scholarly journals Turnover modulates the need for a cost of resistance in adaptive therapy

2020 ◽  
Author(s):  
Maximilian Strobl ◽  
Jeffrey West ◽  
Yannick Viossat ◽  
Mehdi Damaghi ◽  
Mark Robertson-Tessi ◽  
...  
Keyword(s):  
Carrying Capacity ◽  
Selection Criterion ◽  
Standard Of Care ◽  
Therapy Resistance ◽  
Resistant Cell ◽  
Necessary Condition ◽  
Continuous Therapy ◽  
Cost Of Resistance ◽  
The Impact ◽  
Adaptive Therapy

Abstract“Control and conquer” - this is the philosophy behind adaptive therapy, which seeks to exploit intra-tumoural competition to avoid, or at least, delay the emergence of therapy resistance in cancer. Motivated by promising results from theoretical, experimental and, most recently, a clinical study in prostate cancer, there is an increasing interest in extending this approach to other cancers. As such, it is urgent to understand the characteristics of a cancer which determine whether it will respond well to adaptive therapy, or not. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this paper, we study a simple competition model between sensitive & resistant cell populations to investigate whether the presence of a cost is a necessary condition for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. We find that for tumours close to their environmental carrying capacity such a cost of resistance is not required. However, for tumours growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, we show that in such cases it is important to consider the cell turnover in the tumour and we discuss its role in modulating the impact of a cost of resistance. Overall, our work helps to clarify under which circumstances adaptive therapy may be beneficial, and suggests that turnover may play an unexpectedly important role in the decision making process.

scholarly journals The impact of the spatial heterogeneity of resistant cells and fibroblasts on treatment response

2021 ◽  
Author(s):  
Masud M.A ◽  
Jae-Young Kim ◽  
Cheol-Ho Pan ◽  
Eunjung Kim
Keyword(s):  
Cancer Cell ◽  
Spatial Competition ◽  
Adaptive Strategy ◽  
Maximum Tolerated Dose ◽  
Resistant Cell ◽  
Drug Resistant ◽  
Continuous Therapy ◽  
The Impact ◽  
Adaptive Therapy ◽  
Resistant Cells

A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumor's volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Cancer cell migration and increased carrying capacity accelerate the progression of the tumor under both types of treatments by reducing the spatial competition. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. Our simulations show that the spatial architecture of fibroblasts modulates the benefits of adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy in multiple metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations.

scholarly journals Understanding the potential benefits of adaptive therapy for metastatic melanoma

2020 ◽  
Author(s):  
Eunjung Kim ◽  
Joel S. Brown ◽  
Zeynep Eroglu ◽  
Alexander R.A. Anderson
Keyword(s):  
Mathematical Models ◽  
Underlying Mechanism ◽  
Resistant Cell ◽  
Phenotypic Switching ◽  
Patient Specific ◽  
Optimal Timing ◽  
Initial Population ◽  
Continuous Therapy ◽  
Adaptive Therapy ◽  
Resistant Cells

AbstractAdaptive therapy is an evolution-based treatment approach that aims to maintain tumor volume by employing minimum effective drug doses or timed drug holidays. For successful adaptive therapy outcomes, it is critical to find the optimal timing of treatment switch points. Mathematical models are ideal tools to facilitate adaptive therapy dosing and switch time points. We developed two different mathematical models to examine interactions between drug-sensitive and resistant cells in a tumor. The first model assumes genetically fixed drug-sensitive and resistant populations that compete for limited resources. Resistant cell growth is inhibited by sensitive cells. The second model considers phenotypic switching between drug-sensitive and resistant cells. We calibrated each model to fit melanoma patient biomarker changes over time and predicted patient-specific adaptive therapy schedules. Overall, the models predict that adaptive therapy would have delayed time to progression by 6-25 months compared to continuous therapy with dose rates of 6%-74% relative to continuous therapy. We identified predictive factors driving the clinical time gained by adaptive therapy. The first model predicts 6-20 months gained from continuous therapy when the initial population of sensitive cells is large enough, and when the sensitive cells have a large competitive effect on resistant cells. The second model predicts 20-25 months gained from continuous therapy when the switching rate from resistant to sensitive cells is high and the growth rate of sensitive cells is low. This study highlights that there is a range of potential patient specific benefits of adaptive therapy, depending on the underlying mechanism of resistance, and identifies tumor specific parameters that modulate this benefit.

