Isochondodendrine and 2[prime or minute]-norcocsuline: additional alkaloids from Triclisia subcordata induce cytotoxicity and apoptosis in ovarian cancer cell lines

Triclisia subcordata Oliv (Menispermeaceae) is used in herbal medicine for the treatment of cancer and other diseases in Africa. This study aims to isolate minor alkaloids present in this plant and assay their cytotoxic activities. Isochondodendrine and 2[prime or minute]-norcocsuline as two minor alkaloids together with the abundant cycleanine were isolated and identified by mass spectrometry and NMR spectroscopy. Both isochondodendrine and 2[prime or minute]-norcocsuline exhibited in vitro cytotoxicity in four ovarian cancer cell lines (A2780, IGROV-1, OVCAR-8, and OVCAR-4) with IC50 ranges of 3.5-17 [small mu ]M and 0.8-6.2 [small mu ]M respectively. These alkaloids showed mostly slightly weaker potencies when tested using normal human ovarian epithelial cells, IC50 = 10.5 +/- 1.2 [small mu ]M and 8.0 +/- 0.2 [small mu ]M for isochondodendrine and 2[prime or minute]-norcocsuline, respectively. The alkaloids induced apoptosis in ovarian cancer cells because they activated caspases 3/7, induced cleavage of PARP, increased the subG1 population in cell cycle analysis and increased Annexin V/propidium iodide staining. These observations suggest that isochondodendrine and 2[prime or minute]-norcocsuline contributing to the cytotoxic activity of T. subcordata may be suitable starting points for the future development of novel therapeutics to treat ovarian cancer

Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer

<p>Abstract</p> <p>Background</p> <p>Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing.</p> <p>Results</p> <p>The therapy must be initiated at least one day prior to surgical removal of the primary tumor and kept at a Down syndrome level perhaps indefinitely. That means the drug must have virtually no toxicity and not interfere meaningfully with wound healing. This specifically excludes drugs that significantly inhibit the VEGF pathway since that is important for wound healing and because these agents have some toxicity. Endostatin is apparently non-toxic and does not significantly interfere with wound healing since Down syndrome patients have no abnormal wound healing problems.</p> <p>Conclusion</p> <p>We propose a therapy for early stage breast cancer consisting of Endostatin at or above Down syndrome levels starting at least one day before surgery and continuing at that level. This should prevent micrometastatic angiogenesis resulting from surgery or at any time later. Adjuvant chemotherapy or hormone therapy should not be necessary. This can be continued indefinitely since there is no acquired resistance that develops, as happens in most cancer therapies.</p

Are we under-utilizing the talents of primary care personnel? A job analytic examination

BACKGROUND: Primary care staffing decisions are often made unsystematically, potentially leading to increased costs, dissatisfaction, turnover, and reduced quality of care. This article aims to (1) catalogue the domain of primary care tasks, (2) explore the complexity associated with these tasks, and (3) examine how tasks performed by different job titles differ in function and complexity, using Functional Job Analysis to develop a new tool for making evidence-based staffing decisions. METHODS: Seventy-seven primary care personnel from six US Department of Veterans Affairs (VA) Medical Centers, representing six job titles, participated in two-day focus groups to generate 243 unique task statements describing the content of VA primary care. Certified job analysts rated tasks on ten dimensions representing task complexity, skills, autonomy, and error consequence. Two hundred and twenty-four primary care personnel from the same clinics then completed a survey indicating whether they performed each task. Tasks were catalogued using an adaptation of an existing classification scheme; complexity differences were tested via analysis of variance. RESULTS: Objective one: Task statements were categorized into four functions: service delivery (65%), administrative duties (15%), logistic support (9%), and workforce management (11%). Objective two: Consistent with expectations, 80% of tasks received ratings at or below the mid-scale value on all ten scales. Objective three: Service delivery and workforce management tasks received higher ratings on eight of ten scales (multiple functional complexity dimensions, autonomy, human error consequence) than administrative and logistic support tasks. Similarly, tasks performed by more highly trained job titles received higher ratings on six of ten scales than tasks performed by lower trained job titles. Contrary to expectations, the distribution of tasks across functions did not significantly vary by job title. CONCLUSION: Primary care personnel are not being utilized to the extent of their training; most personnel perform many tasks that could reasonably be performed by personnel with less training. Primary care clinics should use evidence-based information to optimize job-person fit, adjusting clinic staff mix and allocation of work across staff to enhance efficiency and effectiveness

Cationic Amino Acid Transporter 2 Enhances Innate Immunity during Helicobacter pylori Infection

Once acquired, Helicobacter pylori infection is lifelong due to an inadequate innate and adaptive immune response. Our previous studies indicate that interactions among the various pathways of arginine metabolism in the host are critical determinants of outcomes following infection. Cationic amino acid transporter 2 (CAT2) is essential for transport of l-arginine (L-Arg) into monocytic immune cells during H. pylori infection. Once within the cell, this amino acid is utilized by opposing pathways that lead to elaboration of either bactericidal nitric oxide (NO) produced from inducible NO synthase (iNOS), or hydrogen peroxide, which causes macrophage apoptosis, via arginase and the polyamine pathway. Because of its central role in controlling L-Arg availability in macrophages, we investigated the importance of CAT2 in vivo during H. pylori infection. CAT2−/− mice infected for 4 months exhibited decreased gastritis and increased levels of colonization compared to wild type mice. We observed suppression of gastric macrophage levels, macrophage expression of iNOS, dendritic cell activation, and expression of granulocyte-colony stimulating factor in CAT2−/− mice suggesting that CAT2 is involved in enhancing the innate immune response. In addition, cytokine expression in CAT2−/− mice was altered from an antimicrobial Th1 response to a Th2 response, indicating that the transporter has downstream effects on adaptive immunity as well. These findings demonstrate that CAT2 is an important regulator of the immune response during H. pylori infection

Precise mapping of the magnetic field in the CMS barrel yoke using cosmic rays

This is the Pre-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2010 IOPThe CMS detector is designed around a large 4 T superconducting solenoid, enclosed in a 12 000-tonne steel return yoke. A detailed map of the magnetic field is required for the accurate simulation and reconstruction of physics events in the CMS detector, not only in the inner tracking region inside the solenoid but also in the large and complex structure of the steel yoke, which is instrumented with muon chambers. Using a large sample of cosmic muon events collected by CMS in 2008, the field in the steel of the barrel yoke has been determined with a precision of 3 to 8% depending on the location.This work is supported by FMSR (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); Academy of Sciences and NICPB (Estonia); Academy of Finland, ME, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); PAEC (Pakistan); SCSR (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MST and MAE (Russia); MSTDS (Serbia); MICINN and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); TUBITAK and TAEK (Turkey); STFC (United Kingdom); DOE and NSF (USA)