The RAS oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab ...achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the KRAS gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the KRAS.sup.G12C mutation. Adagrasib (MRTX849) and other direct KRAS.sup.G12C inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRAS.sup.G12C mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRAS.sup.G12C inhibitors and summarize the ongoing clinical trials of all direct KRAS.sup.G12C inhibitors. Keywords: KRAS.sup.G12C, Cancer, Clinical trial, Direct RAS inhibitor, Sotorasib, Adagrasib, Epidemiology, Immunotherapy, Drug development
Purpose
Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively ...impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis.
Methods
A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion.
Results
Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis.
Conclusions
IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
Marine mesograzers use macroalgae as food and habitat and may have strong top‐down effects on plants and macroalgae. Sympatric mesograzer species often differ regarding host use and feeding behavior, ...which may lead to distinct impacts by these consumers on primary producers. The amphipods Hyale niger and Ampithoe marcuzzii are mesograzers abundant that co‐occur in Brazilian waters and, although they use several macroalgae as habitat, it is unknown how much the food value of these hosts explains the host use pattern by the two mesograzers. Herein, we investigated the abundance and feeding behavior of the sympatric amphipods H. niger and A. marcuzzii. For that, their abundance on the macroalgal hosts Sargassum filipendula, Padina gymnospora, and Dichotomaria marginata was evaluated seasonally in a rocky shore at Fortaleza Beach, state of São Paulo, Brazil. Also, multiple‐choice and no‐choice feeding experiments were carried out at laboratory to evaluate the feeding behavior of these mesograzers. The abundance of H. niger was similar among the three macroalgal hosts (except during winter), while A. marcuzzii was more abundant on Dichotomaria and Padina than Sargassum in all seasons. Moreover, H. niger consumed more Padina than Dichotomaria and Sargassum in both feeding experiments. In turn, A. marcuzzii preferred to feed on Padina when it had a choice and consumed the three macroalgal hosts at similar levels in the no‐choice feeding experiment. Overall, H. niger and A. marcuzzii differ from each other regarding their feeding behavior and host use pattern. In particular, the food value of macroalgae seems to partially explain the host use by A. marcuzzi, but not by H. niger. The differences between H. niger and A. marcuzzii may result in varying impacts on primary producers.
Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased ...expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future.
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Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis ...remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called “cholinergic anti-inflammatory pathway”, suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.
Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL-1 and ...IL-18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL-1β (405%), IL-18 (365%), COX-2 (2,777%) and NF-κB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL-18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis.
The 2019 fire crisis in Amazonia dominated global news and triggered fundamental questions about the possible causes behind it. Here we performed an in-depth investigation of the drivers of active ...fire anomalies in the Brazilian Amazon biome. We assessed a 2003–2019 time-series of active fires, deforestation, and water deficit and evaluated potential drivers of active fire occurrence in 2019, at the biome-scale, state level, and local level. Our results revealed abnormally high monthly fire counts in 2019 for the states of Acre, Amazonas, and Roraima. These states also differed from others by exhibiting in this year extreme levels of deforestation. Areas in 2019 with active fire occurrence significantly greater than the average across the biome had, on average, three times more active fires in the three previous years, six times more deforestation in 2019, and five times more deforestation in the five previous years. Approximately one-third of yearly active fires from 2003 to 2019 occurred up to 1 km from deforested areas in the same year, and one-third of deforested areas in a given year were located up to 500 m from deforested areas in the previous year. These findings provide critical information to support strategic decisions for fire prevention policies and fire combat actions.
Purpose Hemorrhagic cystitis is an important dose limiting side effect of ifosfamide based cancer chemotherapy. Despite chemoprophylaxis inflammation can still be found in cystoscopy guided biopsies. ...Previous studies confirmed the role of TNF-α and IL-1β. We evaluated the protective effect of the IL-1R antagonist anakinra and the anti-TNF-α antibody infliximab in experimental ifosfamide induced hemorrhagic cystitis. Materials and Methods Hemorrhagic cystitis was induced by an injection of ifosfamide (400 mg/kg intraperitoneally) in Swiss wild-type C57Bl/6, IL-1R–/– , TNFR1–/– or TNFR1/R2–/– mice. Mice were treated 30 minutes before ifosfamide with anakinra (100 mg/kg intraperitoneally), infliximab (5 mg/kg intraperitoneally) or vehicle. Visceral nociception was evaluated after hemorrhagic cystitis induction. At 12 hours the animals were sacrificed. Bladders were harvested to assess bladder wet weight, vascular permeability, macroscopic and microscopic findings, muscle contractility, and for cystometrography. Inflammatory cell infiltration was assessed by myeloperoxidase assay and flow cytometry. Results Anakinra attenuated hemorrhage, edema, neutrophil infiltration, visceral hyperalgesia and bladder dysfunction. IL-1R–/– mice also showed milder hemorrhagic cystitis. Infliximab inhibited bladder edema and visceral hyperalgesia without preventing hemorrhage, bladder dysfunction, neutrophils or accumulation. Additionally, the lack of TNFR1 decreased bladder edema but not cell infiltration whereas concomitant deficiency of TNFR1 and TNFR2 resulted in worse hemorrhagic cystitis. Conclusions Anakinra is effective for preventing experimentally ifosfamide induced hemorrhagic cystitis. It seems that neutrophil and macrophage infiltration in this circumstance depends on IL-1 signaling through IL1R. Possibly TNFR2 has a protective role in hemorrhagic cystitis.
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