Abstract:Proper protein turnover is required for cardiac homeostasis and, accordingly, impaired proteasomal function appears to contribute to heart disease. Specific proteasomal degradation mechanisms underlying cardiovascular biology and disease have been identified, and such cellular pathways have been proposed to be targets of clinical relevance. This review summarizes the latest literature regarding the specific E3 ligases involved in heart biology, and the general ways that the proteasome regulates protein quality control in heart disease. The potential for therapeutic intervention in Ubiquitin Proteasome System function in heart disease is discussed. (Circ Res. 2013;112:1046-1058.)

Immune checkpoint inhibitors (ICPis) have revolutionized cancer therapy with broad activities against a wide range of malignancies. However, in many malignancies their efficacy remains limited due to the primary resistance. Furthermore, a high percentage of patients develop progression due to the secondary resistance even after obtaining a response or achieving a stable disease. In this review, we will discuss the mechanisms that underlie the primary and secondary resistance to ICPis in cancer immunotherapy and provide an overview to impart a broad understanding of the critical issues that are encountered in clinical oncology practice.

The ␤-amyloid peptide (A␤) is thought to play a critical role in the pathophysiology of Alzheimer's disease (AD). To study the effects of A␤ on the brain, transgenic mouse models have been developed that express high levels of A␤. These mice show some features of AD, including amyloid plaques and mild cognitive impairment, but not others such as progressive neurodegeneration. We investigated the age-dependent effects of A␤ on synaptic physiology in Tg2576 mice that express human A␤. We report that both basal synaptic activity and long-term potentiation (LTP), as measured in the CA1 region of the hippocampus, were compromised by 7 months of age before plaque deposition. Despite a persistent increase in A␤ levels with age, LTP recovered in 14-month-old mice, with no further loss of basal activity compared with activity measured in 7-month-old mice. Previous work has shown that inhibitors of ␥-secretase, an enzyme critical for A␤ synthesis, can significantly reduce A␤ production and plaque formation in Tg2576 mice. Our data demonstrate that 7-month-old Tg2576 mice treated with an orally available ␥-secretase inhibitor showed a significant improvement in synaptic function and plasticity within days, and the effect was correlated with the extent and duration of A␤ reduction. These results indicate that recovery from A␤-mediated synaptotoxicity can occur rapidly with A␤-lowering therapies. These findings highlight some of the strengths and limitations of using A␤-overexpressing mouse models for Alzheimer's drug discovery.Alzheimer's disease (AD) is characterized clinically by progressive loss of memory and the pathological accumulation of neurofibrillary tangles and amyloid plaques in the brain. Tangles are composed of a fibrillized form of the microtubulebinding protein tau. Amyloid lesions contain ␤-amyloid peptide (A␤) produced endogenously by the proteolytic cleavage of the amyloid precursor protein (APP) by ␤-secretase and ␥-secretase (Wolfe, 2006;Cole and Vassar, 2008). Mutations near the cleavage sites of APP cause early onset AD as do variants in the ␥-secretase subunit presenilin 1. These mutations typically elevate A␤ production or increase A␤42/40 ratios, which result in a more aggregation-prone form of the peptide. Essential to developing disease-modifying therapies for AD is the identification and characterization of relevant preclinical animal models.Transgenic mice that express human disease variants of APP or presenilin 1 develop amyloid plaques, memory impairment, deficits in synaptic function, gliosis, and dystrophic neurites (Ashe, 2006; Gotz and Ittner, 2008;Morrissette et al., 2009). However, despite high levels of A␤ expression, these mice typically lack the overt tau pathology, neurodegeneration, and show only modest cognitive impairment. The full value of these preclinical models of Alzheimer's disease requires an explanation for the incomplete pathology. Tg2576 mice that express the APPsw mutation (K770N, M671L) have been widely studied (Hsiao et al., 1996;Ashe, 2006) as a model for pl...

Background: Pazopanib was approved for advanced soft tissue sarcoma as a second- or third-line therapy based on the clinical trial “Pazopanib for metastatic soft-tissue sarcoma” (PALETTE). We hypothesized that the real-world experiences may be significantly different from the clinical trial results. Methods: We analyzed the response pattern of patients with advanced soft tissue and bone sarcoma who received pazopanib treatment between 1 January 2011 and 31 October 2018 in Kaiser Permanente Northern California. Results: A total of 123 patients with 23 different histologic subtypes were assessable. One patient with low-grade fibromyxoid sarcoma obtained complete response (CR) after 2 months of treatment with pazopanib, 12 patients (9.7%) obtained partial response (PR), 34 patients (27.6%) had stable disease (SD), while 76 patients (61.8%) developed progressive disease (PD). The disease control rate (DCR) was 46.3% (CR + PR + SD). Among the 12 patients with PR, 3 had undifferentiated pleomorphic sarcoma (UPS), 4 had leiomyosarcoma (LMS), 2 had pleomorphic rhabdomyosarcoma, 1 had pleomorphic liposarcoma, 1 had dedifferentiated liposarcoma, and 1 had angiosarcoma. The median duration of response was 9 months. Two patients with Ewing’s sarcoma had SD for 6 and 13 months, and two patients with osteosarcoma had SD for 6 and 9 months. Among 65 patients assessed at 8 weeks, 9 had a response, and 10 had SD. Among 104 patients assessed at 12 weeks, 12 had a response, and 26 had SD. The median progression-free survival (PFS) was approximately 3 months for all 123 cases and for patients with UPS and LMS. Conclusions: Our cohort of patients with advanced soft tissue and bone sarcoma in Northern California treated with pazopanib had diverse histologic subtypes. The response rate (CR + PR) was higher than that of the PALETTE trial, while the DCR and the median PFS were significantly lower. The observation of PR in two patients with liposarcoma and durable SD in several patients with bone sarcoma indicates that pazopanib has activity in liposarcoma and bone sarcoma.

