In eukaryotes, the 20S proteasome contains two chymotrypsin-like, two trypsin-like, and two active sites shown here to have caspase-like specificity. We report that certain sites allosterically regulate each other's activities. Substrates of a chymotrypsin-like site stimulate dramatically the caspase-like activity and also activate the other chymotrypsin-like site. Moreover, substrates of the caspase-like sites inhibit allosterically the chymotrypsin-like activity (the rate-limiting one in protein breakdown) and thus can reduce the degradation of proteins by 26S proteasomes. These allosteric effects suggest an ordered, cyclical mechanism for protein degradation. We propose that the chymotrypsin-like site initially cleaves ("bites") the polypeptide, thereby stimulating the caspase-like sites. Their activation accelerates further cleavage ("chewing") of the fragments, while the chymotrypsin-like activity is temporarily inhibited. When further caspase-like cleavages are impossible, the chymotryptic site is reactivated and the cycle repeated.

Risk-based monitoring (RBM) is a powerful tool for efficiently ensuring patient safety and data integrity in a clinical trial, enhancing overall trial quality. To better understand the state of RBM implementation across the clinical trial industry, the Association of Clinical Research Organizations (ACRO) conducted a landscape survey among its member companies across 6,513 clinical trials ongoing at the end of 2019. Of these trials, 22% included at least 1 of the 5 RBM components: key risk indicators (KRIs), centralized monitoring, off-site/remote-site monitoring, reduced source data verification (SDV), and reduced source document review (SDR). The implementation rates for the individual RBM components ranged 8%–19%, with the most frequently implemented component being centralized monitoring and the least frequently implemented being reduced SDR. When the COVID-19 pandemic emerged in early 2020, additional data were collected to assess its impact on trial monitoring, focusing specifically on trials switching from on-site monitoring to off-site/remote-site monitoring. These mid-pandemic data show that the vast majority of monitoring visits were on-site in February 2020, but an even higher percentage were off-site in April, corresponding with the first peak of the pandemic. Despite this shift, similar numbers of non-COVID-related protocol deviations were detected from February through June, suggesting little or no reduction in monitoring effectiveness. The pre- and mid-pandemic data provide two very different snapshots of RBM implementation, but both support the need to promote adoption of this approach while also highlighting an opportunity to capitalize on the recent shift toward greater RBM uptake in a post-pandemic environment.

To evaluate the diagnostic impact of point-of-care breast ultrasound by trained primary care physicians (PCPs) as part of a breast cancer detection program using clinical breast exam in an underserved region of Peru. Medical records and breast ultrasound images of symptomatic women presenting to the Breast Cancer Detection Model (BCDM) in Trujillo, Peru were collected from 2017–2018. Performance was measured against final outcomes derived from regional cancer center medical records, fine needle aspiration results, patient follow-up (sensitivity, specificity, positive, and negative predictive values), and by percent agreement with the retrospective, blinded interpretation of images by a fellowship-trained breast radiologist, and a Peruvian breast surgeon. The diagnostic impact of ultrasound, compared to clinical breast exam (CBE), was calculated for actual practice and for potential impact of two alternative reporting systems. Of the 171 women presenting for breast ultrasound, 23 had breast cancer (13.5%). Breast ultrasound used as a triage test (current practice) detected all cancer cases (including four cancers missed on confirmatory CBE). PCPs showed strong agreement with radiologist and surgeon readings regarding the final management of masses (85.4% and 80.4%, respectively). While the triage system yielded a similar number of biopsies as CBE alone, using the condensed and full BI-RADS systems would have reduced biopsies by 60% while identifying 87% of cancers immediately and deferring 13% to six-month follow-up. Point-of-care ultrasound performed by trained PCPs improves diagnostic accuracy for managing symptomatic women over CBE alone and enhances access. Greater use of BI-RADS to guide management would reduce the diagnostic burden substantially.

Purpose Breast cancer (BC) is the most common cancer among women in Latin America, yet many countries lack the capacity to provide early detection and diagnostic services. In Peru, mammograms are not readily available in secondary cities, and 57% of women who are diagnosed with BC are diagnosed with stage III and IV disease. To bring services to women in a northern region of Peru, PATH collaborated with Peruvian health institutions at the local, regional, and national levels to design and implement a strategic algorithm with which to increase the early detection of BC in the absence of mammography. Here, we evaluate the impact of training on the quality of clinical breast exam (CBE), ultrasound triage, and fine-needle aspiration (FNA) sampling and the reading of FNA biopsy for triage-positive women. Methods Two hundred twenty-four midwives and 15 doctors were included in two-step training in Trujillo, Peru. CBE trainings were performed using anatomic models and patient exams in 2-day sessions. Team discussion with trainers was used to improve skills. Doctors’ trainings for FNA sampling were led by two international expert pathologists in 2014 and by a Peruvian expert pathologist in 2016. Then in 2017, 43 pretraining and 50 post-training FNA biopsy samples were evaluated for adequacy and quality of diagnosis. Results Since the trainings, 14,223 women have received CBE on an opportunistic basis. Midwives refer abnormal cases (n = 281) for follow-up. All doctors felt well trained for CBE and FNA, whereas five of 15 doctors perceived the need for additional ultrasound training. Quality assessment revealed that the adequacy of FNA samples improved from 26% pretraining to 37% post-training. Of the 43 FNA samples, a low concordance with reviewers was observed in the detection of suspicious/carcinoma (6.9% v 13.9%), whereas full concordance was observed after the training, although the numbers were small. Conclusion In Peru, CBE remains an acceptable and feasible approach if complemented with ultrasound triage and FNA biopsy. Additional efforts are needed to increase coverage through a structured program. Training and continuous monitoring are essential for quality assurance. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc . Ronald Balassanian Stock or Other Ownership: Cerus Corp ($400.00)

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