Metabolomics Analysis and Modeling Suggest a Lysophosphocholines-PAF Receptor Interaction in Fibromyalgia

Fibromyalgia Syndrome (FMS) is a chronic disease characterized by widespread pain, and difficult to diagnose and treat. We analyzed the plasma metabolic profile of patients with FMS by using a metabolomics approach combining Liquid Chromatography-Quadrupole-Time Of Flight/Mass Spectrometry (LC-Q-TOF/MS) with multivariate statistical analysis, aiming to discriminate patients and controls. LC-Q-TOF/MS analysis of plasma (FMS patients: n = 22 and controls: n = 21) identified many lipid compounds, mainly lysophosphocholines (lysoPCs), phosphocholines and ceramides. Multivariate statistical analysis was performed to identify the discriminating metabolites. A protein docking and molecular dynamic (MD) study was then performed, using the most discriminating lysoPCs, to validate the binding to Platelet Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) Receptor (PAFr). Discriminating metabolites between FMS patients and controls were identified as 1-tetradecanoyl-sn-glycero-3-phosphocholine [PC(14∶0/0∶0)] and 1-hexadecanoyl-sn-glycero-3-phosphocholine [PC(16∶0/0∶0)]. MD and docking indicate that the ligands investigated have similar potentialities to activate the PAFr receptor. The application of a metabolomic approach discriminated FMS patients from controls, with an over-representation of PC(14∶0/0∶0) and PC(16∶0/0∶0) compounds in the metabolic profiles. These results and the modeling of metabolite-PAFr interaction, allowed us to hypothesize that lipids oxidative fragmentation might generate lysoPCs in abundance, that in turn will act as PAF-like bioactivators. Overall results suggest disease biomarkers and potential therapeutical targets for FMS.     

Multiple Endocrinopathies Associated with Lithium Therapy

ObjectiveTo illustrate a case of lithium-associated primary hyperparathyroidism, thyrotoxicosis, and nephrogenic diabetes insipidus and to discuss the potential mechanisms for these complications.MethodsWe describe the clinical and laboratory findings in our current patient and review the related medical literature.ResultsA 65-year-old Chinese woman with bipolar affective disorder, who had received maintenance lithium therapy for 10 years, was seen in an acute care hospital because of fever and confusion. Investigations showed that she had primary hyperparathyroidism and hyperthyroidism. She underwent a parathyroidectomy, which revealed a parathyroid adenoma. Her initial subclinical hyperthyroidism evolved into overt hyperthyroidism after use of lithium was discontinued. Therapy was initiated with carbimazole, which was up-titrated briefly; the patient was subsequently weaned off this medication. Her postoperative course was complicated by persistent polyuria in conjunction with a negative fluid balance, consistent with nephrogenic diabetes insipidus. Thus, amiloride therapy was instituted. The results of an objective causality assessment suggested that the primary hyperparathyroidism, hyperthyroidism, and nephrogenic diabetes insipidus were possibly or probably related to the lithium therapy.ConclusionLithium remains an intriguing drug with numerous potential endocrinologic complications. It is important that clinicians prescribing lithium are aware of its side effects and have a strategy for their detection and management. (Endocr Pract. 2007;13:758-763)     

Discovery of Potential New Gene Variants and Inflammatory Cytokine Associations with Fibromyalgia Syndrome by Whole Exome Sequencing

Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder affecting 2% to 5% of the general population. Both genetic and environmental factors may be involved. To ascertain in an unbiased manner which genes play a role in the disorder, we performed complete exome sequencing on a subset of FMS patients. Out of 150 nuclear families (trios) DNA from 19 probands was subjected to complete exome sequencing. Since >80,000 SNPs were found per proband, the data were further filtered, including analysis of those with stop codons, a rare frequency (<2.5%) in the 1000 Genomes database, and presence in at least 2/19 probands sequenced. Two nonsense mutations, W32X in C11orf40 and Q100X in ZNF77 among 150 FMS trios had a significantly elevated frequency of transmission to affected probands (p = 0.026 and p = 0.032, respectively) and were present in a subset of 13% and 11% of FMS patients, respectively. Among 9 patients bearing more than one of the variants we have described, 4 had onset of symptoms between the ages of 10 and 18. The subset with the C11orf40 mutation had elevated plasma levels of the inflammatory cytokines, MCP-1 and IP-10, compared with unaffected controls or FMS patients with the wild-type allele. Similarly, patients with the ZNF77 mutation have elevated levels of the inflammatory cytokine, IL-12, compared with controls or patients with the wild type allele. Our results strongly implicate an inflammatory basis for FMS, as well as specific cytokine dysregulation, in at least 35% of our FMS cohort.     

