Cerebral cavernous malformation proteins, CCM1, CCM2 and CCM3, are decreased in metastatic lesions in a murine breast carcinoma model.

Three genes are associated with cerebral cavernous malformations (CCMs): CCM1, CCM2 and CCM3. These genes participate in microvascular angiogenesis, cell-to-cell junctions, migration and apoptosis. We evaluated the expression in vivo of CCM genes in primary tumors and metastastases in a murine model of metastatic breast carcinoma. We used cell lines obtained from metastasis of 4T1, 4TLM and 4THM breast cancer to liver and heart. These cells were injected into the mammary ridge of Balb/C female mice. After 27 days, the primary tumors, liver and lung were removed and CCM proteins were assessed using immunohistochemistry and western blot analysis. CCM proteins were expressed in primary tumor tissues of all tumor-injected animals; however, no CCM protein was expressed in metastatic tumor cells that migrated into other tissues. CCM proteins still were observed in the lung and liver tissue cells. Our findings suggest that CCM proteins are present during primary tumor formation, but when these cells develop metastatic potential, they lose CCM protein expression. CCM protein expression was lost or reduced in metastatic tissues compared to the primary tumor, which indicates that CCM proteins might participate in tumorigenesis and metastasis.

Effects of Melatonin and Doxorubicin on Primary Tumor And Metastasis in Breast Cancer Model.

BACKGROUND: Melatonin exerts oncostatic effects on breast cancer via immunomodulation and antioxidation. Doxorubicin is an effective chemotherapeutic agent, but parallel studies also provide ample evidence of an off-target effect of Doxorubicin in breast cancer patients. OBJECTIVE: Combinatorial use of doxorubicin and melatonin has not been comprehensively analyzed in breast cancer models. We hypothesized that the anti-oxidative, anti-proliferative and anti-inflammatory effects of melatonin could ameliorate the off-target effects of doxorubicin in breast cancer patients and enhance the anti-tumoral effects of doxorubicin. The goal of the study is to test this hypothesis in cancer cell lines and xenografted mice. METHODS: The effects of Melatonin and doxorubicin on the cell viability were evaluated in 4T1-Brain Metastatic Tumor (4TBM). Furthermore, the effects of melatonin and doxorubicin on the primary tumors and systemic metastasis were evaluated in the xenografted mice. Lung and liver tissues were removed and metastasis analyses were performed. The levels of p65, phospho-STAT3, CD11b+, GR1+, Ki67, and cleaved caspase-3 proteins were determined with immunohistochemistry and western blot analysis. We examined the effects of melatonin and Melatonin+Doxorubicin combination therapy on 4TBM cells. RESULTS: Our results showed that doxorubicin inhibited the proliferation of metastatic breast cancer cells while melatonin did not affect cells. Tumor growth and metastasis were markedly suppressed in melatonin alone and in combination with doxorubicin. The expression of CD11b+ and GR1+ proteins, which are indicators of myeloid-derived suppressor cells (MDSCs), were noted to be reduced in both primary tumor and metastatic tissues in melatonin and doxorubicin groups. CONCLUSION: The combination of melatonin with doxorubicin reduced primary tumor growth and distant metastasis. Based on these results, melatonin is a promising candidate for combinatory use with conventional chemotherapeutics for breast cancer treatment.

Melatonin decreases metastasis, primary tumor growth and angiogenesis in a mice model of breast cancer.

The goal of this study was to mechanistically analyze the effects of pre-treatment or post-treatment melatonin on the metastatic spread in a mice model. Consequently, the effects on the tumor growth, angiogenesis and metastasis were evaluated with immunohistochemical and western blot analysis. 8-10 weeks-old female BALB/c mice (n = 60, 10/group) were used. Liver metastatic cells (4TLM) from 4T1 murine breast carcinoma were previously isolated. Melatonin was administrated either before or after the injection of 4TLM cells into the mammary pad. Tumor and vehicle (%6 ethanol) injections were given to vehicle groups. Tumor group consisted of the mice injected with only 4TLM cells injected to tumor group and no intervention to control group. Necropsies were performed 27 days after injection of 4TLM. Primary tumors and metastatic tissues were removed. Furthermore, changes in lung and liver metastasis and primary tumor growth and angiogenesis were evaluated. In our study neutrophil levels were noted to be increased in peripheral blood of the tumor-bearing mice. Melatonin exerted inhibitory effects on the 4TLM-induced leukocytosis. Melatonin significantly decreased lung and liver metastasis, primary tumor growth and angiogenesis. The results demonstrated that melatonin might have a therapeutic role through reducing systemic inflammatory responses, metastasis, tumor growth and angiogenesis.

Comparison of various tendon repair techniques in extansor zone 3 injuries: an experimental biomechanical cadaver study.

