Lymphocyte populations and their change during five-year glatiramer acetate treatment

Background

The goal of this study was to determine the characteristics that are affected in patients treated with glatiramer acetate (GA).

The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer

IntroductionThis study aimed to characterize the tumor-infiltrating immune cells population in Kras/tumor protein 53 (Trp53)-driven lung tumors and to evaluate the combinatorial antitumor effect with MEK inhibitor (MEKi), trametinib, and immunomodulatory monoclonal antibodies (mAbs) targeting either programmed death -1 (PD-1) or programmed cell death ligand 1 (PD-L1) in vivo.MethodsTrp53^FloxFlox;Kras^G12D/+;Rosa26^{LSL-Luciferase/LSL-Luciferase} (PKL) genetically engineered mice were used to develop autochthonous lung tumors with intratracheal delivery of adenoviral Cre recombinase. Using these tumor-bearing lungs, tumor-infiltrating immune cells were characterized by both mass cytometry and flow cytometry. PKL-mediated immunocompetent syngeneic and transgenic lung cancer mouse models were treated with MEKi alone as well as in combination with either anti–PD-1 or anti–PD-L1 mAbs. Tumor growth and survival outcome were assessed. Finally, immune cell populations within spleens and tumors were evaluated by flow cytometry and immunohistochemistry.ResultsMyeloid-derived suppressor cells (MDSCs) were significantly augmented in PKL-driven lung tumors compared to normal lungs of tumor-free mice. PD-L1 expression appeared to be highly positive in both lung tumor cells and, particularly MDSCs. The combinatory administration of MEKi with either anti–PD-1 or anti–PD-L1 mAbs synergistically increased antitumor response and survival outcome compared with single-agent therapy in both the PKL-mediated syngeneic and transgenic lung cancer models. Theses combinational treatments resulted in significant increases of tumor-infiltrating CD8⁺ and CD4⁺ T cells, whereas attenuation of CD11b⁺/Gr-1^high MDSCs, in particular, Ly6G^high polymorphonuclear-MDSCs in the syngeneic model.ConclusionsThese findings suggest a potential therapeutic approach for untargetable Kras/p53-driven lung cancers with synergy between targeted therapy using MEKi and immunotherapies.     

The value of 18F-DOPA PET-CT in patients with medullary thyroid carcinoma: comparison with 18F-FDG PET-CT

The purpose of this prospective study was to compare the value of DOPA PET-CT with FDG PET-CT in the detection of malignant lesions in patients with medullary thyroid carcinoma (MTC). Twenty-six consecutive patients (10 men, 16 women, mean age 59 ± 14 years) with elevated calcitonin levels were evaluated in this prospective study. DOPA and FDG PET-CT modalities were performed within a maximum of 4 weeks (median 7 days) in all patients. The data were evaluated on a patient- and lesion-based analysis. The final diagnosis of positive PET lesions was based on histopathological findings and/or imaging follow-up studies (i.e., DOPA and/or FDG PET-CT) for at least 6 months (range 6–24 months). In 21 (21/26) patients at least one malignant lesion was detected by DOPA PET, while only 15 (15/26) patients showed abnormal FDG uptake. DOPA PET provided important additional information in the follow-up assessment in seven (27%) patients which changed the therapeutic management. The patient-based analysis of our data demonstrated a sensitivity of 81% for DOPA PET versus 58% for FDG PET, respectively. In four (4/26) postoperative patients DOPA and FDG PET-CT studies were negative in spite of elevated serum calcitonin and CEA levels as well as abnormal pentagastrin tests. Overall 59 pathological lesions with abnormal tracer uptake were seen on DOPA and/or FDG PET studies. In the final diagnosis 53 lesions proved to be malignant. DOPA PET correctly detected 94% (50/53) of malignant lesions, whereas only 62% (33/53) of malignant lesions were detected with FDG PET. DOPA PET-CT showed superior results to FDG PET-CT in the preoperative and follow-up assessment of MTC patients. Therefore, we recommend DOPA PET-CT as a one-stop diagnostic procedure to provide both functional and morphological data in order to select those patients who may benefit from (re-)operation with curative intent as well as guiding further surgical procedures.     

Repair of esophageal atresia with proximal fistula using endoscopic magnetic compression anastomosis (magnamosis) after staged lengthening

We describe the treatment of a patient with long-gap esophageal atresia with an upper pouch fistula, mircogastria and minimal distal esophageal remnant. After 4.5 months of feeding via gastrostomy, a proximal fistula was identified by bronchoscopy and a thoracoscopic modified Foker procedure was performed reducing the gap from approximately 7–5 cm over 2 weeks of traction. A second stage to ligate the fistula and suture approximate the proximal and distal esophagus resulted in a gap of 1.5 cm. IRB and FDA approval was then obtained for endoscopic placement of 10-French catheter mounted magnets in the proximal and distal pouches promoting a magnetic compression anastomosis (magnamosis). Magnetic coupling occurred at 4 days and after magnet removal at 13 days an esophagram demonstrated a 10 French channel without leak. Serial endoscopic balloon dilation has allowed drainage of swallowed secretions as the baby learns bottling behavior at home.     

A comparative study of respiratory function in female non-smoking cotton and jute workers

Valić, F., and Žuškin, E. (1971).Brit. J. industr. Med.,28, 364-368. A comparative study of respiratory function in female non-smoking cotton and jute workers. To compare the effect of cotton and jute dust, respiratory symptoms were studied and respiratory function measured in 60 cotton and 91 jute non-smoking female workers of similar age distribution, similar length of exposure to dust, and exposed to similar respirable airborne dust concentrations. Cotton workers had a significantly higher prevalence of byssinosis, of persistent cough, and of dyspnoea (P < 0·01) than jute workers. Among cotton workers 28·3% were found to have characteristic symptoms of byssinosis, whereas none was found among jute workers.

