18F-FDG PET-CT uptake is a feature of both normal diameter and aneurysmal aortic wall and is not related to aneurysm size

Purpose

Aortic metabolic activity is suggested to correlate with presence and progression of aneurysmal disease, but has been inadequately studied. This study investigates the 2-[¹⁸F] fluoro-2-deoxy-D-glucose (¹⁸F-FDG) uptake in a population of infra-renal abdominal aortic aneurysms (AAA), compared to a matched non-aneurysmal control group.

Methods

The Positron Emission Tomography – Computed Tomography (PET/CT) database was searched for infra-renal AAA. Exclusion criteria were prior repair, vasculitis, and saccular/mycotic thoracic or thoraco-abdominal aneurysms. Matching of 159 non-aneurysmal (<3 cm diameter) controls from the same population was assessed. Infra-renal aortic wall FDG uptake was assessed using visual analysis; maximum standardized uptake value (SUV_max) and target to background mediastinal blood pool ratio (TBR) were documented. Predictors of FDG uptake (age, sex, aortic diameter, hypertension, statin use, and diabetes) were assessed using univariate analysis. Follow-up questionnaires were sent to referring clinicians.

Results

Aneurysms (n?=?151) and controls (n?=?159) were matched (p?>?0.05) for age, sex, diabetes, hypertension, smoking status, statin use, and indication for PET/CT. Median aneurysm diameter was 5.0 cm (range 3.2–10.4). On visual analysis there was no significant difference in the overall numbers with increased visual uptake 24 % (36/151) in the aneurysm group vs. 19 % (30/159) in the controls, p?=?ns. SUV_max was slightly lower in the aneurysm group vs. controls (mean (2 SD) 1.75(0.79) vs. 1.84(0.58), p?=?0.02). However there was no difference in TBR between the AAA group and controls (mean (2 SD) 1.03 (0.46) vs. 1.05(0.31), p?=?0.36). During a median 18 (interquartile range 8–35) months’ follow-up 20 were repaired and four were confirmed ruptured.

Conclusions

The level of metabolic activity as assessed by ¹⁸F-FDG PET/CT in infra-renal AAA does not correlate with aortic size and does not differ between aneurysms and matched controls.     

Emotional distress among adult survivors of childhood cancer

Purpose

The purposes of this study were to estimate the prevalence of emotional distress in a large cohort of adult survivors of childhood cancer and to evaluate the interrelationship of risk factors including cancer-related late effects.

Methods

Adult survivors of childhood cancer (N?=?1,863), median age of 32 years at follow-up, completed comprehensive medical evaluations. Clinically relevant emotional distress was assessed using the Brief Symptom Inventory 18 and was defined as T-scores ≥63. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using multivariable logistic regression models to identify risk factors for distress. Path analysis was used to examine associations among identified risk factors.

Results

Elevated global distress was reported by 15.1 % of survivors. Cancer-related pain was associated with elevated distress (OR 8.72; 95 % CI, 5.32–14.31). Survivors who reported moderate learning or memory problems were more likely to have elevated distress than survivors who reported no learning or memory problems (OR 3.27; 95 % CI, 2.17–4.93). Path analysis implied that cancer-related pain has a direct effect on distress symptoms and an indirect effect through socioeconomic status and learning or memory problems. Similar results were observed for learning or memory problems.

Conclusions

Childhood cancer-related morbidities including pain and learning or memory problems appear to be directly and indirectly associated with elevated distress symptoms decades after treatment. Understanding these associations may help inform intervention targets for survivors of childhood cancer experiencing symptoms of distress.

Implications for Cancer Survivors

A subset of long-term childhood cancer survivors experience significant emotional distress. Physical and cognitive late effects may contribute to these symptoms.     

MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer

Pancreatic cancer has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MUC13, a transmembrane mucin is highly involved in pancreatic cancer progression. Thus, understanding its regulatory molecular mechanisms may offer new avenue of therapy for prevention/treatment of pancreatic cancer. Herein, we report a novel microRNA (miR-145)-mediated mechanism regulating aberrant MUC13 expression in pancreatic cancer. We report that miR-145 expression inversely correlates with MUC13 expression in pancreatic cancer cells and human tumor tissues. miR-145 is predominantly present in normal pancreatic tissues and early Pancreatic Ductal Adenocarcinoma (PDAC) precursor lesions (PanIN I) and is progressively suppressed over the course of development from PanIN II/III to late stage poorly differentiated PDAC. We demonstrate that miR-145 targets 3′ untranslated region of MUC13 and thus downregulates MUC13 protein expression in cells. Interestingly, transfection of miR-145 inhibits cell proliferation, invasion and enhances gemcitabine sensitivity. It causes reduction of HER2, P-AKT, PAK1 and an increase in p53. Similar results were found when MUC13 was specifically inhibited by shRNA directed at MUC13. Additionally, intratumoral injections of miR-145 in xenograft mice inhibited tumor growth via suppression of MUC13 and its downstream target, HER2. These results suggest miR-145 as a novel regulator of MUC13 in pancreatic cancer.     

A Study of Manifestations of Extrapulmonary Tuberculosis in the ENT Region

Though tuberculosis (TB) primarily affects lungs, extra pulmonary tuberculosis (EPTB) is also common, especially in high disease load areas and mainly manifests in ENT region. To study the different manifestations of tuberculosis in ENT region in terms of presentation, disease process, treatment and outcome. Records of patients diagnosed and treated for TB in the ENT region at our institute’s DOTS centre for a two and half year period were analysed for presenting complaints, examination findings, diagnostic features, treatment modes and outcome. Out of 3750 cases diagnosed as TB, 230 had EPTB. 211 cases had ENT manifestations. Majority of the cases were male and in the fourth decade of life. Commonest manifestation was cervical lymphadenopathy with 201 cases. Fine needle aspiration cytology was mostly diagnostic and category I anti TB treatment (AKT) achieved cure. The six cases of TB otitis media presented with ear discharge, sometimes bloody and had varied tympanic membrane findings and facial palsy in two cases with different types and degrees of hearing loss. Diagnosis was confirmed by histology of tissue removed during surgery. Patients completed category I AKT. Hearing and facial palsy did not improve. There were three cases of TB laryngitis and one of nasal TB both of which were confirmed by tissue diagnosis and responded well to AKT. Most of the results in the present study conform to findings of other studies. High degree of suspicion is necessary to reach diagnosis. Category I AKT is effective. Some cases may require surgery.     

Soluble vascular endothelial growth factor receptor-3 suppresses allosensitization and promotes corneal allograft survival

Purpose

To investigate the effect of VEGF-C and VEGF-D blockade via soluble VEGFR-3 (sVEGFR-3) on T cell allosensitization, corneal neovascularization, and transplant survival.

Methods

Corneal intrastromal suture placement and allogeneic transplantation were performed on BALB/c mice to evaluate the effect of sVEGFR-3 on corneal neovascularization. Soluble VEGFR-3 trap was injected intraperitoneally to block VEGF-C/D (every other day starting the day of surgery). Immunohistochemical staining of corneal whole mounts was performed using anti-CD31 (PECAM-1) and anti-LYVE-1 antibodies to quantify the levels of hem- and lymphangiogenesis, respectively. Mixed lymphocyte reaction (MLR) was performed to assess indirect and direct host T cell allosensitization and the frequencies of IFN-γ-producing T cells in the draining lymph nodes were assessed using flow cytometry. Graft opacity and survival was evaluated by slit-lamp biomicroscopy.

Results

Treatment with sVEGFR-3 resulted in a significant blockade of lymphangiogenesis 2 weeks post-transplantation and significantly prolonged corneal allograft survival compared to the control group at 8 weeks post-transplantation (87.5 % vs. 50 %), and this was associated with significant reduction in the frequencies of allosensitized T cells and decreased frequencies of IFN-γ–producing CD4 T cells.

