Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Structure–activity investigation of the potentiating effect of cyano substitution on nitroaniline mutagenicity in the ames test

2,6‐Dicyano‐4‐nitroaniline and 2‐cyano‐4‐nitroaniline (CNNA; 2‐amino‐5‐nitrobenzonitrile) are potent mutagens in the Ames test, even though unsubstituted nitroanilines (NAs) are no more than weak mutagens. These compounds are putative reduction products of many commercial azo dyes, including Disperse Blue 165, Disperse Blue 337, Disperse Red 73, Disperse Red 82, Disperse Violet 33, and Disperse Violet 63. We have examined the mutagenicity in strains TA98 and YG1024 of a series of commercially‐available isomers of CNNA, and some related compounds, to probe the relationship between structure and genotoxic activity in this class of compounds. The potentiating effect of the cyano substituent is seen in many cases; e.g. 2‐amino‐4‐nitrobenzonitrile is a much more potent mutagen than 3‐NA. 2,4‐Dinitrobenzonitrile is also highly mutagenic. Possible mechanisms for the “cyano effect” are considered, with respect to the likely structures of cyanonitroaniline‐DNA adducts and the roles of the enzymes (nitroreductase and acetyl CoA:arylamine N‐acetyltransferase) believed to be involved in the activation of nitroaromatic compounds. Environ. Mol. Mutagen. 59:114–122, 2018. © 2017 Wiley Periodicals, Inc.     

Detecting the developmental toxicity of bFGF in the embryonic stem cell test using differential gene expression of differentiation-related genes

Basic fibroblast growth factor (bFGF) is a mitogenic cytokine that can stimulate mesoderm-and neuroectoderm-originated cell proliferation. This study was performed to investigate the effects of bFGF on cell differentiation and the expression of specific markers at different embryonic developmental stages. We firstly evaluated the embryotoxic potential of bFGF in vitro using a modified EST protocol. Sequentially, we further investigated how bFGF impact the different tissue-special genes and proteins expressions during the differentiation of murine ES cells in vitro and attempt to reveal the effects of bFGF on differentiation processes. This analysis was focused on key tissue- and stage-specific genes involved in ectodermal, mesodermal, and endodermal differentiation, including ectodermal-specific gene Nestin, Oligo2 and Syn, mesodermal-specific gene MHC and MyoD, and endodermal-specific gene GATA6, TTR and ALB, as well as undifferentiated gene Sox-2 and Oct-4. The results demonstrate that bFGF could promote expression of ectodermal-specific genes and protein, but suppress the expressions of endoderm-specific and some mesoderm-specific gene and protein. A conclusion can be drawn that bFGF exhibits weak embryotoxicity and mainly promotes ES cell differentiation towards the ectodermal lineages but suppress differentiation into endoderm lineages. These opposing effects of bFGF on the embryonic development of the three germ layers may be related to its weak embryotoxic potential. More specifically, inhibition of expression of the endodermal-specific markers transthyretin (TTR), and albumin (ALB) by bFGF may be of more value in detecting the embryotoxic potential of bFGF.     

Can physical prehabilitation prevent complications after colorectal cancer surgery in frail older patients?

IntroductionFrail patients with colorectal cancer (CRC) are at increased risk of complications after surgery. Prehabilitation seems promising to improve this outcome and therefore we evaluated the effect of physical prehabilitation on postoperative complications in a retrospective cohort of frail CRC patients.MethodsThe study consisted of all consecutive non-metastatic CRC patients ≥70 years who had elective surgery from 2014 to 2019 in a teaching hospital in the Netherlands, where a physical prehabilitation program was implemented from 2014 on. We performed both an intention-to-treat and per protocol analysis to evaluate postoperative complications in the physical prehabilitation (PhP) and non-prehabilitation (NP) group.ResultsEventually, 334 elective patients were included. The 124 (37.1%) patients in the PhP-group presented with higher age, higher comorbidity scores and walking-aid use compared to the NP-group. Medical complications occurred in 26.6% of the PhP-group and in 20.5% of the NP-group (p = 0.20) and surgical complications in 19.4% and 14.3% (p = 0.22) respectively. In all frailty subgroups, the medical complications were lower in the PhP-group compared to the NP-group (35.9% vs. 45.5% for patients with ≥2 comorbidities, 36.2% vs. 39.1% for ASA score ≥ III, 29.2% vs. 45.8% for walking-aid use). Differences were not significant.ConclusionsIn this study, patients selected for physical prehabilitation had a worse frailty profile and therefore a higher a priori risk of postoperative complications. However, the postoperative complication rate was not increased compared to patients who were less frail at baseline and without prehabilitation. Hence, physical prehabilitation may prevent postoperative complications in frail CRC patients ≥70 years.     

