Effects of carvedilol on human prostate tissue contractility and stromal cell growth pointing to potential clinical implications.

BACKGROUND: Apart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α1-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly used antihypertensive and α1-adrenoceptors are essential for the treatment of voiding symptoms in benign prostatic hyperplasia, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on stromal cell growth. METHODS: Contractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α1-agonists. Growth-related functions were examined in cultured stromal cells. RESULTS: Concentration-response curves for phenylephrine, methoxamine and noradrenaline were right shifted by carvedilol (0.1-10 µM), around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes with 10 µM. Right shifts were reflected by increased EC50 values for agonists, with unchanged Emax values. EFS-induced contractions were reduced by 21-54% with 0.01-1 µM carvedilol, and by 94% by 10 µM. Colony numbers of stromal cells were increased by 500 nM, but reduced by 1-10 µM carvedilol, while all concentrations reduced colony size. Decreases in viability were time-dependent with 0.1-0.3 µM, but complete with 10 µM. Proliferation was slightly increased by 0.1-0.5 µM, but reduced with 1-10 µM. CONCLUSIONS: Carvedilol antagonizes α1-adrenoceptors in the human prostate, starting with concentrations in ranges of known plasma levels. In vitro, effect sizes resemble those of α1-blockers used for the treatment of voiding symptoms, which requires concentrations beyond plasma levels. Bidirectional and dynamic effects on the growth of stromal cells may be attributed to "biased agonism".

Patterned Photonic Actuators with Dynamic Shape-Morphing and Color-Changing Capabilities Fabricated by Athermal Embossing Technology.

Stimuli-responsive patterned photonic actuators, characterized by their patterned nano/microscale structures and capacity to demonstrate synergistic color changes and shape morphing in response to external stimuli, have attracted intense scientific attention. However, traditional patterned photonic actuator systems still face limitations such as cumbersome and time-consuming preparation processes and small-scale deformations. Herein, we introduce a facile approach involving an athermal embossing technique to rapidly fabricate patterned photonic actuators based on near-infrared (NIR) light-responsive liquid crystal elastomers. The resulting patterned photonic actuators demonstrate remarkable features, including brilliant angle-dependent structural color, complex three-dimensional actuation, and good color durability under NIR light stimulation. As illustrative demonstrations of the proof-of-concept, we fabricate two light-fuelled patterned photonic soft actuators: a butterfly-inspired actuator that can produce wing-flapping dynamic changes in structural color, and an origami crane-shaped actuator with shape memory, structural color information storage, and dynamic display properties. This strategy provides distinct insights into the design and fabrication of various patterned photonic soft robotic devices and intelligent actuators.

Testosterone Promotes Nerve Tethering and Acellular Biomaterial Perineural Fibrosis in a Rat Wound Repair Model.

Objective: Nerve scarring after traumatic or iatrogenic exposure can lead to impaired function and pain. Nerve-adjacent biomaterials promoting a regenerative tissue response may help reduce perineural fibrosis. Our prior work suggests that testosterone may promote fibrotic skin scarring, but it is unknown how testosterone alters nerve fibrosis or shifts the response to biomaterials. Approach: Sterilized Lewis rats received either testosterone cypionate (+T) or placebo (-T) biweekly. Fifteen days later, wounds were created over the sciatic nerve and covered with an acellular matrix (AM) or closed via primary closure (PC). At day 42, force gauge testing measured the force required to mobilize the nerve, and wound tissue was analyzed. Results: Nerve mobilization force was greater in +T versus -T wounds (p < 0.01). Nerves tore before gliding in 60% of +T versus 6% of -T rats. Epidermal gap (p < 0.01), scar width (p < 0.01), and cross-sectional scar tissue area (p = 0.02) were greater in +T versus -T rats. +T versus -T rats expressed less Col-3 (p = 0.02) and CD68 (p = 0.02). Nerve mobilization force trended nonsignificantly higher for PC versus AM wounds and for +T versus -T wounds within the AM cohort. Innovation: Testosterone increases nerve tethering in the wound healing milieu, altering repair and immune cell balances. Conclusion: Testosterone significantly increases the force required to mobilize nerves in wound beds and elevates histological markers of scarring, suggesting that testosterone-induced inflammation may increase perineural adhesion. Testosterone may reduce the potential anti-tethering protective effect of AM. Androgen receptor antagonism may represent a therapeutic target to reduce scar-related nerve morbidity.

