Proteomic analysis of hippocampal proteins of F344 rats exposed to 1-bromopropane

1-Bromopropane (1-BP) is a compound used as an alternative to ozone-depleting solvents and is neurotoxic both in experimental animals and human. However, the molecular mechanisms of the neurotoxic effects of 1-BP are not well known. To identify the molecular mechanisms of 1-BP-induced neurotoxicity, we analyzed quantitatively changes in protein expression in the hippocampus of rats exposed to 1-BP. Male F344 rats were exposed to 1-BP at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks by inhalation. Two-dimensional difference in gel electrophoresis (2D-DIGE) combined with matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) were conducted to detect and identify protein modification. Changes in selected proteins were further confirmed by western blot. 2D-DIGE identified 26 proteins with consistently altered model (increase or decrease after both 1- and 4-week 1-BP exposures) and significant changes in their levels (p < 0.05; fold change ≥ ± 1.2) at least at one exposure level or more compared with the corresponding controls. Of these proteins, 19 were identified by MALDI-TOF-TOF/MS. Linear regression analysis of 1-BP exposure level identified 8 differentially expressed proteins altered in a dose-dependent manner both in 1- and 4-week exposure experiments. The identified proteins could be categorized into diverse functional classes such as nucleocytoplasmic transport, immunity and defense, energy metabolism, ubiquitination-proteasome pathway, neurotransmitter and purine metabolism. Overall, the results suggest that 1-BP-induced hippocampal damage involves oxidative stress, loss of ATP production, neurotransmitter dysfunction and inhibition of ubiquitination-proteasome system.     

Exposure to 1-bromopropane induces microglial changes and oxidative stress in the rat cerebellum

1-Bromopropane (1-BP), an alternative to ozone-depleting solvents, is reported to exhibit neurotoxicity and reproductive toxicity in animals and humans. However, the underlying mechanism of the toxicity remains elusive. This study was designed to identify the microglial changes and oxidative stress in the central nervous system (CNS) after 1-BP exposure. Four groups of Wistar-ST rats (n=12 each) were exposed to 0, 400, 800 and 1000ppm of 1-BP, 8h/day for 28 consecutive days. The cerebellum was dissected out in 9 rats of each group and subjected to biochemical analysis, while the brains of the remaining 3 rats were examined immunohistochemically. Exposure to 1-BP increased the levels of oxidative stress markers [thiobarbituric acid reactive substances (TBARS), protein carbonyl and reactive oxygen species (ROS)] in a dose-dependent manner. Likewise, there was also 1-BP dose-dependent increase in nitric oxide (NO) and dose-dependent decrease in protein concentrations in the cerebellum. Immunohistochemical studies showed 1-BP-induced increase in cd11b/c-positive microglia area in the white matter of the cerebellar hemispheres. The results showed that exposure to 1-BP induced morphological change in the microglia and oxidative stress, suggesting that these effects are part of the underlying neurotoxic mechanism of 1-BP in the CNS.     

A Brief Review of the Adult Respiratory Distress Syndrome

The adult respiratory distress syndrome (ARDS) is seen with increasing frequency. It is associated with a variety of conditions even in the absence of preexisting pulmonary diseases. The treatment often includes intubation, using positive-end expiratory pressure (PEEP), and other ancillary support. The mortality rate is high, and physicians caring for such patients should be on guard for disseminated intravascular coagulation, gastrointestinal hemorrhage, and infection.     

Pathological fractures in mycetoma

Pathological fractures in mycetoma are a rarity and only 1 patient was reported in the literature. We report an unexpectedly high incidence of pathological fractures in mycetoma seen at the Mycetoma Research Centre, Khartoum, Sudan over a 10-year period. Plain radiographs of 517 patients with confirmed mycetoma in various body sites were reviewed and correlated with the clinical presentation of the patients. Pathological fractures were detected in 12 patients (2.3%). The explanation of this high incidence is unclear. Pain-reducing agents produced by mycetoma may be the reason that these fractures were overlooked clinically.     

Results and challenges of immune checkpoint inhibitors in colorectal cancer

Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8 + T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8 + T cells to a state of anergy. Immunotherapy, with the so-called immune checkpoint inhibitors (CPIs), has recently been approved in treatment of multiple cancers due to its prolonged disease control and acceptable toxicities. The recent groundbreaking success involving anti-PD-1 CPIs in metastatic CRC with deficient mismatch repair system (dMMR) is promising, with several trials ongoing. Major challenges are ahead in order to determine how, when and for which patients we should use these CPIs in CRC.

Areas covered: This review highlights some promises and challenges concerning personalized immunotherapy in CRC. First results and ongoing breakthrough trials are presented. The crucial role of biomarkers in selecting patient is also discussed.

Expert opinion: As of now, dMMR and POLE mutations (DNA polymerase ε) with ultramutator phenotype are the most powerful predictive biomarkers of CPI efficacy. The most challenging issue is pMMR mCRC and determination of how to convert a ‘nonimmunogenic’ neoplasm into an ‘immunogenic’ neoplasm, a combination of CPIs with radiation or MEK inhibitor probably being the most relevant strategy. Next-generation sequencing (NGS) assays to quantify mutational load could be more reliable predictive biomarkers of CPIs efficacy than PD-L1 expression or immune scores.     

T2 olivary nuclei hyperintensities: A characteristic neuroimaging finding in FIG4-related leukoencephalopathy

FIG4 related leukoencephalopathy has recently been considered as an expanded spectrum of FIG4 related disorders characterized by upper and lower motor neuron involvement, dystonia, intellectual disability, bulbar symptoms with cerebellar atrophy. We report a 7-year-old girl who presented with classic clinical features of FIG4 related leukoencephalopathy and neuroimaging showed characteristic T2 olivary nuclei hyperintensities in addition to bilateral parietal lobe and thalamic hyperintensities and mild cerebellar atrophy. Trio exome sequencing with Sanger confirmation revealed a novel variant c.504C>G in the FIG4 gene. Phase contrast microscopy of skin fibroblast cultures detect enlarged vacuoles in 50% of patient's fibroblasts as opposed to 18.6% vacuolation in cultured control fibroblasts (p < 0.00001), a feature characteristic of fibroblasts with deleterious variants of FIG4. In addition, we have reviewed and compared the phenotypic features of published cases of FIG4 related leukoencephalopathy from literature. This case adds to the delineation of FIG4 related leukoencephalopathy phenotype. The radiological finding of T2 inferior olivary nuclei hyperintensities appear to be characteristic for the phenotype or at least for the cases due to variants in and around the 168th codon and active effort should be made to detect the same as it can add to the genotype phenotype spectrum.