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1.
Int J Clin Pediatr Dent ; 17(7): 838-841, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39372532

ABSTRACT

To determine the pain prevalence and severity of flare-ups associated with before, during, and after pulpectomy procedure in children through systematic review and meta-analysis. Pain associated with root canal is a crucial source of fear for patients (especially child patients) and an important concern of dentists. Pain experienced at pretreatment, during treatment, and posttreatment is foreseen and recalled by child patients. A hand search of relevant journals and defined searching of Medline/PubMed, Cochrane, and EBSCOhost databases identified 2,635 articles reporting flare-ups at different intervals. After further filtering and applying inclusion criteria, three articles were identified for meta-analysis. From three recognized articles in the pretreatment phase, 51.2% of cases reported flare-ups; during treatment, there were 19.8% of cases; and in the posttreatment phase, 100% success rate was seen (i.e., no flares were present). The three included studies were heterogeneous according to I 2 and τ 2 statistics (p <0.001, I 2 = 92.64). Pretreatment pulpectomy-associated flare-ups were high, then dropped significantly to minimal levels in 3 days (during treatment) and continued to drop to lowest levels in 7 days (posttreatment). How to cite this article: Moudgalya MS, Kulkarni P, Tiwari S, et al. Flare-ups in Primary Teeth Before, During, and After Pulpectomy: A Systematic Review and Meta-analysis. Int J Clin Pediatr Dent 2024;17(7):838-841.

2.
J Med Virol ; 96(10): e29945, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39370874

ABSTRACT

Borna disease virus 1 (BoDV-1) is a neurotropic RNA virus that has been linked to fatal BoDV-1 encephalitis (BVE) in humans. Ferroptosis represents a newly recognized kind of programmed cell death that marked by iron overload and lipid peroxidation. Various viral infections are closely related to ferroptosis. However, the link between BoDV-1 infection and ferroptosis, as well as its role in BVE pathogenesis, remains inadequately understood. Herein, we used primary rat cortical neurons, human microglial HMC3 cells, and Sprague‒Dawley rats as models. BoDV-1 infection induced ferroptosis, as ferroptosis characteristics were detected (iron overload, reactive oxygen species buildup, decreased antioxidant capacity, lipid peroxidation, and mitochondrial damage). Analysis via qRT-PCR and Western blot demonstrated that BoDV-1-induced ferroptosis was mediated through Nrf2/HO-1/SLC7a11/GPX4 antioxidant pathway suppression. Nrf2 downregulation was due to BoDV-1 infection promoting Nrf2 ubiquitination and degradation. Following BoDV-1-induced ferroptosis, the PTGS2/PGE2 signaling pathway was activated, and various intracellular lipid peroxidation products and damage-associated molecular patterns were released, contributing to BVE occurrence and progression. More importantly, inhibiting ferroptosis or the ubiquitin‒proteasome system effectively alleviated BVE. Collectively, these findings demonstrate the interaction between BoDV-1 infection and ferroptosis and reveal BoDV-1-induced ferroptosis as an underlying pathogenic mechanism of BVE.


Subject(s)
Borna Disease , Borna disease virus , Ferroptosis , Lipid Peroxidation , NF-E2-Related Factor 2 , Neurons , Rats, Sprague-Dawley , Borna disease virus/physiology , Animals , Rats , Humans , Neurons/virology , Neurons/pathology , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Borna Disease/virology , Borna Disease/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , Cyclooxygenase 2/metabolism , Cyclooxygenase 2/genetics , Microglia/virology , Microglia/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/genetics , Cell Line , Encephalitis/virology , Encephalitis/pathology , Cells, Cultured
3.
Glob Med Genet ; 11(4): 285-296, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39224462

