In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A^131R-chimeric receptor (CR), and those engineered with the low-affinity CD16^158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A^131R-CR T cells was 74 ± 10%, whereas the percentage of CD16^158F-CR T cells was 46 ± 15%. Only CD32A^131R-CR T cells bound panitumumab. CD32A^131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16^158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116^FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A^131R-CR on T cells by cetuximab or panitumumab and CD16^158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A^131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.     

Ultra-Widefield Indocyanine Green Angiography Reveals Patterns of Choroidal Venous Insufficiency Influencing Pachychoroid Disease

PurposeTo compare patterns of choroidal venous drainage in eyes with pachychoroid disease to those of healthy subjects using ultra-widefield indocyanine green angiography (UWF ICGA).MethodsPatients with pachychoroid disease and healthy controls were recruited at two referral centers. UWF ICGA images were used to evaluate the proportion of the postequatorial fundus drained by major vortex vein systems in each quadrant and to study the incidence and topography of choroidal vascular hyperpermeability (CVH) and intervortex venous anastomoses. Widefield swept-source optical coherence tomography (SS-OCT) was used to evaluate choroidal thickness at the posterior pole in eyes with pachychoroid disease.ResultsFifty-two pachychoroid eyes and 26 healthy eyes were evaluated. Eyes with pachychoroid disease showed a significant within-subject variance in the proportion of the postequatorial fundus drained by each vortex vein system (range, 4.1%–48.1%; P < 0.0001) that was not seen in controls (range, 17.3%–31.7%; P = 0.11). CVH was present in all pachychoroid disease eyes and three of 26 controls. Intervortex venous anastomoses were present in 46 of 52 pachychoroid disease eyes and nine of 26 control eyes. Vortex vein systems with large drainage areas showed greater density of CVH spots. SS-OCT demonstrated asymmetric choroidal drainage in the macula of 59% of pachychoroid eyes. CVH and intervortex venous anastomoses were more prominent in areas showing maximal choroidal thickness.ConclusionsIn eyes with pachychoroid disease, imbalanced choroidal venous drainage with congestion of specific vortex vein systems may contribute to a state of choroidal venous insufficiency characterized by regional choroidal thickening, CVH and remodeling of venous drainage routes.     

Correlation between BMI and PASI in patients affected by moderate to severe psoriasis undergoing biological therapy

Obesity is common in psoriatic patients, and it has been shown to be important for many aspects of the condition. In particular, low-calorie diets can improve the symptoms and response to treatment in pustular psoriasis. The present study investigates the influence of body-weight alteration on the disease's clinical manifestations in moderate to severe psoriasis patients treated with biological drugs. Finally, the influence of a caloric restriction was assessed. This observational transversal study enrolled 33 patients attending our Severe Psoriasis Outpatient Clinic, who were treated with biological drugs. Body Mass Index (BMI) was used as a diagnostic indicator of being overweight and of obesity. Waist circumference was also measured. Body weight and Psoriasis Area Severity Index (PASI) index were measured at follow-up visits at 4 and 8 months. Nonparametric test of Mann–Whitney was used to detect the differences between patient groups. Fisher's exact test was performed to evaluate the different results depending on the therapeutic changes of BMI. There was a strong prevalence of overweight-obese individuals in the group with a mean BMI of 30.59 ± 6.94. Waist circumference was also above normal in the majority of the patients. Obese patients had a PASI index higher than the average of the whole group (25.03 ± 12.43), with grade III obese patients having an average PASI of 44 ± 3.37. At the first and second follow-ups, patients who put on weight did not achieve PASI 50; patients who had a stable weight presented variable response to treatment, while patients who decreased their weight achieved PASI 90 or PASI 75 even when not responding at the first. Further studies are needed to understand if the poor response observed in heavier patients is due to biological drugs pharmacokinetics or because therapy should be BMI based rather than administered in fixed doses, posing then an ethical consideration.     

Intraoperative subdural low-noise EEG recording of the high frequency oscillation in the somatosensory evoked potential

Objective

The detectability of high frequency oscillations (HFO, >200 Hz) in the intraoperative ECoG is restricted by their low signal-to-noise ratio (SNR). Using the somatosensory evoked HFO, we quantify how HFO detectability can benefit from a custom-made low-noise amplifier (LNA).

Incidence and spatial distribution of adult-onset primary malignant and other central nervous system tumors in Southern Sardinia,Italy

Neurological Sciences - To study for the first time the incidence of adult-onset CNS tumors in Southern Sardinia, Italy. Clinical records of patients &gt; 18&nbsp;years old who...     

The thickness of facial alveolar bone overlying healthy maxillary anterior teeth

Background: A facial bone (<2 mm) overlying maxillary anterior teeth may be prone to resorptive processes after extraction and immediate implant placement. A thin bone contributes to risk of bone fenestration, dehiscence, and soft‐tissue recession. This study measures the distance between the cemento‐enamel junction (CEJ) and alveolar bone crest and the thickness of facial alveolar bone at points 1 to 5 mm from the bone crest for the six maxillary anterior teeth. Methods : Sixty‐six tomographic scans (31 males and 35 females; aged 17 to 69 years; mean age: 39.9 years) of intact anterior maxilla were randomly selected and evaluated by two calibrated and independent examiners (MG and TP). Results: A high variation of CEJ–bone crest (0.8 to 7.2 mm) was detected. A significantly larger CEJ–bone crest was measured in smokers (P <0.05) and patients who were ≥50 years old (P <0.05). The average bone thickness at 3 mm from the CEJ for the maxillary right central incisor was 1.41 mm and for the maxillary left central incisor was 1.45 mm. For the maxillary right and left lateral incisors, the crestal bone thickness averaged 1.73 and 1.59 mm, respectively. For the maxillary right and left canines, the crestal bone thickness averaged 1.47 and 1.60 mm, respectively. Conclusions : The present study supports the finding of a predominantly thin facial bone overlying the six maxillary anterior teeth. Therefore, it is essential to make informed treatment decisions based on thorough site evaluation before immediate implant placement.     

Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates

Introduction

Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure.

Methods and results

In a randomized, investigator-blind parallel trial, 30 healthy (age 25–32) volunteers were randomized to receive (1) transdermal GTN (0.6?mg/h) administered for 2?h a day for 6?days; (2) oral PETN (80?mg) once a day for 6?days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8?±?2.1%; after IR 1.0?±?2.1%; P?P?P?=?ns; P?P?Discussion We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.