Search Results (34,829)

Cystic fibrosis (CF), the most common hereditary lung disease in Caucasians, is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR). We evaluated CFTR function using a newly developed Ussing chamber system, the Multi Trans Epithelial Current Clamp (MTECC), in an in vitro model of human airway epithelia. Air–liquid interface (ALI) cultures were established from nasal brushings of healthy controls (HC) and CF patients with biallelic CFTR variants. ALI layer thickness was similar between groups (HC: 62 ± 13 µm; CF: 55 ± 9 µm). Immunofluorescence showed apical CFTR expression in HC, but reduced or absent signal in CF cultures. MTECC enabled continuous measurement of transepithelial resistance (Rt), potential difference (PD), and conductance (G_t). G_t was significantly reduced in CF cultures compared to HC (0.825 ± 0.024 vs. −0.054 ± 0.016 mS/cm²), indicating impaired cAMP-inducible ion transport by CFTR. Treatment of CF cultures with elexacaftor, tezacaftor, and ivacaftor (Trikafta^®) increased G_t, reflecting partial restoration of CFTR function. These findings demonstrate the utility of MTECC in detecting functional differences in CFTR activity and support its use as a platform for evaluating CFTR-modulating therapies. Our model may contribute to the development of personalized treatment strategies for CF patients. Full article

Background/Objectives: The detection of ovarian cancer remains challenging due to the lack of reliable serum biomarkers that reflect malignant transformation rather than mere tumor presence. We developed a novel biotest using an immortalized human fallopian tube epithelial cell line (TY), which exhibits anchorage-independent growth (AIG) in response to cancer-associated serum factors. Methods: Sera from ovarian and breast cancer patients, non-cancer controls, and ID8 ovarian cancer-bearing mice were tested for AIG-promoting activity in TY cells. Results: TY cells (passage 96) effectively distinguished cancer sera from controls (68.50 ± 2.12 vs. 17.50 ± 3.54 colonies, p < 0.01) and correlated with serum CA125 levels (r = 0.73, p = 0.03) in ovarian cancer patients. Receiver operating characteristic (ROC) analysis showed high diagnostic accuracy (AUC = 0.85, cutoff: 23.75 colonies). The AIG-promoting activity was mediated by HGF/c-MET and IGF/IGF-1R signaling, as inhibition of these pathways reduced phosphorylation and AIG. In an ID8 mouse ovarian cancer model, TY-AIG colonies strongly correlated with tumor burden (r = 0.95, p < 0.01). Conclusions: Our findings demonstrate that the TY cell-based AIG assay is a sensitive and specific biotest for detecting ovarian cancer and potentially other malignancies, leveraging the fundamental hallmark of malignant transformation. Full article

Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues. Full article

Background: Patients in Intensive Care Units (ICUs) often develop non-thyroidal illness syndrome. Potentially, thyroid hormones may be removed during continuous veno-venous hemodiafiltration (CVVHDF), as their molecular size is smaller than the filter pores’ cutoff. The study’s main aim was to assess whether the serum concentration of thyroid hormones changes over time during CVVHDF. Methods: This was a prospective observational trial that included 30 patients treated in an ICU. All patients developed acute kidney injury (AKI) and had clinical indications for implementation of CVVHDF. Blood samples were collected before initiation of CVVHDF and at 1, 2, 3, 6, 9 and 12 days after. The last sample was collected three days after CVVHDF withdrawal. Thyroid function was evaluated by determining the serum concentration of TSH, thyrotropin-releasing hormone (TRH), free triiodothyronine (fT₃), free thyroxine (fT₄), total triiodothyronine (tT₃), total thyroxine (tT₄) and reverse triiodothyronine (rT₃). We additionally calculated the total activity of peripheral deiodinases (G_D) using a mathematical model. Results: TRH and TSH levels remained mostly within normal ranges. fT4 and tT4 were in normal range or slightly below. In contrast, fT3 and tT3 were undetectably low in most patients throughout. Reverse T3 levels remained within normal limits. There were no statistically significant changes in any thyroid hormone levels over the CVVHDF treatment period. The calculated peripheral G_D activity was lower than normal, but importantly, it did not change significantly over time. Conclusions: Thyroid hormones are not lost due to hemodiafiltration. Decreased deiodinases activity is responsible for alterations in serum concentrations of thyroid hormones in patients during CVVHDF. Full article

