738 research outputs found
A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%-30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC
Diet and Feeding Pattern Affect the Diurnal Dynamics of the Gut Microbiome
SummaryThe gut microbiome and daily feeding/fasting cycle influence host metabolism and contribute to obesity and metabolic diseases. However, fundamental characteristics of this relationship between the feeding/fasting cycle and the gut microbiome are unknown. Our studies show that the gut microbiome is highly dynamic, exhibiting daily cyclical fluctuations in composition. Diet-induced obesity dampens the daily feeding/fasting rhythm and diminishes many of these cyclical fluctuations. Time-restricted feeding (TRF), in which feeding is consolidated to the nocturnal phase, partially restores these cyclical fluctuations. Furthermore, TRF, which protects against obesity and metabolic diseases, affects bacteria shown to influence host metabolism. Cyclical changes in the gut microbiome from feeding/fasting rhythms contribute to the diversity of gut microflora and likely represent a mechanism by which the gut microbiome affects host metabolism. Thus, feeding pattern and time of harvest, in addition to diet, are important parameters when assessing the microbiome’s contribution to host metabolism
Quantitative Methods for Optimizing Patient Outcomes in Liver Transplantation
Liver transplantation continues to be the gold standard for treating patients
with end-stage liver diseases. However, despite the huge success of liver
transplantation in improving patient outcomes, long term graft survival
continues to be a major problem. The current clinical practice in the
management of liver transplant patients is centered around immunosuppressive
multidrug regimens. Current research has been focusing on phenotypic
personalized medicine as a novel approach in the optimization of
immunosuppression, a regressional math modeling focusing on individual patient
dose and response using specific markers like transaminases. A prospective area
of study includes the development of a mechanistic computational math modeling
for optimizing immunosuppression to improve patient outcomes and increase
long-term graft survival by exploring the intricate immune/drug interactions to
help us further our understanding and management of medical problems like
transplants, autoimmunity, and cancer therapy. Thus, by increasing long-term
graft survival, the need for redo transplants will decrease, which will free up
organs and potentially help with the organ shortage problem promoting equity
and equal opportunity for transplants, as well as decreasing the medical costs
associated with additional testing and hospital admissions. Although long-term
graft survival remains challenging, computational and quantitative methods have
led to significant improvements. In this article, we review recent advances and
remaining opportunities. We focus on the following topics: donor organ
availability and allocation with a focus on equity, monitoring of patient and
graft health, and optimization of immunosuppression dosing.Comment: 2 figures, including a graphical abstrac
Galectin-Anchored indoleamine 2,3-dioxygenase tissue-targeted therapeutic enzyme suppresses local inflammation in multiple animal models
Please click Additional Files below to see the full abstract
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Human Skin, Oral, and Gut Microbiomes Predict Chronological Age.
Human gut microbiomes are known to change with age, yet the relative value of human microbiomes across the body as predictors of age, and prediction robustness across populations is unknown. In this study, we tested the ability of the oral, gut, and skin (hand and forehead) microbiomes to predict age in adults using random forest regression on data combined from multiple publicly available studies, evaluating the models in each cohort individually. Intriguingly, the skin microbiome provides the best prediction of age (mean ± standard deviation, 3.8 ± 0.45 years, versus 4.5 ± 0.14 years for the oral microbiome and 11.5 ± 0.12 years for the gut microbiome). This also agrees with forensic studies showing that the skin microbiome predicts postmortem interval better than microbiomes from other body sites. Age prediction models constructed from the hand microbiome generalized to the forehead and vice versa, across cohorts, and results from the gut microbiome generalized across multiple cohorts (United States, United Kingdom, and China). Interestingly, taxa enriched in young individuals (18 to 30 years) tend to be more abundant and more prevalent than taxa enriched in elderly individuals (>60 yrs), suggesting a model in which physiological aging occurs concomitantly with the loss of key taxa over a lifetime, enabling potential microbiome-targeted therapeutic strategies to prevent aging.IMPORTANCE Considerable evidence suggests that the gut microbiome changes with age or even accelerates aging in adults. Whether the age-related changes in the gut microbiome are more or less prominent than those for other body sites and whether predictions can be made about a person's age from a microbiome sample remain unknown. We therefore combined several large studies from different countries to determine which body site's microbiome could most accurately predict age. We found that the skin was the best, on average yielding predictions within 4 years of chronological age. This study sets the stage for future research on the role of the microbiome in accelerating or decelerating the aging process and in the susceptibility for age-related diseases
Diamonds, Digital Health, and Drug Development: Optimizing Combinatorial Nanomedicine
The field of nanomedicine has already seen substantial progress in the clinic, with multiple formulations being evaluated through clinical studies. From poly(lactic-co-glycolic acid) and cyclodextrin-based drug-delivery platforms to metallic nanoparticles for photothermal treatment and imaging, nanotechnology has enabled versatile strategies to treat and to diagnose a wide range of disorders. However, as the field as a whole pushes forward, barriers that have always challenged conventional drug development have already started to impact nanomedicine translation. These include exorbitant costs, substantial time to development, and the uncertainty of achieving major improvements in efficacy or safety. Of note, there has been, until recent advances, a virtual inability to identify optimal drug doses either as monotherapies or components of combination therapy. In this Nano Focus, we assess how the impact of nanotechnology in the clinic can be optimized through systematically designed combinatorial nanotherapy. In addition, we provide a clinical perspective on how a recently unveiled technology platform can substantially alter the landscape of combinatorial nanomedicine, drug development, as well as conventional drug development
