julilili42/papers huggingface dataset:
Prospective intraindividual comparison of a standard 2D TSE MRI protocol for ankle imaging and a deep learning-based 2D TSE MRI protocol with a scan time reduction of 48%
2023-02-19

Abstract Purpose Magnetic resonance imaging (MRI) scan time remains a limited and valuable resource. This study evaluates the diagnostic performance of a deep learning (DL)-based accelerated TSE study protocol compared to a standard TSE study protocol in ankle MRI. Material and methods Between October 2020 and July 2021 forty-seven patients were enrolled in this study for an intraindividual comparison of a standard TSE study protocol and a DL TSE study protocol either on a 1.5 T or a 3 T scanner. Two radiologists evaluated the examinations regarding structural pathologies and image quality categories (5-point-Likert-scale; 1 = “non diagnostic”, 5 = “excellent”). Results Both readers showed almost perfect/perfect agreement of DL TSE with standard TSE in all analyzed structural pathologies (0.81–1.00) with a median “good” or “excellent” rating (4–5/5) in all image quality categories in both 1.5 T and 3 T MRI. The reduction of total acquisition time of DL TSE compared to standard TSE was 49% in 1.5 T and 48% in 3 T MRI to a total acquisition time of 5 min 41 s and 5 min 46 s. Conclusion In ankle MRI the new DL-based accelerated TSE study protocol delivers high agreement with standard TSE and high image quality, while reducing the acquisition time by 48%.
Precise and efficient C-to-U RNA Base Editing with SNAP-CDAR-S
2023-02-19

Abstract Site-directed RNA base editing enables the transient and dosable change of genetic information and represents a recent strategy to manipulate cellular processes, paving ways to novel therapeutic modalities. While tools to introduce adenosine-to-inosine changes have been explored quite intensively, the engineering of precise and programmable tools for cytidine-to-uridine editing is somewhat lacking behind. Here we demonstrate that the cytidine deaminase domain evolved from the ADAR2 adenosine deaminase, taken from the RESCUE-S tool, provides very efficient and highly programmable editing when changing the RNA targeting mechanism from Cas13-based to SNAP-tag-based. Optimization of the guide RNA chemistry further allowed to dramatically improve editing yields in the difficult-to-edit 5’-C C N sequence context thus improving the substrate scope of the tool. Regarding editing efficiency, SNAP-CDAR-S outcompeted the RESCUE-S tool clearly on all tested targets, and was highly superior in perturbing the β-catenin pathway. NGS analysis showed similar, moderate global off-target A-to-I and C-to-U editing for both tools.
Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial.
2023-02-20

603 Background: First-line nivolumab plus cabozantinib (N+C) demonstrated superiority over sunitinib (S) with 25.4 mo minimum follow-up (median, 32.9 mo) in patients (pts) with aRCC in the CheckMate 9ER trial. Here, we report survival, response per blinded independent central review (BICR), and safety after 3 y minimum follow-up in all randomized pts and by IMDC risk score. Methods: Pts were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, region) to N 240 mg flat dose IV Q2W + C 40 mg PO QD vs SUN 50 mg PO for 4 wk (6-wk cycles) until disease progression or unacceptable toxicity (max N treatment, 2 y). Primary endpoint: progression-free survival (PFS) by BICR. Secondary endpoints: overall survival (OS), objective response rate (ORR) by BICR, and safety. Results: In total, 323 pts were randomized to N+C and 328 to S. With 36.5 mo minimum follow-up (median, 44.0 mo), PFS and OS benefits were maintained with N+C vs S in intent-to-treat pts. Median PFS was 16.6 vs 8.4 mo (HR 0.59 [95% CI 0.49–0.71], P &lt; 0.0001) and median OS was 49.5 vs 35.5 mo (HR 0.70 [95% CI 0.56–0.87], P = 0.0014). ORR (95% CI) was higher with N+C vs S (56% [50–62] vs 28% [23–33]), and 13% vs 5% of pts achieved complete response (CR), respectively. Median duration of response was 22.1 vs 16.1 mo for N+C vs S. PFS, OS, and response are reported across prespecified IMDC risk groups in the table. Any-grade treatment-related adverse events (TRAEs) occurred in 97% vs 93% of pts treated with N+C vs S (grade ≥ 3 TRAE, 67% vs 55%). TRAEs led to discontinuation of C only in 10% of pts, N only in 10% of pts, N+C in 7% of pts, N or C in 28% of pts, and S in 11% of pts. Conclusions: After 3 y minimum follow-up, survival and response benefits were maintained with N+C and remained consistent with previous follow-ups. Median OS with N+C improved by 11.8 mo since the previous data cut. Responses with N+C were durable, with higher CR rates with N+C vs S regardless of IMDC risk group. No new safety signals emerged with additional follow-up in either arm. These results continue to support N+C as a first-line treatment for pts with aRCC. Clinical trial information: NCT03141177 . [Table: see text]
Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD
2023-02-20

