Currently, medications used to treat rheumatoid arthritis (RA) are glucocorticoids (GCs) and nonsteroidal anti‐inflammatory drugs (NSAIDs), predominantly used for controlling the pain and inflammation, disease‐modifying antirheumatic drugs (DMARDs), administered as first‐line medication for newly diagnosed RA cases, and biological therapies, used to target and inhibit specific molecules of the immune and inflammatory responses. NSAIDs and other GCs are effective in alleviating the pain, inflammation, and stiffness due to RA. DMARDs that are used for RA therapy are hydroxychloroquine, methotrexate, leflunomide, and sulfasalazine. The biological therapies, on the contrary, are chimeric anti‐CD20 monoclonal antibody, rituximab, inhibitors of tumor necrosis factor‐α (TNF‐α) like etanercept, infliximab, and adalimumab, a recombinant inhibitor of interleukin‐1 (IL‐1), anakinra, and costimulation blocker, abatacept. Moreover, newly under evaluation biological therapies include new TNF‐α inhibitors, JAK inhibitors, anti‐interleukin‐6‐receptor monoclonal antibodies (mABs), and antibodies against vital molecules involved in the survival and development of functional B cells. The new strategies to treat RA has improved the course of the disease and most of the patients are successful in remission of the clinical manifestations if the diagnosis of the disease occur early. The probability of remission increase if the diagnosis happens rapidly and treat‐to‐target approach are implemented. In this review article, we have attempted to go through the treatment strategies for RA therapy both the routine ones and those which have been developed over the past few years and currently under investigation.

Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones.Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients.Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrowderived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs.Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. Clin Cancer Res; 23(15); 4224-32.Ó2017 AACR.

Neuroblastoma is the most common extra‐cranial solid tumor in childhood. Presence of disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and at relapse is a common event in stage M neuroblastomas. Although the clinical heterogeneity of disseminated neuroblastomas is frequently associated with genomic diversity, so far, only little information exists about the genomic status of DTCs. This lack of knowledge is mainly due to the varying amount of BM infiltrating tumor cells, which is usually below 30% even at diagnosis thereby hampering systematic analyses. Thus, a valuable chance to analyze metastatic and relapse clones is, so far, completely unexploited. In this study, we show that the enrichment of tumor cells in fresh or DMSO frozen BM samples with a minimum of 0.05% or 0.1% infiltration rate, respectively, by applying magnetic bead‐based technique increased the DTC content to a sufficient level to allow SNP array analyses in 49 out of 69 samples. In addition, we successfully used non‐enriched BM samples with ≥30% DTCs including non‐stained and immunostained cytospin and BM smear slides for SNP array analyses in 44 cases. We analyzed the genomic profile of DTCs by an ultra‐high density SNP array technique with highest performance detecting all segmental chromosomal aberrations, amplified regions, acquired loss of heterozygosity events and minor aberrations affecting single genes or parts thereof.

Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA‐Seq study of stage 4/M primary tumors, enriched BM‐derived diagnostic and relapse DTCs, as well as the corresponding BM‐derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0.001, |log2FC|>2). Particularly, the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas, for example, genes involved in angiogenesis were downregulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8 × 10−75 log2FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut‐offs (q < 0.01, |log2FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 downregulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2. This first RNA‐Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected downregulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered.

Pesticides are classified into several groups based on their structure, including fungicides, insecticides, herbicides, bactericides, and rodenticides. Pesticides are toxic to both humans and pests. For pest control, a very small amount of pesticides reach their target pests. Therefore, nearly all pesticides move through the environment and exert adverse effects on beneficial biota and public health. These chemicals pollute the water, soil, and atmosphere of the ecosystem. Agricultural workers in greenhouses and open fields, exterminators of house pests, and workers in the pesticide industry are occupationally exposed to pesticides. Pesticide exposure in the general population primarily happens through the consumption of food and water contaminated with pesticide residues; however, substantial exposure can also occur outside or inside the house. Currently, intelligent, responsive, biodegradable, and biocompatible materials have attracted considerable interest for the formulation of green, safe, and efficient pesticides. It was indicated that utilizing nanotechnology to design and prepare targeted pesticides with an environmentally responsive controlled release via chemical modifications and compounds offers great potential for creating new formulations. Furthermore, biopesticides include microbial pesticides, which are naturally happening biochemical pesticides. In addition, pesticidal substances generated by plants with added genetic materials, i.e., plant-incorporated protectants (PIPs), have emerged. Based on the foregoing evidence, various types of pesticides are summarized in this review for the first time. Here, new pesticides including nano-pesticides and biopesticides are discussed while focusing on the most recent findings on targeted and safe nano-formulated biopesticides and nano-pesticides. Graphical Abstract