drug that has been used by generalists for more than 200 years – is now recommended for use only by specialists, it is time to ask who these specialists might be. Those who currently regard themselves as heart failure specialists often focus on devices and cardiac transplantation and are not incentivized for optimizing drug therapy. If patients with cancer have dedicated specialists (i.e. medical oncologists) who devote their energies to optimizing drug therapy, patients with chronic heart failure also need dedicated practitioners who will do the same. Perhaps we can call them ‘medical heart failure specialists’. But we should ask: will national health services pay for physicians to think? (Excerpt from text, p. 852; no abstract available.)