Kwas zoledronowy stosowany przez dwa lata u Chinek z osteoporozą pomenopauzalną zwiększa gęstość mineralną tkanki kostnej i poprawia jakość życia związaną ze stanem zdrowia

Introduction: Osteoporosis is characterised by decreased bone mass and weakened bones, with an increased risk of fractures. Osteoporotic fracture, the most serious complication of osteoporosis, is related not only to lower bone mineral density (BMD), but also falls. Osteoporosis and fractures are associated with a decreased health-related quality of life (HRQL). Zoledronic acid (ZOL) is an intravenous once-yearly bisphosphonate that has been shown to be effective and safe in improving BMD and reducing fracture risk in controlled clinical trials.Material and methods: In this self-controlled, prospective trial, 220 postmenopausal women with osteoporosis (mean age 67 years) received a single infusion of ZOL 5 mg at baseline and month 12. BMD, HRQL and Fall Index (FI) were measured at baseline, and months 12 and 24 (before each use of ZOL). The main outcome measures were the changes in lumbar spine and hip BMD and the changes in HRQL, the Short Form-36 questionnaire (SF-36). Additional comparisons were based on the FI. LSD multiple comparisons were used in the comparisons of BMD, SF-36 domain scores and FI.Results: The patients had significantly higher L1-4, total hip, femoral neck and trochanter BMD (P < 0.05) with improved HRQL (P < 0.05) over two years of treatment of once-yearly ZOL 5mg. FI was reduced (P < 0.05) with oral daily elemental calcium and vitamin D in the treatment course.Conclusions: ZOL improves BMD and HRQL, especially in the physical aspects, over two years of treatment in women with postmenopausal osteoporosis, and can help improve balance ability. (Endokrynol Pol 2014; 65 (2): 96–104)Wstęp: Osteoporoza to schorzenie cechujące się obniżeniem masy kostnej i wytrzymałości mechanicznej kości z towarzyszącym zwiększeniem ryzyka złamań. Złamania osteoporotyczne, będące najpoważniejszym powikłaniem osteoporozy, wiążą się nie tylko z obniżoną gęstością mineralną tkanki kostnej (BMD, bone mineral density) ale też z upadkami. Z osteoporozą i złamaniami wiąże się obniżenie jakości życia związanej ze stanem zdrowia (HRQoL, health-related quality of life). Kwas zoledronowy (ZOL) to bisfosfonian w postaci dożylnej przeznaczony do podawania raz w roku, w przypadku którego w badaniach klinicznych z grupą kontrolną wykazano skuteczność i bezpieczeństwo w zwiększaniu BMD i zmniejszaniu ryzyka złamań.Materiał i metody: Autorzy przeprowadzili samodzielnie kontrolowane, prospektywne badanie z udziałem 220 znajdujących się w wieku pomenopauzalnym kobiet z osteoporozą (średnia wieku 67 lat), które otrzymały jednorazowo roztwór ZOL w dawce 5 mg na początku badania i 12 miesięcy później. Na początku badania, w 12. miesiącu i w 24. miesiącu badania (za każdym razem przed podaniem ZOL) oznaczano BMD, HRQoL i wskaźnik upadków (FI, fall index). Główne punkty końcowe obejmowały zmiany BMD w odcinku lędźwiowym kręgosłupa i BMD w okolicy biodra, a także zmiany HRQoL w kwestionariuszu SF-36. Dodatkowe porównania będą oparte na FI. W porównaniach wartości BMD, liczby punktów w poszczególnych domenach kwestionariusza SF-36 i wartości FI zastosowano metodę wielokrotnych porównań najmniejszej istotnej różnicy.Wyniki: U pacjentek stwierdzono znamiennie większe wartości BMD na poziomie L1–4, BMD w całkowitym obszarze biodra, BMD w obrębie szyjki kości udowej oraz BMD w obrębie krętarza (p < 0,05) oraz znamienną poprawę HRQoL (p < 0,05) w okresie 2 lat leczenia podawanym raz w roku ZOL w dawce 5 mg. Stwierdzono też zmniejszenie FI (p < 0,05) dzięki codziennemu przyjmowaniu wapnia i witaminy D w okresie leczenia.Wnioski: Stosowanie ZOL prowadzi do poprawy BMD i HRQoL, zwłaszcza w aspekcie fizycznym, w okresie 2 lat stosowania u kobiet z osteoporozą pomenopauzalną, i może przyczyniać się do poprawy zdolności utrzymania równowagi. (Endokrynol Pol 2014; 65 (2): 96–104

