Role of the ubiquitin proteasome system in the heart.

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.

Suppression of Aß toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity.

The accumulation of ß-amyloid (Aß) 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 Aß 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 Aß levels by clearing the Aß plaque-like deposits. However, confocal microscopy and subcellular fractionation of amyloid-expressing 7PA2 cells demonstrated that PSA localizes to the cytoplasm. Therefore, PSA and Aß 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 Aß toxicity is indirect was supported by the finding that Aß is not a proteolytic substrate for PSA in vitro. Furthermore, we showed that the enzymatic activity of PSA is not required for rescuing Aß 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 Aß toxicity.

Pain as Initial Presenting Symptom Is Associated With Delay to Seeking Medical Attention, Higher Risk of Relapse, and Shorter Survival in Patients With Early-Stage Extremity or Trunk Synovial Sarcoma.

BackgroundWhether the presenting symptom of pain vs mass impacts survival of early-stage synovial sarcoma is not known. Patients and MethodsThe authors investigated patients with early-stage extremity/trunk synovial sarcoma diagnosed from 2005 to 2017 at Kaiser Permanente Northern California for associations between the presenting symptom and survival. ResultsAmong 56 patients with early-stage extremity/trunk synovial sarcoma, median disease-free survival (DFS) was 20.3 months for the pain-only group (n = 19) vs 50.5 months for the mass ± pain group (n = 37) (p = 0.004), and median overall survival (OS) was 35.7 months vs 53.9 months (p = 0.009), respectively. Median DFS was 26.9 months for the pain ± mass group (n = 32) vs 48.6 months for the mass-only group (n = 24) (p = 0.047), whereas OS was not significantly different (49.6 vs. 53.6 months, p = 0.282). Pain at presentation was associated with a higher incidence of deep tumors and a higher risk of relapse. Cox regression model adjusting for age, sex, race, tumor location, tumor size, and wait-time to seek medical attention showed that pain at presentation was associated with 3-fold worse DFS and OS. ConclusionPain at presentation was an adverse risk factor for patients with early-stage extremity/trunk synovial sarcoma.

Impact of a Virtual Multidisciplinary Sarcoma Case Conference on Treatment Plan and Survival in a Large Integrated Healthcare System.

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.

Fourteen-Day Gemcitabine-Docetaxel Chemotherapy Is Effective and Safer Compared to 21-Day Regimen in Patients with Advanced Soft Tissue and Bone Sarcoma.

Gemcitabine-docetaxel (G-D) combination is an effective chemotherapy for patients with advanced soft tissue and bone sarcoma, first developed with G administered on days 1 and 8, and D on day 8 every 21 days and later modified to be administered every 14 days in 2012. The 14-day regimen has become increasingly adopted. However, its efficacy and toxicities have not been compared. We identified 161 patients with metastatic or locally advanced soft tissue and bone sarcoma treated with either a 14-day or 21-day regimen within Northern California Kaiser Permanente from 1 January 2017 to 30 July 2020 and compared the outcomes and toxicity profiles of patients treated with the either regimen. Seventy-nine (49%) and 82 (51%) patients received the 14-day and the 21-day regimen, respectively, with similar response rate (22.8% and 15.8%, p = 0.26), median progression-free survival (PFS, 4.0 and 3.2 months, p = 0.15), and median overall survival (OS, 12.6 and 14.7 months, p = 0.55). Subset analysis of the untreated patients (approximately 60% of the entire cohort) as well as the patients with leiomyosarcoma only (approximately 50% of the entire cohort) showed that OS was not significantly different between the two regimens. Febrile neutropenia requiring hospitalization occurred in 10 and one patients (p = 0.006) and intolerance leading to discontinuation of chemotherapy occurred in 12 and two patients (p = 0.006) treated with the 21-day and the 14-day regimens, respectively. CDKN2A deletion/mutation or CDK4 amplification was associated with worse median OS (p = 0.06), while a RB1 deletion/mutation was associated with better median PFS (p = 0.05), and these two genomic alterations were mutually exclusive. Our data demonstrate that, compared to the traditional 21-day G-D regimen, the 14-day G-D regimen is equally effective but safer. In addition, CDKN2A and RB1 pathways play significant role on the outcomes of the patients.

Oral treatment with a gamma-secretase inhibitor improves long-term potentiation in a mouse model of Alzheimer's disease.

The beta-amyloid peptide (Abeta) is thought to play a critical role in the pathophysiology of Alzheimer's disease (AD). To study the effects of Abeta on the brain, transgenic mouse models have been developed that express high levels of Abeta. 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 Abeta on synaptic physiology in Tg2576 mice that express human Abeta. 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 Abeta 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 gamma-secretase, an enzyme critical for Abeta synthesis, can significantly reduce Abeta production and plaque formation in Tg2576 mice. Our data demonstrate that 7-month-old Tg2576 mice treated with an orally available gamma-secretase inhibitor showed a significant improvement in synaptic function and plasticity within days, and the effect was correlated with the extent and duration of Abeta reduction. These results indicate that recovery from Abeta-mediated synaptotoxicity can occur rapidly with Abeta-lowering therapies. These findings highlight some of the strengths and limitations of using Abeta-overexpressing mouse models for Alzheimer's drug discovery.

Long-Term Outcomes of Ventral Hernia Repair: An 11-Year Follow-Up.

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.

Feasibility and Value of Establishing a Community-Based Virtual Multidisciplinary Sarcoma Case Conference.

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.

Feasibility and Value of Establishing a Community-Based Virtual Multidisciplinary Sarcoma Case Conference.

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.

Mechanisms of Primary and Secondary Resistance to Immune Checkpoint Inhibitors in Cancer.

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.

Real-World Experiences with Pazopanib in Patients with Advanced Soft Tissue and Bone Sarcoma in Northern California.

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 protein synthesis inhibitor anisomycin reduces sex behavior during a critical period after testosterone treatment in male Syrian hamsters.

Testosterone (T) is critical for maintaining male sexual behavior (MSB) in rodents, in part by altering protein synthesis in a well-defined neural circuit. The specific timing of protein synthesis essential for expression of MSB has never been investigated. We administered the protein synthesis inhibitor anisomycin (Ani) to castrated male Syrian hamsters treated sc with 100 µg T in an aqueous vehicle once weekly; this T regimen maintains MSB while elevating circulating T concentrations for only a few hours after each injection. Hamsters were injected s.c. with the vehicle or 12.5 mg Ani at one of several times relative to T administration; MSB was assessed once per week, 6 days after the previous T injection, for 5 weeks. Anisomycin administered 6-12 h after T injection significantly reduced the expression of sexual behavior, whereas Ani treatment between 3 h before and 3 h after T injection did not impair MSB. This experiment is the first to assess the specific timing of protein synthesis relative to a T pulse that is required for the expression of MSB. The demarcation of a critical interval for T-induced protein synthesis necessary for maintenance of MSB should facilitate specification of the genomic, proteomic, and biochemical cascades that subserve actions of T on male copulation.