ABSTRACT

Some human cancers worldwide may be related to human tumor viruses. Knowing, controlling, and managing the viruses that cause cancers remain a problem. Also, tumor viruses use ubiquitin-proteasome system (UPS) that can alter host cellular processes through UPS. Human tumor viruses cause persistent infections, due to their ability to infect their host cells without killing them. Tumor viruses such as Epstein-Barr virus, hepatitis C virus, hepatitis B virus, human papillomaviruses, human T cell leukemia virus, Kaposi's sarcoma-associated herpesvirus, and Merkel cell polyomavirus are associated with human malignancies. They interfere with the regulation of cell cycle and control of apoptosis, which are important for cellular functions. These viral oncoproteins bind directly or indirectly to the components of UPS, modifying cellular pathways and suppressor proteins like p53 and pRb. They can also cause progression of malignancy. In this review, we focused on how viral oncoproteins bind to the components of the UPS and how these interactions induce the degradation of cellular proteins for their survival.

4.
Cureus ; 16(8): e65958, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39221341

ABSTRACT

Background Understanding patient experiences and opinions is crucial to improving the quality of treatment given as healthcare services in Riyadh continue to expand. This study attempts to evaluate various aspects of patient satisfaction with clinic visits. Objectives To assess and analyze patient satisfaction with clinic visits in Riyadh, Kingdom of Saudi Arabia, in order to identify areas for improvement and enhance the overall quality of healthcare services in the region. Methods This cross-sectional study collected data from 350 adults aged 18 and above in Riyadh, Kingdom of Saudi Arabia. A paper-based questionnaire was distributed using a snowball convenience sampling technique at various locations. The survey assessed different aspects of patient satisfaction, including demographics, accessibility, quality of care, and patient experience. Ethical approval was obtained, and informed consent was acquired from all participants. Results The study's demographic distribution revealed that the majority of participants were female (77.4%), with the largest age group being 24-35 years old (34.9%). Saudi nationals constituted the majority (72.6%). Regarding accessibility and convenience of healthcare services, a significant proportion of participants agreed that the distance between their residence and the health center was reasonable (73.4%). However, opinions were mixed regarding waiting times, with some considering it reasonable (47.4%) and others disagreeing (25.4%). Participants also had varying views on appointment availability, with a notable percentage finding it difficult (33.7%). In terms of continuity of care and communication, most participants agreed that the clinic proactively contacts them for appointments (67.4%), but there were mixed responses regarding the ease of transferring patients to a hospital (37.7% agreed, 13.1% disagreed). The agreement on seeing the same doctor at each visit was moderate (41.1%), and a majority agreed that doctors had easy access to medical records (74.9%). Regarding the quality of care and patient experience, most participants agreed that doctors treated them with respect (83.7%) and that nurses and staff members were respectful and cooperative (54.3%). The majority agreed that health centers provided services during emergencies (78%). In terms of evaluating the quality of medical services and facilities, most participants agreed that vital signs were checked during each visit (78.6%), while satisfaction with laboratory facilities was moderate (60.3%). When it came to doctor-patient communication and counseling, most participants agreed that doctors provided detailed information about their disease and medications (73.4%) and addressed patients' queries (74.9%). However, some participants said that doctors did not inform them well about their disease (23.4%). Most participants agreed that doctors showed empathy and friendliness (73.7%) and allocated adequate time during visits (71.7%). However, satisfaction with post-visit accessibility to the doctor was mixed (35.1% agreed it was easy). Conclusion The findings revealed that while participants expressed satisfaction with certain aspects of care, there were areas requiring improvement. These areas included reducing waiting times, enhancing appointment availability, improving transfer procedures, ensuring consistency in doctor-patient relationships, and enhancing communication and counselling.

