Cadmium specific proteomic responses of a highly resistant Pseudomonas aeruginosa san ai

Pseudomonas aeruginosa san ai is a promising candidate for bioremediation of cadmium pollution, as it resists a high concentration of up to 7.2 mM of cadmium. Leaving biomass of P. aeruginosa san ai exposed to cadmium has a large biosorption potential, implying its capacity to extract heavy metal from contaminated medium. In the present study, we investigated tolerance and accumulation of cadmium on protein level by shotgun proteomics approach based on liquid chromatography and tandem mass spectrometry coupled with bioinformatics to identify proteins. Size exclusion chromatography was used for protein prefractionation to preserve native forms of metalloproteins and protein complexes. Using this approach a total of 60 proteins were observed as up-regulated in cadmium-amended culture. Almost a third of the total numbers of up-regulated were metalloproteins. Particularly interesting are denitrification proteins which are over expressed but not active, suggesting their protective role in conditions of heavy metal exposure. P. aeruginosa san ai developed a complex mechanism to adapt to cadmium, based on: extracellular biosorption, bioaccumulation, the formation of biofilm, controlled siderophore production, enhanced respiration and modified protein profile. An increased abundance of proteins involved in: cell energy metabolism, including denitrification proteins; amino acid metabolism; cell motility and posttranslational modifications, primarily based on thiol-disulfide exchange, were observed. Enhanced oxygen consumption of biomass in cadmium-amended culture versus control was found. Our results signify that P. aeruginosa san ai is naturally well equipped to overcome and survive high doses of cadmium and, as such, has a great potential for application in bioremediation of cadmium polluted sites.

When exposed to cadmium a highly resistant strain P. aeruginosa san ai responds by an increased metalloprotein expression (particularly denitrification proteins), an enhanced respiration, and a pronounced thiol-disulfide protein modifications.     

Fecal microbiota transplantation: a promising strategy in preventing the progression of non-alcoholic steatohepatitis and improving the anti-cancer immune response

Introduction: Non-alcoholic fatty liver disease (NAFLD) has the potential to progress to hepatocellular carcinoma (HCC). However, limited therapies are currently available for the treatment of advanced HCC, and one must strive to search for novel strategies.

Areas covered: We provide insight on current knowledge related to gut microbiota and NAFLD, summarize the sequence linking obesity to HCC and highlight gut dysbiosis in obesity and its consequences on the liver. We detail the impact of the gut microbiota on immune checkpoint inhibitors, and speculate on the role of fecal microbiota transplantation (FMT) in NAFLD and in improving anti-neoplastic immune response.

Expert Opinion: Manipulation of the gut microbiota seems promising in the secondary prevention of NAFLD/NASH and/or in potentiating anti-cancer immune response, notably by a global ‘resetting’ using FMT. However, the composition of a ‘harmful’ gut microbiome in HCC still needs to be characterized, and the impact of FMT on HCC growth needs to be assessed.     

Acute myeloid leukaemia in patients we judge as being older and/or unfit

The definition of older age in AML is arbitrary. In the context of the clinical studies, it starts with age ≥60 or ≥65 years and in recent years ≥70 or 75, depending on the selection of the studied population. In clinical practice, with older age, we often mean that the patient is unfit for intensive chemotherapy. Higher age overlaps with categories such as worse performance status, unfitness, comorbidities, poor-risk cytogenetics, adverse mutation patterns, age-related clonal haematopoiesis and specific disease ontogeny. Intensive induction therapy can result in prolonged overall survival, at least in a subset of elderly patients aged up to 75 years despite the reluctance of some physicians and patients to use treatment regimens perceived as toxic. Venetoclax and azacitidine combination is the new standard of comparison for persons unfit for intensive therapy. New oral hypomethylating agent CC-486 as maintenance therapy led to a prolonged overall survival in a randomized trial of patients ≥55 years of age who were in first complete remission, but not eligible for allogeneic stem cell transplantation. Any therapy is better than no therapy, but a substantial proportion of older patients still receive only palliative care. Making a decision for AML diagnosed in older age should be individualized and shared through the dialog with the patient and relatives or cohabitants, considering medical issues and social factors including personal goals. Although we are witnesses of the advances in basic research and therapy, we are still a very long way from curing older patients with AML.     

Long-term prognosis of patients with early post-infarction angina.

BACKGROUND: Most studies have shown that early post-infarction angina (EPA) implies an unfavorable long-term prognosis among patients with acute myocardial infarction (AMI). However, some studies have failed to establish a link between the occurrence of EPA and increased mortality and recurrent infarction rates. METHODS AND RESULTS: In order to evaluate a long-term prognosis in patients with EPA, we assessed the 5-year prognosis of 80 patients with AMI by the presence or absence of EPA. During the 5-year follow up, the occurrence of death, cardiac death, recurrent infarction, unstable angina, heart failure, revascularization and cardiac events were recorded. A cardiac event was defined as an occurrence of any of the following events: cardiac death, recurrent infarction, unstable angina, heart failure and revascularization. Survival analysis showed no differences between patients with and without EPA in the probability of death (p=NS), cardiac death (p=NS), recurrent myocardial infarction (p=NS) and unstable angina (p=NS). Patients with EPA had a higher probability of developing cardiac events (p=0.0285) and undergoing revascularization procedures (p=0.0188). CONCLUSIONS: EPA increases the risk of patients developing cardiac events and undergoing revascularization procedures, and thereby implies a poor long-term prognosis for patients with AMI.     

Infantile peripheral neuropathy,deafness, and proximal tubulopathy associated with a novel mutation of the RRM2B gene

Mitochondrial DNA depletion syndromes are a group of autosomal recessive hereditary disorders characterized by reduction of the amount of mitochondrial DNA in the affected tissue (muscle, liver, brain, or kidneys). We report a case of an infant with myopathy, deafness, peripheral neuropathy, nephrocalcinosis, proximal renal tubulopathy, moderate lactic acidosis, and a novel mutation of the RRM2B gene.Mitochondrial DNA depletion syndromes are a group of autosomal recessive hereditary disorders characterized by reduction of the mitochondrial DNA amount in the affected tissue (1). Depletion of mitochondrial DNA can affect specific tissues or combination of organs and tissues including muscles, liver, brain, or kidneys (2,3).Different defects of nuclear genes may lead to different clinical manifestations, such as hepatocerebral syndrome, encephalopathy, or myopathy. One of the recently identified genes for mitochondrial DNA depletion syndromes is RRM2B, which encodes an isoform of a small subunit of ribonucleotide reductase. This enzyme plays an essential role in nucleotide synthesis, converting ribonucleotides to deoxyribonucleotides. Since 2008, 14 mutations of RRM2B gene have been reported (3,4). All the reported mutations are unique and there is no mutation that appears in more than one family (1-4).All reported patients had myopathy and primary lactic acidosis. More than a half of them died before the fourth month of age. The oldest patient with RRM2B mutation was a 42 years old woman with clinical findings suggestive of neurogastrointestinal encephalopathy (5). In this report, we review a case of an infant with muscular hypotonia, myopathy, peripheral neuropathy, deafness, nephrocalcinosis, proximal renal tubulopathy, moderate lactic acidosis, and a novel mutation of the RRM2B gene.     

Development of the Croatian model of organ donation and transplantation

During the past ten years, the efforts to improve and organize the national transplantation system in Croatia have resulted in a steadily growing donor rate, which reached its highest level in 2011, with 33.6 utilized donors per million population (p.m.p.). Nowadays, Croatia is one of the leading countries in the world according to deceased donation and transplantation rates. Between 2008 and 2011, the waiting list for kidney transplantation decreased by 37.2% (from 430 to 270 persons waiting for a transplant) and the median waiting time decreased from 46 to 24 months. The Croatian model has been internationally recognized as successful and there are plans for its implementation in other countries. We analyzed the key factors that contributed to the development of this successful model for organ donation and transplantation. These are primarily the appointment of hospital and national transplant coordinators, implementation of a new financial model with donor hospital reimbursement, public awareness campaign, international cooperation, adoption of new legislation, and implementation of a donor quality assurance program. The selection of key factors is based on the authors'' opinions; we are open for further discussion and propose systematic research into the issue.Transplantation is a widely accepted and successful life-saving treatment providing the best therapeutic benefit for hundreds of thousands of patients (1). Unfortunately, many people die while awaiting an organ transplant. A global shortage of organs available for transplantation raises many bioethical concerns, including the dilemma how to allocate limited resources to an unlimited number of needs and thus offer a fair and equal access to organ transplantation to all patients. Great efforts have been made to increase organ donation worldwide, but with only a moderate success in most of the countries. In contrast with this general trend, Croatia has recently experienced a boom in organ donation and transplantation. In 2011, Croatia had the highest rates of utilized cadaveric donors, kidney transplantations, and liver transplantations in the world (2-5) (Figure 1).Open in a separate windowFigure 1The number of kidney transplantations and the number of patients on the waiting list in Croatia between 2008 and 2011.Remarkably, only one decade ago, Croatia was lagging far behind other European countries with a low donation rate (2.7 donors per million population [p.m.p.] in 2000). The continuous improvement of the organization of the Croatian transplant program resulted in a steadily growing donor rate, which reached the highest level in 2011, with 33.6 utilized donors p.m.p (2). We analyzed the factors that might have contributed mostly to this great success.