Month: August 2019

BIRC6 may be a suitable target for inhibition of autophagy-mediated cell survival and for treatment resistance in prostate cancer cells. Targeting autophagy has already been shown to sensitize a variety of cancers to treatment, including prostate cancer. Treatment of prostate cancer cells deficient in argininosuccinate synthetase with siRNAs targeting Beclin-1 or chloroquine, has been BAY 73-4506 reported to inhibit autophagy and increase the sensitivity of such cells to treatment with the anti-cancer agent ADI-PEG20, a pegylated arginine deiminase. In view of the above, it is proposed that targeting BIRC6 in prostate cancer can be used to inhibit autophagy, and thus, autophagy-mediated treatment resistance. This strategy represents a novel approach to sensitizing prostate cancer cells to therapy. However, further work is needed to determine the effectiveness of targeting BIRC6 as a strategy to control autophagy-mediated treatment resistance. The finding that treatment of LNCaP cells with doxorubicin results in a dramatic loss of BIRC6 expression, is consistent with a previous report demonstrating that apoptosis induced by topoisomerase inhibitors etoposide and camptothecin was associated with degradation of BIRC6 protein. The authors concluded that degradation of BIRC6 appears to be a general event during initiation of apoptosis. In the present study we further demonstrated that the doxorubicin-induced BIRC6 decline precedes PARP cleavage, suggesting that BIRC6 may play a causative role in apoptosis induction upon doxorubicin treatment. In addition, our finding that specific siRNAinduced reduction of BIRC6 protein expression in LNCaP cells leads to apoptosis, as indicated by marker expression, raises the possibility that the apoptotic effect of doxorubicin and perhaps of the topoisomerase inhibitors, is based, at least in part, on a reduction of BIRC6 protein expression. This suggests a novel mechanism by which doxorubicin may induce apoptosis by triggering loss of BIRC6. The increase in BIRC6 expression in Gleason 6�C8 clinical prostate cancers, including castration-resistant cancers, suggests an important role for this protein in the development and progression of the disease. In view of the prosurvival function of BIRC6 in prostate cancer cells and in other systems, elevations in the expression of BIRC6 are expected to provide a cytoprotective advantage to prostate cancer cells and promote prostate cancer development and progression. The anti-apoptotic role of BIRC6 could likely be involved in the development of castration-resistant prostate cancer and underlie therapy resistance in this advanced form of the disease. While the large majority of prostate cancer tissues exhibited BIRC6 protein elevations, not all stages of the disease expressed elevated levels of the protein. The expression of BIRC6 over the course of prostate cancer progression reached peak levels in Gleason score 7 cancers but had levels in Gleason score 9�C10 prostate cancers that were similar to those of benign tissues. Our finding is consistent with an earlier study focusing on IAP expressions in various stages of prostate cancer tissues, which demonstrated that increased expression of IAP. While BIRC6 expression may not be required in advanced stage prostate cancer, the resurge of BIRC6 in CRPC may LY2109761 suggest that cellular stress, e.g. castration, may trigger the overexpression of cytoprotective BIRC6.

