A wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery.

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.

High intratumoral plasma cells content in primary prostate cancer defines a subset of tumors with potential susceptibility to immune-based treatments.

BACKGROUND: Data on advanced prostate cancer (PCa) suggest more prior systemic therapies might reduce tumor immune responsiveness. In treatment-naïve primary PCa, recent work correlated intratumoral plasma cell content with enhanced tumor immune-responsiveness. We sought to identify features of localized PCa at a high risk of recurrence following local treatment with high plasma cell content to help focus future immune-based neoadjuvant trials. METHODS: We performed retrospective analyses of molecular profiles from three independent cohorts of over 1300 prostate tumors. We used Wilcoxon Rank Sum to compare molecular pathways between tumors with high and low intratumoral plasma cell content and multivariable Cox proportional hazards regression analyses to assess metastasis-free survival. RESULTS: We validated an expression-based signature for intratumoral plasma cell content in 113 primary prostate tumors with both RNA-expression data and digital image quantification of CD138+ cells (plasma cell marker) based on immunohistochemisty. The signature showed castration-resistant tumors (n = 101) with more prior systemic therapies contained lower plasma cell content. In high-grade primary PCa, tumors with high plasma cell content were associated with increased predicted response to immunotherapy and decreased response to androgen-deprivation therapy. Master regulator analyses identified upregulated transcription factors implicated in immune (e.g. SKAP1, IL-16, and HCLS1), and B-cell activity (e.g. VAV1, SP140, and FLI-1) in plasma cell-high tumors. Master regulators overactivated in tumors with low plasma cell content were associated with shorter metastasis-free survival following radical prostatectomy. CONCLUSIONS: Markers of plasma cell activity might be leveraged to augment clinical trial targeting and selection and better understand the potential for immune-based treatments in patients with PCa at a high risk of recurrence following local treatment.

Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition.

The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in Evi1 lo progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1hi leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1 hi acute myeloid leukemia. SIGNIFICANCE: We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax.See related commentary by Gu et al., p. 1445.This article is highlighted in the In This Issue feature, p. 1426.

Ejaculatory Hood-Sparing Photoselective Vaporization of the Prostate vs Bipolar Button Plasma Vaporization of the Prostate in the Surgical Management of Benign Prostatic Hyperplasia.

Introduction and Objectives: After transurethral prostatectomy, erectile dysfunction and ejaculatory dysfunction are significant concerns for patients. We compared ejaculatory hood-sparing technique in patients who underwent photoselective vaporization of the prostate using the GreenLight Laser (EjS-PVP) with the ejaculatory hood-sparing technique in patients who underwent bipolar button plasma vaporization of the prostate (EjS-BPVP) in the surgical management of benign prostatic hyperplasia (BPH). Materials and Methods: Twenty-seven patients were randomized to either undergo EjS-PVP or EjS-BPVP from August 2016 to March 2018. All of the patients were sexually active with antegrade ejaculation before prostatectomy. We evaluated International Prostate Symptom Score (IPSS), quality of life (QoL), peak flow rate (Qmax), postvoid residual volume (PVR), International Index of Erectile Function and ejaculatory function by the Male Sexual Health Questionnaire (MSHQ). Men were evaluated preoperatively and at 1, 3, and 6 months postoperatively. The primary outcome was ejaculation preservation measured as no change or preservation in antegrade ejaculate at the last follow-up visit by MSHQ (6 months). Results: Twenty-seven patients with a mean age of 65.6 ± 8.4 years underwent either EjS-BPVP or EjS-PVP (Table 1). There were no differences in baseline characteristics between the two groups. Improvements in IPSS, QoL, Qmax, and PVR were durable throughout the study period in both groups. There was no difference in outcomes between groups. Postoperatively, there was no change in ejaculatory function with EjS-BPVP utilizing either 180 W EjS-PVP or bipolar energy. The change in MSHQ Ejaculation Scale was -2.1 and -5.4 at 6 months in both arms. The 6-month ejaculatory preservation rate was 85% in the EjS-PVP group and 78% in the EjS-BPVP group. Conclusions: EjS GreenLight photoselective vaporization and bipolar plasma button vaporization is a safe and effective method for treating men with lower urinary tract symptoms secondary to BPH with maintenance of antegrade ejaculation.

