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Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.

Background Prostate cancer (PCa) is a heterogeneous disease with a variable natural history, genetics, and treatment outcome. The Hedgehog (Hh) signaling pathway is increasingly recognized as being potentially important for the development and progression of PCa. In this retrospective study, we compared the activation status of the Hh signaling pathway between benign and tumor tissue, and evaluated the clinical significance of Hh signaling in PCa. Methods In this tissue microarray (TMA) study, the protein expression of several Hh signaling components and Hh target proteins, along with microvessel density, were compared between benign ( n  = 64) and malignant ( n  = 170) prostate tissue, and correlated with PCa clinicopathological characteristics and biochemical recurrence (BCR). Results The Hh signaling pathway appeared to be more active in PCa than in benign prostate tissue, as demonstrated by lower expression of the negative regulators PTCH1 and GLI3 in the tumor tissue compared to benign. In addition, high epithelial GLI2 expression correlated with higher pathological Gleason score. Overall, higher epithelial GLI3 expression in the tumor was shown to be an independent marker of a favorable prognosis. Conclusion Hh signaling activation might reflect aggressive tumoral behavior, since high epithelial GLI2 expression positively correlates with a higher pathological Gleason score. Moreover, higher epithelial GLI3 expression is an independent marker of a more favorable prognosis.

The anti-diabetes drug metformin has been shown to have anti-neoplastic effects in several tumor models through its effects on energy metabolism and protein synthesis. Recent studies show that metformin also targets Hedgehog (Hh) signaling, a developmental pathway re-activated in several tumor types, including prostate cancer (PCa). Furthermore, we and others have shown that Hh signaling is an important target for radiosensitization. Here, we evaluated the combination of metformin and the Hh inhibitor GANT61 (GLI-ANTagonist 61) with or without ionizing radiation in three PCa cell lines (PC3, DU145, 22Rv1). The effect on proliferation, radiosensitivity, apoptosis, cell cycle distribution, reactive oxygen species production, DNA repair, gene and protein expression was investigated. Furthermore, this treatment combination was also assessed in vivo. Metformin was shown to interact with Hh signaling by inhibiting the effector protein glioma-associated oncogene homolog 1 (GLI1) in PCa cells both in vitro and in vivo. The combination of metformin and GANT61 significantly inhibited PCa cell growth in vitro and enhanced the radiation response of 22Rv1 cells compared to either single agent. Nevertheless, neither the growth inhibitory effect nor the radiosensitization effect of the combination treatment observed in vitro was seen in vivo. Although the interaction between metformin and Hh signaling seems to be promising from a therapeutic point of view in vitro, more research is needed when implementing this combination strategy in vivo.

The ability of the TRAIL/DR5 signaling pathway to induce apoptosis has generally been limited to tumor cells. Here we report that in primary testis explants, addition of TRAIL (0.5 mug/ml) caused a three-fold increase in germ cell apoptosis. Furthermore, exposure of C57BL/6 mice to the testicular toxicant, mono-(2-ethylhexyl) phthalate (MEHP), caused an increased p53 stability and elevated DR5 mRNA levels coincident with increases in the levels of apoptosis in spermatocytes. To further assess the mechanisms responsible for the sensitivity of germ cells to undergo TRAIL/DR5-mediated apoptosis, we used the germ cell lines GC-1spg and GC-2spd(ts) (a temperature sensitive spermatocyte-like cell line that allows for p53 nuclear localization at 32 degrees C but not 37 degrees C). Addition of TRAIL and the anti-DR5 monoclonal antibody, MD5-1, triggered a robust synergistic increase of apoptosis in p53 permissive GC-2 cells (32 degrees C) but not in GC-1 cells. In addition, DR5 levels on the plasma membrane of permissive cells were considerably enhanced concomitant with p53 expression and after MD5-1 treatment. These data represent the first indication that testicular germ cells, specifically spermatocytes, can undergo TRAIL-mediated apoptosis and the clinically relevant observation that pretreatment with a DR5 monoclonal antibody can greatly sensitize their apoptotic response to TRAIL.

Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Further-more, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.

