Macromolecular crowding amplifies allosteric regulation of T-cell protein tyrosine phosphatase.

T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of T-cell receptor and oncogenic receptor tyrosine kinase signaling and implicated in cancer and autoimmune disease. TC-PTP activity is modulated by an intrinsically disordered C-terminal region (IDR) and suppressed in cells under basal conditions. In vitro structural studies have shown that the dynamic reorganization of IDR around the catalytic domain, driven by electrostatic interactions, can lead to TC-PTP activity inhibition; however, the process has not been studied in cells. Here, by assessing a mutant (378KRKRPR383 mutated into 378EAAAPE383, called TC45E/A) with impaired tail-PTP domain interaction, we obtained evidence that the downmodulation of TC-PTP enzymatic activity by the IDR occurs in cells. However, we found that the regulation of TC-PTP by the IDR is only recapitulated in vitro when crowding polymers that mimic the intracellular environment are present in kinetic assays using a physiological phosphopeptide. Our FRET-based assays in vitro and in cells confirmed that the effect of the mutant correlates with an impairment of the intramolecular inhibitory remodeling of TC-PTP by the IDR. This work presents an early example of the allosteric regulation of a protein tyrosine phosphatase being controlled by the cellular environment and provides a framework for future studies and targeting of TC-PTP function.

Comparison of the clinicopathologic features of prostate cancer in US and Chinese populations.

BACKGROUND: Prostate cancer (PCa) is the most common malignant tumor found among men in the United States. Incidence rates of PCa have recently grown in Asian countries, partially due to the comprehensive implementation of early detection systems. Interestingly, a prospective cohort study showed that adopting a westernized dietary pattern was associated with a higher risk of being diagnosed with PCa among Korean and Japanese men. However, a comparison of current clinicopathological features of PCa between American and Chinese men is lacking. In this study, we report the current clinicopathological features of PCa in Chinese men and compare them to those of patients in the USA. MATERIALS AND METHODS: Case cohorts included, in total, 871 PCa cases with prostatectomy sequentially treated since 2017, including 299 cases from USA and 572 cases from two different academic hospitals in China. The parameters, including patient's age, preoperative Prostate-Specific Antigen (PSA) level, Gleason score, Grade Group, stage and tumor focality, were collected, analyzed and compared using two sample t-test, Wilcoxon rank sum test, Pearson's Chi-squared test and Fisher's exact test. RESULTS: Significant differences were demonstrated in the mean age of patients, preoperative PSA levels, extra-prostatic extension, Gleason scores, and Grade Groups (p < 0.05). PCa patients in the Chinese group were older than patients in the USA group (67.81 vs. 63.53, p < 0.01). The preoperative PSA levels in the Chinese group were higher than those in the USA group (11.69 v.s 6.30, p < 0.01). A higher percentage of high Grade Groups (Groups 4 and 5) was observed in the Chinese group (25.7%) compared to the USA cohort (17.11%), while Grade Group 2 was more common in the USA group than in the Chinese group (51.68% vs. 32.52%, p < 0.01). CONCLUSIONS: All these data suggest that the clinicopathologic features of PCa are different between the USA and Chinese populations, which may be influenced by treatment strategies (including surgical case selection criteria).

Leveraging electronic health record systems to create and provide electronic cancer survivorship care plans: a pilot study.

PURPOSE: The Institute of Medicine (IOM) recommends cancer survivors receive survivorship care plans after completing active cancer treatment. However, care plan creation requires significant time and effort, contributing to diminished adoption of this recommendation. Electronic health record (EHR) systems have been proposed as a solution. We assessed the feasibility of creating and delivering care plans within an EHR system. METHODS: Thirty-eight breast cancer survivors without existing care plans were recruited during a follow-up visit to their primary oncologist. Using an EHR template, an oncologist created an individualized care plan for each participant. Time spent creating each plan was recorded. Participant use and feedback were collected. RESULTS: Participants enrolled a median of 19.7 months after diagnosis (range, 4.3 to 57 months). A minority of IOM-recommended plan elements could be automatically imported without any manual entry. The majority of elements required interpretation and manual import by the clinician. However, with an established infrastructure for importing elements, the time needed to create a care plan electronically was short (median, 3 minutes; range 2 to 12 minutes). Most survivors (n = 36; 95%) successfully accessed their care plans online and spent a median of 12 minutes (range, 0.5 to 61.9 minutes) reviewing them. Survivors perceived the plans as useful and did not generally report difficulty in accessing them online or understanding content. CONCLUSION: Rapid care plan creation and delivery within an EHR is possible. Plans were available to all (survivors, oncologists, primary care physicians) via the EHR. Further research is required to explore the barriers to automating data importation into plans as well as the impact of EHR-integrated plans.

