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Penile and scrotal entrapment from a metal ring placed at the base of the penis is a rare, but important clinical dilemma encountered in urology. Emergent presentation to the urologist, after ring placement far longer than safely practiced, risks ischemic and permanent injury to penile, scrotal, and intrascrotal structures. Treating urologists should be aware of the prevalence of metal ring use, their potential complications, and the surgical approach to their safe removal. We present two patients who were identified at our institution with strangulating injuries of retained penile rings. The first patient was a healthy, 43-year-old male with a metal ring retained for 24 hours that was safely removed with industrial bolt cutters. The second patient, a 74-year-old male, died as a result of sepsis from injuries secondary to penoscrotal ischemia after >48 hour ring retention despite prompt removal at emergent presentation. Although rare, sexual practices may include the use of penoscrotal rings. When retained, ischemic injury and edema may lead to strangulation. Emergent removal may require industrial equipment that is not within the confines of normal operating room tools. Tissue injury may be severe and sepsis life-threatening, even after ring removal.

SX-fraction (SXF) is a bioactive glycoprotein with hypoglycemic activity that has been demonstrated in our pilot clinical study. However, how it would actually work in diabetic patients remains unclear. To explore such a mechanism, the effects of SXF on the insulin signal transduction pathway were investigated using skeletal muscle L6 cells in vitro. L6 cells were first differentiated to myotubes expressing several biochemical parameters that were examined in this study. Myotubes were exposed to a high concentration (35 mM) of glucose (Glc) alone or in combination with SXF or insulin for 24 hours. Possible effects of these agents on activities of insulin receptor (IR), IR substrate 1 (IRS-1), and Akt, which are key elements involved in the signal pathway, were assessed using enzyme-linked immunosorbent assay (ELISA). Any changes in Glc uptake were also determined. High Glc indeed led to inactivation of IR, IRS-1, and subsequent Akt in myotubes, indicating an interruption of the signal pathway. However, such inactivation was reversed or reactivated by SXF, presumably aiding the occurrence of successive signaling events. Measurement of Glc uptake to assess the outcome of this signaling cascade showed that high Glc decreased Glc uptake (interfering with the signal pathway), but SXF was capable of overcoming such a suppressive effect, resulting in the increased Glc uptake. Insulin was used as a positive control in this study and all results were nearly compatible to those obtained from SXF. The present study suggests that SXF may specifically target the insulin signal pathway, and, in particular, the IR and IRS-1 therein that trigger the subsequent signaling events. As a result, SXF could activate such an impaired signal pathway through high Glc or under a hyperglycemic milieu, thereby ultimately facilitating Glc uptake. This may then account for possible hypoglycemic action of SXF.

Background Androgen ablation is one of the viable therapeutic options for patients with primary hormone (androgen)-dependent prostate cancer. However, an antibiotic brefeldin A (BFA) has been shown to exhibit the growth inhibitory effect on human cancer cells. We thus investigated if BFA might inhibit proliferation of androgen-responsive prostate cancer LNCaP cells and also explored how it would be carried out, focusing on cell cycle and androgen receptor (AR). Methods Androgen-mediated cellular events in LNCaP cells were induced using 5α-dihydrotestosterone (DHT) as an androgenic mediator. Effects of BFA on non-DHT-stimulated or DHT-stimulated cell growth were assessed. Its growth inhibitory mechanism(s) was further explored; performing cell cycle analysis on a flow cytometer, assessing AR activity by AR binding assay, and analyzing AR protein expression using Western blot analysis. Results DHT (1 nM) was capable of stimulating LNCaP cell growth by ~40% greater than non-stimulated controls, whereas BFA (30 ng/ml) completely inhibited such DHT-stimulated proliferation. Cell cycle analysis showed that this BFA-induced growth inhibition was associated with a ~75% reduction in the cell number in the S phase and a concomitant increase in the G 1 cell number, indicating a G 1 cell cycle arrest. This was further confirmed by the modulations of specific cell cycle regulators (CDK2, CDK4, cyclin D 1 , and p21 WAF1 ), revealed by Western blots. In addition, the growth inhibition induced by BFA was accompanied by a profound (~90%) loss in AR activity, which would be presumably attributed to the significantly reduced cellular AR protein level. Conclusions This study demonstrates that BFA has a potent growth inhibitory activity, capable of completely inhibiting DHT (androgen)-stimulated LNCaP proliferation. Such inhibitory action of BFA appears to target cell cycle and AR: BFA led to a G 1 cell cycle arrest and the down-regulation of AR activity/expression, possibly accounting for its primary growth inhibitory mechanism. Thus, it is conceivable that BFA may provide a more effective therapeutic modality for patients with hormone-dependent prostate cancer.

