Base Line Research Articles

Mitral regurgitation increases systolic strains in remote zone and worsens left ventricular dyssynchrony in a swine model of ischemic cardiomyopathy

BackgroundIschemic mitral regurgitation (IMR) imposes volume overload on the left ventricle (LV), accelerating adverse LV remodeling. In this study, we sought to investigate the impact of volume overload due to IMR on regional myocardial contractile mechanics.MethodsTen Yorkshire swine were induced with myocardial infarction (MI) by occluding the left circumflex coronary artery (LCx). Cardiac MRI was performed at baseline (BL) and 2.5 months (2.5M) post-MI. IMR was quantified with epicardial echocardiography 3 months post-MI. The animals were then assigned to 2 groups: no/mild MR (nmMR, n = 4) and moderate/severe MR (msMR, n = 6). MRI images were analyzed to assess infarction size, end-diastolic and end-systolic volume (EDV and ESV, respectively), ejection fraction (EF), longitudinal strain (LS), circumferential strain (CS), and systolic dyssynchrony index (SDI). The myocardial region was divided into infarction, border, and remote zones based on the LCx-supplied region.ResultsThere was no difference in the infarction size. Group-wise comparison of LS and CS between BL and 2.5M demonstrated that LS and CS in the infarction zone and the border zone decreased at 2.5M in both groups. However, LS and CS in the remote zone were elevated only in the msMR group (LS: −9.81 ± 3.96 vs. −12.58 ± 5.07, p < 0.01; CS; −12.78 ± 3.81 vs. −16.09 ± 3.33, p < 0.01) at 2.5M compared to BL. The SDI of CS was significantly elevated in the msMR group (0.1255 vs. 0.0974, p = 0.015) at 2.5M compared to BL.ConclusionsElevated LS and CS in the remote zone were observed in moderate/severe MR and ventricular dyssynchrony. These elevated cardiac strains, coupled with ventricular dyssynchrony, may contribute to the progression of MR, thereby accelerating heart failure.

#388 IONIS-FB-LRx, an antisense oligonucleotide to complement factor B for treatment of IgA nephropathy

Abstract Background and Aims Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Since overactivity of the complement Alternative Pathway (AP) has been proposed to contribute to pathogenesis of IgAN, it has been hypothesized that a reduction of AP activity would improve proteinuria. IONIS-FB-LRx, (ISIS696844, RO7434656), is an investigational antisense oligonucleotide targeting complement factor B (CFB) mRNA and reduces CFB production in the liver. We have previously demonstrated that administration of IONIS-FB-LRx lowered the production of CFB, a required component of the AP, and led to reduction of AP and reduction in proteinuria in IgAN patients (2023 ASN Abstract#SA-PO926, N = 13 patients). Current abstract provides an update to our previous report extending results to 19 patients treated with IONIS-FB-LRx. Method An exploratory, single-arm, multi-national open-label Ph2 study (NCT04014335) recruited patients with biopsy-confirmed IgAN, proteinuria >1.5 g/d, eGFR >40 mL/min/1.73 m2, and hematuria despite maximum tolerated RAAS blockade and/or stable dose of SGLT-2 inhibitor for a minimum of 6 months. Study drug was administered at Weeks 1, 3, and 5, and then every 4 weeks through Week 25 (Cohort A) and at Week 1 and then every 4 weeks through Week 25 (Cohort B). Primary outcome was change in 24-hr proteinuria at Week 29 (4 weeks after last dose) compared to baseline (BL). Results 19 patients have completed study to date (13Nov2023), 25-62 yr, 42% Female, 11 Asian, and 8 White. Median 24-hr UPCR at BL was 1.56 g/g (IQR 1.23, 2.33 g/g). At Week 29, a 45% geometric mean ratio reduction was observed. There was little change in eGFR at Week 29 compared to BL (mean ± SD; BL 72 ± 22; Week 29 74.6 ± 20 mL/min/1.73 m2). The drug demonstrated an acceptable safety profile with no Treatment Emergent SAEs; the only clinically meaningful laboratory finding was reversible and transient ALT elevation without a change in bilirubin. All patients completed the study and one patient discontinued study drug after 4 months to initiate SGLT-2 inhibitors. That patient experienced a 38% reduction in 24-hr UPCR collected 3 weeks (Week 27) after the last dose of IONIS-FB-LRx, but prior to use of SGLT-2 inhibitors. Conclusion This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-LRx reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-LRx to reduce the progression of IgAN.

Nanoparticle-Modified 3D-Printed Denture Base Resins: Influence of Denture Cleansers on the Color Stability and Surface Roughness In Vitro.

This study aimed to evaluate the influence of denture cleansers on the color, stability, and surface roughness of three-dimensional (3D)-printed denture base resins modified with zirconium dioxide nanoparticles (nano-ZrO2). A total of 440 specimens were fabricated using one heat-polymerized resin, and two 3D-printed resins (NextDent and ASIGA). According to the nano-ZrO2 content, the specimens for each resin were divided into five groups (0%, 0.5%wt, 1%wt, 3%wt, and 5%wt). Each concentration was divided into four subgroups (n = 10) based on the immersion solution (distilled water, sodium hypochlorite, Corega, and Fittydent) and immersion duration (360 and 720 days). The color changes (∆E00) and surface roughness (Ra, µm) of each specimen were measured at different time intervals (base line, 360 days, 720 days) using a spectrophotometer and a non-contact profilometer, respectively. The results were statistically analyzed using ANOVA and a post hoc Tukey's test (α = 0.05). Sodium hypochlorite showed the highest significant color change of all the denture base resins (p < 0.001). The average value of ΔE00 for sodium hypochlorite was significantly higher than the values for the other solutions (Fittydent, Corega, and water) (p < 0.001). Color stability was significantly affected by immersion time for all types of solutions except Corega (p < 0.001). All of the tested immersion solutions (distilled water, sodium hypochlorite, Corega, and Fittydent) showed a significant increase in the surface roughness of all the denture base resins (p < 0.05). Surface roughness was substantially increased by immersion time for all types of solution except Fittydent (p < 0.001). Denture cleansers can result in substantial color change and affect the surface roughness of unmodified and nanoparticle-modified denture base resins. Therefore, the selection of denture cleanser and appropriate types of material is critical for denture longevity.

Biomimetic Remineralization of Artificial Caries Lesions with a Calcium Coacervate, Its Components and Self-Assembling Peptide P11-4 In Vitro.

