Zespół zmęczenia, depresja oraz jakość życia u pacjentów ze stwardnieniem rozsianym

Wstęp. Stwardnienie rozsiane jest przewlekłą chorobą ośrodkowego układu nerwowego o podłożu autoimmunologicznym, w której obok narastającej niesprawności fizycznej występują zaburzenia neuropsychologiczne, prowadzące do znacznego obniżenia jakości życia pacjentów.Cel. Celem badania była ocena częstości występowania zespołu zmęczenia i depresji u pacjentów ze stwardnieniem rozsianym oraz ich wpływ na funkcjonowanie w obszarze fizycznym, poznawczym i psychospołecznym oraz na jakość życia.Materiał i metody. W badaniu wzięło udział 62 pacjentów (37 kobiet i 25 mężczyzn) z remitująco-rzutową postacią stwardnienia rozsianego oraz 15 pacjentów (9 kobiet i 6 mężczyzn) z rwą kulszową, którzy stanowili grupę referencyjną. Częstość występowania zespołu zmęczenia, depresji i jakość życia pacjentów oceniano za pomocą Zmodyfikowanej Skali Wpływu Zmęczenia, Skali Depresji Becka oraz Kwestionariusza Dotyczącego Zdrowia EQ-5D.Wyniki. U pacjentów z remitująco-rzutową postacią stwardnienia rozsianego zmęczenie o średnim nasileniu wykazano u 45,16% (n=28), natomiast depresję u 51,61% chorych (n=32), w tym łagodne zaburzenia depresyjne u 33,87% chorych (n=21), umiarkowane u 11,29% pacjentów (n=7), a nasilone u 6,45% (n=4). Uzyskane wyniki nie różniły się istotnie statystycznie od wyników uzyskanych w grupie referencyjnej. W grupie chorych na stwardnienie rozsiane stwierdzono istotną statystycznie zależność nasilenia depresji od wpływu zmęczenia na funkcjonowanie, głównie w wymiarze psychospołecznym.Wnioski. Zespół zmęczenia i depresja występują u znaczącej części chorych na postać remitująco-rzutową stwardnienia rozsianego, zaburzając funkcjonowanie chorych w wymiarze psychospołecznym i istotnie obniżając ich jakość życia. Nasilenie zmęczenia w wymiarze ogólnym w grupie chorych na postać remitująco-rzutową SM istotnie dodatnio koreluje z nasileniem depresji. (PNN 2017;6(2):81–87)Introduction. Multiple sclerosis is a chronic disease of central nervous system of autoimmunological origin, in which next to an increased physical disability, neuropsychological disorders exist, that lead to significant decrease in patients’ quality of life.Aim. The aim of the study was the assessment of prevalence of fatigue syndrome and depression in patients with multiple sclerosis and their influence on functioning in physical, cognitive and psychosocial dimension as well as on the quality of life.Materials and Methods. 62 patients (37 females and 25 males) with relapsing-remitting subtype of multiple sclerosis and 15 patients with sciatica (9 females and 6 males) as the reference group were included in the study. Prevalence of fatigue syndrome and depression, as well as patients’ quality of life were assessed with use of Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory (BDI) and a standardized instrument for use as a measure of health outcome EQ-5D.Results. Fatigue of moderate intensity was noticed in 45.16% (n=28) of patients with relapsing-remitting subtype of MS, when depression was apparent in 51.61% of patients (n=32), including mild depressive disorders in 33.8% of patients (n=21), moderate in 11.29% of patients and severe in 6.45% (n=4). The obtained results did not reach statistical significance when compared to results obtained in the reference group. Statistically significant dependence between the intensity of depression and influence of fatigue on functioning in psychosocial dimension was mainly observed in the group of patients with multiple sclerosis.Conclusions. Fatigue syndrome and depression occur in significant part of patients with relapsing-remitting subtype of multiple sclerosis, disturbing their functioning in psychosocial dimension and considerably decreasing their quality of life. Increase in fatigue in general dimension has a significantly positive correlation with exacerbation of depression in the group of patients with relapsing-remitting subtype of multiple sclerosis. (JNNN 2017;6(2):81–87

Upregulation of PDL1 Expression by Resveratrol and Piceatannol in Breast and Colorectal Cancer Cells Occurs Via HDAC3/p300-Mediated NFkappaB Signaling

