Cdc6 is a key replication licencing factor with a pivotal role in regulating the process of DNA replication, rendering it an important investigatory focus in tumourigenesis. Indeed, Cdc6 ...overexpression has been found to be a feature in certain tumours and has been associated as an early event in malignancies. With a focus on pancreatic cancer, there are evidence of its convergence in downstream pathways implicated in major genetic alterations found in pancreatic cancer, primarily KRAS. There is also data of its direct influence on protumourigenic processes as a transcriptional regulator, repressing the key tumour suppressor loci CDH1 (E‐Cadherin) and influencing epithelial to mesenchymal transition (EMT). Moreover, gene amplification of Cdc6 as well as of E2F (an upstream regulator of Cdc6) have also been found to be a key feature in tumours overexpressing Cdc6, further highlighting this event as a potential driver of tumourigenesis. In this review, we summarise the evidence for the role of Cdc6 overexpression in cancer, specifically that of pancreatic cancer. More importantly, we recapitulate the role of Cdc6 as part of the DNA damage response and on senescence—an important antitumour barrier—in the context of pancreatic cancer. Finally, recent emerging observations suggest that the potential of the subcellular localisation of Cdc6 in inducing senescence. In this regard, we speculate and hypothesise potentially exploitable mechanisms in the context of inducing senescence via a novel pathway involving cytoplasmic retention of Cdc6 and Cyclin E.
A major challenge in cancer treatment is predicting clinical response to anti-cancer drugs on a personalized basis. Using a pharmacogenomics database of 1,001 cancer cell lines, we trained deep ...neural networks for prediction of drug response and assessed their performance on multiple clinical cohorts. We demonstrate that deep neural networks outperform the current state in machine learning frameworks. We provide a proof of concept for the use of deep neural network-based frameworks to aid precision oncology strategies.
Display omitted
•A machine learning (ML) workflow is designed to predict drug response in cancer patients•Deep neural networks (DNNs) surpass current ML algorithms in drug response prediction•DNNs predict drug response and survival in various large clinical cohorts•DNNs capture intricate biological interactions linked to specific drug response pathways
Sakellaropoulos et al. designed a machine learning workflow to predict drug response and survival of cancer patients. All pipelines are trained on a large panel of cancer cell lines and tested in clinical cohorts. DNN outperforms other machine learning algorithms by capturing pathways that link gene expression with drug response.
The SYMPLICITY HTN-3 randomized, blinded, sham-controlled trial confirmed the safety of renal denervation (RDN), but did not meet its primary efficacy endpoint. Prior RDN studies have demonstrated ...significant and durable reductions in blood pressure. This analysis investigated factors that may help explain these disparate results.
Patients with resistant hypertension were randomized 2 : 1 to RDN (n = 364) or sham (n = 171). The primary endpoint was the difference in office systolic blood pressure (SBP) change at 6 months. A multivariable analysis identified predictors of SBP change. Additional analyses examined the influence of medication changes, results in selected subgroups and procedural factors. Between randomization and the 6-month endpoint, 39% of patients underwent medication changes. Predictors of office SBP reduction at 6 months were baseline office SBP ≥ 180 mmHg, aldosterone antagonist use, and non-use of vasodilators; number of ablations was a predictor in the RDN group. Non-African-American patients receiving RDN had a significantly greater change in office SBP than those receiving sham; -15.2 ± 23.5 vs. -8.6 ± 24.8 mmHg, respectively (P = 0.012). Greater reductions in office and ambulatory SBP, and heart rate were observed with a higher number of ablations and energy delivery in a four-quadrant pattern.
Post hoc analyses, although derived from limited patient cohorts, reveal several potential confounding factors that may partially explain the unexpected blood pressure responses in both the sham control and RDN groups. These hypothesis-generating data further inform the design of subsequent research to evaluate the potential role of RDN in the treatment of resistant hypertension. CLINICALTRIALS.GOV IDENTIFIER: NCT01418261.
BH3-mimetics: recent developments in cancer therapy Townsend, Paul A; Kozhevnikova, Maria V; Cexus, Olivier N F ...
Journal of Experimental and Clinical Cancer Research,
11/2021, Letnik:
40, Številka:
1
Journal Article, Book Review
Recenzirano
Odprti dostop
The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. ...Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.
Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to ...be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.