Pharmacogenetics of cancer chemotherapy

Significant heterogeneity in the efficacy and toxicity of chemotherapeutic agents is observed within cancer populations. Pharmacogenetics (PGx) is the study of inheritance in interindividual variation in drug disposition. The allure of pharmacogenetics, in the treatment of cancer patients, comes from the potential for individualisation of cancer therapy, minimizing toxicity, while maximizing efficacy. In this review we will focus on the current and potential clinical applications of pharmacogenetics in cancer therapy by citing relevant examples and discussing the possible approaches which may be used to establish a reliable, reproducible and cost-effective test for clinically relevant genetic polymorphisms, using easily accessible biological samples (e.g., blood and tumour samples). Ideally, routine management of patients would include analysis of their single nucleotide polymorphism linkage disequilibrium (SNP-LD) profile prior to treatment, allowing stratification of patients into treatment groups, thus individualising their therapy. In order to achieve this ambition, a combination of different approaches (candidate gene, genome-wide and pathway driven) will be required from scientists and clinician scientists, as well as an increased understanding and incorporation of pharmacogenetic aims and endpoints into current and future clinical trials.     

Current therapy of cutaneous melanoma

Melanoma is a growing public health problem. Optimal care of the melanoma patient is multidisciplinary, but plastic surgeons and other surgical specialties play a central role in the management of these patients. Although surgery remains the mainstay of therapy for melanoma, several recent clinical studies have helped to clarify the biology of the disease and have changed the patterns of care for patients with melanoma. The advent of lymphatic mapping for interrogation of regional lymph nodes and interferon as the first effective postsurgical adjuvant therapy have had a major impact on the care of melanoma in the United States and elsewhere. This article will review the current clinical approach and therapy for cutaneous melanoma. The diagnosis, prognostic variables, staging evaluation, current surgical and medical treatment, and follow-up guidelines for patients with all stages of melanoma are reviewed. Recent studies, controversies, and directions of future investigational therapies will be discussed.     

Carbon nanotubes in cancer diagnosis and therapy

During the past years, great progress has been made in the field of nanomaterials given their great potential in biomedical applications. Carbon nanotubes (CNTs), due to their unique physicochemical properties, have become a popular tool in cancer diagnosis and therapy. They are considered one of the most promising nanomaterials with the capability of both detecting the cancerous cells and delivering drugs or small therapeutic molecules to these cells. Over the last several years, CNTs have been explored in almost every single cancer treatment modality, including drug delivery, lymphatic targeted chemotherapy, thermal therapy, photodynamic therapy, and gene therapy. In this review, we will show how they have been introduced into the diagnosis and treatment of cancer. Novel SWNT-based tumor-targeted drug delivery systems (DDS) will be highlighted. Furthermore, the in vitro and in vivo toxicity of CNTs reported in recent years will be summarized.     

The future of bladder control-intravesical drug delivery, a pinch of pepper, and gene therapy

The incidence of urinary incontinence and overactive bladder problems will continue to grow as the population ages. Future treatments are likely to include an implantable drug delivery system, gene therapy, and the intravesical use of the vallinoids capsaicin and resiniferatoxin (RTX). An understanding of the urothelium is essential for effective design of these therapies. Intravesical anticholinergic drug treatment is currently not widely used, but intravesical pumps are under development to provide less cumbersome treatment methods and will provide nonsurgical options for patients who cannot tolerate oral anticholinergic agents. Research on the use of capsaicin as an intravesicular drug has had limited success, but trials have confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. RTX is as effective as capsaicin but without side effects, such as pain and inflammatory neuropeptide release. RTX treatment may eliminate the need for surgical and other drug treatments of lower urinary tract dysfunction in patients with spinal cord injuries. Gene therapy will change the practice of urology by addressing the deficiencies that cause symptoms rather than attacking the symptoms themselves.     