Loss of anterior gradient 2 (Agr2) expression results in hyperplasia and defective lineage maturation in the murine stomach.

Recent studies of epithelial tissues have revealed the presence of tissue-specific stem cells that are able to establish multiple cell lineages within an organ. The stem cells give rise to progenitors that replicate before differentiating into specific cell lineages. The mechanism by which homeostasis is established between proliferating stem or progenitor cells and terminally differentiated cells is unclear. This study demonstrates that Agr2 expression by mucous neck cells in the stomach promotes the differentiation of multiple cell lineages while also inhibiting the proliferation of stem or progenitor cells. When Agr2 expression is absent, gastric mucous neck cells increased in number as does the number of proliferating cells. Agr2 expression loss also resulted in the decline of terminally differentiated cells, which was supplanted by cells that exhibited nuclear SOX9 labeling. Sox9 expression has been associated with progenitor and stem cells. Similar effects of the Agr2 null on cell proliferation in the intestine were also observed. Agr2 consequently serves to maintain the balance between proliferating and differentiated epithelial cells.

Encapsulated papillary carcinoma of the breast: a study of invasion associated markers.

UNLABELLED: Encapsulated papillary carcinoma (EPC) of the breast is a distinct histological subtype characterised by malignant epithelial proliferation supported by fibrovascular stalks. Although EPC typically lacks myoepithelial cells, it shows indolent clinical course. The classification of EPC as an in situ, or invasive disease, remains a matter of debate. METHODS: In this study, the authors investigated a panel of invasion-associated markers in a series of EPC and compared their expression with control groups of non-papillary ductal carcinoma in situ (DCIS) and conventional invasive carcinomas. The expression pattern of four matrix metalloproteinases (MMP-1, MMP-2, MMP-7 and MMP-9), transforming growth factor receptor beta, vascular endothelial growth factor (VEGF) and E-cadherin were assessed in the tumour cell and/or stromal tissue, and the results were analysed. RESULTS: EPC showed higher expression levels of both MMP-1 and MMP-9 compared with DCIS, and no significant differences were observed between EPC and invasive carcinoma. Expression of MMP-2 and MMP-7 levels were similar in EPC and DCIS, but both showed lower levels compared with invasive tumours. EPC showed higher expression of E-cadherin and transforming growth factor receptor ß1 compared with both DCIS and invasive cancer. No difference in the stromal expression of MMPs or tumour expression of VEGF was detected. CONCLUSION: EPC exhibits an expression pattern of invasion-associated markers, which is intermediate in nature between DCIS and invasive cancer, providing further support of the unique biological features of EPC, and which may explain its clinically indolent behaviour.

Diagnostic accuracy of cyst fluid amphiregulin in pancreatic cysts.

BACKGROUND: Accurate tests to diagnose adenocarcinoma and high-grade dysplasia among mucinous pancreatic cysts are clinically needed. This study evaluated the diagnostic utility of amphiregulin (AREG) as a pancreatic cyst fluid biomarker to differentiate non-mucinous, benign mucinous, and malignant mucinous cysts. METHODS: A single-center retrospective study to evaluate AREG levels in pancreatic cyst fluid by ELISA from 33 patients with a histological gold standard was performed. RESULTS: Among the cyst fluid samples, the median (IQR) AREG levels for non-mucinous (n = 6), benign mucinous (n = 15), and cancerous cysts (n = 15) were 85 pg/ml (47-168), 63 pg/ml (30-847), and 986 pg/ml (417-3160), respectively. A significant difference between benign mucinous and malignant mucinous cysts was observed (p = 0.025). AREG levels greater than 300 pg/ml possessed a diagnostic accuracy for cancer or high-grade dysplasia of 78% (sensitivity 83%, specificity 73%). CONCLUSION: Cyst fluid AREG levels are significantly higher in cancerous and high-grade dysplastic cysts compared to benign mucinous cysts. Thus AREG exhibits potential clinical utility in the evaluation of pancreatic cysts.

