T-cell acute lymphoblastic leukemia in a child with ataxia-telangiectasia: case report

We present a patient with acute lymphoblastic leukemia and ataxia-telangiectasia (A-T). The 4-year-old girl is the first child of young nonconsanguineous parents of Serbian origin. Gait problems appearing in the second year of life were treated by physiotherapy. At the age of 4 she was diagnosed with T-cell acute lymphoblastic leukemia and treated according to Berlin-Frankfurt-Munster strategy. Owing to typhlitis developing after 15 days of cytotoxic treatment, frequent radiologic examinations were performed causing profound aplasia. Typhlitis did not respond to conservative treatment but necessitated extensive bowel resection. At that time the A-T was suspected by our team and confirmed by increased chromosomal radiosensitivity and markedly reduced level of A-T mutated protein. Chemotherapy was continued without alkylating agents and further radiologic imaging ran an uncomplicated course. At present, the patient is in first remission and 2.5 years since the beginning of the treatment. We stress the importance of careful initial neurologic evaluation of children with malignancy.     

PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab

Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. In sensitive cell lines, cetuximab induced a G(0)-G(1) arrest without inducing apoptosis. Notably, cetuximab-sensitive but not cetuximab-resistant cell lines were preferentially responsive to EGF-stimulated growth. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTEN-expressing cell lines (14 +/- 5.0% versus 38.5 +/- 6.4% growth inhibition, mean +/- SE; P = 0.008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared with PIK3CA WT controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss (10.8 +/- 4.3% versus 38.8 +/- 5.9% growth inhibition, respectively; P = 0.002), indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy.     

Virome of Ixodes ricinus,Dermacentor reticulatus,and Haemaphysalis concinna Ticks from Croatia

Tick-borne diseases are a serious threat to both public and veterinary health. In this study, we used high-throughput sequencing to characterize the virome of three tick species implicated in the spread of vector-borne disease throughout Croatia. Ten viruses were identified, including seven potential novel species within the viral families Flaviviridae, Nyamiviridae, Rhabdoviridae, Peribunyaviridae, Phenuiviridae, and Nairoviridae.     

Effects of Apnea,Obesity, and Statin Therapy on Proprotein Convertase Subtilisin/Kexin 9 Levels in Patients with Obstructive Sleep Apnea

ObjectivesObstructive sleep apnea (OSA) is a common condition closely related to obesity, insulin resistance, dyslipidemia, and cardiovascular disease. The aim of this study was to explore the possible relationship between OSA and proprotein convertase subtilisin/kexin type 9 (PCSK9).MethodsFull-night polysomnography was performed on 150 participants who were divided into three groups: controls, OSA patients on statin therapy, and OSA patients not on statin therapy. Biochemical markers, plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, and PCSK9 were determined.ResultsPCSK9 was highest in OSA patients on statins compared to the control group and to OSA patients not on statins (p = 0.036 and p = 0.039, respectively), after adjustment for body mass index (BMI). LDL diameter was greater in OSA patients not on statins compared to OSA patients on statins (p = 0.032). PCSK9 was highest in the group of patients with all three risk factors (diagnosed OSA, statins, BMI ≥25 kg/m²) compared to groups with no, one, and two risk factors (p = 0.031, p = 0.001, and p = 0.029, respectively). Presence of OSA, statin therapy, and BMI ≥25 kg/m² when combined were independently associated with higher levels of PCSK9 when adjusted for antihypertensive therapy, small dense LDL, and HDL 3c subclass (odds ratio = 2.849; interquartile range [1.026–7.912], p = 0.044).ConclusionStatin therapy was closely related to PCSK9. OSA along with obesity and statin use induces elevation of PCSK9.     

Diazenecarboxamide UP‐91, a Potential Anticancer Agent,Acts by Reducing Cellular Glutathione Content

Abstract: Glutathione (GSH) is a ubiquitous non‐protein thiol essential for cellular homeostasis and protection. Diazenecarboxamides (diazenes) are new compounds that could, according to their biochemical properties, lower the intracellular GSH content, thus inhibiting the growth of tumour cells. In the present study we examined four such compounds: JK‐914, JK‐918, JK‐1013 and UP‐91. Their cytotoxic effect on the growth of eight human tumour cell lines (glioblastoma, cervical and laryngeal carcinoma cells, mammary carcinoma cells and four drug‐resistant sublines) was determined using a modified colorimetric MTT assay. The rate of reaction of thiophenol (as a model thiol) with diazenes leading to diphenyl disulfide was established by chromatography (TLC). Reactivity of diazenes with GSH under quasi‐physiological conditions was determined by NMR spectroscopy. Intracellular GSH content was examined spectrophotometrically by the procedure developed by Tietze (1969). Diazene UP‐91 reduced significantly the cell survival of all eight examined cell lines, including four drug‐resistant cell lines. Other diazenes did not influence the survival of tumour cells. Reaction time for quantitative conversion of thiophenol to diphenyl disulfide was shortest for diazene UP‐91, which is highly consistent with high reactivity of the same diazene with GSH, observed under quasi‐physiological conditions. UP‐91 reduced intracellular GSH level, while other diazenes had no effect on it. Thus, diazenecarboxamides UP‐91 is a potential anticancer agent that may inhibit the growth of tumour cells due to reduction in glutathione level.     