This study aims to assess the effect of green intellectual capital on corporate economic sustainability in the manufacturing sector of Pakistan. Moreover, it also investigates whether the financial condition of a firm mediates the relationship between green intellectual capital and corporate economic sustainability. Data from the managers of 294 manufacturing firms were collected through a questionnaire and analyzed using SPSS and AMOS. Structural equational modeling has been used for hypotheses testing. Results indicate that green human capital and green relational capital significantly influence corporate economic sustainability while the effect of green structural capital is not significant. The results also elucidate that the financial conditions of a firm significantly mediate the impacts of green human capital, green structural capital, and green relational capital on corporate economic sustainability. Green intellectual capital facilitates the production of eco-friendly products and contributes to reducing waste, cost, time, and emission of harmful gases. Finally, study concludes that organizations should invest in green intellectual capital to meet the objective of corporate economic sustainability.

A role of glyoxalase I (Gly-I), a detoxifying enzyme, in cell viability of prostate cancer was investigated. Cell extracts obtained from 66 prostate tissue specimens and prostatic cancer PC-3 cells were assayed for Gly-I activity using the spectrophotometric method. Gly-I activity was consistently more than eightfold higher in prostate cancer (CAP) specimens (n = 37) than in non-cancerous (NCP) specimens (n = 29). To understand the importance of such a high Gly-I activity in CAP specimens, the effects of methylglyoxal (MG) on PC-3 cells were examined in vitro. MG, a putative toxic glycolytic metabolite, was capable of inducing severe (> 99%) cell death in 24 h, along with a significant reduction in activities of Gly-I as well as glyceraldehyde 3-phosphate dehydrogenase (G3PDH), a key glycolytic enzyme. However, such severe cell death was effectively (approximately 85%) prevented with N-acetylcysteine (NAC), a precursor of reduced glutathione (GSH) that is an essential cofactor for Gly-I, accompanied by the intact Gly-I and G3PDH activities. Therefore, Gly-I may play a critical detoxifying role in glycolysis to maintain cellular activity and viability of prostatic cancer cells.

Superficial bladder tumors are the most prevalent form of bladder cancers and transurethral resection is the primary surgical modality for those tumors. However, nearly 65% of patients will have tumor recurrence in five years while about 15% will have progression to muscle invasion. Thus, the primary therapeutic aim is to prevent multiple recurrences and progression to a more advanced, invasive disease. We here report an 87-year-old white male patient with invasive bladder cancer who received an unconventional oral regimen of D-fraction, the bioactive extract of Maitake mushroom (Grifola frondosa), following endoscopic transurethral resection of bladder tumor. Despite a high risk for disease recurrence, follow-up yet indicated no clinical evidence of progression of residual disease or recurrence of invasive cancer. It has been nearly two years but the patient remains remarkably well and appears to be in remission. To our knowledge, this is the first and only case report of possible disease remission in a bladder cancer patient after the two-year follow-up of D-fraction regimen, so that further studies with long terms are required for drawing a relevant conclusion. Nevertheless, it is conceivable that D-fraction is a natural agent that may have clinical implications in patients with superficial bladder tumors.

