Update on management of pancreatic cancer: a literature review.

BACKGROUND AND OBJECTIVE: Pancreatic cancer is an aggressive malignancy with high mortality. At the time of diagnosis, majority of patients (80-90%) present with either locally advanced unresectable disease or metastatic disease. Even after curative resection, the recurrence rate remains quite high. This article aimed at reviewing the updated management of pancreatic cancer. METHODS: We identified literature by searching Medline and PubMed from January 2010 to June 2023 using the keywords. KEY CONTENT AND FINDINGS: A multidisciplinary approach is essential to optimize the outcomes for both curable and advanced diseases. Management of pancreatic cancer divided into resectable, borderline resectable, locally advanced, and metastatic diseases. Surgery and adjuvant chemotherapy is a standard treatment approach for resectable pancreatic cancer. The recommended adjuvant chemotherapy regimen for patients with good functional status is modified FOLFIRINOX (5-fluorouracil, folinic acid, irinotecan, and oxaliplatin). The recommended adjuvant chemotherapy regimen for patients with suboptimal functional status is gemcitabine plus capecitabine or monotherapy gemcitabine. The optimal treatment strategy for borderline resectable pancreatic cancer is still uncertain. Traditionally, upfront surgery is the choice of treatment. There is increasing evidence showing benefits of neoadjuvant therapy in borderline resectable pancreatic cancer. However, the optimal neoadjuvant treatment regimen was not certain yet. Advancement of chemotherapy has a positive impact for the survival of advanced disease. For patients with good functional status, the recommended first-line systemic chemotherapy for unresectable locally advanced disease or metastatic disease is combination chemotherapy regimens such as FOLFIRINOX, gemcitabine plus nab-paclitaxel. For patients with suboptimal functional status, the recommended first-line systemic chemotherapy for unresectable locally advanced disease or metastatic disease is gemcitabine plus capecitabine or monotherapy gemcitabine. Recently, more researches showed promising results in the use of nanoliposomal irinotecan, targeted agents such as a poly [adenosine diphosphate (ADB)-ribose] polymerase inhibitor, tyrosine receptor kinase (TRK) inhibitors, and immune checkpoint-inhibitors. CONCLUSIONS: Pancreatic cancer is a challenging disease for management. Radical surgery itself is not enough for prolong survival. The improvement of chemotherapy, target agents and immunotherapy with multidisciplinary approach will be the only solution for improvement of survival outcome and quality of life for patients with pancreatic cancer.

Mechanism and clinical implication of gut dysbiosis in degenerative abdominal aortic aneurysm: A systematic review.

The gut microbiome is the entirety of microorganisms and their genomes residing in the gut, characterised by diversity, stability, and resilience. Disrupted gut microbiome has been implicated in multiple disease entities. The aim of this paper is to summarise the rapidly evolving contemporary evidence of gut dysbiosis on the development and progression of abdominal aortic aneurysm (AAA), discuss possible mechanisms, and explore potential microbiota-targeted interventions and prognostic markers for AAA. A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using PubMed, ScienceDirect, Web of Science, Ovid, Embase. Search terms of "microbiome" OR "dysbiosis" OR "microorganism"; AND "aneurysm" OR "dilatation" OR "aorta" were used. Study endpoints included effects of microbiota on AAA formation, effects of specific type of bacteria and its metabolite on AAA formation, and pre- or post-treatment by novel small-molecules/inhibitors. From May to August 2023, a total of twelve animal studies and eight human studies were included. Akkermansia muciniphila, Lactobacillus acidophilus and species from the Bacteroidetes phylum were associated with lower AAA incidence in both animal and human studies, while Proteobacteria phylum, Campylobacter, Fusobacterium and Faecalibacterium prausnitzii were found to be in abundance in the AAA group and were associated with larger aneurysms. The diversity of gut microbiota was inversely correlated with AAA diameter. Three important mechanisms were identified: including trimethylamine N-oxide pathway, butyric acid pathway, and aberrant tryptophan metabolism. With our expanding knowledge of the downstream pathogenic mechanisms of gut dysbiosis, novel therapeutics such as short-chain fatty acids and spermidine, as well as prognostic biomarkers such as TMAO have yielded promising preclinical results. In conclusion, there is strong evidence corroborating the role of gut dysbiosis in the pathogenesis of AAA, wherein its therapeutic and prognostic potential deserves further exploration.

