Metformin promotes antitumor activity of NK cells via overexpression of miRNA-150 and miRNA-155.

OBJECTIVES: Metformin, an oral anti-diabetic drug, is known to possess a powerful antitumor effect by modulating the tumor-immune interaction. The precise influence of metformin on natural killer (NK) cells, a crucial innate immunity player, is not completely understood. In our study, analyses of the effect of metformin on the NK cell functional phenotype were performed, and the potential mechanisms underlying it were investigated. METHODS: BALB/C wild type mice were treated with metformin, and the functional phenotype of splenocytes and potential underlying mechanisms were investigated. RESULTS: Metformin significantly boosts NK cell cytotoxicity and the percentage of NKp46+, FasL+, and interferon (IFN)-γ+ NK cells while decreasing interleukin (IL)-10 producing NK cells. Our research also demonstrated that the simultaneous administration of metformin and 1-methyl-DL-tryptophan (1-MT), a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), significantly increased the NK cells synthesis of IFN-γ, IL-17, perforin, and FasL and NKp46 expression. These findings imply that metformin potentiates NK cell cytotoxicity through mechanisms other than IDO blockade. Metformin administration strongly increased the expression of immunostimulatory microRNA (miRNA)-150 and miRNA-155, while decreasing the expression of immunosuppressive miRNA-146a. CONCLUSIONS: These findings suggest that metformin can directly potentiate NK cell activation and cytotoxicity. This research may contribute to dissecting key mechanisms of metformin exerting antitumor activity to advance the use of metformin as an antitumor agent.

Dual blockage of PD-L/PD-1 and IL33/ST2 axes slows tumor growth and improves antitumor immunity by boosting NK cells.

AIMS: Although separate blockage of either IL33/ST2 or PD-L/PD-1 axes has been shown to be beneficial in many tumors, co-blockage of IL33/ST2 and PD-L/PD-1 hasn't been studied yet. MAIN METHODS: 4T1 breast cancer and CT26 colon cancer were inducted in BALB/C wild type (WT) and BALB/C ST2 knockout mice, after which mice underwent anti PD-1 and anti IL-33 treatment. KEY FINDINGS: Co-blockage of IL33/ST2 and PD-L/PD-1 delayed tumor appearance and slowed tumor growth. Enhanced NK cell cytotoxicity against 4T1 tumor cells in ST2 knockout anti-PD-1 treated mice was associated with overexpression of miRNA-150 and miRNA-155, upregulation of NFκB and STAT3, increased expression of activation markers and decreased expression of immunosuppressive markers in splenic and primary tumor derived NK cells. NK cells from ST2 knockout anti-PD-1 treated mice tend to proliferate more and are less prone to apoptosis. Accumulation of immunosuppressive myeloid derived suppressor cells and regulatory T cells was significantly impaired in spleen and primary tumor of ST2 knockout anti-PD-1 treated mice. SIGNIFICANCE: Co-blockage of IL3/ST2 and PD-L/PD-1 axes impedes tumor progression more efficiently than single blockage of either axes, thus offering potential new approach to immunotherapy of tumors.

Case of rectal angioleiomyoma in a female patient.

Angioleiomyoma represents a benign stromal tumor, which usually occurs in the subcutaneous tissue of the extremities, although its occurrence in the gastrointestinal tract is very rare. A case of rectal angioleiomyoma in a 40 year-old female patient is described here. Six months earlier, the patient suffered from periodical prolapse of an oval tumor from the anus, along with difficulties in bowel movement. A transanal extirpation of the tumor was performed. This is the first reported case in the English literature of a patient presenting with prolapsed angioleiomyoma of the rectum. During the immediate postoperative period, as well as 6 mo later, the patient had an unremarkable postoperative recovery.

Primary colorectal lymphoma: An overview.

Lymphomas represent common hematological malignancies with increasing incidence in recent years. The major site of extranodal non-Hodgkin lymphoma is the gastrointestinal tract. Involvement of the large intestine is rare in comparison to the stomach or small bowel. The disease appears later in life, predominantly in the male population. Complaints are nonspecific, requiring a high index of suspicion in order to establish the diagnosis. The treatment varies from chemotherapy alone to multimodal therapies combining surgery, chemotherapy and radiotherapy. The small number of patients with various histological subtypes and different stage at presentation results in unclear protocol for the treatment of primary colorectal lymphoma. The purpose of this paper is to review current data on primary lymphoma of the colon and rectum while analyzing reported case series and published material on the subject.

The influence of different sub-bandage pressure values on venous leg ulcers healing when treated with compression therapy.