Conclusions

Soluble VEGFR-3 suppresses corneal lymphangiogenesis and allograft rejection and may offer a viable therapeutic modality for corneal neovascularization and corneal transplantation.     

Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis

Polymorphisms in DNA repair and cell cycle genes contribute to increased breast cancer (BC) risk. Their association and interaction in relation to betel quid and tobacco chewing habits need exhaustive multi-analytical investigation to explain BC predisposition due to DNA damage. Polymorphism in TP53-72Arg>Pro, RAD51-135G>C, BRCA2, and CCND1-G870A were examined in 204 BC cases and 217 controls from Northeast Indian population. Multifaceted analytic approaches were used to explore relationships between polymorphisms, tobacco history, and BC susceptibility. Betel quid chewing was identified as the predominant risk factor. CCND-AA and dominant model showed protection towards BC in betel quid chewer (BQC) [(0.28 (0.10–0.77), 0.01 and 0.32 (0.12–0.81), 0.01)] and non-betel quid chewers (NBQC) [(0.26 (0.09–0.78), 0.01 and 0.37 (0.16–0.87), 0.02)]. TP53-Pro/Pro genotype showed protection towards BC in NBQC (0.29 (0.10–0.81), p?=?0.01) and (0.51 (0.32–0.80), p?=?0.003, respectively). RAD51-C allele was associated with BC risk (2.03 (1.26–3.30) 0.002) in BQC. Two BQC cases had BRCA2 8415G>T:K2729N mutation in Exon18. MDR analysis showed best four locus model with TBA 0.6765 (0.005) and CVC of 10/10 in NBQC. Interaction diagram concurred the interactions between TP53 and RAD51 (1.32 %) with independent effect (1.89 %) of CCND1in NBQC. In CART analysis, BQC with CCND1 GG genotype were at risk (OR?=?33.0; 95 % CI?=?6.08–179.07), p?<?0.001) followed by combination of BQC, CCND1, No-Smk, and Alc (OR?=?42.00; 95 % CI?=?5.11–345.11, p?<?0.001). Risk was also observed in BQC, CCND1, No-Smk, Non-Alc, and TP53 combination (OR?=?14.84; 95 % CI?=?3.13–70.34, p?<?0.001) and BQC, CCND1, No-Smk, Non-Alc, TP53 (OR?=?9.40; 95 % CI?=?1.99–44.34, p?<?0.001). NBQC group showed risk with combination of NBQC and TP53 (OR?=?5.54; 95 % CI?=?1.11–27.42, p?=?0.03). Genetic variants in DNA repair and cell cycle genes contribute to BC risk through gene–gene and gene–environmental interactions.     

NMDA agonists and antagonists induce renal culture cell toxicity

The NMDA receptor (NMDAR) is expressed in the renal proximal tubule. NMDAR agonists and antagonists induce cell toxicity in the central nervous system (CNS). We studied the effect of NMDAR agonists and antagonists on renal cell survival in renal culture cells: proximal tubule-like opossum kidney (OK) and distal-tubule-like madine darby canine kidney cells (MDCK) cells. Low dose glutamate had no effect on cell survival. However, 10 mM glutamate induced a 14-fold increase in cell death compared to control cells. Addition of low or high doses of the NMDAR agonist glycine had no effect on cell toxicity. Exposure of cells to the non-competitive NMDAR blocker MK-801 or the competitive NMDAR antagonist CPP induced a time and dose-dependent increase in cell death and apoptosis. The presence of fetal bovine serum in the pre-incubation media attenuated the toxicity caused by MK-801 and CPP. The deleterious effect of NMDAR antagonists on cell survival was specific for OK cells; these substances had no effect on MDCK cell survival. Finally, pre-treatment of OK cells with the renal cytoprotective glycine completely blunted the affect of MK-801 on renal cell survival. We conclude that excessive stimulation or blockade of the renal NMDAR results in cell death.