Background Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. Principles of treatment include early antibiotic administration and operative source control. A further therapeutic option may be open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove inflammatory ascites and ameliorate the systemic damage from SCIAS. Although there is now a biologic rationale for such an intervention as well as non-standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. Methods The Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial that will randomly allocate eligible surgical patients intra-operatively to either formal closure of the fascia or use of the OA with application of an ANPTT dressing. Patients will be eligible if they have free uncontained intra-peritoneal contamination and physiologic derangements exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score ≥ 3 or a World-Society-of-Emergency-Surgery-Sepsis-Severity-Score ≥ 8. The primary outcome will be 90-day survival. Secondary outcomes will be logistical, physiologic, safety, bio-mediators, microbiological, quality of life, and health-care costs. Secondary outcomes will include days free of ICU, ventilation, renal replacement therapy, and hospital at 30 days from the index laparotomy. Physiologic secondary outcomes will include changes in intensive care unit illness severity scores after laparotomy. Bio-mediator outcomes for participating centers will involve measurement of interleukin (IL)-6 and IL-10, procalcitonin, activated protein C (APC), high-mobility group box protein-1, complement factors, and mitochondrial DNA. Economic outcomes will comprise standard costing for utilization of health-care resources. Discussion Although facial closure after SCIAS is considered the current standard of care, many reports are suggesting that OA management may improve outcomes in these patients. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only. Trial registration ClinicalTrials.gov , NCT03163095 .

Humans are destined to explore space, yet critical illness and injury may be catastrophically limiting for extraterrestrial travel. Humans are superorganisms living in symbiosis with their microbiomes, whose genetic diversity dwarfs that of humans. Symbiosis is critical and imbalances are associated with disease, occurring within hours of serious illness and injury. There are many characteristics of space flight that negatively influence the microbiome, especially deep space itself, with its increased radiation and absence of gravity. Prolonged weightlessness causes many physiologic changes that are detrimental; some resemble aging and will adversely affect the ability to tolerate critical illness or injury and subsequent treatment. Critical illness–induced intra-abdominal hypertension (IAH) may induce malperfusion of both the viscera and microbiome, with potentially catastrophic effects. Evidence from animal models confirms profound IAH effects on the gut, namely ischemia and disruption of barrier function, mechanistically linking IAH to resultant organ dysfunction. Therefore, a pathologic dysbiome, space-induced immune dysfunction and a diminished cardiorespiratory reserve with exacerbated susceptibility to IAH, imply that a space-deconditioned astronaut will be vulnerable to IAH-induced gut malperfusion. This sets the stage for severe gut ischemia and massive biomediator generation in an astronaut with reduced cardiorespiratory/immunological capacity. Fortunately, experiments in weightless analogue environments suggest that IAH may be ameliorated by conformational abdominal wall changes and a resetting of thoracoabdominal mechanics. Thus, review of the interactions of physiologic changes with prolonged weightlessness and IAH is required to identify appropriate questions for planning exploration class space surgical care. L’humanité est à l’aube d’une nouvelle ère d’exploration spatiale, mais le risque de maladies et blessures graves pourrait restreindre de manière catastrophique le potentiel des voyages dans l’espace. L’être humain est un superorganisme vivant en symbiose avec son microbiote, dont la diversité génétique éclipse celle de l’hôte. Cette symbiose est essentielle : tout déséquilibre est associé à une dégradation de l’état de santé dans les heures suivant l’occurrence d’une blessure ou d’une maladie grave. Bon nombre de caractéristiques propres au vol spatial ont des répercussions négatives sur le microbiote; l’espace lointain présente des dangers particuliers en raison de l’exposition accrue au rayonnement et de l’absence de gravité. L’exposition prolongée à l’apesanteur cause une myriade de changements physiologiques nuisant à la santé. Certains ressemblent à des processus de vieillissement et réduiront la capacité à tolérer une blessure ou une maladie grave et son traitement. L’hypertension intra-abdominale (HIA) causée par une maladie grave peut réduire la perfusion des viscères et du microbiote, ce qui peut avoir des conséquences catastrophiques. Des études sur modèle animal ont confirmé les effets profondément délétères de l’HIA sur les intestins par l’apparition d’une ischémie et une altération de la barrière intestinale; cette découverte permettrait d’établir un lien mécanistique entre l’HIA et la défaillance d’organes résultante. Par conséquent, une dysbiose pathologique, associée à un dysfonctionnement immunitaire en apesanteur et à une réduction de la réserve cardiorespiratoire accompagnée d’une exacerbation de la susceptibilité à l’HIA, pourrait signifier qu’un astronaute exposé à l’effet déconditionnant de l’apesanteur serait vulnérable aux problèmes de perfusion de l’intestin découlant de l’HIA. Ce problème pourrait à son tour mener à une ischémie intestinale grave et à une production massive de biomédiateurs chez un astronaute présentant déjà une capacité cardiorespiratoire et immunitaire réduite. Heureusement, des expériences dans des environnements simulant l’apesanteur semblent indiquer que les effets de l’HIA pourraient être contrés par des changements conformationnels de la paroi abdominale et un rétablissement de la mécanique thoracoabdominale. Par conséquent, un examen des interactions des changements physiologiques associés à un état d’apesanteur prolongé et à l’HIA est requis pour déterminer les questions à poser afin de planifier adéquatement les soins chirurgicaux en contexte d’exploration spatiale.

