ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection

Summary:  The immune system is capable of recognizing and eliminating an enormous array of pathogens due to the extremely diverse antigen receptor repertoire of T and B lymphocytes. However, the development of lymphocytes bearing receptors with unique specificities requires the generation of programmed double strand breaks (DSBs) coupled with bursts of proliferation, rendering lymphocytes susceptible to mutations contributing to oncogenic transformation. Consequently, mechanisms responsible for monitoring global genomic integrity must be activated during lymphocyte development to limit the oncogenic potential of antigen receptor locus recombination. Mutations in ATM (ataxia-telangiectasia mutated), a kinase that coordinates DSB monitoring and the response to DNA damage, result in impaired T-cell development and predispose to T-cell leukemia. Here, we review recent evidence providing insight into the mechanisms by which ATM promotes normal lymphocyte development and protects from neoplastic transformation.     

In vivo multiple-mouse imaging at 1.5 T.

A multiple-mouse solenoidal MR coil was developed for in vivo imaging of up to 13 mice simultaneously to screen for tumors on a 1.5 T clinical scanner. For the coil to be effective as a screening tool, it should permit acquisition of MRIs in which orthotopic tumors with diameters >2 mm are detectable in a reasonable period of time (<1 hr magnet time) and their sizes accurately measured. Using a spin echo sequence, we demonstrated that this coil provides sufficient sensitivity for moderately high resolution images (156-176 microm in plane-resolution, 1.5 mm slice thickness). This spatial resolution permitted detection of primary brain tumors in transgenic/knockout mice and orthotopic xenografts. Brain tumor size as measured by MRI was correlated with size measured by histopathology (P < 0.001). Metastatic tumors in the mouse lung were also successfully imaged in a screening setting. The multiple mouse coil is simple in construction and may be implemented without any significant modification to the hardware or software on a clinical scanner.     

Hydrocarbon poisoning: a review

This article reviews the mechanisms of pulmonary injury associated with hydrocarbon poisoning. The evolution of clinical and radiographic changes is discussed, along with appropriate treatment. Preventing aspiration in the emergency department is the most effective therapy for these children in the first few hours after ingestion.     

Comparative nuclear magnetic resonance studies of diffusional water permeability of red blood cells from different species. VIII. Adult and fetal guinea pig (Cavia procellus)

The diffusional water permeability (P _d) of adult, pregnant female and fetal guinea-pig red blood cells (RBCs) was measured by a doping nuclear magnetic resonance (NMR) technique on control cells and following inhibition withp-chloromercuribenzene sulphonate (PCMBS). The values ofP _d were around 5.0 × 10^?3 cm/s at 15 °C, 5.3 × 10-3 cm/s at 20 °C, 6.6 × 10^?3 cm/s at 25 °C, 7.5 × 10^?3 cm/s at 30 °C and 8.6 × 10^?3 cm/s at 37 °C with no significant differences between adult, pregnant female and fetal RBCs. Systematic studies on the effects of PCMBS on water diffusion indicated that the maximal inhibition was reached in 10 min at 37 °C with 0.1 mm PCMBS. The values of maximal inhibition ranged from 70%–77% at 15–30 °C to 57%–63% at 37 °C in the case of adult and from 64%–67% at 15–30 °C to 51% at 37 °C in the case of fetal RBCs. The basal permeability to water was estimated at 1.1 × 10^?3 cm/s at 15 °C ,1.3 × 10^?3 cm/s at 20 °C, 1.6 × 10^?3 cm/s at 25 °C, 2.2 × 10^?3 cm/s at 30 °C and 3.2 × 10^?3 cm/s at 37 °C for adult and slightly higher values for fetal guinea pig RBCs as 1.6 × 10^?3 cm/s at 15 °C, 2.0 × 10^?3 cm/s at 20 °C, 2.4 × 10^?3 cm/s at 25 °C, 2.6 × 10^?3 cm/s at 30 °C and 4.2 × 10^?3 cm/s at 37 °C. The activation energy of water diffusion was around 22 kJ/ mol, with no significant differences between the adult pregnant female and fetal RBCs, and increased to about 40 kJ/mol in the case of adult and pregnant RBCs and 34 kJ/mol for fetal RBCs after incubation with PCMBS in conditions of maximal inhibition of water diffusion. The membrane polypeptide electrophoretic pattern of adult and fetal guinea-pig RBCs was compared with its human counterpart. The guinea-pig membrane contained higher amounts of spectrin (band 1 and 2), whereas the proteins in bands 4.1, 4.2 and 6 were present in lower amounts. Considerable differences in polypeptides migrating in the region of bands 7 and 8 and in front of them were apparent between the two sources of RBC membranes where some bands were present only in the guinea-pig RBC membranes. The adult guinea-pig membranes contained smaller amounts of proteins migrating in band 4.5 and lacked band 8.     

Occurrence of HLA Types in H. Influenzae Type B Disease

We have studied 50 Caucasoid children under 7 years of age with Haemophilus influenzae b disease. Half of the patients (Group A) had invasive disease shown by positive blood and/or spinal fluid culture. The other half (Group B) had noninvasive disease characterized by fever, nasopharyngitis, negative blood culture, and positive throat culture. Age, number of other siblings under 12 years old in the family, immune response, antibody production and genetic markers were compared in the two groups. Significant difference between the two groups was only seen in their genetic markers. HLA-B12 was present in 52% of Group A patients as opposed to 16% in Group B patients (P less than .01). HLA-Bw40 was present in 24% of group B patients and absent in all Group A patients (P less than .01). These findings would suggest that susceptibility and resistance towards developing invasive type b disease may be genetically determined.     

