Noblestephenson2294

Several phenotypes that impact the capacity of cancer cells to survive and proliferate are dynamic. Here we used the number of cells in colonies as an assessment of fitness and devised a novel method called Dynamic Fitness Analysis (DynaFit) to measure the dynamics in fitness over the course of colony formation. DynaFit is based on the variance in growth rate of a population of founder cells compared with the variance in growth rate of colonies with different sizes. DynaFit revealed that cell fitness in cancer cell lines, primary cancer cells, and fibroblasts under unhindered growth conditions is dynamic. Key cellular mechanisms such as ERK signaling and cell-cycle synchronization differed significantly among cells in colonies after 2 to 4 generations and became indistinguishable from randomly sampled cells regarding these features. In the presence of cytotoxic agents, colonies reduced their variance in growth rate when compared with their founder cell, indicating a dynamic nature in the capacity to survive and proliferate in the presence of a drug. This finding was supported by measurable differences in DNA damage and induction of senescence among cells of colonies. selleckchem The presence of epigenetic modulators during the formation of colonies stabilized their fitness for at least four generations. Collectively, these results support the understanding that cancer cell fitness is dynamic and its modulation is a fundamental aspect to be considered in comprehending cancer cell biology and its response to therapeutic interventions. SIGNIFICANCE Cancer cell fitness is dynamic over the course of the formation of colonies. This dynamic behavior is mediated by asymmetric mitosis, ERK activity, cell-cycle duration, and DNA repair capacity in the absence or presence of a drug.Cancer-associated cachexia, characterized by muscle wasting, is a lethal metabolic syndrome without defined etiology or established treatment. We previously found that p300 mediates cancer-induced muscle wasting by activating C/EBPβ, which then upregulates key catabolic genes. However, the signaling mechanism that activates p300 in response to cancer is unknown. Here, we show that upon cancer-induced activation of Toll-like receptor 4 in skeletal muscle, p38β MAPK phosphorylates Ser-12 on p300 to stimulate C/EBPβ acetylation, which is necessary and sufficient to cause muscle wasting. Thus, p38β MAPK is a central mediator and therapeutic target of cancer-induced muscle wasting. In addition, nilotinib, an FDA-approved kinase inhibitor that preferentially binds p38β MAPK, inhibited p300 activation 20-fold more potently than the p38α/β MAPK inhibitor, SB202190, and abrogated cancer cell-induced muscle protein loss in C2C12 myotubes without suppressing p38α MAPK-dependent myogenesis. Systemic administration of nilotinib at a low dose (0.5 mg/kg/day, i.p.) in tumor-bearing mice not only alleviated muscle wasting, but also prolonged survival. Therefore, nilotinib appears to be a promising treatment for human cancer cachexia due to its selective inhibition of p38β MAPK. SIGNIFICANCE These findings demonstrate that prevention of p38β MAPK-mediated activation of p300 by the FDA-approved kinase inhibitor, nilotinib, ameliorates cancer cachexia, representing a potential therapeutic strategy against this syndrome.

To summarise the evidence for non-pharmacological management of low back pain (LBP) in athletes, a common problem in sport that can negatively impact performance and contribute to early retirement.

Five databases (EMBASE, Medline, CINAHL, Web of Science, Scopus) were searched from inception to September 2020. The main outcomes of interest were pain, disability and return to sport (RTS).

Among 1629 references, 14 randomised controlled trials (RCTs) involving 541 athletes were included. The trials had biases across multiple domains including performance, attrition and reporting. Treatments included exercise, biomechanical modifications and manual therapy. There were no trials evaluating the efficacy of surgery or injections. Exercise was the most frequently investigated treatment; no RTS data were reported for any exercise intervention. There was a reduction in pain and disability reported after all treatments.

While several treatments for LBP in athletes improved pain and function, it was unclear what the most effective treatments were, and for whom. Exercise approaches generally reduced pain and improved function in athletes with LBP, but the effect on RTS is unknown. No conclusions regarding the value of manual therapy (massage, spinal manipulation) or biomechanical modifications alone could be drawn because of insufficient evidence. High-quality RCTs are urgently needed to determine the effect of commonly used interventions in treating LBP in athletes.

