Differing biophysical properties underpin the unique signaling potentials within the plant phytochrome photoreceptor families.

Many aspects of photoperception by plants and microorganisms are initiated by the phytochrome (Phy) family of photoreceptors that detect light through interconversion between red light- (Pr) and far-red light-absorbing (Pfr) states. Plants synthesize a small family of Phy isoforms (PhyA to PhyE) that collectively regulate photomorphogenesis and temperature perception through redundant and unique actions. While the selective roles of these isoforms have been partially attributed to their differing abundances, expression patterns, affinities for downstream partners, and turnover rates, we show here from analysis of recombinant Arabidopsis chromoproteins that the Phy isoforms also display distinct biophysical properties. Included are a hypsochromic shift in the Pr absorption for PhyC and varying rates of Pfr to Pr thermal reversion, part of which can be attributed to the core photosensory module in each. Most strikingly, PhyB combines strong temperature dependence of thermal reversion with an order-of-magnitude faster rate to likely serve as the main physiological thermosensor, whereby thermal reversion competes with photoconversion. In addition, comparisons of Pfr occupancies for PhyA and PhyB under a range of red- and white-light fluence rates imply that low-light environments are effectively sensed by PhyA, while high-light environments, such as full sun, are effectively sensed by PhyB. Parallel analyses of the Phy isoforms from potato and maize showed that the unique features within the Arabidopsis family are conserved, thus indicating that the distinct biophysical properties among plant Phy isoforms emerged early in Phy evolution, likely to enable full interrogation of their light and temperature environments.

Successful expanded clinic network collaboration and patient tracing for retention in HIV care.

BACKGROUND: There are more than 7,800 people living with human immunodeficiency virus (HIV) in Victoria, Australia. Crucial in maximising the individual and population level benefits from antiretroviral therapy (ART) is understanding how to achieve patient retention in care and the factors that drive it. This study was an expansion of a 2015 assessment of HIV-care retention in Victoria, which sought out to determine whether the inclusion of a broader range of HIV-healthcare sites would yield more accurate estimates of retention in HIV-care. We aimed to improve our understanding of HIV-care retention in Victoria, Australia, identify people living with HIV (PLHIV) with unknown outcomes, and attempt to re-engage PLHIV in care. METHODS: A network of 15 HIV-care sites was established in Victoria, Australia across diverse care settings which ranged from low-caseload rural sites to high-caseload metropolitan GP clinics and hospitals. Individuals who had an HIV viral load (VL) performed in both calendar years of 2016 and 2017 were classified as retained in care. Individuals with a VL test in 2016 but not in 2017 were considered to potentially have unknown outcomes as they may have been receiving care elsewhere, have disengaged from care or died. For this group, an intervention of cross-referencing partially de-identified data between healthcare sites, and contact tracing individuals who still had unknown outcomes was performed. RESULTS: For 5223 individuals considered to be retained in care across 15 healthcare sites in the study period, 49 had unconfirmed transfers of care to an alternative provider and 79 had unknown outcomes. After the intervention, the number of unconfirmed care transfers was reduced to 17 and unknown outcomes reduced to 51. These changes were largely attributed to people being reclassified as confirmed transfers of care. Retention in care estimates that did not include the patient outcome of confirmed transfer of care ranged from 76.2 to 95.8% and did not alter with the intervention. However, retention in care estimates which considered confirmed transfers and those that re-entered care at a new site as retained in care significantly increased across five of the sites with estimates ranging from 80.9 to 98.3% pre-intervention to 83.3-100% post-intervention. Individuals whose outcomes remained unknown post-intervention were more often men who have sex with men (MSM) when compared to other categories (person who injects drugs (PWID), combined PWID/MSM, men who identify as heterosexual or unknown) (74.5% vs. 53.5%, [p = 0.06]) and receiving ART at their last HIV-care visit (84.3% vs. 67.8% [p = 0.09]). CONCLUSION: This study confirmed high retention in HIV-care and low numbers of people disengaged from HIV-care in Victoria. This was demonstrated across a larger number of sites with varying models of care than a prior assessment in 2015. These data align with national and state targets aiming for 95% of PLHIV retained in HIV-care.