Arsenic speciation in saliva of acute promyelocytic leukemia patients undergoing arsenic trioxide treatment

Arsenic trioxide has been successfully used as a therapeutic in the treatment of acute promyelocytic leukemia (APL). Detailed monitoring of the therapeutic arsenic and its metabolites in various accessible specimens of APL patients can contribute to improving treatment efficacy and minimizing arsenic-induced side effects. This article focuses on the determination of arsenic species in saliva samples from APL patients undergoing arsenic treatment. Saliva samples were collected from nine APL patients over three consecutive days. The patients received 10 mg arsenic trioxide each day via intravenous infusion. The saliva samples were analyzed using high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry. Monomethylarsonous acid and monomethylmonothioarsonic acid were identified along with arsenite, dimethylarsinic acid, monomethylarsonic acid, and arsenate. Arsenite was the predominant arsenic species, accounting for 71.8 % of total arsenic in the saliva. Following the arsenic infusion each day, the percentage of methylated arsenicals significantly decreased, possibly suggesting that the arsenic methylation process was saturated by the high doses immediately after the arsenic infusion. The temporal profiles of arsenic species in saliva following each arsenic infusion over 3 days have provided information on arsenic exposure, metabolism, and excretion. These results suggest that saliva can be used as an appropriate clinical biomarker for monitoring arsenic species in APL patients. [Figure: see text

Arsenic on the Hands of Children after Playing in Playgrounds

Increasing concerns over the use of wood treated with chromated copper arsenate (CCA) in playground structures arise from potential exposure to arsenic of children playing in these playgrounds. Limited data from previous studies analyzing arsenic levels in sand samples collected from CCA playgrounds are inconsistent and cannot be directly translated to the amount of children’s exposure to arsenic. The objective of this study was to determine the quantitative amounts of arsenic on the hands of children in contact with CCA-treated wood structures or sand in playgrounds. We compared arsenic levels on the hands of 66 children playing in eight CCA playgrounds with levels of arsenic found on the hands of 64 children playing in another eight playgrounds not constructed with CCA-treated wood. The children’s age and duration of playtime were recorded at each playground. After play, children’s hands were washed in a bag containing 150 mL of deionized water. Arsenic levels in the hand-washing water were quantified by inductively coupled plasma mass spectrometry. Our results show that the ages of the children sampled and the duration of play in the playgrounds were similar between the groups of CCA and non-CCA playgrounds. The mean amount of water-soluble arsenic on children’s hands from CCA playgrounds was 0.50 μg (range, 0.0078–3.5 μg). This was significantly higher (p < 0.001) than the mean amount of water-soluble arsenic on children’s hands from non-CCA playgrounds, which was 0.095 μg (range, 0.011–0.41 μg). There was no significant difference in the amount of sand on the children’s hands and the concentration of arsenic in the sand between the CCA and non-CCA groups. The higher values of arsenic on the hands of children playing in the CCA playgrounds are probably due to direct contact with CCA-treated wood. Washing hands after play would reduce the levels of potential exposure because most of the arsenic on children’s hands was washed off with water. The maximum amount of arsenic on children’s hands from the entire group of study participants was < 4 μg, which is lower than the average daily intake of arsenic from water and food

Increased Mortality Associated with Well-Water Arsenic Exposure in Inner Mongolia, China

We conducted a retrospective mortality study in an Inner Mongolian village exposed to well water contaminated by arsenic since the 1980s. Deaths occurring between January 1, 1997 and December 1, 2004 were classified according to underlying cause and water samples from household wells were tested for total arsenic. Heart disease mortality was associated with arsenic exposure, and the association strengthened with time exposed to the water source. Cancer mortality and all-cause mortality were associated with well-water arsenic exposure among those exposed 10–20 years. This is the first study to document increased arsenic-associated mortality in the Bayingnormen region of Inner Mongolia

Reactive Oxygen Species Hydrogen Peroxide Mediates Kaposi's Sarcoma-Associated Herpesvirus Reactivation from Latency

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H2O2. Mechanistically, H2O2 induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H2O2 scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival