Citations

Stimulation of T lymphocytes with stromal cell‐derived factor‐1alpha (SDF‐1alpha/CXCL12) results in colocalization of the chemokine receptor, CXCR4, and the T cell receptor (TCR). Internalization of the colocalized complex can initiate prolonged activation of the extracellular signal‐regulated kinases (ERK) ERK1 and ERK2, gene transcription, cytokine expression and migration. The molecular mechanisms behind the internalization of the colocalized complex are incompletely characterized. In this study, we show that there are multiple sites in the CXCR4 C‐terminus that influence the internalization of the CXCR4/TCR complex in Jurkat and JRT3 T cells. A mutation of amino acids 328 and 329 in the CXCR4 C‐terminus, an important beta‐arrestin binding site, significantly reduced internalization in Jurkat cells. Deletion mutations in the CXCR4 C‐terminus also significantly reduced internalization in Jurkat cells. Basal internalization in Jurkat cells was decreased by an element(s) in amino acids 342–352. Basal internalization was induced by an element(s) in amino acids 334–342. Basal internalization in JRT3 cells was increased by an element in amino acids 322–334. SDF‐1alpha induced internalization was similarly regulated by the TCR. Research was supported by the Summer Undergraduate Research Fellowship at Mayo Clinic and Mayo Graduate School.

Background: Vascular risk factors have been associated with risk of cognitive decline, with increasing evidence that midlife exposure to these risk factors may be most important in conferring late-life risk of cognitive impairment. We explored associations between vascular risk factors measured in midlife and the development of dementia over 25 years in the biracial Atherosclerosis Risk in Communities (ARIC) cohort. Methods: Participants in the ARIC study were recruited from four U.S. communities in 1987-1989, at ages 45-64, with four additional in-person visits, surveillance for hospitalizations, annual phone calls, and repeated cognitive evaluations over a 25-year period. In 2011-2013, ARIC participants were seen for the ARIC Neurocognitive Study (ARIC-NCS), and underwent a detailed neurocognitive battery and informant interviews. Through adjudicated review, dementia cases were defined. Additional dementia cases were identified through the telephone interview for cognitive status (TICS) or informant interview for those participants not attending ARIC-NCS; or by a prior dementia ICD-9 code during a hospitalization. Results: Of 15,744 participants in the cohort, 1516 cases of dementia were identified, of whom over one third were among black participants. Risk of dementia was highest in individuals of black race, with less than a high school education, older age, APOE ε4 carriage, and who, at ARIC baseline, had hypertension, diabetes, or were current smokers (table). APOE ε4 and smoking were each stronger risk factors for dementia in whites than in blacks. Discussion: Vascular risk factors measured in midlife are associated with increased risk of dementia in this biracial cohort, in black and white participants. The risk associated with diabetes nears the increased risk associated with having an APOE ε4 allele. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

Background There is heterogeneity in the names and anatomical descriptions of regional anesthetic techniques. This may have adverse consequences on education, research, and implementation into clinical practice. We aimed to produce standardized nomenclature for abdominal wall, paraspinal, and chest wall regional anesthetic techniques. Methods We conducted an international consensus study involving experts using a three-round Delphi method to produce a list of names and corresponding descriptions of anatomical targets. After long-list formulation by a Steering Committee, the first and second rounds involved anonymous electronic voting and commenting, with the third round involving a virtual round table discussion aiming to achieve consensus on items that had yet to achieve it. Novel names were presented where required for anatomical clarity and harmonization. Strong consensus was defined as ≥75% agreement and weak consensus as 50% to 74% agreement. Results Sixty expert Collaborators participated in this study. After three rounds and clarification, harmonization, and introduction of novel nomenclature, strong consensus was achieved for the names of 16 block names and weak consensus for four names. For anatomical descriptions, strong consensus was achieved for 19 blocks and weak consensus was achieved for one approach. Several areas requiring further research were identified. Conclusions Harmonization and standardization of nomenclature may improve education, research, and ultimately patient care. We present the first international consensus on nomenclature and anatomical descriptions of blocks of the abdominal wall, chest wall, and paraspinal blocks. We recommend using the consensus results in academic and clinical practice.