Rate of postdates induction using first-trimester ultrasound to determine estimated due date: Wellington Regional Hospital audit.

AIM: The aim of this audit was to examine the effect of using first-trimester (<14 weeks) ultrasound scan to determine EDD (US EDD) on the rate of induction for postdates pregnancies at Wellington Regional Hospital. METHODS: Women with singleton live pregnancies who had postdates (≥41 weeks) induction at Wellington Hospital during January 2009 to November 2009 were identified using a computerised database [Perinatal Information Management System (PIMS)]. The first-trimester ultrasound images and reports for these women were retrieved and reviewed by a specialist in obstetric ultrasound. Only ultrasound studies that had technically satisfactory images at <14 weeks were included. RESULTS: A total of 329 women with a singleton live pregnancy were induced for postdates during the study period. Of these women, 50 (15.2%) were not ≥41 weeks on PIMS EDD and therefore on the best available evidence should not have been induced for being postdates. Of the remaining 279 women, 158 had first-trimester scans available for review. Forty-three of 158 (27%) were <41 weeks when US EDD was used. CONCLUSIONS: The rate of postdates inductions at Wellington NRH could be decreased by 38% if induction was limited to women over 41-week gestation and by using US EDD as opposed to last menstrual period EDD. The use of early gestational scans (<14 weeks) to estimate EDD lowers the rate of postdates induction. This is very similar to the observed findings in literature.

The human adenocarcinoma-associated gene, AGR2, induces expression of amphiregulin through Hippo pathway co-activator YAP1 activation.

Anterior Gradient Homolog 2 (AGR2) is expressed by the normal intestine and by most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, breast, ovary, and prostate. Xenografts of human adenocarcinoma cell lines in nude mice previously demonstrated that AGR2 supports tumor growth. In addition, AGR2 is able to induce in vitro a transformed phenotype in fibroblast and epithelial cell lines. The mechanism underlying the growth promoting effects of AGR2 is unknown. The present study shows that AGR2 induces expression of amphiregulin (AREG), a growth promoting EGFR ligand. Induced AREG expression in adenocarcinoma cells is able to rescue the transformed phenotype that is lost when AGR2 expression is reduced. Additional experiments demonstrate that AGR2 induction of AREG is mediated by activation of the Hippo signaling pathway co-activator, YAP1. Thus AGR2 promotes growth by regulating the Hippo and EGF receptor signaling pathways.

Strategies for more effective monitoring and evaluation systems in HIV programmatic scale-up in resource-limited settings: Implications for health systems strengthening.

Program monitoring and evaluation (M&E) has the potential to be a cornerstone of health systems strengthening and of evidence-informed implementation and scale-up of HIV-related services in resource-limited settings. We discuss common challenges to M&E systems used in the rapid scale-up of HIV services as well as innovations that may have relevance to systems used to monitor, evaluate, and inform health systems strengthening. These include (1) Web-based applications with decentralized data entry and real-time access to summary reporting; (2) timely feedback of information to site and district staff; (3) site-level integration of traditionally siloed program area indicators; (4) longitudinal tracking of program and site characteristics; (5) geographic information systems; and (6) use of routinely collected aggregate data for epidemiologic analysis and operations research. Although conventionally used in the context of vertical programs, these approaches can form a foundation on which data relevant to other health services and systems can be layered, including prevention services, primary care, maternal-child health, and chronic disease management. Guiding principles for sustainable national M&E systems include country-led development and ownership, support for national programs and policies, interoperability, and employment of an open-source approach to software development.