Treatment of Parkinson's Disease with L-Dopa: A Current Appraisal

Interest in l-dopa therapy for Parkinson''s disease has been considerably enhanced since the recent release of this drug to all medical practitioners. Our experience in the use of l-dopa in 83 patients who have been treated during the past 22 months is presented to provide a practical approach to the administration of l-dopa. Many parkinsonian patients can be treated advantageously on an outpatient basis without the need for initial hospitalization. Some of the common side effects of l-dopa administration can be averted or controlled by a cautious and slow build-up to the optimal dosage level. In the majority (78%) of parkinsonian patients who had been carefully selected for treatment the drug had a beneficial effect on akinesia and rigidity. In the remainder, therapy had to be discontinued because of undesirable side effects or a limited response.     

Limitations of Current Approaches For The Treatment of Acromegaly

Objective: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.Methods: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly.Results: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit.Conclusion: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.Abbreviations:AACE = American Association of Clinical EndocrinologistsAE = adverse eventATG = AutogelCFRT = conventional fractionated radiotherapyDA = dopamine agonistENDO = Endocrine SocietyGH = growth hormoneGHRA = growth hormone receptor antagonistIGF-1 = insulin-like growth factor 1LAR = long-acting releaseLFT = liver function testSC = subcutaneousSRS = stereotactic radiosurgerySSA = somatostatin analoguesst = somatostatin receptorsst₂ = somatostatin receptor subtype 2sst₅ = somatostatin receptor subtype 5TSS = transsphenoidal surgery     

Gene therapy for arthritis – where do we stand?

The successful use of biologicals in the treatment of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis has had a major impact on the management of these conditions. The challenge in the development of gene therapy as an alternative to these current treatments is to demonstrate that such therapy is more advantageous for patients from the therapeutic and safety points of view. Also, it will need to be demonstrated that gene therapy for the arthritides is economically feasible and that patient populations worldwide will be able to access these treatments.     

Gene therapy for arthritis--where do we stand?

The successful use of biologicals in the treatment of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis has had a major impact on the management of these conditions. The challenge in the development of gene therapy as an alternative to these current treatments is to demonstrate that such therapy is more advantageous for patients from the therapeutic and safety points of view. Also, it will need to be demonstrated that gene therapy for the arthritides is economically feasible and that patient populations worldwide will be able to access these treatments.     

Optimal use of blood in trauma patients

Injury is rapidly becoming the leading cause of death worldwide, and uncontrolled hemorrhage is the leading cause of potentially preventable death. In addition to crystalloid and/or colloid based resuscitation, severely injured trauma patients are routinely transfused RBCs, plasma, platelets, and in some centers either cryoprecipitate or fibrinogen concentrates or whole blood. Optimal timing and quantity of these products in the treatment of hypothermic, coagulopathic and acidotic trauma patients is unclear. The immediate availability of these components is important, as most hemorrhagic deaths occur within the first 3–6 h of patient arrival. While there are strongly held opinions and longstanding traditions in their use, there are little data within which to logically guide resuscitation therapy. Many current recommendations are based on euvolemic elective surgery patients and incorporate laboratory data parameters not widely available in the first few minutes after patient arrival. Finally, blood components themselves have evolved over the last 30 years, with great attention paid to product safety and inventory management, yet there are surprisingly limited clinical outcome data describing the long term effects of these changes, or how the components have improved clinical outcomes compared to whole blood therapy. When focused on survival of the rapidly bleeding trauma patient, it is unclear if current component therapy is equivalent to whole blood transfusion. In fact data from the current war in Iraq and Afghanistan suggest otherwise. All of these factors have contributed to the current situation, whereby blood component therapy is highly variable and not driven by long term patient outcomes. This review will address the issues raised above and describe recent trauma patient outcome data utilizing predetermined plasma:platelet:RBC transfusion ratios and an ongoing prospective observational trauma transfusion study.     

Indication Alerts Intercept Drug Name Confusion Errors during Computerized Entry of Medication Orders

Background

Confusion between similar drug names is a common cause of potentially harmful medication errors. Interventions to prevent these errors at the point of prescribing have had limited success. The purpose of this study is to measure whether indication alerts at the time of computerized physician order entry (CPOE) can intercept drug name confusion errors.

