Chemoradiotherapy or chemotherapy as adjuvant treatment for resected gastric cancer: should we use selection criteria?

BackgroundThe management of gastric adenocarcinoma is essentially based on surgery followed by adjuvant treatment. Adjuvant chemotherapy (CT) as well as chemoradiotherapy (CTRT) have proven their effectiveness in survival outcomes compared to surgery alone. However, there is little data comparing the two adjuvant approaches. This study aimed to compare the prognosis and survival outcomes of patients with gastric adenocarcinoma operated and treated by adjuvant radio-chemotherapy or chemotherapyMaterials and methodsWe retrospectively evaluated 80 patients with locally advanced gastric cancer (LGC) who received adjuvant treatment. We compared survival outcomes and patterns of recurrence of 53 patients treated by CTRT and those of 27 patients treated by CT.ResultsAfter a median follow-up of 38.48 months, CTRT resulted in a significant improvement of the 5-year PFS (60.9% vs. 36%, p = 0.03) and the 5-year OS (55.9% vs. 33%, p = 0.015) compared to adjuvant CT. The 5-year OS was significantly increased by adjuvant CTRT (p = 0.046) in patients with lymph node metastasis, and particularly those with advanced pN stage (p = 0.0078) and high lymph node ratio (LNR) exceeding 25% (p = 0.012). Also, there was a significant improvement of the PFS of patients classified pN2–N3 (p = 0.022) with a high LNR (p = 0.018). CTRT was also associated with improved OS and PFS in patients with lymphovascular and perineural invasion (LVI and PNI) compared to chemotherapy.ConclusionThere is a particular survival benefit of adding radiotherapy to chemotherapy in patients with selected criteria such as lymph node involvement, high LNR LVI, and PNI.     

Is ‘Self-Medication’ a Useful Term to Retrieve Related Publications in the Literature? A Systematic Exploration of Related Terms

BackgroundSelf-Medication (SM), i.e. using medications to treat oneself, is a major concern for health researchers and policy makers. The terms “self medication” or “self-medication” (SM terms) have been used to explain various concepts while several terms have also been employed to define this practice. Hence, retrieving relevant publications would require exhaustive literature screening. So, we assessed the current situation of SM terms in the literature to improve the relevancy of search outcomes.MethodsIn this Systematic exploration, SM terms were searched in the 6 following databases and publisher’s portals till April 2012: Web of Science, Scopus, PubMed, Google scholar, ScienceDirect, and Wiley. A simple search query was used to include only publications with SM terms. We used Relative-Risk (RR) to estimate the probability of SM terms use in related compared to unrelated publications. Sensitivity and specificity of SM terms as keywords in search query were also calculated. Relevant terms to SM practice were extracted and their Likelihood Ratio positive and negative (LR+/-) were calculated to assess their effect on the probability of search outcomes relevancy in addition to previous search queries. We also evaluated the content of unrelated publications. All mentioned steps were performed in title (TI) and title or abstract (TIAB) of publications.Results1999 related and 1917 unrelated publications were found. SM terms RR was 4.5 in TI and 2.1 in TIAB. SM terms sensitivity and specificity respectively were 55.4% and 87.7% in TI and 84.0% and 59.5% in TIAB. “OTC” and “Over-The-Counter Medication”, with LR+ 16.78 and 16.30 respectively, provided the most conclusive increase in the probability of the relevancy of publications. The most common unrelated SM themes were self-medication hypothesis, drug abuse and Zoopharmacognosy.ConclusionsDue to relatively low specificity or sensitivity of SM terms, relevant terms should be employed in search queries and clear definitions of SM applications should be applied to improve the relevancy of publications.     