The purpose of this study was to evaluate the relationship between the cardiac and sympathetic baroreflex sensitivities within healthy, young individuals. The gains in cardiac (as measured by changes in R‐R interval, RRI, and heart rate, HR) and sympathetic (as measured by changes in muscle sympathetic nerve activity, MSNA) baroreflex during rapid changes in arterial blood pressure were compared in 27 normotensive individuals (18 men and 9 women; age 24 yrs ±1.24; body mass index 24 ±0.51 cm/kg 2 , mean ±SEM). Heart rate, arterial blood pressure (brachial artery catheter), and peroneal MSNA were recorded under resting conditions (HR 58 ±1.6 bpm; SBP 124 ±2.7 mmHg; DBP 71 ±1.7 mmHg; MAP 87 ±1.7 mmHg; MSNA BF 17 ±1.6 bursts/min) as well as during rapid changes in arterial blood pressure induced by sequential boluses of nitroprusside and phenylephrine (Modified Oxford technique). Integrated baroreflex sensitivities for MSNA and HR were analyzed using the slopes of the linear portions of the MSNA‐diastolic blood pressure and RRI‐systolic blood pressure relationships, respectively. When individual cardiac baroreflex sensitivity was compared to sympathetic baroreflex sensitivity, no correlation (R 2 =0.0003) was found. These results indicate that although both cardiac and sympathetic efferents function in baroreflex control of the autonomic system, there does not appear to be a direct correlation in their function within healthy normotensive individuals. Research Support: NIH HL083947 and Swedish Medical Council grant 12170

Walking tests, such as the 6-min walk test (6MWT), are popular methods of estimating peak oxygen uptake (VO2peak) in clinical populations. However, the strength of the distance vs. VO2peak relationship is not strong, and there are no equations for estimating ventilatory threshold (VT), which is important for training prescription and prognosis. Since the 6MWT is often limited by walking mechanics, prediction equations that include simple additional predictors, such as the terminal rating of perceived exertion (RPE), hold the potential for improving the prediction of VO2max and VT. Therefore, this study was designed to develop equations for predicting VO2peak and VT from performance during the 6MWT, on the basis of walking performance and terminal RPE. Clinically stable patients in a cardiac rehabilitation program (N = 63) performed the 6MWT according to the American Thoracic Society guidelines. At the end of each walk, the subject provided their terminal RPE on a 6–20 Borg scale. Each patient also performed a maximal incremental treadmill test with respiratory gas exchange to measure VO2peak and VT. There was a good correlation between VO2peak and 6MWT distance (r = 0.80) which was improved by adding the terminal RPE in a multiple regression formula (6MWT + RPE, R2 = 0.71, standard error of estimate, SEE = 1.3 Metabolic Equivalents (METs). The VT was also well correlated with walking performance, 6MWT distance (r = 0.80), and was improved by the addition of terminal RPE (6MWT + RPE, R2 = 0.69, SEE = 0.95 METs). The addition of terminal RPE to 6MWT distance improved the prediction of maximal METs and METs at VT, which may have practical applications for exercise prescription.

Abstract Background Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but remains infrequently and inconsistently measured in clinical trials and poorly managed in clinical settings. A recently completed systematic review of pain in ADPKD identified 26 different outcome measures. None of these measures were considered appropriate as a core outcome measure due to the lack of patient-important dimensions, inadequate content, relatively long duration of completion time and limited evidence to support psychometric robustness. Methods We convened an international Standardized Outcomes in Nephrology–Polycystic Kidney Disease consensus workshop involving 21 patients/caregivers and 40 health professionals (clinicians, nurses, researchers, policy makers and industry representatives) from 18 countries to discuss the identification or development of a core outcome measure for pain. Results Four themes were identified highlighting fundamental issues for the measurement of pain in ADPKD: distressing and disrupting life participation; variability and ambiguity in defining pain; stigma, frustration and adaptation to pain; and ensuring validity and feasibility of pain measures. Conclusions Existing measures were found to be insufficient in capturing pain as a core outcome and there was consensus on the need for a new validated measure that is simple, succinct and addresses the impact of pain on life participation. This measure will facilitate the appropriate prioritization of pain in all trials and guide clinical decision making in people with ADPKD.