MicroRNA-139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL.

BACKGROUND: We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next-generation sequencing-based whole miRNome sequencing and quantitative polymerase chain reaction-based validation analysis. In this study, we examined the mechanism of action of miR-139-5p, one of the downregulated miRNAs identified in the panel. METHODS: Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan-Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 to confirm its targets as well as examine pathways through which miR-139 may function using cell-based assays. RESULTS: Low miR-139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR-139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33-0.82). Overexpression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR-139 based on multiple miRNA-binding sites in 3'-untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR-139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR-139 treatment, which was reversed by the addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. CONCLUSIONS: miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.

Defining early vs late fetal growth restriction by placental pathology.

INTRODUCTION: Although early and late fetal growth restriction have been suggested to be distinct entities, the optimal gestational age cut-off that differentiates the two conditions is currently unclear and has been arbitrarily set in previous studies between 32 and 37 weeks. We aimed to use placental pathology findings to determine that optimal gestational age cut-off between early and late fetal growth restriction. MATERIAL AND METHODS: A retrospective cohort study of all women with singleton gestation who gave birth to a neonate diagnosed as small-for-gestational age (small-for-gestational age, defined as birthweight <10th percentile for gestational age) at a tertiary referral center between January 2001 and December 2015, and for whom placental pathology was available. Placental abnormalities were classified into lesions associated with maternal vascular malperfusion (MVM), fetal vascular malperfusion, placental hemorrhage and chronic villitis. Placental findings were analyzed as a function of gestational age at birth. The analysis was repeated in the subgroups of women without hypertensive complications of pregnancy (to reflect changes associated with isolated small-for-gestational age) and of neonates with severe small-for-gestational age (defined as birthweight <5th percentile), which are more likely to represent true fetal growth restriction. RESULTS: A total of 895 women met the inclusion criteria. The only histological finding that changed with gestational age was MVM pathology, which decreased in frequency with increasing gestational age. We identified a considerable drop in the rate of MVM lesions at 33 weeks of gestation. The rate of MVM pathology in placentas of infants born before 330/7  weeks was significantly higher than that observed in placentas of infants born at 330/7  weeks or longer: 71.6% vs 27.4%, P < 0.001 for ≥2 MVM lesions, and 35.5% vs 3.5%, P < 0.001 for ≥3 MVM lesions. These findings persisted in the subgroups of women without hypertensive complications of pregnancy (n = 662) and of neonates with severe small-for-gestational age (n = 464). CONCLUSIONS: Using placental pathology as a direct measure of the mechanisms underlying fetal growth restriction, the optimal gestational age at birth cut-off which differentiates early from late fetal growth restriction appears to be 330/7  weeks.

Concordance of chlamydia infections of the rectum and urethra in same-sex male partnerships: a cross-sectional analysis.

BACKGROUND: Our study aimed to describe the concordance of chlamydia infections of the rectum and urethra in men who have sex with men (MSM) and their male partners. METHODS: This was a cross-sectional study of chlamydia in MSM and their male sexual partners both attending Melbourne Sexual Health Centre (MSHC), Australia, between February 2011 and March 2015. We excluded partnerships where testing for chlamydia at both the rectum and urethra were not undertaken. RESULTS: Our study included 473 partnerships (946 men). 30 men had urethral chlamydia, of whom 14 (47%, 95% CI 28 to 66) had a partner with rectal chlamydia. 46 men had rectal chlamydia, of whom 14 (30%, 95% CI 18 to 46) had a partner with urethral chlamydia. The proportion of men with rectal chlamydia when their partner had urethral chlamydia was significantly higher than the proportion of men with urethral chlamydia when their partner had rectal chlamydia (McNemar's p = 0.02). CONCLUSIONS: This is the first study of chlamydia concordance in male sexual partnerships and suggests that transmission of chlamydia between the urethra and rectum may be less efficient than has been reported for transmission between the urethra and cervix in heterosexual couples. It also suggests that transmission from the urethra to the rectum may be more efficient than in the opposite direction.

MiR-301a regulates E-cadherin expression and is predictive of prostate cancer recurrence.

BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression post-transcriptionally. Dysregulation of miRNA has been implicated in the development and progression of prostate cancer. Through next generation miRNA sequencing, we recently identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. Of the five miRNAs, miR-301a had the strongest association with prostate cancer recurrence. Overexpression of miR-301a in prostate cancer cells, PC3, and LNCaP resulted in increased growth both in vitro and in xenografted tumors. We therefore sought to examine its role in prostate carcinogenesis in greater detail. METHODS: We examined the effect of miR-301a expression on biochemical recurrence and metastasis among 585 men treated with radical prostatectomy for prostate cancer. We examined the mechanism of growth deregulation by miR-301a in prostate cancer cells using analysis of the miRome of prostate cancer cell lines, quantitative PCR, and Western blotting. RESULTS: High levels of miR-301a (above the median) were associated with an increased risk of biochemical recurrence (adjusted hazard ratio [aHR] 1.42, 95% confidence interval (CI) 1.06-1.90, P = 0.002) but not of metastasis (aHR 0.84, 95%CI 0.41-1.70, P = 0.6) after adjustment for known prognostic factors. RNA transcriptome sequencing analysis of miR-301a overexpressing prostate cancer cell lines identified the tumor suppressor p63 as a potential direct miR-301a target. Transcriptome sequencing, qPCR and Western blotting showed that miR-301a induced epithelial-mesenchymal transition (EMT) in prostate cancer cells through a pathway initiated by p63 inhibition. Luciferase assay verified p63 as a direct target of miR-301a. Loss of p63 resulted in miR-205 downregulation, releasing Zeb1 and Zeb2 from inhibition, culminating in Zeb1/Zeb2 suppression of E-cadherin. This pathway of growth alteration mediated by miR-301a upregulation was shown to be valid in prostate cancer cell lines and patient-derived tumors. CONCLUSIONS: These data indicate that miR-301a functions as an oncogene in prostate cancer by directly targeting the p63 tumor suppressor leading to loss of E-cadherin and EMT. Hence, miR-301a may serve as a novel biomarker in prostate cancer as well as a therapeutic target for prostate cancer management. Prostate 76:869-884, 2016. © 2016 Wiley Periodicals, Inc.

A Pilot Study to Evaluate the Role of Magnetic Resonance Imaging for Prostate Cancer Screening in the General Population.

PURPOSE: To our knowledge the role of magnetic resonance imaging as a first line screening test for prostate cancer is unknown. We performed a pilot study to evaluate the feasibility of prostate magnetic resonance imaging as the primary screening test for prostate cancer. MATERIALS AND METHODS: We recruited unselected men from the general population. Prostate multiparametric magnetic resonance imaging and random or targeted biopsies were performed in all patients, in addition to prostate specific antigen testing. We compared the performance of prostate magnetic resonance imaging and prostate specific antigen test results to predict prostate cancer. RESULTS: Of the 47 recruited patients 18 (38.3%) had cancer while 29 (61.7%) had no evidence of cancer. The adjusted OR of prostate cancer was significantly higher for magnetic resonance imaging score than for prostate specific antigen level (2.7, 95% CI 1.4-5.4, p = 0.004 vs 1.1, 95% CI 0.9-1.4, p = 0.21). Among the 30 patients with a normal prostate specific antigen (less than 4.0 ng/ml) the positive predictive value in those with a magnetic resonance imaging score of 4 or more was 66.7% (6 of 9) and the negative predictive value in those with a magnetic resonance imaging score of 3 or less was 85.7% (18 of 21, p = 0.004). CONCLUSIONS: In this pilot study we determined the feasibility of using multiparametric prostate magnetic resonance imaging as the primary screening test for prostate cancer. Initial results showed that prostate magnetic resonance imaging was better to predict prostate cancer than prostate specific antigen in an unselected sample of the general population.

Inferior vena cava filter penetration into right proximal ureter.

Inferior vena cava (IVC) filter penetration into the renal collecting system is an infrequent event. We report a case of IVC filter penetration into the right proximal ureter resulting in gross hematuria, hydronephrosis and stone formation.

