Association of the p85 regulatory subunit of phosphatidylinositol 3- kinase with an essential erythropoietin receptor subdomain

Using an active, HAI epitope-tagged form of the murine erythropoietin (EPO) receptor and via direct coimmunoprecipitation, the p85 regulatory subunit of phosphatidyl inositol-3 kinase (p85/PI3-K) is shown to associate with the EPO receptor in transfected FDC-P1 cell lines. Coimmunoprecipitation of p85 with epitope-tagged EPO receptors was observed initially in FDC-HER cells labeled metabolically with [32P]orthophosphate, and association of these factors was confirmed by Western analyses of receptor immunoprecipitates using p85 antiserum. Interestingly, this association occurred in the absence of ligand, and exposure of FDC-HER cells to EPO did not detectably affect levels of receptor-associated p85 or overall levels of p85 phosphorylation. However, EPO was observed to stimulated the rapid formation of phosphatidylinositol 32P-phosphate in FDC-HER and FDC-ER cells. Through baculovirus-mediated expression of epitope-tagged EPO receptor forms in SF9 cells, domains for p85 association were mapped. Analyses of receptor forms with cytosolic truncations and deletions delineated a candidate subdomain for p85 binding to an essential extended box-2 region (P329-E374; including a putative motif for SH2 binding, Y343LVL). These findings extend a mechanistic alignment between the EPO receptor and protein tyrosine kinase-encoding receptors that likewise activate PI3-K, and expand the importance of further defining pathways to PI3-K activation.     

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation

Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta. We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression.     

Nephroprotective effects of pentoxifylline in experimental myoglobinuric acute renal failure

The nephroprotective effects of pentoxifylline, a methylxantine, were studied in glycerol-induced acute renal failure. Glycerol treated rats exhibited collecting duct and medullary ascending limb dilation and casts, with focal tubular damage, confined mainly to the superficial cortex. In the interstitium focal mononuclear infiltration was observed. In some glomeruli there was swelling of mesangial spaces and mesangial cells. Pentoxifylline injected to glycerol pretreated rats exerted a protective effect. Only few groups of proximal tubules in the subcapsulary region of renal cortex showed necrosis and tubulorhexis. There were not leukocyte infiltrations or vascular congestion. Morphometric analysis showed increased surface area fraction of tubular lumen in rats treated with glycerol (p < 0.01) compared to those in controls. Intratubular cast formations in rats treated with glycerol alone were significantly higher than in rats given pentoxifylline in addition to glycerol. Kidney cortex ectopeptidases (APA, APN and DPP IV) were not significantly changed after glycerol administration. Serum creatinine and blood urea were markedly increased in glycerol treated rats, however, pentoxifylline reduced significantly their levels. This study in glycerol-induced acute renal failure showed a marked renal morphologic and functional protection by pentoxifylline.     

Use of femur length/abdominal circumference ratio in detecting the macrosomic fetus

The femur length/abdominal circumference ratio, expressed as FL/AC X 100, was determined in 156 fetuses and evaluated as a predictor of fetal macrosomia within one week prior to delivery. The normal range (mean +/- 2 SD) in the 105 normal-weight fetuses was 22.0 +/- 2, while the normal range in the 51 macrosomic fetuses was 20.5 +/- 2; these differences were highly significant (P = less than .0001). The predictive power of a positive ratio was 68%, with a sensitivity of 63%. This ratio was particularly useful in the subset (n = 9) of macrosomic fetuses whose mothers were diabetic, correctly identifying 89% of this group. Because it is age independent, this ratio should prove most helpful in identifying fetuses at risk for macrosomia in patients whose dates are not known, since it may become abnormal before the fetal weight falls above the 90th percentile at term (3,900 g). In patients whose dates are known, early fetal macrosomia is best predicted by evaluating the abdominal circumference against normal standards for age.     