Nevertheless, the elevation of BIRC6 in castrationresistant cancers suggests that the protein may provide a potential therapeutic target for the disease. Targeting BIRC6 as an inhibitor of apoptosis and potential enhancer of autophagy may be useful for sensitizing prostate cancer cells to anti-cancer therapies. It may be noted that drugs targeting other IAP family members, e.g., XIAP and survivin, have shown promise for use as sensitizers in prostate cancer therapy. Antisense inhibitors of XIAP led to sensitization of castration-resistant prostate cancer cells to cisplatin and TNFrelated apoptosis-inducing ligand ; in PC3 prostate cancer xenografts, they caused sustained tumor regression in combination with docetaxel. In conclusion, the present study indicates for the first time that the BIRC6 gene and its product are potentially valuable targets for treatment of prostate cancers showing elevated BIRC6 expression. Overuse of healthcare services is often cited as a driver of rising healthcare costs and is an indicator of poor quality care. Anecdotal reports and studies of select populations suggest that the use of proton pump inhibitors has increased since their introduction in the late 1980s. PPIs are used to treat gastrointestinal conditions such as MK-1775 gastroesophageal reflux disease and peptic ulcer disease or in patients who may be at high risk for these diseases. Although PPIs are generally believed to be safe medications, recent studies indicate that there may be harms associated with their use such as pneumonia and fracture. Overuse of PPIs may put patients at unnecessary risk for these harms and may also contribute to rising health care costs. One study has documented increased PPI use in the U.S. outpatient setting but to our knowledge, no studies have examined very recent national trends in PPI use in the U.S. outpatient setting, the characteristics of patients on PPIs, the characteristics of physicians who prescribe PPIs, and trends in Regorafenib indications for their use. Knowledge of these trends and characteristics may inform patients, physicians, payers, and policymakers who want to receive or deliver high quality, high value care. We used data from two national surveys of visits to ambulatory physicians to describe recent trends in the use of PPIs in the ambulatory setting. We explored potential reasons for these trends by looking at changes in the prevalence of newly prescribed PPIs, changes in histamine blocker use, and changes in the prevalence of indications for their use. The NAMCS and NHAMCS use a three-stage sampling design. The first stage is based on geographic location, the second stage identifies offices in each geographic location, and the third stage samples visits within each office. The visits sampled take place during a one week period that is randomly assigned for each practice. Between 20% and 100% of the visits that week are sampled depending on the size of the practice. The NCHS weighs each visit so that the data can be used for national estimates. Each visit weight accounts for selection probability, adjusts for nonresponse, and accounts for other factors so that the national estimates properly reflect the scope of ambulatory visits in the U.S. Physicians in the fields of anesthesiology, radiology, and pathology are excluded from the survey. Physicians who participate in the survey cannot participate again for at least three years. There has been no change in the sampling design for our study period.

Increased risk of hip fracture with long-term PPI use. Further, literature also suggests that the benefits of PPIs may be overstated particularly for Enzalutamide prophylaxis in hospitalized patients. In fact, a recent literature review found no significant difference in stress ulcer prevalence in hospitalized patients who received H2-blockers and PPIs. If, in fact, such a high percentage of patients are on PPIs for no reason, we may be putting patients at undue risk. Our study is limited primarily by the data available through the NAMCS and NHAMCS. First, our evaluation is at the visit level, not at the patient level so the percentages we report of percent of visits, not percent of patients. It is possible that there is not a direct correlation between the number of patients on PPIs and their use LY2109761 documented at the visit level or it is possible that patients on PPIs have more visits than patients not on PPIs. We did, however, look at trends across years and documented medication use, diagnoses, and symptoms at the visit level for multiple years. Second, our data are limited to what is documented from the patient record. Although the surveys do ask for over-the-counter medications, it is possible that PPIs that are available over-the-counter may not be documented in the patient record. Conversely, we may be overestimating potentially inappropriately used PPIs because not all symptoms, diagnoses, and medications are documented in NAMCS and NHAMCS. We also do not know whether PPIs were prescribed on an as needed basis or the duration of therapy. Lastly, it is possible that patients remain on PPIs long-term because of rebound symptoms when they are removed from PPIs. In summary, we found a large and significant increase in PPI use in the U.S. outpatient setting since 2002 but no increase in PPI use without a documented indication or in new PPI prescriptions. Nevertheless, the majority of patients on PPIs in all years had no documented indication. Our findings confirm what has been documented in smaller settings, older studies and international settings. Our findings suggest that inappropriate PPI use is not necessarily increasing but is still an important public health problem. While growing evidence points out important adverse associations with PPIs, they do remain effective drugs for their specified indications. More research is needed to fully understand the scope of overuse of PPIs in the ambulatory setting. These methods include more granular reviews of their use in the ambulatory setting or studies to understand why physicians prescribe and patients use PPIs when the indications are not clear. Further research should also address methods to change physician and patient decisions regarding their use. Interventions such as education, treatment guidelines, and decision support systems may address this problem. Ultimately, however, physicians, payers, policymakers, and even patients should be tasked with evaluating the need for PPI therapy, especially for long-term use. Prolapse of the pelvic organs represents failure of a complex dynamic system of pelvic floor support. Results obtained in our laboratories, together with the phenotype of lysyl oxidase-like 1 null mice, have led us to propose that pelvic organ prolapse is caused by altered balance between matrix synthesis, particularly elastic fibers, and protease activation.