Exposure to cotton but also to jute dust caused significant reductions of FEV_1·0, FVC, and PEF (P < 0·01) over the first working shift in the week. Functional grading of jute and cotton dust effects has shown that about 30% of cotton workers had functional grades F1 and F2, while only 13% of jute workers were found in the same grades (F1). It is concluded that cotton dust may be considered more active than jute though the latter cannot be considered inactive.

     

Histamine Blocks Interleukin 2 (IL-2) Gene Expression and Regulates IL-2 Receptor Expression

Histamine inhibited the roliferative response of human peripheral blood mononuclear cells (PBMCT to the T cell mitoFen Phytohema P (PHA-P) in a dose-dependent fashion. This inhibition was mePutiated via the H₂ receptor since cimetidine, a known H₂ antagonist, removed the inhibition, whereas the addition of the H₁ antagonist Diphenhdramine did not. Inhibition occurred durin the inductive phase of the cell cycle, since histamine added 24 hours aBter PHA-P stimulation had no effect on subsequent T cell proliferation, and was attributable to inhibition of interleukin-2 (IL-2) gene expression. Both secreted IL-2 and messenger RNA coding for IL-2 were inhibited by histamine. In contrast, histamne exerted no inhibitory effect on the expression of cell surface receptors for IL-2 as determined by flow cytometry. Furthermore, histamine-treated cells retained full responsiveness to exogenously administered IL-2, which completely reversed the anti-proliferative effect of histamine. In some donors, histamine enhanced the ercentage of IL-2 receptor positive cells. Stimulated PBMC from AIDS KS patients as a group, displayed a lower ercentage of IL-2 receptor bearing cells, which was significantly increased gy the addition of histamine even at concentrations as low as 10^--⁶ M and peaking at 10^--³ M. These findings indicate that histamine exerts its anti-proliferative effects on T cells by inhibiting IL-2 production, via blockade of IL-2 gene expression. In addition, histamine seems to exert immunomodulating effects on IL-2 receptor expression, particularly in those individuals with AIDS-KS.     

Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development.

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.     

Specific alcoholic beverages and physical and mental health among adolescents

OBJECTIVE: This study investigated the longitudinal inter-relationships among the consumption of specific alcoholic beverages (beer, wine and distilled spirits), physical symptoms and psychological distress. Two causal processes were examined for each type of beverage: (1) the use of alcohol to cope with pre-existing psychological distress and physical symptoms; (2) the impairment effects of alcohol on subsequent physical and mental health. METHOD: Data were collected at three points in time (baseline, 3-year follow-up, 6-year follow-up) from a household sample of 1,270 youths who were ages 12, 15 and 18 at the baseline interview. RESULTS: Consumption of all three beverages increased through early adolescence and leveled off at ages 18 and 21, and males reported more beer use than females. Structural equation models showed that the use of all three alcoholic beverages contributed significantly to longitudinal increases in physical symptoms, but not to changes in psychological distress. In contrast, no evidence supported the coping hypothesis. Finally, there were no significant interaction effects involving beverage type, gender or age on physical symptoms. CONCLUSIONS: The results suggested that the physical impairment process operated similarly for beer, wine and distilled spirits, for males and females, and for adolescents of different ages.     

Simultaneous exposure to airborne flour particles and thermal load as cause of respiratory impairment

Summary In order to estimate whether only simultaneous exposure to both airborne flour particles and unfavorable thermal environment alone cause the development of nonspecific respiratory disease or whether sole exposure to flour aerosols is likely to cause impairment of the respiratory system, a group of 80 millers and 130 bakers, all nonsmokers, were examined. Both millers and bakers were exposed to approximately the same concentration of airborne flour particles but the latter worked under considerable thermal load. It was found that between millers and bakers the difference in the prevalence of respiratory symptoms was not statistically significant. Although the differences between the mean measured and the mean predicted ventilatory function parameters (FVC, FEV₁, PEF, MEF 50%, MEF 75%) were significant both in millers and bakers, they did not differ significantly between these two groups. This finding suggests that exposure to flour dust may cause the development of chronic nonspecific respiratory disease and a reduction of ventilatory lung capacity irrespective of simultaneous heat load.     

Desulfovibrio magneticus RS-1 contains an iron- and phosphorus-rich organelle distinct from its bullet-shaped magnetosomes

Intracellular magnetite crystal formation by magnetotactic bacteria has emerged as a powerful model for investigating the cellular and molecular mechanisms of biomineralization, a process common to all branches of life. Although magnetotactic bacteria are phylogenetically diverse and their crystals morphologically diverse, studies to date have focused on a few, closely related species with similar crystal habits. Here, we investigate the process of magnetite biomineralization in Desulfovibrio magneticus sp. RS-1, the only reported species of cultured magnetotactic bacteria that is outside of the α-Proteobacteria and that forms bullet-shaped crystals. Using a variety of high-resolution imaging and analytical tools, we show that RS-1 cells form amorphous, noncrystalline granules containing iron and phosphorus before forming magnetite crystals. Using NanoSIMS (dynamic secondary ion mass spectroscopy), we show that the iron-phosphorus granules and the magnetite crystals are likely formed through separate cellular processes. Analysis of the cellular ultrastructure of RS-1 using cryo-ultramicrotomy, cryo-electron tomography, and tomography of ultrathin sections reveals that the magnetite crystals are not surrounded by membranes but that the iron-phosphorus granules are surrounded by membranous compartments. The varied cellular paths for the formation of these two minerals lead us to suggest that the iron-phosphorus granules constitute a distinct bacterial organelle.