Reducing the Risks of the Financial Sector to Ensure Sustainable Growth of the Russian Еconomy

2019 ◽  
Vol 12 (3) ◽  
pp. 86-92
Author(s):  
T. I. Minina ◽  
V. V. Skalkin
Keyword(s):  
Economic Growth ◽  
Monetary Policy ◽  
Financial Sector ◽  
Developed Countries ◽  
Sustainable Growth ◽  
Necessary Condition ◽  
Real Sector ◽  
Financial Instruments ◽  
The Real ◽  
The Impact

Russia’s entry into the top five economies of the world depends, among other things, on the development of the financial sector, being a necessary condition for the economic growth of a developed macroeconomic and macro-financial system. The financial sector represents a system of relationships for the effective collection and distribution of economic resources, their deployment according to public demand, reducing the risk of overproduction and overheating of the economy.Therefore, the subject of the research is the financial sector of the Russian economy.The purpose of the research was to formulate an approach to alleviating the risks of increasing financial costs in the real sector of the economy by reducing the impact of endogenous risks expressed as financial asset “bubbles” using the experience of developed countries in the monetary policy.The paper analyzes a macroeconomic model applied to the financial sector. It is established that the economic growth is determined by the growth and, more important, the qualitative development of the financial sector, which leads to two phenomena: overproduction in the real sector and an increase in asset prices in the financial sector, with a debt load in both the real and financial sectors. This results in decreasing the interest rate of the mega-regulator to near-zero values. In this case, since the mechanisms of the conventional monetary policy do not work, the unconventional monetary policy is used when the mega-regulator buys out derivative financial instruments from systemically important institutions. As a conclusion, given deflationally low rates, it is proposed that the megaregulator should issue its own derivative financial instruments and place them in the financial market.

Workplace Spirituality and Organizational Commitment: An Empirical Exploration

2017 ◽  
Vol 10 (02) ◽  
Author(s):  
Naval Garg
Keyword(s):  
Organizational Commitment ◽  
Sense Of Community ◽  
Workplace Spirituality ◽  
Necessary Condition ◽  
Continuance Commitment ◽  
Six Dimensions ◽  
The Impact ◽  
Structured Questionnaire

The paper aims to empirically explore the impact of six dimensions of workplace spirituality on three types of organizational commitment. Six dimensions of workplace spirituality used for the study are Swadharma, Lokasangraha, authenticity, sense of community, Karma capital and Krityagyata. Components of organizational commitment are affective, normative and continuance commitment. A sample of 541 employees working in various organizations was given a structured questionnaire. Correlations, regressions and Necessary Condition Analysis(NCA) were carried out. The paper has enriched the field of workplace spirituality by contributing to existing literature via adding one more construct of Indian spirituality i.e. Krityagyata. Paper concludes that workplace spirituality climate helps in promoting organizational commitment. NCA elicited necessity of various dimensions of workplace spirituality for healthy organizational commitment.

scholarly journals Impact of simple, specific, verbal instructions on the quality of bowel preparation in hospitalized patients undergoing colonoscopy: a multicenter randomized controlled trial

2021 ◽  
Vol 09 (03) ◽  
pp. E378-E387
Author(s):  
Konstantinos Triantafyllou ◽  
Paraskevas Gkolfakis ◽  
Alexandros Skamnelos ◽  
Georgia Diamantopoulou ◽  
Athanasios Dagas ◽  
...  
Keyword(s):  
Bowel Preparation ◽  
Controlled Trial ◽  
Statistical Significance ◽  
Intervention Group ◽  
Standard Of Care ◽  
Hospitalized Patients ◽  
Verbal Instructions ◽  
Multicenter Randomized Controlled Trial ◽  
The Impact

