Κυριακή 19 Φεβρουαρίου 2023

Antitumor therapy for breast cancer: Focus on tumor‐associated macrophages and nanosized drug delivery systems

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Antitumor therapy for breast cancer: Focus on tumor-associated macrophages and nanosized drug delivery systems

TAMs come from either bone marrow or the yolk sac. According to the polarized phenotype, there are two main types of macrophages, M1-type, which exerts pro-inflammatory and anti-tumor effects, and M2-type, which exerts anti-inflammatory and protumor effects. The major strategies used to target TAMs for BC therapy include depleting macrophages, blocking recruitment, reprogramming to attain an anti-tumor phenotype, and increasing phagocytosis. NDDSs can carry a variety of therapeutic reagents to target TAMs and realize combination therapies in BC.


Abstract

Background

In breast cancer (BC), tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment and are closely related to poor prognosis. A growing number of studies have focused on the role of TAMs in BC progression and therapeutic strategies targeting TAMs. As an emerging treatment, the application of nanosized drug delivery systems (NDDSs) in the treatment of BC by targeting TAMs has attracted much attention.

Aims

This review is to summarize the characteristics and treatment strategies targeting TAMs in BC and to clarify the applications of NDDSs targeting TAMs in the treatment of BC by targeting TAMs.

Materials & Methods

The existing results related to characteristics of TAMs in BC, BC treatment strategies by targeting TAMs, and the applications of NDDSs in these strategies are described. Through analyzing these results, the advantages and disadvantages of the treatment strategies using NDDSs are discussed, which could provide advices on designing NDDSs for BC treatment.

Results

TAMs are one of the most prominent noncancer cell types in BC. TAMs not only promote angiogenesis, tumor growth and metastasis but also lead to therapeutic resistance and immunosuppression. Mainly four strategies have been used to target TAMs for BC therapy, which include depleting macrophages, blocking recruitment, reprogramming to attain an anti-tumor phenotype, and increasing phagocytosis. Since NDDSs can efficiently deliver drugs to TAMs with low toxicity, they are promising approaches for targeting TAMs in tumor therapy. NDDSs with various structures can deliver immunotherapeutic agents and nucleic acid therapeutics to TAMs. In addition, NDDSs can realize combination therapies.

Discussion

TAMs play a critical role in the progression of BC. An increasing number of strategies have been proposed to regulate TAMs. Compared with free drugs, NDDSs targeting TAMs improve drug concentration, reduce toxicity and realize combination therapies. However, in order to achieve better therapeutic efficacy, there are still some disadvantages that need to be considered in the design of NDDSs.

Conclusion

TAMs play an important role in the progression of BC, and targeting TAMs is a promising strategy for BC therapy. In particular, NDDSs targeting TAMs have unique advantages and are potential treatments for BC.

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Biomechanical influence of narrow‐diameter implants placed at the crestal and subcrestal level in the maxillary anterior region. A 3D finite element analysis

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Abstract

Purpose

To evaluate the tendency of movement, stress distribution, and microstrain of single-unit crowns in simulated cortical and trabecular bone, implants, and prosthetic components of narrow-diameter implants with different lengths placed at the crestal and subcrestal levels in the maxillary anterior region using 3D finite element analysis.

Materials and Methods

Six 3D models were simulated using Invesalius 3.0, Rhinoceros 4.0, and SolidWorks software. Each model simulated the right anterior maxillary region including a Morse taper implant of Ø 2.9 mm with different lengths (7 mm, 10 mm, and 13 mm) placed at the crestal and subcrestal level and supporting a cement-retained monolithic single crown in the area of tooth #12. The finite element analysis was performed using ANSYS 19.2. The simulated applied force was 178 N at 0°, 30°, and 60°. The results were analyzed using maps of displacement, von Mises stress (vM), maximum principal stress, and microstrain.

Results

Models with implants at the subcrestal level showed greater displacement. von Mises stress increased in the implant and prosthetic components when implants were placed at the subcrestal level compared with the crestal level; the length of the implants had a low influence on the stress distribution. Higher stress and strain concentrations were observed in the cortical bone of the subcrestal placement, independent of implant length. Non-axial loading influenced the increased stress and strain in all the evaluated structures.

Conclusions

Narrow-diameter implants positioned at the crestal level showed a more favorable biomechanical behavior for simulated cortical bone, implants, and prosthetic components. Implant length had a smaller influence on stress or strain distribution than the other variables.

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Equity in adjuvant radiotherapy utilization in locally advanced head and neck cancer: A SEER‐data based study

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Abstract

Background

Not all patients with locally advanced head and neck cancer (HNC) who are eligible for adjuvant radiotherapy (RT) following upfront surgery appear to receive it.

Methods

Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Selected patients from 2009 to 2018 had locally advanced HNC, underwent upfront surgery, and were eligible for adjuvant RT. Multivariable logistic regression and chi-squared test were used to analyze available patient and tumor characteristics.

