Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived ...compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a “position statement” on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.
Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been ...designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant. Deletion of caspase-8 sensitized AML to birinapant, whereas combined loss of caspase-8 and the necroptosis effector MLKL (mixed lineage kinase domain-like) prevented birinapant/IDN-6556-induced death, showing that inhibition of caspase-8 sensitizes AML cells to birinapant-induced necroptosis. However, loss of MLKL alone did not prevent a caspase-dependent birinapant/IDN-6556-induced death, implying that AML will be less likely to acquire resistance to this drug combination. A therapeutic breakthrough in AML has eluded researchers for decades. Demonstrated antileukemic efficacy and safety of the birinapant/emricasan combination in vivo suggest that induction of necroptosis warrants clinical investigation as a therapeutic opportunity in AML.
The timing of retears after arthroscopic rotator cuff repair Chona, Deepak V.; Lakomkin, Nikita; Lott, Ariana ...
Journal of shoulder and elbow surgery,
November 2017, 2017-Nov, 2017-11-00, 20171101, Letnik:
26, Številka:
11
Journal Article
Recenzirano
Little is known about the time dependence of the failure rate of surgically repaired rotator cuffs. Retears are significant, as they are common and may lead to less satisfactory outcomes and ...additional operations. Their timing is critical foundational information for understanding failure mechanisms. However, this remains unclear. Currently, there exist a number of studies that have reported retear rates at specific time points. Combining data from these publications can reveal when cuffs retear, which will help inform expectations and guidelines for progression of activity after surgery.
PubMed, Medline, and Embase were searched for studies relating to rotator cuff repair. Abstracts and articles were evaluated on the basis of predefined inclusion and exclusion criteria. Data were extracted from those publications that satisfied all requirements, and regression analysis was performed.
Thirteen articles were included in the final meta-analysis. Retear rates for medium tears increased for approximately 15 months and leveled off at approximately 20%. Retear rates for large tears progressed steadily for about 12 months and approached an upper limit of approximately 40%. Retear rates for massive tears ranged from 20% to 60%, but the distribution of retear rate over time for these cuff tears is not clear from these data.
Retear rates for medium and large tears generally increase until at least 10-15 months after surgery, after which they are likely to level off. Retear rates for massive tears are variable and may follow a time course different from that of other tear sizes. Retear rates depend on size of the original tear.
Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft ...connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the glycine and serine residue (GS) activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development. Hum Mutat 0, 1-12, 2008.
The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International ...Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Nineteen of 207 respondents had kidney stones, revealing a worldwide prevalence of 9.2%. In a confirmatory follow-up study of subjects participating in a longitudinal FOP natural history study, 9 of 114 individuals reported a history of kidney stones (7.9%). In both study populations patients with kidney stones were found to be more functionally impaired compared to those without nephrolithiasis. The prevalence of kidney stones in the adult FOP population of the Unites States was 15.8% (9/57 individuals) compared to a sex- and age-weighted prevalence of 4.5% (p=4×10−5) in the general population. Although geographical variation exists, patients with FOP have an approximately three-fold greater prevalence of kidney stones than the general population. This unusually high prevalence may be due to high bone turnover from chronic immobilization, or to unknown mechanistic effects of the activating FOP mutation in activin A receptor, type I/activin-like kinase-2 (ACVR1/ALK2), increasing the disease burden and morbidity in this already disabling condition.
The AspireAssist System (AspireAssist) is an endoscopic weight loss device that is comprised of an endoscopically placed percutaneous gastrostomy tube and an external device to facilitate drainage of ...about 30% of the calories consumed in a meal, in conjunction with lifestyle (diet and exercise) counseling.
In this 52-week clinical trial, 207 participants with a body-mass index (BMI) of 35.0-55.0 kg/m
were randomly assigned in a 2:1 ratio to treatment with AspireAssist plus Lifestyle Counseling (n=137; mean BMI was 42.2±5.1 kg/m
) or Lifestyle Counseling alone (n=70; mean BMI was 40.9±3.9 kg/m
). The co-primary end points were mean percent excess weight loss and the proportion of participants who achieved at least a 25% excess weight loss.
At 52 weeks, participants in the AspireAssist group, on a modified intent-to-treat basis, had lost a mean (±s.d.) of 31.5±26.7% of their excess body weight (12.1±9.6% total body weight), whereas those in the Lifestyle Counseling group had lost a mean of 9.8±15.5% of their excess body weight (3.5±6.0% total body weight) (P<0.001). A total of 58.6% of participants in the AspireAssist group and 15.3% of participants in the Lifestyle Counseling group lost at least 25% of their excess body weight (P<0.001). The most frequently reported adverse events were abdominal pain and discomfort in the perioperative period and peristomal granulation tissue and peristomal irritation in the postoperative period. Serious adverse events were reported in 3.6% of participants in the AspireAssist group.
The AspireAssist System was associated with greater weight loss than Lifestyle Counseling alone.
Glenoid bone deficiency and eccentric posterior wear are difficult problems faced by shoulder arthroplasty surgeons. Numerous options and techniques exist for addressing these issues. ...Hemiarthroplasty with concentric glenoid reaming may be a viable alternative in motivated patients in whom glenoid component failure is a concern. Total shoulder arthroplasty has been shown to provide durable pain relief and excellent function in patients, and numerous methods and techniques can assist in addressing bone loss and eccentric wear. However, the ideal amount of version correction in cases of severe retroversion has not yet been established. Asymmetric reaming is a commonly used technique to address glenoid version, but correction of severe retroversion may compromise bone stock and component fixation. Bone grafting is a technically demanding alternative for uncontained defects and has mixed clinical results. Specialized glenoid implants with posterior augmentation have been created to assist the surgeon in correcting glenoid version without compromising bone stock, but clinical data on these implants are still pending. Custom implants or instruments based on each patient's unique glenoid anatomy may hold promise. In elderly, sedentary patients in whom bone stock and soft-tissue balance are concerns, reverse total shoulder arthroplasty may be less technically demanding while still providing satisfactory pain relief and functional improvements.