5.
BMC Public Health ; 24(1): 2442, 2024 Sep 09.
Article in English | MEDLINE | ID: mdl-39251956

ABSTRACT

BACKGROUND: This study aimed to investigate the relationship between migration background and the utilization of preventive healthcare services. METHODS: Cross-sectional data from wave 5 in the year 2014, with a sample size of 7,684 individuals, were extracted from the nationally representative German Ageing Survey. The survey included community-dwelling individuals aged 40 years and above, with migration background serving as the primary independent variable. The outcomes measured included participation in cancer screenings, flu vaccinations, and routine health check-ups. Multiple logistic regressions were used to examine the association between migration background and preventive healthcare services. RESULTS: Regressions showed that the presence of a migration background with personal migration experience (compared with not having a migration background) was associated with a lower likelihood of using preventive healthcare services. More precisely, compared to individuals not having a migration background, individuals with a migration background and personal migration experience had a lower likelihood of routine health check-ups (OR = 0.76, 95% CI: 0.61 to 0.95), flu vaccinations (OR = 0.75, 95% CI: 0.59 to 0.95) and cancer screenings (OR = 0.71, 95% CI: 0.57 to 0.89). In contrast, there was no significant association between the presence of a migration background without personal migration experience (compared with not having a migration background) and the use of preventive healthcare services. CONCLUSION: In conclusion, results showed differences between individuals without migration background and individuals with migration background (and with personal migration experience) in terms of using preventive healthcare services. It may be helpful to specifically address individuals with migration background (and with migration experience) in terms of using preventive healthcare services.


Subject(s)
Preventive Health Services , Humans , Germany , Female , Male , Preventive Health Services/statistics & numerical data , Middle Aged , Cross-Sectional Studies , Aged , Adult , Patient Acceptance of Health Care/statistics & numerical data , Aged, 80 and over
6.
Cancers (Basel) ; 16(17)2024 Sep 03.
Article in English | MEDLINE | ID: mdl-39272922

ABSTRACT

Protein degradation is a biological phenomenon essential for cellular homeostasis and survival. Selective protein degradation is performed by the ubiquitination system which selectively targets proteins that need to be eliminated and leads them to proteasome degradation. In this narrative review, we focus on the ubiquitin-conjugating enzyme E2 O (UBE2O) and highlight the role of UBE2O in many biological and physiological processes. We further discuss UBE2O's implications in various human diseases, particularly in leukemias and solid cancers. Ultimately, our review aims to highlight the potential role of UBE2O as a therapeutic target and offers new perspectives for developing targeted treatments for human cancers.

7.
Cells ; 13(17)2024 Sep 06.
Article in English | MEDLINE | ID: mdl-39273066

ABSTRACT

Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin-proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway.


Subject(s)
Cullin Proteins , Hedgehog Proteins , Proteasome Endopeptidase Complex , Signal Transduction , Ubiquitination , Animals , Proteasome Endopeptidase Complex/metabolism , Hedgehog Proteins/metabolism , Hedgehog Proteins/genetics , Mice , NIH 3T3 Cells , Cullin Proteins/metabolism , Cullin Proteins/genetics , Zinc Finger Protein GLI1/metabolism , Zinc Finger Protein GLI1/genetics , Humans , Gene Expression Regulation
8.
Healthcare (Basel) ; 12(17)2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39273802

ABSTRACT

Muscle imbalances in the upper body can lead to ineffective movement patterns and potential injury. The purpose of this study was to investigate the muscle activity, impact, and muscle activation ratio of the serratus anterior (SA), upper trapezius (UT), lower trapezius (LT), and pectoralis major (PM) during the knee push-up plus (KPUP) exercise under various loads. METHOD: Electromyography assessed scapular muscle activity in 32 healthy adults (15 males, 17 females) during three KPUP variations. RESULTS: PM and UT showed no significant activity differences across loads, whereas SA and LT did. SA activity was significantly higher in the weighted KPUP (WKPUP) 3 kg than that in KPUP and WKPUP 1 kg. LT activity was also significantly higher in WKPUP 3 kg compared to KPUP and WKPUP 1 kg, with KPUP showing higher activity than WKPUP 1 kg. PM/SA ratios remained consistent across loads, while UT/LT ratios varied significantly, being notably lower at 3 kg compared to 0 kg and 1 kg. Similarly, UT/SA ratios differed significantly among loads, being notably lower at 3 kg and 1 kg compared to 0 kg. CONCLUSION: WKPUP with 3 kg demonstrated significantly higher SA and LT activity compared to KPUP and WKPUP 1 kg. The lowest UT/LT ratio was observed during the WKPUP 3 kg, suggesting its effectiveness for optimizing muscle activation balance during KPUP exercises. These findings may inform the development of exercise protocols aimed at improving scapular stabilization.

9.
Sci Rep ; 14(1): 21681, 2024 09 17.
Article in English | MEDLINE | ID: mdl-39289469

ABSTRACT

Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft tissue sarcomas. This study determined the value of perfusion-weighted imaging with dynamic-contrast-enhancement (PWI/DCE) morphologic, qualitative, and semiquantitative features for predicting UPS pathology-assessed treatment effect (PATE). This retrospective study included 33 surgically excised extremity UPS patients with pre-surgical MRI. Volumetric tumor segmentation from PWI/DCE was obtained at Baseline (BL), Post-Chemotherapy (PC), and Post-Radiation Therapy (PRT). The surgical specimens' PATE separated cases into Responders (R) (≥ 90%, 16 patients), Partial-Responders (PR) (89 - 31%, 10 patients), and Non-Responders (NR) (≤ 30%, seven patients). Seven semiquantitative kinetic parameters and maps were extracted from time-intensity curves (TICs), and 107 radiomic features were derived. Statistical analyses compared R vs. PR/NR. At PRT, 79% of R displayed a "Capsular" morphology (P = 1.49 × 10-7), and 100% demonstrated a TIC-type II (P = 8.32 × 10-7). 80% of PR showed "Unipolar" morphology (P = 1.03 × 10-5), and 60% expressed a TIC-type V (P = 0.06). Semiquantitative wash-in rate (WiR) was able to separate R vs. PR/NR (P = 0.0078). The WiR radiomics displayed significant differences in the first_order_10 percentile (P = 0.0178) comparing R vs. PR/NR at PRT. The PWI/DCE TIC-type II curve, low WiR, and "Capsular" enhancement represent PRT patterns typically observed in successfully treated UPS and demonstrate potential for UPS treatment response assessment.


Subject(s)
Contrast Media , Sarcoma , Humans , Female , Male , Middle Aged , Aged , Adult , Retrospective Studies , Sarcoma/diagnostic imaging , Sarcoma/therapy , Sarcoma/pathology , Sarcoma/radiotherapy , Treatment Outcome , Magnetic Resonance Imaging/methods , Aged, 80 and over , Radiomics
10.
Biol Reprod ; 2024 Sep 06.
Article in English | MEDLINE | ID: mdl-39239833

ABSTRACT

Dcaf17, also known as DDB1- and CUL4-associated factor 17, is a member of the DCAF family and acts as the receptor for the CRL4 ubiquitin E3 ligase complex. Several previous studies have reported that mutations in Dcaf17 cause Woodhouse-Sakati Syndrome (WSS), which results in oligoasthenoteratozoospermia (OAT) and male infertility. As a model to explore the role of Dcaf17 in the male reproductive system, we created Dcaf17-deficient male golden hamsters using CRISPR-Cas9 technology, the results of which demonstrate that deletion of Dcaf17 led to abnormal spermatogenesis and infertility. To uncover the underlying molecular mechanisms involved, we conducted single-cell RNA sequencing (scRNA-seq) analysis to evaluate the effect of Dcaf17 deficiency on transcriptional levels in spermatogenic cells during various stages of spermatogenesis. These data emphasize the significant regulatory role played by Dcaf17 in early spermatogenic cells, with many biological processes being affected, including spermatogenesis, and protein degradation. Dysregulation of genes associated with these functions ultimately leads to abnormalities. In summary, our findings highlight the critical function of Dcaf17 in spermatogenesis and male fertility and clarify the specific stage at which Dcaf17 exerts its effects, while simultaneously providing a novel animal model for the study of Dcaf17.

