Abstract The expression level of PD‐L1 is one of the most widely used predictive markers of immune checkpoint blockade (ICB) efficacy in the clinic, suggesting the importance of regulating PD‐L1 expression. However, no published reports have addressed the systematic exploration of the regulation of immune checkpoint molecules from the perspective of mutual exclusion (ME) in gene expression. The ME analysis, based on gene plasticity, provides a novel perspective on the intergenic regulatory paradigm. Here, multiple negative regulators of PD‐L1 expression are identified, and dual‐specificity phosphatase 9 (DUSP9) is selected for intensive study. DUSP9 negatively regulates PD‐L1 expression in multiple tumor cells, and mechanistically, DUSP9 dephosphorylates STAT3 to mediate the inhibitory role. In syngeneic tumor models, the combination of DUSP9 targeting and PD‐1 antibody can enhance therapeutic sensitivity. The clinical data demonstrated that elevated DUSP9 expression is correlated with diminished PD‐1/PD‐L1 antibody response rates. Consequently, DUSP9 emerges as a promising target for enhancing treatment response in combination with PD‐1 antibody, and functions as a potential marker for predicting the efficacy of tumor immunotherapy. This research demonstrates an efficient method for identifying negative regulators of highly plastic genes (HPGs), which can predict immunotherapy responses and identify new targets for combination therapy with ICB.
Abstract Hyperglycemia impairs stem cell–mediated bone regeneration, yet the responsible immunometabolic block remains undefined. We identify a neutrophil–Pad4–metabolite axis that suppresses osteogenesis. In rat models of chronic and intermittent hyperglycemia, neutrophils activate ERK/JNK–AP‑1, upregulate Pad4, and generate 4‑guanidinobutyric acid (4‑GBA). 4‑GBA binds alkaline phosphatase (ALP) on jawbone mesenchymal stem cells (JBMSCs), inhibits ALP, and reduces mineralization. Padi4 deletion accelerates socket healing under hyperglycemia. To restore osteogenesis, we engineer GBASpongel, a peptide hydrogel that captures 4‑GBA at the defect. Local GBASpongel treatment rescues ALP activity, osteogenic gene expression, and bone formation in hyperglycemic rats, and improves jawbone regeneration in hyperglycemic rabbits and beagle dogs. Binding assays show micromolar affinity between 4‑GBA and ALP. Transcriptomic and metabolomic analyses corroborate pathway activation and rescue. Neutrophil-derived 4-GBA directly links hyperglycemia to impaired JBMSC function, and locally targeting this metabolite provides a translational approach to restore bone healing in dysglycemia.
Minimally invasive surgery presents challenges such as dynamic tissue motion and a limited field of view. Accurate tissue tracking has the potential to support surgical guidance, improve safety by helping avoid damage to sensitive structures, and enable context-aware robotic assistance during complex procedures. In this work, we propose a novel method for markerless 3D tissue tracking by leveraging 2D Tracking Any Point (TAP) networks. Our method combines two CoTracker models, one for temporal tracking and one for stereo matching, to estimate 3D motion from stereo endoscopic images. We evaluate the system using a clinical laparoscopic setup and a robotic arm simulating tissue motion, with experiments conducted on a synthetic 3D-printed phantom and a chicken tissue phantom. Tracking on the chicken tissue phantom yielded more reliable results, with Euclidean distance errors as low as 1.1 mm at a velocity of 10 mm/s. These findings highlight the potential of TAP-based models for accurate, markerless 3D tracking in challenging surgical scenarios.
