The multifaced role of stat3 in cancer and its implication for anticancer therapy

Signal transducer and activator of transcription (STAT) 3 is one of the most complex regulators of transcription. Constitutive activation of STAT3 has been reported in many types of tumors and depends on mechanisms such as hyperactivation of receptors for pro-oncogenic cytokines and growth factors, loss of negative regulation, and excessive cytokine stimulation. In contrast, somatic STAT3 mutations are less frequent in cancer. Several oncogenic targets of STAT3 have been recently identified such as c-myc, c-Jun, PLK-1, Pim1/2, Bcl-2, VEGF, bFGF, and Cten, and inhibitors of STAT3 have been developed for cancer prevention and treatment. However, despite the oncogenic role of STAT3 having been widely demonstrated, an increasing amount of data indicate that STAT3 functions are multifaced and not easy to classify. In fact, the specific cellular role of STAT3 seems to be determined by the integration of multiple signals, by the oncogenic environment, and by the alternative splicing into two distinct isoforms, STAT3α and STAT3β. On the basis of these different conditions, STAT3 can act both as a potent tumor promoter or tumor suppressor factor. This implies that the therapies based on STAT3 modulators should be performed considering the pleiotropic functions of this transcription factor and tailored to the specific tumor type

Direct-acting antivirals and visceral leishmaniasis: A case report

Background: Visceral leishmaniasis is a vector-borne parasitic disease caused by protozoa belonging to the genus Leishmania. The clinical presentation of visceral leishmaniasis strictly depends on the host immunocompetency, whereas depressive conditions of the immune system impair the capability to resolve the infection and allow reactivation from sites of latency of the parasite. Case presentation: We describe a case of visceral leishmaniasis (VL) that occurred in a patient with chronic hepatitis C treated with direct-acting antiviral drugs (DAA). The hypothesized mechanism is the alteration of protective inflammation mechanisms secondary to DAA therapy. Downregulation of type II and III IFNs, their receptors, which accompany HCV clearance achieved during treatment with sofosbuvir and ribavirin might have a negative impact on a risk for reactivation of a previous Leishmania infection. We know indeed that IFN-\u3b3 is important to enhance killing mechanisms in macrophages, which are the primary target cells of Leishmania. Conclusion: Since VL is endemic in Sicily as well as in other countries of the Mediterranean basin, physicians should be aware of the possible unmasking of cryptic Leishmania infection by DAAs

Chronic tobacco smoking and neuropsychological impairments:A systematic review and meta-analysis

The link between neuropsychological impairments and chronic tobacco smoking is not clear and in the current literature there is a lack of robust analyses investigating this association. A systematic review of the literature was conducted in order to identify relevant longitudinal and cross-sectional studies conducted from 1946 to 2017. A meta-analysis was performed from 24 studies testing the performance of chronic tobacco smokers compared with non-smokers on neuropsychological tests related to eight different neuropsychological domains. The results revealed a cross-sectional association between neuropsychological impairments and chronic tobacco smoking in cognitive impulsivity, non-planning impulsivity, attention, intelligence, short term memory, long term memory, and cognitive flexibility, with the largest effect size being related to cognitive impulsivity (SDM = 0.881, p <0.005), and the smallest effect size being related to intelligence (SDM = 0.164, p < 0.05) according to Cohen’s benchmark criteria. No association was found between chronic smoking and motor impulsivity (SDM = 0.105, p = 0.248). Future research is needed to investigate further this association by focusing on better methodologies and alternative methods for nicotine administration.PostprintPeer reviewe

Multifaceted impairments in impulsivity and brain structural abnormalities in opioid dependence and abstinence