Introduction The treatment of closed humeral shaft fractures tends to be successful with functional bracing. Treatment failure due to iatrogenic conversion to an open fracture has not been described in the literature. We present a case series of patients that experienced open humeral shaft fractures after initially being treated with functional bracing for closed humeral shaft fractures and describe what factors are associated with this complication. Materials and methods This was a retrospective case series performed at three level 1 trauma centers across North America. All nonoperatively treated humeral shaft fractures were reviewed from 2001 to 2023. Patients were included if they sustained a humeral shaft fracture, > 18 years old, were initially treated non-operatively with functional bracing which subsequently converted to an open fracture. Eight patients met inclusion criteria. All included patients were eventually treated with irrigation, debridement, and open reduction and internal fixation. Outcomes assessed included mortality rate, time until the fracture converted from closed to open, need for further surgery, and bony union. Descriptive statistics were used in analysis. Results The eight included patients on average were 65 ± 21.4 years old and had a body mass index (BMI) of 25.6 ± 5.2. Six patients were initially injured due to a fall. Time until the fractures became open on average was 5.2 ± 3.6 weeks. Three patients (37.5%) died within 1.8 ± 0.6 years after initial injury. The average Charlson Comorbidity Index (CCI) score was 4.5 ± 3.4. Three patients (37.5%) had dementia. Common characteristics among this cohort included a history of visual disturbances (50.0%), cerebrovascular accident (50.0%), smoking (50.0%), and alcohol abuse (50.0%). Conclusion Conversion from a closed to open humeral shaft fracture after functional bracing is a potentially devastating complication. Physicians should be especially cognizant of patients with a low BMI, history of falling or visual disturbance, dementia, age ≥ 65, decreased sensorimotor protection, and significant smoking or alcohol history when choosing to use functional bracing as the final treatment modality. Level of Evidence : IV.

Background Insulinomas are the most common tumour of the endocrine pancreas in dogs. These malignant tumours have a high metastatic rate and limited chemotherapeutic options. The multi‐receptor tyrosine kinase inhibitor sunitinib malate has benefit in the treatment of metastatic insulinoma in people. Toceranib phosphate, an analogous veterinary agent, may provide benefit for dogs. Methods A retrospective study describing the extent and duration of clinical outcomes and adverse events (AEs) in dogs diagnosed with insulinoma and receiving toceranib. Results Records for 30 dogs diagnosed with insulinoma and having received toceranib were identified from a medical record search of five university and eight referral hospitals. The median progression‐free interval and overall survival time were 561 days (95% confidence interval (CI): [246, 727 days]) and 656 days (95% CI: [310, 1045 days]), respectively. Of the dogs for which the canine Response evaluation criteria for solid tumours tool could be applied, the majority (66.7%) showed either a complete response, partial response or stable disease. Time to clinical progression was associated with prior intervention and type of veterinary practice. Larger dogs were at increased risk for disease progression and death. No novel AEs were reported. Conclusions Most dogs diagnosed with insulinoma and receiving toceranib appeared to have a clinical benefit. Randomised, prospective studies are needed to better elucidate and objectively quantify the potential effect and survival benefit of toceranib therapy for management of insulinoma in dogs.