Methods and Findings

A retrospective observational study of alerts provided to prescribers in a public, tertiary hospital and ambulatory practice with medication orders placed using CPOE. Consecutive patients seen from April 2006 through February 2012 were eligible if a clinician received an indication alert during ordering. A total of 54,499 unique patients were included. The computerized decision support system prompted prescribers to enter indications when certain medications were ordered without a coded indication in the electronic problem list. Alerts required prescribers either to ignore them by clicking OK, to place a problem in the problem list, or to cancel the order. Main outcome was the proportion of indication alerts resulting in the interception of drug name confusion errors. Error interception was determined using an algorithm to identify instances in which an alert triggered, the initial medication order was not completed, and the same prescriber ordered a similar-sounding medication on the same patient within 5 minutes. Similarity was defined using standard text similarity measures. Two clinicians performed chart review of all cases to determine whether the first, non-completed medication order had a documented or non-documented, plausible indication for use. If either reviewer found a plausible indication, the case was not considered an error. We analyzed 127,458 alerts and identified 176 intercepted drug name confusion errors, an interception rate of 0.14±.01%.

Conclusions

Indication alerts intercepted 1.4 drug name confusion errors per 1000 alerts. Institutions with CPOE should consider using indication prompts to intercept drug name confusion errors.     

Gluten-free diet in the management of patients with irritable bowel syndrome,fibromyalgia and lymphocytic enteritis

An evaluation of the effect of 1 year of a gluten-free diet was performed in patients with irritable bowel syndrome and fibromyalgia syndrome displaying lymphocytic enteritis. Gluten withdrawal produced a slight but significant improvement of the functional symptoms, suggesting that gluten might be partly responsible for this clinical picture. This hypothesis should be confirmed by a double-blind placebo-controlled trial since it cannot be ruled out that the studied patients displayed a subjective sensation of improvement due to the placebo effect of gluten withdrawal. Further investigations are needed before recommending gluten withdrawal in patients with fibromyalgia and lymphocytic enteritis.In their paper published in a recent issue of Arthritis Research and Therapy, Rodrigo and colleagues evaluated the effect of 1 year of a gluten-free diet on the clinical evolution of irritable bowel syndrome (IBS) plus fibromyalgia syndrome (FMS) in patients with lymphocytic enteritis (LE) [1]. The study sample included 97 adult females with IBS and FMS, of whom 58 had LE and the remaining 39 had a normal intraepithelial lymphocytic (IEL) count. All subjects fulfilled the Rome III criteria for IBS and the American College of Rheumatology 1990 criteria for FMS and none of them satisfied the diagnostic criteria for celiac disease diagnosis (absence of villous atrophy and negativity for tissue transglutaminase antibodies).IBS and FMS are two chronic functional disorders that are found in a high number of people in the general population and are frequently detected in the same subject [2]. A subset of patients complaining of IBS and FMS displays LE, a morphological finding that by itself is not specific for celiac disease, also being found in many other pathological conditions such as food allergy, autoimmune disorders, Helicobacter pylori infection, nonsteroidal anti-inflammatory drug treatment and common variable immunodeficiency [3].The spectrum of gluten-related disorders has recently acquired a new syndrome, defined as nonceliac gluten sensitivity according to the criteria established in the two Consensus Conferences held in London and Munich [4]. This new clinical entity is characterized by IBS-like symptoms and several extraintestinal manifestations occurring after gluten ingestion in patients without celiac disease and wheat allergy. In a recent prospective multicenter survey of 486 patients with nonceliac gluten sensitivity, IBS and FMS were respectively detected in 47% and 31% of cases and about one-third of these patients had LE [5].Along with IBS-related and FMS-related symptoms, the patients studied by Rodrigo and colleagues also showed other manifestations resembling the clinical picture of nonceliac gluten sensitivity such as skin rash, cognitive dysfunction, headache, numbness, anxiety and depression [1].In Rodrigo and colleagues’ paper, the gluten-free diet produced a slight but significant improvement of both IBS-related (chronic abdominal pain, changes in intestinal habit, bloating) and FMS-related symptoms (chronic widespread pain, generalized tender points, fatigue and restless sleep) in the LE subgroup versus the non-LE subgroup. These results stress the potential role of gluten as a trigger of the clinical manifestations of IBS and FMS and indicate that LE might be useful to identify those patients who potentially benefit from gluten withdrawal. One relevant limitation of this study is the lack of a double-blind placebo-controlled challenge, which is the only procedure to confirm the role of gluten proteins in the development of these clinical manifestations. Indeed, it cannot be ruled out that some patients displayed a subjective sensation of improvement due to the placebo effect of a gluten-free diet [6]. The search for antigliadin antibodies could be of help to elucidate whether gluten can be partly responsible for the clinical picture observed in Rodrigo and colleagues’ patients. Indeed, antigliadin antibodies (particularly those belonging to the IgG class) are the only marker observed in patients with symptoms elicited by gluten ingestion, being positive in more than 50% of cases [7]. These antibodies are not specific for gluten-related symptoms, but their finding in patients with symptoms potentially evoked by gluten ingestion should be regarded as an indication for a gluten-free diet trial in patients with LE [8]. Antigliadin antibodies of the IgG class are closely related to the gluten-induced symptoms and tend to disappear very quickly (within a few weeks) together with the remission of symptoms after a gluten-free diet [9].An interesting finding emerging from the Spanish study is that about 20% of IBS/FMS patients with LE had relatives with celiac disease, whereas no familial case of celiac disease was observed among patients without LE [1]. In the same guise, familial cases of FMS were found, although to a lesser extent, only in the group with LE (7%). These data suggest that first-degree relatives of IBS/FMS patients with LE should be carefully investigated for the possible presence of undetected cases of celiac disease and FMS. For LE, the mean IEL number reported in Rodrigo and colleagues’ paper was 35/100. This result confirms that LE found in gluten-sensitive patients is mild, with a lower mean IEL number than that usually observed in celiac disease patients (usually >40/100) [10].The caution in the conclusions of Rodrigo and colleagues’ study is appreciable and shareable. A gluten-free diet is not appropriate in patients with IBS/FMS with normal intestinal mucosa (normal IEL count). Moreover, although the reported results suggest a significant improvement of symptomatology after a gluten-free diet in the LE subgroup, further studies including double-blind placebo-controlled trials are needed before proposing gluten withdrawal in IBS/FMS patients with LE.     

