Citations

Abstract Estrogen receptor positive (ER+) breast cancer is treated with endocrine therapy but intrinsic resistance occurs in ˜1/3 of patients and acquired resistance in ˜1/5 of the remainder. While many resistance mechanisms have been explored, clinical trials testing associated therapeutics have had mixed outcomes. Understanding mechanisms of resistance and finding therapeutic strategies to target them, therefore, remain important challenges. In this study we discover an intriguing link between mismatch repair (MMR) deficiency, specifically of the MutL complex (MLH1/3, PMS1/2), and endocrine therapy resistance in ER+ disease. We find a direct role for MutL loss in inducing endocrine therapy resistance in vitro and in vivo by knocking down multiple MutL genes using CRISPR and stable shRNA approaches validated using standard rescue experiments. We identify the underlying mechanism: MutL deficiency in ER+ breast cancer abrogates Chk2-mediated feedback inhibition of CDK4/6 that appears necessary for endocrine therapy responsiveness. Consequently, pharmacological targeting of CDK4/6 in vitro and in vivo significantly inhibits growth of endocrine therapy resistant MutL-deficient ER+ breast cancer cells. These results are corroborated by data from a neoadjuvant clinical trial demonstrating that cell cycle regulation of MutL-mutant tumors is estrogen-independent but CDK4/6 dependent. The results of this study provide important biological and clinically relevant insights. 1) a novel role for MMR in endocrine therapy resistance 2) A mechanism underlying the effectiveness of CDK4/6 inhibitors in some de novo endocrine therapy resistant tumors. While there are currently no biomarkers to guide the use of CDK4/6 inhibitors for ER+ breast cancer, markers of MMR dysregulation could identify patients in whom CDK4/6 inhibition may, most effectively, prevent disease recurrence. Citation Format: Haricharan S, Punturi N, Singh P, Holloway KR, Anurag M, Schmelz J, Schmidt C, Lei JT, Suman V, Hunt K, Olson Jr JA, Hoog J, Li S, Huang S, Edwards DP, Kavuri SM, Bainbridge MN, Ma CX, Ellis MJ. Loss of mismatch repair predicts resistance to endocrine therapy and sensitivity to CDK4/6 inhibitors in ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-01.

The inapplicability of Beer's law to densitometry of dyes in whole blood or other nonhomogeneous media has been long known. When using a densitometer whose output is directly proportional to the light transmitted, a simple transformation— log X = log (x – x0)—can be employed to allow rapid, accurate estimation of dye concentration. This is facilitated by use of an optical density ruler. The transformation, X = x – x0, can be made mechanically, by shifting the infinity position of the ruler with reference to the zero light transmission position, or electrically, by appropriate use of zero suppression in the densitometer circuit. The transformation results in an exponential (logarithmic) relationship between light transmitted and concentration of the dye (indocyanine green). Readings of relative optical density obtained by use of the ruler are multiplied by a calibration constant to calculate dye concentration. The principles of the transformation have been applied to the determination of the optimal zero suppression required for maintenance of constant sensitivity of the densitometer in the presence of various levels of background dye. densitometer calibration; indocyanine green densitometer; calibration of dye-dilution curves; correction of dye-dilution curves Submitted on September 13, 1963

The assumption that the rate of blood flow past the sampling site is constant is basic to the Stewart-Hamilton estimation of cardiac output. Pulsatile flow might be expected to cause random and systematic errors. In this study dye-dilution curves were recorded simultaneously from two or three sites (pulmonary artery, aortic root, thoracic aorta, femoral artery) after injections of dye into the inferior vena cava, right ventricle, pulmonary artery, or left atrium of anesthetized dogs. The color of the indocyanine-protein complex formed after injection of the dye stabilized rapidly. Such stabilization is required for continuous photometric quantitation of dilution curves with juxtaposed injection and sampling sites. Areas of curves from the central circulation did not differ significantly from each other; they averaged 2.5% less than areas of curves recorded simultaneously from the femoral artery. Heart rate had no consistent influence. The large variability in estimates of cardiac output from curves recorded from the pulmonary artery after injection into the right ventricle was diminished with injection farther upstream. Submitted on May 29, 1961

