AMP-activated protein kinase (AMPK) as a potential therapeutic target independent of PI3K/Akt signaling in prostate cancer

Depletion of cellular energy activates the AMP-activated protein kinase (AMPK) to favor energy-producing catabolic processes during tumorigenesis. Using a panel of in vitro cell lines and resected tumors, we investigated the therapeutic value of manipulating AMPK in prostate cancer (PC). Phospho-AMPK expression was significantly elevated in human PC cells and clinical PC samples. In clinical PC, we observed a trend for increasing phospho-AMPK with increasing Gleason sum score; Phospho-AMPK expression was associated with phospho-ACC (p=0.0023). Using the paired PC3 and PC3M cells to model progressive androgen-independent PC, treatment with either 5-aminoimidazole-4-carboxamide riboside (AICAR) or A-769662 suppressed proliferation, migration and invasion in both cell lines, and down-regulated mTOR and P70S6Ki levels regardless of the Akt status. Involvement of AMPK was confirmed by Compound C (AMPK inhibitor) and siRNA-mediated AMPK silencing. Despite similar functional responses in PC3 and PC3M cells, AMPK activation resulted in sustained phospho-Akt activation in PC3M cells, but not in PC3 cells. This prompted the addition of the PI3K inhibitor LY-294002 to AICAR treatment of PC3M cells in a proliferation assay. Interestingly, we found no synergistic effects upon combined treatment. Collectively, these findings support AMPK as a potential therapeutic target independent of PI3K/Akt signalling

Anthropogenic Sulfate and Asian Dust Signals in Snow from Tien Shan, Northwest China

Snow samples were collected from a 0.5 m snowpack at Glacier No. I and near Bogda Feng, eastern Tien Shan, northwest China. Samples that were melted in the field were analyzed for chloride, nitrate, sulfate, sodium, potassium, magnesium, calcium, and microparticles. Eight samples were returned frozen and were analyzed for the above ions plus ammonium, acetate, formate, methylsulfonate, and hydrogen peroxide. There was no significant difference in measured major ion concentrations between the melted and frozen samples. Measured cations in both sets of samples were two to three times greater than measured anions. Calcium and sodium are the dominant cations while sulfate is the dominant measured anion. High ion burdens are associated with dusty layers in the snowpack, indicating that dust from the vast arid regions of central Asia is the dominant source for major ions in Tien Shan snow. The significant increase in sulfate and decrease in the cation: anion ratio in Bogda Feng snow relative to Glacier No. I snow suggest that anthropogenic emissions from Urtimqi are an important source of sulfate to precipitation downwind from the city

Incidental seminal vesicle amyloidosis observed in diagnostic prostate biopsies—are routine investigations for systemic amyloidosis warranted?

Seminal vesicle (SV) amyloidosis is a well-documented histological entity, but it is observed infrequently. Its incidence is on the rise, which is probably related to the increasing use of prostate biopsies to investigate patients with elevated serum prostate-specific antigen levels. Here, we report seven cases of incidental SV amyloidosis over a 3-year period and consider their relationship to the previously suggested aetiological factors. Based on our series, we conclude that incidental localized SV amyloidosis observed in diagnostic prostate biopsies does not warrant formal investigations for systemic amyloidosis

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research