Nucleic acid-based therapeutics that control gene expression have been steadily progressing towards achieving their full clinical potential throughout the last few decades. Rapid progress has been ...achieved in RNAi-based therapy by optimizing high specificity and gene silencing efficiency using chemically modified siRNAs. Since 2018, four siRNA drugs - patisiran, givosiran, lumasiran, and inclisiran, were approved by the US FDA, providing a testament to the promise of RNAi therapeutics. Despite these promising results, safe and efficient siRNA delivery at the target site remains a major obstacle for efficient siRNA-based therapeutics. In this review, we have outlined the synergistic effects of emerging dual ribose modifications, including 2',4'- and 2',5'-modifications, 5'-E/Z-vinylphosphonate, and northern methanocarbacyclic (NMC) modifications that have contributed to drug-like effects in siRNA. These modifications enhance nuclease stability, prolong gene silencing efficiency, improve thermal stability, and exhibit high tissue accumulation. We also highlight the current progress in siRNA clinical trials. This review will help to understand the potential effects of dual ribose modifications and provides alternative ways to use extensive 2'-modifications in siRNA drugs. Moreover, the minimal number of these dual ribose modifications could be sufficient to achieve the desired therapeutic effect. In future, detailed in vivo studies using these dual ribose modifications could help to improve the therapeutic effects of siRNA. Rational design could further open doors for the rapid progress in siRNA therapeutics.
Lemierre Syndrome: A Meta-analysis Gore, Mitchell R.
International Archives of Otorhinolaryngology,
07/2020, Letnik:
24, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Abstract
Introduction
Lemierre syndrome, or postpharyngitis anaerobic sepsis, is an infrequent but life-threatening infection that often involves thrombosis of the internal jugular vein. The role of ...anticoagulation in addition to antibiotics and surgical treatment remains uncertain.
Objectives
1) To perform a meta-analysis on outcomes and treatment of Lemierre syndrome; and 2) to evaluate the effect of anticoagulation in Lemierre syndrome on vessel recanalization and on mortality.
Data Synthesis
A Pubmed database search was conducted using the keywords
Lemierre syndrome
. A total of 427 studies were identified and reviewed. Data were extracted on patient demographics, treatment type including use and type of anticoagulation, type of antibiotics, presence and location of vessel thrombosis, presence of cranial neuropathies, recanalization of thrombosed vessels on follow-up imaging, organisms isolated on wound or blood cultures, and mortality. The primary outcome variables examined were the effect of anticoagulation on vessel recanalization and mortality. After the review, 359 studies totaling 394 patients between 1990 and 2017 had partial or complete data that could be analyzed. In total, 50 patients had sufficient data on the effect of anticoagulation on vessel recanalization, and 194 had sufficient data on the effect of anticoagulation on mortality. The odds ratio for anticoagulation and vessel recanalization was 1.6 (95% confidence interval = 0.3 to 9.4;
p
= 0.6). The odds ratio for anticoagulation and death was 0.6 (95% confidence interval = 0.1 to 2.9;
p
= 0.5).
Conclusion
The present meta-analysis did not demonstrate a statistically significant effect on vessel recanalization or mortality for patients treated with anticoagulation versus patients not anticoagulated in the Lemierre syndrome literature.
In humans, exposure to early life adversity has profound implications for susceptibility to developing neuropsychiatric disorders later in life. Studies in rodents have shown that stress experienced ...during early postnatal life can have lasting effects on brain development. Glucocorticoids and sex steroids are produced in endocrine glands and the brain from cholesterol; these molecules bind to nuclear and membrane-associated steroid receptors. Unlike other steroids that can also be made in the brain, neurosteroids bind specifically to neurotransmitter receptors, not steroid receptors. The relationships among steroids, neurosteroids, and stress are multifaceted and not yet fully understood. However, studies demonstrating altered levels of progestogens, androgens, estrogens, glucocorticoids, and their neuroactive metabolites in both developmental and adult stress paradigms strongly suggest that these molecules may be important players in stress effects on brain circuits and behavior. In this review, we discuss the influence of developmental and adult stress on various components of the brain, including neurons, glia, and perineuronal nets, with a focus on sex steroids and neurosteroids. Gaining an enhanced understanding of how early adversity impacts the intricate systems of brain steroid and neurosteroid regulation could prove instrumental in identifying novel therapeutic targets for stress-related conditions.
