Citations

Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

Abstract Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

Background and Objectives: Mitigating post-operative complications is a key metric of success following interbody fusion. LLIF is associated with a unique complication profile when compared to other approaches, and while numerous studies have attempted to report the incidence of post-operative complications, there is currently no consensus regarding their definitions or reporting structure. The aim of this study was to standardize the classification of complications specific to lateral lumbar interbody fusion (LLIF). Materials and Methods: A search algorithm was employed to identify all the articles that described complications following LLIF. A modified Delphi technique was then used to perform three rounds of consensus among twenty-six anonymized experts across seven countries. Published complications were classified as major, minor, or non-complications using a 60% agreement threshold for consensus. Results: A total of 23 articles were extracted, describing 52 individual complications associated with LLIF. In Round 1, forty-one of the fifty-two events were identified as a complication, while seven were considered to be approach-related occurrences. In Round 2, 36 of the 41 events with complication consensus were classified as major or minor. In Round 3, forty-nine of the fifty-two events were ultimately classified into major or minor complications with consensus, while three events remained without agreement. Vascular injuries, long-term neurologic deficits, and return to the operating room for various etiologies were identified as important consensus complications following LLIF. Non-union did not reach significance and was not classified as a complication. Conclusions: These data provide the first, systematic classification scheme of complications following LLIF. These findings may improve the consistency in the future reporting and analysis of surgical outcomes following LLIF.

TPS7587 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of MCL, but these agents are not curative. cBTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life), which collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL, which can manifest as acquired resistance to BTKi. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates and was well tolerated in patients (pts) with MCL regardless of prior therapy (including cBTKi), number of prior lines of therapy, or reason for prior cBTKi discontinuation. Pirtobrutinib was approved by the FDA in January 2023 for R/R MCL after 2 prior lines of therapy including a BTKi. The objective of this study is to establish whether pirtobrutinib is superior to investigator’s choice of cBTKi in pts with previously treated, BTKi naïve MCL. Methods: BRUIN MCL-321 (NCT04662255) is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator’s choice of cBTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in pts with previously treated, BTKi naïve MCL. Approximately 500 pts will be randomized 1:1 and stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Enrollment for this study is ongoing. Adults with a diagnosis of MCL who have received ≥ 1 prior line of systemic therapy for MCL and are BTKi naïve are eligible. Pts must have measurable disease by imaging per Lugano criteria and have progressed on or relapsed following the most recent line of therapy. A history of current or prior CNS involvement, significant cardiovascular disease, stroke or intracranial hemorrhage within 6 months of randomization, and autologous stem cell transplant (SCT), allogeneic SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization are key exclusion criteria. Progression-free survival (PFS) per Lugano criteria assessed by an independent review committee is the primary endpoint. Overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and pt reported outcomes are secondary endpoints. Clinical trial information: NCT04662255 .

Objective To evaluate whether transcatheter or surgical aortic valve replacement (TAVR or SAVR) affects clinical and haemodynamic outcomes in symptomatic patients with moderately-severe aortic stenosis (AS). Methods Echocardiographic evidence of severe AS for enrolment in the Evolut Low Risk trial was based on site-reported measurements. For this post hoc analysis, core laboratory measurements identified patients with symptomatic moderately-severe AS (1.0<aortic valve area (AVA)<1.5 cm2, 3.0<peak velocity<4.0 m/s and 20≤mean gradient (MG) <40 mm Hg). Clinical outcomes were reported through 2 years. Results Moderately-severe AS was identified in 113 out of 1414 patients (8%). Baseline AVA was 1.1±0.1 cm2, peak velocity 3.7±0.2 m/s, MG 32.7±4.8 mm Hg and aortic valve calcium volume 588 (364, 815) mm3. Valve haemodynamics improved following TAVR (AVA 2.5±0.7 cm2, peak velocity 1.9±0.5 m/s and MG 8.4±4.8 mm Hg; p<0.001 for all) and SAVR (AVA 2.0±0.6 cm2, peak velocity 2.1±0.4 m/s and MG 10.0±3.4 mm Hg; p<0.001 for all). At 24 months, the rates of death or disabling stroke were similar (TAVR 7.7% vs SAVR 6.5%; p=0.82). Kansas City Cardiomyopathy Questionnaire overall summary score assessing quality of life improved from baseline to 30 days after TAVR (67.0±20.6 to 89.3±13.4; p<0.001) and SAVR (67.5±19.6 to 78.3±22.3; p=0.001). Conclusions In symptomatic patients with moderately-severe AS, AVR appears to be beneficial. Determination of the clinical and haemodynamic profile of patients who can benefit from earlier isolated AVR needs further investigation in randomised clinical trials.

Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

Abstract Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.