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.     

microRNA-622 acts as a tumor suppressor in hepatocellular carcinoma

microRNAs (miRNAs) are important regulators of tumor development and progression. In this study, we aimed to explore the expression and role of miR-622 in hepatocellular carcinoma (HCC). We found that miR-622 was significantly downregulated in human HCC specimens compared to adjacent noncancerous liver tissues. miR-622 downregulation was significantly associated with aggressive parameters and poor prognosis in HCC. Enforced expression of miR-622 significantly decreased the proliferation and colony formation and induced apoptosis of HCC cells. In vivo studies demonstrated that miR-622 overexpression retarded the growth of HCC xenograft tumors. Bioinformatic analysis and luciferase reporter assays revealed that miR-622 directly targeted the 3′-untranslated region (UTR) of mitogen-activated protein 4 kinase 4 (MAP4K4) mRNA. Ectopic expression of miR-622 led to a significant reduction of MAP4K4 expression in HCC cells and xenograft tumors. Overexpression of MAP4K4 partially restored cell proliferation and colony formation and reversed the induction of apoptosis in miR-622-overexpressing HCC cells. Inhibition of JNK and NF-κB signaling phenocopied the anticancer effects of miR-622 on HCC cells. Taken together, miR-622 acts as a tumor suppressor in HCC and restoration of miR-622 may provide therapeutic benefits in the treatment of HCC.     

Lipid A as a Drug Target and Therapeutic Molecule

In this review, lipid A, from its discovery to recent findings, is presented as a drug target and therapeutic molecule. First, the biosynthetic pathway for lipid A, the Raetz pathway, serves as a good drug target for antibiotic development. Several assay methods used to screen for inhibitors of lipid A synthesis will be presented, and some of the promising lead compounds will be described. Second, utilization of lipid A biosynthetic pathways by various bacterial species can generate modified lipid A molecules with therapeutic value.     

From the Cover: Echolocating bats rely on an innate speed-of-sound reference

Animals must encode fundamental physical relationships in their brains. A heron plunging its head underwater to skewer a fish must correct for light refraction, an archerfish shooting down an insect must “consider” gravity, and an echolocating bat that is attacking prey must account for the speed of sound in order to assess its distance. Do animals learn these relations or are they encoded innately and can they adjust them as adults are all open questions. We addressed this question by shifting the speed of sound and assessing the sensory behavior of a bat species that naturally experiences different speeds of sound. We found that both newborn pups and adults are unable to adjust to this shift, suggesting that the speed of sound is innately encoded in the bat brain. Moreover, our results suggest that bats encode the world in terms of time and do not translate time into distance. Our results shed light on the evolution of innate and flexible sensory perception.

Every organism must reliably sense its environment in order to survive and reproduce (1). Some sensory systems are innate and unalterable (2), allowing for efficient use even by naïve newborn animals (3–5). Others require learning or experience-dependent development—usually during a critical period during ontogeny (6, 7), though sometimes retained through adulthood (8), allowing for adapting sensing to changing environments (9, 10). The ability to accurately estimate distances with sub-centimeter accuracy is a hallmark of bat echolocation (11–13). Bats achieve this accuracy by means of delay-tuned neurons—neurons that are activated by specific call–echo time delays, supposedly encoding target distance (14–19), although it should be noted that some work suggests that the tuning width of delay-tuned neurons might not allow the accuracy that bats exhibit in delay perception (20). Though delay tuning has been shown to be (at least partially) innate at the neural level (21), this has never been tested behaviorally. Namely, when a newborn bat takes off for the first time, does its brain correctly translate time delays into distance?Translating time into distance relies on a reference of the speed of sound (SOS). This physical characteristic of the environment is not as stable as it may seem. The SOS may change considerably due to various environmental factors such as humidity, altitude, and temperature (22). Bats (Chiroptera) are a specious and widely distributed order of highly mobile and long-lived animals. They therefore experience a range of SOSs (with more than 5% variation, see below) between species, among species, and even within the life of a single individual. We therefore speculated that the reference of the SOS may not be innate to allow for the environmentally dependent SOS experienced by each animal.To test this, we examined the acquisition of the SOS reference by exposing neonatal bats to an increased SOS environment from birth (Materials and Methods). We reared two groups of bats from birth to independent flight in two flight chambers: six bats in normal air (henceforth: “air pups”) and five bats in a helium-enriched air environment (Heliox), where the speed of sound was 15% higher (henceforth: “Heliox pups”). Notably, Heliox pups were never active and did not echolocate in non-Heliox environment (Materials and Methods). This 15% shift is higher than the ecological range and was chosen because it is high enough to enable us to document behavioral changes but low enough so as to allow the bats to function (that is, to fly despite the change in air density). In order to feed, the bats had to fly to a target positioned 1.3 m away from their wooden slit roost. Once the bats learned to fly to the target independently (after ca. 9 wk), we first documented their echolocation in the environment where they were brought up, and we then moved them to the other treatment for testing (Materials and Methods). Because bats adjust their echolocation parameters to the distance of the target, before and during flight (23), we used their echolocation to assess the bats’ target range estimates. If the SOS reference is learned based on experience, the bats raised in Heliox should have learned a faster reference, so that when they flew in normal air, they would have perceived the target as farther than it really was. We also ran the same experiments on adult bats to test adult plasticity.     

