Novel combination treatments targeting chronic myeloid leukemia stem cells

Chronic myeloid leukemia (CML) is currently considered incurable in most patients. Stem cell transplantation, an accepted curative option for which extensive experience has been gained, is limited by high morbidity and mortality rates, particularly in older patients. Tyrosine kinase inhibitors targeting BCR-ABL are widely used and induce remission in a high proportion of patients, but resistance and incomplete response to these agents portends eventual relapse and disease progression. Although BCR-ABL inhibitors eradicate most CML cells, they are largely ineffective against the reservoir of quiescent leukemic stem cells (LSCs). Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research. To date, evidence obtained from in vitro studies, animal models, and clinical CML specimens suggests that an effective approach may be to partner existing BCR-ABL inhibitors with compounds targeting key stem cell molecular effectors, including Wnt/β-catenin, hedgehog pathway components, histone deacetylase (HDAC), transforming growth factor-β (TGF-β), Janus kinase 2, promyelocytic leukemia protein, and arachidonate 5-lipoxygenase (ALOX5). Novel combinations may sensitize LSCs to BCR-ABL inhibitors, thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care.     

In vitro efficacy of a one-bottle adhesive system with three restorative materials

The shear bond strength to dentin of a new single-bottle adhesive with three restorative materials (composite resin, compomer, and amalgam) was evaluated. The results were statistically different (ANOVA, p < 0.05). Groups 1 and 2 were not significantly different from each other, but both were statistically higher than Group 3. The fracture mode was not related to the shear bond strength values.     

Genetic diversity and population structure of Mycobacterium tuberculosis in Casablanca, a Moroccan city with high incidence of tuberculosis

Although lower-resource countries have by far the highest burden of tuberculosis, knowledge of Mycobacterium tuberculosis population structure and genetic diversity in these regions remains almost nonexistent. In this paper, 150 Moroccan M. tuberculosis isolates circulating in Casablanca were genotyped by random amplified polymorphic DNA analysis using 10 different primers and by mycobacterial interspersed repetitive units-variable number of tandem repeats typing at 12 loci. The population genetic tests revealed a basically clonal structure for this population, without excluding rare genetic exchanges. Genetic analysis also showed a notable genetic polymorphism for the species M. tuberculosis, a weak cluster individualization, and an unexpected genetic diversity for a population in such a high-incidence community. Phylogenetic analyses of this Moroccan sample also supported that these isolates are genetically heterogeneous.     

Monitoring of maternal and infantile care activities: experience of Tunisia basic health care services

In the feamework of quality assessment, the basic service for health care of Tunis introduced in 1997 a service managing tool for prenatal activity monitoring. This paper aims to present the way this tool should be used its setting up within the basic health structures and its principal effects on the quality process. Prenatal activity monitoring is a process that allows evaluation, control and dysfunction level identification of a health program: it also permits a microplanification in order to compensate for its failings. The first step consists in calculating the 5 following covering determining factors: target population, material or, human resources availability, the service at one's disposal's use rate, the appropriate coverage rate according to a precise way in which the consultations are linked to each other concerning this program and the effective coverage rate including the required quality indicator for the care. A graph permits to visualize these different rates. The second step consists in identifying the bottleneck and the most relevant correcting actions to be conducted in relation with either the available human resources or the material resources or the process of health care by using an "intemal audit". Setting up this tool required many training sessions and supervisions for the Tunis health care services. It proved efficient enough in order to improve the actual coverage of the population especially in the responsibility area of the staff members for certain preventive programs as prenatal services or children's growth follow up. It allowed a better documentation of the consultation activity and the objective analysis of the inherent problems to the recommended program. The solutions were taken locally and dependes on the decision maker's will.     