The application of calcium coacervates (CCs) may hold promise for dental hard tissue remineralization. The aim of this study was to evaluate the effect of the infiltration of artificial enamel lesions with a CC and its single components including polyacrylic acid (PAA) compared to that of the self-assembling peptide P11-4 in a pH-cycling (pHC) model. Enamel specimens were prepared from bovine incisors, partly varnished, and stored in demineralizing solution (DS; pH 4.95; 17 d) to create two enamel lesions per sample. The specimens were randomly allocated to six groups (n = 15). While one lesion per specimen served as the no-treatment control (NTC), another lesion (treatment, T) was etched (H3PO4, 5 s), air-dried and subsequently infiltrated for 10 min with either a CC (10 mg/mL PAA, 50 mM CaCl2 (Ca) and 1 M K2HPO4 (PO4)) (groups CC and CC + DS) or its components PAA, Ca or PO4. As a commercial control, the self-assembling peptide P11-4 (CurodontTM Repair, Credentis, Switzerland) was tested. The specimens were cut perpendicularly to the lesions, with half serving as the baseline (BL) while the other half was exposed to either a demineralization solution for 20 d (pH 4.95; group CC + DS) or pHC for 28 d (pH 4.95, 3 h; pH 7, 21 h; all five of the other groups). The difference in integrated mineral loss between the lesions at BL and after the DS or pHC, respectively, was analyzed using transversal microradiography (ΔΔZ = ΔZpHC - ΔZbaseline). Compared to the NTC, the mineral gain in the T group was significantly higher in the CC + DS, CC and PAA (p < 0.05, Wilcoxon). In all of the other groups, no significant differences between treated and untreated lesions were detected (p > 0.05). Infiltration with the CC and PAA resulted in a consistent mineral gain throughout the lesion body. The CC as well as its component PAA alone promoted the remineralization of artificial caries lesions in the tested pHC model. Infiltration with PAA further resulted in mineral gain in deeper areas of the lesion body.

Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Comparison of Hemodynamic Effect of Propofol and Ketofol during Induction of Anaesthesia in General Surgery Patients

Objective: To determine the comparison of homodynamic effect of propofol and ketofol duringinduction in general surgery patients.Study design: Randomized control trialSetting: Department of Anesthesia, Surgical ICU and Pain management, Civil Hospital Karachi.Duration: Seven months from June 2019 to January 2020.Methods: Patients scheduled for elective general surgery procedures, aged 20 to 60 years, bothmale and female patients were included. Patients were randomly allocated into two groups.Group A received a combination of ketofol while Group B received propofol as the inductionagent. After recording of the base line values of mean arterial pressure patient was induced usingpropofol or ketofol. Mean arterial pressure readings were noted at 30 seconds after druginjection, as well as at 1 minute, 5 minutes, and 10 minutes after intubation, to capture theimmediate hemodynamic effects of the drugs and to observe any potential changes over timefollowing intubation.Results: The average age of the patients was 37.38±13.78 years. Out of 64 patients, 30(46.9%)were male and 34(53.1%) were female. Homodynamic effect was significantly high in thosepatients who received ketofol than those who received propofol (100% vs. 59.4% p=0.0005).The findings observed also with significant differences in hemodynamic effects between the twogroups, even after controlling for age, gender, and ASA classification (p-&amp;lt;0.05).Conclusion: Combination of Ketofol with ketofol was observed to be the betterhemodynamically as compared to Propofol. Additionally, the use of ketofol reduces the cost ofinduction and decreasing the economic burden on the patient.

Abstract PO1-15-12: Circulating tumor DNA (ctDNA) for prediction of pathologic complete response (pCR) after 12 weeks of pembrolizumab + trastuzumab + pertuzumab in HER2-enriched early breast cancer: WSG-Keyriched-1 trial

Abstract Background ctDNA testing is emerging as an important biomarker in early breast cancer (eBC). However, its value in prediction of tumor response to de-escalated, chemotherapy-free neoadjuvant therapy (NAT) remains underexplored. In WSG-Keyriched-1 (NCT03988036), a single-arm phase 2 trial, we investigated for the first time a chemotherapy-free NAT with dual HER2 blockade and pembrolizumab in HER2- enriched HER2+ eBC. In this pre-specified translational analysis, we evaluated whether ctDNA measurement could predict pCR. Methods 48 patients (pts) with HER2 2+ (ISH+) or 3+ eBC (stage I-III) and HER2-enriched subtype by PAM50 were included. Pts received pembrolizumab (200 mg), trastuzumab biosimilar (loading dose (LD) 8 mg/kg bodyweight (BW), maintenance dose (MD) 6 mg/kg BW), and pertuzumab (LD 840 mg/kg BW, MD 420 mg/kg BW) q3w for 12 weeks. Primary objective was pCR (ypT0/is ypN0). ctDNA was analyzed in 92 plasma samples collected from 31 pts at baseline (BL) and week 3 of NAT and 30 pts at end of treatment (EOT). Sequencing libraries with unique molecular identifiers were constructed from cell-free DNA and hybridization panels with ≤50 patient-specific somatic mutations from tumor sequencing were used for enrichment. Libraries were sequenced to an ultra-high depth of 100,000×. Sequencing data was analyzed using a combination of public pipelines (megSAP and umiVar2 for mapping and deduplication) and custom in-house scripts (to extract the allele counts for patient-specific variants). To reduce the error rate, only corrected reads with ≥4 duplicates were used. p-value for ctDNA detection was calculated using the total variant count, depth and sample-specific error. Association between ctDNA with pCR and other clinical parameters were assessed with Chi-square or Fisher’s exact test and univariable logistic regression. Additionally, bivariable logistic regressions for pCR were performed with ctDNA and either cT, cN, or grade. Results ctDNA was detected (ctDNA+) in 58.0% (n=18/31) of pts at BL, 9.7% (n=3/31) at week 3, and 10% (n=3/30) at EOT. ctDNA was cleared by week 3 in 83.3% of pts (n=15/18). Compared with ctDNA-negative cases (ctDNA-) at BL, those ctDNA+ more often had cT2-3 disease (94.4%, n=17/18, vs 38.5%, n=5/13; p=.001) and lymph node involvement (61.1%, n=11/18, vs 0%, n=0/13; p&amp;lt; .001). 72.2% (n=13/18) of ctDNA+ and 61.5% (n=8/13) of ctDNA- cases at BL were grade 3 (p=.53). Each of the 3 pts who remained ctDNA+ at week 3 was node-positive; all pts remaining ctDNA- at week 3 were node-negative. pCR rate was 38.9% (n=7/18) in ctDNA+ vs 76.9% (n=10/13) in ctDNA- pts at BL (p=.067), 0% (n=0/3) in ctDNA+ vs 60.7% (n=17/28) in ctDNA- at week 3 (p=.081), and 33.3% (n=1/3) in ctDNA+ vs 59.3% (n=16/27) in ctDNA- at EOT (p=.565). pCR rate was highest in pts who remained ctDNA- throughout week 3 (76.9%, n=10/13), compared to pts with ctDNA cleared by week 3 (46.7%, n=7/15), and pts remaining ctDNA+ (0%, n=0/3, p=.024). ctDNA at BL was predictive for pCR in univariable analysis (odds ratio, OR 0.22, 95%CI 0.04- 0.93, area under curve, AUC=0.69). Bivariable models including ctDNA and grade yielded the highest accuracy for analyses with ctDNA at BL (AUC=0.77), week 3 (AUC=0.79), and with ctDNA change from BL to week 3 (AUC=0.87). Conclusions Absence of ctDNA prior to and during NAT, as well as early clearance of ctDNA associates with a higher pCR rate in eBC pts with HER2-enriched intrinsic subtype treated with chemotherapy-free pembrolizumab plus dual HER2 blockade. These results are in line with prior data with more intensive therapy from I-SPY 2 and NeoALTTO trials in HER2+ eBC and indicate that ctDNA analysis during NAT appears feasible for real- time monitoring of response to treatment and could be used to guide escalation/de-escalation strategies. Further trials with a larger number of pts and pre-designed follow-up are needed to confirm the role of ctDNA for prediction of tumor response and relapse. Citation Format: Monika Graeser, Sherko Kuemmel, Oleg Gluz, Christopher Schroeder, Leon Schuetz, Olga Kelemen, Stephan Ossowski, Katarzyna Jozwiak, Mattea Reinisch, Athina Kostara, Iris Scheffen, Kerstin Lüdtke-Heckenkamp, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens-Uwe Blohmer, Matthias Christgen, Stephan Bartels, Hans-Heinrich Kreipe, Enrico Pelz, Ulrike Nitz, Peter Schmid, Nadia Harbeck, Andreas Hartkopf. Circulating tumor DNA (ctDNA) for prediction of pathologic complete response (pCR) after 12 weeks of pembrolizumab + trastuzumab + pertuzumab in HER2-enriched early breast cancer: WSG-Keyriched-1 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-15-12.