PURPOSE: To compare five different repair techniques for extensor tendon zone III modified Kessler (MK), double-modified Kessler (DMK), modified Kessler epitendinous (MKE), double-modified Kessler epitendinous (DMKE), and running-interlocking horizontal mattress (RIHM) in terms of shortening, stiffness, gap formation, and ultimate load to failure. METHODS: A total of 35 human cadaver fingers were randomly assigned to five suture techniques with 7 fingers each and were tested under dynamic and static loading conditions. RESULTS: DMK was found to be superior over MK in terms of ultimate load to failure (36 N vs. 24 N, respectively), shortening (1.75 vs. 2.20 mm, respectively) and gap formation. However, these two methods had similar characteristics in terms of stiffness. The addition of epitendinous sutures to the repair methods resulted in approximately 40% increase in ultimate load to failure, whereas epitendinous sutures had no effect on shortening. DMKE was found to be superior over MKE in terms of shortening (1.77 vs. 2.22 mm, respectively). However, these two methods had similar characteristics in terms of mean ultimate load to failure and stiffness. RIHM was found to be superior over the other four methods in terms of ultimate load to failure (89 N), stiffness, and shortening (0.75 mm). CONCLUSION: RIHM was found to be stronger and more durable for extensor tendon zone III than the other techniques in terms of ultimate load to failure and stiffness.

Mutualistic Effects of the Myeloid-Derived Suppressor Cells and Cancer Stem Cells in the Tumor Microenvironment.

Myeloid-derived suppressor cells (MDSCs) are derived from myeloid progenitor cells present in the bone marrow. When the differentiation of the myeloid progenitor cells is impaired, MDSCs arise. The immunosuppressive functions of the MDSCs are significantly upregulated in the tumor microenvironment. MDSCs are promoted by many inflammatory molecules. Likewise, chemokines, cytokines, and enzymes that are secreted by MDSCs mediate tumor cell invasion, proliferation, survival, and adhesion. Cancer stem cells (CSCs) are known as malignant cancer cells with characteristics such as self-regeneration and differentiation. Cancer stem cells have been the focus of many cancer studies for many years. Recently, MDSCs have also become the focus of cancer researchers. According to a hypothesis, both CSCs and MDSCs have mutual effects on the development of cancer. Therefore, the aims of this review are to summarize the link between CSCs and MDSCs and to describe the immunosuppressor metastatic properties of the MDSCs.

Diabetes mellitus accelerates fatty degeneration of the supraspinatus muscle after tendon tear: An experimental study in rats.

OBJECTIVES: This study aims to evaluate the effect of diabetes mellitus (DM) on intramuscular fatty degeneration after a full-thickness supraspinatus (SS) tendon tear in rats. MATERIALS AND METHODS: The study included 24 adult male Wistar Albino rats (age, 18 to 24 weeks; weighing, 320-380 g) randomized into a sham group (n=6), control group (n=6) and experimental group (n=12). Rats with fasting blood glucose levels ≥250 mg/dL at each measurement after an injection of streptozotocin were accepted to have DM. On the seventh day of the study, the SS muscles of the rats in the experimental and control groups were cut from the insertion. All animals were performed euthanasia four weeks after the surgical procedure and SS muscles were excised completely. Fatty degeneration in the SS muscle was assessed histologically and immunohistochemically with oil red O and peroxisome proliferator-activated receptor gamma (PPAR-γ) staining using histological score (H-score) and quantitative methods. RESULTS: More intense oil red O and PPAR-γ staining was observed in all regions of the SS muscles of the experimental group compared to control and sham groups (p<0.05). CONCLUSION: The results of this study showed that DM accelerates intramuscular fatty degeneration after SS tendon tears. Fatty degeneration should be monitored closely in diabetic patients with rotator cuff tear who were selected for conservative treatment and early surgical treatment should be considered as an option.

Evaluation of the origin and branching patterns of the iliolumbar artery and its implications on pelvic and vertebral surgery.

OBJECTIVES: To evaluate the origin, distribution pattern, branches, and neighboring structures of the iliolumbar artery (ILA) concerning the anterolateral surgical approaches to the spine. METHODS: This study was performed in the Anatomy Department of Medical School, Mersin University, Mersin, Turkey between 2014 and 2015. Pelvises of 11 male formalin-fixed human cadavers were dissected by anterior and posterior approaches under surgical microscope. The origins, distribution patterns, calibers, and distances to certain structures were measured. RESULTS: The ILA was found as a single trunk on 17 sides arising either from the IIA (12 sides, 70.6%) or the PT (5 sides, 29.4%). The average caliber of those originated from the posterior trunk was significantly larger (p=0.010). The ILA started as a single trunk in 17 sides, while its lumbar and iliac branches separately originating from different arteries in 4 sides. The close relation of the posterior rami of both the lumbar and iliac branches with transverse process and spinal nerve were noted. CONCLUSION: Findings suggest that the ILA and its branches may have different and significant patterns, which may be crucial to consider during certain surgical procedures, such as far lateral disc herniation and posterior pelvic fixations.