The capacity of sublingual allergen immunotherapy (SLIT) to provide effective symptom relief in pollen-induced seasonal allergic rhinitis is often questioned, despite evidence of clinical efficacy ...from meta-analyses and well-powered, double-blind, placebo-controlled randomized clinical trials. In the absence of direct, head-to-head, comparative trials of SLIT and symptomatic medication, only indirect comparisons are possible.
We performed a meta-analysis of classes of products (second-generation H1-antihistamines, nasal corticosteroids and grass pollen SLIT tablet formulations) and single products (the azelastine-fluticasone combination MP29-02, and the leukotriene receptor antagonist montelukast) for the treatment of seasonal allergic rhinitis in adults, adolescents and/or children. We searched the literature for large (n >100 in the smallest treatment arm) double-blind, placebo-controlled randomized clinical trials. For each drug or drug class, we performed a meta-analysis of the effect on symptom scores. For each selected trial, we calculated the relative clinical impact (according to a previously published method) on the basis of the reported post-treatment or season-long nasal or total symptom scores: 100 × (scorePlacebo - scoreActive)/scorePlacebo.
Twenty-eight publications on symptomatic medication trials and ten on SLIT trials met our selection criteria (total number of patients: n = 21,223). The Hedges' g values from the meta-analyses confirmed the presence of a treatment effect for all drug classes. In an indirect comparison, the weighted mean (range) relative clinical impacts were -29.6% (-23% to -37%) for five-grass pollen SLIT tablets, -19.2% (-6% to -29%) for timothy pollen SLIT tablets, -23.5% (-7% to -54%) for nasal corticosteroids, -17.1% (-15% to -20%) for MP29-02, -15.0% (-3% to -26%) for H1-antihistamines and -6.5% (-3% to -10%) for montelukast.
In an indirect comparison, grass pollen SLIT tablets had a greater mean relative clinical impact than second-generation antihistamines and montelukast and much the same mean relative clinical impact as nasal corticosteroids. This result was obtained despite the presence of methodological factors that mask the clinical efficacy of SLIT for the treatment of seasonal allergic rhinitis.
Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted ...therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite dephosphorylation of the key translation regulator, 4E-BP1, which markedly inhibits the initiation step of mRNA translation. Consequently, metformin reduces the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong antileukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus represents a promising new strategy for AML therapy.
The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The ...mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S65 residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Direct inhibition of the translation initiating complex thus represents an attractive option for the development of new therapies in AML.
The growth and survival of acute myeloid leukemia (AML) cells are enhanced by the deregulation of signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt and mammalian target of rapamycin ...(mTOR). Major efforts have thus been made to develop molecules targeting these activated pathways. The mTOR serine/threonine kinase belongs to two separate complexes: mTORC1 and mTORC2. The mTORC1 pathway is rapamycin sensitive and controls protein translation through the phosphorylation of 4E-BP1 in most models. In AML, however, the translation process is deregulated and rapamycin resistant. Furthermore, the activity of PI3K/Akt and mTOR is closely related, as mTORC2 activates the oncogenic kinase Akt. We therefore tested, in this study, the antileukemic activity of the dual PI3K/mTOR ATP-competitive inhibitor NVP-BEZ235 compound (Novartis).
The activity of NVP-BEZ235 was tested in primary AML samples (n = 21) and human leukemic cell lines. The different signaling pathways were analyzed by Western blotting. The cap-dependent mRNA translation was studied by 7-methyl-GTP pull-down experiments, polysomal analysis, and (3)Hleucine incorporation assays. The antileukemic activity of NVP-BEZ235 was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation, and survival.
The NVP-BEZ235 compound was found to inhibit PI3K and mTORC1 signaling and also mTORC2 activity. Furthermore, NVP-BEZ235 fully inhibits the rapamycin-resistant phosphorylation of 4E-BP1, resulting in a marked inhibition of protein translation in AML cells. Hence, NVP-BEZ235 reduces the proliferation rate and induces an important apoptotic response in AML cells without affecting normal CD34(+) survival.
Our results clearly show the antileukemic efficiency of the NVP-BEZ235 compound, which therefore represents a promising option for future AML therapies.
To compare the analgesic effect of ultrasound-guided Transversus Abdominis Plane (TAP) block versus Continuous Wound Infusion (CWI) with levobupivacaine after caesarean delivery.
We recruited ...parturients undergoing elective caesareans for this multicenter study. Following written informed consent, they received a spinal anaesthetic without intrathecal morphine for their caesarean section. The postoperative analgesia was randomized to either a bilateral ultrasound guided TAP block (levobupivicaine = 150 mg) or a CWI through an elastomeric pump for 48 hours (levobupivacaine = 150 mg the first day and 12.5 mg/h thereafter). Every woman received regular analgesics along with oral morphine if required. The primary outcome was comparison of the 48-hour area under the curve (AUC) pain scores. Secondary outcomes included morphine consumption, adverse events, and persistent pain one month postoperatively.
Recruitment of 120 women was planned but the study was prematurely terminated due to the occurrence of generalized seizures in one patient of the TAP group. By then, 36 patients with TAP and 29 with CWI had completed the study. AUC of pain at rest and during mobilization were not significantly different: 50 22.5-80 in TAP versus 50 27.5-130 in CWI (P = 0.4) and 190 130-240 versus 160 112.5-247.5 (P = 0.5), respectively. Morphine consumption (0 0-20 mg in the TAP group and 10 0-32.5 mg in the CWI group (P = 0.09)) and persistent pain at one month were similar in both groups (respectively 29.6% and 26.6% (P = 0.73)).