Propensity score-matched evaluation of palliative transurethral resection and holmium laser enucleation of the prostate for bladder outlet obstruction in patients with prostate cancer.

BACKGROUND: While transurethral resection of the prostate (TURP) is the standard-of-care, Holmium laser enucleation of the prostate (HoLEP) is widely accepted as a size-independent method for surgical treatment of patients with lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction (BOO). However, in an ageing society an increasing number of patients presents with BOO due to locally advanced prostate cancer. There is currently no guidelines recommendation as to the enucleation or resection technique. Therefore, we compared intraoperative performance, postoperative outcomes, and safety for palliative (p)TURP and (p)HoLEP. METHODS: We conducted a retrospective, propensity score-matched analysis of 1373 and 2705 men who underwent TURP or HoLEP for LUTS/BOO between 2014 and 2021, respectively. Patients were matched for age, prostate size and preoperative international prostate symptom score (IPSS). Patients were stratified by technique and groups were compared for perioperative parameters, safety, and functional outcomes. RESULTS: While postoperative symptoms and urodynamic parameters improved irrespective of technique, we report significantly increased resection and enucleation times for palliative indication. For corresponding efficiency parameters, we observed a two-fold higher surgical performance (g/min) for both techniques in patients without prostate cancer. While adverse events were comparable between groups, we found a two-fold higher hemoglobin drop in palliative patients. CONCLUSIONS: Currently, there is no standard-of-care for patients with BOO and locally advanced prostate cancer. Our data show that both TURP and HoLEP offer adequate symptom improvement and comparable safety profiles. While HoLEP is feasible even in larger prostates, both procedures become more difficult in patients with prostate cancer. Taken together, this study covers an important gap in current literature, helping urological surgeons to make evidence-based decisions for the benefit of their patients.

Androgenic steroids induce pathologic scarring in a preclinical porcine model via dysfunctional extracellular matrix deposition.

Hypertrophic scarring is a major source of morbidity. Sex hormones are not classically considered modulators of scarring. However, based on increased frequency of hypertrophic scarring in patients on testosterone, we hypothesized that androgenic steroids induce abnormal scarring and developed a preclinical porcine model to explore these effects. Mini-swine underwent castration, received no testosterone (noT) or biweekly testosterone therapy (+T), and underwent excisional wounding. To create a delayed wound healing model, a subset of wounds were re-excised at 2 weeks. Scars from postoperative day 42 (POD42) and delayed wounds (POD28) were harvested 6 weeks after initial wounding for analysis via histology, bulk RNA-seq, and mechanical testing. Histologic analysis of scars from +T animals showed increased mean fibrosis area (16 mm2noT, 28 mm2+T; p = .007) and thickness (0.246 mm2noT, 0.406 mm2+T; p < .001) compared to noT. XX+T and XY+T scars had greater tensile burst strength (p = .024 and p = .013, respectively) compared to noT swine. Color deconvolution analysis revealed greater deposition of type I and type III collagen as well as increased collagen type I:III ratio in +T scars. Dermatopathologist histology scoring showed that +T exposure was associated with worse overall scarring (p < .05). Gene ontology analysis found that testosterone exposure was associated with upregulation of cellular metabolism and immune response gene sets, while testosterone upregulated pathways related to keratinization and laminin formation on pathway analysis. In conclusion, we developed a preclinical porcine model to study the effects of the sex hormone testosterone on scarring. Testosterone induces increased scar tissue deposition and appears to increase physical strength of scars via supraphysiologic deposition of collagen and other ECM factors. The increased burst strength seen in both XX and XY animals suggests that hormone administration has a strong influence on scar mechanical properties independent of chromosomal sex. Anti-androgen topical therapies may be a promising future area of research.

Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle.

