Targeting Vacuolar H+-ATPases as a New Strategy against Cancer

Abstract Growing evidence suggests a key role of tumor acidic microenvironment in cancer development, progression, and metastasis. As a consequence, the need for compounds that specifically target the mechanism(s) responsible for the low pH of tumors is increasing. Among the key regulators of the tumor acidic microenvironment, vacuolar H+-ATPases (V-ATPases) play an important role. These proteins cover a number of functions in a variety of normal as well as tumor cells, in which they pump ions across the membranes. We discuss here some recent results showing that a molecular inhibition of V-ATPases by small interfering RNA in vivo as well as a pharmacologic inhibition through proton pump inhibitors led to tumor cytotoxicity and marked inhibition of human tumor growth in xenograft models. These results propose V-ATPases as a key target for new strategies in cancer treatment. [Cancer Res 2007;67(22):10627–30

Diaqua­bis­[4-(4H-1,2,4-triazol-4-yl)benzoato-κ2 O,O′]nickel(II)

In the title compound, [Ni(C9H6N3O2)2(H2O)2], the NiII atom lies on a twofold rotation axis and is six-coordinated by two bidentate chelating 4-(1,2,4-triazol-4-yl)benzoate ligands and two water mol­ecules in a distorted octa­hedral geometry. Inter­molecular O—H⋯N hydrogen bonds link the complex mol­ecules into a two-dimensional network parallel to (010)

Effects of facet joint degeneration on stress alterations in cervical spine C5–C6: A finite element analysis

It has been demonstrated that articular facet degeneration can cause local strain alterations and induce neck pain. This study aims to quantify the biomechanical effects of normal and degenerated C5–C6 articular facets, and evaluate the correlation of mechanical strain between healthy and degenerated spine. A 3-dimensional finite element (FE) model of the C5–C6 cervical spine was developed [Model 0 (M0)]. The asymmetric models of C5–C6 bilateral articular facet joint were established separately to mimic articular facet joint degeneration. The capsule ligament stiffness of C5–C6 unilateral facet joint was altered with minimum and maximum threshold to simulate capsule ligaments' lesion and calcification [Model 1 (M1) and Model 2 (M2), respectively]. Besides, the cervical C5–C6 unilateral articular facet joint direction was changed by 5° and 10° forward to imitate the moderate joint hyperplasia and severe osteophyte (Model 3 and Model 4 respectively). M1 increased the rotation range of ipsilateral side (left), while M2 reduced, and both had limited effect on the contralateral side (right). The angle increased in Model 3 (M3) (61°) and Model 4 (M4) (55°) comparing to M0 during the axial rotation, and the angle of M4 was larger. M3 and M4 increased the nucleus pulposus pressure with and without controlled angular displacement during axial rotation. The pressure of nucleus pulpous increased during M1 rotating to the abnormal side but decreased when rotating to the other side, but the results of M2 were opposite. The capsule ligament stiffness made an impact on segmental mobility and vertebral spatial position, and the sagittal angle of articular facet joint exerted an influence on disc pressure distribution

The rising death burden of atrial fibrillation and flutter in low-income regions and younger populations

ObjectiveThe aim of the study was to depict the global death burden of atrial fibrillation and/or flutter (AFF) between 1990 and 2019 and predict this burden in the next decade.MethodsWe retrieved annual death data on cases and rates of AFF between 1990 and 2019 from the Global Burden of Disease (GBD) Study 2019 and projected the trends for 2020–2029 by developing the Bayesian age-period-cohort model.ResultsThe global number of deaths from AFF increased from 117,038.00 in 1990 to 315,336.80 in 2019. This number is projected to reach 404,593.40 by 2029. The age-standardized mortality rates (ASMRs) of AFF have increased significantly in low- to middle-sociodemographic index (SDI) regions, which will surpass that in high SDI regions and reach above 4.60 per 100,000 by 2029. Globally, women have a higher ASMR than men, which is largely attributed to disproportionately higher mortality in women than men in lower SDI regions. Notably, AFF-related premature mortality continues to worsen worldwide. A pandemic of high systolic blood pressure and high body mass index (BMI) largely contributes to AFF-associated death. In particular, low- to middle-SDI regions and younger populations are increasingly affected by the rapidly growing current and future risk of high BMI.ConclusionThe global death burden of AFF in low-income countries and younger generations have not been sufficiently controlled in the past and will continue growing in the future, which is largely attributed to metabolic risks, particularly for high BMI. There is an urgent need to implement effective measures to control AFF-related mortality

Expression of Dickkopf-1 and Beta-Catenin Related to the Prognosis of Breast Cancer Patients with Triple Negative Phenotype

BACKGROUND AND AIM: We investigated the prognostic importance of dickkopf-1(DKK1) and beta-catenin expression in triple negative breast cancers. METHODS: The expression of DKK1 and beta-catenin was evaluated in breast cell lines using RT-PCR and western blot. Immunohistochemistry was used to characterize the expression pattern of DKK1 and beta-catenin in 85 triple negative breast cancers and prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression modeling. RESULTS: The expression of DKK1 was confirmed in hormone-resistant breast cell lines MDA-MB-231, MDA-MB-231-HM and MDA-MB-435. Expression of DKK1 in triple negative breast cancers correlated with cytoplasmic/nuclear beta-catenin (p = 0.000). Elevated expression of DKK1 and cytoplasmic/nuclear beta-catenin in triple negative cancers indicate poor outcome of patients. DKK1 was also a prognostic factor for patients with earlier stage or no lymph node metastasis. CONCLUSION: DKK1 together with beta-catenin might be important prognostic factors in triple negative breast carcinoma. DKK1 might be a valuable biomarker in predicting the prognosis of patients with earlier stage or no lymph node metastasis. It is possible that through further understanding of the role of Wnt/beta-catenin pathway activation, beta-catenin would be a potential therapeutic target for the triple negative breast cancer

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