Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.

Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.

BRD4-PRC2 represses transcription of T-helper 2-specific negative regulators during T-cell differentiation.

BRD4 is a well-recognized transcriptional activator, but how it regulates gene transcriptional repression in a cell type-specific manner has remained elusive. In this study, we report that BRD4 works with Polycomb repressive complex 2 (PRC2) to repress transcriptional expression of the T-helper 2 (Th2)-negative regulators Foxp3 and E3-ubiqutin ligase Fbxw7 during lineage-specific differentiation of Th2 cells from mouse primary naïve CD4+ T cells. Brd4 binds to the lysine-acetylated-EED subunit of the PRC2 complex via its second bromodomain (BD2) to facilitate histone H3 lysine 27 trimethylation (H3K27me3) at target gene loci and thereby transcriptional repression. We found that Foxp3 represses transcription of Th2-specific transcription factor Gata3, while Fbxw7 promotes its ubiquitination-directed protein degradation. BRD4-mediated repression of Foxp3 and Fbxw7 in turn promotes BRD4- and Gata3-mediated transcriptional activation of Th2 cytokines including Il4, Il5, and Il13. Chemical inhibition of the BRD4 BD2 induces transcriptional de-repression of Foxp3 and Fbxw7, and thus transcriptional downregulation of Il4, Il5, and Il13, resulting in inhibition of Th2 cell lineage differentiation. Our study presents a previously unappreciated mechanism of BRD4's role in orchestrating a Th2-specific transcriptional program that coordinates gene repression and activation, and safeguards cell lineage differentiation.

Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth.

The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.

Omipalisib Inhibits Esophageal Squamous Cell Carcinoma Growth Through Inactivation of Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) and ERK Signaling.

BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a life-threatening digestive tract malignancy with no known curative treatment. This study aimed to investigate the antineoplastic effects of omipalisib and its underlying molecular mechanisms in ESCC using a high throughput screen. MATERIAL AND METHODS MTT assay and clone formation were used to determine cell viability and proliferation. Flow cytometry was conducted to detect cell cycle distribution and apoptosis. Global gene expression and mRNA expression levels were determined by RNA sequencing and real-time PCR, respectively. Protein expression was evaluated in the 4 ESCC cell lines by Western blot analysis. Finally, a xenograft nude mouse model was used to evaluate the effect of omipalisib on tumor growth in vivo. RESULTS In the pilot screening of a 1404-compound library, we demonstrated that omipalisib markedly inhibited cell proliferation in a panel of ESCC cell lines. Mechanistically, omipalisib induced G0/G1 cell cycle arrest and apoptosis. RNA-seq, KEGG, and GSEA analyses revealed that the PI3K/AKT/mTOR pathway is the prominent target of omipalisib in ESCC cells. Treatment with omipalisib decreased expression of p-AKT, p-4EBP1, p-p70S6K, p-S6, and p-ERK, therefore disrupting the activation of PI3K/AKT/mTOR and ERK signaling. In the nude mouse xenograft model, omipalisib significantly suppressed the tumor growth in ESCC tumor-bearing mice without obvious adverse effects. CONCLUSIONS Omipalisib inhibited the proliferation and growth of ESCC by disrupting PI3K/AKT/mTOR and ERK signaling. The present study supports the rationale for using omipalisib as a therapeutic approach in ESCC patients. Further clinical studies are needed.

A novel fluorescent probe for the early detection of prostate cancer based on endogenous zinc sensing.

BACKGROUND: The early detection of prostate cancer can significantly optimize the prognosis, prolong patient lifespan, and improve quality of life. It has been well documented that prostate cancer tissues have lower zinc content than normal prostate tissues due to an impairment of the zinc accumulation mechanism. METHODS: A novel diketopyrrolopyrrole (DPP)-based fluorescent zinc ion probe named DPP-C2 was prepared. The fluorescent intensity of this novel molecule is in direct proportion to environmental zinc concentration. Malignant (DU145 and PC3 cells) and normal prostate epithelial RWPE-1 cells were tested. Prostate cancer tissues were also cultured and observed as tissue sections. The probe was also intravenously administered to tumor-bearing (DU145 and PC3 cells) nude mice and observed under a whole-body fluorescence live-imaging system. RESULTS: The probe showed minimal cytotoxicity to malignant and normal prostate cells. The RWPE-1 cells showed not only stronger baseline fluorescence but also a significant increase in signal intensity after culturing in a zinc-supplemented medium. In human prostate sections, the pathologically confirmed cancer tissues exhibited weaker fluorescence signals than normal and benign hyperplastic tissues. With proper excitation, prostate tissues revealed more intense fluorescence signals than tumor tissues, whereas other surrounding tissues showed almost no fluorescence. CONCLUSIONS: The novel zinc ion fluorescent probe DPP-C2 is low toxic and showed potential application for the early detection of prostate cancer based on endogenous zinc sensing.

Staged male genital reconstruction with a local flap and free oral graft: a case report and literature review.

BACKGROUND: Male genital skin loss is a common disease in urology. However, male genital skin loss accompanying a penile urethra defect is rarely reported. Herein, we describe a novel surgical technique using a composite local flap and oral mucosal graft to reconstruct the penis, which may provide a new solution for patients with similar conditions. CASE PRESENTATION: A 36-year-old male with a penile urethra defect and a large area of genital skin loss required urethral reconstruction. The meatus had descended to the penoscrotal junction. This procedure was divided into three stages. The first stage of the surgery involved burying the nude penile shaft beneath the skin of the left anteromedial thigh for coverage of the skin defect. The second stage consisted of releasing the penis and expanding the size of the urethral plate for further urethroplasty. The third stage consisted of reconstruction of the anterior urethra 6 months later. Postoperatively, the patient reported satisfactory voiding. The maximal flow rate (MFR) was 22.2 ml/s with no postvoiding residual urine at the 24-month follow-up visit. No edema, infection, hemorrhage, or cicatricial retraction were observed. The patient's erectile function was satisfactory, and his international index of erectile function-5 score (IIEF-5 score) was 23 at the 24-month follow-up visit. Additionally, the presence of nocturnal penile tumescence demonstrated that he had normal erectile function. CONCLUSIONS: This procedure is an effective surgical option for men with complete foreskin and penile urethra defects. It could also be extended as a treatment strategy when composite local or pedicle transposition flaps and free grafts are needed for specific patients.

Survival analysis of patients with invasive extramammary Paget disease: implications of anatomic sites.

BACKGROUND: Extramammary Paget disease (EMPD) is a rare malignant dermatosis with poorly defined outcomes. We investigated clinical characteristics of invasive EMPD at different anatomic sites and by subject demographics to determine prognostic factors for overall survival (OS). METHODS: All patient data were collected from the Surveillance, Epidemiology, and End Results (SEER) program, 1973-2013, of the U.S. National Cancer Institute. Patients with invasive EMPD of skin, vulva/labia, vagina, scrotum/penis, or other sites were included. After excluding patients with unknown radiation status, data of 2001 patients were analyzed. Primary endpoint was EMPD mortality by anatomic sites. Independent variables included patients' demographic data, concurrent malignancy (ie, non-EMPD related cancers), tumor size, distant metastasis, and surgery and/or radiation or not. RESULTS: Multivariate regression analysis showed that mortality was significantly higher in patients with vaginal EMPD than in patients with vulvar/labial EMPD (adjusted hazard ratio [aHR] = 3.26, p < 0.001). Patients with distant metastasis had higher mortality than those without (aHR = 3.36, p < 0.001). Patients who received surgery had significantly lower mortality than those who did not receive surgery (aHR = 0.77, p = 0.030), and those treated with radiation had significantly higher mortality than those who did not receive radiation (aHR = 1.60, p = 0.002). Older age was associated with significantly increased mortality (aHR = 1.09, p < 0.001), and mortality was significantly higher in males than in females (aHR = 1.42, p = 0.008). CONCLUSIONS: In conclusion, among EMPD patients, mortality is higher in patients with vaginal EMPD than in those with vulvar/labial EMPD and higher in those who are older, those with concurrent malignancy or distant metastasis. Mortality is also higher in males than in females. Surgery is a protective factor and radiation is a risk factor for OS. Greater understanding of EMPD clinical characteristics, and considering EMPD in differential diagnosis of chronic genital and perianal dermatoses may provide support for early EMPD diagnosis and definitive surgical treatment.

Aberrant miR-21 and miR-200b expression and its pro-fibrotic potential in hypertrophic scars.

