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Πέμπτη 16 Φεβρουαρίου 2023

Checkpoint blockade and BRAF/MEK therapy in the therapeutic setting improved the overall survival after sentinel node biopsy – a retrospective study comparing patients with primary care between 1998‐2009 and 2010‐2017

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Abstract

Immunotherapies using checkpoint blockade and BRAF/MEK therapies have improved overall survival (OS) in patients with unresectable melanoma metastases. In this retrospective study, we aimed to demonstrate the resulting increase in melanoma-specific survival (MSS) and OS after the excision of primary melanomas (≥1 mm thick) and sentinel lymph node (SN) biopsy (SNB).

Using Kaplan - Meier estimates and Cox models, we compared two consecutive cohorts. Patients in cohort 1 (N = 518) underwent SNB between 1998 and 2009, and patients in cohort 2 (N = 460) between 2010 and 2017, when checkpoint blockade and BRAF/ (MEK) inhibition became available for the treatment of unresectable relapses.

The median follow-up times were 120 months and 73 months, respectively. While recurrence-free and distant metastasis-free survival rates remained very similar, MSS and OS increased in favor of cohort 2. The estimated 5-year OS rate of SN-positive patients increased by 14.3% (78.5% vs 64.2%, logrank test: P=0.005). The MSS benefit was significant even with low SN tumor burden (metastasis diameter <1 mm). On multivariate analyses, the risk-reduction in favor of cohort 2 was significant in the total population and in the SN-negative and SN-positive subgroups. In SN-positive patients, besides the availability of modern therapies, SN metastasis diameter, and ulceration were independent factors of MSS and OS.

Treatment of unresectable melanoma recurrences with modern drug therapies results in significantly higher survival rates in a population with SNB. The survival benefit measured from primary melanoma affects both the SN-positive and SN-negative subpopulations.

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Operation early‐bird: Investigating altered light exposure in military barracks on sleep and performance—a placebo‐controlled study

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Summary

The manipulation of light exposure in the evening has been shown to modulate sleep, and may be beneficial in a military setting where sleep is reported to be problematic. This study investigated the efficacy of low-temperature lighting on objective sleep measures and physical performance in military trainees. Sixty-four officer-trainees (52 male/12 female, mean ± SD age: 25 ± 5 years) wore wrist-actigraphs for 6 weeks during military training to quantify sleep metrics. Trainee 2.4-km run time and upper-body muscular-endurance were assessed before and after the training course. Participants were randomly assigned to either: low-temperature lighting (LOW, n = 19), standard-temperature lighting with a placebo "sleep-enhancing" device (PLA, n = 17), or standard-temperature lighting (CON, n = 28) groups in their military barracks for the duration of the course. Repeated-measures ANOVAs were run to identify significant differences with post hoc ana lyses and effect size calculations performed where indicated. No significant interaction effect was observed for the sleep metrics; however, there was a significant effect of time for average sleep duration, and small benefits of LOW when compared with CON (d = 0.41–0.44). A significant interaction was observed for the 2.4-km run, with the improvement in LOW (Δ92.3 s) associated with a large improvement when compared with CON (Δ35.9 s; p = 0.003; d = 0.95 ± 0.60), but not PLA (Δ68.6 s). Similarly, curl-up improvement resulted in a moderate effect in favour of LOW (Δ14 repetitions) compared with CON (Δ6; p = 0.063; d = 0.68 ± 0.72). Chronic exposure to low-temperature lighting was associated with benefits to aerobic fitness across a 6-week training period, with minimal effects on sleep measures.
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Autophagy and its role in osteosarcoma

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Autophagy and its role in osteosarcoma

In this review, we summarized the role of autophagy in OS proliferation, metastasis, chemotherapy, radiotherapy, and immunotherapy. And we think that autophagy-related genes and pathways could serve as potential targets for OS therapy.