How many forms of perseveration? Evidence from cancellation tasks in right hemisphere patients

Neglect patients' performance during cancellation tasks is characterized by left sided omissions and, in many cases, by the production of inappropriate material of various kinds in the ipsilesional space, e.g. additional marks over already cancelled targets, marks drawn away from targets, scribbles, irrelevant drawings. It is unclear whether these behaviours, which have collectively been called perseverative, are functionally and anatomically connected and whether they correlate with the severity of neglect. Here we report a retrospective study on 33 right brain damaged patients with neglect after right hemisphere lesions in whom we measured the intensity of perseveration of the three following kinds: (1) ‘additional marks' (AM) perseveration where patients cancelled a target with two or more well separated marks; (2) ‘scribble’ perseveration, where patients, instead of cancelling the target with a single pen stroke as required by the task, performed multiple pen strokes without breaking the pen-to-paper contact, with the final product being a scribble; (3) ‘flying marks’ (FM) perseveration where patients produced cancellation marks well away from the targets. We found that AM and FM perseveration correlated with neglect severity, while ‘scribble’ perseveration did not. The lesion-symptom mapping showed three separate anatomical areas in the right hemisphere: ‘scribble’ perseveration was associated with lesions of the orbitofrontal cortex and caudate nucleus; AM perseveration was associated with damage to the rolandic operculum, superior temporal gyrus and inferior frontal gyrus; FM perseveration was associated with damage to the dorsal premotor cortex and the temporal pole. Neglect severity followed damage to a region which grossly corresponds to the sum of the regions associated with AM and FM perseveration respectively. This complex behavioural and anatomical pattern is interpreted in terms of a three-factor model, in which AM perseveration is caused by a deficit of disengagement of attention from the right side (also causing omissions), FM perseveration is caused by directional hypokinesia (also causing left-side omissions), and ‘scribble’ perseveration is the consequence of a failure to inhibit an initiated motor act, which is completely separate (both anatomically and functionally) from the disorder inducing omissions.     

Innovations in CNS drug discovery: differentiating strategies to treat depression

Over the past two decades, the clinical management of depression has been revolutionized by the introduction of selective serotonin re-uptake inhibitors and serotonin/noradrenaline re-uptake inhibitors. However, despite this progress, several unmet medical needs remain. These challenges, which collectively represent the next frontier for antidepressant drug discovery, range from improving efficacy in treatment-resistant patients, to accelerating onset of therapeutic activity, to reducing deleterious side effects such as emesis or sexual dysfunction. The present review addresses some of the innovative approaches designed to create novel therapies that improve in one or more of these areas. Additionally, the authors propose that to discover truly novel disease-modifying agents we must improve our appreciation of disease etiology, pathophysiology and genetics. Therefore, while it is still very early in the characterization of these strategies – as well as our general understanding of disease progression – the next several years should allow sufficient time for one (or more) of these approaches to differentiate themselves from current therapies.     

Successful management of steroid‐resistant vascular tumors associated with the Kasabach–Merritt phenomenon using sirolimus

Vascular tumors associated with Kasabach–Merritt phenomenon (KMP) are life‐threatening and the mortality is as high as 10–30%. Steroids are considered the primary choice for drug therapy. However, there are many steroid‐resistant cases. In the present study, analyzed data are presented to support the use of sirolimus in clinical practise for the treatment of corticosteroid‐resistant vascular tumors with KMP in eight infants between June 2015 and April 2017 in a single hospital. The time to initial response was 6.8 ± 2.7 days. The average stabilization time for the platelet count was 19.1 ± 8.5 days. At the time of publication, the average duration of sirolimus treatment was 14.1 ± 4.0 months, and the average time for sirolimus treatment as a single agent was 12.6 ± 4.2 months. The side‐effects were tolerable and included oral ulcer, fever, pain, skin rash and transient ascension of serum transaminase and cholesterol. Our study indicated that sirolimus therapy is an effective and safe method for the treatment of corticosteroid resistant vascular tumors associated with KMP in infants.     

凝血因子Ⅺ--抗血栓形成的新靶点

近年来血栓性疾病发病率上升，严重危害人类的健康。目前临床使用的抗血栓药物存在出血的毒副作用。大量研究表明，凝血因子Ⅺ(factor Ⅺ，FⅪ)基因剔除或缺陷无出血倾向，却可以抑制闭塞性血栓形成。近年来开展的以FⅪ为靶点的抗血栓研究已取得了一定进展。本文就FⅪ作为抗血栓药物新靶点的依据，FⅪ在血栓形成中的作用及其作为抗血栓药物靶点的研究进展做一综述，以期为研究新的抗血栓药物提供思路。