Effective therapies are urgently needed to safely target TDP-43 pathology as it is closely associated with the onset and development of devastating diseases such as frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 pathology is present as a co-pathology in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Our approach is to develop a TDP-43-specific immunotherapy that exploits Fc gamma-mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP-43 function. Thus, using both in vitro mechanistic studies in conjunction with the rNLS8 and CamKIIa inoculation mouse models of TDP-43 proteinopathy, we identified the key targeting domain in TDP-43 to accomplish these therapeutic objectives. Targeting the C-terminal domain of TDP-43 but not the RNA recognition motifs (RRM) reduces TDP-43 pathology and avoids neuronal loss in vivo. We demonstrate that this rescue is dependent on Fc receptor-mediated immune complex uptake by microglia. Furthermore, monoclonal antibody (mAb) treatment enhances phagocytic capacity of ALS patient-derived microglia, providing a mechanism to restore the compromised phagocytic function in ALS and FTD patients. Importantly, these beneficial effects are achieved while preserving physiological TDP-43 activity. Our findings demonstrate that a mAb targeting the C-terminal domain of TDP-43 limits pathology and neurotoxicity, enabling clearance of misfolded TDP-43 through microglia engagement, and supporting the clinical strategy to target TDP-43 by immunotherapy. SIGNIFICANCE STATEMENT: TDP-43 pathology is associated with various devastating neurodegenerative disorders with high unmet medical needs such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Thus, safely and effectively targeting pathological TDP-43 represents a key paradigm for biotechnical research as currently there is little in clinical development. After years of research, we have determined that targeting the C-terminal domain of TDP-43 rescues multiple patho-mechanisms involved in disease progression in two animal models of FTD/ALS. In parallel, importantly, our studies establish that this approach does not alter the physiological functions of this ubiquitously expressed and indispensable protein. Together, our findings substantially contribute to the understanding of TDP-43 pathobiology and support the prioritization for clinical testing of immunotherapy approaches targeting TDP-43.
Phase 3 KEYNOTE-905/EV-303: Perioperative pembrolizumab (pembro) or pembro + enfortumab vedotin (EV) for muscle-invasive bladder cancer (MIBC).
2023-02-20

TPS585 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC + PLND). However, a substantial proportion of patients (pts) with MIBC are ineligible to receive cisplatin-based chemotherapy. In the phase 1b/2 KEYNOTE-869/EV-103 study, promising antitumor activity was shown in cisplatin-ineligible pts with metastatic urothelial carcinoma treated with the PD-1 inhibitor pembro combined with the nectin-4–directed antibody-drug conjugate EV. This multicenter, open-label, randomized, phase 3 KEYNOTE-905/EV-303 study (NCT03924895) is designed to evaluate the efficacy and safety of perioperative pembro alone or in combination with EV compared with RC + PLND alone in pts with MIBC who are ineligible for or decline cisplatin-based treatment. Methods: Approximately 857 adults who are cisplatin ineligible or decline cisplatin-based treatment with treatment-naive MIBC (T2-T4aN0M0 or T1-T4aN1M0), have an Eastern Cooperative Oncology Group performance status score of 0-2, and have a predominant (≥50%) urothelial histology will be randomly assigned to arm A (neoadjuvant pembro 200 mg intravenously [IV] every 3 weeks [Q3W] up to 3 cycles followed by RC + PLND and adjuvant pembro 200 mg IV Q3W up to 14 cycles), arm B (RC + PLND followed by observation), or arm C (neoadjuvant EV 1.25 mg/kg + pembro 200 mg IV Q3W up to 3 cycles followed by RC + PLND and adjuvant EV + pembro up to 6 cycles and adjuvant pembro 200 mg IV Q3W up to 8 cycles). In both the neoadjuvant and adjuvant phases of arm C, pembro will be administered on day 1 and EV will be administered on days 1 and 8 of each cycle. Dual primary end points are pathologic complete response as assessed by central pathologic review and event-free survival. Secondary end points include overall survival, disease-free survival, pathologic downstaging rates, and safety and tolerability. Enrollment is ongoing in Africa, Asia, Europe, and North America. Clinical trial information: NCT03924895 .
EEG and pupillometric signatures of working memory overload
2023-02-20