Preservation-based approaches to restore posterior teeth with amalgam,resin or a combination of materials

This review is a systematic assessment, from the literature, of the status quo of dental amalgam, resin-based composite and glass-ionomer restorations for carious lesions as it applies to new concepts, coupled with clinical research. Scientifically based and practical new materials and techniques are recommended to include in contemporary practice throughout the world. Clinical and laboratory studies which have been carried out in light of modern conservative principles, and in light of the current emphasis of treating dental caries as a disease process were reviewed and discussed. An approach to managing carious lesions based upon selected advantages of dental amalgam, resin-based composite and glass-ionomer technology applied to what is termed "preservation-based" approaches to restoring teeth has been synthesized. Researched evidence contradicts the notion of "extension for prevention" in favor of maintaining sound tooth structure which would translate into more patients with healthy dentitions for entire lifetimes.     

Evaluation of IS6110 as amplification target for direct tuberculosis diagnosis

We describe in the present study an evaluation of the IS6110 repetitive element in the rapid diagnosis of pulmonary and extrapulmonary tuberculosis by polymerase chain reaction (PCR). A pair of oligonucleotide primers was designed to amplify a 201-bp DNA fragment of IS6110. The amplified DNA was detected by ethidium bromide stained agarose gel electrophoresis and confirmed by Sal I digestion and Southern blot hybridization with a 32P-labeled probe. To detect the presence of amplification inhibitors, an internal control DNA that used the same primers as for the target sequence was added to each PCR reaction. PCR results were compared with the results of acid fast stained smears, cultures, and clinical data in 102 sputum and 41 extrapulmonary specimens. With the exception of four samples, M. tuberculosis was detected by PCR in all smear- and culture-positive cases and in all smear-negative, culture positive cases. Additionally, PCR was able to detect 6 cases that were smear and culture negative but clinically strongly suspected of tuberculosis. The final PCR sensitivity and specificity were 93.1% and 95.18%, respectively. One M. tuberculosis strain isolated from a sputum was found to lack IS6110. This study shows that (1) PCR diagnosis based on IS6110 reached the best sensitivity and specificity but must be considered carefully since some M. tuberculosis strains lack IS6110; and (2) PCR must be interpreted in conjunction with clinical and radiological data when it is discordant with conventional methods results.     

Phase 2 Study of Talazoparib in Patients With Homologous Recombination Repair–Deficient Squamous Cell Lung Cancer: Lung-MAP Substudy S1400G

PurposeThis signal finding study (S1400G) was designed to evaluate the efficacy of talazoparib in advanced stage squamous cell lung cancer harboring homologous recombination repair deficiency.Patients and MethodsThe full eligible population (FEP) had tumors with a deleterious mutation in any of the study-defined homologous recombination repair genes and without prior exposure to a PARP inhibitor. The primary analysis population (PAP) is a subset of FEP with alteration in ATM, ATR, BRCA1, BRCA2, or PALB2. Treatment consisted of talazoparib 1 mg daily continuously in 21-day cycles. A 2-stage design with exact 93% power and 1-sided 0.07 type I error required enrollment of 40 patients in the PAP in order to rule out an overall response rate (ORR) of 15% or less if the true ORR is ≥ 35%.ResultsThe study enrolled 47 patients in the FEP, of whom 24 were in the PAP. The median age for the FEP was 66.7 years; 83% were male and 85% white. ORR in the PAP was 4% (95% confidence interval [CI], 0, 21) with disease control rate of 54% (95% CI, 33, 74). Median progression-free survival and overall survival were 2.4 months (95% CI, 1.5-2.8) and 5.2 months (95% CI, 4.0-10), respectively. In the FEP, ORR was 11% (95% CI, 3.6, 23), the disease control rate was 51% (95% CI, 36, 66), and the median duration of response was 1.8 months (95% CI, 1.3, 4.2). Median progression-free and overall survival were 2.5 months and 5.7 months, respectively.ConclusionsS1400G failed to show sufficient level of efficacy for single agent talazoparib in a biomarker defined subset of squamous lung cancer with homologous recombination repair deficiency.