While several treatments for LBP in athletes improved pain and function, it was unclear what the most effective treatments were, and for whom. Exercise approaches generally reduced pain and improved function in athletes with LBP, but the effect on RTS is unknown. No conclusions regarding the value of manual therapy (massage, spinal manipulation) or biomechanical modifications alone could be drawn because of insufficient evidence. High-quality RCTs are urgently needed to determine the effect of commonly used interventions in treating LBP in athletes.For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics. SIGNIFICANCE The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers.This article is highlighted in the In This Issue feature, p. 995.Published series on COVID-19 support the notion that patients with cancer are a particularly vulnerable population. There is a confluence of risk factors between cancer and COVID-19, and cancer care and treatments increase exposure to the virus and may dampen natural immune responses. The available evidence supports the conclusion that patients with cancer, in particular with hematologic malignancies, should be considered among the very high-risk groups for priority COVID-19 vaccination.

Individuals who accompany a loved one through medical assistance in dying (MAiD) have to live with the experience and the psychological, moral and social consequences of their involvement in the process long after the death occurs.

To explore the legacy of a MAiD death for individuals who accompanied a loved one through the process.

Using a qualitative descriptive approach we conducted semi-structured interviews to collect data from family members who had accompanied a loved one through MAiD. Data were analysed using conventional content analysis.

16 family members of 14 patients who received MAiD at a Canadian hospital with an interdisciplinary MAiD programme.

The main theme in the analysis is the opposing tensions experienced by individuals who accompany a loved one through a MAiD death, which we conceptualise as a double-edge experience. This double-edge experience is illustrated through four thematic opposing tensions (1) support for patient autonomy and ambivalence about the MAiD choice, (2) gratitude for suffering relieved for loved one and grief for lost time with loved one, (3) time as a gift and time as a burden and (4) positive legacy and challenging bereavement experience.

The nature of the MAiD experience for involved families is rooted in complexity, ambiguity and ambivalence and thus resists easy categorisation. Families would benefit from structured psychosocial and spiritual supports that acknowledge this complexity, along with MAiD-specific bereavement support following the death.

The nature of the MAiD experience for involved families is rooted in complexity, ambiguity and ambivalence and thus resists easy categorisation. Families would benefit from structured psychosocial and spiritual supports that acknowledge this complexity, along with MAiD-specific bereavement support following the death.

To evaluate the impact of provision and timing of palliative care (PC) on potentially inappropriate end-of-life care to patients with cancer in a mixed generalist-specialist PC model.

A retrospective population-based observational study using a national administrative health insurance database. All 43 067 adults in the Netherlands, who were diagnosed with or treated for cancer during the year preceding their death in 2017, were included. Main exposure was either generalist or specialist PC initiated >30 days before death (n=16 967). Outcomes were measured over the last 30 days of life, using quality indicators for potentially inappropriate end-of-life care.

In total, 14 504 patients (34%) experienced potentially inappropriate end-of-life care; 2732 were provided with PC >30 days before death (exposure group) and 11 772 received no PC or ≤30 days before death (non-exposure group) (16% vs 45%, p<0.001). Most patients received generalist PC (88%). Patients provided with PC >30 days before death were 5 times less likely to experience potentially inappropriate end-of-life care (adjusted OR (AOR) 0.20; (95% CI 0.15 to 0.26)) than those with no PC or PC in the last 30 days. Both early (>90 days) and late (>30 and≤90 days) PC initiation had lower odds for potentially inappropriate end-of-life care (AOR 0.23 and 0.19, respectively).

Timely access to PC in a mixed generalist-specialist PC model significantly decreases the likelihood of potentially inappropriate end-of-life care for patients with cancer. Generalist PC can play a substantial role.

Timely access to PC in a mixed generalist-specialist PC model significantly decreases the likelihood of potentially inappropriate end-of-life care for patients with cancer. Generalist PC can play a substantial role.