Flare Up Reaction During Provocation Test to Glatiramer Acetate in a Patient With Allergy to Interferon Beta1a

Glatiramer acetate (GA) is a synthetic amino acid polymer, used for relapsing-remitting multiple sclerosis. The most common adverse effect of GA is a skin reaction at the injection site with a probable IgE-mediated mechanism. We report a case of a 45-year-old woman with multiple sclerosis and urticaria to interferon-β1a, who underwent a challenge test to GA. She presented itching wheals at the intradermal sites. A month later the patient repeated the test and presented the same reactions of the first test. The next day she continued the test with subcutaneous injections. One hour later she presented a flare up of the reactions appeared during the previous 2 tests. No reactions appeared at the subcutaneous injection sites. The patient also presented dyspnea. Flare-up reactions are characterized by the reactivation of previously positive reactions to intradermal or skin tests triggered by patch testing and after systemic provocation with an allergen. The phenomenon is not common to drugs. The mechanisms involved in this reaction seem to be heterogeneous and are not completely understood. To our knowledge this is the first case of allergic reaction to GA manifested as a flare-up reaction during challenge test.     

Association between single limb standing test results and healthcare costs among community-dwelling older adults

Background and objectiveIdentifying risks for older adults who will require healthcare resources is critical for the government, healthcare providers, and consumers. The objective of this study was to examine the relationship between the results of the single limb standing (SLS) test and healthcare costs among community-dwelling older adults.MethodsWe used data obtained from a population-based prospective cohort study of the residents of Tadami town in Fukushima Prefecture, Japan. The participants were above 60 years of age and had undergone annual health check-ups, and data on their healthcare costs over the two-year study period were available. A censored regression model adjusted for potential confounders was used to estimate the mean difference in total healthcare costs between participants who could remain standing on a single limb for at least 30 s and those who could not.ResultsHealthcare costs of participants who passed the SLS test were significantly lower than those who did not. The mean difference between the two groups’ healthcare costs was 4064 USD (95 % confidence interval: 2661–5467 USD, p < 0.05). After adjusting for potential confounders, the mean difference between the two groups was smaller (1686 USD) but remained statistically significant (95 % confidence interval: 125–3246 USD, p < 0.05).ConclusionsAmong community-dwelling older adults, limited static balance (SLS time <30 s) was found to be associated with high healthcare costs in the two years after the SLS test. The SLS test may help identify individuals at high risk of becoming frequent users of healthcare services in the future.     

Frequency of and risk factors for reversion of QuantiFERON test in healthcare workers in an intermediate-tuberculosis-burden country

ObjectivesHigh-risk healthcare workers (HCWs) are often screened for latent tuberculosis infection (LTBI) using QuantiFERON tests (QFTs), with annual serial tests often showing reversion from positive to negative results. We assessed the frequency of and risk factors for reversion of QFTs in HCWs in an intermediate-tuberculosis burden country.MethodsWe enrolled high-risk HCWs at a tertiary-care hospital in South Korea, who were assessed by QFTs at least twice between 2017 and 2019.ResultsOf the 1870 HCWs screened, 1542 (82%) had persistent negative results, 229 (12%) had persistent positive results, 53 (3%) showed reversion, and 46 (2%) showed conversion from negative to positive. Multivariate analysis comparing the characteristics of the 229 HCWs with persistent positive results and the 53 who experienced reversion showed that older age (adjusted odds ratio (aOR): 0.96; 95% confidence interval (CI): 0.92–0.99), male sex (aOR: 0.29; 95% CI: 0.11–0.78) and high (≥0.70 IU/mL) baseline QFT results (aOR: 0.15; 95% CI: 0.07–0.31) were inversely associated with reversion. Using an ROC curve-derived cut-off of <0.738 IU/mL, the area under the curve was 0.79. Of 53 HCWs with reversion, 36 (78%) had below 0.738 IU/mL of baseline QFT, while 181 (79%) of 229 HCWs without reversion had above 0.738 IU/mL of baseline QFT.ConclusionReversion during serial testing is unlikely in HCWs who are male, older in age, and have higher baseline QFT results. Serial testing without LTBI treatment may be indicated in HCWs who are female, younger and, especially, have lower QFT results.