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Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS -mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.

Objectives: Current standard of care after a First-Time patellar instability event is non-operative management, with exceptions for patients with osteochondral fracture or loose body requiring immediate surgical intervention, patients with significant pathoanatomy, or contralateral patellar instability. For recurrent patellar instability, there is controversy as to when isolated medial patellofemoral ligament reconstruction (MPFL-R) is enough. The purpose of this study is to determine (1) the comparative outcomes of isolated MPFL-R after first-time patellar instability (FTPI) and recurrent patellar instability (RPI) and (2) the impact of osteochondral injury on outcomes after surgical treatment of FTPI. Methods: A prospective, multicenter cohort study (JUPITER: Justifying Patellar Instability Treatment by Results) database was queried for patients who underwent patellar stabilization surgery (PSS) between December 2016 and September 2022. Patients were included if they underwent a medial patellofemoral ligament reconstruction (MPFL-R) for FTPI or RPI. Those with less than 2 years of clinical follow-up, revision PSS, or concomitant bony procedures at the time of MPFL-R were excluded. Independent t-tests were performed to compare means for continuous variables, and chi-squared tests were performed to compare frequency for categorical variables, between groups. Results: A total of 739 patients met inclusion criteria with a mean age of 15.6 ± 3.3 years, and 59.9% female sex. FTPI occurred in 216 (27.2%) patients, and of these 104 (48.1%) sustained an operative chondral or osteochondral lesion. Those with FTPI had a significantly greater trochlear depth (2.9 mm vs. 2.6 mm; P = .048), but a significantly lower rate of pathological trochlear bump > 5 mm (52.3% vs. 67.8%; P = .008) than those with RPI (Table 1). Among the FTPI cohort, those with treatment of a chondral lesion were less likely to have patella alta (Caton-Deschamps Index > 1.3) (14.9% vs. 41.3%, P = .006), and less frequently had a mild or severe J-sign (25.0% vs. 42.7%, p = .016) than those without a chondral intervention (Table 2). Postoperatively, there were no differences with rates of recurrent instability (8.3% vs. 12.3%; P = .130) or return to sport (90.4% vs. 94.5%; P = .182) between FTPI and RPI, respectively (Table 3). There were no differences with rates of recurrent instability (7.6% vs. 9.1%; P = .807) or return to sport (89.1% vs. 91.7%; P = .755) between those with or without a chondral intervention, respectively (Table 4). Conclusions: This study demonstrates no difference in rates of recurrent post-operative instability between FTPI and RPI with rates consistent with the current literature. MPFL reconstruction remains as a durable surgical treatment option for patients presenting with either FTPI or RPI with relatively low rates of recurrent instability. In this patient population, patella alta was found to be protective of osteochondral injury which is also consistent with existing literature. Continued, long-term investigation is needed to understand outcomes for First-Time patellar instability and to better define the indications for surgical interventions in this population.

Abstract Synchronous squamous cell carcinoma (SCC) and chronic lymphocytic leukemia (CLL) in the parotid gland is rare, with limited evidence on personalized treatment. We report a 75-year-old male with prior cutaneous SCC who presented with a hypermetabolic parotid mass and cervical lymphadenopathy; fine needle aspiration confirmed SCC. Surgery revealed poorly differentiated SCC and CLL in multiple lymph nodes. He underwent radiotherapy but developed regional SCC relapse without systemic CLL symptoms. Recurrence in the ear required extensive surgical resection and reconstruction. Genetic profiling showed high tumor mutational burden (>50 mutations/Mb) and mutations in ARID1B, CDKN2A, MSH2, PMS2, and TP53. He received six cycles of cemiplimab followed by cetuximab-based targeted therapy, based on rising circulating DNA levels. This case emphasizes the value of genetic profiling and tools like TMB, FISH, and immunohistochemistry for risk stratification and personalized treatment in managing advanced or complex parotid malignancies, including synchronous SCC and CLL, to optimize patient outcomes.

Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.