The post-traumatic hypertrophic scar (HS) is a fibrotic disease with excessive extracellular matrix (ECM) production by fibroblasts in response to tissue injury. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNA in hypertrophic scar formation is unclear. Abnormal expression of miRNA in fibrosis has been investigated in several studies. The transforming growth factor ß1 (TGF-ß1) promotes fibroblasts proliferation, the synthesis of collagen and other extracellular matrix, and ultimately leads to the formation of the HS by inducing excessive deposition of ECM. We identified two miRNAs whose expression was correlated with fibrotic diseases: miR-21 and miR-200b. This study further confirmed that after stimulation with TGF-ß1, the expression of miR-21 was increased, whereas the mRNA level of SMAD7 was decreased in fibroblasts. TGF-ß1 reduced the expression of miR-200b, while it augmented that of Zinc finger E-box-binding homeobox 1(Zeb1). Our experiments demonstrated that the expression of miR-21 and miR-200b are related to a disorder, and the TGF-ß/miR-21/Smad7 and TGF-ß/miR200b/Zeb1 pathways might participate in the pathogenesis of HS. Thus, a novel, beyond the traditional methods, approach for HS treatment via miRNA therapeutics could have been provided.

Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells.

Men with sickle cell disease (SCD) risk developing priapism. Recognizing that SCD is a disease of hypoxia, we investigated the effect of hypoxia on gene expression in corporal smooth muscle (CSM) cells. Rat CSM cells in vitro were treated with CoCl2 or low oxygen tension to mimic hypoxia. Hypoxic conditions increased expression of genes previously associated with priapism in animal models. Variable coding sequence a1 (Vcsa1; the rat opiorphin homologue, sialorphin), hypoxia-inducible factor 1a (Hif-1a), and A2B adenosine receptor (a2br) were increased by 10-, 4-, and 6-fold, respectively, by treatment with CoCl2, whereas low oxygen tension caused increases in expression of 3-, 4-, and 1.5-fold, respectively. Sialorphin-treated CSM cells increased expression of Hif-1a and a2br by 4-fold, and vcsa1-siRNA treatment reduced expression by ∼50%. Using a Hif-1a inhibitor, we demonstrated up-regulation of a2br by sialorphin is dependent on Hif-1a, and knockdown of vcsa1 expression with vcsa1-siRNA demonstrated that hypoxic-up-regulation of Hif-1a is dependent on vcsa1. In CSM from a SCD mouse, there was 15-fold up-regulation of opiorphin at a life stage prior to priapism. We conclude that in CSM, opiorphins are master regulators of the hypoxic response. Opiorphin up-regulation in response to SCD-associated hypoxia activates CSM "relaxant" pathways; excessive activation of these pathways results in priapism.

Diabetes attenuates urothelial modulation of detrusor contractility and spontaneous activity.

OBJECTIVES: To investigate the effect of diabetes on urothelial modulation of bladder contractility. METHODS: Bladder strips (urothelium intact or denuded) were prepared from 8-week-old streptozotocin-induced diabetic (n = 19) and non-diabetic control rats (n = 10). The effect of modulators of MaxiK (iberiotoxin and tetraethylammonium) and Kv7 (XE991 and retigabine) potassium channel activity were investigated for their effects on both carbachol-induced force generation and spontaneous contractile activity. RESULTS: In bladder strips from non-diabetic animals, the presence of the urothelium resulted in marked sensitivity to carbachol-induced force generation by modulators of MaxiK and Kv7 channel activity, whereas in the diabetic animal urothelial sensitivity to these agents was significantly diminished. Urothelial-intact bladder strips from non-diabetic animals were more sensitive to modulators of Kv7 activity in reducing the amplitude of spontaneous phasic contractions than urothelial-denuded bladder strips, whereas in diabetic animals the presence or absence of the urothelium did not alter the sensitivity to modulators of Kv7 activity. Spontaneous activity in the presence of tetraethylammonium was not affected by the urothelium in bladder strips from either diabetic or non-diabetic animals. CONCLUSIONS: The presence of the urothelium in bladders from non-diabetic animals modulates the activity of potassium blockers to affect bladder contractility, whereas in the diabetic bladder this effect is attenuated. These findings could help to explain the lack of success of pharmaceutical treatments targeting potassium channels to treat bladder pathology in patients with diseases imparing urothelial function.

A Self-Powered Hydrogel/Nanogenerator System Accelerates Wound Healing by Electricity-Triggered On-Demand Phosphatase and Tensin Homologue (PTEN) Inhibition.