Safety, tolerability, and pharmacokinetics of a single orally inhaled dose of PUR3100, a dry powder formulation of dihydroergotamine versus intravenous dihydroergotamine: A Phase 1 randomized, double-blind study in healthy adults.

BACKGROUND: Intravenous dihydroergotamine (DHE) has well-established efficacy for the acute treatment of migraine, but its use is limited by the need for in-hospital administration and the nausea/vomiting associated with a high maximum plasma concentration (Cmax). Inhalation is an alternative to intravenous dosing. The surface area of the lung allows for rapid absorption of a self-administered dose. OBJECTIVE: This study evaluated the safety, tolerability, and systemic pharmacokinetics (PK) of a dry powder formulation (PUR3100) DHE when delivered via inhalation compared to intravenous delivery. METHODS: In this double-blind, double-dummy Phase 1 study, healthy volunteers (N = 26) were randomized (1:1:1:1) to one of four groups: orally inhaled placebo plus intravenous DHE 1.0 mg or orally inhaled PUR3100 (0.5, 1.0, or 1.5 mg) plus intravenous placebo. Blood samples were drawn pre-dose and at time points post-dose over 48 h. Standard PK and safety parameters were assessed and values for Cmax and area under plasma concentration time curve (AUC) were used to assess comparative exposures of PUR3100 versus intravenous DHE. RESULTS: All doses of PUR3100 were associated with a lower incidence of nausea (21% vs. 86%), vomiting (0% vs. 29%), and headache (16% vs. 57%) compared to intravenous DHE. The PK profile of PUR3100 versus intravenous DHE was characterized by a similar mean time to Cmax (5 vs. 5.5 min), with reduced AUC0-2h (1120-4320 vs. 6340), and a lower Cmax (3620-14,400 vs. 45,000). Compared to intravenous DHE 1.0 mg, the highest nominal PUR3100 dose (1.5 mg), which delivers a fine-particle dose of approximately 0.9 mg to the lungs, had a geometric mean ratio percentage (90% confidence interval [CI]) for Cmax of 32% [17.2, 59.6] and AUC0-inf of 93% (62.9, 138.5), the latter of which was not significantly different. CONCLUSIONS: Inhaled PUR3100 is associated with rapid systemic PK within the therapeutic window and an improved safety profile relative to intravenous DHE.

Influence of an Exercise-Specific Face Mask on Physiological and Perceptual Responses to Graded Exercise.

The impact of exercise-specific face masks (ESFMs) in aerobically fit individuals on physiological, perceptual, respiratory, and performance responses remains unclear. How ESFMs mitigate exercise-induced bronchoconstriction (EIB) is also unknown. Thus, this study aimed to determine how an ESFM altered within-exercise physiological, perceptual, respiratory, and performance responses to graded treadmill exercise. Twenty-four individuals (11 females) completed a discontinuous graded exercise test on a treadmill under two conditions (ESFM and unmasked). Physiological, respiratory function, and perceptual measures were assessed. Performance was determined by time to exhaustion. Statistical analyses included linear mixed-effects modeling, repeated measures analysis of variance, and pairwise comparisons using an alpha value of 0.05. ESFM use significantly impaired performance (median = -150.5 s) and decreased arterial oxygen saturation at maximal intensity (mean = -3.7%). Perceptions of air hunger and work of breathing were elevated across submaximal and maximal intensities. Perceived exertion and breathing discomfort were significantly elevated submaximally but not maximally. Spirometry measures were not significantly different at termination but were significantly improved at submaximal intensities in participants with and without EIB. ESFM use in fit individuals increased perceptual discomfort, impaired performance, and augmented arterial desaturation. Respiratory function improvements were observed but were accompanied by adverse perceptual sensations. Despite this, performance impairments may limit the real-world utility of ESFMs for athletes.

Risk Factors Associated with Missing Incidents among Persons Living with Dementia: A Scoping Review.

Worldwide, over 55-million people have dementia, and the number will triple by 2050. Persons living with dementia are exposed to risks secondary to cognitive challenges including getting lost. The adverse outcomes of going missing include injuries, death, and premature institutionalization. In this scoping review, we investigate risk factors associated with going missing among persons living with dementia. We searched and screened studies from four electronic databases (Medline, CINAHL, Embase, and Scopus), and extracted relevant data. We identified 3,376 articles, of which 73 met the inclusion criteria. Most studies used quantitative research methods. We identified 27 variables grouped into three risk factor domains: (a) demographics and personal characteristics, (b) health conditions and symptoms, and (c) environmental and contextual antecedents. Identification of risk factors associated with getting lost helps to anticipate missing incidents. Risk factors can be paired with proactive strategies to prevent incidents and inform policies to create safer communities.