Results

Of 12 549 patients, 84.5% underwent adjuvant RT, 15.5% did not. Characteristics associated with lowest adjuvant RT utilization included cancers of the larynx (p < 0.0001) and gingivae (p < 0.0001), age 80 and above (p < 0.0001), unpartnered status (p < 0.0001), and residence within a nonmetropolitan area (p < 0.0024).

Conclusions

Tumor subsite, age, partnered status, and rural/urban residence correlate with omission of adjuvant RT in locally advanced HNC.

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An evaluation of mechanical and biophysical skin parameters at different body locations

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Abstract

Background

Skin is the largest organ in the body, representing an important interface to monitor health and disease. However, there is significant variation in skin properties for different ages, genders and body regions due to the differences in the structure and morphology of the skin tissues. This study aimed to evaluate the use of non-invasive tools to discriminate a range of mechanical and functional skin parameters from different skin sites.

Materials and methods

A cohort of 15 healthy volunteers was recruited following appropriate informed consent. Four well-established CE-marked non-invasive techniques were used to measure four anatomical regions: palm, forearm, sole and lower lumbar L3, using a repeated measures design. Skin parameters included trans-epidermal water loss (TEWL), pH (acidity), erythema, stratum corneum hydration and stiffness and elasticity using Myoton Pro (skin and muscle probe). Differences between body locations for each parameter and the intra-rater reliability between days were evaluated by the same operator.

Results

The results indicate that parameters differed significantly between skin sites. For the Myoton skin probe, the sole recorded the highest stiffness value of 1006 N/m (SD ± 179), while the lower lumbar recorded the least value of 484 N/m (SD ± 160). The muscle indenter Myoton probe revealed the palm's highest value of 754 N/m (± 108), and the lower lumbar recorded the least value of 208 N/m (SD ± 44). TEWL values were lowest on the forearm, averaging 11 g/m2/h, and highest on the palm, averaging 41 g/m2/h. Similar skin hydration levels were recorded in three of the four sites, with the main difference being observed in the sole averaging 13 arbitrary units. Erythema values were characterised by a high degree of inter-subject variation, and no significant differences between sites or sides were observed. The Myoton Pro Skin showed excellent reliability (intra-class correlation coefficients > 0.70) for all sites with except ion of one site right lower back; the Myoton pro muscle probes showed good to poor reliability (0.90–017), the corneometer showed excellent reliability (>0.75) among all the sites tested, and the TEWL showed Good to poor reliability (0.74–0.4) among sites.

Conclusion

The study revealed that using non-invasive methods, the biophysical properties of skin can be mapped, and significant differences in the mechanical and functional properties of skin were observed. These parameters were reliably recorded between days, providing a basis for their use in assessing and monitoring changes in the skin during health and disease.

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Multifunctional Two-Dimensional Bi2Se3 Nanodiscs for Anti-Inflammatory Therapy of Inflammatory Bowel Diseases

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Publication date: Available online 17 February 2023

Source: Acta Biomaterialia

Author(s): Cong Zhang, Qingrong Li, Jie Shan, Jianghao Xing, Xiaoyan Liu, Yan Ma, Haisheng Qian, Xulin Chen, Xianwen Wang, Lian-Ming Wu, Yue Yu

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Assessment of attenuation of varicella‐zoster virus vaccines based on genomic comparison

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Abstract

Live attenuated varicella zoster virus (VZV) vaccines are used to prevent chickenpox and shingles. Single nucleotide polymorphisms (SNPs) that occur during the attenuation of parental strains are critical indicators of vaccine safety. To assess the attenuation of commercial VZV vaccines, genetic variants were comprehensively examined through high-throughput sequencing of viral DNA isolated from four VZV vaccines (Barycela, VarilRix, VariVax, and SKY Varicella). Whole-genome comparison of the four vaccines with the wild-type strain (Dumas) revealed that the sequences are highly conserved on a genome-wide scale. Among the 196 common variants across the four vaccines, 195 were already present in the genome of the parental strain (pOka), indicating that the variants occurred during the generation of the parental strain from the Dumas strain. Compared to the pOka genome, the vaccines exhibited distinct variant frequencies on a genome-wide and within an attenuation-related open reading frame (ORF). In particular, attenuation-associated 42 SNPs showed that Barycela, VarilRix, VariVax, and SKY Varicella are in ascending order regarding similarity with pOka-like genotypes, which in turn, might provide genomic evidence for the levels of attenuation. Finally, the phylogenetic network analysis demonstrated that genetic distances from the parental strain correlated with the attenuation levels of the vaccines.

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The prevalence and influencing factors of gag reflex in children aged 7‐14 years in the dental setting

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Abstract

Background

Gag reflex may occur in patients of all ages and often considered having a multifactorial etiology.