Abstract PS12-02: Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer

Abstract Background The PACE trial for HR+/HER2- metastatic breast cancer (MBC) prospectively evaluated whether continuation of the CKD4/6 inhibitor (CDK4/6i) palbociclib (P) beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in endocrine therapy (ET) to fulvestrant (F), improved outcomes beyond change to F alone, as well as explored the activity of a palbociclib, fulvestrant, and avelumab (P+F+A) triplet. The primary analysis did not show improvement in progression-free survival (PFS) with F+P versus F alone. In this analysis, an evaluation of serial translational PACE samples was performed to gain insights into the mutational landscape of HR+/HER2- MBC after prolonged exposure to CDK4/6i, evaluate early mutational dynamics with ongoing therapy, and identify potential genetic markers predictive of treatment response. Additionally, the identification of acquired mutations at the time of tumor progression could provide valuable information about mechanisms of treatment resistance. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after &amp;gt; 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to F alone, F+P, or F+P+A, with tumor assessments every 8 weeks. Correlative samples including circulating tumor DNA (ctDNA) were collected at baseline (BL), times of tumor assessments (C3D1), and end of study/progression (EOT). Targeted NGS (Guardant360) to evaluate mutations (somatic single nucleotide variants and indels) was performed. Kaplan-Meier survival curves were used for assessing PFS and the log-rank test for comparisons. McNemar’s test with continuity correction was used to test the changes in the frequency of mutations. Results Of the 220 randomized pts, 211 contributed ctDNA samples (200 at BL, 129 at C3D1, 146 at EOT). Characteristics of the correlative science population were similar to the intention to treat population. At BL, the most common mutations observed were ESR1 (57%), TP53 (38%), PIK3CA (36%), GATA3 (20%) ATM (12%) and Rb1 (12%). The presence of a PIK3CA mutation vs WT-PIK3CA at BL was associated with shorter PFS in the F alone arm (p=0.001) but not in the F+P or F+P+A arms. ESR1 mutations present at baseline were D538G (34%), Y537S (21%), Y537N (15%), E380Q (10%) and L536H (4%). At C3D1, the most common mutations observed were ESR1 (47%), TP53 (33%), PIK3CA (26.1), GATA3 (18.1), ATM (13%) and PTEN (8.6%). Including only BL and C3D1 matched samples (N=124), the prevalence of ESR1 mutations decreased after 2 cycles of treatment (57% at BL vs 44% at C3D1), predominantly observed in the F+P+A arm. For those in any arm with at least 6 months of disease stability on study (N=53), the presence of an ESR1 D538G mutation decreased during therapy, with 38% having a mutation at BL, 24% at C3D1, and no pts gaining ESR1 D538G at C3D1. The prevalence of PIK3CA mutations also decreased on treatment (32% at BL to 24% at C3D1), with the greatest decrease in the F+P arm. A predictive model correlating early genomic dynamics and associations with outcome will be presented. Conclusions The PACE trial offers one of the largest clinical trial cohorts describing the genomic landscape of HR+/HER2- MBC post-CDK4/6 exposure. Results from this correlative study provide a comprehensive mutational landscape post-CDK4/6i, demonstrate associations between mutations and clinical outcomes, and suggest the potential value of early ctDNA dynamics in this setting. Citation Format: Rinath Jeselsohn, Jingxin Fu, Yue Ren, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy Miller, Yara Abdou, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Naomi Ko, Yuan Liu, Harold Burstein, Michelle DeMeo, Sara Tolaney, Erica Mayer. Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-02.