Cytosolic Access of Mycobacterium tuberculosis: Critical Impact of Phagosomal Acidification Control and Demonstration of Occurrence In Vivo

Mycobacterium tuberculosis (Mtb) uses efficient strategies to evade the eradication by professional phagocytes, involving—as recently confirmed—escape from phagosomal confinement. While Mtb determinants, such as the ESX-1 type VII secretion system, that contribute to this phenomenon are known, the host cell factors governing this important biological process are yet unexplored. Using a newly developed flow-cytometric approach for Mtb, we show that macrophages expressing the phagosomal bivalent cation transporter Nramp-1, are much less susceptible to phagosomal rupture. Together with results from the use of the phagosome acidification inhibitor bafilomycin, we demonstrate that restriction of phagosomal acidification is a prerequisite for mycobacterial phagosomal rupture and cytosolic contact. Using different in vivo approaches including an enrichment and screen for tracking rare infected phagocytes carrying the CD45.1 hematopoietic allelic marker, we here provide first and unique evidence of M. tuberculosis-mediated phagosomal rupture in mouse spleen and lungs and in numerous phagocyte types. Our results, linking the ability of restriction of phagosome acidification to cytosolic access, provide an important conceptual advance for our knowledge on host processes targeted by Mtb evasion strategies.     

Preload-Based Starling-Like Control for Rotary Blood Pumps: Numerical Comparison with Pulsatility Control and Constant Speed Operation

In this study, we evaluate a preload-based Starling-like controller for implantable rotary blood pumps (IRBPs) using left ventricular end-diastolic pressure (PLVED) as the feedback variable. Simulations are conducted using a validated mathematical model. The controller emulates the response of the natural left ventricle (LV) to changes in PLVED. We report the performance of the preload-based Starling-like controller in comparison with our recently designed pulsatility controller and constant speed operation. In handling the transition from a baseline state to test states, which include vigorous exercise, blood loss and a major reduction in the LV contractility (LVC), the preload controller outperformed pulsatility control and constant speed operation in all three test scenarios. In exercise, preload-control achieved an increase of 54% in mean pump flow (QP-) with minimum loading on the LV, while pulsatility control achieved only a 5% increase in flow and a decrease in mean pump speed. In a hemorrhage scenario, the preload control maintained the greatest safety margin against LV suction. PLVED for the preload controller was 4.9 mmHg, compared with 0.4 mmHg for the pulsatility controller and 0.2 mmHg for the constant speed mode. This was associated with an adequate mean arterial pressure (MAP) of 84 mmHg. In transition to low LVC, QP- for preload control remained constant at 5.22 L/min with a PLVED of 8.0 mmHg. With regards to pulsatility control, QP- fell to the nonviable level of 2.4 L/min with an associated PLVED of 16 mmHg and a MAP of 55 mmHg. Consequently, pulsatility control was deemed inferior to constant speed mode with a PLVED of 11 mmHg and a QP- of 5.13 L/min in low LVC scenario. We conclude that pulsatility control imposes a danger to the patient in the severely reduced LVC scenario, which can be overcome by using a preload-based Starling-like control approach.     

Estimation of 24-Hour Intraocular Pressure Peak Timing and Variation Using a Contact Lens Sensor

Purpose

To compare estimates of 24-hour intraocular pressure (IOP) peak timing and variation obtained using a contact lens sensor (CLS) and using a pneumatonometer.

Methods

Laboratory data collected from 30 healthy volunteers (ages, 20-66 years) in a randomized, controlled clinical trial were analyzed. Participants were housed for 24 hours in a sleep laboratory. One randomly selected right or left eye was fitted with a CLS that monitored circumferential curvature in the corneoscleral region related to the change of IOP. Electronic output signals of 30 seconds were averaged and recorded every 5 minutes. In the contralateral eye, habitual IOP measurements were taken using a pneumatonometer once every two hours. Simulated 24-hour rhythms in both eyes were determined by cosinor fitting. Simulated peak timings (acrophases) and simulated data variations (amplitudes) were compared between the paired eyes.

Results

Bilateral change patterns of average 24-hour data for the group were in parallel. The simulated peak timing in the CLS fitted eye occurred at 4:44 AM ± 210 min (mean ± SD) and the IOP peak timing in the contralateral eye at 4:11 AM ± 120 min (P=0.256, Wilcoxon signed-rank test). There was no significant correlation between the simulated data variations in the paired eyes (P=0.820, linear regression).