Smooth muscle contraction by Pim kinases and ZIPK has been suggested, but evidence for lower urinary tract organs or using Pim-selective inhibitor concentrations is not yet available. Here, we assessed effects of the Pim inhibitors AZD1208 and TCS PIM-1 and the dual ZIPK/Pim inhibitor HS38 on contractions of human prostate and bladder tissues and of porcine interlobar arteries. Human tissues were obtained from radical prostatectomy and radical cystectomy and renal interlobar arteries from pigs. Contractions were studied in an organ bath. Noradrenaline-, phenylephrine- and methoxamine-induced contractions were reduced (up to > 50%) with 500-nM AZD1208 in prostate tissues and to lesser degree and not consistently with all agonists in interlobar arteries. A total of 100-nM AZD1208 or 500-nM TCS PIM-1 did not affect agonist-induced contractions in prostate tissues. Decreases in agonist-induced contractions with 3-µM HS38 in prostate tissues and interlobar arteries were of small extent and did not occur with each agonist. Carbachol-induced contractions in detrusor tissues were unchanged with AZD1208 (500 nM) or HS38. Electric field stimulation-induced contractions were not affected with AZD1208 or HS38 in any tissue, but slightly reduced with 500-nM TCS PIM-1 in prostate tissues. Concentration-dependent effects of Pim inhibitors suggest lacking Pim-driven smooth muscle contraction in the prostate, bladder, and interlobar arteries but point to organ-specific functions of off-targets. Procontractile functions of ZIPK in the prostate and interlobar arteries may be limited and are lacking in the detrusor.

Precapillary Pulmonary Arterial Hypertension Despite Contrary Anchoring Bias.

We present the case of a patient with risk factors and a noninvasive evaluation that suggested postcapillary pulmonary hypertension, but in fact had invasive hemodynamics consistent with precapillary pulmonary hypertension. A thorough hemodynamic evaluation of pulmonary hypertension must be performed, as treatment is linked to the underlying physiology. (Level of Difficulty: Advanced.).

The Impact of Laser Energy on Functional Outcome Following Holmium Laser Enucleation of the Prostate.

OBJECTIVE: To assess the impact of total laser energy applied, as well as enucleation efficiency on short-term functional outcomes for patients treated for lower urinary tract symptoms (LUTS) with Holmium laser enucleation of the prostate (HoLEP). METHODS: A retrospective analysis of 1593 consecutive patients who underwent HoLEP for LUTS due to benign prostate obstruction in a tertiary care center between January 2018 and January 2021 was performed. Perioperative parameters and short-term functional outcome were evaluated. Spearman's rank correlation and linear regression analysis was applied to identify the relationship between total laser energy applied or enucleation efficiency and functional outcome (P < .05). RESULTS: Median weight of enucleated tissue was 65g, median tissue retrieval percentage was 72.2% and median surgery speed was 0.8g/min. Median laser energy applied was 48.8 kJ, median enucleation efficiency was 1.4g/kJ. No significant correlation between the total laser energy and postoperative International Prostate Symptom Score (IPSS), peak urinary flow (Qmax) or postvoid residual urine volume (PVR) was found (P-range: .473-.969). Likewise, no correlation was found between enucleation efficiency and postoperative IPSS, Qmax, and PVR (P-range: .080-.932). Perioperative improvement of functional outcome (delta IPSS, delta Qmax, and delta PVR) did not correlate with total laser energy applied (P-range: .211-.785) or with enucleation efficiency (P-range: .118-.543). Those results were confirmed in linear regression analysis. CONCLUSION: The results of this study reveal that functional outcome following HoLEP are not dependant on the amount of laser energy applied or enucleation efficiency. Our results should support the increased use of HoLEP as surgical treatment option for LUTS due to BPH.

Selective inhibition of neurogenic, but not agonist-induced contractions by phospholipase A2 inhibitors points to presynaptic phospholipase A2 functions in contractile neurotransmission to human prostate smooth muscle.

BACKGROUND: Phospholipases A2 (PLA2 ) may be involved in α1 -adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1 -adrenergic contractions of the prostate, is still unknown. While α1 -adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2 . Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1 -adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls. RESULTS: Frequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS-induced contractions, nor contractions by α1 -adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM). CONCLUSIONS: Our findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1 -adrenergic agonists occur PLA2 -independent. Lacking sensitivity to montelukast excludes an involvement of PLA2 -derived leukotrienes in promotion of contractile neurotransmission.

"Revision Phalloplasty: Evaluation, Algorithms and Techniques for Salvage After Major Complications".

