Immunomodulatory Synthetic Glycocluster Molecule Prevents Melanoma Growth in vivo.

Triacedimannose (TADM) is a synthetic trivalent acetylated glycocluster and a transmembrane macrophage activator independent of the mannose receptor. TADM induces Th1-type immune responses and suppresses Th2-type cytokines in acute and chronic allergic inflammation models in vivo. We, therefore, wanted to test whether TADM could also facilitate anti-tumour tissue responses similar to what has been observed for the immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4. A syngeneic mouse melanoma model was selected since metastatic melanoma has been successfully targeted by checkpoint inhibitors in the clinic. TADM inhibited the growth of B16 mouse melanoma tumours at levels comparable to an anti-PD-1 antibody. TADM-treated tumours encompassed significantly more apoptotic cells as measured by TUNEL staining, and interferon-gamma (IFN-γ) expression was increased in the spleens of TADM-treated mice compared to untreated controls. TADM-treated mice also demonstrated increased Ly6C low monocytes and neutrophils in the spleens. However, TADM-treated tumours showed no discernible differences in infiltrating immune cells. TADM can alone suppress the growth of melanoma tumours. TADM likely activates M1 type macrophages, type N1 neutrophils, and CD8+ and Th1 T cells, suppressing the type 2 immune response milieu of melanoma tumour with a strong type 1 immune response.

Tissue sealants may reduce haematoma and complications in face-lifts: A meta-analysis of comparative studies.

The use of tissue sealants has increased among different surgical specialities. Face-lift and rhytidoplasty may cause several complications such as haematoma, ecchymosis, oedema, seroma, skin necrosis, wound dehiscence and wound infection. However, administration of tissue sealants may prevent the occurrence of some complications. We performed a meta-analysis of studies that compared tissue sealant use with controls to evaluate the outcomes. A systematic literature search was performed. The primary outcome was the incidence of haematoma. Secondary outcomes were wound drainage amount, oedema, ecchymosis, seroma, skin necrosis and hypertrophic scarring. Thirteen studies involving 2434 patients were retrieved and included in the present analysis. A statistically significantly decrease in post-operative haematoma [risk ratio (RR), 0.37; 95% CI, 0.18-0.74; p = 0.005] and wound drainage (MD, -16.90, 95% CI = -25.71, -8.08, p < 0.001) was observed with tissue sealant use. A significant decrease in oedema was detected (RR, 0.30; 95% CI, 0.11-0.85, p = 0.02) but not in ecchymosis, seroma, skin necrosis, and hypertrophic scarring with tissue sealant use. The use of tissue sealants prevents post-operative haematomas and reduces wound drainage. Previous studies have shown a similar trend, but the power of this meta-analysis could verify this perception. LEVEL OF EVIDENCE: III.

The Efficiency of Sclerotherapy in the Treatment of Vascular Malformations: A Retrospective Study of 63 Patients.

Background and Aims. Vascular malformations are a vast group of congenital malformations that are present at birth. These malformations can cause pain, pressure, and cosmetic annoyance as well as downturn growth and development in a child in the case of high flow. Sclerotherapy has become an important tool in the treatment of vascular malformations. However, little is known about the success rate of sclerotherapy. Material and Methods. In this study, the efficiency of sclerotherapy in the treatment of vascular anomalies was investigated retrospectively in 63 patients treated in Turku University Hospital between 2003 and 2013. Results. Out of the 63 patients investigated, 83% (53) had venous malformations (VMs) and 9% (5) were defined as having arteriovenous malformations (AVMs). Patients with a VM were operated on, in 14% (8) out of all VM cases. Hence 86% (45) of patients with a VM received adequate help to their symptoms solely from sclerotherapy. The duration of treatment for the 14% of the VM patients that needed a surgical procedure was prolonged by 7-9 months, that is, by 41%. Conclusions. Sclerotherapy is an effective method in the treatment of VMs with a satisfactory clinical response in patients symptoms in 84% of cases.

One-cm Versus 2-cm Excision Margins for Patients With Intermediate Thickness Melanoma: A Matched-Pair Analysis.