Abstract Understanding the physiological correlates of cognitive overload has implications for gauging the limits of human cognition, developing novel methods to define cognitive overload, and mitigating the negative outcomes associated with overload. Most previous psychophysiological studies manipulated verbal working memory load in a narrow range (an average load of 5 items). It is unclear, however, how the nervous system responds to a working memory load exceeding typical capacity limits. The objective of the current study was to characterize the central and autonomic nervous system changes associated with memory overload, by means of combined recording of electroencephalogram (EEG) and pupillometry. Eighty‐six participants were presented with a digit span task involving the serial auditory presentation of items. Each trial consisted of sequences of either 5, 9, or 13 digits, each separated by 2 s. Both theta activity and pupil size, after the initial rise, expressed a pattern of a short plateau and a decrease with reaching the state of memory overload, indicating that pupil size and theta possibly have similar neural mechanisms. Based on the described above triphasic pattern of pupil size temporal dynamics, we concluded that cognitive overload causes physiological systems to reset, and release effort. Although memory capacity limits were exceeded and effort was released (as indicated by pupil dilation), alpha continued to decrease with increasing memory load. These results suggest that associating alpha with the focus of attention and distractor suppression is not warranted.
CaboPoint: Interim results from a phase 2 study of cabozantinib after checkpoint inhibitor (CPI) therapy in patients with advanced renal cell carcinoma (RCC).
2023-02-20

606 Background: First line CPI-based therapy is the standard of care for advanced RCC. There is a lack of prospective data for cabozantinib after 1L CPI regimens, which is addressed in this study. Methods: CaboPoint (ClinicalTrials.gov identifier: NCT03945773) is an ongoing Phase 2, multicenter, open-label study of cabozantinib in adults with unresectable, locally advanced, or metastatic clear cell RCC who have progressed after 1L CPI-based therapy. Prior treatment with cabozantinib was not permitted. Patients received cabozantinib in two independent cohorts (cohort A [post nivolumab + ipilimumab] and cohort B [post CPI + vascular endothelial growth factor targeted therapy]). Both cohorts received cabozantinib (60 mg/day as starting dose) until study end (18 months after last patient’s enrollment). The primary endpoint was objective response rate (ORR) in Cohort A per RECIST 1.1 evaluated by independent central review; ORR by investigator review has been included as a secondary endpoint for both cohorts. Here we report results from the pre-planned interim analysis of ORR based on investigator assessment in both cohorts that occurred when 80% of patients in cohort A reached at least 3 months of treatment. Results: At the time of this interim analysis, 88 patients had 3 months of follow up (60 in cohort A and 28 in cohort B). Baseline characteristics were similar across cohorts. Patients had an Eastern Cooperative Oncology Group status of 0 (55.0% / 60.7%) and an intermediate or poor International Metastatic RCC Database Consortium risk (46.3% and 13.0% / 40.7% and 11.1%). The most common prior treatment in cohort B was pembrolizumab + axitinib (71.4%), followed by avelumab + axitinib (28.6%). ORR and best overall response at three months of follow-up as assessed by the Investigator are shown in the table. Conclusions: In this interim analysis, cabozantinib demonstrated preliminary efficacy in patients with advanced RCC after progression on CPI-based combination therapy, irrespective of 1L regimen. The CaboPoint trial is ongoing, with the final analysis anticipated in September 2023. Clinical trial information: NCT03945773 . [Table: see text]
Nivolumab plus ipilimumab for the treatment of post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC): Additional results from the randomized phase 2 CheckMate 650 trial.
2023-02-20