Abstract PO3-05-11: Enhancing the interpretation of real-world quality of life (QoL) in patients (pts) with hormone receptor positive human epidermal growth factor 2 negative (HR+/HER2−) advanced breast cancer (ABC) enrolled in the POLARIS trial

Abstract Background POLARIS is a prospective, observational real-world study of pts with HR+/HER2− ABC receiving palbociclib in routine clinical practice. We have previously shown that palbociclib treatment did not have any significant adverse impact on pt QoL when assessed by the EORTC-QLQ-C30 questionnaire,1 consistent with published clinical trial findings. Now, to enhance interpretation, we sought to characterize EORTC scores (using updated POLARIS data) into terms that are meaningful to pts, physicians, and other stakeholders, using a similar approach to established clinical problem threshold methodology.2 Methods EORTC data were collected at baseline (BL), monthly for the first 3 months, and every 3 months thereafter until palbociclib discontinuation. Response options for each EORTC question (ordinal scale from 1=very poor to 7=excellent) were grouped into “favorable” (taking a conservative approach of using only responses 5, 6 or 7) and “less favorable” (response of ≤4) for the two items on global health status/QoL. The proportion of pts with favorable or less favorable response was compared between subgroups (line of therapy, age, race, bone metastases, visceral metastases, and dose modification) at timepoints BL, month 6, 12, and 18 using Fisher’s exact test. Results Between January 2017 and December 2018, 1285 pts were enrolled, of whom 1250 received at least one dose of palbociclib and subsequently analyzed as part of the final data cut of 09 Jan 2023. EORTC Q29 ‒ Overall Health completion rates were 1167/1250 (93.4%) at baseline, 732/1250 (58.6%) at month 6, 484/1250 (38.7%) at month 12, and 353/1250 (28.2%) at month 18 (Table). The proportion of pts with a favorable response for EORTC Q29 was consistently higher than with a not favorable response (BL, 56.1% vs 43.9%; month 6, 69.3% vs 30.7%; month 12, 68.6% vs 31.4%; and month 18, 70.0% vs 30.0%; Table). When analyzed by subgroup, no significant differences were observed in the proportion of pts with a favorable (to less favorable) response for any subgroup covariate, except for age at BL; however, this significance was not observed at month 6, 12 or 18 (Table). Similar results were observed for EORTC Q30 – Overall QoL (data not shown). Conclusions The proportion of pts indicating a favorable response in the EORTC questionnaire Overall Health and Overall QoL questions increased or were maintained in pts with HR+/HER2− ABC treated with palbociclib from BL through to month 18 across overall and all subgroups. It is important to note that these data are conditional on the pts who responded to the questions, whose numbers diminished over time. XX XX Citation Format: Gabrielle Rocque, Joanne Blum, Yan Ji, Timothy Pluard, John Migas, Shailendra Lakhanpal, Erin Jepsen, Eric Gauthier, Yao Wang, Monica Montelongo, Joseph C. Cappelleri, Connie Chen, Meghan Karuturi, Debu Tripathy. Enhancing the interpretation of real-world quality of life (QoL) in patients (pts) with hormone receptor positive human epidermal growth factor 2 negative (HR+/HER2−) advanced breast cancer (ABC) enrolled in the POLARIS trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-11.

Abstract PO4-05-07: Differential dynamics of fragmentomic and epigenetic circulating tumor DNA (ctDNA) features in first-line Palbociclib and Ribociclib treatment for Hormone Receptor (HR) positive, HER2 negative metastatic breast cancer (MBC)

Abstract Background: Cyclin-dependent kinase inhibitors (CDK4/6i) in combination with endocrine therapy (ET) represent the cornerstone for the management of HR positive, HER2 negative MBC. However, the lack of prospective cohorts comparing the distinctions among palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABE) poses a significant clinical knowledge gap. The aim of this ancillary analysis was to explore the differential clinical impact of CDK4/6i by leveraging new ctDNA biomarkers in a prospective clinical study. Methods: A total of 114 patients (pts) with HR positive, HER2 negative MBC were prospectively enrolled in the multicenter MAGNETIC.1 study (CRO-2018-56) from January 2018 to January 2023. At baseline (BL) and every 3 months (mos.), ctDNA samples were collected concurrently with radiological restaging. The samples were then analyzed through methylation-specific (MS) droplet digital PCR (ddPCR), ddPCR fragmentomics, and next generation sequencing. Matched pairs of variations were tested through Wilcoxon signed rank test, and survival was analyzed by log-rank test. Results: Out of the 114 pts enrolled, 59 received PAL, 48 RIB, and 16 ABE. In the de novo subgroup, 51.4 % of pts were treated with PAL, 42.9% with RIB, and 5.7% with ABE. Among the pts who received PAL, 7 harbored an ESR1 mutation at BL (D538G: 2, H377R: 1, Y537N: 1, Y537S: 3). Additionally,12 pts had PIK3CA mutations, and 2 pts had AKT1 mutations. In the RIB group, 5 and 2 pts, respectively, had a PIK3CA- and AKT-mutated MBC, while no ESR1 mutations were detected. When comparing matched pairs of variations, it was found that at BL, at first radiological restaging (T1), and at 6 mos. after initiation of CDK4/6i (T2), only PAL showed significantly higher levels of promoter A and B methylation (promA and promB) at T1 (P = 0.0005 and P = 0.0056, respectively for promA and promB), A significant decrease in promA and promB levels was detected at T2 for PAL (P = 0.0005 and P &amp;lt; 0.0001 respectively for promA and promB) but not for RIB. Both PAL and RIB demonstrated a significant decrease in ctDNA short fragments at T1 (P = 0.0263 for PAL and P = 0.0001 for RIB), However, PAL showed a significant rebound at T2, with an increase in 80% of samples (P = 0.0014). The same was not seen with RIB. After a median follow-up of 34.8 mos., there were no significant differences between PAL and RIB in terms of PFS (P= 0.2573) and OS (P= 0.3783). The PFS rates at 12 and 24 mos. were 69% and 48% for PAL, and 76% and 64% for RIB. The OS rates at 12 and 24 mos. were 94% and 84% for PAL, compared to 97% and 82% of RIB, respectively. Conclusions This analysis of MAGNETIC.1 highlighted significant differences in ctDNA biomarkers between palbociclib and ribociclib, suggesting their potential impact on the development of endocrine resistance. Further biomarker-driven clinical trials leveraging this concept are needed to refine the sequencing algorithms for CDK4/6i. Citation Format: Claudia Noto, Linda Cucciniello, Elisabetta Molteni, Silvia Bolzonello, Alessandra Franzoni, Lucia Da Ros, Silvia Buriolla, Arianna Dri, Lorenzo Foffano, Simon Spazzapan, Stefania Russo, Brenno Pastò, Giulia Cudia, Giada Targato, Serena Della Rossa, Marta Bonotto, Alessandro Marco Minisini, Giuseppe Damante, Barbara Belletti, Lorenzo Gerratana, Fabio Puglisi. Differential dynamics of fragmentomic and epigenetic circulating tumor DNA (ctDNA) features in first-line Palbociclib and Ribociclib treatment for Hormone Receptor (HR) positive, HER2 negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-07.