Prognostic and Diagnostic Potential of the Structural Neuroanatomy of Depression

Background

Depression is experienced as a persistent low mood or anhedonia accompanied by behavioural and cognitive disturbances which impair day to day functioning. However, the diagnosis is largely based on self-reported symptoms, and there are no neurobiological markers to guide the choice of treatment. In the present study, we examined the prognostic and diagnostic potential of the structural neural correlates of depression.

Methodology and Principal Findings

Subjects were 37 patients with major depressive disorder (mean age 43.2 years), medication-free, in an acute depressive episode, and 37 healthy individuals. Following the MRI scan, 30 patients underwent treatment with the antidepressant medication fluoxetine or cognitive behavioural therapy (CBT). Of the patients who subsequently achieved clinical remission with antidepressant medication, the whole brain structural neuroanatomy predicted 88.9% of the clinical response, prior to the initiation of treatment (88.9% patients in clinical remission (sensitivity) and 88.9% patients with residual symptoms (specificity), p = 0.01). Accuracy of the structural neuroanatomy as a diagnostic marker though was 67.6% (64.9% patients (sensitivity) and 70.3% healthy individuals (specificity), p = 0.027).

Conclusions and Significance

The structural neuroanatomy of depression shows high predictive potential for clinical response to antidepressant medication, while its diagnostic potential is more limited. The present findings provide initial steps towards the development of neurobiological prognostic markers for depression.     

Molecular mapping the presence of druggable targets in preinvasive and precursor breast lesions: A comprehensive review of biomarkers related to therapeutic interventions

The analysis of clinical breast samples using biomarkers is integral to current breast cancer management. Currently, a limited number of targeted therapies are standard of care in breast cancer treatment. However, these targeted therapies are only suitable for a subset of patients and resistance may occur. Strategies to prevent the occurrence of invasive lesions are required to reduce the morbidity and mortality associated with the development of cancer. In theory, application of targeted therapies to pre-invasive lesions will prevent their progression to invasive lesions with full malignant potential. The diagnostic challenge for pathologists is to make interpretative decisions on early detected pre-invasive lesions. Overall, only a small proportion of these pre-invasive lesions will progress to invasive carcinoma and morphological assessment is an imprecise and subjective means to differentiate histologically identical lesions with varying malignant potential. Therefore differential biomarker analysis in pre-invasive lesions may prevent overtreatment with surgery and provide a predictive indicator of response to therapy. There follows a review of established and emerging potential druggable targets in pre-invasive lesions and correlation with lesion morphology.     