BACKGROUND: Venous leg ulcers (VLU) have a huge social and economic impact. An estimated 1.5% of European adults will suffer a venous ulcer at some point in their lives. Despite the widespread use of bandaging with high pressure in the treatment of this condition, recurrence rates range between 25% to 70%. Numerous studies have suggested that the compression system should provide sub-bandage pressure values in the range from 35 mm Hg to 45 mm Hg in order to achieve the best possible healing results. METHODS: An open, randomized, prospective, single-center study was performed in order to determine the healing rates of VLU when treated with different compression systems and different sub-bandage pressure values. One hundred thirty-one patients (72 women, 59 men; mean age, 59-years-old) with VLU (ulcer surface >3 cm(2); duration >3 months) were randomized into three groups: group A - 42 patients who were treated using an open-toed, elastic, class III compression device knitted in tubular form (Tubulcus, Laboratoires Innothera, Arcueil, France); group B - 46 patients treated with the multi-component bandaging system comprised of Tubulcus and one elastic bandage (15 cm wide and 5 cm long with 200% stretch, Niva, Novi Sad, Serbia); and group C - forty-three patients treated with the multi-component bandaging system comprised of Tubulcus and two elastic bandages. Pressure measurements were taken with the Kikuhime device (TT MediTrade, Soro, Denmark) at the B1 measuring point in the supine, sitting, and standing positions under the three different compression systems. RESULTS: The median resting values in the supine and standing positions in examined study groups were as follows: group A - 36.2 mm Hg and 43.9 mm Hg; group B - 53.9 mm Hg and 68.2 mm Hg; group C - 74.0 mm Hg and 87.4 mm Hg. The healing rate during the 26-week treatment period was 25% (13/42) in group A, 67.4% (31/46) in group B, and 74.4% (32/43) in group C. The success of compression treatment in group A was strongly associated with the small ulcer surface (<5 cm(2)) and smaller calf circumference (CC; <38 cm). On the other hand, compliance in group A was good. In groups B and C, compliance was poor in patients with small CC, but the healing rate was high, especially in patients with large ulcers and a large CC (>43 cm). CONCLUSION: The results obtained in this study indicate that better healing results are achieved with two or multi-component compression systems than with single-component compression systems and that a compression system should be individually determined for each patient according to individual characteristics of the leg and CC. Target sub-bandage pressure value (B1 measuring point in the sitting position) of the compression system needed for the ulcer healing could be determined according to a simple formula, CC + CC/2.

Coiling of the left common carotid artery as a cause of transient ischemic attacks.

Coiling of the artery is a rare morphologic entity that is most frequently described in the internal carotid arteries. In other arteries, coiling is rarely reported because it remains asymptomatic. Herein, we present a case of 67-year-old female patient with a history of transient ischemic attacks during the last year. Color duplex scan and arteriography did not show any significant changes in the internal carotid arteries. However, an unusual coiling of almost 360 degrees was noted in left common carotid artery. Partial resection of left common carotid artery was performed. In an 8-month follow-up period, neurologic symptoms resolved, and patient is well.

Peripheral nerve conduction study in workers exposed to a mixture of organic solvents in paint and lacquer industry.

AIM: To compare levels of combined exposure to white spirit, toluene, butyl acetate, ethyl acetate, and xylene in the manufacturing of paint, cartridge, drying, and top-coat sections of paint and lacquer industry, and peripheral nerve conduction parameters in the exposed workers. METHODS: The exposed group comprised 120 workers while the control group included 110 workers who had never been exposed to the above listed organic solvents. Nerve conduction studies of the radial and tibial anterior nerve were performed in both groups. RESULTS: Motor and sensitive conduction velocity, as well as terminal latency of the radial and tibial anterior nerve showed significant changes in exposed workers in comparison to those of the control group (p<0.001). These parameters were significantly changed in workers with long length exposure to the toxic agents. In early stages of exposure, neural conduction parameters of the radial nerve were the most sensitive parameters in detecting subclinical peripheral nerve changes (p<0.001). There was significant correlation between the nerve conduction changes and urinary levels of hippuric and methyl-hippuric acids (p<0.01). CONCLUSION: The results of the study suggest neurotoxic effects of the mixture of white spirit, toluene, butyl acetate, ethyl acetate, and xylene detected in paint and lacquer industry. Standard measurement of the urinary levels of hippuric and methyl-hippuric acids could be a useful indicator of need for nerve conduction studies and the subclinical peripheral neuropathy screening in exposed workers.