Can men with lower urinary tract symptoms (LUTs) predict voided volumes?

PURPOSE: To determine if patients can accurately estimate volumes voided in a bladder diary, and to determine the patient characteristics that are most predictive of accuracy in volume estimation in the workup of lower urinary tract symptoms (LUTs). METHODS: We prospectively collected data on 180 consecutive patients undergoing a workup for LUTs at a tertiary care facility. Data collected include American Urological Association Symptom Scores (AUASS), flow time and rate, and one time measurement of voided volume into a blinded uroflow. Baseline characteristics and demographics were recorded. Descriptive statistics and linear regression analysis were performed to examine predictors of estimated voiding volume (mL) in SAS Version 9.4 (SAS Institute, Inc., Cary, NC, USA). RESULTS: Median age and BMI were 64 years (SD = 15.4) and 26.9 kg/m2 (SD = 4.6), respectively. The median estimated voided volume and actual voided volume were 120 mL (range 1-480) and 101.5 mL (range 6.5-622.0), respectively. On linear regression analysis, 47.1% of patients estimated volume voided with a 20% margin of error, and 63.2% of patients estimated with a 30% margin of error. Each 1-year increase in age correlated with a 2% decrease in the odds of estimating voided volume within 20% of actual volume (p < 0.05). For each 1 unit increase in flow rate, there was an 8% (p < 0.005) increase in the odds of estimating voided volume within 20% of actual volume. CONCLUSIONS: Just under half of patients can accurately estimate volume voided with a margin of error of 20%.

Emerging drugs for the treatment of benign prostatic hyperplasia.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common condition affecting over 50% of men as they reach their 5th decade of life. This leads to a number of sequelae such as lower urinary tract symptoms, urinary retention and a decrease in quality of life. Currently, the available treatments for BPH are alpha blockers and 5-alpha reductase inhibitors. Clinical studies have demonstrated these medical options are effective in alleviating a patient's symptoms, however there are a number of side effects. There is a paucity of information regarding long-term use of these medications. The purpose of this review is to identify potential and emerging medications for the treatment of BPH. Areas covered: Articles used in this review were retrieved from Pubmed, Google and through searching the PharmaProjects database over the last 10 years, giving the reader an in-depth knowledge about the current pharmacological agents available and other potential treatments for BPH. Expert opinion: The new paradigm of BPH treatment depends on addressing a patient's specific constellation of symptoms. This allows to tailor therapy of increasing efficacy and reduce adverse events that our patients have by increasing dosage.

An epitope tag alters phosphoglycerate dehydrogenase structure and impairs ability to support cell proliferation.

BACKGROUND: The gene encoding the serine biosynthesis pathway enzyme PHGDH is located in a region of focal genomic copy number gain in human cancers. Cells with PHGDH amplification are dependent on enzyme expression for proliferation. However, dependence on increased PHGDH expression extends beyond production of serine alone, and further studies of PHGDH function are necessary to elucidate its role in cancer cells. These studies will require a physiologically relevant form of the enzyme for experiments using engineered cell lines and recombinant protein. RESULTS: The addition of an N-terminal epitope tag to PHGDH abolished the ability to support proliferation of PHGDH-amplified cells despite retention of some activity to convert 3-PG to PHP. Introducing an R236E mutation into PHGDH eliminates enzyme activity, and this catalytically inactive enzyme cannot support proliferation of PHGDH-dependent cells, arguing that canonical enzyme activity is required. Tagged and untagged PHGDH exhibit the same intracellular localization and ability to produce D-2-hydroxyglutarate (D-2HG), an error product of PHGDH, arguing that neither mislocalization nor loss of D-2HG production explains the inability of epitope-tagged PHGDH to support proliferation. To enable studies of PHGDH function, we report a method to purify recombinant PHGDH and found that untagged enzyme activity was greater than N-terminally tagged enzyme. Analysis of tagged and untagged PHGDH using size exclusion chromatography and electron microscopy found that an N-terminal epitope tag alters enzyme structure. CONCLUSIONS: Purification of untagged recombinant PHGDH eliminates the need to use an epitope tag for enzyme studies. Furthermore, while tagged PHGDH retains some ability to convert 3PG to PHP, the structural alterations caused by including an epitope tag disrupts the ability of PHGDH to sustain cancer cell proliferation.