Conclusions

The 24-hour CLS data showed a simulated peak timing close to the 24-hour IOP peak timing obtained using the pneumatonometer. However, the simulated variations of 24-hour data in the paired eyes were not correlated. Estimated 24-hour IOP rhythms using the two devices should not be considered interchangeable.     

Pancreatic beta-cells: From generation to regeneration

The pancreas is composed of two main compartments consisting of endocrine and exocrine tissues. The majority of the organ is exocrine and responsible for the synthesis of digestive enzymes and for their transport via an intricate ductal system into the duodenum. The endocrine tissue represents less than 2% of the organ and is organized into functional units called islets of Langerhans, comprising alpha-, beta-, delta-, epsilon- and PP-cells, producing the hormones glucagon, insulin, somatostatin, ghrelin and pancreatic polypeptide (PP), respectively. Insulin-producing beta-cells play a central role in the control of the glucose homeostasis. Accordingly, absolute or relative deficiency in beta-cells may ultimately lead to type 1 and/or type 2 diabetes, respectively. One major goal of diabetes research is therefore to understand the molecular mechanisms controlling the development of beta-cells during pancreas morphogenesis, but also those underlying the regeneration of adult injured pancreas, and assess their significance for future cell-based therapy. In this review, we will therefore present new insights into beta-cell development with focus on beta-cell regeneration.     

UvrD controls the access of recombination proteins to blocked replication forks

Blocked replication forks often need to be processed by recombination proteins prior to replication restart. In Escherichia coli, the UvrD repair helicase was recently shown to act at inactivated replication forks, where it counteracts a deleterious action of RecA. Using two mutants affected for different subunits of the polymerase III holoenzyme (Pol IIIh), we show here that the anti-RecA action of UvrD at blocked forks reflects two different activities of this enzyme. A defective UvrD mutant is able to antagonize RecA in cells affected for the Pol IIIh catalytic subunit DnaE. In this mutant, RecA action at blocked forks specifically requires the protein RarA (MgsA). We propose that UvrD prevents RecA binding, possibly by counteracting RarA. In contrast, at forks affected for the Pol IIIh clamp (DnaN), RarA is not required for RecA binding and the ATPase function of UvrD is essential to counteract RecA, supporting the idea that UvrD removes RecA from DNA. UvrD action on RecA is conserved in evolution as it can be performed in E. coli by the UvrD homologue from Bacillus subtilis, PcrA.     

Identification of the missing trans-acting enoyl reductase required for phthiocerol dimycocerosate and phenolglycolipid biosynthesis in Mycobacterium tuberculosis

Phthiocerol dimycocerosates (DIM) and phenolglycolipids (PGL) are functionally important surface-exposed lipids of Mycobacterium tuberculosis. Their biosynthesis involves the products of several genes clustered in a 70-kb region of the M. tuberculosis chromosome. Among these products is PpsD, one of the modular type I polyketide synthases responsible for the synthesis of the lipid core common to DIM and PGL. Bioinformatic analyses have suggested that this protein lacks a functional enoyl reductase activity domain required for the synthesis of these lipids. We have identified a gene, Rv2953, that putatively encodes an enoyl reductase. Mutation in Rv2953 prevents conventional DIM formation and leads to the accumulation of a novel DIM-like product. This product is unsaturated between C-4 and C-5 of phthiocerol. Consistently, complementation of the mutant with a functional pks15/1 gene from Mycobacterium bovis BCG resulted in the accumulation of an unsaturated PGL-like substance. When an intact Rv2953 gene was reintroduced into the mutant strain, the phenotype reverted to the wild type. These findings indicate that Rv2953 encodes a trans-acting enoyl reductase that acts with PpsD in phthiocerol and phenolphthiocerol biosynthesis.     

Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors

We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite.