Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?

Signal transducer and activator of transcription 3 (STAT3) controls many biological processes including differentiation, survival, proliferation, and angiogenesis. In normal healthy cells, STAT3 is tightly regulated to maintain a momentary active state. However, aberrant or constitutively activated STAT3 has been observed in many different cancers and constitutively activated STAT3 has been shown to associate with poor prognosis and tumor progression. For this reason, STAT3 has been studied as a possible target in the treatment of many different types of cancers. However, despite decades of research, a FDA-approved STAT3 inhibitor has yet to emerge. In this review, we will analyze past studies targeting STAT3 for drug discovery, understand possible causes of failure in these studies, and provide potential insights for future efforts to overcome these roadblocks

14-3-3σ Contributes to Radioresistance by Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G2–M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2–M phase following DNA-damaging treatments. We showed that 14-3-3σ contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2–M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSB). The increased NHEJ repair activity was due to 14-3-3σ–mediated upregulation of PARP1 expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2–M arrest following IR was due to 14-3-3σ–induced Chk2 expression. Implications: These findings reveal an important molecular basis of 14-3-3σ function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers

Corrigendum: eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation

[This corrects the article DOI: 10.3389/fcell.2020.00753.]

eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation

Translation initiation in protein synthesis regulated by eukaryotic initiation factors (eIFs) is a crucial step in controlling gene expression. eIF3a has been shown to regulate protein synthesis and cellular response to treatments by anticancer agents including cisplatin by regulating nucleotide excision repair. In this study, we tested the hypothesis that eIF3a regulates the synthesis of proteins important for the repair of double-strand DNA breaks induced by ionizing radiation (IR). We found that eIF3a upregulation sensitized cellular response to IR while its downregulation caused resistance to IR. eIF3a increases IR-induced DNA damages and decreases non-homologous end joining (NHEJ) activity by suppressing the synthesis of NHEJ repair proteins. Furthermore, analysis of existing patient database shows that eIF3a expression associates with better overall survival of breast, gastric, lung, and ovarian cancer patients. These findings together suggest that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating the synthesis of DNA repair proteins and, thus, eIIF3a likely contributes to the outcome of cancer patients treated with DNA-damaging strategies including IR

Hedonic contrast and the short-term stimulation of appetite

Hedonic contrast describes how liking for one item is influenced by the recent experience of other items which differ in hedonic valence. In the context of food stimuli, there is abundant evidence that hedonic contrast alters liking, but limited information on its impact on intake, and the aim here was to further clarify how hedonic impact modifies intake. Participants (96 female volunteers) rated and consumed ad libitum a sequence of four bowls of a snack (potato crisps) in one of three conditions. In the Palatable (salted crisps) and Bland (unsalted crisps) conditions, all four bowls were the same. In the Contrast condition participants alternated between salted and unsalted crisps. In total, significantly more was consumed in the Palatable (35.0 ± 2.6 g) than Bland (26.6 ± 2.4 g) condition, but most was consumed in the Contrast condition (37.0 ± 1.6 g). The impact of hedonic contrast was seen in the third serving, where those in the Contrast condition consumed the most of any serving, and significantly more than in Palatable or Bland conditions, and at the final serving, when those in the Contrast condition consumed significantly less than in Bland or Palatable conditions. Rated liking for the foods showed a similar pattern, with liking decreasing across servings in Palatable and Bland conditions. However, liking was influenced by the preceding serving in the Contrast condition, and the change in liking produced by contrast predicted subsequent intake. Overall, these data provide clear evidence that hedonic contrast can influence consumption, with intake driven by this adjusted liking

A proposed systems approach to the evaluation of integrated palliative care

<p>Abstract</p> <p>Background</p> <p>There is increasing global interest in regional palliative care networks (PCN) to integrate care, creating systems that are more cost-effective and responsive in multi-agency settings. Networks are particularly relevant where different professional skill sets are required to serve the broad spectrum of end-of-life needs. We propose a comprehensive framework for evaluating PCNs, focusing on the nature and extent of inter-professional collaboration, community readiness, and client-centred care.</p> <p>Methods</p> <p>In the absence of an overarching structure for examining PCNs, a framework was developed based on previous models of health system evaluation, explicit theory, and the research literature relevant to PCN functioning. This research evidence was used to substantiate the choice of model factors.</p> <p>Results</p> <p>The proposed framework takes a systems approach with system structure, process of care, and patient outcomes levels of consideration. Each factor represented makes an independent contribution to the description and assessment of the network.</p> <p>Conclusions</p> <p>Realizing palliative patients' needs for complex packages of treatment and social support, in a seamless, cost-effective manner, are major drivers of the impetus for network-integrated care. The framework proposed is a first step to guide evaluation to inform the development of appropriate strategies to further promote collaboration within the PCN and, ultimately, optimal palliative care that meets patients' needs and expectations.</p