Objective

The aim of the study was to evaluate the prevalence and influencing factors of gag reflex in Turkish children aged 7-14 years in the dental setting.

Methods

This cross-sectional study was carried out among 320 children aged between 7-14 years. First, an anamnesis form which include sosyodemographic status, monthly level of income, children past medical, and dental experiences was filled by mothers. Children's fear levels were evaluated using the Dental Subscale of Children's Fear Survey Schedule(CFSS-DS) while mother's anxiety levels using the Modified Dental Anxiety Scale(MDAS). The revised dentist section of gagging problem assessment questionnaire (GPA-R-de) were used for both children and mothers. Statistical analysis were done with SPSS program.

Results

The prevalence of gag reflex among children was 34.1%, among mothers was 20.3%. The association between child and mother gagging was found statistically significant (χ2=53.121, p<0.001). When the mother of the child gagged, the risk of child gagging increases 6.83 times (p<0.001). Higher CFSS-DS scores of children increase risk of gagging (OR=1.052, p=0.023). Children who were previously treated mostly in public hospitals significantly more likely to gag compared with private dental clinics (OR=10.990, p<0.001).

Conclusion

It was concluded that negative past dental experiences, previous dental treatments with local anesthesia, history of hospital admission, number and place of previous dental visits, dental fear level of children, and low education level and gagging of mother have an influence on the gagging of children.

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The ability of magnetic resonance imaging to predict lymph node metastases and the risk of recurrence in rectal cancer

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Abstract

Aim

This study aimed to examine the diagnostic accuracy and prognostic value of magnetic resonance imaging (MRI) detected lymph nodes in rectal cancer.

Method

We evaluated 806 rectal cancer patients consecutively operated on between 2015 and 2018 at Helsinki University Hospital. In total, 485 patients met the inclusion criteria of presenting with stage I–III disease and were intended for curative treatment at the time of diagnosis. The effect of MRI-detected clinical lymph node status (cN) on cumulative overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) was calculated using the Kaplan–Meier analysis.

Results

Negative predictive value (NPV) of MRI-lymphnode negativity was 74.8%. Positive predictive value of lymph node metastasis was only 48.6%. In the Kaplan–Meier survival analysis, OS (p = 0.989), DSS (p = 0.911), and DFS (p = 0.109) did not significantly differ according to MRI nodal status. However, cumulative disease-free survival significantly (p < 0.001) differed according to the histopathological lymph node metastasis status (pN).

Conclusions

MRI detected lymph node positivity appears insufficiently precise and cannot predict disease recurrence or survival. Therefore, it should not serve as an independent risk factor when considering neoadjuvant treatment options for rectal cancer patients.

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LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes

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Abstract

Background

The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD.

Objective

To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment.

Methods

In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30).

Results

Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances.

Conclusions

The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Frequent EGFR exon 20 insertion in the so‐called peripheral‐type squamous cell neoplasm of uncertain malignant potential: a variant of bronchiolar adenoma or underrecognized entity?

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Frequent EGFR exon 20 insertion in the so-called peripheral-type squamous cell neoplasm of uncertain malignant potential: a variant of bronchiolar adenoma or underrecognized entity?


Introduction

Herein we describe a series of rare peripheral pulmonary neoplasms temporarily termed "peripheral type squamous cell neoplasm of uncertain malignant potential(PSCN-UMP)" and investigate their relationship to bronchiolar adenoma (BA) and squamous cell carcinoma (SCC).

Materials and methods

The histologic and immunohistochemical features of ten PSCN-UMPs and six BAs were compared. Whole exome sequencing (WES) and bioinformatics analysis were performed to further compare the genetic features of PSCN-UMPs, BAs, and NSCLCs.

Results

All PSCN-UMPs were peripherally located and histologically characterized by the lepidic, nested, and papillary proliferation of relatively bland squamous cells, accompanied by entrapped hyperplastic reactive pneumocytes. The basal squamous cells co-expressed TTF1 and squamous markers. Both cellular components exhibited bland morphology and a low proliferative activity. The six BAs met the morphologic and immunophenotypic features of proximal-type BA. Genetically, driver mutations, including frequent EGFR exon 20 insertions, were found in PSCN-UMPs, while the KRAS mutation, BRAF mutation, and ERC1::RET fusion were detected in BAs. PSCN-UMPs also shared some alterations with BAs in mutational signatures, while copy number variants (CNV) were enriched in MET and NKX2-1 in PSCN-UMP and MCL1, MECOM, SGK1, and PRKAR1A in BA.

Conclusion

PSCN-UMPs exhibited the proliferation of bland squamous cells accompanied by entrapped pneumocytes and frequent EGFR exon 20 insertions, which showed distinct features from BAs and SCCs. Recognition of this specific entity will help to expand the morphologic and molecular spectrum of peripheral lung squamous neoplasms.

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