Abstract PS05-07: Early prediction of response to Neoadjuvant Immunotherapy in Triple Negative Breast Cancer (TNBC) with DCE-MRI

Abstract Purpose: Neoadjuvant immunotherapy (NIT) in combination with neoadjuvant chemotherapy (NCT) was recently approved for treatment of TNBC patients with increased rates of pathologic complete response (pCR) compared to NCT alone. The aim of this study was to evaluate if dynamic contrast-enhanced (DCE)-MRI performed after 2 and/or 4 cycles of NIT + NCT, can predict which patients will achieve pCR, potentially triaging them to continuation of NIT+NCT or, when appropriate, to de-escalation trials. Alternatively, identified chemoresistant tumors who are unlikely to achieve pCR may be directed to other treatment strategies, including novel targeted trials, and avoid the unnecessary toxicity of NIT. Methods and Materials: Preliminary analysis included 64 patients from prospective IRB-approved study (NCT02276443) with stage I-III TNBC who underwent DCE-MRI at baseline (BL), after 2 cycles (C2), and 4 cycles (C4) of NIT combined with standard of care NCT (Paclitaxel +/- carboplatin). Tumor volumes were calculated using 3 axis measurements of the index lesion at the DCE MRI and percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. pCR was assessed at surgery after completion of neoadjuvant treatment. Correlation between pCR and TVR was evaluated using ROC analysis. Results: 59% (38/64) of TNBC patients achieved pCR after NIT+NCT. DCE-MRI after 2 cycles of NIT+NCT was able to predict pCR with an AUC of 0.71 (95% CI: 0.57-0.84). TVR &amp;gt;90% at C2 predicted pCR with PPV 86%, and TVR &amp;lt; 35% predicted chemoresistance with NPV 100%. Following 4 cycles of treatment DCE-MRI was able to predict pCR with an AUC of 0.81 (95% CI: 0.69-0.92). TVR &amp;gt;95% at C4 was predictive of chemosensitivity with PPV 82%, while TVR &amp;lt; 75% was predictive of chemoresistance with NPV 100%. Conclusions: DCE-MRI volumetric changes early during NIT + NCT were able to predict pCR status of TNBC patients as either excellent responders or nonresponders, triaging them to SOC neoadjuvant therapy with option for de-escalation trials, or targeted therapies, respectively. These preliminary results will be validated in the larger cohort after completion of the ongoing prospective clinical trial. Citation Format: Gaiane Rauch, Mary Guirguis, Miral Patel, Rosalind Candelaria, Rania Mohamed, Tanya Moseley, H. T. Carisa Le-Petross, Jessica Leung, Gary Whitman, Deanna Lane, Marion Scoggins, Frances Perez, Jia Sun, Sanaz Pashapoor, Zhan Xu, Jason White, Peng Wei, Brandy Reed, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Anil Korkut, Lei Huo, Kelly Hunt, Alyson Clayborn, Jennifer Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Wei Yang, Jingfei Ma, Beatriz Adrada. Early prediction of response to Neoadjuvant Immunotherapy in Triple Negative Breast Cancer (TNBC) with DCE-MRI [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-07.

Abstract PO3-25-11: Unprecedented responses to neoadjuvant sequential administration of Tocilizumab followed by cisplatin/docetaxel for locally advanced triple negative breast cancer patients

Abstract Background: Triple negative breast cancer (TNBC) remains a challenge for clinicians due to its aggressive behavior and scarcity of effective treatment. Interleukin 6 (IL-6) is well known to contribute to poor therapeutic gain, tumor relapse and aggressive tumor growth. Here we have explored targeting the IL-6 signaling pathway by Tocilizumab (Actemra) as a new potential therapeutic approach for the treatment of TNBC. Methods: The study population includes thirty (30) patients with (T2-T4, N0-3) stage (IIB-III) TNBC treated uniformly with Tocilizumab followed with cisplatin/docetaxel according to a traditional 3+3 design using a sentinel patient at each cohort. Eligible patients received Tocilizumab on day 1 followed by cisplatin/docetaxel on day 2 every 4 weeks for a total of six cycles. The primary end points were pathological complete response in breast and axilla (pCR) (ypT0/ypN0) and assessment for tolerability/toxicities profiles. Additionally, the status of the BRCA1 and BRCA2 genes was determined in all patients. Results: Eligible patients who were enrolled in this phase I/II trial had a median age of 42 years, with 63% premenopausal and 67% had nodal involvement at base line. The median tumor size was 45 mm (range 25-150 mm), stage III A/B 26% and stage IIIC 50%. Germline BRCA1/2 mutations represented 27%. The overall pCR and (RCB class 0+1) were 66% and 69%, respectively. Interestingly, pCR reached 81% in axilla, and 100% in patients with tumors bearing BRCA1/2 mutations. Interestingly, tocilizumab affected the blood level of several pro-carcinogenic cytokines. Conclusions: To our knowledge this novel therapeutic strategy is the first to report the inhibition of a cytokine signaling (a new class of biological therapy) in combination with chemotherapy for the intricate and hard-to-treat TNBC patients with unprecedented responses and acceptable tolerability/toxicities, which merits further investigation. Pending Patents: US Patent Application No. 18/122,839 European Patent Application No. 23 162 694.6 Citation Format: Taher Al-Tweigeri, Noura Alraouji, Asma Tulbah, Syed Akhtar, Meshari Alzahrani, Saleh Najjar, Dahish Ajarim, Kauser Suleman, Adher Al Sayed, Abdelilah Aboussekhra. Unprecedented responses to neoadjuvant sequential administration of Tocilizumab followed by cisplatin/docetaxel for locally advanced triple negative breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-11.

THE IMPACT OF SOCIOECONOMIC STATUS ON OUTCOMES FROM TREATMENT FOR FEMOROACETABULAR IMPINGEMENT

There is little known about how patient socioeconomic status impacts clinical outcomes in hip preservation surgery. The aim of this study was to evaluate the relationship between indices of multiple deprivation, funding provider (NHS Funded or Private Funded) and clinical outcomes following surgery for femoroacetabular impingement (FAI)The study analysed the data of 5590 patients recorded in the NAHR who underwent primary hip arthroscopic treatment for FAI between November 2013 and July 2023. Records were matched to the UK National index of multiple deprivation using the lower layer super output area. Using iHOT12 score, patient reported outcome measures were analysed at base line and 1 year following surgery.2358 records were matched to LLSOA deciles. Between the lowest (most deprived) 3 deciles and the highest (least deprived) the average baseline iHOT12 score was 28.98 (n=366) and 35.33 (n=821). The proportion of patients receiving treatment through NHS funding compared to independent funding for the most deprived, 292 (90%) 37 (10%) respectively compared to the least deprived 515 (70%) and 244 (30%) respectively. At 1year, iHOT12 scores for each group were 51.64 (29.1 SD) compared to 61.5 (28.06 SD) respectively.The study demonstrates that patients from lower socioeconomic backgrounds had poorer baseline and one-year post-surgery iHOT12 scores compared to those from higher socioeconomic strata. Furthermore, a higher reliance on NHS funding was observed among the most deprived, while more affluent patients predominantly opted for private funding. These findings underscore the significant influence of socioeconomic status on both the quality of healthcare received and recovery outcomes in hip preservation surgery, calling attention to the need for more equitable healthcare solutions.