Thyroglossal duct cysts (TDCs) and branchial cleft cysts (BCCs) are common congenital neck anomalies that typically present in children. However, their occurrence in the parapharyngeal space is exceedingly rare. Standard management usually involves elective resection via a transcervical approach. We report two atypical cases in adult patients where these masses were located in the parapharyngeal space and were successfully managed with transoral resection.Patient A, an 81-year-old male, presented with a parapharyngeal TDC causing intermittent compressive symptoms for over five decades. Patient B, a 56-year-old male, had an incidentally discovered parapharyngeal BCC. Both lesions were transorally excised without complications. We discuss the imaging characteristics, the importance of maintaining a wide differential diagnosis, and the feasibility of transoral resection for these rare presentations, especially when the masses are situated superiorly and medially in the parapharynx. A comprehensive literature review of parapharyngeal TDCs and BCCs is provided, highlighting the rarity of these congenital neck masses in such locations and the role of transoral excision in their management.
ABSTRACT Objective The purpose of this study was to compare the efficacy and user experience (UX) of a pre‐formed rigid stylet commonly used in endotracheal intubations to a novel, articulating (user‐controlled) stylet. Methods The participants were a mixture of undergraduates, medical students, residents, and attendings who attempted to intubate cadavers using both traditional and novel stylets via video laryngoscopy, after which they were surveyed using the NASA Task Load Index (NASA‐TLX) form. Results We found the novel stylet to have improved UX, scoring lower in physical demand, effort, temporal demand, and frustration compared to the traditional stylet on the NASA‐TLX. The traditional stylet scored lower on mental effort. There was no difference in how participants viewed their performance. Conclusion There was no difference in how participants viewed their performance. This preclinical study for this novel stylet showed promising results in terms of ease of use. Level of Evidence 3.
Inner ear cell regeneration from stem/progenitor cells provides potential therapeutic strategies for the restoration of sensorineural hearing loss (SNHL), however, the efficiency of regeneration is low and the functions of differentiated cells are not yet mature. Biomaterials have been used in inner ear cell regeneration to construct a more physiologically relevant 3D culture system which mimics the stem cell microenvironment and facilitates cellular interactions. Currently, these biomaterials include hydrogel, conductive materials, magneto-responsive materials, photo-responsive materials, etc. We analyzed the characteristics and described the advantages and limitations of these materials. Furthermore, we reviewed the mechanisms by which biomaterials with different physicochemical properties act on the inner ear cell regeneration and depicted the current status of the material selection based on their characteristics to achieve the reconstruction of the auditory circuits. The application of biomaterials in inner ear cell regeneration offers promising opportunities for the reconstruction of the auditory circuits and the restoration of hearing, yet biomaterials should be strategically explored and combined according to the obstacles to be solved in the inner ear cell regeneration research.
Kriste Kaikaryte, Greta Gedvilaite, Renata Balnyte
et al.
Aim: The purpose of this work was to investigate the prevalence of <i>SIRT1</i> rs3818292, rs3758391, and rs7895833 single nucleotide polymorphisms and SIRT1 serum levels associated with multiple sclerosis (MS) in the Lithuanian population. Methods: A total of 250 MS patients and 250 healthy controls were included in the study. Genotyping was performed using the RT-PCR method. Statistical analysis was performed using “IBM SPSS version 29.0”. The serum SIRT1 level was determined by the ELISA method. Results: We found that rs3818292 was associated with increased odds of developing MS under the dominant (<i>p</i> = 0.007) and allelic genetic (<i>p</i> = 0.004) models. rs3758391 was associated with increased odds of developing under the co-dominant (<i>p</i> < 0.001), overdominant (<i>p</i> < 0.001), dominant (<i>p</i> < 0.001), and allelic (<i>p</i> = 0.002) genetic models. rs7895833 was associated with increased odds of developing MS under co-dominant (<i>p</i> < 0.001), overdominant (<i>p</i> < 0.001), dominant (<i>p</i> < 0.001), and allelic (<i>p</i> < 0.001) genetic models. Additional sex-differentiated analysis within females revealed that the rs3758391 was associated with an increased odds ratio for the occurrence of MS among the co-dominant (<i>p</i> = 0.006), dominant (<i>p</i> = 0.002), and allelic (<i>p</i> = 0.001). rs7895833 was associated with an increased odds ratio for the development of MS under the co-dominant (<i>p</i> < 0.001), overdominant (<i>p</i> < 0.001), dominant (<i>p</i> < 0.001), and allelic (<i>p</i> < 0.001) genetic models. Age-differentiated analysis showed that rs3758391 was associated with an increased odds ratio for the development of MS in younger patients under the codominant (<i>p</i> = 0.002), overdominant (<i>p</i> = 0.003), and dominant (<i>p</i> = 0.004) genetic models. rs7895833 was associated with an increased odds ratio for the occurrence of MS under the overdominant genetic model (<i>p</i> = 0.013). In elderly patients, rs3818292 was associated with an increased odds ratio for the occurrence of MS under the dominant (<i>p</i> = 0.008) and allelic (<i>p</i> = 0.009) genetic models. rs7895833 was associated with an increased odds ratio for the occurrence of MS under the codominant (<i>p</i> = 0.011 and <i>p</i> = 0.012), dominant (<i>p</i> = 0.001), and allelic (<i>p</i> < 0.001) genetic models. We also found that serum SIRT1 levels were statistically significantly different between MS patients and control group subjects (<i>p</i> < 0.001). In addition, comparison of SIRT1 levels between study groups and genotypes showed that rs3818292 AA (<i>p</i> = 0.001), rs3758391 CT (<i>p</i> < 0.001), and rs7895833 AA (<i>p</i> = 0.002) and AG (<i>p</i> = 0.004) had higher SIRT1 levels in the control group than in the MS group. All results were provided after strict Bonferroni correction. Conclusions: Genetic variations in <i>SIRT1</i> rs3818292, rs3758391, and rs7895833 are associated with multiple sclerosis, with possible differences in gender and age, as well as lower serum SIRT1 levels.
Vibeke Backer, Andreas Porsborg, Victor Hansen
et al.
Abstract Background Chronic cough, more than 8 weeks, can either be without co-morbidity called unexplained chronic cough (UCC) or with co-morbidity called refractory chronic cough (RCC). Using datasets from the Danish National Prescription Registry (Prescription Registry) and Danish National Patient Registry (Patient Registry) we wanted to investigate the prevalence and factors of importance of cough in a Nationwide registry. Material and methods Inclusion criteria were patients 18–90 years with at least one final cough diagnosis (ICD-10 DR05/DR059) in Patient registry or patients who have redeemed ≥2 prescriptions for relevant cough-medication within a 90-day harvest in the Prescription registry from 2008 to 2017. To validate this study’s chosen proxy on chronic cough an analysis of the Patient registry sub-population with a contact of ≥8 weeks and then final diagnosis code DR05/DR059 was also performed. The population was divided into UCC and RCC. Results Of the 104,216 patients from the Prescription registry, 52,727 were classified as having UCC and 51,489 were classified with RCC. From the Patient registry 34,260 were included, of whom 12,278 had UCC and 21,982 had RCC. Cough were frequently found among females (p < 0.0001). Both genders were around 2 years older in RCC than UCC (p < 0.0001) Spirometry was performed in 69 and 57%, X-ray in 73 and 58% and asthma challenge test performed in 13 and 5% (UCC and RCC, respectively, p < 0.0001). The frequency of co-morbidities such as heart failure, rheumatologic disease, pulmonary embolism, and diabetes was < 10%. Conclusion Many patients suffer from chronic cough or cough requiring medications, with or without co-morbidity; frequently found among menopausal women. Most patients had a substantial work-up performed. The high frequency and the resources consuming work-up program call for systematic coding of disease, systematic patient evaluation and more specific treatment options. The study was approved (ID: no. P-2019-191).