Characterization of perioperative androgen profiles in men with bladder cancer undergoing radical cystectomy

BackgroundPrior studies have demonstrated declines in androgen levels in men with cancer and patients undergoing anesthesia and surgery. In this study, we hypothesized that decreased serum androgen levels are prevalent in male patients undergoing radical cystectomy (RC) for bladder cancer and that it persists in the postoperative period. We characterized perioperative androgen hormonal profiles and examined for associated changes indicative of sarcopenia on computed tomography scans in men undergoing RC.MethodsWe implemented a prospective observational trial in men with newly diagnosed non-metastatic bladder cancer undergoing RC. Baseline pre-operative total testosterone (TT), free testosterone (FT), and luteinizing hormone (LH) were obtained on morning lab draws with 30 days of surgery. TT and FT were then repeated on postoperative days (POD) 2, 3, 30, and 90. The threshold for normal TT was defined as >300 ng/dl, consistent with the AUA Guidelines for Evaluation and Management of Testosterone Deficiency. We evaluated postoperative changes in weight and psoas muscle cross-sectional area using computed tomography scans to assess for sarcopenic changes.ResultsUnivariable statistical analysis was performed. 25 patients were enrolled. The mean patient age was 68.9 years. The mean pre-operative TT was 308 ng/dl, and 12/23 (52.5%) patients had low testosterone. Mean TT onPOD 2 and 3 were 166 ng/dl and 161 ng/dl, respectively (range 24–345). 19/20 (95%) of men who had morning lab draws had decreased TT. The mean TT at 30 days was 253 ng/dl with 37.5% of men having low TT. Mean TT at 90 days was 306 ng/dl. The mean FT levels were 43 ng/dl, 29.25 ng/dl, 28.2 ng/dl, 40.89 ng/dl, and 42.62 ng/dl at baseline, POD 2, POD 3, POD 30, and POD 90, respectively. Mean LH at baseline was 9.9 IU/L. Average weight loss at 30- and 90- days postop was -4.29 and -4.38 kilograms, respectively. Weight loss was persistent with only 3/23 (13%) returning to their presurgery weight by 90 days. Despite significant declines in weight and perioperative TT, no significant differences in psoas muscle cross-sectional area were observed (net change -92 mm², P= 0.13)ConclusionsPerioperative disruption of androgen levels is prevalent in men undergoing RC. Our trial demonstrates a pre-op, immediate postop, 30- and 90-day postoperative prevalence of low TT of 52%, 95%, 63%, and 37.5%, respectively. Significant changes in baseline weight were noted, although no significant changes in psoas muscle cross-sectional area were observed, limiting conclusions regarding a link between changes in androgens and sarcopenia in this setting.     

Targeting angiogenesis in ovarian cancer

Results of standard chemotherapy in ovarian cancer are hampered by the development of drug resistance leading to disease recurrence. This prompted interest in the development of therapies targeting critical pathways responsible for tumor progression. Angiogenesis is a key process that enables ovarian cancer growth and metastasis in the peritoneal space. Its regulation relies on signaling mechanisms initiated by the vascular endothelial growth factor, the platelet-derived growth factor, the fibroblast growth factor, angiopoietins, and others. These pathways are not only important to the modulation of the tumor microenvironment and vasculature, but also control cancer cell proliferation and survival. In this review, we discuss preclinical evidence supporting the rationale for inhibiting these pathways and provide an overview for the clinical development of agents targeting them. Clinical trials evaluating such agents alone and in combination with chemotherapy are ongoing. Early clinical results position antiangiogenic therapy at the forefront of change to the standard treatment of difficult to treat ovarian cancer.     

Reusable magnetic PdxCoy nanoalloys confined in mesoporous carbons for green Suzuki–Miyaura reactions

We report herein Pd_xCo_y nanoalloys confined in mesoporous carbons (Pd_x–Co_y@MC) prepared by an eco-friendly one-pot approach consisting in the co-assembly of readily available and non-toxic carbon precursors (phloroglucinol, glyoxal) with a porogen template (pluronic F-127) and metallic salts (H₂PdCl₄ and Co(NO₃)₂·6H₂O) followed by thermal annealing. Three Pd_xCo_y@MC materials with different alloy compositions were prepared (C1: x/y = 90/10; C2: x/y = 75/25; C3 and C4: x/y = 50/50). The nanoalloys were uniformly distributed in the carbon framework and the particle sizes depended on the alloy composition. These composites were then used for Suzuki–Miyaura reactions using either H₂O or a 1 : 1 H₂O/EtOH mixture as solvent. The Pd₅₀Co₅₀@MC catalyst C3 proved to be the most efficient catalyst (in terms of efficiency and magnetic recovery) affording the coupling products in good to excellent yields. After reaction, C3 was recovered quantitatively by simple magnetic separation and reused up to six times without loss of efficiency. The amount of palladium lost in the reaction mixture after magnetic separation was very low (ca. 0.1 % wt of the amount initially used).

(Pd_x–Co_y)@MC were prepared in one-pot via an eco-friendly route and used many times for Suzuki reactions in H₂O or H₂O/EtOH mixture.