11.
Front Immunol ; 15: 1436174, 2024.
Article in English | MEDLINE | ID: mdl-39315102

ABSTRACT

The ubiquitin-proteasome system (UPS) plays a crucial role in modulating the proliferation, activation, and normal functioning of immune cells through the regulation of protein degradation and function. By influencing the expression of immune checkpoint-associated proteins, the UPS modulates T cell-mediated anti-tumor immune responses and can potentially facilitate the immune escape of tumor cells. Additionally, the UPS contributes to the remodeling of the tumor immunosuppressive microenvironment (TIME) by regulating B cells, dendritic cells (DCs), macrophages, and Treg cells. Targeting the UPS in conjunction with immune checkpoint-associated proteins, and combining these with other therapeutic approaches, may significantly enhance the efficacy of combination therapies and pave the way for novel cancer treatment strategies. In this review, we first summarize the composition and alterations of the TIME, with a particular emphasis on the role of the UPS in TIME and its interactions with various immune cell types. Finally, we explore the potential of combining UPS-targeted therapies with immunotherapy to substantially improve the effectiveness of immunotherapy and enhance patient survival outcomes.


Subject(s)
Neoplasms , Proteasome Endopeptidase Complex , Tumor Microenvironment , Ubiquitin , Humans , Tumor Microenvironment/immunology , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/immunology , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/drug therapy , Ubiquitin/metabolism , Animals , Immunotherapy/methods , Combined Modality Therapy
12.
Eur J Health Econ ; 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39299943

ABSTRACT

This paper analyses the structure of and variability in taxation and prescription drug distribution policies and quantifies the impact of such policies on the cost of prescription drugs to health systems in 35 countries. Taxes on prescription drugs remain highly prevalent (83% of the sample) although 63% of the sample countries implement a lower than standard VAT rate. Three remuneration types of the wholesale and retail distribution chain have been identified. Wholesale and retail distributors are remunerated on a regressive mark-up basis, which is price-dependent, although fixed fees and fixed percentages, which are non-price dependent, are also highly prevalent. Price component analysis for three groups of products classed as high-, medium- and low-priced suggests that mark-ups plus taxes varied significantly across countries and products, and ranged from 5% to 187% of ex-factory prices. Average margins also vary significantly by countries and products ranging 5-65% of retail prices. The cost of distribution and taxation contributes significantly to prescription drug costs for health systems. Although distribution chain remuneration raises efficiency and overall affordability questions, these need to be considered together with the regulatory framework shaping market structure of the distribution chain, as well as any prevailing horizontal and vertical integration policies. The overall cost of prescription drugs could be reduced immediately by eliminating taxation; this could go some way to alleviate fiscal pressures on health budgets, whilst avoiding resource re-allocation from health to other sectors.

13.
Indian J Surg Oncol ; 15(Suppl 3): 497-500, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39328731

ABSTRACT

Low-grade myofibroblastic sarcoma (LGMS) is categorized as an extremely rare malignant neoplasia of myofibroblasts. To date, only 38 cases describing patients diagnosed with LGMS in the oro-maxillofacial region have been reported in the scientific literature. Here, we introduce a rare case report and, for the first time, also provide a recent update of the literature and a clear review regarding the immunohistochemical panel to diagnose this entity.

14.
Cureus ; 16(7): e65397, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39184763

ABSTRACT

This study examined the impact of incorporating pull-up exercises into the training routines of competitive swimmers on their performance outcomes. Eight swimmers (average age 21 ± 6.7 years, height 178 ± 5.3 cm, body mass 73 ± 7.0 kg) were selected and participated in a 10-week intervention, during which pull-up exercises were added to their regular strength training sessions. Performance was evaluated through tests measuring the sprint start speed and 50-meter freestyle swim times before and after the intervention. Statistical analyses showed significant improvements in swimming explosive strength, as measured by a 15-meter time trial (p = 0.014). In addition, resistance to explosive strength, as indicated by total time in a 50-meter time trial, improved significantly (p = 0.008), particularly in the first 25 meters (p = 0.014), although not in the second 25 meters (p = 0.078). These findings highlight the critical role of upper body strength and power in enhancing swimming performance, especially in sprint events. In conclusion, incorporating pull-up exercises into training regimens appears promising for improving upper body strength and power among swimmers. Future research should address the study's limitations by using larger, more homogeneous samples and more rigorously controlling variables such as age, gender, and training schedules. These efforts could provide clearer insights into the effectiveness of pull-up exercises in optimizing swimming performance, particularly in sprint disciplines.

