Patterns of relapse after successful completion of initial therapy in primary central nervous system lymphoma: a case series

Journal of Neuro-Oncology - Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin’s lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of...     

Comparison between orlistat plus l-carnitine and orlistat alone on inflammation parameters in obese diabetic patients

To evaluate the effects of 1-year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and inflammatory parameters in obese type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated the following parameters at baseline and after 3, 6, 9, and 12 months: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c) ), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), adiponectin (ADN), leptin, tumor necrosis factor-α (TNF-α), vaspin, and high-sensitivity C-reactive protein (Hs-CRP). We observed a better decrease in body weight, glycemic profile, HOMA-IR, LDL-C, and ADN and a faster improvement in FPI, TC, Tg, leptin, TNF-α, Hs-CRP with orlistat plus L-carnitine compared to orlistat alone. We also recorded an improvement in vaspin with orlistat plus l-carnitine not reached with orlistat alone. Orlistat plus L-carnitine gave a better improvement in body weight, glycemic and lipid profile compared to orlistat alone; furthermore, a faster and better improvement in inflammatory parameters was observed with orlistat plus L-carnitine compared to orlistat alone.     

Is further screening of men with baseline PSA < 1 ng ml−1 worthwhile? The discussion continues—Results of the Swiss ERSPC (Aarau)

Recent studies indicate frequent early PSA retesting unrelated of men's baseline PSA, which increases the harms of early detection especially among men with low PSA. The current study investigates the PCa incidence among men with baseline PSA <1.0 ng ml^?1 in order to adjust retest intervals for more targeted early detection. Between 1998 and 2012, 2,416 men with baseline PSA <1.0 ng ml^?1 were prospectively observed. Primary endpoint was PCa diagnosis. Negative predictive value (NPV) and number needed to screen (NNS) to detect one PCa were calculated. During a median follow‐up time of 12.1 years, 54 (2.2%) PCa were diagnosed with n = 26 (48.1%) among men with baseline PSA of 0.75 ≤ 1.0 ng ml^?1 (upper baseline PSA quartile). The 10‐year probability of being diagnosed with PCa increased significantly from 0.19% (baseline PSA < 0.40 ng ml^?1) to 2.0% (baseline PSA 0.40 ≤ 0.56 ng ml^?1), 2.5% (baseline PSA 0.56 ≤ 0.75 ng ml^?1) over 4.4% (baseline PSA 0.75 ≤ 1.0 ng ml^?1) (all p values <0.0001), respectively. The frequency of Gleason ≥7 PCa increased from 1 (0.17%) to 8 (1.4%), 5 (0.8) over 11 (1.8%) in these groups. The 8‐year NPV for Gleason ≥ 7 PCa were 99.8 (baseline PSA < 0.40 ng ml^?1), 99.8 (baseline PSA 0.40 ≤ 0.56 ng ml^?1), 100 (baseline PSA 0.56 ≤ 0.75 ng ml^?1) and 99.5 (baseline PSA 0.75 ≤ 1.0 ng ml^?1), respectively. During 12 years, the numbers were 99.8, 98.6, 99.2, and 98.2, respectively. Therefore, due to the very low rate of Gleason ≥ 7 PCa, further screening might be omitted in men with baseline PSA < 0.4 ng ml^?1. Between 0.4 and 1.0 ng ml^?1, an 8‐year interval can be discussed.     

Small-molecule synergist of the Wnt/beta-catenin signaling pathway

The Wnt/beta-catenin signaling pathway regulates cell fate and behavior during embryogenesis, adult tissue homeostasis, and regeneration. When inappropriately activated, the pathway has been linked to colorectal cancer and melanoma, and when attenuated it may contribute to Alzheimer's disease and osteoporosis. Small molecules that modulate Wnt signaling will likely provide new insights into the regulation of this key developmental pathway and ultimately provide pharmacological agents to control Wnt signaling in vivo. To this end, we screened a library of 100,000 small molecules for activity in a cell-based assay of Wnt/beta-catenin signaling and discovered a purine derivative, QS11, that synergizes with Wnt-3a ligand in the activation of Wnt/beta-catenin signal transduction. Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/beta-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells.     

Identification of novel genetic variants in the mutational hotspot region 14 kb upstream of the LCT gene in a Mexican population

Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (～14?kb) of the lactase (LCT) gene. One is typically found in Europeans, LCT –13910C?>?T, several others are found in East Africans and Arabs, e.g. LCT –13907C?>?G and LCT –13915T?>?G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501?bp region spanning the LCT –13910C?>?T hotspot was successfully performed in 150 samples. The frequency of the European-type LCT –13910?T-allele was q?=?0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least one LCT –13910?T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation.     

Glomerular hypertension and injury in desoxycorticosterone-salt rats on antihypertensive therapy

Uninephrectomized male Munich-Wistar rats received either weekly subcutaneous injections of vehicle and water for drinking; injections of desoxycorticosterone (DOC) and 1% saline (SALT) for drinking; or DOC and SALT with hydrochlorthiazide, hydralazine, reserpine and KCl added. All studies were performed six weeks after UNX. At that time, rats receiving DOC and SALT alone were hypertensive and had significantly more proteinuria and morphologic evidence of glomerular injury than rats given vehicle and tap water which were normotensive. Antihypertensive therapy normalized mean arterial pressure in DOC-SALT rats, but failed to prevent proteinuria, mesangial expansion or focal segmental glomerular lesions. Micropuncture studies revealed that glomerular capillary pressure was elevated in both untreated and treated DOC-SALT animals. We conclude that drugs which successfully reduce systemic blood pressure may fail to correct glomerular capillary hypertension in DOC-SALT rats. As persistence of intrarenal hypertension is associated with significant glomerular injury, normalization of glomerular capillary pressure rather than systemic arterial pressure is crucial to the prevention of glomerular injury in this model.     

Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1

Background  

Polymorphisms in the MHC class 1-like gene known as HFE have been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants of HFE are relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors.