Inflammatory Myofibroblastic Tumor of the Temporal Bone: A Histologically Nonmalignant Lesion with Fatal Outcome

Introduction: Inflammatory myofibroblastic tumor (IMFT) of the temporal bone is an unusual but distinct clinicopathologic entity. Case Report: We report the case of a 75-year-old patient with an IMFT located in the temporal bone. Symptoms included VI, X, XI, and XII cranial nerves palsies. Computed tomography and magnetic resonance images are described. The lesion was locally aggressive and outcome was fatal. IMFT was identified by analysis of postmortem specimen with histopathologic and immunohistochemical confirmation. Discussion: IMFT can be locally destructive lesions. Involvement of the skull base and cervical spine is indistinguishable from an aggressive infection or a malignant tumor and can be fatal as in our case report. The difficulties in establishing clinicopathologic diagnosis, radiological imaging characteristics, and treatment are discussed.     

Modifying Choroidal Neovascularization Development with a Nutritional Supplement in Mice

We examined the effect of nutritional supplements (modified Age Related Eye Disease Study (AREDS)-II formulation containing vitamins, minerals, lutein, resveratrol, and omega-3 fatty acids) on choroidal neovascularization (CNV). Supplements were administered alone and combined with intravitreal anti-VEGF in an early-CNV (diode laser-induced) murine model. Sixty mice were evenly divided into group V (oral vehicle, intravitreal saline), group S (oral supplement, intravitreal saline), group V + aVEGF (oral vehicle, intravitreal anti-VEGF), and group S + aVEGF (oral supplement, intravitreal anti-VEGF). Vehicle and nutritional supplements were administered daily for 38 days beginning 10 days before laser. Intravitreal injections were administered 48 h after laser. Fluorescein angiography (FA) and flat-mount CD31 staining evaluated leakage and CNV lesion area. Expression of VEGF, MMP-2 and MMP-9 activity, and NLRP3 were evaluated with RT-PCR, zymography, and western-blot. Leakage, CNV size, VEGF gene and protein expression were lower in groups V + aVEGF, S + aVEGF, and S than in V (all p < 0.05). Additionally, MMP-9 gene expression differed between groups S + aVEGF and V (p < 0.05) and MMP-9 activity was lower in S + aVEGF than in V and S (both p < 0.01). Levels of MMP-2 and NLRP3 were not significantly different between groups. Nutritional supplements either alone or combined with anti-VEGF may mitigate CNV development and inhibit retinal disease involving VEGF overexpression and CNV.     

Validity of the modified shuttle walk test to assess cardiorespiratory fitness after exercise intervention in overweight/obese adults with primary hypertension

The study aimed to assess whether the Modified Shuttle Walk Test (MSWT) can detect changes in cardiorespiratory fitness (CRF) in overweight/obese people with hypertension (HTN) after an exercise intervention evaluating the equation presented in the previous research by Jurio-Iriarte et al. Participants (N= 248) performed a peak cardiorespiratory exercise test (CPET) and MSWT before and after 16-weeks of different types of aerobic exercise intervention. The formula of Jurio-Iriarte et al. was used to predict peak oxygen uptake (V?O_2peak). The correlation between measured and predicted V?O_2peak was strong (r= 0.76, P< 0.001) with a standard error of estimate (SEE) of 4.9 mL·kg^?1·min^?1; SEE%= 17%. The intraclass correlation coefficient indicates a moderate level of association and agreement (ICC= 0.69; 95% CI 0.34–0.82; P< 0.001) between the measured and predicted V?O_2peak. When analyzing obese participants alone (N= 128), MSWT equation was more accurate compared to the whole sample (ICC= 0.76; 95% CI 0.52–0.87). The relationship between the change of measured and predicted V?O_2peak at follow-up was weak (r= 0.42, P< 0.001) with a 31% SEE, and a low level of association and agreement (ICC= 0.31; 95% CI 0.06–0.49; P< 0.001). In conclusion, although MSWT does not accurately predict CRF in people with HTN after exercise intervention and questions its validity, the new equation may have practical application to estimate V?O_2peak for obese people with HTN when CPET is not available.

Abbreviations: AC: Attention Control; BM: Body Mass; BP: Blood Pressure; CI: Confidence Interval; CRF: Cardiorespiratory Fitness; CPET: Cardiopulmonary Exercise Test; HTN: Primary Hypertension; HR: Heart Rate; HV-HIIT: High-Volume and High-Intensity Interval Training; ICC: Intraclass Correlation Coefficient; LV-HIIT: Low-Volume and High-Intensity Interval Training; MICT: Moderate-intensity continuous training; MSWT: Modified Shuttle Walk Test; SD: Standard Deviation; SEE: Standard Error of Estimate; V?O_2peak: Peak Oxygen Uptake.     

Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo-inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo-osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by (1)H-magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline-containing compounds, creatine/phosphocreatine, and N-acetyl-aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients.     

Most of ADP x glucose linked to starch biosynthesis occurs outside the chloroplast in source leaves

Sucrose and starch are end products of two segregated gluconeogenic pathways, and their production takes place in the cytosol and chloroplast of green leaves, respectively. According to this view, the plastidial ADP.glucose (ADPG) pyrophosphorylase (AGP) is the sole enzyme catalyzing the synthesis of the starch precursor molecule ADPG. However, a growing body of evidences indicates that starch formation involves the import of cytosolic ADPG to the chloroplast. This evidence is consistent with the idea that synthesis of the ADPG linked to starch biosynthesis takes place in the cytosol by means of sucrose synthase, whereas AGP channels the glucose units derived from the starch breakdown. To test this hypothesis, we first investigated the subcellular localization of ADPG. Toward this end, we constructed transgenic potato plants that expressed the ADPG-cleaving adenosine diphosphate sugar pyrophosphatase (ASPP) from Escherichia coli either in the chloroplast or in the cytosol. Source leaves from plants expressing ASPP in the chloroplast exhibited reduced starch and normal ADPG content as compared with control plants. Most importantly however, leaves from plants expressing ASPP in the cytosol showed a large reduction of the levels of both ADPG and starch, whereas hexose phosphates increased as compared with control plants. No pleiotropic changes in photosynthetic parameters and maximum catalytic activities of enzymes closely linked to starch and sucrose metabolism could be detected in the leaves expressing ASPP in the cytosol. The overall results show that, essentially similar to cereal endosperms, most of the ADPG linked to starch biosynthesis in source leaves occurs in the cytosol.     

Regulation of antiapoptotic MCL-1 function by gossypol: mechanistic insights from in vitro reconstituted systems

Small-molecule drugs that induce apoptosis in tumor cells by activation of the BCL-2-regulated mitochondrial outer membrane permeabilization (MOMP) pathway hold promise for rational anticancer therapies. Accumulating evidence indicates that the natural product gossypol and its derivatives can kill tumor cells by targeting antiapoptotic BCL-2 family members in such a manner as to trigger MOMP. However, due to the inherent complexity of the cellular apoptotic network, the precise mechanisms by which interactions between gossypol and individual BCL-2 family members lead to MOMP remain poorly understood. Here, we used simplified systems bearing physiological relevance to examine the impact of gossypol on the function of MCL-1, a key determinant for survival of various human malignancies that has become a highly attractive target for anticancer drug design. First, using a reconstituted liposomal system that recapitulates basic aspects of the BCL-2-regulated MOMP pathway, we demonstrate that MCL-1 inhibits BAX permeabilizing function via a “dual-interaction” mechanism, while submicromolar concentrations of gossypol reverse MCL-1-mediated inhibition of functional BAX activation. Solution-based studies showed that gossypol competes with BAX/BID BH3 ligands for binding to MCL-1 hydrophobic groove, thereby providing with a mechanistic explanation for how gossypol restores BAX permeabilizing function in the presence of MCL-1. By contrast, no evidence was found indicating that gossypol transforms MCL-1 into a BAX-like pore-forming molecule. Altogether, our findings validate MCL-1 as a direct target of gossypol, and highlight that making this antiapoptotic protein unable to inhibit BAX-driven MOMP may represent one important mechanism by which gossypol exerts its cytotoxic effect in selected cancer cells.     

Functionalised collagen spheres reduce H2O2 mediated apoptosis by scavenging overexpressed ROS

Excess reactive oxygen species (ROS) has been implicated in numerous diseases including cancer, cardiovascular and neurodegenerative diseases. Overexpression of ROS can lead to oxidative stress and subsequently to H₂O₂-mediated cell apoptosis. In this study, it was demonstrated that biodegradable PLGA microspheres coated with collagen type I and decorated with MnO₂ nanoparticles acted as ROS scavengers controlling the H₂O₂-mediated apoptosis of cells undergoing oxidative stress. The results showed that the functionalized collagen spheres can protect cells even under very harsh conditions of oxidative stress.     

Efficacy and safety of chemotherapy in older versus non-older patients with advanced gastric cancer: A real-world data,non-inferiority analysis

Objective

Advanced gastric cancer (AGC) is a common neoplasm in older adults. Nevertheless, there are few specific management data in the literature. The aim of this study was to assess non-inferiority of survival and efficacy-related outcomes of chemotherapy used in older vs non-older patients with AGC.