β2-Microglobulin in patients with urothelial cancer

β2-Microglobulin (β2-mi) is found on the surface of most nucleated cells, and in cancer patients its increased production and liberation into the blood has been described. We studied serum and urinary levels of β2-mi in 29 patients with urinary bladder cancer (UBC) and 38 patients with upper-tract urothelial cancer (UTUC). A statistically significant (P < 0.01) increase in serum β2-mi levels was demonstrated in patients with UTUC as compared with controls, whereas urinary excretion of β2-mi was increased (P < 0.05) in both UTUC and bladder cancer patients. β2-Mi production was studied in a 72-h culture of peripheral blood mononuclear cells (PBMC) under basal conditions and after stimulation with concanavalin A (Con A) or phytohemagglutinin (PHA). Basal production of β2-mi by control unstimulated PBMC was 89.3 ± 5; that of PHA-stimulated PBMC, 189 ± 22 μg/10⁶ cells; and that of Con A-stimulated PBMC, 210 ± 32 μg/10⁶ cells. β2-Mi production by PBMC of cancer patients was not statistically significantly different from the control value, ruling out the possibility of an increased production by lymphocytes in these patients. Increased production of β2-mi was demonstrated in 48-h ureteral and urinary bladder-cancer cell cultures, ranging from 440 to 2,600 μg. Serum β2-mi was found to be increased to values of over 2.7 mg/l in 4 UBC and 12 UTUC patients with normal serum creatinine levels. Tumor surgery in those patients with increased serum β2-mi resulted in normalization of the serum β2-mi levels; urinary β2-mi excretion was not significantly changed by surgery. This study establishes that increased serum levels of β2-mi found in patients with urothelial cancer and normal glomerular function might be due to the increased production by tumor cells. However, activation of the immune response by mononuclear cells to the neoplasm cannot be excluded.     

Narrative review of artificial intelligence in diabetic macular edema: Diagnosis and predicting treatment response using optical coherence tomography

Diabetic macular edema (DME), being a frequent manifestation of DR, disrupts the retinal symmetry. This event is particularly triggered by vascular endothelial growth factors (VEGF). Intravitreal injections of anti-VEGFs have been the most practiced treatment but an expensive option. A major challenge associated with this treatment is determining an optimal treatment regimen and differentiating patients who do not respond to anti-VEGF. As it has a significant burden for both the patient and the health care providers if the patient is not responding, any clinically acceptable method to predict the treatment outcomes holds huge value in the efficient management of DME. In such situations, artificial intelligence (AI) or machine learning (ML)-based algorithms come useful as they can analyze past clinical details of the patients and help clinicians to predict the patient''s response to an anti-VEGF agent. The work presented here attempts to review the literature that is available from the peer research community to discuss solutions provided by AI/ML methodologies to tackle challenges in DME management. Lastly, a possibility for using two different types of data has been proposed, which is believed to be the key differentiators as compared to the similar and recent contributions from the peer research community.     

Patients with Acute Lacunar Infarction Have Benefit from Intravenous Thrombolysis

Introduction: Usefulness of intravenous thrombolysis in patients with acute lacunar cerebral infarction is questionable. The aim of this study was to evaluate the efficacy and safety of intravenous thrombolysis in patients with lacunar infarction in comparison with patients with nonlacunar infarction as well as with patients with lacunar infarction who were not treated with intravenous thrombolysis. Materials and methods: In the first part of the study, among patients with acute ischemic stroke treated with intravenous thrombolysis, characteristics and outcomes of 46 patients with lacunar and 221 patients with nonlacunar infarction were compared. In the second part, 46 patients with lacunar infarction treated with intravenous thrombolysis were compared with 45 lacunar infarction patients who were not treated with intravenous thrombolysis. Results: Patients with lacunar infarction had a lower National Institutes of Health Stroke Scale score (9.2 versus 13.9, P < .001), a greater Alberta Stroke Program Early computed tomography (CT) score (9.7 versus 9.2, P?=?.002), a lower prevalence of atrial fibrillation (6.5% versus 41.2%, P < .001), and significantly more frequently an excellent outcome after 3 months (76.1% versus 36.2%, P < .001) compared with patients with nonlacunar infarction. Among patients with lacunar infarction, an excellent outcome at discharge was significantly more frequent in the intravenous thrombolysis group (41.3% versus 15.6%, P?=?.01), and the length of hospitalization was significantly shorter (9.5 days versus 14.3 days, P?=?.002). There was no hemorrhagic transformation among patients with lacunar infarction treated with intravenous thrombolysis. Conclusion: Intravenous thrombolysis has proven to be effective and safe in patients with lacunar infarction and should always be applied if there are no absolute contraindications.