22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 trial, nivolumab (NIVO) 1 mg/kg (N1) plus ipilimumab (IPI) 3 mg/kg (I3) Q3W × 4 doses showed clinical activity in patients (pts) with post-chemotherapy (post-CT) mCRPC, particularly those with high tumor mutational burden (TMB), but early toxicity contributed to treatment discontinuations. Here, we report results from pts with post-CT mCRPC receiving alternative NIVO+IPI dosing regimens vs IPI alone vs cabazitaxel (CABA) in CheckMate 650. Methods: Newly enrolled pts previously treated with docetaxel for mCRPC were randomized 2:2:1:2 to cohorts D1 (NIVO 3 mg/kg [N3] + IPI 1 mg/kg [I1] Q3W × 4 doses then NIVO 480 mg Q4W), D2 (N1 Q3W × 8 doses + I3 Q6W × 4 doses then NIVO 480 mg Q4W), D3 (I3 Q3W × 4 doses), or D4 (CABA 20 or 25 mg/m 2 Q3W + prednisone 10 mg × 10 doses). Crossover from cohorts D3 and D4 to cohort D1 was allowed after radiographic progressive disease. Outcomes included safety, objective response rate (ORR), prostate-specific antigen response rate (PSA-RR; confirmed PSA decline ≥ 50% from baseline), radiographic progression-free survival (rPFS) per blinded independent central review (BICR), and overall survival (OS). Associations between efficacy and TMB were assessed. Results: Overall, 259 pts were randomized (D1, n = 73; D2, n = 74; D3, n = 38; D4, n = 74). Median (range) follow-up for OS was 23.3 (6.0–31.5) months. In the NIVO+IPI cohorts (D1 and D2), median duration of therapy was 2.8 and 2.4 months; the median number of IPI doses received was 4 and 2, and 15% and 26% of pts discontinued due to study drug toxicity, respectively. Two pts died due to study drug toxicity (1 each in cohorts D1 and D2). Key safety and efficacy data are shown. Several pts in cohorts D1 and D2 showed notable reductions (75-100%) in tumor size and PSA. Approximately one-third of pts in cohorts D3 and D4 crossed over to D1. Based on preliminary analyses in small numbers of evaluable pts, there was no clear and consistent association between efficacy and tissue or blood TMB in the NIVO+IPI cohorts (D1 and D2). Conclusions: These results further support the clinical activity of NIVO+IPI in select pts with post-CT mCRPC. Detailed evaluations of the characteristics of responders to NIVO+IPI, including more expansive biomarker analyses, are warranted. Clinical trial information: NCT02985957 . [Table: see text]
Physiologically based pharmacokinetic modeling of tacrolimus for food–drug and CYP3A drug–drug–gene interaction predictions
2023-02-20

Abstract The immunosuppressant and narrow therapeutic index drug tacrolimus is metabolized mainly via cytochrome P450 (CYP) 3A4 and CYP3A5. For its pharmacokinetics (PK), high inter‐ and intra‐individual variability can be observed. Underlying causes include the effect of food intake on tacrolimus absorption as well as genetic polymorphism in the CYP3A5 gene. Furthermore, tacrolimus is highly susceptible to drug–drug interactions, acting as a victim drug when coadministered with CYP3A perpetrators. This work describes the development of a whole‐body physiologically based pharmacokinetic model for tacrolimus as well as its application for investigation and prediction of (i) the impact of food intake on tacrolimus PK (food–drug interactions [FDIs]) and (ii) drug–drug(−gene) interactions (DD[G]Is) involving the CYP3A perpetrator drugs voriconazole, itraconazole, and rifampicin. The model was built in PK‐Sim® Version 10 using a total of 37 whole blood concentration–time profiles of tacrolimus (training and test) compiled from 911 healthy individuals covering the administration of tacrolimus as intravenous infusions as well as immediate‐release and extended‐release capsules. Metabolism was incorporated via CYP3A4 and CYP3A5, with varying activities implemented for different CYP3A5 genotypes and study populations. The good predictive model performance is demonstrated for the examined food effect studies with 6/6 predicted FDI area under the curve determined between first and last concentration measurements (AUC last ) and 6/6 predicted FDI maximum whole blood concentration (C max ) ratios within twofold of the respective observed ratios. In addition, 7/7 predicted DD(G)I AUC last and 6/7 predicted DD(G)I C max ratios were within twofold of their observed values. Potential applications of the final model include model‐informed drug discovery and development or the support of model‐informed precision dosing.
Perioperative enfortumab vedotin (EV) plus pembrolizumab (pembro) versus chemotherapy in cisplatin-eligible patients (pts) with muscle-invasive bladder cancer (MIBC): Phase 3 KEYNOTE-B15/EV-304.
2023-02-20