Programmed cell death ligand 1 (PDL1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD1/PDL1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PDL1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PDL1 in tumor cells may help to improve the response to PDL1 blockade therapies. In this study, we investigated whether resveratrol, a grape-derived stilbenoid with immunoregulatory activity, modulates the expression of PDL1 in breast and colorectal cancer cells. The surface expression of PDL1 was determined by flow cytometry in cancer cells treated with resveratrol and/or piceatannol. Each stilbenoid alone induced PDL1 and when used in combination, elicited a synergistic upregulation of PDL1 in some cell lines. The induction of PDL1 by the combined use of stilbenoids was most pronounced in the Cal51 triple-negative breast cancer (TNBC) and SW620 colon cancer cells. The observed induction of PDL1 was transcriptionally mediated by nuclear factor (NF)-kappaB, as shown by NFkappaB reporter assays, the nuclear accumulation of the p65 subunit of NFkappaB, inhibition by the IKK inhibitor, BMS345541, and histone the modification inhibitors, resminostat, entinostat or anacardic acid. Combined treatment with resveratrol and piceatannol also decreased tumor cell survival as indicated by the upregulation of the DNA damaging marker, gammaH2AX, the cleavage of caspase 3, the downregulation of the survival markers, p38-MAPK/cMyc, and G1-to-S cell cycle arrest

Assessment of Red Blood Cell Distribution Width as a Prognostic Marker in Chronic Lymphocytic Leukemia

Red blood cell distribution width (RDW) is a quantitative measure of the variability in size of circulating erythrocytes. It was recently reported that RDW is a prognostic factor for infection diseases, cardiovascular and pulmonary diseases, as well as some neoplasms. Moreover, RDW is remarkably strong predictor of longevity, including all causes of death, for adults aged 45 years and older. To explain this occurrence it was proposed that persistent IGFs/mTOR signaling is one of the factors that play a role in affecting the RDW and mortality.The above observations induced us to analyze the prognostic role of RDW in chronic lymphocytic leukemia (CLL) being the most frequent type of adult leukemia in Western countries. The obtained results have shown that RDW may be considered as a potential CLL prognostic marker. Elevated RDW level at the moment of diagnosis was associated with advanced disease and presence of other poor prognostic factors. It is also connected with overall survival indicating shorter time in patients with elevated RDW. It is possible that the presently observed correlation between mortality and RDW of the CLL patients is affected by their metabolic (IGF-1/mTOR driven)- rather than chronological- aging. The patients with high level of RDW are expected to have an increased persistent level of IGF-1/mTOR signaling. Within the framework of personalized therapy, these CLL patients therefore would be expected to be more sensitive to the treatment with mTOR inhibitors

Therapeutic targeting of replicative immortality

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed “senescence,” can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells’ heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy

Cancer prevention and therapy through the modulation of the tumor microenvironment

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer

Immune evasion in cancer: mechanistic basis and therapeutic strategies

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re- emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, deregulated metabolism etc. In this review, we will discuss the advances made towards understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection

Genomic instability in human cancer: molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology

Simvastatin and purine analogs have a synergic effect on apoptosis of chronic lymphocytic leukemia cells

Despite many therapeutic regimens introduced recently, chronic lymphocytic leukemia (CLL) is still an incurable disorder. Thus, there is an urgent need to discover novel, less toxic and more effective drugs for CLL patients. In this study, we attempted to assess simvastatin, widely used as a cholesterol-lowering drug, both as a single agent and in combination with purine analogs—fludarabine and cladribine—in terms of its effect on apoptosis and DNA damage of CLL cells. The experiments were done in ex vivo short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (named γH2AX) and activated ATM kinase (ataxia telangiectasia mutated kinase), reporters of DNA damage. Results of our study revealed that simvastatin induced apoptosis of CLL cells concurrently with lowering of BCL-2/BAX ratio, and its pro-apoptotic effect is tumor-specific, not affecting normal lymphocytes. We observed that combinations of simvastatin+fludarabine and simvastatin+cladribine had a synergic effect in inducing apoptosis. Interestingly, the rate of apoptosis caused by simvastatin alone and in combination was independent of markers of disease progression like ZAP-70 and CD38 expression or clinical stage according to Rai classification. We have also seen an increase in γH2AX expression in parallel with activation of ATM in most of the analyzed samples. The results suggest that simvastatin can be used in the treatment of CLL patients as a single agent as well as in combination with purine analogs, being equally effective both in high-risk and good-prognosis patients. One of the mechanisms of simvastatin action is inducing DNA damage that ultimately leads to apoptosis