Aggressive prostatic adenocarcinoma with urothelial-like morphology, with frequent CK7/CK20/HMWK expression and occasional diffuse neuroendocrine features: A clinicopathologic study of 12 cases.

INTRODUCTION: Prostatic adenocarcinoma can occasionally display urothelial carcinoma morphology, which prompts immunohistochemistry (IHC) studies to determine its lineage. Typically, prostate cancer is characterized by the lack of cytokeratin (CK) 7, CK20 and high molecular weight keratin (HMWK) expression, as opposed to bladder cancer. METHODS: We report a series of 12 prostatic adenocarcinoma cases with unusual urothelial-like morphology, diagnosed at two academic institutions in Toronto between 2018 and 2023, and analyzed by immunohistochemistry for prostatic, urothelial, and neuroendocrine marker expression. We collected patient age, androgen deprivation therapy (ADT) status, tumour site, histomorphology, Grade group (GG) and results of genetic testing. RESULTS: The median age of the 12 patients included in this case series was 75.5 years (range 41-85). A history of prostatic cancer was noted in 7/12 (58%) patients. Five of nine (56%) patients had elevated serum PSA level at diagnosis. Six of eleven (55%) patients had prior ADT. Tumour sites were prostate (n = 6), bladder (n = 3), liver metastases (n = 2), and lung metastasis (n = 1). GGs of the primary tumours were GG3 (n = 1) and GG5 (n = 8). The observed urothelial-like morphology was diffuse in ten cases, and focal in two cases. CK7 was strong/diffuse in 8/11 tested cases, and focal weak in one case. CK20, HMWK, p63 and GATA3 were patchy/focal/weak/moderate in 3/6, 4/7, 4/8 and 2/9 cases, respectively. Ten (83%) cases were positive for at least one prostatic marker; eight (67%) cases had loss/weak staining of at least one prostatic marker. AR loss was seen in 2/7 (29%) cases. Seven of ten (70%) cases had diffuse/strong expression of at least one neuroendocrine marker. No trend was evident between prior ADT/AR status and any IHC result. Molecular analyses for DNA damage repair (DDR) genes (n = 6) demonstrated one ATM deletion (bladder). In addition, one TMPRSS2:ERG fusion (lung metastasis) was identified. CONCLUSION: This series comprises high-grade and/or metastatic prostatic adenocarcinoma cases with distinctive urothelial-like morphology and frequent aberrant CK7/CK20/HMWK expression. Their histomorphology, highly suggestive of an urothelial origin, represents a diagnostic pitfall that can lead to considerable management repercussions. The fact that a high proportion of the reported cases had loss/weak expression of at least one of the tested prostatic-specific markers, and occasionally a diffuse positivity for neuroendocrine markers highlights the importance of (1) clinical history and (2) utilization of broad IHC panels to correctly diagnose such unusual prostate cancer cases.

(18)F-FDG PET/CT predicts survival in patients with inflammatory breast cancer undergoing neoadjuvant chemotherapy.

PURPOSE: The objective of this study was to evaluate the role of (18)F-FDG PET/CT in predicting overall survival in inflammatory breast cancer patients undergoing neoadjuvant chemotherapy. METHODS: Included in this retrospective study were 53 patients with inflammatory breast cancer who had at least two PET/CT studies including a baseline study before the start of neoadjuvant chemotherapy. Univariate and multivariate analyses were performed to assess the effects on survival of the following factors: tumor maximum standardized uptake value (SUVmax) at baseline, preoperatively and at follow-up, decrease in tumor SUVmax, histological tumor type, grade, estrogen, progesterone, HER2/neu receptor status, and extent of disease at presentation including axillary nodal and distant metastases. RESULTS: By univariate analysis, survival was significantly associated with decrease in tumor SUVmax and tumor receptor status. Patients with decrease in tumor SUVmax had better survival (P = 0.02). Patients with a triple-negative tumor (P = 0.0006), a Her2/neu-negative tumor (P = 0.038) or an ER-negative tumor (P = 0.039) had worse survival. Multivariate analysis confirmed decrease in tumor SUVmax and triple-negative receptor status as significant predictors of survival. Every 10% decrease in tumor SUVmax from baseline translated to a 15% lower probability of death, and complete resolution of tumor FDG uptake translated to 80% lower probability of death (P = 0.014). Patients with a triple-negative tumor had 4.11 times higher probability of death (P = 0.004). CONCLUSION: Decrease in tumor SUVmax is an independent predictor of survival in patients with inflammatory breast cancer undergoing neoadjuvant chemotherapy. Further investigation with prospective studies is warranted to clarify its role in assessing response and altering therapy.

