CD274 (PDL1) and JAK2 genomic amplifications in pulmonary squamous‐cell and adenocarcinoma patients

Aims

CD274 (PDL1) and JAK2 (9p24.1) gene amplifications have been recently described in pulmonary carcinomas in association with programmed death‐ligand 1 (PD‐L1) expression. Furthermore, PTEN loss has been explored preclinically in relation to PD‐L1 expression. Our aim was to determine whether these genomic alterations affect PD‐L1 expression levels in non‐small‐cell lung cancer.

Methods and results

PD‐L1 and PTEN expression determined by immunohistochemistry (IHC), and CD274, JAK2 and PTEN copy number alterations (CNAs) determined by fluorescence in‐situ hybridisation, were studied in 171 pulmonary carcinoma specimens. PD‐L1 expression was positive in 40 cases (23.3%), and CD274 amplification was present in 14 tumours (8.8%). Concordance between both events was found in 12 of 14 amplified cases (P = 0.0001). We found nine JAK2‐amplified cases (5.7%), seven with PD‐L1 expression (P = 0.0006). Moreover, six of the seven cases had JAK2 and CD274 coamplification (9p24.1 genomic amplification). Remarkably, the average PD‐L1 IHC score was higher in these amplified cases (230 versus 80; P = 0.001). Non‐statistical associations were observed between PD‐L1 expression and PTEN loss and PTEN deletions.

Conclusions

We describe a subset of patients (8.2%) who had 9p24.1 amplifications resulting in high expression of PD‐L1. Our results provide evidence for genomic up‐regulation of PD‐L1 expression in non‐small‐cell lung cancer.     

Body fluid distribution in elderly subjects with congestive heart failure

The aims of this study were to investigate body fluid changes in elderly patients suffering from congestive heart failure (CHF) and to identify the fluid measurement that best characterizes fluid overload states in CHF patients by comparison with normal hydration in the elderly. In a case-controlled experimental design, 72 elderly subjects (65-98 yr), 38 healthy and 34 with CHF, were studied. Total body water (TBW) and extracellular water (ECW) were determined by dilution methods; fat-free mass (FFM) and fat mass (FM) were determined by dual-energy X-ray absorptiometry (DEXA). In healthy subjects, the FFM hydration expressed as TBW% FFM (males 72.0 +/- 4.3 vs females 72.4 +/- 5.0%) and ECW% TBW (males 47.3 +/- 3.4 vs females 47.8 +/- 5.1) were similar in both genders. ECW in liters for FFM and for TBW (ECW% TBW), corrected for body weight, was greater in the group with CHF than in the control group, in both sexes. Among the relative fluid measures, only ECW% TBW [odds ratio (OR) 1.5] independently predicted fluid retention. Having an ECW% TBW greater than 50% corresponded to an OR of about 10. In conclusion, elderly patients suffering from CHF have a characteristic increase in body fluid levels, mainly affecting the extracellular compartment, and ECW% TBW is a useful indicator of fluid retention.     

Genetic characterization of the paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia: A case report and review of the literature

Paraimmunoblastic variant of small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is characterized by a diffuse proliferation of cells, called paraimmunoblasts, normally located on the pseudoproliferation centers. Patients usually present with multiple lymphadenopathies and a rapid and aggressive progression of the disease. We report a case with paraimmunoblastic variant of SLL/CLL genetically well-characterized by conventional cytogenetics, comparative genomic hybridization (CGH), IgH/BCL-1, IgH/BCL-2, and p53 fluorescent in situ hybridization (FISH) probes and polymerase chain reaction (PCR) for detection of IgH/BCL-2 translocation. A complex karyotype was found, with p53 deletion confirmed by CGH and FISH; however, no translocations involving either BCL-2 or BCL-1 and the immunoglobulin heavy chain gene were identified. A literature review shows only 20 previously reported cases, 6 of which involve genetic studies.     

The role of oestrogens in the adaptation of islets to insulin resistance

Pregnancy is characterized by peripheral insulin resistance, which is developed in parallel with a plasma increase of maternal hormones; these include prolactin, placental lactogens, progesterone and oestradiol among others. Maternal insulin resistance is counteracted by the adaptation of the islets of Langerhans to the higher insulin demand. If this adjustment is not produced, gestational diabetes may be developed. The adaptation process of islets is characterized by an increase of insulin biosynthesis, an enhanced glucose-stimulated insulin secretion (GSIS) and an increase of β–cell mass. It is not completely understood why, in some individuals, β–cell mass and function fail to adapt to the metabolic demands of pregnancy, yet a disruption of the β–cell response to maternal hormones may play a key part. The role of the maternal hormone 17β-oestradiol (E2) in this adaptation process has been largely unknown. However, in recent years, it has been demonstrated that E2 acts directly on β–cells to increase insulin biosynthesis and to enhance GSIS through different molecular mechanisms. E2 does not increase β–cell proliferation but it is involved in β–cell survival. Classical oestrogen receptors ERα and ERβ, as well as the G protein-coupled oestrogen receptor (GPER) seem to be involved in these adaptation changes. In addition, as the main production of E2 in post-menopausal women comes from the adipose tissue, E2 may act as a messenger between adipocytes and islets in obesity.     