Background: Particulated juvenile articular cartilage (PJAC) implantation has demonstrated promising early results in the treatment of symptomatic articular cartilage defects of the patella. However, some uncertainty exists regarding the stability of this cell-based technique in lesions that are not well contained or shouldered. Purpose: To compare clinical and magnetic resonance imaging (MRI) outcomes of PJAC treatment in shouldered versus unshouldered full-thickness cartilage defects of the patella. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review of prospectively collected data from an institutional knee registry was conducted to identify patients treated with PJAC for full-thickness symptomatic patellar cartilage lesion between January 2009 and August 2017. Cartilage defects were graded arthroscopically according to the Outerbridge classification and characterized as shouldered or unshouldered. For the primary outcome, postoperative MRI studies were read by a musculoskeletal fellowship-trained radiologist who characterized the percentage of fill based on both coronal and sagittal images. Patient-reported outcome measures (PROMs) were obtained at baseline and 2-year follow-up. MRI and PROM results were compared between the shouldered and unshouldered cohorts. Results: A total of 64 knees in 60 patients (mean age, 26.3 ± 7.6 years) were identified, of which 62 (97%) knees underwent a concomitant patellar stabilization or offloading procedure. There were 32 (50%) shouldered and 32 (50%) unshouldered defects. On postoperative MRI, 68.8% of shouldered lesions demonstrated 67% to 100% fill, compared with 59.4% of unshouldered lesions; 12.5% of shouldered lesions and 15.6% of unshouldered lesions demonstrated 34% to 66% fill; and 18.8% of shouldered lesions and 25.0% of unshouldered lesions demonstrated 0% to 33% fill ( P = .604). At 2 years, significant improvements were observed in Knee Injury and Osteoarthritis Outcome Score (KOOS) Quality of Life (QOL) (23.1 to 65.3; P < .001), International Knee Documentation Committee (IKDC) (41.2 to 76.0; P < .001), KOOS Physical Function Shortform (PS) (34.8 to 13.9; P < .001), Kujala (52.0 to 87.5; P < .001), 12-Item Short Form Survey (SF-12) Physical Health (39.5 to 51.5; P < .001), Veterans Rand 12 Item Health Survey (VR-12) Physical Health (40.7 to 52.8; P < .001), Veterans Rand 6D (0.66 to 0.79; P < .001), SF-12 Mental Health (48.9 to 53.4; P = .015), and VR-12 Mental Health (49.4 to 54.0; P = .019) values. No significant change was observed in Pediatric Functional Activity Brief Scale score (9.1 to 10.3; P = .384). All PROMs were equivalent between shouldered and unshouldered defects at the 2-year follow-up ( P = .318-.980). There was a greater improvement in both KOOS PS (27.2 vs 10.7; P = .015) and Kujala (44.3 vs 26.9; P = .039) values from baseline to the 2-year follow-up in the shouldered group. Conclusion: PJAC implantation with concomitant patellar stabilization led to significantly improved PROMs for both shouldered and unshouldered patellar cartilage lesions over time. Additionally, minimal differences were observed between shouldered and unshouldered defects treated with PJAC at the 2-year follow-up.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P &lt; 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Abstract Background & Aims Pregnancy can be a complex and risk-filled event for women with inflammatory bowel disease (IBD). High-quality studies in this population are lacking, with limited data on medications approved to treat IBD during pregnancy. For patients, limited knowledge surrounding pregnancy impacts pregnancy rates, medication adherence, and outcomes. Limited provider knowledge leads to highly varied practices in care affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike. The Global Consensus Consortium is a group of 39 IBD and content experts and 7 patient advocates from 6 continents who convened to review and assess current data and come to an agreement on best practices based on these data. Methods The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process was used when sufficient published data were available and the RAND (Research and Development) process in those instances where expert opinion was needed to guide consistent practice. Recommendations were informed by the guiding principle that maternal health best supports infant health. Results The topics were divided into ten categories with 34 GRADE recommendations and 35 consensus statements. Conclusions Overall, the goal of the group was to provide data-driven and practical guidance to improve the care of women with IBD around the globe based on the best available research.

Background: Intracardiac thrombosis (ICT) during liver transplantation (LT) is a rare but life-threatening complication with limited data regarding its risk factors, management, and outcomes. This study aimed to identify factors associated with ICT development, define predictors of intraoperative outcomes, and propose a novel classification and management algorithm for ICT. Methods: A multicenter, international retrospective case-control study was conducted on liver transplant recipients from seven centers between January 2005 and December 2023. ICT cases were identified through transesophageal echocardiography (TEE) or autopsy and matched 1:1 with controls. Results: Among 11 077 liver transplant recipients screened, 133 patients (1.2%) developed ICT. ICT occurred predominantly after reperfusion (58%). Compared to controls, ICT cases exhibited higher preoperative international normalized ratio ( P = 0.001) and fibrinogen levels ( P = 0.014). Post-reperfusion syndrome ( P < 0.001), disseminated intravascular coagulation ( P < 0.001), and primary graft failure ( P = 0.002) were also more common in the ICT group. Continuous veno-venous hemofiltration during surgery (odds ratio [OR] 8.20, 95% confidence interval [CI]: 2.09–38.1; P = 0.004) was associated with ICT development. ICT was associated with markedly higher rates of cardiac arrest ( P < 0.001) and intraoperative mortality ( P < 0.001), with thrombus location in the left heart chambers representing a significant predictor of mortality (OR 20.7, 95% CI: 6.25–81.3; P < 0.001). ICT grades 2 and 3 were associated with a markedly increased risk of intraoperative cardiac arrest ( P < 0.05). Importantly, delayed use of TEE was strongly associated with intraoperative death (OR 6.27, 95% CI: 1.45–27.1; P = 0.014). The 90-day mortality was 43% in ICT cases compared to 4.5% in controls, while 1-year mortality was 46% versus 10.5%, respectively. Conclusions: ICT during LT is a rare but severe complication associated with intraoperative mortality and poor short-term survival. Coagulation profile and intraoperative management play critical roles in ICT development. The early use of TEE enables timely diagnosis and intervention, improving patient outcomes. We propose a novel ICT classification offering a systematic framework for risk stratification and management to mitigate progression and mortality.

Abstract Taxanes are frontline chemotherapeutics that stabilize microtubules, induce mitotic arrest, and drive tumor remission. However, their off-target effects in healthy tissues, most notably cutaneous axon degeneration underlying chemotherapy-induced peripheral neuropathy (CIPN), remain poorly understood. Here, we show that paclitaxel induces microtubule fasciculation in epidermal keratinocytes through the mitotic kinesin Eg5, thereby initiating CIPN. Mechanistically, paclitaxel enhances Eg5-dependent fasciculation of detyrosinated (stabilized) microtubules, which constrict and breach the nuclear lamina. This deformation triggers tension-dependent NADPH oxidase-mediated nuclear ROS (X-ROS) formation upstream of mmp13 transcription, a pathway we previously demonstrated drives sensory axon degeneration. Employing a cross-species framework spanning zebrafish, mice, human skin biopsies, and a breast adenocarcinoma cell line, we uncover a conserved paclitaxel–Eg5 mechanism leading to fasciculation of stable microtubules in both healthy epidermis and cancer cells. These findings highlight the dualistic nature of paclitaxel action and underscore the challenge of preserving anticancer efficacy while preventing neurotoxic side effects.