Expression of <Emphasis Type="Italic">VHL</Emphasis> tumor suppressor mRNA and miR-92a in papillary thyroid carcinoma and their correlation with clinical and pathological parameters

A growing body of evidence suggests a role of the von Hippel–Lindau (VHL) tumor suppressor gene in the progression of papillary thyroid carcinoma (PTC). Our previous study of VHL in PTCs showed that lower VHL expression was associated with aggressive tumor features, but we found no evidence for VHL downregulation through common genetic or epigenetic modifications. Several studies pointed to a role of microRNA-92a (miR-92a) in the regulation of VHL expression in different cancers. In the present study, we examined the expression levels of VHL mRNA and miR-92a in 42 pairs of PTCs and matched non-tumor thyroid tissues by means of quantitative RT-PCR. We explored the correlation between them and their association with clinicopathological parameters. The results revealed that both VHL and miR-92a were either up- or downregulated in PTCs compared to corresponding non-tumor tissues. On univariate analysis, lower VHL levels were significantly associated with extrathyroid spread (P = 0.022) and capsular invasion (P = 0.032). Multivariate analysis confirmed the association of low VHL with extrathyroid spread (OR 0.246, 95% CI 0.069–0.872, P = 0.038). Higher miR-92a among PTC tissues associated with the presence of nodal metastases (univariate analysis: P = 0.012; multivariate: OR 4.703, 95% CI 1.109–19.938, P = 0.036). A negative correlation between VHL and miR-92a was observed in a subgroup of PTCs having vascular invasion (P = 0.033, r = ? 0.673). The data here reported demonstrate that the expression of both VHL and miR-92a is deregulated in PTC tissues and that in some PTCs they may have opposite roles. These roles, as well as their diagnostic and/or prognostic utility, remain to be clarified.     

Ability of FDG PET and CT radiomics features to differentiate between primary and metastatic lung lesions

Purpose

To evaluate the ability of CT and PET radiomics features to classify lung lesions as primary or metastatic, and secondly to differentiate histological subtypes of primary lung cancers.

Methods

A cohort of 534 patients with lung lesions were retrospectively studied. Radiomics texture features were extracted using the LIFEx package from semiautomatically segmented PET and CT images. Histology data were recorded in all patients. The patient cohort was divided into a training and a validation group and linear discriminant analysis (LDA) was performed to classify the lesions using both direct and backward stepwise methods. The robustness of the procedure was tested by repeating the entire process 100 times with different assignments to the training and validation groups. Scoring metrics included analysis of the receiver operating characteristic curves in terms of area under the curve (AUC), sensitivity, specificity and accuracy.

Results

Radiomics features extracted from CT and PET datasets were able to differentiate primary tumours from metastases in both the training and the validation group (AUCs 0.79?±?0.03 and 0.70?±?0.04, respectively, from the CT dataset; AUCs 0.92?±?0.01 and 0.91?±?0.03, respectively, from the PET dataset). The AUC cut-off thresholds identified by LDA using direct and backward elimination strategies were ?0.79?±?0.06 and ?0.81?±?0.08, respectively (CT dataset) and ?0.69?±?0.05 and ?0.68?±?0.04, respectively (PET dataset). For differentiation between primary subgroups based on CT features, the AUCs in the training and validation groups were 0.81?±?0.02 and 0.69?±?0.04 for adenocarcinoma (Adc) vs. squamous cell carcinoma (Sqc) or “Other”, 0.85?±?0.02 and 0.70?±?0.05 for Sqc vs. Adc or Other, and 0.77?±?0.03 and 0.57?±?0.05 for Other vs. Adc or Sqc. The same analyses for the PET data revealed AUCs of 0.90?±?0.10 and 0.80?±?0.04, 0.80?±?0.02 and 0.61?±?0.06, and 0.97?±?0.01 and 0.88?±?0.04, respectively.

Conclusion

PET radiomics features were able to differentiate between primary and metastatic lung lesions and showed the potential to identify primary lung cancer subtypes.

     

The GAVI Financing Task Force: One model of partner collaboration

The Global Alliance for Vaccines and Immunization, now called the GAVI Alliance, was launched in 2000 as a coalition of partners, including countries, international organizations, bilateral donors, the vaccine production industry, and nongovernmental organizations; most activities were to be implemented through these partner organizations. Four task forces were established at the outset to define issues relevant to GAVI Alliance goals and to recommend actions. This paper describes the innovations and outputs of the Financing Task Force (FTF), which worked in three areas: country support to sustainably finance vaccines and immunization programs in the context of introducing new vaccines; vaccine supply and demand issues as they impact vaccine choice, production costs and price/dose; innovative financing mechanisms for vaccines and immunization programs through, for example, capital markets. This analysis particularly focuses on the FTF's work on financial sustainability. Through its partnership, the FTF was able to leverage organizational change in its participating organizations, in the countries supported by the GAVI Alliance, and in the policies of GAVI itself. These achievements, along with areas where the desired outcome was not achieved, are summarized with lessons that may be useful to other multi-partner health alliances.