Changes in physical activity in people with idiopathic pulmonary fibrosis before and after virtual pulmonary rehabilitation: a feasibility study

BackgroundPulmonary rehabilitation (PR) is recommended for the treatment of people with idiopathic pulmonary fibrosis (IPF). Physical activity is an important health behaviour, closely linked to survival in people with IPF. Little is known about the impact of virtual (V) PR on physical activity in people with IPF.ObjectiveTo explore the feasibility of conducting a trial to explore effect of virtual PR on objectively measured physical activity in people with IPF.MethodsAll patients with a diagnosis of IPF in a stable phase of the disease were invited to participate in VPR: a 10 week exercise programme delivered twice-weekly for one hour. Data were collected at baseline (BL) and post VPR (10 weeks): Kings Brief Interstitial Lung Disease (K-BILD), Exercise capacity (6-minute walk test (6MWT) or 1-minute sit-to-stand (STS)) and Physical Activity. Physical activity was measured with a triaxial accelerometer for seven days. Screening, recruitment, adherence and safety data were collected.Results68 people were screened for this study. N = 16 participants were recruited to the study. There was one dropout. N = 15 completed VPR. All results reported in mean (standard deviation) (SD). Participants attended 18.1(2.0) of the 20 sessions. No adverse events were detected. The mean age of participants was 71.5(11.5) years, range: 47–95 years; 7 M:9 F. Mean (SD) FEV1 2.3(0.3)L, FVC 2.8(0.7)L. No statistically significant changes were observed in outcome measures apart from exercise capacity. Light physical activity increased from 152(69.4) minutes per day (n = 16) to 161.9(88.7) minutes per day (n = 14), mean change (SD) (CI) p-value: 9.9 (39.8) [-12.3 to 30.9] p = 0.4. Moderate-to-vigorous physical activity increased from 19.1(18.6) minutes per day (n = 16) to 25.7(28.3) minutes per day (n = 14), mean change (SD) (CI) p-value: 6.7 (15.5) [-2.1 to 15.1] p = 0.1. Step count increased from 3838(2847) steps per day (n = 16) to 4537(3748) steps per day (n = 14), mean change (SD) (CI) p-value: 738 (1916) [-419.3 to 1734.6] p = 0.2. K-BILD (n = 15) increased from 55.1(7.4) at BL to 55.7(7.9) post VPR mean change (SD) [95% confidence interval] (CI) p-value: 1.7(6.5) [-1.7 to 5.3], p = 0.3. 6MWT (n = 5) increased from 361.5(127.1) to 452.2(136.1) meters, mean change (SD) (CI) p-value: 63.7 (48.2) [-3.8 to 123.6], p = 0.04 and 1-minute STS increased from 17.6(3.0) (n = 11) to 23.7(6.3) (n = 10), mean change (SD) (CI) p-value 5.8 (4.6) [2.6 to 9.1], p = 0.003.ConclusionVPR can improve physical activity in people with IPF. A number of important feasibility issues included recruitment, retention, adherence and safety have been reported which are crucial for future research in this area. A fully powered trial is needed to determine the response of people with IPF to PR with regard to physical activity.

Central α2-adrenergic mechanisms differentially affect baroreflex control of sympathetic and cardiovagal outflow

This study aimed to investigate the impact of central α2-adrenergic mechanisms on arterial baroreflex control of sympathetic and cardiovagal outflow in healthy humans. R-R interval (ECG), blood pressure (brachial arterial catheter), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured in eight healthy participants (5 females; 28±7 years). Sympathetic action potentials (AP) were extracted from the filtered MSNA neurogram (continuous wavelet transform) during a 5-minute baseline (BSL) and an intravenous dexmedetomidine infusion consisting of a loading dose (LD; 10 minutes at 0.225 μg/kg/hr) and a maintenance dose (MD; ~0.15 μg/kg/hr). Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and diastolic blood pressure. The linear relationship between R-R interval and systolic blood pressure (sequence technique) quantified cardiovagal baroreflex gain. Mixed-effects analyses and post-hoc t-tests were performed. Data are reported as mean ± SD. Dexmedetomidine reset the baroreflex threshold operating points for all sympathetic AP clusters downwards to lower firing probabilities (cluster 4; BSL: 20±6, LD: 13±8, MD: 6±5%, both p&lt;0.01 vs. BSL) and leftwards to lower diastolic pressures (BSL: 72±9, LD: 69±8, MD: 65±10 mmHg, both p&lt;0.01 vs. BSL). Dexmedetomidine reduced baroreflex threshold gain for the subpopulation of medium-sized sympathetic APs (cluster 4; BSL: -6.5±2.0, LD: -2.6±1.6, MD: -2.0±0.7 %/mmHg, both p&lt;0.01 vs. BSL). Dexmedetomidine did not affect baroreflex threshold gain of small (cluster 1; BSL: -1.9±1.1, LD: -1.3±1.6, MD: -1.1±0.8 %/mmHg, both P&gt;0.88 vs. BSL) or large AP clusters (cluster 9; BSL: -0.8±0.4, LD: -0.8±1.0, MD: -0.2±0.7 %/mmHg, both P&gt;0.98 vs. BSL). Dexmedetomidine reset the cardiovagal baroreflex to lower systolic pressures but did not affect R-R interval (BSL: 1035±261, LD: 1025±308, MD: 1005±292ms, Main effect P=0.45) or gain (BSL: 24±11, LD: 30±20, MD: 26±25 ms/mmHg, Main effect P=0.63). These findings suggest that central α2-adrenergic mechanisms differentially affect arterial baroreflex control of sympathetic and cardiovagal outflow in humans by minimally affecting cardiovagal baroreflex gain but strongly affecting the baroreflex gain for the subpopulation of medium-sized sympathetic APs. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dose-Response Effects of Short-Term Rhodiola rosea Supplementation on Anaerobic Exercise Performance in Resistance-Trained Athletes: A Randomized, Crossover, Double-Blind, and Placebo-Controlled Study

