Razine antinuklearnoga antitijela i reumatoidnoga faktora u radnika izloženih silicijevu dioksidu

A lot of workers in industries such as foundry, stonecutting, and sandblasting are exposed to higher than permissible levels of crystalline silica. Various alterations in humoral immune function have been reported in silicosis patients and workers exposed to silica dust. The aim of this study was to measure antinuclear antibody (ANA) and rheumatoid factor (RF) levels in foundry workers exposed to silica and to compare them with a control group without such exposure. ANA and RF were measured in 78 exposed and 73 non-exposed workers, and standard statistical methods were used to compare them. The two groups did not significantly differ in age and smoking. Mean work duration of the exposed and non-exposed workers was (14.9±4.72) years and (12.41±6.3) years, respectively. Ten exposed workers had silicosis. ANA was negative in all workers in either group. Its mean titer did not differ significantly between the exposed and control workers [(0.39±0.15) IU mL-1 vs. (0.36±0.17) IU mL-1, respectively]. RF was positive in two workers of each group. Other studies have reported an increase in ANA and RF associated with exposure to silica dust and silicosis. In contrast, our study suggests that exposure to silica dust does not increase the level of ANA and RF in exposed workers.Mnogi su radnici izloženi kristalnomu silicijevu dioksidu u razinama iznad dopuštenih. U oboljelih od silikoze i radnika izloženih prašinama koje sadržavaju silicijev dioksid zamijećen je niz oštećenja humoralne obrane. Budući da su radnici u ljevaonicama izloženi visokim razinama kristalnoga silicijeva dioksida, u njih bismo očekivali ovakve humoralne poremećaje. Cilj je ovog ispitivanja bio izmjeriti i usporediti razine antinuklearnih protutijela (ANA) i reumatoidnoga faktora (RF) u krvi radnika u ljevaonici izloženih silicijevu dioksidu i neizložene kontrolne skupine. ANA i RF izmjereni su u 78 izloženih radnika i 73 neizložena radnika te su uspoređeni s pomoću standardnih statističkih metoda. Dvije se skupine nisu bitno razlikovale u broju pušača i u dobi. Prosječna duljina radnog vijeka izloženih radnika bila je (14,9±4,72) godine, a neizloženih (12,41±6,3) godine. Deset izloženih radnika imalo je silikozu. Nalazi ANA bili su negativni u obje skupine radnika. Srednja vrijednost titra ANA iznosila je (0,39±0,15) IU mL-1 u izloženih ispitanika, a (0,36±0,17) IU mL-1 u kontrola, što je statistički zanemariva razlika. Nalaz RF-a bio je pozitivan u dva izložena te dva kontrolna radnika. Naše ispitivanje upućuje na to da prašine silicijeva dioksida ne uzrokuju porast razina ANA i RF-a u izloženih radnika

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization

Zeb2 (Sip1/Zfhx1b) is a member of the zinc-finger E-box-binding (ZEB) family of transcriptional repressors previously demonstrated to regulate epithelial-to-mesenchymal transition (EMT) processes during embryogenesis and tumor progression. We found high Zeb2 mRNA expression levels in HSCs and hematopoietic progenitor cells (HPCs), and examined Zeb2 function in hematopoiesis through a conditional deletion approach using the Tie2-Cre and Vav-iCre recombination mouse lines. Detailed cellular analysis demonstrated that Zeb2 is dispensable for hematopoietic cluster and HSC formation in the aorta-gonadomesonephros region of the embryo, but is essential for normal HSC/HPC differentiation. In addition, Zeb2-deficient HSCs/HPCs fail to properly colonize the fetal liver and/or bone marrow and show enhanced adhesive properties associated with increased beta 1 integrin and Cxcr4 expression. Moreover, deletion of Zeb2 resulted in embryonic (Tie2-Cre) and perinatal (Vav-icre) lethality due to severe cephalic hemorrhaging and decreased levels of angiopoietin-1 and, subsequently, improper pericyte coverage of the cephalic vasculature. These results reveal essential roles for Zeb2 in embryonic hematopoiesis and are suggestive of a role for Zeb2 in hematopoietic-related pathologies in the adult. (Blood. 2011; 117(21): 5620-5630

Distinct leukocyte populations and cytokine secretion profiles define tumoral and peritumoral areas in renal cell carcinoma.

Renal cell carcinoma (RCC) is a common malignancy frequently diagnosed at the metastatic stage. We performed a comprehensive analysis of the tumor immune microenvironment (TIME) in RCC patients, including the peritumoral tissue microenvironment, to characterize the phenotypic patterns and functional characteristics of infiltrating immune cells. T cells from various compartments (peripheral blood, tumor, peritumoral area, and adjacent healthy renal tissue) were assessed using flow cytometry and Luminex analyses, both before and after T cell-specific stimulation, to evaluate activation status and migratory potential. Our findings demonstrated that tumor-infiltrating lymphocytes (TILs) exhibited heightened cytokine production compared to peritumoral T cells (pTILs), acting as the primary source of cytotoxic markers (IFN-γ, granzyme B, and FasL). CD8 <sup>+</sup> T cells primarily employed Fas Ligand for cytotoxicity, while CD4 <sup>+</sup> T cells relied on CD107a. In addition, a statistically significant negative correlation between patient mortality and the presence of CD4 <sup>+</sup> CD107 <sup>+</sup> pTILs was demonstrated. The engagement with the PD-1/PD-L1 pathway was also more evident in CD4 <sup>+</sup> and CD8 <sup>+</sup> pTILs as opposed to TILs. PD-L1 expression in the non-leukocyte fraction of the tumor tissue was relatively lower than in their leukocytic counterparts and upon stimulation, peripheral blood T cells displayed much stronger responses to stimulation than TILs and pTILs. Our results suggest that tumor and peritumoral T cells exhibit limited responsiveness to additional activation signals, while peripheral T cells retain their capacity to respond to stimulatory signals

Developing 3D SEM in a broad biological context

When electron microscopy (EM) was introduced in the 1930s it gave scientists their first look into the nanoworld of cells. Over the last 80 years EM has vastly increased our understanding of the complex cellular structures that underlie the diverse functions that cells need to maintain life. One drawback that has been difficult to overcome was the inherent lack of volume information, mainly due to the limit on the thickness of sections that could be viewed in a transmission electron microscope (TEM). For many years scientists struggled to achieve three-dimensional (3D) EM using serial section reconstructions, TEM tomography, and scanning EM (SEM) techniques such as freeze-fracture. Although each technique yielded some special information, they required a significant amount of time and specialist expertise to obtain even a very small 3D EM dataset. Almost 20 years ago scientists began to exploit SEMs to image blocks of embedded tissues and perform serial sectioning of these tissues inside the SEM chamber. Using first focused ion beams (FIB) and subsequently robotic ultramicrotomes (serial block-face, SBF-SEM) microscopists were able to collect large volumes of 3D EM information at resolutions that could address many important biological questions, and do so in an efficient manner. We present here some examples of 3D EM taken from the many diverse specimens that have been imaged in our core facility. We propose that the next major step forward will be to efficiently correlate functional information obtained using light microscopy (LM) with 3D EM datasets to more completely investigate the important links between cell structures and their functions.status: publishe