Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient’s quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca²⁺ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30–100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.     

Tumor-Stroma Ratio and Programmed Cell Death Ligand 1 Expression in Preoperative Biopsy and Matched Laryngeal Carcinoma Surgical Specimen

Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic and immune cells in the tumor microenvironment. Tumor to stroma ratio (TSR) has been associated with prognosis in different malignancies. The aims of this exploratory investigation were to analyze for the first time the: (i) association between TSR, PD-L1 expression and other clinical–pathological features in laryngeal squamous cell carcinoma (LSCC) biopsies and paired surgical specimens; (ii) prognostic and predictive role of TSR and PD-L1. TSR, PD-L1 expression (in terms of combined positive score [CPS]), and other clinical–pathological features were analyzed in biopsies and surgical specimens of 43 consecutive LSCC cases. A CPS < 1 evaluated on surgical specimens was associated with a low TSR (stroma rich) on both biopsies and surgical specimens (p = 0.0143 and p = 0.0063). Low TSR showed a significant negative prognostic value when evaluated on both biopsies and surgical specimens (HR = 8.808, p = 0.0003 and HR = 11.207, p = 0.0002). CPS ≥ 1 appeared to be a favorable prognostic factor (HR = 0.100, p = 0.0265). The association between bioptic and surgical specimen TSR and PD-L1 expression should be further investigated for a potential impact on targeted treatments, also with regard to immunotherapeutic protocols.     

Reusable abstractions for modeling languages

Model-driven engineering proposes the use of models to describe the relevant aspects of the system to be built and synthesize the final application from them. Models are normally described using Domain-Specific Modeling Languages (DSMLs), which provide primitives and constructs of the domain. Still, the increasing complexity of systems has raised the need for abstraction techniques able to produce simpler versions of the models while retaining some properties of interest. The problem is that developing such abstractions for each DSML from scratch is time and resource consuming.     

Channel estimation using implicit training

In this paper, a new method to perform channel estimation is presented. It is shown that accurate estimation can be obtained when a training sequence is actually arithmetically added to the information data as opposed to being placed in a separate empty time slot: hence, the word "implicit." A closed-form solution for the estimation variance is derived, as well as the Cramer-Rao lower bound. Conditions are derived for the training sequences that result in a channel estimation performance that is independent of the channel characteristics. In addition, estimation performance is shown to be independent of the modulation format. A procedure to synthesize optimal training sequences is presented, and the problem of synchronization is solved. The performance of the algorithm is then compared with other methods that use explicit training under GSM-like environmental conditions, and the new algorithm is shown to be competitive with these. Finally, comparisons are also carried out against blind methods over realistic bandlimited channels, and these show that the new method exhibits good performance.     

Adolescents' perceptions of process and specialty group therapy.

82 emotionally disturbed adolescents (mean age 16.4 yrs) living in a residential treatment center rated their perceptions of process and specialty group therapies. Ongoing process groups were rated as more helpful for relating to staff and peers, and specialty groups were considered more helpful for cognitive, social, and interpersonal skill development. Despite the findings that both types of group therapy were helpful in different ways, all Ss preferred to deal with their problems in individual therapy. These findings challenge the popular notion that adolescents prefer group therapy to individual psychotherapy, suggesting a need to offer both individual and group therapies to optimize treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Usefulness of exercise test in programming dual chamber pacemakers

Prospectively, we studied 42 patient to evaluate the usefulness of treadmill exercise to programme pacemaker DDD in relation to the functioning upper frequency (relation between block frequency of pacemaker and the upper rate frequency). We excluded patient who had no treadmill exercise test after implant pacemaker. During stress 7 (17%) patient presented AV conduction 1:1 (group I); 16 (38%) second degree AV block type Wenckebach (group II); 14 (33%) second degree AV block 2:1 (group III); and 5 (12%) showed inhibition of the pacemaker by intrinsic activity (group IV). Block frequency of the pacemaker in group I and II was superior in regard of the upper rate frequency, 156.85 +/- 22.16 vs 141.43 +/- 20.82 and 135.25 +/- 11.54 vs 121.25 +/- 5.9, respectively. In group III and IV, it was lower, 120.36 +/- 15.31 vs 138.57 +/- 13.29 and 121.0 +/- 7.38 vs 142.0 +/- 14.39. The comparative analysis of the block frequency of the pacemaker in relation with the upper rate frequency showed statistically significant differences (p < 0.05) between groups I and II, and between the group I and III. The appearance of second degree AV block 2:1 is nonphysiologic, is rather due to an abrupt falling in the cardiac output. This phenomenon is able to be predicted and corrected by programming with the use the telemetry with parameters as the AV delay, as well as upper rate frequency and post-ventricular refractory atrial period.