Satisfiability, sequence niches, and molecular codes in cellular signaling
Biological information processing as implemented by regulatory and signaling
networks in living cells requires sufficient specificity of molecular
interaction to distinguish signals from one another, but much of regulation and
signaling involves somewhat fuzzy and promiscuous recognition of molecular
sequences and structures, which can leave systems vulnerable to crosstalk. This
paper examines a simple computational model of protein-protein interactions
which reveals both a sharp onset of crosstalk and a fragmentation of the
neutral network of viable solutions as more proteins compete for regions of
sequence space, revealing intrinsic limits to reliable signaling in the face of
promiscuity. These results suggest connections to both phase transitions in
constraint satisfaction problems and coding theory bounds on the size of
communication codes
Rules for biological regulation based on error minimization
The control of gene expression involves complex mechanisms that show large
variation in design. For example, genes can be turned on either by the binding
of an activator (positive control) or the unbinding of a repressor (negative
control). What determines the choice of mode of control for each gene? This
study proposes rules for gene regulation based on the assumption that free
regulatory sites are exposed to nonspecific binding errors, whereas sites bound
to their cognate regulators are protected from errors. Hence, the selected
mechanisms keep the sites bound to their designated regulators for most of the
time, thus minimizing fitness-reducing errors. This offers an explanation of
the empirically demonstrated Savageau demand rule: Genes that are needed often
in the natural environment tend to be regulated by activators, and rarely
needed genes tend to be regulated by repressors; in both cases, sites are bound
for most of the time, and errors are minimized. The fitness advantage of error
minimization appears to be readily selectable. The present approach can also
generate rules for multi-regulator systems. The error-minimization framework
raises several experimentally testable hypotheses. It may also apply to other
biological regulation systems, such as those involving protein-protein
interactions.Comment: biological physics, complex networks, systems biology,
transcriptional regulation
http://www.weizmann.ac.il/complex/tlusty/papers/PNAS2006.pdf
http://www.pnas.org/content/103/11/3999.ful
Structural Mechanism for the Specific Assembly and Activation of the Extracellular Signal Regulated Kinase 5 (ERK5) Module
Mitogen-activated protein kinase (MAPK) activation depends on a linear binding motif found in all MAPK kinases (MKK). In addition, the PB1 (Phox and Bem1) domain of MKK5 is required for extracellular signal regulated kinase 5 (ERK5) activation. We present the crystal structure of ERK5 in complex with an MKK5 construct comprised of the PB1 domain and the linear binding motif. We show that ERK5 has distinct protein-protein interaction surfaces compared with ERK2, which is the closest ERK5 paralog. The two MAPKs have characteristically different physiological functions and their distinct protein-protein interaction surface topography enables them to bind different sets of activators and substrates. Structural and biochemical characterization revealed that the MKK5 PB1 domain cooperates with the MAPK binding linear motif to achieve substrate specific binding, and it also enables co-recruitment of the upstream activating enzyme and the downstream substrate into one signaling competent complex. Studies on present day MAPKs and MKKs hint on the way protein kinase networks may evolve. In particular, they suggest how paralogous enzymes with similar catalytic properties could acquire novel signaling roles by merely changing the way they make physical links to other proteins
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Aspiration therapy for the treatment of obesity: 4-year results of a multicenter randomized controlled trial.
BackgroundThe AspireAssist is the first Food and Drug Administration-approved endoluminal device indicated for treatment of class II and III obesity.ObjectivesWe earlier reported 1-year results of the PATHWAY study. Here, we report 4-year outcomes.SettingUnited States-based, 10-center, randomized controlled trial involving 171 participants with the treatment arm receiving Aspiration Therapy (AT) plus Lifestyle Therapy and the control arm receiving Lifestyle Therapy (2:1 randomization).MethodsAT participants were permitted to continue in the study for an additional year up to a maximum of 5 years providing they maintained at least 10% total weight loss (TWL) from baseline at each year end. For AT participants who continued the study, 5 medical monitoring visits were provided at weeks 60, 68, 76, 90, and 104 and thereafter once every 13 weeks up to week 260. Exclusion criteria were a history of eating disorder or evidence of eating disorder on a validated questionnaire. Follow-up weight, quality of life, and co-morbidities were compared with the baseline levels. In addition, rates of serious adverse event, persistent fistula, withdrawal, and A-tube replacement were reported. All analyses were performed using a per-protocol analysis.ResultsOf the 82 AT participants who completed 1 year, 58 continued to this phase of the trial. Mean baseline body mass index of these 58 patients was 41.6 ± 4.5 kg/m2. At the end of first year (at the beginning of the follow-up study), these 58 patients had a body mass index of 34.1 ± 5.4 kg/m2 and had achieved an 18.3 ± 8.0% TWL. On a per protocol basis, patients experienced 14.2%, 15.3%, 16.6%, and 18.7% TWL at 1, 2, 3, and 4 years, respectively (P < .01 for all). Forty of 58 patients (69%) achieved at least 10% TWL at 4 years or at time of study withdrawal. Improvements in quality of life scores and select cardiometabolic parameters were also maintained through 4 years. There were 2 serious adverse events reported in the second through fourth years, both of which resolved with removal or replacement of the A tube. Two persistent fistulas required surgical repair, representing approximately 2% of all tube removals. There were no clinically significant metabolic or electrolytes disorders observed, nor any evidence for development of any eating disorders.ConclusionsThe results of this midterm study have shown that AT is a safe, effective, and durable weight loss alternative for people with class II and III obesity and who are willing to commit to using the therapy and adhere to adjustments in eating behavior
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