Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

Background: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. Methods: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. Findings: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. Interpretation: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. Funding: The UK National Institute for Health Research Health Technology Assessment Programme

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Fatty acid esters of phloridzin induce apoptosis of human liver cancer cells through altered gene expression.

Phloridzin (phlorizin or phloretin 2'-O-glucoside) is known for blocking intestinal glucose absorption. We have investigated the anticarcinogenic effect of phloridzin and its novel derivatives using human cancer cell lines. We have synthesised novel acylated derivatives of phloridzin with six different long chain fatty acids by regioselective enzymatic acylation using Candida Antarctica lipase B. The antiproliferative effects of the new compounds were investigated in comparison with the parent compounds, phloridzin, aglycone phloretin, the six free fatty acids and chemotherapeutic drugs (sorafenib, doxorubicin and daunorubicin) using human hepatocellular carcinoma HepG2 cells, human breast adenocarcinoma MDA-MB-231 cells and acute monocytic leukemia THP-1 cells along with normal human and rat hepatocytes. The fatty acid esters of phloridzin inhibited significantly the growth of the two carcinoma and leukemia cells while similar treatment doses were not toxic to normal human or rat hepatocytes. The antiproliferative potency of fatty esters of phloridzin was comparable to the potency of the chemotherapeutic drugs. The fatty acid esters of phloridzin inhibited DNA topoisomerases IIα activity that might induce G0/G1 phase arrest, induced apoptosis via activation of caspase-3, and decreased ATP level and mitochondrial membrane potential in HepG2 cells. Based on the high selectivity on cancer cells, decosahexaenoic acid (DHA) ester of phloridzin was selected for gene expression analysis using RT2PCR human cancer drug target array. Antiproliferative effect of DHA ester of phloridzin could be related to the down regulation of anti-apoptotic gene (BCL2), growth factor receptors (EBFR family, IGF1R/IGF2, PDGFR) and its downstream signalling partners (PI3k/AKT/mTOR, Ras/Raf/MAPK), cell cycle machinery (CDKs, TERT, TOP2A, TOP2B) as well as epigenetics regulators (HDACs). These results suggest that fatty esters of phloridzin have potential chemotherapeutic effects mediated through the attenuated expression of several key proteins involved in cell cycle regulation, DNA topoisomerases IIα activity and epigenetic mechanisms followed by cell cycle arrest and apoptosis

Response surface optimization for recovery of polyphenols and carotenoids from leaves of Centella asiatica using an ethanol‐based solvent system

Response surface methodology has been used to optimize the extraction conditions for total phenolics and carotenoids from leaves of Centella asiatica. Solvent concentration (30%–100%), extraction temperature (30–60°C), and extraction time (30–90 min) were used as the independent variables. A second‐order polynomial model produced a satisfactory fitting of the experimental data with regard to total phenolics (R2 = 84.75%, p &lt; 0.004) and carotenoid (R2 = 78.74, p &lt; 0.019) contents. The optimum extraction conditions of ethanol concentration, extraction temperature, and extraction time for phenolics were 6.1%, 70.2°C, and 110.5 min and for carotenoids, the optimum parameters were 100%, 70.2°C, and 110.5 min, respectively. The optimal predicted contents for total phenolics (9.03 mg Gallic Acid Equivalent (GAE)/g DW) and carotenoid (8.74 mg/g DW) values in the extracts were agreed with the experimental values obtained with optimum extraction conditions for each response, and also they possess significantly higher total antioxidant capacity

Influence of Boiling, Steaming and Frying of Selected Leafy Vegetables on the In Vitro Anti-inflammation Associated Biological Activities

The aim of the present study was to evaluate the effect of cooking (boiling, steaming, and frying) on anti-inflammation associated properties in vitro of six popularly consumed green leafy vegetables in Sri Lanka, namely: Centella asiatica, Cassia auriculata, Gymnema lactiferum, Olax zeylanica, Sesbania grnadiflora, and Passiflora edulis. The anti-inflammation associated properties of methanolic extracts of cooked leaves were evaluated using four in vitro biological assays, namely, hemolysis inhibition, proteinase inhibition, protein denaturation inhibition, and lipoxygenase inhibition. Results revealed that the frying of all the tested leafy vegetables had reduced the inhibition abilities of protein denaturation, hemolysis, proteinase, and lipoxygenase activities when compared with other food preparation methods. Steaming significantly increased the protein denaturation and hemolysis inhibition in O. zeylanica and P. edulis. Steaming of leaves increased inhibition activity of protein denaturation in G. lactiferum (by 44.8%) and P. edulis (by 44%); hemolysis in C. asiatica, C. auriculata, and S. grandiflora; lipoxygenase inhibition ability in P. edulis (by 50%), C. asiatica (by 400%), and C. auriculata leaves (by 250%); proteinase inhibition in C. auriculata (100%) when compared with that of raw leaves. In general, steaming and boiling in contrast to frying protect the health-promoting properties of the leafy vegetables

Activity of human topoisomerase II of HepG2 cells.

<p>The cells were incubated with 100 µM of fatty acid esters of phloridzin (Pz) in comparison with parent compounds phloridzin, phloretin (aglycone) or sorafenib for 24 h. A. Lanes 1 Pz-oleic acid, lane 2: Pz-stearic acid, lane 3: Pz-linoleic acid, lane 4: Pz-α-linolenic acid, lane 5: Pz-DHA, lane 6: Pz-EPA, lane 7: phloridzin, lane 8: sorafenib, and lane 9: phloretin. The data are representative of three separate, independent experiments. B. Percentage inhibition.</p