Commercialization of antifungal peptides

There remains an urgent and very much unmet medical need for new antifungal therapies. Ideally, the next generation of treatments for nosocomial and community-acquired infections, including those caused by Candida spp, Aspergillus spp, Cryptococcus spp and Fusarium spp, will be more efficacious, with higher therapeutic indices and broader activity spectra than existing antifungal drug classes. Moreover, future antifungal therapeutics should have novel modes of action/drug targets that at least minimise, if not negate, the risk of acquired resistance developing in their target fungal pathogen populations. In short, developing the next generation of antifungals is a tall order and whoever is successful in doing so must address the various and well-described shortcomings of what remains at present, a very limited choice of largely small molecule-based therapeutics against the fungal infection spectrum. Novel peptide antifungals engineered from a template of mammalian, amphibian and even insect endogenous antimicrobial peptides (AMPs) have clear potential to meet these requirements and consequent clinical success in a range of fungal diseases. This potential will hopefully be realised in the future as any number of the promising preclinical candidate antifungal peptides identified to date are developed further towards the clinic. The size of the ever-increasing market potential as well as unmet clinical need for new antifungal treatments is such that succeeding in delivering novel peptide antifungals as safe and potently efficacious therapies for the future will have a significant health-economic impact.     

Commercialization of antifungal peptides

There remains an urgent and very much unmet medical need for new antifungal therapies. Ideally, the next generation of treatments for nosocomial and community-acquired infections, including those caused by Candida spp, Aspergillus spp, Cryptococcus spp and Fusarium spp, will be more efficacious, with higher therapeutic indices and broader activity spectra than existing antifungal drug classes. Moreover, future antifungal therapeutics should have novel modes of action/drug targets that at least minimise, if not negate, the risk of acquired resistance developing in their target fungal pathogen populations. In short, developing the next generation of antifungals is a tall order and whoever is successful in doing so must address the various and well-described shortcomings of what remains at present, a very limited choice of largely small molecule-based therapeutics against the fungal infection spectrum. Novel peptide antifungals engineered from a template of mammalian, amphibian and even insect endogenous antimicrobial peptides (AMPs) have clear potential to meet these requirements and consequent clinical success in a range of fungal diseases. This potential will hopefully be realised in the future as any number of the promising preclinical candidate antifungal peptides identified to date are developed further towards the clinic. The size of the ever-increasing market potential as well as unmet clinical need for new antifungal treatments is such that succeeding in delivering novel peptide antifungals as safe and potently efficacious therapies for the future will have a significant health-economic impact.     

High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma

Therapy options for patients with metastatic melanoma (MM) have considerably improved over the past decade. However, many patients still need effective therapy after unsuccessful immunotherapy, especially patients with BRAF-negative tumors who lack the option of targeted treatment second line. Therefore, the elucidation of efficient and personalized therapy options for these patients is required. In this study, three patient-derived cancer cells (PDCs) were established from NRAS Q61-positive MM patients. The response of PDCs and five established melanoma cell lines (two NRAS-positive, one wild type, and two BRAF V600-positive) was evaluated toward a panel of 527 oncology drugs using high-throughput drug sensitivity and resistance testing. The PDCs and cell lines displayed strong responses to MAPK inhibitors, as expected. Additionally, the PDCs and cell lines were responsive to PI3K/mTOR, mTOR, and PLK1 inhibitors among other effective drugs currently undergoing clinical trials. Combinations with a MEK inhibitor were tested with other targeted agents to identify effective synergies. MEK inhibitor showed synergy with multikinase inhibitor ponatinib, ABL inhibitor nilotinib, PI3K/mTOR inhibitor pictilisib, and pan-RAF inhibitor LY3009120. The application of the patients’ cancer cells for functional drug testing ex vivo is one step further in the process of identifying potential agents and agent combinations to personalize treatment for patients with MM. Our preliminary study results suggest that this approach has the potential for larger-scale drug testing and personalized treatment applications in our expansion trial. Our results show that drug sensitivity and resistance testing may be implementable in the treatment planning of patients with MM.