BACKGROUND: Phalloplasty is among the most complex and technically demanding reconstructive surgeries. As a larger pool of surgeons perform this difficult procedure, more patients will present with major complications. There is little published on the comprehensive evaluation and management of these patients, particularly those needing correction of multiple ongoing complications, which may require consideration of starting over with a new microsurgical procedure versus salvage of the existing flap. METHODS: A literature review on complications of phalloplasty was conducted in combination with drawing upon the experience of two high-volume phalloplasty teams (Johns Hopkins/Brigham & Women's Hospital and GU Recon/Buncke Clinic) in treating patients with severe post-surgical issues. The purpose was to analyze critical factors and develop algorithms for secondary revision. RESULTS: Common complications of phalloplasty include urethral strictures and fistulae, diverticula, excess bulk, phalloplasty malposition, hypertrophic/keloidal scarring, and partial/total flap loss. In severe cases, local flaps or free flaps may be required for reconstruction. The decision to revise the existing neophallus or start over with a new flap for phalloplasty is particularly critical. Multidisciplinary team collaboration is essential to develop comprehensive plans that will resolve multiple concomitant problems while meeting patient goals for a functional and aesthetic neophallus. CONCLUSIONS: Preserving the original flap for phalloplasty is ideal when feasible. Additional local or free flaps are sometimes necessary in situations of significant tissue loss. In severe cases, complete redo phalloplasty is required. The algorithms proposed provide a conceptual framework to guide surgeons in analyzing and managing severe complications following phalloplasty.

Quantification of senescence-associated secretory phenotype proteins in the vaginal secretions of pre- and postmenopausal women with and without prolapse.

Objectives: Cellular senescence has been proposed as a pathophysiologic driver in the development of pelvic organ prolapse (POP), especially during aging. In this study, we aimed to determine if markers of cell senescence can be quantified from vaginal secretions collected from pre- and postmenopausal women with and without POP. Methods: Vaginal swabs were collected from 81 women in four groups: premenopausal with (pre-P) and without prolapse (pre-NP), and postmenopausal with (post-P) and without prolapse (post-NP). Multiplex immunoassays (MagPix) were then used to detect and quantify the presence of 10 SASP proteins in vaginal secretions. Results: The total protein concentration of vaginal secretions differed significantly among the four groups (P = 0.003) with highest mean concentrations in pre-P [16, interquartile range (IQR) = 4.6, 38.3 µg/µL] and lowest mean concentrations in post-P (4.4, IQR = 2.6, 7 µg/µL). The normalized concentrations of several SASP markers differed significantly among groups, with the highest concentrations being seen in the post-P group, and the lowest concentrations being in the pre-NP group. Using these key markers, we then constructed receiver-operator curves to determine the relative sensitivity and specificity of these markers in predicting prolapse. Conclusions: In this study, we found that SASP proteins can be detected and quantified in vaginal secretions. Several of these markers were differentially expressed among the four groups studied, with the highest normalized concentrations of SASP markers found among postmenopausal women with prolapse. Overall, the data support the theory that senescence is associated with prolapse during aging but that other factors may be important in younger women who develop POP before menopause.

Gender-Affirming Vaginoplasty: A Comparison of Algorithms, Surgical Techniques and Management Practices across 17 High-volume Centers in North America and Europe.

Penile inversion vaginoplasty is the most common gender-affirming genital surgery performed around the world. Although individual centers have published their experiences, expert consensus is generally lacking. Methods: Semistructured interviews were performed with 17 experienced gender surgeons representing a diverse mix of specialties, experience, and countries regarding their patient selection, preoperative management, vaginoplasty techniques, complication management, and postoperative protocols. Results: There is significant consistency in practices across some aspects of vaginoplasty. However, key areas of clinical heterogeneity are also present and include use of extragenital tissue for vaginal canal/apex creation, creation of the clitoral hood and inner labia minora, elevation of the neoclitoral neurovascular bundle, and perioperative hormone management. Pathway length of stay is highly variable (1-9 days). Lastly, some surgeons are moving toward continuation or partial reduction of estrogen in the perioperative period instead of cessation. Conclusions: With a broad study of surgeon practices, and encompassing most of the high-volume vaginoplasty centers in Europe and North America, we found key areas of practice variation that represent areas of priority for future research to address. Further multi-institutional and prospective studies that incorporate patient-reported outcomes are necessary to further our understanding of these procedures.

[Laser Techniques in the Treatment of Benign Prostatic Syndrome]. / Lasertechniken in der Behandlung des benignen Prostatasyndroms.