PurposeAs oxidative stress (OXS) has been shown to play a primary role in renal ischemia/reperfusion injury (RIRI), we investigated whether antioxidant such as ethyl pyruvate (EPy) might effectively prevent RIRI. Possible prophylactic effects of EPy and mannitol (Mann), one of perioperative agents often used, were tested against harmful OXS in vitro.MethodsHydrogen peroxide (H2O2) was used to exert OXS on the renal proximal tubular MDCK cells. Severity of OXS and protective effects of EPy and Mann were assessed by lipid peroxidation assay and cell viability test, respectively. The cytotoxic mechanism of H2O2 was explored by examining the status of glycolysis, metabolic signaling pathways, cell cycle, and induction of apoptosis.ResultsAlthough H2O2 (500 µM) increased OXS by ~ 3.5 times of controls, EPy (1 mM) fully reduced it to the basal level. Cell viability declined to merely 10% by H2O2 was regained to > 90% with EPy. Hexokinase activity and ATP level also declined significantly by H2O2, but they sustained 80–90% with EPy. Additionally, H2O2 led to the modulations of metabolic signaling regulators, a G1 cell cycle arrest, and induction of apoptosis, which were yet prevented with EPy. Unlike EPy, Mann had virtually little effects.ConclusionsOXS can indeed lead to the significant cell viability reduction through its adverse cellular effects, ultimately resulting in RIRI. However, EPy appears to prevent these effects and protect MDCK cells, while Mann does not. Thus, EPy could be a more effective prophylactic renoprotective agent (than Mann) against oxidative renal cell injury including RIRI.

Abstract Disclosure: E. Mills: None. J. Tsoutsouki: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S. Clarke: None. M. Young: None. E. Alexander: None. S. Nyunt: None. A. Yeung: None. M. Choudhury: None. A. Newman: None. P. Bech: None. A. Abbara: None. M. Swedrowska: None. B. Forbes: None. A. Comninos: None. W. Dhillo: None. Background: Kisspeptin administration by intravenous or subcutaneous routes activates hypothalamic GnRH neurons to stimulate downstream reproductive hormone release and is under rapid development for treating common reproductive disorders, including hypothalamic amenorrhea (HA). However, these invasive routes limit patient acceptability and clinical use. Intranasal administration offers a novel non-invasive delivery route, which would be clinically preferable to patients and clinicians. Herein, we compare the reproductive endocrine responses after intranasal kisspeptin administration in healthy women to women with HA. Methods: Randomized, double-blinded, placebo-controlled, crossover study in 12 healthy (ovulatory) women during the follicular phase (mean age ± SEM 22.1 ± 0.9 yrs, BMI 22.1 ± 0.8 kg/m2) and 10 women with HA (age 25.8 ± 2.7 yrs, BMI 19.9 ± 1.3 kg/m2). After intranasal delivery of kisspeptin-54 (12.8 nmol/kg) or 0.9% saline (placebo), reproductive hormones were measured every 15 minutes for 4 hours. Groups were compared by unpaired t-tests. Results: Intranasal kisspeptin-54 administration rapidly and robustly stimulated gonadotropin release in both study cohorts. However, LH and FSH release were significantly augmented in women with HA, compared to healthy women: mean area under the curve (AUC) for the change in LH across 4 hours 96.0 ± 45.8 h·IU/L (healthy women) vs. 600.6 ± 146.7 h·IU/L (women with HA) (P = 0.002). Consistently, mean AUC for the change in FSH was -36.1 ± 23.4 h·IU/L (healthy women) vs. 474.9 ± 237.3 h·IU/L (women with HA) (P = 0.02). The mean maximal increase in LH following kisspeptin-54 was over three-fold greater in women with HA at 4.4 ± 0.2 IU/L vs. 1.4 ± 0.3 IU/L in healthy women (P < 0.001). Similarly, the mean maximal increase in FSH was over ten-fold greater in women with HA at 3.1 ± 0.3 IU/L vs. 0.3 ± 0.1 IU/L in healthy women (P = 0.03). Summary: Intranasal kisspeptin robustly stimulates reproductive hormone release in healthy women, with an even greater stimulation in women with HA. Therefore, intranasal kisspeptin offers not only a novel, effective, safe, and non-invasive route of administration for the management of reproductive disorders but also a potential simple diagnostic test to identify women with HA. Presentation: Sunday, July 13, 2025