In cases of morphine-free spinal anesthesia for cesarean delivery, no difference between TAP block and CWI for postoperative analgesia was suggested. TAP block may induce seizures in this specific context. Consequently, such a technique after a caesarean section cannot be recommended.
ClinicalTrials.gov NCT01151943.
Abstract Background Iron chelation therapy (CT) improves survival in thalassemia major but its beneficial effects on survival in MDS patients remain uncertain. Methods We analyzed, by multivariate ...analysis, survival and causes of deaths in 97 low or intermediate 1 IPSS patients regularly transfused as outpatients, chelated or not, who were included during a month period and followed for 2.5 years. Results 44 (45%) of patients were not chelated and 53 (55%) received CT, mainly with deferoxamine, for at least 6 months (median duration of chelation 36 months, range 6–131+). During the follow-up period, 66 of the 97 patients died, including 51% and 73% of chelated and non-chelated patients, respectively. Median overall survival was 53 months and 124 months in non-chelated and in chelated patients ( p < 0.0003). Causes of death did not significantly differ between the two groups ( p = 0.51). In multivariate Cox analysis, adequate chelation was the strongest independent factor associated with better OS. Conclusion Iron chelation therapy appears to improve survival in heavily transfused lower risk MDS, but prospective randomized studies are required to confirm our findings, and to determine more precisely the mechanisms of this potential survival benefit.
A number of clinical trials support the use of standardized cranberry supplement products for prevention of urinary tract infections; however, products that are not well-characterized for sufficient ...levels of bioactive components may contribute to negative clinical outcomes. Cranberry supplements for consumer use are not regulated and can be formulated different ways using cranberry juice, pomace or various combinations. This can lead to consumer confusion regarding effectiveness of individual products. The current study compared two commercial supplement products, one made from cranberry juice extract and the other from a blend of whole cranberry. The influence of formulation and proanthocyanidin (PAC) solubility on in vitro and ex vivo P-fimbriated Escherichia coli bacterial anti-adhesion activity (AAA) was determined. Both supplement products as well as whole, frozen cranberries were chromatographically separated into crude polyphenolic, sugar and acid fractions. In vitro AAA testing of all fractions confirmed that only those containing soluble PACs elicited activity. The cranberry juice extract product had higher soluble PAC content than the whole cranberry blended product, which contained mainly insoluble PACs. The influence of soluble and insoluble PAC levels in each product on the urinary (ex vivo) AAA was determined following ingestion. The juice extract product was associated with significantly higher urinary AAA than that of the whole berry blended product when consumed once daily over the 1-week intervention period.
Purpose
PSA is known to be lowered in obese patients. There is a lack of data regarding patients with prostate cancer. Our objective was to prospectively assess the relationship PSA concentration, ...PSA mass and BMI in a cohort of patients with localized prostate cancer.
Methods
A prospective, multicenter cohort study was conducted including patients undergoing radical prostatectomy. Clinical and biological data were collected for each patient before surgery.
Results
A total of 1343 patients were analyzed. Mean age was 64.0 years. Mean weight was 82.2 kg and mean BMI was 26.8 kg/m
2
. Mean PSA concentration was 8.7 ng/mL and mean PSA mass 29.3 ng.
On univariate analysis, an association was found between PSA mass and either BMI, weight and waist circumference. No association was found between PSA concentration and each weight parameters.
On multivariate analysis, obesity was not an independent predictor of PSA concentration (
p =
0.73). Independent predictors of PSA concentration were cardiovascular disease (negative association,
p =
0.034), predominant Gleason 4 (positive association,
p <
0.001) and pT3a (positive association,
p <
0.001).
BMI was an independent predictor of PSA mass (positive association,
p =
0.009). PSA mass was negatively associated with TT (
p =
0.015) and cardiovascular disease (
p =
0.003), and positively associated with BT (
p =
0.032), Gleason grade ≥ 4 + 3 (
p <
0.001) and pT3a (
p <
0.001).
Conclusion
In this prospective study of patients with localized prostate cancer, higher BMI was associated with higher PSA mass but not with higher PSA concentration. Screening obese patients with a specific PSA method does not appear to be critical.
The specific involvement of the sex steroids in the growth of the prostatic tissue remains unclear. Sex steroid concentrations in plasma and in fresh surgical samples of benign central prostate were ...correlated to prostate volume.
Monocentric prospective study performed between September 2014 and January 2017. Age, obesity parameters, and both serum and intraprostatic concentrations of sex steroids were collected complying with the latest Endocrine Society guidelines and the steroids assessed by GC/MS. Statistical calculations were adjusted for age and body mass index (BMI).
Thirty-two patients, equally divided between normal- and high-volume prostate groups, were included in the analysis. High-volume prostate patients were older, heavier and had higher BMI. Comparison adjusted for age and BMI showed higher DHT concentrations in high-volume prostate. Both normal- and high-volume prostate tissues concentrate sex steroids in a similar way. Comparison of enzymatic activity surrogate marker ratios within tissue highlighted similar TT/E1 and TT/E2 ratios, and higher DHT/E1 ratio and lower DHT/PSA ratio in the high-volume prostates.
STERPROSER trial provides evidence for higher DHT concentration in highvolume prostates, that could reflect either higher 5-alpha reductase expression or lower expression of downstream metabolizing enzymes such as 3a-hydoxysteroid dehydrogenase.
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