The accumulation of β-amyloid (Aβ) peptide in the brain is one of the pathological hallmarks of Alzheimer's disease and is thought to be of primary aetiological significance. In an unbiased genetic screen, we identified puromycin-sensitive aminopeptidase (PSA) as a potent suppressor of Aβ toxicity in a Drosophila model system. We established that coexpression of Drosophila PSA (dPSA) in the flies' brains improved their lifespan, protected against locomotor deficits, and reduced brain Aβ levels by clearing the Aβ plaque-like deposits. However, confocal microscopy and subcellular fractionation of amyloid-expressing 7PA2 cells demonstrated that PSA localizes to the cytoplasm. Therefore, PSA and Aβ are unlikely to be in the same cellular compartment; moreover, when we artificially placed them in the same compartment in flies, we could not detect a direct epistatic interaction. The consequent hypothesis that PSA's suppression of Aβ toxicity is indirect was supported by the finding that Aβ is not a proteolytic substrate for PSA in vitro. Furthermore, we showed that the enzymatic activity of PSA is not required for rescuing Aβ toxicity in neuronal SH-SY5Y cells. We investigated whether the stimulation of autophagy by PSA was responsible for these protective effects. However PSA's promotion of autophagosome fusion with lysosomes required proteolytic activity and so its effect on autophagy is not identical to its protection against Aβ toxicity.

PURPOSE: Management of soft tissue and bone sarcoma presents many challenges, both diagnostically and therapeutically, and requires multidisciplinary collaboration; however, such collaboration is often challenging to establish, especially in the community setting. We share our experiences of a virtual multidisciplinary sarcoma case conference (VMSCC). METHODS: We conducted retrospective review of the VMSCC data—initially via Webex, now Microsoft Teams—and the surveys of referring physicians to understand the feasibility and value of the VMSCC. RESULTS: The VMSCC was established in March 2013 in Kaiser Permanente Northern California with consistent participation of the Departments of Musculoskeletal Oncology (orthopedic oncology), Musculoskeletal Radiology, Pathology, Medical Oncology, Radiation Oncology, Nuclear Medicine, Surgical Oncology, and Genetics. Pediatric Oncology participated ad hoc when pediatric sarcoma cases were presented. Referrals were from multiple specialties and regions, including the Kaiser Permanente Mid-Atlantic and Hawaii regions. From March 2013 to December 2019, 1,585 cases were reviewed encompassing 36 histologic types. More than 300 cases were reviewed per year from 2017 to 2019. Survey results of referring physicians demonstrate that the VMSCC enhanced the confidence of treating physicians, and its recommendations frequently led to treatment changes. CONCLUSION: Establishing a valuable community-based VMSCC is feasible. VMSCC recommendations frequently led to treatment changes and improved the confidence of treating physicians.

PURPOSE: Quantifying the impact of a multidisciplinary cancer case conference on patient outcome and care quality remains challenging. PATIENTS AND METHODS: We prospectively investigated the impact of our virtual multidisciplinary sarcoma case conference (VMSCC) on treatment plan in patients presented to the VMSCC from July to October 2020 (prospective cohort) and retrospectively in patients with metastatic or locally advanced high-grade soft-tissue sarcoma (STS) reviewed in the VMSCC in 2016 and 2017 (high-grade STS cohort). We also investigated the factors related to the nonadherence to the VMSCC-recommended plan in both cohorts. RESULTS: In both cohorts, approximately 28% of the patients were referred to the VMSCC for review without a treatment plan. In significantly more cases, referring physicians outside of the sarcoma group did not have a plan formulated before the VMSCC review compared with the referring physicians within the sarcoma group. In 28.2% (prospective cohort) and 19.5% (high-grade STS cohort) of the patients, VMSCC recommended a different plan. The adherence to the VMSCC-recommended plan was 87.9% and 83.1%, respectively. The causes of the nonadherence were primarily due to disease progression or patient’s decision against recommended therapy. The median overall survival for the high-grade STS cohort was 26 months. CONCLUSION: VMSCC affected the treatment plan in approximately 50% of the patients in both cohorts. The median overall survival of the patients with high-grade STS reviewed by the VMSCC in our cohort is comparable with the literature.

Background: Ventral hernia repair (VHR) is one of the most common general surgery procedures; however, few studies with long-term follow-up of VHR outcomes exist. Methods: We performed a retrospective review of VHRs performed from 2000 to 2009 at a single institution. Our primary outcome was recurrence, and secondary outcomes were reoperations and complications including seroma, hematomas, abdominal wall abscess, wound infections, and mesh infections. Results: Our sample population (n=420; mean age 46.3±11.7 years) included 230 females (54.8%), and cases included laparoscopic (n=31; 7.5%), laparoscopic converted to open (n=7; 1.7%), and open (n=373, 90%). As compared to suture repairs, mesh repair was associated with lower rates of complications (25.7% vs 29.5%, p=0.10) and recurrence (12.8% vs 15.2%, p=0.67). Laparoscopic repairs had lower rates of complications than open repairs (25% vs 26.8%; p=0.70) but similar rates of recurrence (13.8% and 13.6%; p=0.53). After logistic regression, obesity, chronic obstructive pulmonary disease, component separation technique, and prolonged operating time (>75th percentile) were associated with increased complications. Conclusion: Obesity is a modifiable risk factor and must be addressed in patients undergoing VHRs. Mesh repair does not increase the risk of adverse long-term outcomes and may be performed safely in patients undergoing VHR.