Disclosure: C. Izzi-Engbeaya: None. M. Choudhury: None. B. Patel: None. B. Muzi: None. A. Qayum: None. E.G. Mills: None. M. Ahsan: None. M. Phylactou: None. S. Clarke: None. L. Aslett: None. A.N. Comninos: None. A. Abbara: None. T. Tan: None. W.S. Dhillo: None. Background: Kisspeptin neurons in the hypothalamus are believed to play a role in mediating the interaction between metabolic and reproductive health. Functional neuroanatomical connections exist between kisspeptin neurons and appetite-regulating neurons in the arcuate nucleus of the hypothalamus. Female (but not male) global kisspeptin receptor knockout mice have reduced food intake compared to controls. However, studies of kisspeptin administration have yielded conflicting results, with either decreased, or unchanged food intake reported in rodent studies. Consistent with some of the literature, kisspeptin administration does not influence food intake in men. However, the effects of kisspeptin on food intake have not previously been studied in women. Research Question: What is the effect of kisspeptin administration on food intake in women? Methodology: A randomized controlled crossover study was performed in women with overweight or obesity (BMI >25 kg/m2) who were not in receipt of exogenous oral and/or transdermal estrogens or progestins. Each woman attended two study visits in random order following an overnight fast. During each study visit they received either a 2-hour intravenous infusion of kisspeptin-54 at a rate of 1.0 nmol/kg/hr, or a rate-matched vehicle infusion. The study was single-blinded, with participants unaware of the infusion identity. Participants were given an ad libitum meal 45 minutes after the start of each infusion. Blood samples were taken for reproductive and metabolic profiling, and visual analogue scales (VAS) to assess hunger were completed at regular intervals throughout both study visits. Data are presented as mean±SD. Results: 17 women (age 49±12 years, BMI 34±7 kg/m2) completed both study visits. As expected, LH levels were higher during kisspeptin than during vehicle infusion (p<0.01), confirming bioactivity of the kisspeptin dose. Pre-meal estradiol levels were similar during kisspeptin and vehicle infusions (p=0.34). There were no differences in pre-meal hunger VAS scores 30 mins after the start of the infusion (kisspeptin 5.2±2.7 vs vehicle 5.9±2.3, p=0.33) or bodyweight-adjusted food intake (kisspeptin 6.8±3.7 kcal/kg vs vehicle 6.2±2.8 kcal/kg, p=0.33). There were also no differences in glucose (p=0.97) or insulin (p=0.68) levels between kisspeptin and vehicle infusions. Conclusions: Acute intravenous administration of a biologically active dose of kisspeptin did not affect food intake or hunger in women with overweight or obesity. Furthermore, kisspeptin administration did not alter fasting or post-prandial glucose levels. This is the first study to examine the effects of kisspeptin on hunger and food intake in women and provides reassuring safety data for the ongoing development of kisspeptin-based therapeutics. Presentation: Friday, June 16, 2023

Aim: Mushroom extract, PDF, is a bioactive proteoglucan with anticancer/antitumor activity, and Vitamin K3 (VK3) is a synthetic VK derivative with antitumor activity as well. An unconventional approach using these two agents was tested to see their anticancer effects on bladder cancer cells in vitro. Methods: Human bladder cancer T24 cells were treated with PDF, VK3, or their combination, and cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. To explore the anticancer mechanism, cell cycle and epigenetic alterations were specifically studied. Results: PDF ≥ 500 μg/mL led to a ~ 35% reduction in cell viability while VK3 had little effects. However, when PDF (300 μg/mL) was combined with VK3 (5 μM), a ~ 75% cell viability reduction was attained. This specific combination induced a G1 cell cycle arrest with the downregulation of G1-specific regulators. In addition, histone deacetylase was inactivated while histones 3 and 4 were highly acetylated. Two apoptotic regulators were significantly activated with PDF/VK3 combination as well. Conclusion: The specific combination of PDF and VK3 appears to potentiate anticancer effect on T24 cells. This is primarily attributed to a G1 cell cycle arrest with chromatin modifications, ultimately leading to apoptosis. Thus, the PDF/VK3 combination may offer a potential therapeutic option for bladder cancer.