Abstract Background The efficacy of bevacizumab in non-small cell lung cancer (NSCLC) patients is unsatisfactory, and the selection of suitable patients is still challenging. Given the epigenetic modifications can contribute to an aberrant regulation of angiogenesis and microenvironment, we investigated DNA methylation profiles to determine clinical benefit of bevacizumab in NSCLC patients. Methods Genome-wide DNA methylation profiling was performed in NSCLC patients treated with chemotherapy in combination with bevacizumab. Patients were divided into better prognosis group (A group) and inferior prognosis group (B group) based on their survival. The difference of methylation patterns and respective functional enrichment analysis were performed between two groups. Prognostic DNA methylation signature for bevacizumab was established with the least absolute shrinkage and selection operator regression analyses. TISIDB database was further used to infer immunological relationship for prognostic related DNA methylation. Results Twenty patients were included in this study, and significantly distinct methylation patterns were observed between patients with different prognosis. Related genes of different methylation regions were significantly enriched in the biological process of cell projection assembly, neutrophil mediated immunity, and pathway of VEGFA-VEGFR2 signaling pathway, neutrophil degranulation. A 10-gene DNA methylation signature for prognosis prediction was established with the C-index of 0.76. And host genes of signature were found to be related to the abundance of ActCD4, Th1, ActCD8, NKT and neutrophil cells. Conclusion The 10-gene DNA methylation signature could serve as a novel biomarker to predict the clinical benefit of bevacizumab therapy and improve this anti-tumor approach for NSCLC patients.
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
ABSTRACT Purpose: to characterize and compare the reading fluency performance of public- and private-school fifth-grade students. Methods: a total of 44 elementary-school fifth-grade students of both sexes, aged 10 to 11 years, participated in the study and were divided into Group I (GI, with 25 public-school students) and Group II (GII, with 19 private school students). They were submitted to the Assessment of Reading Fluency Performance (ADFLU). The performance analysis was based on the number of correct words per minute, incorrect words per minute, total reading time, and reading speed. The data analysis was made with statistical tests, with significance set at p-value ≤0.05, for the inter- and intragroup comparisons. Results: in the analysis per group, there was a significant difference in the total reading time between the texts in GI, and in the reading speed between the texts, in GII. In the comparison between the groups, all variables had a significant difference, with a better performance in GII. Conclusion: the reading fluency performance of public- and private-school fifth-graders was characterized. The performance of the private-school students was superior to that of the public-school students.
Although stem cell-derived extracellular vesicles (EVs) have been shown to facilitate regeneration of injured tissue, there is no report that evaluates the immune-modulating effect of stem cell-derived EVs on Th2-mediated inflammation. In this study, we evaluated the immunomodulatory effects of adipose stem cells (ASCs)-derived EVs on Th2-mediated inflammation induced by Aspergillus protease antigen in lung epithelial cells. The EVs were isolated from supernatant of ASCs and the diameters of EVs were measured by using dynamic light scattering. The mice primary lung epithelial cells and mouse lung epithelial cell line (MLE12) were pre-treated with 200 ng/ml of Aspergillus protease and then treated with 1 μg/ml of ASC-derived EVs. Real time PCR was performed to determine the expression levels of eotaxin, IL-25, TGF-β, and IL-10 mRNAs after EV treatment. To evaluate the role of EVs in macrophage polarization and dendritic cells (DCs) differentiation, in vitro bone marrow-derived macrophage and DCs stimulation assay was performed. EV treatment significantly decreased the expression of eotaxin and IL-25 and increased TGF-β and IL-10 in both lung epithelial cells. EV treatment significantly increased the expression of co-stimulatory molecules such as CD40, CD80, and CD 86 in immature DCs. Furthermore, EV treatment significantly enhanced the gene expression of M2 macrophage marker such as Arg1, CCL22, IL-10, and TGF-β. In conclusion, EVs of ASCs ameliorated Th2-mediated inflammation induced by Aspergillus protease antigen through the activation of dendritic cells and M2 macrophage, accompanied by down-regulation of eotaxin and IL-25, and up-regulation of TGF-β and IL-10 in mouse lung epithelial cells. Keywords: Mesenchymal stromal cells, Extracellular vesicles, Immunosuppression, Macrophages, Dendritic cells, Transforming growth factor beta, Interleukin-10
Key Clinical Message Here, we report a novel deletion (copy number variation: CNV) in the GJB2 gene observed in a Japanese hearing loss patient. The deleted segment started in the middle of the GJB2 gene, but the GJB6 gene remained intact. This partial deletion in the GJB2 gene highlights the need for further improvements in GJB2 screening.
