Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor

Tumors exploit immunoregulatory checkpoints that serve to attenuate T cell responses as a means of circumventing immunologic rejection. Programmed death ligand 1 (PD-L1) is a negative regulator of T cell function and is frequently expressed by solid tumors. By engaging programmed death 1 (PD-1) on activated T cells, PD-L1(+) tumors directly render tumor-specific T cells, including adoptively transferred T cells, functionally exhausted. As a strategy to overcome tumor PD-L1 effects on adoptively transferred T cells, we sought to convert PD-1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with that of CD28. Rather than becoming exhausted upon engagement of PD-L1(+) tumors, we hypothesized that CD8(+) cytotoxic T lymphocytes (CTL) genetically modified to express this PD1:CD28 chimera would exhibit enhanced functional attributes. Here we show that cell surface expressed PD1:CD28 retains the capacity to bind PD-L1 resulting in T cell costimulation as evidenced by increased levels of ERK phosphorylation, augmentation of cytokine secretion, increased proliferative capacity, and enhanced expression of effector molecule Granzyme B. We provide evidence that this chimera could serve as a novel engineering strategy to overcome PD-L1 mediated immunosuppression.     

Sperm preparation: DNA damage by comet assay in normo- and teratozoospermics

The present study was carried out on semen samples of human fertile and infertile subjects, teratozoospermics (TZs) and idiopathics (IDs), with neat semen and sperm prepared by swim up or Percoll density gradient centrifugation procedures. Sperm morphology analysis revealed that only head and midpiece defects in TZs and IDs were significantly (P < 0.001) higher compared to fertile subjects. Infertile subjects indicated significantly higher (P < 0.001) sperm DNA damage compared to fertile subjects. Fertile subjects with sperm prepared from neat and Percoll density gradient centrifugation exhibited a comet tail DNA percentage of 20% and 15%, respectively. The TZs and IDs infertile subjects had higher levels of comet tail DNA of 33% and 25% and 25% and 19%, respectively. A significant (F = 24.01; P = 0.0059) decrease in mean comet head DNA percentage or sperm DNA integrity was observed in neat samples from fertile and infertile subjects by Repeated Measures ANOVA. In Percoll prepared samples from fertile, TZs, and IDs, there was a significant increase in sperm DNA integrity. Similarily, there was a decrease in abnormal sperm morphology in swim up and Percoll prepared sperm compared to neat samples. The Percoll density gradient centrifugation procedure yields sperm with an increase in sperm DNA integrity relative to swim up. Sperm DNA damage of TZs with both sperm preparation methods was significantly (P < 0.01) higher when compared to fertile and IDs. But the level of DNA damage was higher in IDs compared to fertile subjects. Compared to the other methods tested, the Percoll method yielded sperm with improved DNA integrity. In conjunction with semen analysis, the assessment of nuclear integrity improves the characterization of the semen sample and may be used as a tool for allocating the patients to specific assisted reproductive treatments.     

Endoscopic ultrasound drainage of pancreatic pseudocyst: a prospective comparison with conventional endoscopic drainage

BACKGROUND AND STUDY AIMS: Pancreatic pseudocysts are a complication in up to 20% of patients with pancreatitis. Endoscopic management of pseudocysts by a conventional transenteric technique, i. e. conventional transmural drainage (CTD), or by endoscopic ultrasound-guided drainage (EUD), is well described. Our aim was to prospectively compare the short-term and long-term results of CTD and EUD in the management of pseudocysts. PATIENTS AND METHODS: A total of 99 consecutive patients underwent endoscopic management of pancreatic pseudocysts according to this predetermined treatment algorithm: patients with bulging lesions without obvious portal hypertension underwent CTD; all remaining patients underwent EUD. Patients were followed prospectively, with cross-sectional imaging during clinic visits. We compared short-term and long-term results (effectiveness and complications) at 1 and 6 months post procedure. RESULTS: 46 patients (37 men) underwent EUD and 53 patients (39 men) had CTD. The mean age of the entire group was 50 +/- 13 years. There were no significant differences between the two groups regarding short-term success (93% vs. 94%) or long-term success (84% vs. 91%); 68 of the 99 patients completed 6 months of follow-up. Complications occurred in 19% of EUD vs. 18% of CTD patients, and consisted of bleeding in three, infection of the collection in eight, stent migration into the pseudocyst in three, and pneumoperitoneum in five. All complications but one could be managed conservatively. CONCLUSIONS: No clear differences in efficacy or safety were observed between conventional and EUS-guided cystenterostomy. The choice of technique is likely best predicated by individual patient presentation and local expertise.     

