JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.     

Mycobacterial lipoarabinomannan induces nitric oxide and tumor necrosis factor alpha production in a macrophage cell line: down regulation by taurine chloramine.

Avirulent mycobacterium H37Ra lipoarabinomannan (LAM) elicited nitric oxide (NO) and tumor necrosis factor alpha in a dose-dependent manner in a murine macrophage cell line, RAW 264.7 cells. H37Ra LAM and recombinant gamma interferon were highly synergistic for NO production. The production of NO and the release of tumor necrosis factor alpha stimulated by H37Ra LAM plus recombinant gamma interferon in RAW 264.7 cells are inhibited by taurine chloramine.     

Response of salivary peroxidase to exercise intensity

Oral peroxidase, one of the most important salivary antioxidant enzymes, is subjected to alternation due to various body conditions. The aim of this study was to assess the effect of exercise intensity on salivary peroxidase activity. Using a randomized design, ten healthy male university students (mean age, 23.22; s _x = 2.34 years) completed treadmill runs with initial velocity 6.73 km/h at the rate of 1.58 km/h increase every 3 min until exhaustion. Unstimulated whole saliva collected over a 5-min period in pre-weighed tubes before, immediately after exercise, and 1 h after exercise was analyzed for total protein and saliva peroxidase activity. The saliva flow rate ranged from 0.08 to 1.40 ml min⁻¹ at rest and was not significantly affected by the exercise. Peroxidase activity in each sample was measured using 4-amino antipyrine as substrate. In the incremental exhaustion run and also at 75% VO_2max, the secretion rates of peroxidase increased. No significant changes in saliva flow rate were observed in any treadmill run. Treadmill runs at 75% VO_2max and to exhaustion increased the activity of peroxidase immediately after exercise which decreased after 1 h. It was concluded that short-duration, high-intensity exercise increases the activity rate of peroxidase despite no change in the saliva flow rate. These effects appear to be associated with changes in sympathetic activity and not the hypothalamic pituitary adrenal axis.     

Modification of formalin-induced nociception by different histamine receptor agonists and antagonists.

The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20-40 microg/mouse i.c.v.) or subcutaneous (1-10 mg/kg s.c.) injection of HTMT (H(1) receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H(1) receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 mug/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H(2) receptor agonist, 30 mg/kg i.p.) and ranitidine (H(2) receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H(3) receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H(3) receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetit-induced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H(3) receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H(1) and H(3) receptor activations increase sensitivity to nociceptive stimulus in the formalin test.     

The role of microsatellites as a prognostic factor in primary malignant melanoma

OBJECTIVE: To determine the impact of microsatellites as a prognostic factor in primary cutaneous melanoma. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center.Patients A total of 504 patients with a history of primary melanoma observed for 2 years or having experienced a first relapse. MAIN OUTCOME MEASURES: Overall survival (OS) and relapse-free survival (RFS). RESULTS: Forty-five patients had evidence of microsatellites in their primary melanoma. Presence of microsatellites significantly correlated with the presence of several other histologic high-risk factors such as tumor thickness, ulceration, Clark level, vascular factors, and mitotic rate. Univariate analysis demonstrated decreased RFS and OS in patients with microsatellites. Presence of microsatellites was associated with increased locoregional metastasis but not distant metastasis. In multivariate analysis, with the inclusion of 6 other clinical and histologic factors, presence of microsatellites was a significant predictor of RFS but not OS. Patients with clinical macrosatellites had a trend toward worsening OS compared with those with microsatellites. CONCLUSIONS: The presence of microsatellites is intimately tied to other markers of melanoma aggressiveness. Microsatellites appear to predict locoregional relapse and RFS but neither distant metastasis nor OS. These results may have implications for patient care as well as the inclusion of microsatellites in stage III of the current classification.     

Efficacious response with low-dose indapamide therapy in the treatment of type II diabetic patients with normal renal function or moderate renal insufficiency and moderate hypertension

We examined the efficacy of low daily dose (1.25 mg/day) of indapamide in the treatment of high blood pressure in patients with diabetes mellitus with normal renal function and those with moderate renal insufficiency (serum creatinine <1.5 mg/dl). The study was an open label one of four months duration. Twenty-eight patients were enrolled in the study and only 15 completed it. Within 2 weeks of therapy, systolic blood pressure fell from 173 +/- 4.5 to 144 +/- 2.0 mm Hg and diastolic blood pressure from 96 +/- 2.1 to 80 +/- 1.8 mm Hg (p < 0.01) and blood pressure remained at these levels throughout the study. The results show that low dose indapamide is effective in the treatment of moderate hypertension in patients with diabetes mellitus who have normal renal function or moderate renal insufficiency. Therefore, this dose of 1.25 mg/day is recommended for the treatment of such patients.     

Does interval time between pulsed dye laser treatments for port-wine stains influence outcome? A systematic review and meta-analysis

Lasers in Medical Science - The pulsed dye laser (PDL) is the standard treatment for port-wine stains (PWS). Maximal improvement occurs after multiple treatment sessions; however, the optimal...     

Impact of Bariatric Surgery on Carotid Intima-Media Thickness in Patients with Morbid Obesity: a Prospective Study and Review of the Literature

Obesity Surgery - One of the main causes of mortality among obese patients is cardiovascular disease (CVD). Carotid intima-media thickness (CIMT) is an independent predictor for atherosclerosis and...