Abstract

Osteosarcoma (OS) is the most common bone malignancy and preferably occurs in children and adolescents. Despite significant advances in surgery and chemotherapy for OS over the past few years, overall survival rates of OS have reached a bottleneck. Thus, extensive researches aimed at developing new therapeutic targets for OS are urgently needed. Autophagy, a conserved process which allows cells to recycle altered or unused organelles and cellular components, has been proven to play a critical role in multiple biological processes in OS. In this article, we summarized the association between autophagy and proliferation, metastasis, chemotherapy, radiotherapy, and immunotherapy of OS, revealing that autophagy-related genes and pathways could serve as potential targets for OS therapy.
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Embolization in Juvenile Nasopharyngeal Angiofibroma Surgery: A Systematic Review and Meta‐Analysis

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Embolization in Juvenile Nasopharyngeal Angiofibroma Surgery: A Systematic Review and Meta-Analysis

How are clinical outcomes of juvenile nasopharyngeal angiofibroma (JNA) resection affected by preoperative embolization and the type of embolization used? In this systematic review and meta-analysis, the use of preoperative embolization was shown to decrease blood loss during JNA resection and direct embolization provided improved recurrence and complication rates compared to transarterial embolization. Preoperative direct puncture embolization in JNA resection may reduce intraoperative and postoperative complications.


Objective

To compare outcomes of juvenile nasopharyngeal angiofibroma (JNA) resection between embolized and non-embolized cohorts, and between transarterial embolization (TAE) and direct puncture embolization (DPE).

Data Sources

Per PRISMA guidelines, PubMed, Embase, Web of Science, Scopus, and Cochrane databases were searched for publications prior to or in 2021.

Materials and Methods

Original English manuscripts investigating the resection of JNA with and without preoperative embolization were included. Embolization type, recurrence rate, complication rates, blood loss, and transfusions were extracted. Risk of bias was assessed by the Risk of Bias in Non-randomized Studies—of Interventions method.

Results

There were 61 studies with 917 patients included. Preoperative embolization was performed in 79.3% of patients. Of those embolized, 75.8% (N = 551) underwent TAE and 15.8% (N = 115) underwent DPE. JNA recurrence in embolized patients was lower than in non-embolized patients (9.3% vs. 14.4%; odds ratio [OR]: 0.61, 95% confidence interval [CI]: 0.35, 1.06). DPE resulted in lower rates of disease recurrence (0% vs. 9.5%; OR: 0.066, 95% CI: 0.016, 0.272) and complications (1.8% vs. 21.9%; OR: 0.07, 95% CI: 0.02, 0.3) than TAE. A random effects Bayesian model was performed to analyze the difference in mean blood loss in 6 studies that included both embolized and non-embolized patients. This analysis showed a mean reduction in blood loss of 798 mL in the embolized group.

Conclusions

We found embolization decreases blood loss in JNA resection. DPE led to improved recurrence and complication rates when compared to TAE, but future prospective studies are needed to further evaluate which embolization technique can optimize outcomes in JNA.

Level of Evidence

NA Laryngoscope, 2023
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Onychomycosis associated with diabetic foot syndrome: a systematic review

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via Mycoses

Abstract

Background

A systematic review was conducted to investigate the prevalence of onychomycosis in patients with diabetes. The association of onychomycosis with risk factors in patients with diabetic foot syndrome was also examined.

Methods

The recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist were applied, and the included studies were assessed using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) method. Searches were conducted in October 2022 using PubMed (Medline) and Scopus for clinical studies, clinical trials, comparative studies, observational studies, and randomised clinical trials or controlled clinical trials addressing the prevalence and consequences of onychomycosis in patients with diabetes, diagnoses, or treatments. Two authors performed the study selection and data extraction, and any discrepancies between the two reviewers were resolved through discussion with a third reviewer.

Results

The systematic review included nine studies that met the inclusion criteria, and these studies enrolled 5426 patients with diabetes. Among these patients, 28.55% had onychomycosis that was mainly caused by Trichophyton rubrum. A significant association was found between the occurrence of onychomycosis and the presence of diabetic neuropathy (p=0.012) and elevated glycosylated haemoglobin values (p=0.039). There was no significant association between onychomycosis and ulceration (p=0.185). Eight studies had a grade 4 level of evidence and a grade C recommendation, and one study had a grade 1b level of evidence and a grade A recommendation.

Conclusion

The information described in the literature is insufficient and heterogeneous regarding the association of risk factors and ulceration in patients with diabetic foot compared with developing onychomycosis. There is also a need to implement onychomycosis diagnostic testing instead of relying only on a clinical diagnosis. Additional prospective, randomised, comparative studies are needed to increase the quality of studies in the literature.
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In vivo PIWI slicing in mouse testes deviates from rules established in vitro [LETTER TO THE EDITOR]

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Argonautes are small RNA-binding proteins, with some having small RNA-guided endonuclease (slicer) activity that cleaves target nucleic acids. One cardinal rule that is structurally defined is the inability of slicers to cleave target RNAs when nucleotide mismatches exist between the paired small RNA and the target at the cleavage site. Animal-specific PIWI clade Argonautes associate with PIWI-interacting RNAs (piRNAs) to silence transposable elements in the gonads, and this is essential for fertility. We previously demonstrated that purified endogenous mouse MIWI fails to cleave mismatched targets in vitro. Surprisingly, here we find using knock-in mouse models that target sites with cleavage-site mismatches at the 10th and 11th piRNA nucleotides are precisely sliced in vivo. This is identical to the slicing outcome in knock-in mice where targets are base-paired perfectly with the piRNA. Additionally, we find that pachytene piRNA-guided slicing in both these situations failed to initiate phased piRNA production from the specific target mRNA we studied. Instead, the two slicer cleavage fragments were retained in PIWI proteins as pre-piRNA and 17–19 nt by-product fragments. Our results indicate that PIWI slicing rules established in vitro are not respected in vivo, and that all targets of PIWI slicing are not substrates for piRNA biogenesis.
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RNA:RNA interaction in ternary complexes resolved by chemical probing [ARTICLE]

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RNA regulation can be performed by a second targeting RNA molecule, such as in the microRNA regulation mechanism. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) probes the structure of RNA molecules and can resolve RNA:protein interactions, but RNA:RNA interactions have not yet been addressed with this technique. Here, we apply SHAPE to investigate RNA-mediated binding processes in RNA:RNA and RNA:RNA-RBP complexes. We use RNA:RNA binding by SHAPE (RABS) to investigate microRNA-34a (miR-34a) binding its mRNA target, the silent information regulator 1 (mSIRT1), both with and without the Argonaute protein, constituting the RNA-induced silencing complex (RISC). We show that the seed of the mRNA target must be bound to the microRNA loaded into RISC to enable further binding of the compensatory region by RISC, while the naked miR-34a is able to bind the compensatory region without seed interaction. The method presented here provi des complementary structural evidence for the commonly performed luciferase-assay-based evaluation of microRNA binding-site efficiency and specificity on the mRNA target site and could therefore be used in conjunction with it. The method can be applied to any nucleic acid-mediated RNA- or RBP-binding process, such as splicing, antisense RNA binding, or regulation by RISC, providing important insight into the targeted RNA structure.
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Z-RNA biology: a central role in the innate immune response? [MINI-REVIEW]

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Z-RNA is a higher-energy, left-handed conformation of RNA, whose function has remained elusive. A growing body of work alludes to regulatory roles for Z-RNA in the immune response. Here, we review how Z-RNA features present in cellular RNAs—especially containing retroelements—could be recognized by a family of winged helix proteins, with an impact on host defense. We also discuss how mutations to specific Z-contacting amino acids disrupt their ability to stabilize Z-RNA, resulting in functional losses. We end by highlighting knowledge gaps in the field, which, if addressed, would significantly advance this active area of research.
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Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model

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imageHypothesis The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear. Background Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents. Methods RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N-acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined. Results The estimated 50% lethal concentration dose for gentamicin was 805.6 μM, which was 46-fold higher than that for cisplatin (17.5 μM). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% (p
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Looking for Synergies in Healthy Upper Limb Motion: A Focus on the Wrist

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Recent studies on human upper limb motion highlighted the benefit of dimensionality reduction techniques to extrapolate informative joint patterns. These techniques can simplify the description of upper limb kinematics in physiological conditions, serving as a baseline for the objective assessment of movement alterations, or to be imple mented in a robotic joint. However, the successful description of kinematic data requires a proper alignment of the acquisitions to correctly estimate kinematic patterns and their motion variability. Here, we propose a structured methodology to process and analyze upper limb kinematic data, considering time warping and task segmentation to register task execution on a common normalized completion time axis. Functional principal component analysis (fPCA) was used to extract patterns of motion of the wrist joint from the data collected by healthy participants performing activities of daily living. Our results suggest that wrist trajectories can be described as a linear combination of few functional principal components (fPCs). In fact, three fPCs explained more than 85% of the variance of any task. Wrist trajectories in the reaching phase of movement were highly correlated among participants and significantly more than trajectories in the manipulation phase ( $text{p}< 0.01$ ). The se findings may be useful in simplifying the control and design of robotic wrists, and could aid the development of therapies for the early detection of pathological conditions.
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