15.
Child Abuse Negl ; 155: 106955, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39094278

ABSTRACT

Online child sexual abuse material (CSAM) is a growing problem. Prevention charities, such as Stop It Now! UK, use online messaging to dissuade users from viewing CSAM and to encourage them to consider anonymous therapeutic interventions. This experiment used a honeypot website that purported to contain barely legal pornography, which we treated as a proxy for CSAM. We examined whether warnings would dissuade males (18-30 years) from visiting the website. Participants (n = 474) who attempted to access the site were randomly allocated to one of four conditions. The control group went straight to the landing page (control; n = 100). The experimental groups encountered different warning messages: deterrence-themed with an image (D3; n = 117); therapeutic-themed (T1; n = 120); and therapeutic-themed with an image (T3; n = 137). We measured the click through to the site. Three quarters of the control group attempted to enter the pornography site, compared with 35 % to 47 % of the experimental groups. All messages were effective: D3 (odds ratio [OR] = 5.02), T1 (OR = 4.06) and T2 (OR = 3.05). Images did not enhance warning effectiveness. We argue that therapeutic and deterrent warnings are useful for CSAM-prevention.


Subject(s)
Erotica , Internet , Humans , Erotica/psychology , Erotica/legislation & jurisprudence , Male , Adolescent , Adult , Young Adult , Child Abuse, Sexual/prevention & control , Child Abuse, Sexual/legislation & jurisprudence , Child , United Kingdom
16.
J Bone Miner Res ; 39(10): 1486-1492, 2024 Sep 26.
Article in English | MEDLINE | ID: mdl-39216107

ABSTRACT

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.


Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder caused by mutations in the ACVR1 gene. People with FOP experience growth of new bone in places where bone does not usually develop. Soft tissues (like skeletal muscles) and connective tissues (like tendons and ligaments) are gradually replaced by bone beyond the normal skeleton­a process called heterotopic ossification (HO). People with FOP experience flare-ups, which are painful swellings of the soft tissues. In this clinical study in people with FOP, we looked at the number of flareups, whether flareups were linked to new HO lesions, and the impact of garetosmab (a monoclonal antibody) on flareups. At random, about half the patients received placebo, or inactive drug, with the other half receiving garetosmab, the study drug. Of the patients who received placebo, 71% had flare-ups and 59% percent of those who had flare-ups also had a new HO lesion, which was not always related to the location of the flare-up. We have previously shown that garetosmab reduces the number of flareups patients report. In this study, we show that garetosmab reduces the length and pain severity of flare-ups too. The treatment effects were maintained for the whole study.


Subject(s)
Myositis Ossificans , Humans , Myositis Ossificans/drug therapy , Myositis Ossificans/pathology , Adult , Double-Blind Method , Male , Female , Middle Aged , Symptom Flare Up , Ossification, Heterotopic/drug therapy , Ossification, Heterotopic/diagnostic imaging , Ossification, Heterotopic/pathology
17.
Mol Clin Oncol ; 21(4): 69, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39113850

ABSTRACT

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade, aggressive soft tissue sarcoma (STS) with a poor prognosis, and no definitive or effective treatment is currently available for it. Pazopanib, an orally available multiple tyrosine kinase inhibitor, has been approved for the treatment of advanced STS. The present study documents the case of a 51-year-old man with advanced UPS with coamplification of platelet-derived growth factor receptor A (PDGFRA), vascular endothelial growth factor receptor 2 (VEGFR2) and stem cell factor receptor (KIT) genes. The patient exhibited a marked and sustained response to pazopanib. The patient presented with a retroperitoneal tumour with pancreatic head lymph node metastasis, and bone metastases in the second/fifth thoracic vertebrae and left femur. Based on the histological analysis of the retroperitoneal tumour and femoral mass, the patient was diagnosed with UPS. Palliative radiation therapy was administered to the left femur and second/fifth thoracic vertebrae to prevent fractures. After radiation therapy, the patient achieved a partial response after eight courses of doxorubicin. A comprehensive genomic profiling analysis (FoundationOne® CDx) revealed coamplification of PDGFRA, VEGFR2 and KIT genes. Hence, pazopanib was initiated as a second-line treatment. Notably, the retroperitoneal tumour shrank, and no new lesions developed for 3 years after the initiation of pazopanib treatment. This response suggests that the coamplification of PDGFRA, VEGFR2 and KIT may predict favourable outcomes in response to pazopanib.