Fibrodysplasia ossificans progressiva is a rare and disabling genetic condition characterized by congenital malformation of the great toes and by progressive heterotopic ossification in specific ...anatomic patterns. Most patients with fibrodysplasia ossificans progressiva are misdiagnosed early in life before the appearance of heterotopic ossification and undergo diagnostic procedures that can cause lifelong disability. Recently, the genetic cause of fibrodysplasia ossificans progressiva was identified, and definitive genetic testing for fibrodysplasia ossificans progressiva is now available before the appearance of heterotopic ossification.
We recently evaluated 7 children for diagnosis of fibrodysplasia ossificans progressiva before the onset of heterotopic ossification. A medical history, physical examination, and skeletal survey were obtained on all of the patients, as well as clinical genetic testing for the canonical fibrodysplasia ossificans progressiva mutation.
All 7 of the children (4 girls and 3 boys; ages 3 months to 6 years) had congenital malformations of the great toes, but none had radiographic evidence of heterotopic ossification at the time of evaluation. Five of the 7 children had soft tissue lesions of the neck and back, suggestive of early fibrodysplasia ossificans progressiva flare-ups, 3 of whom had undergone invasive diagnostic procedures that exacerbated their condition. Two children had no history or signs of soft tissue swelling or flare-ups. DNA sequence analysis found that all 7 of the children had the recurrent fibrodysplasia ossificans progressiva missense mutation, a single nucleotide substitution (c.617G>A) at codon 206 in the glycine-serine activation domain of activin receptor IA, a bone morphogenetic protein type 1 receptor.
Clinical suspicion of fibrodysplasia ossificans progressiva early in life on the basis of malformed great toes can lead to early clinical diagnosis, confirmatory diagnostic genetic testing, and the avoidance of additional harmful diagnostic and treatment procedures. This is the first report of genetic confirmation of fibrodysplasia ossificans progressiva before the appearance of heterotopic ossification. Pediatricians should be aware of the early diagnostic features of fibrodysplasia ossificans progressiva, even before the appearance of heterotopic ossification. This awareness should prompt early genetic consultation and testing and the institution of assiduous precautions to prevent iatrogenic harm.
Individuals who have fibrodysplasia ossificans progressiva develop an ectopic skeleton because of genetic dysregulation of bone morphogenetic protein (BMP) signaling in the presence of inflammatory ...triggers. The identity of progenitor cells that contribute to various stages of BMP-induced heterotopic ossification relevant to fibrodysplasia ossificans progressiva and related disorders is unknown. An understanding of the cellular basis of heterotopic ossification will aid in the development of targeted, cell-specific therapies for the treatment and prevention of heterotopic ossification.
We used Cre/loxP lineage tracing methods in the mouse to identify cell lineages that contribute to all stages of heterotopic ossification. Specific cell populations were permanently labeled by crossing lineage-specific Cre mice with the Cre-dependent reporter mice R26R and R26R-EYFP. Two mouse models were used to induce heterotopic ossification: (1) intramuscular injection of BMP2/Matrigel and (2) cardiotoxin-induced skeletal muscle injury in transgenic mice that misexpress BMP4 at the neuromuscular junction. The contribution of labeled cells to fibroproliferative lesions, cartilage, and bone was evaluated histologically by light and fluorescence microscopy. The cell types evaluated as possible progenitors included skeletal muscle stem cells (MyoD-Cre), endothelium and endothelial precursors (Tie2-Cre), and vascular smooth muscle (Smooth Muscle Myosin Heavy Chain-Cre SMMHC-Cre).
Vascular smooth muscle cells did not contribute to any stage of heterotopic ossification in either mouse model. Despite the osteogenic response of cultured skeletal myoblasts to BMPs, skeletal muscle precursors in vivo contributed minimally to heterotopic ossification (<5%), and this contribution was not increased by cardiotoxin injection, which induces muscle regeneration and mobilizes muscle stem cells. In contrast, cells that expressed the vascular endothelial marker Tie2/Tek at some time in their developmental history contributed robustly to the fibroproliferative, chondrogenic, and osteogenic stages of the evolving heterotopic endochondral anlagen. Importantly, endothelial markers were expressed by cells at all stages of heterotopic ossification. Finally, muscle injury and associated inflammation were sufficient to trigger fibrodysplasia ossificans progressiva-like heterotopic ossification in a setting of chronically stimulated BMP activity.
Tie2-expressing progenitor cells, which are endothelial precursors, respond to an inflammatory trigger, differentiate through an endochondral pathway, contribute to every stage of the heterotopic endochondral anlagen, and form heterotopic bone in response to overactive BMP signaling in animal models of fibrodysplasia ossificans progressiva. Thus, the ectopic skeleton is not only supplied by a rich vasculature, but appears to be constructed in part by cells of vascular origin. Further, these data strongly suggest that dysregulation of the BMP signaling pathway and an inflammatory microenvironment are both required for the formation of fibrodysplasia ossificans progressiva-like lesions.
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