A Rare Disease Presentation of Malignant Fungating Acral Melanoma of the Hand.

Malignant melanoma is relatively uncommon and accounts for 1%-3% of all malignant tumors. Malignant melanoma of the hand is exceptionally rare and highly malignant, with rapid progression if left untreated. Early clinical symptoms can be overlooked, and the tumor is often at a late stage when patients seek care, prompting amputation of the affected region. We present a case of a 48-year-old man who presented with a rapidly progressive, large, fungating mass of the distal aspect of the little finger diagnosed as malignant melanoma. We describe the presentation and treatment of this patient, who ultimately underwent partial amputation of the fifth metacarpal. Histologic analysis demonstrated nodular melanoma.

Efficacy of high dose tranexamic acid (TXA) for hemorrhage: A systematic review and meta-analysis.

BACKGROUND: Standard dose (≤ 1 g) tranexamic acid (TXA) has established mortality benefit in trauma patients. The role of high dose IV TXA (≥2 g or ≥30 mg/kg as a single bolus) has been evaluated in the surgical setting, however, it has not been studied in trauma. We reviewed the available evidence of high dose IV TXA in any setting with the goal of informing its use in the adult trauma population. METHODS: We searched MEDLINE, EMBASE and unpublished sources from inception until July 27, 2022 for studies that compared standard dose with high dose IV TXA in adults (≥ 16 years of age) with hemorrhage. Screening and data abstraction was done independently and in duplicate. We pooled trial data using a random effects model and considered randomized controlled trials (RCTs) and observational cohort studies separately. We assessed the individual study risk of bias using the Cochrane Risk of Bias for RCTs and the Newcastle-Ottawa Scale for observational cohort studies. The overall certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: We included 20 studies with a combined total of 12,523 patients. Based on pooled RCT data, and as compared to standard dose TXA, high dose IV TXA probably decreases transfusion requirements (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.76 to 0.97, moderate certainty) but with possibly no effect on blood loss (mean difference [MD] 43.31 ml less, 95% CI 135.53 to 48.90 ml less, low certainty), and an uncertain effect on thromboembolic events (OR 1.33, 95% CI 0.86 to 2.04, very low certainty) and mortality (OR 0.70, 95% CI 0.37 to 1.32, very low certainty). CONCLUSION: When compared to standard dose, high dose IV TXA probably reduces transfusion requirements with an uncertain effect on thromboembolic events and mortality. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level IV.

The accuracy of Fetoplacental Doppler in distinguishing between growth restricted and constitutionally small fetuses.

INTRODUCTION: Fetoplacental Doppler is considered to be a key tool for the diagnosis of placenta-mediated fetal growth restriction(FGR). We aimed to determine the diagnostic accuracy of fetoplacental Doppler for specific placental diseases. METHODS: A retrospective cohort study of all women with a singleton pregnancy and an antenatal diagnosis of SGA fetus(estimated fetal weight <10th centile for gestational age), who underwent fetoplacental Doppler assessment within 2 weeks before birth. Primary exposure was any abnormal Doppler result, defined as an abnormal umbilical artery(UA) Doppler, middle cerebral artery(MCA) Doppler, cerebroplacental-ratio(CPR), or umbilico-cerebral ratio(UCR). Study outcomes were abnormal placental pathology: maternal vascular malperfusion(MVM), villitis of unknown etiology(VUE), or fetal vascular malperfusion(FVM). RESULTS: A total of 558 women with a singleton SGA fetus were included, of whom 239(42.8%) had an abnormal fetoplacental Doppler findings. UA Doppler had the lowest detection rate for abnormal placental pathology. MCA Doppler exhibited a significantly higher detection rate for all types of pathology. CPR and UCR exhibited highest detection rates for all types of placental pathology, however, were also associated with the highest false positive rate. The combination of fetoplacental Doppler with the severity of SGA and maternal hypertensive status achieved a high negative predictive value MVM lesions(97%). In contrast, fetoplacental Doppler did not improve the negative predictive value for non-MVM pathology(VUE or FVM). DISCUSSION: Among SGA fetuses, the combination of UA and MCA Doppler is highly accurate in ruling out FGR due to MVM placental pathology, but is of limited value in excluding FGR due to underlying non-MVM pathologies.

Development of a Clinically Applicable NanoString-Based Gene Expression Classifier for Muscle-Invasive Bladder Cancer Molecular Stratification.

Transcriptional profiling of muscle-invasive bladder cancer (MIBC) using RNA sequencing (RNA-seq) technology has demonstrated the existence of intrinsic basal and luminal molecular subtypes that vary in their prognosis and response to therapy. However, routine use of RNA-seq in a clinical setting is restricted by cost and technical difficulties. Herein, we provide a single-sample NanoString-based seven-gene (KRT5, KRT6C, SERPINB13, UPK1A, UPK2, UPK3A and KRT20) MIBC molecular classifier that assigns a luminal and basal molecular subtype. The classifier was developed in a series of 138 chemotherapy naïve MIBCs split into training (70%) and testing (30%) datasets. Further, we validated the previously published CK5/6 and GATA3 immunohistochemical classifier which showed high concordance of 96.9% with the NanoString-based gene expression classifier. Immunohistochemistry-based molecular subtypes significantly correlated with recurrence-free survival (RFS) and disease-specific survival (DSS) in univariable (p = 0.006 and p = 0.011, respectively) and multivariate cox regression analysis for DSS (p = 0.032). Used sequentially, the immunohistochemical- and NanoString-based classifiers provide faster turnaround time, lower cost per sample and simpler data analysis for ease of clinical implementation in routine diagnostics.

Prostate MRI versus PSA screening for prostate cancer detection (the MVP Study): a randomised clinical trial.

OBJECTIVES: Our objective was to compare prostate cancer detection rates between patients undergoing serum prostate-specific antigen (PSA) vs magnetic resonance imaging (MRI) for prostate cancer screening. DESIGN: Phase III open-label randomised controlled trial. SETTING: Single tertiary cancer centre in Toronto, Canada. PARTICIPANTS: Men 50 years of age and older with no history of PSA screening for ≥3 years, a negative digital rectal exam and no prior prostate biopsy. INTERVENTIONS: Patients were recommended to undergo a prostate biopsy if their PSA was ≥2.6 ng/mL (PSA arm) or if they had a PIRADS score of 4 or 5 (MRI arm). Patients underwent an end-of-study PSA in the MRI arm. PRIMARY AND SECONDARY OUTCOME MEASURES: Adenocarcinoma on prostate biopsy. Prostate biopsy rates and the presence of clinically significant prostate cancer were also compared. RESULTS: A total of 525 patients were randomised, with 266 in the PSA arm and 248 in the MRI arm. Due to challenges with accrual and study execution during the COVID-19 pandemic, the study was terminated early. In the PSA arm, 48 patients had an abnormal PSA and 28 (58%) agreed to undergo a prostate biopsy. In the MRI arm, 25 patients had a PIRADS score of 4 or 5 and 24 (96%) agreed to undergo a biopsy. The relative risk for MRI to recommend a prostate biopsy was 0.52 (95% CI 0.33 to 0.82, p=0.005), compared with PSA. The cancer detection rate for patients in the PSA arm was 29% (8 of 28) vs 63% (15 of 24, p=0.019) in the MRI arm, with a higher proportion of clinically significant cancer detected in the MRI arm (73% vs 50%). The relative risk for detecting cancer and clinically significant with MRI compared with PSA was 1.89 (95% CI 0.82 to 4.38, p=0.14) and 2.77 (95% CI 0.89 to 8.59, p=0.07), respectively. CONCLUSIONS: Prostate MRI as a stand-alone screening test reduced the rate of prostate biopsy. The number of clinically significant cancers detected was higher in the MRI arm, but this did not reach statistical significance. Due to early termination, the study was underpowered. More patients were willing to follow recommendations for prostate biopsy based on MRI results. TRIAL REGISTRATION NUMBER: NCT02799303.

