Citations

The vasoactive properties of exogenous adenosine triphosphate (ATP) are unique because it has the dual ability to induce robust vasodilation as well as blunt sympathetic vasoconstriction, similar to what is observed in contracting human skeletal muscle. ATP‐mediated vasodilation and exercise hyperemia are dependent, in part, on activation of inwardly rectifying potassium (K IR ) channels and subsequent smooth muscle cell hyperpolarization, with a modest reliance on the production of nitric oxide (NO) and prostaglandins (PGs). However, recent studies from our laboratory indicate that these pathways are not obligatory for contracting skeletal muscle to blunt α 1 ‐adrenergic vasoconstriction. Given the specific role of K IR channels in ATP‐mediated vasodilation, the primary purpose of this study was to determine whether the ability of ATP to blunt α 1 ‐adrenergic vasoconstriction is dependent upon K IR channel activity in humans. A secondary purpose was to determine whether the ability of ATP to blunt α 1 ‐adrenergic vasoconstriction is dependent upon activation of K IR channels and Na + /K + ‐ATPase, as well as the synthesis of NO and PGs. In a total of 13 young subjects we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra‐arterial infusion of phenylephrine (PE; α 1 ‐agonist) during infusion of ATP or a control vasodilator(s) (Protocol 1 (n=7): adenosine (ADO), and sodium nitroprusside (SNP); Protocol 2 (n=6): ADO). Vasomotor responses were assessed before and after blockade of signaling pathways that contribute to ATP‐mediated vasodilation (Protocol 1: K IR channels (barium chloride); Protocol 2: combined blockade of K IR channels, Na + /K + ‐ATPase (ouabain), NO (L‐NMMA), PGs (Ketorolac)). Protocol 1: ATP significantly attenuated PE‐mediated vasoconstriction relative to both SNP and ADO (Δ FVC: ATP: −16 ± 2; ADO: −38 ± 6; SNP: −59 ± 6%; P<0.05 vs ADO and SNP). Blockade of K IR channels significantly attenuated ATP mediated vasodilation ~40% (P<0.05 vs. control), but had no effect on the ability of ATP to blunt PE‐ mediated vasoconstriction (Δ FVC: −6 ± 5%; P>0.05 vs. control). Protocol 2: Despite combined blockade of K IR , Na + /K + ‐ATPase, NO, and PGs resulting in profound attenuation of ATP‐mediated vasodilation (−~60%; P<0.01 vs. control), ATP was still able to blunt PE‐mediated vasoconstriction (Δ FVC: −4 ± 14%; P=0.50 vs. control). Together these studies highlight that while NO, PGs, and vascular smooth muscle hyperpolarization (via K IR channel activation) are contributors to the normal vasodilatory response to exercise and exogenous ATP, these pathways are not obligatory for exercise or ATP to blunt α 1 ‐adrenergic vasoconstriction in humans. Support or Funding Information Support: HL119337, HL095573

Substantial evidence indicates that red blood cells (RBCs) can act as a ‘sensor’ for oxygen demand in addition to their traditional role as an oxygen ‘carrier’, in that they are able to stimulate vasodilation and increase oxygen delivery to the tissue through the release of ATP in direct proportion to the degree of hemoglobin (Hb) deoxygenation. However, RBCs from older adults have an impaired ability to release ATP in response to Hb deoxygenation compared to RBCs from young adults, yet the underlying cause of this remains unknown. RBC membrane deformability has been shown to decrease with advancing donor age, thus we hypothesized that increasing membrane deformability (via the Rho‐kinase inhibitor Y‐27632) would restore ATP release from RBCs of older adults, while decreasing membrane deformability (via the cell‐stiffening agent diamide) would impair ATP release from RBCs of young adults. Isolated RBC ATP release in response to normoxic (PO 2 ~110 mmHg) and hypoxic (PO 2 ~20 mmHg) stimuli was quantified in RBCs from young (23 ± 3 years; n = 11 for Y‐27632 and diamide) and older (68 ± 7 years; n = 11 and 6 for Y‐27632 and diamide, respectively) adults using the luciferin‐luciferase technique following RBC incubation with either saline (control), Y‐27632, or diamide. The relative change in ATP release from normoxia to hypoxia in saline control conditions was impaired in RBCs from older (41.5 ± 12.1% and 63.5 ± 18.5%) vs. young (110.4 ±12.7% and 146.0 ± 29.3%) adults (P < 0.05; control trials for Y‐27632 and diamide, respectively). Y‐27632 improved RBC ATP release in older adults (98.8 ± 19.8%) such that it was not different from the young control (P > 0.05), whereas diamide decreased RBC ATP release in young adults (57.4 ± 8.4%) such that it was not different from the older control (P > 0.05). Preliminary data from our laboratory indicate that these drugs affected RBC membrane deformability as expected based on other reports of the effects of Y‐27632 and diamide on RBC membrane deformability. We conclude that decreased membrane deformability contributes to the impaired ability of RBCs from older adults to release ATP in response to Hb deoxygenation, and that this may have implications for impaired vascular control with advancing age. Support or Funding Information HL095573, HL119337, F31HL126377

Introduction Symptom burden management is a major goal of pancreatic cancer care given that most patients are diagnosed late. Early palliative care is recommended in addition to concurrent active treatment; however, disparities exist. We sought to determine the factors associated with inpatient palliative treatment among pancreatic cancer patients and compare treatment outcomes in terms of mortality, discharge disposition and resource utilization. Methods We conducted a retrospective study of 22,053 pancreatic cancers using the National Inpatient Sample (NIS) database (January - December 2020). Patient and hospital characteristics, mortality, discharge disposition, length of stay (LOS), hospital costs and charges were compared between pancreatic cancer patients based on palliative treatment. Multivariate regression was used to evaluate patient and hospital characteristics and outcomes associated with palliative treatment. Results A total number of 3839 (17.4%) patients received palliative care. Patients who received palliative care were more likely to be older, Medicaid insured, and nonobese. Patients were less likely to receive palliative care if they are males, Medicare insured, had a lower Charlson comorbidity score, or treated in Urban nonteaching hospitals. Patients who received palliative care displayed higher odds of in-hospital mortality and prolonged LOS. The adjusted additional mean hospital cost and charges in patients who received palliative care were lower by $1459, and $4222 respectively. Conclusions Inpatient palliative treatment in pancreatic cancer patients is associated with an older age, a higher comorbidity burden, non-obesity, insurance status and urban teaching hospitals. Our study suggests that inpatient palliative treatment decreased hospital resource utilization without prolonging survival.

Abstract BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. METHODS The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR). RESULTS 39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were &gt;20-fold the in vitro IC50 for PARP inhibition. CONCLUSIONS While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.

AbstractCancer and its treatment produce deleterious symptoms across the phases of care. Poorly controlled symptoms negatively affect quality of life and result in increased health-care needs and hospitalization. The Improving the Management of symPtoms during And following Cancer Treatment (IMPACT) Consortium was created to develop 3 large-scale, systematic symptom management systems, deployed through electronic health record platforms, and to test them in pragmatic, randomized, hybrid effectiveness and implementation trials. Here, we describe the IMPACT Consortium’s conceptual framework, its organizational components, and plans for evaluation. The study designs and lessons learned are highlighted in the context of disruptions related to the COVID-19 pandemic.

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare coronary anomaly that can present in childhood or adulthood with a multitude of symptoms depending on the age of presentation. It should be suspected in infants presenting with heart failure in the setting of left ventricular systolic dysfunction and associated mitral regurgitation from papillary muscle ischemia. Adults with ALCAPA may present with cardiac ischemic symptoms. Prompt diagnosis with echocardiography and cross-sectional chest imaging is important to guide surgical intervention and improve the patients’ survival and prognosis. The goal of surgery is to establish a dual-coronary system with mid-term results revealing progressive recovery of left ventricular function and improvement in mitral regurgitation. Patients with ALCAPA should maintain life-long follow-up with a cardiologist with congenital heart disease expertise for surveillance of post-operative complications.

Abstract Background Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aβ pathology and tauopathy in vivo. Methods CatD knockout (KO) mice were crossed to human amyloid precursor protein (hAPP) transgenic mice, and amyloid burden was quantified by ELISA and immunohistochemistry (IHC). Tauopathy in CatD-KO mice, as initially suggested by Gallyas silver staining, was further characterized by extensive IHC and biochemical analyses. Controls included human tau transgenic mice (JNPL3) and another mouse model characterized by pronounced lysosomal dysfunction (Krabbe A). Additional experiments examined the effects of CatD inhibition on tau catabolism in vitro and in cultured neuroblastoma cells with inducible expression of human tau. Results Deletion of CatD in hAPP transgenic mice triggers large increases in cerebral Aβ, manifesting as intense, exclusively intracellular aggregates; extracellular Aβ deposition, by contrast, is neither triggered by CatD deletion, nor affected in older, haploinsufficient mice. Unexpectedly, CatDKO mice were found to develop prominent tauopathy by just ~ 3 weeks of age, accumulating sarkosyl-insoluble, hyperphosphorylated tau exceeding the pathology in aged JNPL3 mice. CatDKO mice exhibit pronounced perinuclear Gallyas silver staining reminiscent of mature neurofibrillary tangles in human AD, together with widespread phospho-tau immunoreactivity. Striking increases in sarkosyl-insoluble phospho-tau (~ 1250%) are present in CatD-KO mice, but notably absent from Krabbe A mice collected at an identical antemortem interval. In vitro and in cultured cells, we show that tau catabolism is slowed by blockade of CatD proteolytic activity, including via competitive inhibition by Aβ42. Conclusions Our findings support a major role for CatD in the proteostasis of both Aβ and tau in vivo. To our knowledge, CatD-KO mice are the only model to develop detectable Aβ acumulation and profound tauopathy in the absence of overexpression of hAPP or human tau with disease-associated mutations. Given that tauopathy emerges from disruption of CatD, which can itself be potently inhibited by Aβ42, our findings suggest that impaired CatD activity may represent a key mechanism linking amyloid accumulation and tauopathy in AD.