Electrical stimulation therapy (EST) has been established as an effective strategy to accelerate wound healing by stimulating cell proliferation and migration, ultimately promoting re-epithelialization and vascularization, two key processes that significantly influence the rate of wound healing. Phosphatase and tensin homologue (PTEN), a widely expressed protein in somatic cells, works as a "brake" regulating cell differentiation, proliferation, and migration. Given that this "brake" also works in cell electrical responses, there is a hypothesis that PTEN inhibition may amplify the efficacy of EST in wound treatment. However, long-term inhibition of PTEN may result in DNA damage and reduce DNA repair, which poses a significant challenge to the safe use of PTEN inhibitors. To address this issue, we developed a system that combines PTEN inhibitor loaded electro-responsive hydrogel (BPV@PCP) with a wearable direct current pulse piezoelectric nanogenerator (PENG). The PENG converts the rat's motions into electric fields that synchronously charge the wound edge tissue and BPV@PCP. Electric field intensity was lower when the rat was quiet or anesthetized, which is insufficient to trigger an effective PTEN inhibitor release. However, when the rat was in action, the electric field intensity exceeded 625 mV/mm, resulting in a rapid drug release. This on-demand PTEN inhibition accelerated wound healing by amplifying cell electric responsiveness while avoiding negative effects associated with continuous overinhibition of PTEN. Notably, this system improves vascularization not only by improving endothelial cell electric responsiveness but also through the paracrine pathway, in which electrical stimulation and PTEN inhibition synergically promote VEGF secretion.

Silk Nanocarrier with Tunable Size to Improve Transdermal Capacity for Hydrophilic and Hydrophobic Drugs.

Transdermal drug delivery is an attractive option for multiple disease therapies as it reduces adverse reactions and improves patient compliance. Water-dispersible ß-sheet rich silk nanofiber carriers have hydrophobic properties that benefit transdermal delivery but still show inferior transdermal capacities. Thus, hydrophobic silk nanofibers were fabricated to fine-tune their size and endow them with desirable transdermal delivery capacities. Silk nanocarrier length was shortened from 2000 nm to approximately 40 nm after ultrasonic treatment. In vitro human skin and in vivo animal studies revealed different transdermal behaviors for silk nanocarriers at different nanosizes. Silk nanocarriers passed slowly through the corneum without destroying the corneum structure. Improved transdermal capacity was achieved for smaller size carriers. Both hydrophilic and hydrophobic drugs could be loaded onto silk nanocarriers, suggesting a promising future for different disease therapies. No cytotoxicity and skin irritation were identified for silk nanocarriers, which strengthened their superiority as transdermal carriers. Therefore, silk nanocarriers <100 nm may promote the percutaneous absorption of active cargos for disease therapy and cosmetic applications.

An Active Vibration Isolation and Compensation System for Improving Optical Image Quality: Modeling and Experiment.

Optical detection equipment (ODE) is subjected to vibrations that hamper the quality of imaging. In this paper, an active vibration isolation and compensation system (VICS) for the ODE is developed and systematically studied to improve the optical imaging quality. An active vibration isolator for cameras is designed, employing a dual-loop control strategy with position compensation and integral force feedback (IFF) control, and establishing the mapping relationship between vibration and image quality. A performance metric for evaluating images is also proposed. Finally, an experimental platform is constructed to verify its effectiveness. Based on the experimental results, it can be concluded that the proposed VICS effectively isolates vibrations, resulting in a reduction of 13.95 dB in the peak at the natural frequency and an 11.76 Hz widening of the isolation bandwidth compared with the system without it. At the same time, the experiments demonstrate that the image performance metric value increases by 46.03% near the natural frequency.

Production and Biological Effects of Extracellular Vesicles from Adipose-Derived Stem Cells Were Markedly Increased by Low-Intensity Ultrasound Stimulation for Promoting Diabetic Wound Healing.

Diabetic wound treatment has posed a significant challenge in clinical practice. As a kind of cell-derived nanoparticles, extracellular vesicles produced by adipose-derived stem cells (ADSC-EVs) have been reported to be potential agents for diabetic wound treatment. However, ADSC-EV yield is insufficient to meet the demands of clinical therapy. In this study, a novel method involving the use of low-intensity ultrasound stimulation on ADSCs is developed to promote EV secretion for clinical use. A proper low-intensity ultrasound stimulation parameter which significantly increases ADSC-EV quantity has been found. In addition, EVs secreted by ADSCs following low-intensity ultrasound stimulation (US-EVs) are enriched in wound healing-related miRNAs. Moreover, US-EVs promote the biological functions of fibroblasts, keratinocytes, and endothelial cells in vitro, and promote diabetic wound healing in db/db mice in vivo through re-epithelialization, collagen production, cell proliferation, keratinocyte differentiation and migration, and angiogenesis. This study proposes low-intensity ultrasound stimulation as a new method for promoting significant EV secretion by ADSCs and for improving the diabetic wound-healing potential of EVs, which will meet the clinical needs for these nanoparticles. The production of extracellular vesicles of adipose-derived stem cells is obviously promoted by a low-intensity ultrasound stimulation method, and the biological effects of promoting diabetic wound healing were markedly increased in vitro and in vivo.

Preparation of therapy-grade extracellular vesicles from adipose tissue to promote diabetic wound healing.

Background: Treatment of diabetic wounds is a major challenge in clinical practice. Extracellular vesicles (EVs) from adipose-derived stem cells have shown effectiveness in diabetic wound models. However, obtaining ADSC-EVs requires culturing vast numbers of cells, which is hampered by the need for expensive equipment and reagents, extended time cost, and complicated procedures before commercialization. Therefore, methods to extract EVs from discarded tissue need to be developed, for immediate application during surgery. For this reason, mechanical, collagenase-digestive, and constant in-vitro-collective methods were designed and compared for preparing therapy-grade EVs directly from adipose tissue. Methods: Characteristics and quantities of EVs were detected by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting firstly. To investigate the biological effects of EVs on diabetic wound healing, angiogenesis, proliferation, migration, and inflammation-regulation assays were then evaluated in vitro, along with a diabetic wound healing mouse model in vivo. To further explore the potential therapeutic mechanism of EVs, miRNA expression profile of EVs were also identified and analyzed. Results: The adipose tissue derived EVs (AT-EVs) were showed to qualify ISEV identification by nanoparticle tracking analysis and Western blotting and the AT-EVs yield from three methods was equal. EVs also showed promoting effects on biological processes related to diabetic wound healing, which depend on fibroblasts, keratinocytes, endothelial cells, and macrophages both in vitro and in vivo. We also observed enrichment of overlapping or unique miRNAs originate from different types of AT-EVs associated with diabetic wound healing for further investigation. Conclusion: After comparative analyses, a mechanical method was proposed for preparing immediate clinical applicable EVs from adipose tissue that would result in reduced preparation time and lower cost, which could have promising application potential in treating diabetic wounds.

Coffee consumption and all-cause and cardiovascular mortality in older adults: should we consider cognitive function?

Background: The association between coffee and mortality risk has been found in most previous studies, and recent studies have found an association between coffee consumption and cognition. However, there is still a lack of research exploring whether the association between coffee and mortality is influenced by cognitive function. Objective: The purpose of this study was to explore the association of coffee, caffeine intake in coffee and decaffeinated coffee with all-cause mortality and cardiovascular disease (CVD) mortality in older adults with different cognitive performances. Methods: The study was based on data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Coffee and caffeine consumption data were obtained from two 24-h dietary recalls. Individual cognitive functions were assessed by CERAD-word learning test (CERAD-WLT), animal fluency test (AFT), and digit symbol substitution test (DSST). In addition, principal component analysis (PCA) was performed with the above test scores to create global cognitive score. The lowest quartile of scores was used to classify cognitive performance. Cox regression and restricted cubic spline (RCS) were applied to assess the relationship between coffee and caffeine consumption and mortality. Results: In the joint effects analysis, we found that those with cognitive impairment and who reported without drinking coffee had the highest risk of all-cause and cardiovascular mortality compared with others. In the analysis of population with cognitive impairment, for all-cause mortality, those who showed cognitive impairment in the AFT displayed a significant negative association between their total coffee consumption and mortality {T3 (HR [95% CI]), 0.495 [0.291-0.840], p = 0.021 (trend analysis)}. For DSST and global cognition, similar results were observed. Whereas for CERAD-WLT, restricted cubic spline (RCS) showed a "U-shaped" association between coffee consumption and mortality. For CVD mortality, a significant negative trend in coffee consumption and death was observed only in people with cognitive impairment in AFT or DSST. In addition, we observed that decaffeinated coffee was associated with reduced mortality in people with cognitive impairment. Conclusion: Our study suggested that the association between coffee consumption and mortality is influenced by cognition and varies with cognitive impairment in different cognitive domains.

A GLUT1 inhibitor-based fluorogenic probe for Warburg effect-targeted drug screening and diagnostic imaging of hyperglycolytic cancers.

Increased expression of glucose transporters, especially GLUT1 has been proven to be involved in the Warburg effect. Therefore, GLUT1-targeted oncological approaches are being successfully employed for clinical tumor diagnostic imaging (e.g. the 18F-FDG/PET), drug delivery and novel anticancer drug development. Despite the long history of the Warburg effect-targeted cancer diagnosis, other than antibody labeling, there have been no imaging tools developed for direct detection of the GLUT1 expression. Herein, we report the new strategy of using a non-antibody GLUT1 binding probe for Warburg effect-based tumor detection and diagnostic imaging. By specifically inhibits the transport function of GLUT1, the newly designed fluorescent probe, CUM-5, was found to be a useful tool not only for sensitive GLUT1-mediated cancer cell detection, but also for cell-based high-throughput GLUT inhibitor screening. In in vivo studies, CUM-5 shows clear advantages including desirable tumor-to-normal tissue contrast and excellent tumor selectivity (Tm/Bkg and Tm/Torg), as well as high fluorescence stability (long response time) and ideal physiological biocompatibility. In particular, the GLUT1 inhibitor probe offers the potential use for glycolysis-based diagnostic imaging in triple-negative breast cancer which is claimed to have unsatisfactory results with FDG/PET diagnosis, thus remaining a highly metastatic and lethal disease with a need for sensitive and precise identification.

An extracellular matrix-mimicking, bilayered, heterogeneous, porous, nanofibrous scaffold for anterior urethroplasty in a rabbit model.

Anterior urethral reconstruction is still a challenging clinical task, and tissue engineering technology offers new options for anterior urethroplasty. In this work, we evaluated an extracellular matrix (ECM) mimicking scaffold for anterior urethral reconstruction in a New Zealand white rabbit model. After the creation of a urethral defect, the ECM-mimicking scaffold was applied in six rabbits, and small intestinal submucosa (SIS) was used in three rabbits. The outcomes of urethrography and histological analysis were evaluated six months postoperatively. A larger urethral diameter was observed in the ECM-mimicking scaffolds (3.01 ± 0.12 mm) than in the SIS grafts (0.95 ± 0.07 mm). Urethral fistulae and stenosis were observed in the SIS grafts. Urothelial and smooth muscle cells were observed in all rabbits, but the ECM-mimicking scaffold showed better performance. The ECM-mimicking scaffold may be an effective clinical treatment option for congenital and acquired urethral pathologies.

Successful Penile Replantation and the Role of Postreplantation Sildenafil Therapy: Report of 2 Cases and Literature Review.

Penile amputation is a rare clinical emergency necessitating urgent urologic and microsurgical intervention. Microvascular replantation has become a conventional form of management, associated with significantly increased viability of the implanted tissue and a lower rate of complications. However, postreplantation treatment intended to promote early recovery of sexual function has been reported only seldomly. Here we report 2 cases of successful penile replantation with postreplantation daily sildenafil therapy. The patients were followed for 24 months and 8 months, respectively, from the date of repair. First intercourse was achieved at 92 days and 105 days, respectively. This is the first report of the use of phosphodiesterase type 5 inhibitors in postoperative care of penile replantation. Fu S, Zheng D, Xie M, et al. Successful Penile Replantation and the Role of Postreplantation Sildenafil Therapy: Report of 2 Cases and Literature Review. Sex Med 2019;7:352-356.

Diketopyrrolopyrrole-based fluorescence probes for the imaging of lysosomal Zn2+ and identification of prostate cancer in human tissue.

A series of diketopyrrolopyrrole-based fluorescent probes (DPP-C2, LysoDPP-C2, LysoDPP-C3, and LysoDPP-C4) have been developed for the detection of low pH and Zn2+ in an AND logic fashion. The chelation of Zn2+ or the protonation of a morpholine moiety within these probes results in a partial increase in the fluorescence intensity, an effect ascribed to suppression of one possible photo-induced electron transfer (PET) pathway. In contrast, a large increase in the observed fluorescence intensity is observed at low pH and in the presence of Zn2+; this is rationalized in terms of both possible PET pathways within the probes being blocked. Job plots, fluorescence titration curves, and isothermal titration calorimetry proved consistent with a 1 : 1 Zn2+ complexation stoichiometry. Each probe demonstrated an excellent selectivity towards Zn2+ and the resulting Zn2+ complexes demonstrated pH sensitivity over the 3.5-9 pH range. Fluorescence imaging experiments confirmed that LysoDPP-C4 was capable of imaging lysosomal Zn2+ in live cells. Little evidence of cytotoxicity was seen. LysoDPP-C4 was successfully applied to the bioimaging of nude mice, wherein it was shown capable of imaging the prostate. Histological studies using a human sample revealed that LysoDPP-C4 can discriminate cancerous prostate tissue from healthy prostate tissue.