Thymoquinone, a monoterpene molecule is chemically known as 2-methyl-5-isopropyl-1, 4-benzoquinone. It is abundantly present in seeds of
L. that is popularly known as black cumin or black seed and ...belongs to the family
. A large number of studies have revealed that thymoquinone is the major active constituent in
oil this constituent is responsible for the majority of the pharmacological properties. The beneficial organoprotective activities of thymoquinone in experimental animal models of different human diseases are attributed to the potent anti-oxidant and anti-inflammatory properties. Thymoquinone has also been shown to alter numerous molecular and signaling pathways in many inflammatory and degenerative diseases including cancer. Thymoquinone has been reported to possess potent lipophilicity and limited bioavailability and exhibits light and heat sensitivity. Altogether, these physiochemical properties encumber the successful formulation for the delivery of drug in oral dosages form and restrict the pharmaceutical development. In recent past, many efforts were undertaken to improve the bioavailability for clinical usage by manipulating the physiochemical parameters. The present review aimed to provide insights regarding the physicochemical characteristics, pharmacokinetics and the methods to promote pharmaceutical development and endorse the clinical usage of TQ in future by overcoming the associated physiochemical obstacles. It also enumerates briefly the pharmacological and molecular targets of thymoquinone as well as the pharmacological properties in various diseases and the underlying molecular mechanism. Though, a convincing number of experimental studies are available but human studies are not available with thymoquinone despite of the long history of use of black cumin in different diseases. Thus, the clinical studies including pharmacokinetic studies and regulatory toxicity studies are required to encourage the clinical development of thymoquinone.
Epithelial-myoepithelial carcinoma is an uncommon malignant neoplasm seen most frequently in the salivary glands, representing approximately 1 to 2% of salivary gland tumors. Less than 600 cases have ...been reported in the literature since its initial description in 1972. The aim of this study was to examine demographic, site, stage, and survival factors in patients with epithelial-myoepithelial carcinoma.
The 1973-2014 SEER (Surveillance, Epidemiology, and End Results) cancer database was queried for patients treated for epithelial-myoepithelial carcinoma. The data was analyzed for patient T (tumor), N (nodal), and M (metastasis) stage, tumor site, and demographic characteristics. The Kaplan-Meier model was used to estimate actuarial survival.
A total of 468 patients were identified. White patients represented 78.0% of the total. There were 291 female patients and 177 male patients. Overall 5-, 10-, and 20-year survival was 72.7%, 59.5%, and 38.3%, respectively. Mean survival time was 165.5 months. Parotid gland was the most common site with 57.7% of patients, with submandibular gland representing 9.8% of patients. Distant metastasis (M) status was unknown in 33.3%, with 2.6% being M1, 3.0% being MX, and 61.1% M0. Nodal metastasis (N) status was unknown in 33.3%, while 4.4% were N+, 4.7% were NX, and 57.5% were N0. 88.2% of patients had surgery as part or all of the treatment regimen. Univariate Kaplan-Meier analysis showed that AJCC overall stage, primary tumor (T) stage, nodal (N) stage, presence of distant metastasis (M1), age at diagnosis, race, and non-surgical treatment significantly affected survival. On multivariate analysis age, race, AJCC stage, T, N, M stage, and treatment type were significant.
Epithelial-myoepithelial carcinoma is a malignant, histologically biphasic neoplasm most frequently seen in the parotid gland. The nodal and distant metastasis rates are low. Age at diagnosis, race, AJCC stage, T, N, M stage, and treatment type all significantly affected survival.
Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory ...impairments. Shank3B knockout mice also exhibit social memory deficits. The CA2 region of the hippocampus integrates numerous inputs and sends a major output to the ventral CA1 (vCA1). Despite finding few differences in excitatory afferents to the CA2 in Shank3B knockout mice, we found that activation of CA2 neurons as well as the CA2-vCA1 pathway restored social recognition function to wildtype levels. vCA1 neuronal oscillations have been linked to social memory, but we observed no differences in these measures between wildtype and Shank3B knockout mice. However, activation of the CA2 enhanced vCA1 theta power in Shank3B knockout mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can invoke latent social memory function.
