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This article is linked to Armandi et al papers. To view these articles, visit https://doi.org/10.1111/apt.17941 and https://doi.org/10.1111/apt.18119
Primary sclerosing cholangitis (PSC) is a chronic progressive disease, usually associated with underlying inflammatory bowel diseases (IBDs), with a prevalence of 60-80% in western countries. Herein, ...we review the current knowledge about the association between PSC and IBD in terms of clinical approach and long-term patient management. A PubMed search was conducted for English-language publications from 2000 through 2015 using the following keywords: primary sclerosing cholangitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, diagnosis, therapy, follow-up, and epidemiology. In terms of diagnosis, liver function tests and histology are currently used. The medical treatment options for PSC associated with IBD do not differ from the cases of PSC alone, and include ursodeoxycholic acid and immunosuppressive agents. These treatments do not seem to improve survival, even if ursodeoxycholic acid given at low doses may be chemopreventive against colorectal cancer (CRC). Liver transplantation is the only potential curative therapy for PSC with reported survival rates of 85 and 70% at 5 and 10 years after transplant; however, there is a risk for PSC recurrence, worsening of IBD activity, and de-novo IBD occurrence after liver transplantation. PSC-IBD represents an important public health concern, especially in view of the increased risk for malignancy, including CRC. Long-life annual surveillance colonoscopy is usually recommended, although the exact timescale is still unclear. Further studies are required both to clarify whether annual colonoscopy is cost-effective, especially in younger patients, and to identify potential pharmaceutical agents and genetic targets that may retard disease progression and protect against CRC.
SARS2‐CoV‐2 breakout in Italy caused a huge number of severely ill patients with a serious increase in mortality. Although lungs seem to be the main target of the infection, very few information are ...available about liver involvement, possibly evocating a systemic disease. Post‐mortem wedge liver biopsies from 48 patients died from severe pulmonary COVID‐19 disease with respiratory failure were collected from two main hospitals in northern Italy. No patient had clinical symptoms of liver disease or signs of liver failure before and during hospitalization; for each of them liver function tests were available. All liver samples showed minimal inflammation features. Histological pictures compatible with vascular alterations were observed, characterized by increase in number of portal vein branches associated with lumen massive dilatation, partial or complete luminal thrombosis of portal and sinusoidal vessels, fibrosis of portal tract, focally markedly enlarged and fibrotic. SARS‐CoV‐2 was found in 15 of 22 samples tested by in situ hybridization method. Our preliminary results confirm the clinical impression that liver failure is not a main concern and this organ is not the target of significant inflammatory damage. Histopathological findings are highly suggestive for marked derangement of intrahepatic blood vessel network secondary to systemic changes induced by virus that could target not only lung parenchyma but also cardiovascular system, coagulation cascade and endothelial layer of blood vessels. It still remains unclear if the mentioned changes are directly related to virus infection or if SARS‐CoV‐2 triggers a series of reactions leading to striking vascular alterations.
According to several studies, the onset of the Borderline Personality Disorder (BPD) depends on the combination between genetic and environmental factors (GxE), in particular between biological ...vulnerabilities and the exposure to traumatic experiences during childhood. We have searched for studies reporting possible alterations in several biological processes and brain morphological features in relation to childhood trauma experiences and to BPD. We have also looked for epigenetic mechanisms as they could be mediators of the effects of childhood trauma in BPD vulnerability.
We prove the role of alterations in Hypothalamic-Pituitary-Adrenal (HPA) axis, in neurotrasmission, in the endogenous opioid system and in neuroplasticity in the childhood trauma-associated vulnerability to develop BPD; we also confirm the presence of morphological changes in several BPD brain areas and in particular in those involved in stress response. Not so many studies are available on epigenetic changes in BPD patients, although these mechanisms are widely investigated in relation to stress-related disorders. A better comprehension of the biological and epigenetic mechanisms, affected by childhood trauma and altered in BPD patients, could allow to identify "at high risk" subjects and to prevent or minimize the development of the disease later in life.
The recent SARS CoV-02 pandemic has put enormous pressure on intensive care staff, making it imperative to relieve them of repetitive tasks with little added value such as drug replenishment. We ...propose a decision support system based on a hybrid policy to manage the inventory of critical drugs with low and intermittent demand at an Intensive Care Unit (ICU). Demand forecasting is at the heart of any inventory policy. We claim that in the ICU setting drug demand patterns must be therapy based. Heterogeneous data have been collected during an on site study, and information have been extracted to provide a faithful abstract representation of the ward as a system, as well as the potential evolutions of ICU patients clinical conditions. Together with medical guidelines, this provides the foundation of a therapy based demand forecasting tool. This study integrates schedule optimization and demand forecasting, and exploits simulation for evaluation purpose in the long run. At the beginning of every period, drug orders are optimally scheduled with respect to forecast demand. Then, scheduled orders are deployed day by day and confronted with the real demand in a simulated environment. Potential stock outs trigger rush orders to restore safety stocks. The comparison between the proposed policy and a standard policy mimicking current practice in an ICU ward shows that information on therapy patterns can be successfully incorporated into drug replenishment processes to reduce the number of rush orders, a primary goal in designing an efficient system.
Monitoring soil water content at high spatio-temporal resolution and coupled to other sensor data is crucial for applications oriented towards water sustainability in agriculture, such as precision ...irrigation or phenotyping root traits for drought tolerance. The cost of instrumentation, however, limits measurement frequency and number of sensors. The objective of this work was to design a low cost "open hardware" platform for multi-sensor measurements including water content at different depths, air and soil temperatures. The system is based on an open-source ARDUINO microcontroller-board, programmed in a simple integrated development environment (IDE). Low cost high-frequency dielectric probes were used in the platform and lab tested on three non-saline soils (ECe1: 2.5 < 0.1 mS/cm). Empirical calibration curves were subjected to cross-validation (leave-one-out method), and normalized root mean square error (NRMSE) were respectively 0.09 for the overall model, 0.09 for the sandy soil, 0.07 for the clay loam and 0.08 for the sandy loam. The overall model (pooled soil data) fitted the data very well (R2 = 0.89) showing a high stability, being able to generate very similar RMSEs during training and validation (RMSE(training) = 2.63; RMSE(validation) = 2.61). Data recorded on the card were automatically sent to a remote server allowing repeated field-data quality checks. This work provides a framework for the replication and upgrading of a customized low cost platform, consistent with the open source approach whereby sharing information on equipment design and software facilitates the adoption and continuous improvement of existing technologies.
BACKGROUND: Prostate cancer is the second most common cause of cancer worldwide after lung cancer. There is increasing evidence that diet and lifestyle plays a crucial role in prostate cancer biology ...and tumourigenesis. Prostate cancer itself represents a good model of cancer in which to look for chemopreventive agents due to the high disease prevalence, slowly progressive nature, and long latency period. Dietary agents have gained considerable attention, often receiving much publicity in the media. AIM: To review the key evidence available for potential chemopreventive nutrients. METHODS: The methodology for this review involved a PubMed search from 1990 to 2013 using the key-words “diet and prostate cancer”, “nutrition and prostate cancer”, “dietary factors and prostate cancer”, “prostate cancer epidemiology”, “prostate cancer prevention”, “prostate cancer progression”. RESULTS: Red meat, dietary fat and milk intake should be minimised as they appear to increase the risk of prostate cancer. Fruit and vegetables and polyphenols may be preventive in prostate cancer, but further studies are needed to draw more solid conclusions and to clarify their role in patients with an established diagnosis of prostate cancer. Selenium and vitamin supplements cannot be advocated for the prevention of prostate cancer and indeed higher doses may be associated with a worse prognosis. There is no specific evidence regarding benefits of probiotics or prebiotics in prostate cancer. CONCLUSIONS: From the wealth of evidence available, many recommendations can be made although more randomised control trials are required. These need to be carefully designed due to the many confounding factors and heterogeneity of the population.
Nucleophosmin (NPM1) mutations represent an attractive therapeutic target in acute myeloid leukemia (AML) because they are common (∼30% AML), stable, and behave as a founder genetic lesion. ...Oncoprotein targeting can be a successful strategy to treat AML, as proved in acute promyelocytic leukemia by treatment with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO), which degrade the promyelocytic leukemia (PML)–retinoic acid receptor fusion protein. Adjunct of ATRA to chemotherapy was reported to be beneficial for NPM1-mutated AML patients. Leukemic cells with NPM1 mutation also showed sensibility to ATO in vitro. Here, we explore the mechanisms underlying these observations and show that ATO/ATRA induce proteasome-dependent degradation of NPM1 leukemic protein and apoptosis in NPM1-mutated AML cell lines and primary patients' cells. We also show that PML intracellular distribution is altered in NPM1-mutated AML cells and reverted by arsenic through oxidative stress induction. Interestingly, similarly to what was described for PML, oxidative stress also mediates ATO-induced degradation of the NPM1 mutant oncoprotein. Strikingly, NPM1 mutant downregulation by ATO/ATRA was shown to potentiate response to the anthracyclin daunorubicin. These findings provide experimental evidence for further exploring ATO/ATRA in preclinical NPM1-mutated AML in vivo models and a rationale for exploiting these compounds in chemotherapeutic regimens in clinics.
•ATRA and ATO affect NPM1 protein levels in AML cells and induce cell growth inhibition and apoptosis.•AML cells with mutated NPM1 respond to ATRA/ATO, and this might be exploited therapeutically.
Abstract Barth syndrome (BTHS) is a lethal rare genetic disorder, which results in cardiac dysfunction, severe skeletal muscle weakness, immune issues and growth delay. Mutations in the TAFAZZIN ...gene, which is responsible for the remodeling of the phospholipid cardiolipin (CL), lead to abnormalities in mitochondrial membrane, including alteration of mature CL acyl composition and the presence of monolysocardiolipin (MLCL). The dramatic increase in the MLCL/CL ratio is the hallmark of patients with BTHS, which is associated with mitochondrial bioenergetics dysfunction and altered membrane ultrastructure. There are currently no specific therapies for BTHS. Here, we showed that cardiac mitochondria isolated from TAFAZZIN knockdown (Taz KD ) mice presented abnormal ultrastructural membrane morphology, accumulation of vacuoles, pro-fission conditions and defective mitophagy. Interestingly, we found that in vivo treatment of Taz KD mice with a CL-targeted small peptide (named SS-31) was able to restore mitochondrial morphology in tafazzin-deficient heart by affecting specific proteins involved in dynamic process and mitophagy. This agrees with our previous data showing an improvement in mitochondrial respiratory efficiency associated with increased supercomplex organization in Taz KD mice under the same pharmacological treatment. Taken together our findings confirm the beneficial effect of SS-31 in the amelioration of tafazzin-deficient dysfunctional mitochondria in a BTHS animal model.
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