A major challenge in cancer treatment is predicting the clinical response to anti-cancer drugs on a personalized basis. The success of such a task largely depends on the ability to develop ...computational resources that integrate big “omic” data into effective drug-response models. Machine learning is both an expanding and an evolving computational field that holds promise to cover such needs. Here we provide a focused overview of: 1) the various supervised and unsupervised algorithms used specifically in drug response prediction applications, 2) the strategies employed to develop these algorithms into applicable models, 3) data resources that are fed into these frameworks and 4) pitfalls and challenges to maximize model performance. In this context we also describe a novel in silico screening process, based on Association Rule Mining, for identifying genes as candidate drivers of drug response and compare it with relevant data mining frameworks, for which we generated a web application freely available at: https://compbio.nyumc.org/drugs/. This pipeline explores with high efficiency large sample-spaces, while is able to detect low frequency events and evaluate statistical significance even in the multidimensional space, presenting the results in the form of easily interpretable rules. We conclude with future prospects and challenges of applying machine learning based drug response prediction in precision medicine.
•RCA was compared to natural aggregates (limerock) used in road construction.•The pH of RCA leachate ranged 10.6–12.3 while natural aggregate ranged 7.4–8.9.•Al, Ba, Cr, Mo, Ni, Sb, and Sr exceeded ...risk-based water quality thresholds.•Soil acidity neutralizes RCA leachate pH to an extent; an appropriate model is shown.•Groundwater dilution should minimize risk from pH elevation in aquifers.
Recycled Concrete Aggregate (RCA) is often used as a replacement for natural aggregate in road construction activities because of its excellent mechanical properties, and this trend should increase as more transportation departments include RCA in specifications and design manuals. Concerns raised by some engineers and contractors include impacts from leachate generated by RCA, both from transport of metals to water sources and the impact of a high pH leachate on corrosion of underlying metal drainage pipes. In this study, RCA collected from various regions of Florida exhibited pH ranging from 10.5 to 12.3. Concentrations of Al, Ba, Cr, Fe, Mo, Na, Ni, Sb, and Sr measured using batch leaching tests exceeded applicable risk-based thresholds on at least some occasions, but the concentrations measured suggest that risk to water supplies should be controlled because of dilution and attenuation. Two mechanisms of pH neutralization were evaluated. Soil acidity plays a role, but laboratory testing and chemical modeling found that at higher liquid-to-solid ratios the acidity is exhausted. If high pH leachate did reach groundwater, chemical modeling indicated that groundwater dilution and carbonation would mitigate groundwater pH effects.
The characteristic feature of healthy living organisms is the preservation of homeostasis. Compelling evidence highlight that the DNA damage response and repair (DDR/R) and immune response (ImmR) ...signaling networks work together favoring the harmonized function of (multi)cellular organisms. DNA and RNA viruses activate the DDR/R machinery in the host cells both directly and indirectly. Activation of DDR/R in turn favors the immunogenicity of the incipient cell. Hence, stimulation of DDR/R by exogenous or endogenous insults triggers innate and adaptive ImmR. The immunogenic properties of ionizing radiation, a prototypic DDR/R inducer, serve as suitable examples of how DDR/R stimulation alerts host immunity. Thus, critical cellular danger signals stimulate defense at the systemic level and vice versa. Disruption of DDR/R-ImmR cross talk compromises (multi)cellular integrity, leading to cell-cycle-related and immune defects. The emerging DDR/R-ImmR concept opens up a new avenue of therapeutic options, recalling the Hippocrates quote "everything in excess is opposed by nature."