Background: Rhodiola rosea (RR) has garnered attention for its potential ergogenic effects on athletic performance. The mechanisms underlying these effects are believed to involve improved energy metabolism and reduced exercise-induced oxidative stress. Methods: Twenty-seven resistance-trained individuals (13 males, 14 females; 22±3y; 170.4±10.7cm; 75.4±21.9kg) underwent three conditions in a randomized sequence: a low-dose RR (LD: 200mg/d of RR combined with 1.3g/d of maltodextrin), a high-dose RR (HD: 1.5g/d of RR), and a placebo (PL: 1.5g/d of maltodextrin), following an initial baseline (BL) assessment. Participants took supplements for seven days and a 7-day washout before transitioning to the subsequent conditions. Data were analyzed using a two-way (within-within) analysis of variance (p≤0.05) with LSD's post hoc when appropriate. Results: Participants' strength was evaluated using the one repetition maximum (1RM) test at BL and after each treatment phase. In the bench press, both RR doses exhibited significant enhancements compared to BL and PL, with weights being BL (69.6±39.7kg), PL (69.8±39.1kg), LD (72.2±41.1kg), and HD (73.4±41.4kg; p=0.001). Similarly, in the leg press, weights for both RR doses showed marked improvements over BL and PL, registering at BL (314.4±113.5kg), PL (326.2±117.0kg), LD (350.1±136.1kg), and HD (362.1±134.6kg; p&lt;0.001). Muscular endurance was further probed, with participants conducting three sets at 60% of their 1RM for both exercises. In the bench press, the HD treatment showed a significant edge over BL and PL, with weights being BL (42.5±22.9kg), PL (43.2±23.0kg), LD (43.8±23.1kg), and HD (44.7±23.6kg; p=0.007). In the leg press, both RR doses outperformed BL and PL, with weights being BL (188.6±68.2kg), PL (195.1±68.6kg), LD (209.1±80.2kg), and HD (218.6±79.1kg; p&lt;0.001). Regarding total lifting volume, both RR doses surpassed the BL measurements, with the HD regimen exceeding the PL. The volumes were BL (9792.7±4962.7kg), PL (11019.6±5389.2kg), LD (11805.1±5086.2kg), and HD (15344.8±10878.1kg; p&lt;0.001). During the bench press evaluations, a significant uptick in mean power was observed post-RR supplementation for both dosages when compared to BL and PL, with power outputs being BL (200.7±124.4W), PL (204.1±124.4W), LD (221.6±139.6W), and HD (230.5±145.9W; p=0.007). However, metrics such as peak power, average velocity, and the outcomes of the Wingate test remained statistically unchanged (p&gt;0.05). CONCLUSION: RR supplementation can enhance anaerobic performance in athletes, especially at higher doses. While it improved strength and endurance, some metrics, like peak power, remained unaffected. Further research is needed to understand RR's benefits fully. This study was self-funded, with the researchers covering all expenses. This approach ensures the research's independence from potential biases associated with external funding or grants. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dose-Response Effects of Short-Term Rhodiola rosea Supplementation on Cognitive Function and Readiness to Perform in Athletes: A Randomized, Crossover, Double-Blind, and Placebo-Controlled Study

Background: Rhodiola rosea (RR) is renowned for its adaptogenic qualities across diverse cultures. Contemporary research delves deeper into its potential neuroprotective capabilities and role in augmenting cognitive functions. Given the imperative nature of peak cognitive performance in athletes, the influence of RR supplementation has emerged as a focal point of scientific inquiry. This study elucidates the dose-response relationship of short-term RR consumption on cognitive prowess in resistance-trained athletes. Methods: Twenty-seven resistance-trained athletes (13 males, 14 females; 22±3 y; 170.4±10.7 cm; 75.4±21.9 kg) completed a baseline (BL) and three distinct conditions in random order: low-dose RR (LD: 200 mg/d of RR combined with 1.3 g/d of maltodextrin), high-dose RR (HD: 1.5 g/d of RR), and a placebo (PL: 1.5 g/d of maltodextrin). Each supplementation phase lasted 7d, separated by a 7-day washout period before commencing the subsequent condition. After the supplementation, participants undertook a Stroop color-word test and completed a readiness to perform using a visual analog scale. Data were analyzed using a two-way (within-within) analysis of variance (p≤0.05) with LSD's post hoc when appropriate. RESULTS: Participants were assessed using the Stroop Word-Color test at BL and following each treatment phase. In the Word section, there was a significant improvement. Post hoc analysis revealed that both RR doses surpassed BL and PL results. The scores were as follows: BL [107.8±10.6 counts (c)], PL (118.4±11.7 c), LD (122.0±15.1 c), and HD (125.2±16.2 c; p&lt;0.001). Participants completed tasks more swiftly in the Color section after taking both RR doses than at BL. The results were: BL (79.3±12.3 c), PL (85.3±10.6 c), LD (88.0±11.1 c), and HD (91±24.8 c; p&lt;0.031). In the Word-Color section, both RR doses led to significant cognitive enhancements, with scores being BL (94.0±18.5 c), PL (104.3±16.2 c), LD (108.9±20.6 c), and HD (113.0±18.3 c; p&lt;0.001). When all domains were summed, a notable enhancement was observed. Subsequent post hoc analysis indicated that both RR dosages exceeded the scores of BL and PL. The respective scores were: BL (281.1±31.1 c), PL (307.9±29.7 c), LD (318.9±36.5 c), and HD (329.6±47.8 c; p&lt;0.001). No significant alterations were noted in readiness (p&gt;0.05). CONCLUSION: This study underscores RR as a potential cognitive enhancer for athletes. Both the low and high doses of RR yielded significant benefits in the Stroop Word-Color test, suggesting a dose-responsive relationship. However, RR did not influence the athletes' sense of readiness. While the findings are promising, further research is essential to determine RR's comprehensive effects and ideal dosing. The researchers personally financed this study, bearing all costs. Such a method guarantees the research's autonomy, free from potential influences that might come with external financial support or grants. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Seizures and Post-Ictal Respiratory Recovery in Kcnj16−/− Sprague-Dawley Rats