BACKGROUND: Optimum excision margins used in the removal of intermediate thickness melanomas remain unclear. OBJECTIVE: This study's aim was to compare the clinical outcomes of 1-cm margins with 2-cm margins in patients with a tumor thickness of 1.1- to 4.0-mm. MATERIALS AND METHODS: This was a retrospective study, which was based on a matched-pairs design. Equal patient cohorts were constructed in terms of gender, age, Breslow thickness, and the anatomic location of the primary lesion. There were 80 patients whom underwent an excision with a 1-cm margin and 80 patients with a 2-cm margin. Follow-up data were analyzed by the Kaplan-Meier method and a Cox regression model. RESULTS: After a median follow-up time of 41 months, there were no differences in relapse-free survival or melanoma-specific survival between study groups. The wound was closed directly in 62 patients (78%) in the 1-cm group and in 36 patients (45%) in the 2-cm group (p < .001). CONCLUSION: A 1-cm excision margin may be sufficient in melanomas of 1.1 to 2.0 mm in Breslow thickness based on these findings of low recurrence. With thicker tumors (2.1-4.0 mm), this recommendation cannot be given due to inherent study limitations.

EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma.

Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell-specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer.

Effectiveness of local anaesthetic pain catheters for abdominal donor site analgesia in patients undergoing free lower abdominal flap breast reconstruction: A meta-analysis of comparative studies.

The use of an infusion pain pump with local wound catheters has increased among different surgical specialities. Autologous breast reconstruction with deep inferior epigastric perforator (DIEP) and transverse rectus abdominis myocutaneous (TRAM) flaps may cause severe abdominal donor site morbidity, and infusion devices delivering local anaesthetic are suggested to improve postoperative analgesia. This study performed a meta-analysis comparing pain pump use vs control to evaluate this issue. A systematic literature search was performed. Primary outcome was the amount of opioid use. Secondary outcomes were the amount of antiemetic drugs and the length of hospital stay. Five studies involving 248 patients were retrieved and included in the present analysis. A significantly decreased use of opioids was observed after using pain pump vs control (MD = -15.13, 95% CI = -24.20, -6.06, p = 0.001). Although not statistically significant, the pooled results showed a trend toward reduction of antiemetic medicament use (MD = -0.71, 95% CI = -2.14, 0.72, p = 0.33) and hospital stay time (MD = -0.53, 95% CI = -1.18, 0.11, p = 0.10). The use of local anaesthetic pain catheters for abdominal donor sites in microsurgical breast reconstruction might be associated with a decreased use of narcotics and antiemetic medicaments and shorter hospital stay. Further studies are needed to validate this promising treatment modality.

Expression of insulin signaling transmitters and glucose transporters at the protein level in the rat testis.

Insulin receptor substrate (IRS) proteins are key mediators in insulin signaling from the insulin receptor. It takes place through receptor-mediated tyrosine phosphorylation of IRS proteins. The aim of the present article is to demonstrate the distribution of IRS 1-3, glucose transporters 1-4 (GLUT 1-4), signal regulatory protein 1alpha (SIRP1alpha), PKB, and PI 3-kinase in the rat testis to see if signal transduction mediated by these proteins is active in testicular cells. Wistar rats were used as donors of testis tissue. Expression of these genes was studied at the protein level by using immunohistochemistry and Western blotting. IRS-1, IRS-2, GLUT 1, GLUT 2, GLUT 3, and SIRP1alpha were strongly expressed in the Sertoli cells (except GLUT 1), early spermatocytes, peritubular myoid cells, macrophage-like interstitial cells, and testicular endothelial cells in all the testes investigated by immunohistochemistry. IRS-2 was also expressed in the Leydig cells. Immunoblotting experiments demonstrated the presence of about 26-67 kDa reactive with anti- IRS-1, IRS-2, GLUT 1, GLUT 2, GLUT 3, PKB, and SIRP1alpha. The present results suggest that proteins like insulin and certain cytokines using IRS-1, IRS-2, GLUT 1, GLUT 2, GLUT 3, PKB, and SIRP1alpha in their signal transduction can have effects on the different types of testicular cells in the rat.