The management of the clinically N0 neck in patients with head and neck cancers still remains controversial. Elective neck dissection is traditionally recommended when the subside of the head and neck, such as the oral cavity and supraglottic area, confers at least a 15–20% risk of lymphatic spread. However, elective neck dissection may cause an increase in patient morbidity and mortality rates. The emergence of sentinel lymph biopsy provides the possibility of accurate pathological staging of the cervical node with a less invasive procedure. The present review will summarize the role of sentinel lymph node biopsy and its application areas when evaluating occult metastases in patients with head and neck cancers.
Ali R Khoshdel, Benyamin Mousavi-Asl, Babak Shekarchi
et al.
Background: Chronic exposure to noise is known to cause a wide range of health problems including extracellular matrix (ECM) proliferation and involvement of cardiovascular system. There are a few studies to investigate noise-induced vascular changes using noninvasive methods. In this study we used carotid artery intima-media thickness (CIMT) and aortic augmentation as indices of arterial properties and cystatin C as a serum biomarker relating to ECM metabolism. Materials and Methods: Ninety-three male participants were included in this study from aeronautic technicians: 39 with and 54 without a history of wide band noise (WBN) exposure. For better discrimination, the participants were divided into the two age groups: <40 and >40 years old. Adjusted aortic augmentation index (AI) for a heart rate equal to 75 beats per minute (AIx@HR75) were calculated using pulse wave analysis (PWA). CIMT was measured in 54 participants who accepted to undergo Doppler ultrasonography. Serum cystatin C was also measured. Results: Among younger individuals the mean CIMT was 0.85 ± 0.09 mm and 0.75 ± 0.22 mm in the in the exposed and the control groups respectively. Among older individuals CIMT had a mean of 1.04 ± 0.22 mm vs. 1.00 ± 0.25 mm for the exposed vs. the control group. However, in both age groups the difference was not significant at the 0.05 level. A comparison of AIx@HR75 between exposure group and control group both in younger age group (5.46 ± 11.22 vs. 8.56 ± 8.66) and older age group (17.55 ± 10.07 vs. 16.61 ± 5.77) revealed no significant difference. We did not find any significant correlation between CIMT and AIx@HR75 in exposed group (r = 0.314, P value = 0.145) but the correlation was significant in control group (r = 0.455, P value = 0.019). Serum cystatin C level was significantly lower in individuals with WBN exposure compared to controls (441.10 ± 104.70 ng/L vs. 616.89 ± 136.14, P value < 0.001) both in younger and older groups. Conclusion: We could not find any evidence for the association of WBN exposure with arterial properties, but cystatin C was significantly lower in the exposed group.
Specialist (Assisting Professor).Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo.Send correspondence to: Lidio Granato. Rua Cesario Motta Junior, 112. Departamento de Otorrinolaringologia. Vila Buarque. Sao Paulo - SP. CEP: 01221-020.Paper submitted to the BJORL-SGP (Publishing Management System - Brazilian Journal of Otorhinolaryngology) on January 4, 2011;and accepted on March 24, 2011. cod. 7497.
M. Avelino, Thaís Gomes Abrahão Elias, Renata Martins Dayrel Rezende
et al.
MD, Pediatric Hematologist (MD, Pediatric Hematologist).Hospital da Crianca de Goiânia.Send correspondence to: Rua 86, no 160. Hospital da Crianca. Setor Sul. Goiânia - GO.Paper submitted to the BJORL-SGP (Publishing Management System – Brazilian Journal of Otorhinolaryngology) on January 1, 2011;and accepted on April 30, 2011. cod. 7527