Abstract BACKGROUND: Patients with ROC have limited treatment options in later lines of therapy, as many become platinum-resistant or -ineligible. Poly(ADP-ribose) polymerase inhibitor (PARPi) treatment is one option, however these agents are currently not approved for BRCAwt patients in the treatment setting. Niraparib, a PARPi, has demonstrated increased progression-free survival vs placebo as maintenance therapy for platinum-responsive ROC. Niraparib was effective regardless of BRCAmut or homologous recombination deficiency (HRD) status, although an increased treatment effect was observed in the HRDpos population. QUADRA (NCT02354586) evaluated niraparib treatment in heavily pretreated ROC patients, regardless of BRCAmut or HRD status, platinum sensitivity, or prior PARPi use. METHODS: Eligible patients had grade 2-3 serous ROC, ≥3 prior chemotherapy lines, and measurable disease. Patients were evaluated for BRCAmut and HRD status (MyChoice HRD Test). Patients received niraparib 300 mg once daily until progression; dose could be lowered to 200 mg or 100 mg due to treatment-emergent adverse events (TEAEs). The primary endpoint was objective response rate (ORR) per RECIST v1.1 in patients treated in 4th or 5th line who were HRDpos, platinum sensitive, and PARPi naïve. RESULTS: 463 patients were treated. Of these, 161 were platinum refractory, 151 platinum resistant, and 120 platinum sensitive to their last line of platinum therapy. Of note, 83 patients were primary platinum resistant or refractory (42 and 41, respectively). Median number of prior lines of therapy was 4 (range 2-16), and 27% of patients were treated in 6th or later line. 100% of patients received prior platinum, 99.6% received prior taxane, 81% received prior doxorubicin, 63% received prior bevacizumab, and 59% received prior gemcitabine. In the primary efficacy population (N=45), ORR was 29% (95% CI: 16-44, P=0.0003), disease control rate (DCR) was 71% (95% CI: 56-84), and duration of response (DOR) was 9.2 months (95% CI: 5.9-NE); overall survival (OS) was not reached (95% CI: 18.5-NE). The efficacy outcomes in all 456 patients with measurable disease at baseline treated in 4th or later line demonstrated a DCR of 49% with 2 complete responses (CR), 36 partial responses (PR), and 187 patients with stable disease (SD). The responses were durable with a median DOR of 9.4 months, a clinical benefit rate (CR+PR+SD) at 16 weeks of 29%, and median OS of 17.2 months (95% CI: 14.9-19.8) among all patients treated in 4th or later line. 266 (57.5%) patients had grade ≥3 treatment-related TEAEs. Grade ≥3 thrombocytopenia event (thrombocytopenia or decreased platelet count) by dose at onset of the event was 27.5% at 300 mg, 4.7% at 200 mg, and 2.7% at 100 mg. The other most common grade ≥3 TEAEs were anemia (26.3%) and neutropenia (8.2%). Hematologic TEAEs were most frequent in the first month and decreased in frequency and severity after dose reduction during months 2-3. CONCLUSIONS: Niraparib demonstrated durable anticancer activity in this heavily treated (≥3 lines) ROC population, including platinum-resistant or BRCAwt patients. Toxicities were consistent with previous niraparib studies. DISCLOSURE Funded by TESARO, Inc. Citation Format: Kathleen Moore, Angeles Secord, Melissa Geller, David Miller, Noelle Cloven, Gini Fleming, Andrea E. Wahner Hendrickson, Masoud Azodi, Paul Disilvestro, Amit Oza, Mihaela Cristea, Jonathan S. Berek, John Chan, Yong Li, Kaiming Sun, Katarina Luptakova, Ursula A. Matulonis, Bradley J. Monk. QUADRA: A PHASE 2, OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE SINGLE-AGENT NIRAPARIB TREATMENT IN PATIENTS WITH RELAPSED OVARIAN CANCER (ROC) WHO HAVE RECEIVED ≥3 PRIOR CHEMOTHERAPY REGIMENS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-101.

AbstractBackgroundThe novel Coronavirus (SARS‐CoV‐2) has caused almost 2 million deaths worldwide. Both Food and Drug Administration and European Medicines Agency have recently approved the first COVID‐19 vaccines, and a few more are going to be approved soon.MethodsSeveral different approaches have been used to stimulate the immune system in mounting a humoral response. As more traditional approaches are under investigation (inactivated virus vaccines, protein subunit vaccines, recombinant virus vaccines), more recent and innovative strategies have been tried (non‐replicating viral vector vaccines, RNA based vaccines, DNA based vaccines).ResultsSince vaccinations campaigns started in December 2020 in both the US and Europe, gastroenterologists will be one of the main sources of information regarding SARS‐CoV 2 vaccination for patients in their practice, including vulnerable patients such as those with Inflammatory Bowel Disease (IBD), patients with chronic liver disease, and GI cancer patients.ConclusionsThus, we must ourselves be well educated and updated in order to provide unambiguous counseling to these categories of vulnerable patients. In this commentary, we aim to provide a comprehensive review of both approved COVID‐19 vaccines and the ones still under development, and explore potential risks, benefits and prioritization of vaccination.