TPS588 Background: Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC+PLND) is the standard of care for cisplatin-eligible pts with MIBC; however, up to 50% of pts will experience disease recurrence or progression following treatment. Pembro and EV monotherapies are approved for use in select pts with metastatic urothelial carcinoma (mUC). Furthermore, results of the phase 1/2 KEYNOTE-869/EV-103 study showed encouraging antitumor activity and an acceptable safety profile with first-line combination therapy EV + pembro in cisplatin-ineligible pts with mUC. The open-label, multicenter, phase 3, randomized KEYNOTE-B15/EV-304 study (NCT04700124) will compare the efficacy and safety of perioperative EV + pembro versus neoadjuvant cisplatin-based chemotherapy in cisplatin-eligible pts with MIBC. Methods: Eligible pts will have histologically confirmed UC/MIBC (T2-T4aN0M0 or T1-T4aN1M0) with predominant urothelial histology (≥50%), nonmetastatic disease (N≤1, M0) confirmed by blinded independent central review (BICR), ECOG performance status of 0-1, no prior systemic therapy for MIBC, and agree to undergo curative RC+PLND. Approximately 784 pts will be randomly assigned 1:1 to Arm A (4 cycles of neoadjuvant EV + pembro, followed by RC+PLND, followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembro) or Arm B (4 cycles of neoadjuvant chemotherapy [gemcitabine + cisplatin] followed by RC+PLND, followed by observation). Neoadjuvant and adjuvant pembro 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W) on day 1 (pembro + EV) and day 8 (EV) of each cycle. Neoadjuvant chemotherapy is gemcitabine 1000 mg/m 2 + cisplatin 70 mg/m 2 Q3W on day 1 (gemcitabine + cisplatin) and day 8 (gemcitabine) of each cycle. Stratification factors are disease stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), PD-L1 combined positive score (≥10 vs &lt;10), and geographic region (United States vs European Union vs most of the world). Imaging by CT (preferred) or MRI will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. Imaging will occur following cystectomy then Q12W through year 2 and at discontinuation, then Q24W in year 3 and beyond. Adverse events (AEs) will be monitored throughout the study and for 30 days following cessation of treatment (90 days for serious AEs). The primary end points are pathologic complete response rate and event-free survival by BICR. Secondary end points are OS, DFS, pathologic downstaging rate, safety and tolerability, and patient-reported outcomes. KEYNOTE-B15/EV-304 is enrolling in Africa, Asia, Australia, Europe, and North America. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT04700124 .
Radiographic, Biomechanical and Histological Characterization of Femoral Fracture Healing in Aged CD-1 Mice
2023-02-20

With a gradually increasing elderly population, the treatment of geriatric patients represents a major challenge for trauma and reconstructive surgery. Although, it is well established that aging affects bone metabolism, it is still controversial if aging impairs bone healing. Accordingly, we investigated fracture healing in young adult (3–4 months) and aged (16–18 months) CD-1 mice using a stable closed femoral fracture model. Bone healing was analyzed by radiographic, biomechanical and histological analysis at 1, 2, 3, 4 and 5 weeks after fracture. Our results demonstrated an increased callus diameter to femoral diameter ratio in aged animals at later time points of fracture healing when compared to young adult mice. Moreover, our biomechanical analysis revealed a significantly decreased bending stiffness at 3 and 4 weeks after fracture in aged animals. In contrast, at 5 weeks after fracture, the analysis showed no significant difference in bending stiffness between the two study groups. Additional histological analysis showed a delayed endochondral ossification in aged animals as well as a higher amounts of fibrous tissue at early healing time points. These findings indicate a delayed process of callus remodeling in aged CD-1 mice, resulting in a delayed fracture healing when compared to young adult animals. However, the overall healing capacity of the fractured femora was not affected by aging.