Tophaceous gout in the elderly: a clinical case review

Gout is the most common cause of arthritis in the elderly. Its incidence among older people has risen worldwide due to an increase in risk factors such as renal diseases, metabolic syndrome, and a diet rich in purines. In older age, tophaceous gout may affect different joints from its classical presentation, due to other concomitant musculoskeletal diseases, but specific data on its epidemiology and clinical aspects in the elderly are limited to a few case reports. The present review focuses on the distinctive aspects of tophaceous gout in the elderly, revisiting all our clinical cases seen from 1990 to December 2011. Our findings indicate that: tophaceous gout can affect several joints in the elderly, including some unusual sites; its incidence is similar in both genders in the elderly even if the latency period between its initial diagnosis and the onset of tophi is higher in men; and vertebral localizations are rising and often solitary. The components of metabolic syndrome are the most common medical conditions associated with tophaceous gout. In conclusion, tophaceous gout in the elderly may be a growing medical problem and cause of disability in years, partly because of the new sites involved.     

Rate limit of protein elastic response is tether dependent

The elastic restoring force of tissues must be able to operate over the very wide range of loading rates experienced by living organisms. It is surprising that even the fastest events involving animal muscle tissues do not surpass a few hundred hertz. We propose that this limit is set in part by the elastic dynamics of tethered proteins extending and relaxing under a changing load. Here we study the elastic dynamics of tethered proteins using a fast force spectrometer with sub-millisecond time resolution, combined with Brownian and Molecular Dynamics simulations. We show that the act of tethering a polypeptide to an object, an inseparable part of protein elasticity in vivo and in experimental setups, greatly reduces the attempt frequency with which the protein samples its free energy. Indeed, our data shows that a tethered polypeptide can traverse its free-energy landscape with a surprisingly low effective diffusion coefficient D_eff ∼ 1,200 nm²/s. By contrast, our Molecular Dynamics simulations show that diffusion of an isolated protein under force occurs at D_eff ∼ 10⁸ nm²/s. This discrepancy is attributed to the drag force caused by the tethering object. From the physiological time scales of tissue elasticity, we calculate that tethered elastic proteins equilibrate in vivo with D_eff ∼ 10⁴–10⁶ nm²/s which is two to four orders magnitude smaller than the values measured for untethered proteins in bulk.     

Endothelial Dysfunction is a Marker of Systemic Response to the Cardiac Resynchronization Therapy in Heart Failure

BackgroundCardiac resynchronization therapy (CRT) induces a significant improvement in patients with heart failure (HF), who are often characterized by the presence of endothelial dysfunction (ED) with impaired flow-mediated vasodilation (FMD). We aimed to study the ED in patients with HF candidates to CRT with defibrillator (CRT-D).Methods and ResultsWe studied 57 consecutive patients affected by HF and undergoing CRT-D. At the baseline we recorded a high prevalence of ED (64.9%) with impaired FMD (4.1 ± 3.8%). After 12 months of CRT, we reported a marked increase of the mean FMD (8.8 ± 4.8% vs 4.1 ± 3.8%; P < .05) along with significant improvement of left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), New York Heart Association (NYHA) functional class, and 6-minute walk test (6MWT); 42 patients (73.7%) were classified as responders according to standard criteria. FMD was related to LVEF (r = 0.169; P < .05), LVESV (r = ?0.169; P < .05), NYHA functional class (r = ?0.27; P < .051), and 6MWT (r = 0.360; P < .01).ConclusionsED is not an independent predictor of CRT response, but it is able to intercept the systemic effects of CRT and is an affordable marker of response to CRT, especially in patients unable to perform the 6MWT.     

Association between dietary folate intake and serum insulin-like growth factor-1 levels in healthy old women

ObjectiveHigh serum levels of insulin-like growth factor-1 (IGF-1) seem to coincide with higher rates of some types of cancer and the risk of all-cause mortality in old people. Eating vegetables seems to reduce IGF-1 levels because they are rich in micronutrients such as vitamins. This study investigates the possible association between vitamin intake and IGF-1 levels in a representative group of healthy elderly women with Mediterranean dietary habits.DesignThis cross-sectional study included 124 healthy women with a mean age of 71.3 ± 4.2 years and a mean body mass index (BMI) of 27.37 ± 3.48 kg/m² attending a mild fitness program twice a week at public gyms in Padova. The main parameters considered were IGF-1 (measured by chemiluminescence) and diet, assessed on the basis of a 3-day record and a questionnaire on the frequency with which they usually ate certain foods.ResultsThe mean IGF-1 level for the sample as a whole was 136.2 ± 38.9 μg/l, and was significantly lower in women with a higher folate intake (p = 0.04). On simple linear analysis, the vitamins found associated with serum IGF-1 levels were: folates (r: ? 0.25; p = 0.003); vitamin E (r: ? 0.21; p = 0.01); vitamin D (r: ? 0.17; p = 0.03); and riboflavin (r: ? 0.16; p = 0.03). After removing the effect of calorie, protein, carbohydrate and fat intake, and other known potential confounders (age, BMI, alcohol intake), only folate intake correlated with IGF-1 levels (r = ? 0.17; p = 0.04).ConclusionA folate-rich diet could have the effect of lowering circulating IGF-1 levels in elderly women.