To address the role of atrial natriuretic factor (ANF) in hypothyroidism in the control of cardiorenal-endocrine function during volume loading, the relationships between atrial pressure, ANF, the renin-angiotensin-aldosterone system, and renal hemodynamic and excretory function were examined during and after acute 10% body wt saline volume infusion in pentobarbital-anesthetized hypothyroid dogs (n = 8). Hormonal changes before and after thyroidectomy were also evaluated. Four to 6 wk after thyroidectomy, ANF decreased and arginine vasopressin (AVP) and plasma renin activity (PRA) increased. Acute saline volume expansion caused an increase in ANF and decreases in AVP and PRA. Atrial pressure increased throughout volume expansion. Despite the absence of an increase in glomerular filtration rate (GFR) during volume expansion, urinary sodium excretion increased due to a marked rise in fractional excretion of sodium. These studies demonstrate that in hypothyroidism 1) ANF is decreased; 2) despite the decrease in basal ANF, increases in atrial pressure can stimulate relase of ANF; 3) despite the absence of an increase in GFR during volume expansion, fractional excretion of sodium increases associated with an increase in ANF; and 4) a lack of an increase in GFR during volume expansion is not related to an inability to increase ANF.

Blood is nonhomogeneous; hence, the relationship between light transmission and increasing concentration of dye in whole blood is never the perfect exponential curve predicted by Beer's law. Instead, as the concentration of indocyanine green is increased to high levels (40 mg/liter) the light transmission decreases exponentially toward an asymptote at 6–8% transmission for nearly monochromatic densitometers (half-band width: 13–20 mμ), but at 30–40% for densitometers using light of wide-band width. Consequently, following recording of a dilution curve, circulating background dye reduces the change in transmission per unit increase in dye concentration in subsequent curves. This decrease in sensitivity cannot be compensated for by a simple increase in the sensitivity of the densitometer or in the intensity of its light source. Compensation can be attained, however, if increasing densitometer sensitivity is associated with the automatic scale expansion provided when a suppressed zero point is used. At correct zero suppression, the deflection for zero output of the densitometer coincides with the asymptotic transmission value mentioned above. indicator-dilution in circulation; blood flow measurement; blood optical density; dye dilution technic; cardiac output measurement Submitted on April 15, 1963

Congestive heart failure (CHF) is a pathophysiological condition associated with increased plasma levels of atrial natriuretic factor (ANF), a peptide hormone of cardiac origin that participates in the homeostatic control of intravascular volume and vascular tone. Atrial myocytes serve as the principal source of ANF under physiological conditions, although recent studies have demonstrated that ventricular myocardium may also synthesize ANF in models of CHF associated with ventricular hypertrophy. The current study was designed to investigate the roles of atrial and ventricular myocardium to synthesize, store, and release ANF during the evolution of tachycardia-induced CHF in the dog. The present study demonstrates a persistent elevation of plasma ANF during the evolution of CHF. In acute CHF (3 h), plasma ANF increased independent of cardiac ANF synthesis. In chronic CHF (15 and 30 days), plasma ANF is maintained by an increase in atrial synthesis and release of the peptide, without recruitment of ventricular ANF synthesis. The present study demonstrates that in acute CHF the increase in plasma ANF is regulated by release of stored peptide, and in chronic CHF the persistent elevation of plasma ANF is maintained by an increase in atrial synthesis of ANF.

Background: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. Methods: Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ≥40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. Results: The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls ( P <0.0001 for all) but lower than PVOD ( P ≤0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50–70]) than in PVOD (median, 91 [interquartile range, 82–103]). PASP correlated with arterial percent medial thickness ( r =0.41) and arterial %IT ( r =0.35) but more strongly with venous %IT ( r =0.49) and IV %IT ( r =0.55) ( P <0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. Conclusions: In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Increasing rates of burnout—with accompanying stress and lack of engagement—among faculty, residents, students, and practicing physicians have caused alarm in academic medicine. Central to the debate among academic medicine’s stakeholders are oft-competing issues of social accountability; cost containment; effectiveness of academic medicine’s institutions; faculty recruitment, retention, and satisfaction; increasing expectations for faculty; and mission-based productivity. The authors propose that understanding and fostering what contributes to faculty and institutional vitality is central to preventing burnout during times of change. They first look at faculty vitality and how it is threatened by burnout, to provide a framework for a greater understanding of faculty well-being. Then they draw on higher education literature to determine how vitality is defined in academic settings and what factors affect faculty vitality within the context of academic medicine. Next, they propose a model to explain and examine faculty vitality in academic medicine, followed by a discussion of the need for a greater understanding of faculty vitality. Finally, the authors offer conclusions and propose future directions to promote faculty vitality. The authors encourage institutional decision makers and other stakeholders to focus particular attention on the evolving expectations for faculty, the risk of extensive faculty burnout, and the opportunity to reduce burnout by improving the vitality and resilience of these talented and crucial contributors. Faculty vitality, as defined by the institution, has a critical role in ensuring future institutional successes and the capacity for faculty to thrive in a complex health care economy.