Laser Techniques in the Treatment of Benign Prostatic Syndrome Abstract: Lasers have a wide range of applications in endourological therapy. Not only in the treatment of stones, but also in the treatment of benign prostatic syndrome (BPS), their importance continues to grow. The endourological treatment of BPH with different laser techniques will be discussed in more detail in the following. The physical differences between the individual lasers will be explained first, followed by the treatment options that can be performed with a laser. The main focus will be on the concrete comparison of the treatment methods, especially in clinical contexts. In particular, the duration of surgery, length of hospitalisation, risk of post-operative bleeding, catheterisation duration, risk of urinary retention and risk of post-operative complications such as retrograde ejaculation, bladder neck sclerosis, urethra stricture and adenoma recurrence will be listed and compared for the most important methods. Nevertheless, the distribution of TURP to laser is still 30:1 in favour for TURP [1].

[Benign Prostate Hyperplasia - Current Medical Therapy, New Developments, and Side Effects]. / Benigne Prostatahyperplasie.

Benign Prostate Hyperplasia - Current Medical Therapy, New Developments, and Side Effects Abstract: Lower urinary tract symptoms (LUTS) consist of both voiding and storage symptoms. Urethral obstruction leading to voiding symptoms is most commonly attributed to benign prostatic hyperplasia (BPH), where hyperplastic growth and increased smooth muscle tone in the hyperplastic prostate may lead to benign prostate obstruction (BPO). Spontaneous contractions of the detrusor muscle may cause storage symptoms, which are referred to as overactive bladder (OAB). With a considerable proportion of patients suffering from "mixed LUTS", a combination of voiding and storage symptoms, LUTS affect a large portion of the population worldwide, with major impact on quality of life (QoL). A demographic shift in society, will lead to higher incidence and prevalence of LUTS, with a growing economic burden. Standard-of-care medical treatment for LUTS/BPO includes α1-adrenoceptor antagonists and phosphodiesterase-5 (PDE-5) inhibitors, for reduction of prostate smooth muscle tone, and 5α-reductase inhibitors (5-ARI) to slow down disease progression. Medical therapy for LUTS/OAB includes muscarinic receptor antagonists, and ß3-agonists for relief of spontaneous bladder contractions. When left untreated, LUTS may cause considerable adverse events, ranging from acute urinary retention with kidney failure, and recurring infections, to social withdrawal, and depression.

Efficacy, Efficiency, and Safety of En-bloc vs Three-lobe Enucleation of the Prostate: A Propensity Score-matched Analysis.

OBJECTIVE: To assess efficacy, efficiency, and safety in holmium laser enucleation of the prostate (HoLEP), we directly compared intraoperative performance, postoperative outcomes, and safety in the original 3-lobe enucleation technique with the more recent en-bloc method. As HoLEP is widely accepted as a size-independent method for surgical treatment of patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO), detailed understanding of its benefits is mandatory. METHODS: We conducted a retrospective, propensity score-matched analysis of 1,396 men who underwent HoLEP for LUTS/BPO between 2017 and 2020. We included 606 patients in the final analysis (en-bloc n = 303; 3-lobe n = 303), who were matched for prostate size (50 cc), age, body mass index, and preoperative international prostate symptom score. Patients were then stratified by technique, and groups were compared for perioperative parameters, safety, and short-term functional outcomes. RESULTS: While postoperative symptoms and urodynamic parameters improved irrespective of technique, we report significantly less adverse events (Clavien-Dindo classification ≥II vs

A New Bacterial Adenosine-Derived Nucleoside as an Example of RNA Modification Damage.

The fields of RNA modification and RNA damage both exhibit a plethora of non-canonical nucleoside structures. While RNA modifications have evolved to improve RNA function, the term RNA damage implies detrimental effects. Based on stable isotope labelling and mass spectrometry, we report the identification and characterisation of 2-methylthio-1,N6-ethenoadenosine (ms2 ϵA), which is related to 1,N6-ethenoadenine, a lesion resulting from exposure of nucleic acids to alkylating chemicals in vivo. In contrast, a sophisticated isoprene labelling scheme revealed that ms2 ϵA biogenesis involves cleavage of a prenyl moiety in the known transfer RNA (tRNA) modification 2-methylthio-N6-isopentenyladenosine (ms2 i6 A). The relative abundance of ms2 ϵA in tRNAs from translating ribosomes suggests reduced function in comparison to its parent RNA modification, establishing the nature of the new structure in a newly perceived overlap of the two previously separate fields, namely an RNA modification damage.