18.
Cureus ; 16(7): e64112, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39119420

ABSTRACT

Introduction Laboratory testing is done before surgery to identify body abnormalities that cannot be detected through clinical evaluation alone. Patients going in for low- or intermediate-risk surgeries are often encouraged to undergo a battery of tests as usual. This cross-sectional observational study evaluated the status of routine pre-operative laboratory tests in American Society of Anaesthesiologists (ASA) Grade I, II, and III adults undergoing elective surgery at a maternity hospital, as well as the impact of these tests on the outcome of the pre-anaesthetic check-up (PAC). Methods The present observational study was conducted on 500 patients scheduled for elective surgery under anaesthesia. The procedures included routine gynaecological and obstetric surgeries like abdominal hysterectomy, suction evacuation, laparotomy for ectopic pregnancy, diagnostic biopsy, and lower segment caesarean section, among others. A designated anaesthesiologist gathered information from the completed PAC sheets. As per the standard departmental policy, each patient underwent a clinical examination and routine investigations at the PAC clinic. In addition to demographic and other variables, laboratory test results and any peri-operative interventions performed due to abnormalities were assessed. Investigations already done, asked by anaesthesiologists, and referral services sought were noted. The impact of these investigations on anaesthetic decision-making was noted. Data were expressed in frequencies and percentages and statistically analysed using INSTAT software (GraphPad Prism Software Inc., La Zolla, USA). Results The age and weight of the patients range from 20 to 70 years and 55 to 95 kg. Most patients belonged to ASA Grade II (n=348, 69.6%). Hypothyroidism was the most common abnormal finding (n=122, 22.4%). Anaemia, hypertension, and diabetes were detected in n=8 (1.6%), n=82 (16.4%), and n=34 (6.8%) of patients, respectively. In 488 (97.6%) patients, one or more of the investigations from the list were pending. Based on the results of various preoperative laboratory investigations, 87 (17.4%) patients were advised of multiple specialty opinions before surgery. A total of 453 (90.6%) patients attending the clinic were recommended to review their PACs after their pending investigations and specialist consultations were completed. At the same time, n=41 (8.2%) was found to be fit for surgery, and n=6 (1.2%) was found unfit for surgery and was postponed. Conclusions The incidence of tests with abnormal results was a little high in our study. One reason could be that a particular group of patients is included in the study. Preoperative laboratory investigations substantially increase the costs. Not many patients with abnormal tests may require changes in their peri-anaesthetic management. Nonetheless, laboratory tests can help ensure the patient is in an ideal preoperative condition. Pre-operative laboratory investigations should be advised on a case-by-case basis to avoid inconveniencing the patient, delaying the surgical procedure, and driving up the cost of surgical treatment.