Rapunzel's syndrome: gastric bezoars and endoscopic management

The diagnosis of bezoar formation may be difficult secondary to the nonspecific clinical presentation. Once a diagnosis is reached, the clinician has many options for management. These management options are largely based on the size and composition of the bezoar along with the experience or preference of the operator. Once a bezoar has been safely treated, steps should be taken to avoid recurrence, because many patients may be at risk for reformation.     

Bartonella quintana associated neuroretinitis

We report an observational case of Bartonella quintana-associated neuroretinitis. The patient had a positive IgM IFA titer for Bartonella quintana early in the disease. After treatment, the neuroretinitis and IgM resolved. Given the patient's history, symptoms, response to treatment, and IgM course, we believe his neuroretinitis was secondary to Bartonella quintana.     

Trends in the incidence rates of tonsil and base of tongue cancer in England, 1985�C2006

INTRODUCTION

The aim of this study was to investigate whether incidence rates of tonsil and base of tongue cancer in England are increasing using data from the UK cancer registry.

SUBJECTS AND METHODS

Cancer registrations for oral cavity and oropharynx cancer from 1985–2006 in England were obtained from the National Cancer Information Service. Population estimates were obtained from the Office for National Statistics. Age-adjusted incidence rates and age-specific incidence rates were calculated. The sexes were considered separately as incidence rates are known to differ significantly between men and women. Linear regression was performed to establish whether there was a relationship between incidence rates and time.

RESULTS

There has been an increase in all oral cavity and oropharyngeal cancer in the study period. Linear regression analysis suggests that approximately 90% of the variance in age-adjusted incidence rates for men and women for tonsil, base of tongue and other oral cavity cancer is explained by the passage of time. For other oropharyngeal cancer, the variance is 62% and 46% in men and women, respectively. The estimated annual percentage change from 1985 to 2006 in age-adjusted incidence rates for tonsil and base of tongue cancer is 5.7% and 6.7% for men, and 4.3% and 6.5% for women, respectively.

CONCLUSIONS

This study confirms a wide-spread clinical impression that there has been an increase in age-adjusted incidence rates, between 1985 and 2006, in all oral cavity cancer in England. The age range 40–69 years has seen the biggest increases in age-specific incidence rates for tonsil and base of tongue cancer. This reflects the findings of similar studies in other countries.     

Acute myeloid leukemia

Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML provide recommendations on the diagnostic evaluation and workup for AML, risk assessment based on cytogenetic and molecular features, treatment options for induction and consolidation therapies for younger and older (age ≥ 65 years) adult patients, and key supportive care considerations.     

Density-equalizing mapping and scientometric benchmarking of European allergy research

Due to the great socioeconomic burden of allergic diseases, research in this field which is important for environmental medicine is currently increasing. Therefore the European Union has initiated the Global Allergy and Asthma European network (GA2LEN). However, despite increasing research in the past years detailed scientometric analyses have not been conducted so far. This study is the first scientometric analysis in a field of growing interest. It analyses scientific contributions in European allergy research between 2001 and 2007. Three different meetings of the European Academy of Allergy and Clinical Immunology were analysed for contributions and an increase in both the amount of research and networks was found.