This study was part funded by an unrestricted educational grant provided by Schering-Plough, a grant by an anonymous trust and the Scottish Mental Health Research Network.Background: Chronic opioid exposure, as a treatment for a variety of disorders or as drug of misuse, is common worldwide, but behavioural and brain abnormalities remain under-investigated. Only a small percentage of patients who receive methadone maintenance treatment (MMT) for previous heroin misuse eventually achieve abstinence and studies on such patients are rare. Method: The Cambridge Neuropsychological Test Automated Battery and T1 weighted magnetic resonance imaging (MRI) were used to study a cohort of 122 male individuals: a clinically stable opioid-dependent patient group receiving MMT (n = 48), an abstinent previously MMT maintained group (ABS) (n = 24) and healthy controls (n = 50). Results: Stable MMT participants deliberated longer and placed higher bets earlier in the Cambridge Gambling Task (CGT) and showed impaired strategic planning compared with healthy controls. In contrast, ABS participants showed impairment in choosing the least likely outcome, delay aversion and risk adjustment on the CGT, and exhibited non-planning impulsivity compared with controls. MMT patients had widespread grey matter reductions in the orbitomedial prefrontal cortex, caudate, putamen and globus pallidus. In contrast, ABS participants showed midbrain–thalamic grey matter reductions. A higher methadone dose at the time of scanning was associated with a smaller globus pallidus in the MMT group. Conclusions: Our findings support an interpretation of heightened impulsivity in patients receiving MMT. Widespread structural brain abnormalities in the MMT group and reduced brain structural abnormality with abstinence suggest benefit of cessation of methadone intake. We suggest that a longitudinal study is required to determine whether abstinence improves abnormalities, or patients who achieve abstinence have reduced abnormalities before methadone cessation.Publisher PDFPeer reviewe

Chemical exchange saturation transfer MRI shows low cerebral 2-deoxy-D-glucose uptake in a model of Alzheimer's Disease

Glucose is the central nervous system's only energy source. Imaging techniques capable to detect pathological alterations of the brain metabolism are useful in different diagnostic processes. Such techniques are also beneficial for assessing the evaluation efficacy of therapies in pre-clinical and clinical stages of diseases. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a possible alternative to positron emission tomography (PET) imaging that has been widely explored in cancer research in humans and animal models. We propose that pathological alterations in brain 2-deoxy-D-glucose (2DG) uptake, typical of neurodegenerative diseases, can be detected with CEST MRI. Transgenic mice overexpressing a mutated form of amyloid precusrsor protein (APP23), a model of Alzheimer's disease, analyzed with CEST MRI showed a clear reduction of 2DG uptake in different brain regions. This was reminiscent of the cerebral condition observed in Alzheimer's patients. The results indicate the feasibility of CEST for analyzing the brain metabolic state, with better image resolution than PET in experimental models

Enteric Absorption of Ciprofloxacin During Tube Feeding in the Critically Ill

To determine the pharmacokinetic properties of ciprofloxacin in the critically ill, we studied seven mechanically ventilated patients with pneumonia during entcral feedings. Subjects received ciprofloxacin 750 mg every 12 h via nasogastric tube and serial serum drug concentrations were measured after the first and fourth dose. After the initial dose, the maximum serum concentration ranged from 1.24–3.06 mg/L, and the area under the time curve from 0–12 h ranged from 3.2–19.65 mg.h/L. Similar levels were noted after dose four. Gastrointestinal absorption of ciprofloxacin in tube fed critically ill patients was decreased, but well above MIC values for many pathogenic bacteria

Rickettsia typhi and Haemophagocytic Syndrome

Appropriate therapy (dexamethasone, cyclosporin, and etoposide) could save the patient in those cases in which the pathogen-direct therapy has not been sufficient by itself to control the disease

In vitro antileishmanial activity of trans-stilbene and terphenyl compounds

Leishmaniasis are globally widespread parasitic diseases which often leads to death if left untreated. Currently available drugs present different drawbacks, so there is an urgent need to develop new, safe and cost-effective drugs against leishmaniasis. In this study we tested a small library of trans-stilbene and terphenyl derivatives against promastigote, amastigotes and intramacrophage amastigote forms of Leishmania infantum. Two compounds of the series, the trans-stilbene 3 and the terphenyl 11, presented the best activity and safety profiles. Terphenyl 11 showed a leshmanicidal activity higher than pentostam and the ability to induce apoptosis selectively in Leishmania infantum while saving macrophages and primary epithelial cells. Our data indicate that terphenyl compounds, as well as stilbenes, are endowed with leishmanicidal activity, showing potential for further studies in the context of leishmanial therapy