Epilepsy is a common neurological disorder (3.5 million in the US), of which ~1/3 continue to experience repeated seizures failing to benefit from anti-seizure medication. Poor seizure control puts patients with drug-resistant epilepsies at increased risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is thought to result from severe post-ictal cardiorespiratory suppression. We’ve previously shown that Salt-Sensitive (SS) rats lacking 18 base pairs in the Kcnj16 gene (SS Kcnj16−/−), corresponding to a 6 amino acid (AA163-168) deletion in the second TM domain of Kir5.1, are susceptible to audiogenic seizures. Repeated seizures (1/day for 10 days) in this rat model resulted in ictal apnea, post-ictal respiratory suppression, diminished chemoreflexes, and high spontaneous mortality (PMID: 33232300). Here we generated additional Kcnj16−/− mutants on the outbred Sprague Dawley (SD Kcnj16−/−) genetic background to test the hypothesis that Kcnj16 mutations (T64I substitution; AA64-68 deletion (M7), and AA64-81 deletion (M8)) in the first TM domain of Kir5.1 causes: 1) audiogenic seizures, 2) progressive exacerbation of post-ictal ventilatory dysfunction, and 3) seizure-induced mortality. Ventilation (whole-body plethysmography) and seizure severity (Racine Score; HD video) were measured in male and female SD Kcnj16−/− rats for 20 minutes (min; baseline (BL)) before exposure to an auditory stimulus (2 min) and for 20 min of recovery. Mixed frequency white noise (WN) or a 10 kHz tone (85-95 dB) reproducibly elicited generalized tonic-clonic seizures (GTCSs) in all three SD mutants (T64I, M7, and M8). In SD Kcnj16−/− rats (T64I n=2, M7 n=3, M8 n=7, wild type n=2), 1 seizure/day for 10 days led to ictal apneas and transient post-ictal respiratory changes along with increases in body temperature (+1°C) following seizures, where breath frequency initially decreased (-25% of BL) before increasing (+40%) at 5 min post-stimulus and normalizing by 20 min. Tidal volume increased ~+80% from BL in the first 5 min and returned to BL by 20 min post-ictal. Minute ventilation was decreased (-10%) from BL within 1 min, increased to +60% by 5 minutes and returned to BL within 20 min post-stimulus. In contrast to previous SS Kcnj16−/− rat data, SD Kcnj16−/− rat post-ictal breathing patterns were unchanged across the 10-day seizure protocol, and we observed 100% survival. Our preliminary data suggests that Kcnj16 mutations at multiple sites can elicit the audiogenic seizure phenotype, but that SD Kcnj16−/− mutant rats appear resistant to repeated seizure-induced post-ictal ventilatory dysfunction and mortality — i.e. a potentially useful SUDEP-resistant model of repeated seizures. Funded by NIH HL122358. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glomerular Hyperfiltration and Th17 Responses Promote Glomerulosclerosis Following Nephron Loss

Objective: Chronic kidney disease (CKD) affects 37 million Americans resulting in $87 billion healthcare cost annually. Impaired renal autoregulation in obesity, diabetes and hypertension causes elevated glomerular capillary pressure and whole-kidney hyperfiltration, leading to progressive glomerulosclerosis and CKD. In advanced CKD with less than 50% functional nephron mass, single-nephron hyperfiltration causes further nephron loss, ultimately leading to hypofiltration and end-state kidney disease. Increased renal perfusion pressure directly drives T cell infiltration to the kidney. We and others have shown that T helper (Th) 17 cells promote vascular stiffening in hypertension and renal interstitial fibrosis after ischemia-reperfusion injury, but their roles in glomerulosclerosis and CKD are poorly understood. We hypothesized that glomerular hypertension and hyperfiltration promote renal fibrosis through Th17-mediated immune responses. Methods: We investigated the causal roles of glomerular hyperfiltration and Th17 responses in a mouse CKD model induced by reduced kidney mass (RKM), which involved right kidney nephrectomy and partial renal artery ligation in the left kidney such that the functional renal mass is reduced by ~ 5/6. Male 129/S6 mice received sham or RKM surgery at 8 weeks of age, and blood pressure (BP, by radiotelemetry), glomerular filtration rate (GFR, by transcutaneous FITC-sinistrin) and serum/urine CKD markers were assessed at baseline (BL) and week 1, 2, 3, 4, 8, and 12 post-surgery. Results: BP and GFR of RKM mice were identical to sham controls at BL (n=4-6). Immediately after the RKM procedure, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. BP increased by 29 mmHg first week after 5/6 ablation (144 ± 8 vs BL 112 ± 2 mmHg, p&lt;0.05, 2-way ANOVA), exposing the remnant nephrons to increased renal perfusion pressure. Serum creatinine, blood urea nitrogen and urinary albumin were significantly elevated by week 2. BP and CKD markers remained elevated through week 12 in the 5/6 ablation mice. The GFR of ablated mice gradually increased to 38% of BL at day 3, 57% at week 1 and 68% at week 2, suggesting that systemic hypertension and impaired renal autoregulation may have caused substantial single-nephron hyperfiltration in the remnant kidney mass. GFR plateaued at ~ 70% of BL in week 3-4 then declined to 48% at week 8-12 when glomerular, interstitial, and microvascular fibrosis developed as evidence by Periodic Acid Schiff and Picro Sirius Red staining. Supporting a causal role of hemodynamic derangements in CKD progression, calcium channel blocker amlodipine, a potent vasodilator, dose dependently (5-10 mg/kg/day, n=7-9) exacerbated glomerular hyperfiltration, glomerulosclerosis and mortality despite marked BP-lowering effects. Importantly, the adaptive increase of GFR in the first 2 weeks post 5/6 ablation was accompanied by significant increase of renal Th17 cells, which not only preceded the infiltration of CD11b+ myeloid cells, F4/80+ monocyte/macrophages and T regulatory cells, but also the glomerulosclerosis and GFR decline in week 8. Conclusions: Our data suggest that glomerular hyperfiltration causes progressive nephron loss and kidney fibrosis, at least in part, through Th17-mediated renal inflammation. To further establish causality, ongoing studies will assess if Th17 blockade ameliorates glomerulosclerosis and retard CKD progression. Funding: This work was supported by NIDDK R01 DK094907, R01 DK113632, R01 DK128677 to THL, and K01 DK126972 to JW. JW is also supported by an American Heart Association Second Century Early Faculty Independence Award (23SCEFIA1148464), a University of Rochester Environmental Health Science Center pilot award (Prime sponsor: NIEHS P30ES001247), and a University of Rochester Program for Advanced Immune Bioimaging Pilot Award (Prime Sponsor: NIAID P01AI102851). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Towards a Framework for Performance Management and Machine Learning in a Higher Education Institution

Towards a Framework for Performance Management and Machine Learning in a Higher Education Institution