Expression of insulin receptor substrates 1-3, glucose transporters GLUT-1-4, signal regulatory protein 1alpha, phosphatidylinositol 3-kinase and protein kinase B at the protein level in the human testis.

Insulin receptor substrates (IRS) mediate the biological actions of insulin, growth factors and cytokines. This action is via receptor-mediated tyrosine phosphorylation of IRS proteins. The aim of present study was to demonstrate the distribution of IRS-1-3, the glucose transporter class I subfamily (GLUT-1-4), signal regulatory protein 1alpha (SIRP1alpha), protein kinase B (PKB) and phosphatidylinositol kinase (PI3-K) in the human testis to determine whether signal transduction mediated by these proteins is active in testicular cells. In the present study, the expression of IRS-1-3, GLUT-1-4, SIRP1alpha, P13-K and PKB was studied in the human testis at the protein level using immunohistochemistry and western blotting. A positive immunoreaction for IRS-1 was found in the human testis in peritubular myoid cells and macrophage-like interstitial cells. A positive immunoreaction for GLUT-3 was found in the human testis in Sertoli cells, peritubular myoid cells, early spermatocytes, macrophage-like interstitial cells and cells in the small vessels walls. Western blotting demonstrated IRS-1, IRS-2 and GLUT-3 proteins in the human testis. Expression of IRS-3, GLUT-1, GLUT-2, GLUT-4, SIRP1alpha, P13-K and PKB was not detected in the human testis. The results of the present study suggest that proteins like insulin and certain cytokines using IRS-1, IRS-2 and GLUT-3 in their signal transduction pathways can have effects on different cell types of the testis in humans.

Immunohistochemical detection of glucose transporters class I subfamily in the mouse, rat and human testis.

A family of glucose transporters (GLUT) mediates the cellular uptake of glucose at the plasma membrane by facilitated diffusion. We investigated the presence of isoforms GLUT1-4 of class I subfamilies in different types of cells in the mouse, rat and human testis by indirect immunofluorescence technique. Immunocytochemical analyses demonstrated that GLUT1 was expressed in the rat testis, GLUT2 in the mouse and rat testis, GLUT3 in the mouse, rat and human testis and GLUT4 was not presented in the testis at all. A very intensive positive immunoreaction for GLUT3 was found in Sertoli cells, peritubular myoid cells, macrophage-like interstitial cells, testicular endothelial cells and early spermatocytes. GLUT3 positive cells were not found in the luminal part of Sertoli cells, spermatids or Leydig cells. The present results suggest that glucose uptake in different testicular cells is mediated by GLUT1, GLUT2 and GLUT3 and the GLUT3 was the prominent glucose transporter type in the testicular cells.

Analysis of 508 infertile male patients in south-western Finland in 1980-2000: hormonal status and factors predisposing to immunological infertility.

OBJECTIVE: To analyse the factors predisposing to male immunological infertility from the hospital records of 508 patients that had been treated for infertility in the Turku University Central Hospital from 1980 to 2000. In addition, the hormonal status was investigated at the beginning of treatment. RESULTS: Patients with a history of mumps, or either a fresh varicocele or a history of varicocele had statistically significant lower levels of MAR antisperm antibodies (ASAs) than patients with no such conditions. Repair of varicocele (either surgical or embolisation), showed a statistically significant enhancement of the total sperm cell counts in ejaculates, but it appeared not to have any influence on other parameters of the semen analysis (mobility and morphology). Of all male infertility patients, 66.3% had normal hormonal status at the beginning of treatment, 12.6% of patients had hypotestosteronemia and 22.1% had subclinical hypogonadism. Patients with subclinical hypogonadism had lower total sperm cell count in ejaculates than patients with normal hormonal status although they had statistically significant more offspring. In addition, it appeared that mumps orchitis as well as smoking and alcohol abuse are risk factors for subclinical hypogonadism. CONCLUSION: No clear predisposing factor for male immunological infertility could be found. However, patients with subclinical hypogonadism differed from other male infertility patients and thus may form a special group among the male infertility patients.