Extensive breaking of genetic code degeneracy with non-canonical amino acids.

Genetic code expansion (GCE) offers many exciting opportunities for the creation of synthetic organisms and for drug discovery methods that utilize in vitro translation. One type of GCE, sense codon reassignment (SCR), focuses on breaking the degeneracy of the 61 sense codons which encode for only 20 amino acids. SCR has great potential for genetic code expansion, but extensive SCR is limited by the post-transcriptional modifications on tRNAs and wobble reading of these tRNAs by the ribosome. To better understand codon-tRNA pairing, here we develop an assay to evaluate the ability of aminoacyl-tRNAs to compete with each other for a given codon. We then show that hyperaccurate ribosome mutants demonstrate reduced wobble reading, and when paired with unmodified tRNAs lead to extensive and predictable SCR. Together, we encode seven distinct amino acids across nine codons spanning just two codon boxes, thereby demonstrating that the genetic code hosts far more re-assignable space than previously expected, opening the door to extensive genetic code engineering.

Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38hiCD127- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.

Evaluation of the Potential for Drug-Drug Interactions with Inhaled Itraconazole Using Physiologically Based Pharmacokinetic Modelling, Based on Phase 1 Clinical Data.

Itraconazole is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), associated with numerous drug-drug interactions (DDI). PUR1900, a dry powder formulation of itraconazole for oral inhalation, results in high lung and low systemic exposure. This project used physiologically based pharmacokinetic (PBPK) modeling to assess the DDI potential of inhaled PUR1900, using midazolam as a "victim drug." The basic and mechanistic static models evaluated the DDI potential of PUR1900, assuming 5 mg of midazolam coadministration at steady-state itraconazole exposure. Subsequently, Simcyp® PBPK simulation software and pharmacokinetic data from a Phase 1 clinical trial with PUR1900 (NCT03479411) were used to optimize an existing itraconazole PBPK model. The model was applied to investigate the potential for CYP3A4 DDI when 5 mg of midazolam is co-administered with inhaled PUR1900 at a steady state in a virtual healthy population at PUR1900 doses up to 40 mg per day. The basic static and mechanistic static models suggested a strong likelihood for DDI with inhaled PUR1900. The PBPK model was consistent with PUR1900 Phase 1 trial data. The geometric mean Cmax and AUC ratios of midazolam at a maximum dose of 40 mg PUR1900 were 1.14 and 1.26, respectively, indicating a minimal likelihood of DDI with inhaled PUR1900. The low systemic exposure of itraconazole when administered as PUR1900 results in minimal to no CYP3A4 inhibition, reducing the concern of drug-drug interactions. As the risk of CYP3A4 DDI is predicted to be significantly lower when itraconazole is administered via oral inhalation as PUR1900, it is likely that PUR1900 can be safely used for the treatment of pulmonary fungal infections in patients taking pharmaceuticals currently contraindicated with oral itraconazole.

Do Female University Varsity Athletes Have a Greater Risk of Injury Within a Competitive Varsity Season?

Previous varsity sport injury research has analyzed how acute and chronic injury severity, type, and location differs between sport and sexes, with limited research in time to injury. Canadian university varsity sport injury research is especially sparse and mostly retrospective. Thus, we aimed to understand injury differences in male and female competitive university athletes competing in the same sport. Athletes who competed on the basketball, volleyball, soccer, ice hockey, football (male), rugby (female), and wrestling teams were eligible for the study. There were 182 male and 113 female athletes who provided informed consent to be prospectively followed over a season. Injury date, type, location, chronicity, and events missed due to injury were recorded on a weekly basis. Overall, the percentage of male (68.7%) and female (68.1%) athletes injured was not different. No overall sex differences (variables collapsed) were observed in injury chronicity, location, type, events lost, mean number of injuries, or time to injury. Within sport differences existed for mean number of injuries, injury location, type of injury, and events missed. Mean time to injury in female basketball (28 days) and volleyball athletes (14 days) was significantly shorter compared to male basketball (67 days) and volleyball (65 days). Time to a concussion was significantly shorter in females overall compared to males. These results indicate that Canadian female university age athletes are not inherently more susceptible to injury, but female athletes within certain sports may have increased injury risk which could shorten time to injury (basketball, volleyball) and increase the number of events missed due to injury (hockey).

EGCG inactivates a pore-forming toxin by promoting its oligomerization and decreasing its solvent-exposed hydrophobicity.

Natural proteinaceous pore-forming agents can bind and permeabilize cell membranes, leading to ion dyshomeostasis and cell death. In the search for antidotes that can protect cells from peptide toxins, we discovered that the polyphenol epigallocatechin gallate (EGCG) interacts directly with melittin from honeybee venom, resulting in the elimination of its binding to the cell membrane and toxicity by markedly lowering the extent of its solvent-exposed hydrophobicity and promoting its oligomerization into larger species. These physicochemical parameters have also been shown to play a key role in the binding to cells of misfolded protein oligomers in a host of neurodegenerative diseases, where oligomer-membrane binding and associated toxicity have been shown to correlate negatively with oligomer size and positively with solvent-exposed hydrophobicity. For melittin, which is not an amyloid-forming protein and has a very distinct mechanism of toxicity compared to misfolded oligomers, we find that the size-hydrophobicity-toxicity relationship also rationalizes the pharmacological attenuation of melittin toxicity by EGCG. These results highlight the importance of the physicochemical properties of pore forming agents in mediating their interactions with cell membranes and suggest a possible therapeutic approach based on compounds with a similar mechanism of action as EGCG.

Technology Acceptance of a Mobile Application to Support Family Caregivers in a Long-Term Care Facility.

BACKGROUND: Family caregivers are unpaid individuals who provide care to people with chronic conditions or disabilities. Family caregivers generally do not have formal care-related training. However, they are an essential source of care. Mobile technologies can benefit family caregivers by strengthening communication with care staff and supporting the monitoring of care recipients. OBJECTIVE: We conducted a mixed-method study to evaluate the acceptance and usability of a mobile technology called the Smart Care System. METHODS: Using convenience sampling, we recruited 27 family caregivers to evaluate the mobile Smart Care System (mSCS). In the quantitative phase, we administered initial and exit questionnaires based on the Unified Theory of Acceptance and Use of Technology. In the qualitative phase, we conducted focus groups to explore family caregivers' perspectives and opinions on the usability of the mSCS. With the quantitative data, we employed univariate, bivariate, and partial least squares analyses, and we used content analysis with the qualitative data. RESULTS: We observed a high level of comfort using digital technologies among participants. On average, participants were caregivers for an average of 6.08 years (standard deviation [SD] = 6.63), and their mean age was 56.65 years (SD = 11.62). We observed a high level of technology acceptance among family caregivers (7.69, SD = 2.11). Behavioral intention (ß = 0.509, p-value = 0.004) and facilitating conditions (ß = 0.310, p-value = 0.049) were statistically significant and related to usage behavior. In terms of qualitative results, participants reported that the mobile application supported care coordination and communication with staff and provided peace of mind to family caregivers. CONCLUSION: The technology showed high technology acceptance and intention to use among family caregivers in a long-term care setting. Facilitating conditions influenced acceptance. Therefore, it would be important to identify and optimize these conditions to ensure technology uptake.

Machine learning prediction of atrial fibrillation in cardiovascular patients using cardiac magnetic resonance and electronic health information.

Background: Atrial fibrillation (AF) is a commonly encountered cardiac arrhythmia associated with morbidity and substantial healthcare costs. While patients with cardiovascular disease experience the greatest risk of new-onset AF, no risk model has been developed to predict AF occurrence in this population. We hypothesized that a patient-specific model could be delivered using cardiovascular magnetic resonance (CMR) disease phenotyping, contextual patient health information, and machine learning. Methods: Nine thousand four hundred forty-eight patients referred for CMR imaging were enrolled and followed over a 5-year period. Seven thousand, six hundred thirty-nine had no prior history of AF and were eligible to train and validate machine learning algorithms. Random survival forests (RSFs) were used to predict new-onset AF and compared to Cox proportional-hazard (CPH) models. The best performing features were identified from 115 variables sourced from three data domains: (i) CMR-based disease phenotype, (ii) patient health questionnaire, and (iii) electronic health records. We evaluated discriminative performance of optimized models using C-index and time-dependent AUC (tAUC). Results: A RSF-based model of 20 variables (CIROC-AF-20) delivered an overall C-index of 0.78 for the prediction of new-onset AF with respective tAUCs of 0.80, 0.79, and 0.78 at 1-, 2- and 3-years. This outperformed a novel CPH-based model and historic AF risk scores. At 1-year of follow-up, validation cohort patients classified as high-risk of future AF by CIROC-AF-20 went on to experience a 17.3% incidence of new-onset AF, being 24.7-fold higher risk than low risk patients. Conclusions: Using phenotypic data available at time of CMR imaging we developed and validated the first described risk model for the prediction of new-onset AF in patients with cardiovascular disease. Complementary value was provided by variables from patient-reported measures of health and the electronic health record, illustrating the value of multi-domain phenotypic data for the prediction of AF.