Abstract Background and study aims Bowel preparation for colonoscopy is frequently inadequate in hospitalized patients. We explored the impact of specific verbal instructions on the quality of inpatients bowel preparation and factors associated with preparation failure. Patients and methods Randomized (1:1), two strata (mobilized vs. bedridden; 3:2) trial of consecutive inpatients from four tertiary centers, who received either specific, verbal instructions or the standard of care (SOC) ward instructions about bowel preparation. The rate of adequate bowel preparation (Boston Bowel Preparation Score [BBPS] ≥ 6, no segment < 2) comprised the primary endpoint. Mean BBPS score, good (BBPS score ≥ 7, no segment score < 2) and excellent (BBPS = 9) were among secondary endpoints. Results We randomized 300 inpatients (180 mobile) aged 71.7 ± 15.1 years in the intervention (49.7 %) and SOC (50.3 %) groups, respectively. Overall, more patients in the intervention group achieved adequate bowel preparation, but this difference did not reach statistical significance neither in the intention-to-treat [90/149 (60.4 %) vs. 82/151 (54.3 %); P = 0.29] nor in the per-protocol analysis [90/129 (69.8 %) vs. 82/132 (62.1 %); P = 0.19]. Overall BBPS score did not differ statistical significantly in the two groups, but the provision of specific verbal instructions was associated with significant higher rates of good (58.1 % vs. 43.2 %; P = 0.02) and excellent (31.8 % vs. 16.7 %; P = 0.004) bowel preparation compared to the SOC group. Administration of same-day bowel preparation and patient American Society of Anesthesiologists score > 2 were identified as risk factors for inadequate bowel preparation. Conclusions Provision of specific verbal instructions did not increase the rate of adequate bowel preparation in a population of mobilized and bedridden hospitalized patients.

scholarly journals Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Dou ◽  
Dapeng Zhao ◽  
Xiaohua Chen ◽  
Caipeng Xu ◽  
Xiaodong Jin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Aberrant Splicing ◽  
Clinical Role ◽  
Splicing Isoforms ◽  
The Impact ◽  
Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

scholarly journals Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

2021 ◽  
Vol 22 (8) ◽  
Author(s):  
Federica Pecci ◽  
Luca Cantini ◽  
Alessandro Bittoni ◽  
Edoardo Lenci ◽  
Alessio Lupi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Cancer Progression ◽  
Checkpoint Inhibitors ◽  
Tnm Classification ◽  
Standard Of Care ◽  
First Line Therapy ◽  
Combination Strategies ◽  
The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

scholarly journals Implementation of a Rapid Phenotypic Susceptibility Platform for Gram-Negative Bloodstream Infections With Paired Antimicrobial Stewardship Intervention: Is the Juice Worth the Squeeze?

2021 ◽  
Author(s):  
Evan D Robinson ◽  
Allison M Stilwell ◽  
April E Attai ◽  
Lindsay E Donohue ◽  
Megan D Shah ◽  
...  
Keyword(s):  
Median Time ◽  
Antimicrobial Stewardship ◽  
A Priori ◽  
Bloodstream Infections ◽  
Standard Of Care ◽  
Post Intervention ◽  
Gram Negative ◽  
Stewardship Program ◽  
Days Of Therapy ◽  
The Impact

Abstract Background Implementation of the Accelerate PhenoTM Gram-negative platform (RDT) paired with antimicrobial stewardship program (ASP) intervention projects to improve time to institutional-preferred antimicrobial therapy (IPT) for Gram-negative bacilli (GNB) bloodstream infections (BSIs). However, few data describe the impact of discrepant RDT results from standard of care (SOC) methods on antimicrobial prescribing. Methods A single-center, pre-/post-intervention study of consecutive, nonduplicate blood cultures for adult inpatients with GNB BSI following combined RDT + ASP intervention was performed. The primary outcome was time to IPT. An a priori definition of IPT was utilized to limit bias and to allow for an assessment of the impact of discrepant RDT results with the SOC reference standard. Results Five hundred fourteen patients (PRE 264; POST 250) were included. Median time to antimicrobial susceptibility testing (AST) results decreased 29.4 hours (P &lt; .001) post-intervention, and median time to IPT was reduced by 21.2 hours (P &lt; .001). Utilization (days of therapy [DOTs]/1000 days present) of broad-spectrum agents decreased (PRE 655.2 vs POST 585.8; P = .043) and narrow-spectrum beta-lactams increased (69.1 vs 141.7; P &lt; .001). Discrepant results occurred in 69/250 (28%) post-intervention episodes, resulting in incorrect ASP recommendations in 10/69 (14%). No differences in clinical outcomes were observed. Conclusions While implementation of a phenotypic RDT + ASP can improve time to IPT, close coordination with Clinical Microbiology and continued ASP follow up are needed to optimize therapy. Although uncommon, the potential for erroneous ASP recommendations to de-escalate to inactive therapy following RDT results warrants further investigation.

scholarly journals COVD-25. THE PARADOXICAL EFFECTS OF COVID-19 ON CANCER CARE IN THE NEURO-ONCOLOGY SETTING

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii26-ii26
Author(s):  
Nicole Cort ◽  
Alex Broom ◽  
Katherine Kenny ◽  
Alexander Page ◽  
Jennifer Durling ◽  
...  
Keyword(s):  
Cancer Care ◽  
Standard Of Care ◽  
Adult Brain ◽  
Evidence Based ◽  
Negative Consequences ◽  
Traditional Practice ◽  
Delivery Of Care ◽  
Paradoxical Effects ◽  
Oncology Care ◽  
The Impact

Abstract COVID-19 has caused ongoing interruptions to healthcare systems worldwide, shifting care to virtual platforms, and placing significant economic and logistical burdens on clinical practice. The pandemic has created uncertainty in delivering the standard of care, both in areas of cancer diagnosis and treatment, especially within neuro-oncology. Due to the pandemic, care and operational planning goals have shifted to infection prevention, modifying recommendations to decrease viral transmission and increasing telemedicine use, potentially creating a burden on implementing evidence-based medicine. These dynamics have since begun to redefine traditional practice and research regimens, impacting the comprehensive care that cancer patients can and should receive; and the enduring consequences for the delivery of healthcare. The impact of COVID-19 on oncology practice and trials might endure well beyond the short- to mid-term of the active pandemic. Therefore, these shifts must be accompanied by improved training and awareness, enhanced infrastructure, and evidence-based support to harness the positives and offset the potential negative consequences of the impacts of COVID-19 on cancer care. To address these paradoxical effects, we will conduct iterative, qualitative (face-to-face/video conference) interviews with neuro-oncology clinical and research professionals and adult brain tumor patients receiving care during the pandemic. We will capture unique aspects of oncology care: the lived, subjective, situated, and contingent accounts of patients and medical professionals, especially during a pandemic. We will also specifically compare the impact of telehealth during the pandemic on delivery of care to complex neuro-oncology patients. A summary of this in-depth, qualitative approach will result in a sophisticated understanding of neuro-oncology care on the frontline at a time of crisis, as experienced during a pandemic, to articulate best practices for future implementation.

scholarly journals Research on the Relationship between Shared Leadership and Individual Creativity-Qualitative Comparative Analysis on the Basis of Clear Set

2021 ◽  
Vol 13 (10) ◽  
pp. 5445
Author(s):  
Muyun Sun ◽  
Jigan Wang ◽  
Ting Wen
Keyword(s):  
Comparative Analysis ◽  
Environmental Factors ◽  
Shared Leadership ◽  
Management Practices ◽  
Qualitative Comparative Analysis ◽  
Necessary Condition ◽  
The Individual ◽  
The Impact ◽  
The Relationship ◽  
Sufficient And Necessary Condition

Creativity is the key to obtaining and maintaining competitiveness of modern organizations, and it has attracted much attention from academic circles and management practices. Shared leadership is believed to effectively influence team output. However, research on the impact of individual creativity is still in its infancy. This study adopts the qualitative comparative analysis method, taking 1584 individuals as the research objects, underpinned by a questionnaire-based survey. It investigates the influence of the team’s shared leadership network elements and organizational environmental factors on the individual creativity. We have found that there are six combination of conditions of shared leadership and organizational environmental factors constituting sufficient combination of conditions to increase or decrease individual creativity. Moreover, we have noticed that the low network density of shared leadership is a sufficient and necessary condition of reducing individual creativity. Our results also provide management suggestions for practical activities during the team management.

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