Background Diabetes mellitus (DM) is a risk factor for morbidity and mortality in patients with heart failure. The effect of DM on post–left ventricular assist device (LVAD) implantation outcomes is unclear. This study sought to investigate whether patients with DM had worse outcomes than patients without DM after LVAD implantation and whether LVAD support resulted in a better control of DM. Methods and Results We retrospectively reviewed 341 consecutive adults who underwent implantation of LVAD from 2007 to 2016. Patient characteristics and adverse events were studied and compared between patients with and without DM. One hundred thirty-one patients (38%) had DM. Compared with patients without DM, those with DM had higher rates of ischemic cardiomyopathy, LVAD implantation as destination therapy, and increased baseline body mass index. In a proportional hazards (Cox) model with adjustment for relevant covariates and median follow-up of 16.1 months, DM was associated with increased risk of all-cause mortality (hazard ratio, 1.73; 95% confidence interval: 1.18–2.53; P =0.005) and increased risk of nonfatal LVAD-related complications, including a composite of stroke, pump thrombosis, and device infection (hazard ratio, 2.1; 95% confidence interval: 1.35–3.18; P =0.001). Preoperative hemoglobin A1c was not significantly associated with mortality or adverse events among patients with DM. LVAD implantation resulted in a remarkable decrease in hemoglobin A1c levels (7.4±1.9 pre-LVAD versus 6.0±1.5 and 6.3±1.4 after 3 and 12 months post-LVAD, respectively; P <0.0001) and a significant reduction in requirements of DM medications. Conclusions DM is associated with increased rates of all-cause mortality and major adverse events despite favorable glycemic control after LVAD implantation.

Background: Arthroplasty implants commonly contain elemental metal that may undergo wear-related release. Recently, cases of hip implant-associated myocardial injury have been reported. However, we are not aware of any previous study that has systematically measured myocardial metal levels or examined the relationship with total hip arthroplasty (THA). Methods: Archives of our institution were queried for autopsies of individuals who had undergone THA between 1990 and 2013. Myocardial tissue samples were analyzed for cobalt (Co) and chromium (Cr) levels with inductively coupled plasma mass spectroscopy. Seventy-five Co/Cr-on-polyethylene THA cases were included (mean age at time of death = 77.4 years; 49% women) as were 73 non-arthroplasty controls matched for age, sex, and history of hypertension and diabetes mellitus. Results: Significantly higher median myocardial concentrations of Co were observed in individuals with THA compared with controls (0.12 versus 0.06 μg/g, p < 0.0001). The median Co concentration was 69% higher in patients who had undergone THA revision (0.169 μg/g) than in those who underwent primary THA (0.100 μg/g; p = 0.004). In general, higher Co levels were observed in those with multiple replaced joints, although this finding only trended toward significance. Cardiomegaly, interstitial fibrosis, and decreased ejection fraction were observed more frequently in the postmortem samples of patients with implants than in those of controls (p = 0.0002, 0.044, and 0.0039, respectively). Conclusions: We believe this to be the first study to quantify metal levels in cardiac tissue in patients with and without joint replacement. The elevated Co levels, in concert with cardiomegaly and increased interstitial fibrosis found during autopsy, in the arthroplasty cohort are novel, important findings. Although Co levels were significantly elevated above those in controls, the majority were below those seen in clinical case reports of death from Co cardiotoxicity associated with metal-on-metal prostheses. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.