Concomitant Bouveret's syndrome and biliary obstruction: A tailored treatment approach for an elderly patient.

INTRODUCTION AND IMPORTANCE: Bouveret's syndrome is a very rare form of gallstone ileus, that occurs when a sizable gallstone enters the gastrointestinal tract via a bilioenteric fistula and is impacted in the pylorus or proximal duodenum, causing gastric outlet obstruction. It usually occurs in a geriatric population with multiple comorbidities, and causes significant morbidities and mortalities. CASE PRESENTATION: An 88-year-old patient with concomitant Bouveret's syndrome and biliary obstruction was presented. The duodenal obstructed stone and biliary stone were successfully removed by endoscopic approach. The patient resumed diet on day-1 and recovered smoothly. CLINICAL DISCUSSION: Due to the rarity of Bouveret's syndrome, there are no standardized recommendations for the management of these patients, including open, laparoscopic surgical approach or endoscopic approach. Minimally invasive treatment was tailored to the condition of the patient and clinical findings. CONCLUSION: The best approach is the one tailored to each patient, with the consideration of the patient's medical condition, age, comorbidities, life expectancy, and available expertise. This article highlights the key features of the disease, and the precautions during endoscopic treatment.

Anticipatory Anxiety, Familiarization, and Performance: Finding the Sweet Spot to Optimize High-Quality Data Collection and Minimize Subject Burden.

Accurate baseline data are essential for researchers to determine an intervention's effects yet may be affected by anticipatory anxiety and assessment familiarity. Familiarization sessions help establish accurate baseline data. High-intensity functional training (HIFT) elicits performance outcomes based on constantly varied workouts. It is unclear how familiarization affects anticipatory anxiety and workout performance among HIFT novices. Familiarization was hypothesized to decrease anxiety and improve workout performance. Sixteen college-aged subjects (62.5% women, 20.2 ± 1.14 years) completed one introductory and four sessions of the same workout. All subjects were recreationally trained with no HIFT experience. State and trait anxiety were assessed at the first session. During the workout sessions, state anxiety (SQALS) was assessed upon arrival at the gym (SQALS 1), after learning the workout protocol (SQALS 2), and when the workout concluded (SQALS 3). A significant main effect of the number of previous sessions on workout performance was observed (p = 0.011). A repeated-measures ANOVA showed a main effect of time on SQALS 1 (p < 0.001), SQALS 2 (p < 0.001), and SQALS 3 (p < 0.001). Our results suggest implementing two familiarization sessions for our HIFT-based workout was sufficient to decrease anxiety and establish a baseline measurement. Future research should examine if this remains true for other types of HIFT-based workouts.

Machine Learning Patient-Specific Prediction of Heart Failure Hospitalization Using Cardiac MRI-Based Phenotype and Electronic Health Information.