RNA interference (RNAi), a gene regulatory process mediated by small interfering RNAs (siRNAs), has made remarkable progress as a potential therapeutic agent against various diseases. However, RNAi ...is associated with fundamental challenges such as poor systemic delivery and susceptibility to the nucleases. Targeting ligand-bound delivery vehicles has improved the accumulation of drug at the target site, which has resulted in high transfection efficiency and enhanced gene silencing. Recently, folate receptor (FR)-mediated targeted delivery of siRNAs has garnered attention due to their enhanced cellular uptake and high transfection efficiency toward tumor cells. Folic acid (FA), due to its small size, low immunogenicity, high
stability, and high binding affinity toward FRs, has attracted much attention for targeted siRNA delivery. FRs are overexpressed in a large number of tumors, including ovarian, breast, kidney, and lung cancer cells. In this review, we discuss recent advances in FA-mediated siRNA delivery to treat cancers and inflammatory diseases. This review summarizes various FA-conjugated nanoparticle systems reported so far in the literature, including liposome, silica, metal, graphene, dendrimers, chitosan, organic copolymers, and RNA nanoparticles. This review will help in the design and development of potential delivery vehicles for siRNA drug targeting to tumor cells using an FR-mediated approach.
Adult-born granule cells (abGCs) project to the CA2 region of the hippocampus, but it remains unknown how this circuit affects behavioral function. Here, we show that abGC input to the CA2 of adult ...mice is involved in the retrieval of remote developmental memories of the mother. Ablation of abGCs impaired the ability to discriminate between a caregiving mother and a novel mother, and this ability returned after abGCs were regenerated. Chemogenetic inhibition of projections from abGCs to the CA2 also temporarily prevented the retrieval of remote mother memories. These findings were observed when abGCs were inhibited at 4–6 weeks old, but not when they were inhibited at 10–12 weeks old. We also found that abGCs are necessary for differentiating features of CA2 network activity, including theta-gamma coupling and sharp wave ripples, in response to novel versus familiar social stimuli. Taken together, these findings suggest that abGCs are necessary for neuronal oscillations associated with discriminating between social stimuli, thus enabling retrieval of remote developmental memories of the mother by their adult offspring.
Pharmacological induction of fetal hemoglobin (HbF) expression is an effective therapeutic strategy for the management of beta-hemoglobinopathies such as sickle cell disease. DNA methyltransferase ...(DNMT) inhibitors 5-azacytidine (5-aza) and 5-aza-2'-deoxycytidine (decitabine) have been shown to induce fetal hemoglobin expression in both preclinical models and clinical studies, but are not currently approved for the management of hemoglobinopathies. We report here the discovery of a novel class of orally bioavailable DNMT1-selective inhibitors as exemplified by GSK3482364. This molecule potently inhibits the methyltransferase activity of DNMT1, but not DNMT family members DNMT3A or DNMT3B. In contrast with cytidine analog DNMT inhibitors, the DNMT1 inhibitory mechanism of GSK3482364 does not require DNA incorporation and is reversible. In cultured human erythroid progenitor cells (EPCs), GSK3482364 decreased overall DNA methylation resulting in de-repression of the gamma globin genes HBG1 and HBG2 and increased HbF expression. In a transgenic mouse model of sickle cell disease, orally administered GSK3482364 caused significant increases in both HbF levels and in the percentage HbF-expressing erythrocytes, with good overall tolerability. We conclude that in these preclinical models, selective, reversible inhibition of DNMT1 is sufficient for the induction of HbF, and is well-tolerated. We anticipate that GSK3482364 will be a useful tool molecule for the further study of selective DNMT1 inhibition both in vitro and in vivo.
The lateral roentgenographic findings in 159 initially asymptomatic persons were reviewed at a 10-year interval. A questionnaire was used at the time of the last roentgenogram to determine the ...incidence of pain.
To identify the number of persons who experienced pain during that 10-year period, describe the roentgenographic changes, and determine the association between the development of symptoms and roentgenographic findings.
It is well established that degenerative changes of the cervical spine increase with age and may occur in asymptomatic persons. However, it is unknown whether pain is more likely to develop in persons with degenerative changes than in those with normal roentgenograms.
Lateral cervical roentgenograms were obtained in 200 asymptomatic persons, 100 women and 100 men, to obtain normal values of cervical lordosis and degenerative changes in persons aged 20-65 years. Ten years later, 159 participants had repeat roentgenograms and were administered a questionnaire regarding the presence or absence of pain.
There was an increase in the number of subluxations and an increase in degenerative changes. Pain developed in 15% of participants in the 10-year interval. The presence of degenerative changes at C6-C7 on the initial roentgenogram was a statistically significant predictor of pain.
With age, there is an increase in the number of subluxations and the incidence and severity of degenerative changes. Pain is more likely to develop in persons with degenerative changes at C6-C7.
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