Hot Seat Diagnosis.

CONTEXT.­: Competency-based medical education relies on frequent formative in-service assessments to ascertain trainee progression. Currently at our institution, trainees receive a summative end-of-rotation In-Training Evaluation Report based on feedback collected from staff pathologists. There is no method of simulating report sign-out. OBJECTIVE.­: To develop a formative in-service assessment tool that is able to simulate report sign-out and provide case-by-case feedback to trainees. Further, to compare time- versus competency-based assessment models. DESIGN.­: Twenty-one pathology trainees were assessed for 20 months. Hot Seat Diagnosis by trainees and trainee assessment by pathologists were recorded in the laboratory information system. In the first iteration, trainees were assessed by using a time-based assessment scale on their ability to diagnose, report, use ancillary tests, comment on clinical implications, and provide intraoperative consultation and/or gross cases. The second iteration used a competency-based assessment scale. Trainees and pathologists completed surveys on the effectiveness of the In-Training Evaluation Report versus the Hot Seat Diagnosis tool. RESULTS.­: Scores from both iterations correlated significantly with other assessment tools including the Resident In-Service Examination (r = 0.93, P = .04 and r = 0.87, P = .03). The competency-based model was better able to demonstrate improvement over time and stratify junior versus senior trainees than the time-based model. Trainees and pathologists rated Hot Seat Diagnosis as significantly more objective, detailed, and timely than the In-Training Evaluation Report, and effective at simulating report sign-out. CONCLUSIONS.­: Hot Seat Diagnosis is an effective tool for the formative in-service assessment of pathology trainees and simulation of report sign-out, with the competency-based model outperforming the time-based model.

The biodistribution of [153Gd]Gd-labeled magnetic resonance contrast agents in a transgenic mouse model of renal failure differs greatly from control mice.

Nephrogenic systemic fibrosis occurs in renally impaired patients who have undergone contrast enhanced MR examination using intravenous gadolinium-based contrast agents. The effect of impaired kidney function on the biodistribution of gadolinium-based contrast agents was investigated using radiolabeled (153/Nat) gadolinium-DOTA, (153/Nat) gadolinium-DTPA, and (153/Nat) gadolinium-DTPA-BMA in a transgenic mouse model of renal impairment. Renally impaired animals had more activity associated with their tissues than did control mice, and this increase varied according to the radiotracer injected. For example, after 7 days, renally impaired animals that received (153/Nat) Gd-DOTA had 3-fold (P < 0.037) more activity in their bone tissue, whereas renally impaired animals receiving (153/Nat) Gd-DTPA and (153/Nat) Gd-DTPA-BMA had 8-fold (P < 0.0001) and 24-fold (P < 0.0001) more activity in their bone tissue, respectively. These findings demonstrate that renal impairment dramatically alters the tissue distribution of Gd(3+) ions in vivo, which are likely a critical factor in the development of nephrogenic systemic fibrosis.

Mir-139 Regulates Autophagy in Prostate Cancer Cells Through Beclin-1 and mTOR Signaling Proteins.

BACKGROUND/AIM: We previously identified a panel of five miRNAs (including miR-139) associated with biochemical recurrence and metastasis in prostate cancer patients. MATERIALS AND METHODS: We examined miR-139 transfected PC3, DU145 and LNCaP cells by morphology as well as by cell-based assays, confocal microscopy and immunoblotting. RESULTS: We found that treatment of prostate cancer cells with miR-139 resulted in phenotypic changes characteristic of autophagic cells. MiR-139 increased the autophagy-related conversion of the microtubule-associated protein light chain 3 (LC3-I to LC3-II) that was specifically inhibited by the miR-139 antagomir. The upregulation of LC3 II was further confirmed by confocal microscopy. miR-139 regulated activation of both mTOR and Beclin1 the two important autophagy-related molecules. We found that upon miR-139 treatment, the cargo adaptor protein p62 which is degraded during autophagy, accumulates. CONCLUSION: These results suggest that miR-139 is inducing autophagic flux blockade leading to apoptosis in prostate cancer cells through the mTOR and Beclin-1 proteins.

Preparation and biological evaluation of 64Cu-CB-TE2A-sst2-ANT, a somatostatin antagonist for PET imaging of somatostatin receptor-positive tumors.

UNLABELLED: Recently, the somatostatin receptor subtype 2 (SSTR2) selective antagonist sst2-ANT was determined to have a high affinity for SSTR2. Additionally, 111In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-sst2-ANT showed high uptake in an SSTR2-transfected, tumor-bearing mouse model and suggested that radiolabeled SSTR2 antagonists may be superior to agonists for imaging SSTR2-positive tumors. This report describes the synthesis and evaluation of 64Cu-CB-4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-sst2-ANT (64Cu-CB-TE2A-sst2-ANT) as a PET radiopharmaceutical for the in vivo imaging of SSTR2-positive tumors. METHODS: Receptor-binding studies were performed to determine the dissociation constant of the radiopharmaceutical 64Cu-CB-TE2A-sst2-ANT using AR42J rat pancreatic tumor cell membranes. The internalization of 64Cu-CB-TE2A-sst2-ANT was compared with that of the 64Cu-labeled agonist 64Cu-CB-TE2A-tyrosine3-octreotate (64Cu-CB-TE2A-Y3-TATE) in AR42J cells. Both radiopharmaceuticals were also compared in vivo through biodistribution studies using healthy rats bearing AR42J tumors, and small-animal PET/CT of 64Cu-CB-TE2A-sst2-ANT was performed. RESULTS: The dissociation constant value for the radiopharmaceutical was determined to be 26 +/- 2.4 nM, and the maximum number of binding sites was 23,000 fmol/mg. 64Cu-CB-TE2A-sst2-ANT showed significantly less internalization than did 64Cu-CB-TE2A-Y3-TATE at time points from 15 min to 4 h. Biodistribution studies revealed that the clearance of 64Cu-CB-TE2A-sst2-ANT from the blood was rapid, whereas the clearance of 64Cu-CB-TE2A-sst2-ANT from the liver and kidneys was more modest at all time points. Tumor-to-blood and tumor-to-muscle ratios were determined to be better for 64Cu-CB-TE2A-sst2-ANT than those for 64Cu-CB-TE2A-Y3-TATE at the later time points, although liver and kidney uptake was significantly higher. Small-animal imaging using 64Cu-CB-TE2A-sst2-ANT revealed excellent tumor-to-background contrast at 4 h after injection, and standardized uptake values remained high even after 24 h. CONCLUSION: The PET radiopharmaceutical 64Cu-CB-TE2A-sst2-ANT is an attractive agent, worthy of future study as a PET radiopharmaceutical for the imaging of somatostatin receptor-positive tumors.

Uterine wall partial thickness necrosis following combined B-Lynch and Cho square sutures for the treatment of primary postpartum hemorrhage.

BACKGROUND: Postpartum hemorrhage (PPH) is a significant factor in maternal morbidity and mortality. Successful techniques using compression sutures to control PPH have been described, in some cases using a combination of techniques. We describe a case in which compression sutures to control PPH were complicated by subsequent myometrial necrosis. CASE: A healthy 32-year-old woman, gravida 3, para 0, underwent Caesarean section at 41 weeks' gestation after failure to progress in labour. One B-Lynch plus two Cho sutures were used to control postpartum hemorrhage. During a subsequent pregnancy, a large triangular myometrial defect was identified in the mid-anterior uterine wall and two smaller defects in the posterior wall. CONCLUSION: Patients should be informed about the possible complications of the use of compression sutures and the need to undergo postoperative follow-up to confirm uterine wall integrity. We propose the establishment of a national registry of women who undergo placement of compression sutures, in order to document the efficacy and the long-term and short-term complications of this procedure.