Hypertension represents a significant global public health concern, contributing to vascular and renal morbidity, cardiovascular mortality, and economic burden. The opportunity to influence clinical ...outcomes through hypertension management is therefore paramount. Despite adherence to multiple available medical therapies, a significant proportion of patients have persistent blood pressure elevation, a condition termed resistant hypertension. Recent recognition of the importance of the renal sympathetic and somatic nerves in modulating blood pressure and the development of a novel procedure that selectively removes these contributors to resistant hypertension represents an opportunity to provide clinically meaningful benefit across wide and varied patient populations. Early clinical evaluation with catheter‐based, selective renal sympathetic denervation in patients with resistant hypertension has mechanistically correlated sympathetic efferent denervation with decreased renal norepinephrine spillover and renin activity, increased renal plasma flow, and has demonstrated clinically significant, sustained reductions in blood pressure. The SYMPLICITY HTN‐3 Trial is a pivotal study designed as a prospective, randomized, masked procedure, single‐blind trial evaluating the safety and effectiveness of catheter‐based bilateral renal denervation for the treatment of uncontrolled hypertension despite compliance with at least 3 antihypertensive medications of different classes (at least one of which is a diuretic) at maximal tolerable doses. The primary effectiveness endpoint is measured as the change in office‐based systolic blood pressure from baseline to 6 months. This manuscript describes the design and methodology of a regulatory trial of selective renal denervation for the treatment of hypertension among patients who have failed pharmacologic therapy. Clin. Cardiol. 2012. doi: 10.1002/clc.22008
Dr. Kandzari receives research/grant support and consulting honoraria from Medtronic CardioVascular, Abbott Vascular and Boston Scientific; Dr. Bhatt receives honoraria from WebMD and research grants from Amarin, AstraZeneca, Bristol‐Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, and The Medicines Company. Dr. Oparil receives research/grant support from Merck and Co., NHLBI, Novartis, and Takeda, honoraria from Daiichi Sankyo and Pfizer, and is a consultant for Bayer, Medtronic, Novartis, Pfizer, and Daiichi Sankyo. Dr. Rocha‐Singh is a consultant for Medtronic, Covidien, and Cardiosonic. Dr. Flack receives grant/research support from NIH, Daiichi Sankyo, sanofi aventis, and Novartis. He is on the Speaker Bureau for Novartis, Daiichi Sankyo, and Boehringer Ingleheim, and is a consultant for Glaxo‐Smith‐Kline, Novartis, NIH, Daiichi Sankyo, and Boehringer Ingleheim, Medtronic, and Back Beat Hypertension. Dr. Katzen is a consultant for Abbott, CRBard, Boston Scientific, WL Gore, and Medtronic. Dr. Massaro is a member of the Data Safety Monitoring Board and will no longer participate as a member of the SYMPLICITY HTN‐3 Steering Committee. Dr. Leon, Dr. O'Neill, and Dr. Esler have nothing to disclose. Dr. Negoita, Dr. Sobotka, and Craig Straley are employees of Medtronic, Inc. Dr. Bakris receives grant/clinical trial support (paid directly to University of Chicago) from Forest Laboratories, Medtronic, and Relapysa, and is a consultant to Takeda, Abbott, CVRx, Johnson & Johnson, Eli Lilly, and the Food and Drug Administration. Dr. Bakris is on the Speaker Bureau for Takeda, and the Boards of the National Kidney Foundation and the American Society of Hypertension. He is Editor for the American Journal of Nephrology and Associate Editor for Diabetes Care and Nephrology Dialysis and Transplantation.
The treatment of patients with diffuse large B-cell lymphoma (DLBCL) with cardiac comorbidity is problematic, because this group may not be able to receive anthracycline-containing ...chemoimmunotherapy. We designed a single-arm phase II multicenter trial of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) in patients considered unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity.
Sixty-one of 62 patients received R-GCVP, administered on day 1 with gemcitabine repeated on day 8 of a 21-day cycle. Median age was 76.5 years. All patients had advanced disease; 27 (43.5%) had left ventricular ejection fraction of ≤ 50%, and 35 (56.5%) had an ejection fraction of > 50% and comorbid cardiac risk factors such as ischemic heart disease, diabetes mellitus, or hypertension Corrected. Primary end point was overall response rate at the end of treatment.
Thirty-eight patients (61.3%; 95% CI, 49.2 to 73.4) achieved disease response (complete response CR, n = 18; undocumented/unconfirmed CR, n = 6; partial response, n = 14). Two-year progression-free survival for all patients was 49.8% (95% CI, 37.3 to 62.3), and 2-year overall survival was 55.8% (95% CI, 43.3 to 68.4). Thirty-four patients experienced grade ≥ 3 hematologic toxicity. There were 15 cardiac events, of which seven were grade 1 to 2, five were grade 3 to 4, and three were fatal, reflecting the poor cardiac status of the study population.
Our phase II multicenter trial showed that the R-GCVP regimen is an active, reasonably well-tolerated treatment for patients with DLBCL for whom anthracycline-containing immunochemotherapy was considered unsuitable because of coexisting cardiac disease.
PDF