19.
Diagn Pathol ; 19(1): 110, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39143618

ABSTRACT

AIMS: Compared to primary breast sarcoma (BSs), radiotherapy-induced sarcoma (RIS) is a less frequent type of secondary breast sarcoma. Undifferentiated pleomorphic sarcoma (UPS) is an even rarer occurrence within the RIS category. This study aimed to present the clinicopathologic and molecular features of breast radiotherapy-induced UPS. METHODS: A retrospective study was conducted at the Third Affiliated Hospital of Soochow University to analyze three patients with radiation-induced undifferentiated pleomorphic sarcoma (UPS) following breast cancer, spanning from 2006 to 2023. The clinical and pathological variables were extracted from the medical records, while immunohistochemistry was employed to analyze the immunophenotypes of these tumors. Genomic characteristics were assessed through DNA and RNA sequencing techniques. Another 15 cases from the literature were also reviewed to better characterize the tumor. RESULTS: The affected areas encompass the chest wall and breasts, with an incubation period ranging from 6 to 17 years. The tumor cells exhibit pleomorphism and demonstrate a high degree of pathological mitosis. Notably, two cases displayed an accelerated disease progression, characterized by recurrent tumors and metastases occurring within short intervals of 48 and 7 months respectively subsequent to the initial diagnosis. The two prevailing identified genes were TP53 (2/3, 66.7%) and RB1 (1/3, 33.3%). Through analysis of somatic copy number variation (CNV), it was discovered that two oncogenes, MCL1 (1/3, 33.3%) and MYC (1/3, 33.3%), had experienced gains in CNV. The Tumor Mutational Burden (TMB) values for case 1, case 2, and case 3 were 5.9 mut/Mb, 1.0 mut/Mb, and 3.0 mut/Mb, respectively. Moreover, the analysis of RNA-NGS (next-generation sequencing) revealed the presence of a novel gene fusion, named COL3A1-GULP1, in case 2. CONCLUSIONS: Based on our thorough analysis of research findings and previous reports, it is evident that radiotherapy-induced UPS exhibits a highly diverse and frequently severe clinical and biological behavior. Identifying tumor formation using genome sequencing can help understand its biological behavior and determine personalized treatments.


Subject(s)
Breast Neoplasms , Neoplasms, Radiation-Induced , Sarcoma , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Sarcoma/genetics , Sarcoma/pathology , Neoplasms, Radiation-Induced/genetics , Neoplasms, Radiation-Induced/pathology , Middle Aged , Retrospective Studies , Adult , Biomarkers, Tumor/genetics , Aged , Retinoblastoma Binding Proteins/genetics , Ubiquitin-Protein Ligases
20.
Scand J Pain ; 24(1)2024 Jan 01.
Article in English | MEDLINE | ID: mdl-39158005

ABSTRACT

OBJECTIVES: The objective was to determine whether specific physical activity (PA) or psychological stress factors are associated with different definitions of flare-ups (pain-defined flares [PDFs]: periods of increased pain lasting at least 2 h, when pain intensity is distinctly worse than it has been recently; and non-pain-defined flares [NPDFs]: obviously uncomfortable feelings, such as fatigue, loss of function, or emotional/psychosocial fluctuations, without major fluctuations in pain intensity based on 11-point scales) among people with lumbar radicular pain. METHODS: This was a case-crossover study. Participants with acute or subacute lumbar radicular pain completed serial face-to-face or online assessments for 6 weeks at 3-day intervals to determine whether they experienced sciatica flare-ups (PDF/NPDF) after specific types of PA or psychological stresses. RESULTS: A total of 152 participants were enroled. There were 597 PDF and 323 NPDF case periods and 800 control periods. The odds of PDFs were increased by prolonged walking and standing, and the odds of NPDFs were increased by prolonged sitting, mental distress, and depressed mood. According to the multivariable analyses, prolonged sitting (OR: 3.0, 95% CI: 1.7-5.5), prolonged walking (OR: 6.2, 95% CI: 3.9-9.9), and prolonged standing (OR: 5.6, 95% CI: 3.3-9.5) were significantly associated with the odds of PDFs, and prolonged sitting (OR: 3.4, 95% CI: 1.8-6.2), mental distress (OR: 6.7, 95% CI: 2.5-17.5), and depressed mood (OR: 5.8, 95% CI: 2.6-12.8) associated with the odds of NPDFs. CONCLUSIONS: Prolonged sitting, walking, and standing triggered the occurrence of PDF. Prolonged sitting, mental distress, and depressed mood triggered the occurrence of NPDF.


Subject(s)
Cross-Over Studies , Humans , Male , Female , Middle Aged , Risk Factors , Adult , Low Back Pain/psychology , Symptom Flare Up , Stress, Psychological , Exercise , Walking/physiology , Sciatica , Radiculopathy/physiopathology , Radiculopathy/psychology , Sitting Position , Pain Measurement/methods , Psychological Distress , Depression
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