Background: Heart failure (HF) hospitalization is a dominant contributor of morbidity and healthcare expenditures in patients with systolic HF. Cardiovascular magnetic resonance (CMR) imaging is increasingly employed for the evaluation of HF given capacity to provide highly reproducible phenotypic markers of disease. The combined value of CMR phenotypic markers and patient health information to deliver predictions of future HF events has not been explored. We sought to develop and validate a novel risk model for the patient-specific prediction of time to HF hospitalization using routinely reported CMR variables, patient-reported health status, and electronic health information. Methods: Standardized data capture was performed for 1,775 consecutive patients with chronic systolic HF referred for CMR imaging. Patient demographics, symptoms, Health-related Quality of Life, pharmacy, and routinely reported CMR features were provided to both machine learning (ML) and competing risk Fine-Gray-based models (FGM) for the prediction of time to HF hospitalization. Results: The mean age was 59 years with a mean LVEF of 36 ± 11%. The population was evenly distributed between ischemic (52%) and idiopathic non-ischemic cardiomyopathy (48%). Over a median follow-up of 2.79 years (IQR: 1.59-4.04) 333 patients (19%) experienced HF related hospitalization. Both ML and competing risk FGM based models achieved robust performance for the prediction of time to HF hospitalization. Respective 90-day, 1 and 2-year AUC values were 0.87, 0.83, and 0.80 for the ML model, and 0.89, 0.84, and 0.80 for the competing risk FGM-based model in a holdout validation cohort. Patients classified as high-risk by the ML model experienced a 34-fold higher occurrence of HF hospitalization at 90 days vs. the low-risk group. Conclusion: In this study we demonstrated capacity for routinely reported CMR phenotypic markers and patient health information to be combined for the delivery of patient-specific predictions of time to HF hospitalization. This work supports an evolving migration toward multi-domain data collection for the delivery of personalized risk prediction at time of diagnostic imaging.

A Brain-Permeable Aminosterol Regulates Cell Membranes to Mitigate the Toxicity of Diverse Pore-Forming Agents.

The molecular composition of the plasma membrane plays a key role in mediating the susceptibility of cells to perturbations induced by toxic molecules. The pharmacological regulation of the properties of the cell membrane has therefore the potential to enhance cellular resilience to a wide variety of chemical and biological compounds. In this study, we investigate the ability of claramine, a blood-brain barrier permeable small molecule in the aminosterol class, to neutralize the toxicity of acute biological threat agents, including melittin from honeybee venom and α-hemolysin from Staphylococcus aureus. Our results show that claramine neutralizes the toxicity of these pore-forming agents by preventing their interactions with cell membranes without perturbing their structures in a detectable manner. We thus demonstrate that the exogenous administration of an aminosterol can tune the properties of lipid membranes and protect cells from diverse biotoxins, including not just misfolded protein oligomers as previously shown but also biological protein-based toxins. Our results indicate that the investigation of regulators of the physicochemical properties of cell membranes offers novel opportunities to develop countermeasures against an extensive set of cytotoxic effects associated with cell membrane disruption.

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-ß and α-Synuclein and Suppress the Toxicity of Their Oligomers.

The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-ß peptide (Aß) and of α-synuclein (αS), which are associated with Alzheimer's and Parkinson's diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aß and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aß and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer's and Parkinson's diseases.

Allergic Diseases Caused by Aspergillus Species in Patients with Cystic Fibrosis.

Aspergillus spp. are spore forming molds; a subset of which are clinically relevant to humans and can cause significant morbidity and mortality. A. fumigatus causes chronic infection in patients with chronic lung disease such as asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). In patients with CF, A. fumigatus infection can lead to allergic disease, such as allergic bronchopulmonary aspergillosis (ABPA) which is associated with high rates of hospitalizations for acute exacerbations and lower lung function. ABPA results from TH2 immune response to Aspergillus antigens produced during hyphal growth, marked by high levels of IgE and eosinophil activation. Clinically, patients with ABPA experience difficulty breathing; exacerbations of disease and are at high risk for bronchiectasis and lung fibrosis. Oral corticosteroids are used to manage aspects of the inflammatory response and antifungal agents are used to reduce fungal burden and lower the exposure to fungal antigens. As the appreciation for the severity of fungal infections has grown, new therapies have emerged that aim to improve treatment and outcomes for patients with CF.

Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers.

The aberrant aggregation of proteins is implicated in the onset and pathogenesis of a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Mounting evidence indicates that misfolded protein oligomers produced as intermediates in the aggregation process are potent neurotoxic agents in these diseases. Because of the transient and heterogeneous nature of these elusive aggregates, however, it has proven challenging to develop therapeutics that can effectively target them. Here, we review approaches aimed at reducing oligomer toxicity, including (1) modulating the oligomer populations (e.g., by altering the kinetics of aggregation by inhibiting, enhancing, or redirecting the process), (2) modulating the oligomer properties (e.g., through the size-hydrophobicity-toxicity relationship), (3) modulating the oligomer interactions (e.g., by protecting cell membranes by displacing oligomers), and (4) reducing oligomer toxicity by potentiating the protein homeostasis system. We analyze examples of these complementary approaches, which may lead to the development of compounds capable of preventing or treating neurodegenerative disorders associated with protein aggregation.