T-cell-engaging antibodies are a promising new type of treatment for patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma, which has changed the prognosis and evolution of these patients in clinical trials. Bispecific antibodies (BsAbs) bind to two different targets (B and T lymphocytes) at the same time and in this way mimic the action of CAR (chimeric antigen receptor) T-cells. They are the T-cell-engaging antibodies most used in practice and are a solution for patients who do not respond to second- or later-line therapies, including chemoimmunotherapy, followed by salvage chemotherapy and hematopoietic stem cell transplantation. They are a therapeutic option for patients who are ineligible for CAR T-cell therapy and are also active in those with prior exposure to CAR T-cell treatment. A remarkable advantage of BsAbs is their rapid availability, even if the disease progresses rapidly, unlike CAR T-cell treatment, and they avoid the practical and financial challenges raised by autologous CAR T-cell therapies. CAR-T has been proven to have better efficacy compared to BsAbs, but cytokine release syndrome and neurotoxicity have appeared significantly more frequently in patients treated with CAR T-cells. The possibility of combining BsAbs with chemotherapy and their administration for relapses or as a frontline therapy is being studied to increase their efficacy. BsAbs are a life-saving therapy for many patients with diffuse large B-cell malignant non-Hodgkin’s lymphoma (NHL) who have a poor prognosis with classical therapies, but are not without adverse effects and require careful monitoring. Full article

Low uptake of pre-exposure prophylaxis (PrEP) for HIV prevention among Black women has been partly attributed to barriers related to patient-provider communication. The goal of this paper was to investigate the association between exposure to the #ShesWell campaign and Black women’s communication about PrEP with a healthcare provider (HCP). We conducted a cross-sectional survey of 403 sexually active, Black women after the initial phase of #ShesWell and used multivariable regression models to analyze whether exposure to #ShesWell was associated with talking to an HCP about PrEP or intention to discuss PrEP with an HCP in the future. Approximately 33% of women surveyed reported exposure to #ShesWell. Campaign exposure was significantly associated with talking to an HCP in the past year about PrEP (OR = 4.96, p = 0.001) and intention to discuss PrEP with an HCP in the next six months (B = 0.29, p = 0.038). Stronger beliefs that doctors should initiate sexual health conversations were positively associated with past PrEP conversations (OR = 2.32, p < 0.001) and future intention (B = 0.11, p = 0.029). Greater comfort discussing prevention (B = 0.35, p < 0.001), self-efficacy discussing PrEP (B = 0.29, p = 0.001), and concern about getting HIV (B = 0.51, p < 0.001) were also associated with intention to discuss PrEP with an HCP. Findings highlight the potential for communication campaigns to motivate patient-provider communication about PrEP, addressing a reported barrier to PrEP uptake among Black women. Full article

Cefepime-enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination showing good activity against multidrug-resistant (MDR) Gram-negative bacteria producing a variety of β-lactamases. In this systematic review, we aimed to evaluate the available data on resistance to this drug. We performed a thorough search of four databases (Embase, PubMed, Scopus, and Web of Science), as well as backward citation searching, to identify studies containing data on resistance to cefepime-enmetazobactam. The data were extracted and analyzed according to the breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Food and Drug Administration (FDA), or the specific breakpoints reported by the authors of the respective studies. Analysis based on the type of lactamases produced by the isolates was also performed. Ten studies reported in vitro susceptibility testing and mechanisms of antimicrobial resistance. The total number of isolates was 15,408. The activity of cefepime-enmetazobactam against β-lactamase-producing isolates was variable. The resistance of the studied extended-spectrum β-lactamase (ESBL)-producing and ampicillin C β-lactamase (AmpC)-producing isolates was low (0–2.8% and 0%, respectively). The resistance was higher among oxacillinase-48 β-lactamase (OXA-48)-producing and Klebsiella pneumoniae carbapenemase (KPC)-producing isolates (3.4–13.2% and 36.7–57.8%, respectively). High resistance was noted among metallo-β-^lactamase (MBL)-producing isolates (reaching 87.5% in one study), especially those producing New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase (VIM), which had the highest rates of resistance. The high activity of cefepime-enmetazobactam against Enterobacterales and selected lactose non-fermenting Gram-negative pathogens, including ESBL-producing and AmpC-producing isolates, makes it a potential carbapenem-sparing agent. The drug should be used after in vitro antimicrobial susceptibility testing in patients with infections caused by OXA-48, KPC, and MBL-producing isolates. Full article

Background: Thyroid eye disease (TED) is a rare autoimmune orbital disorder predominantly associated with Graves’ disease. It is characterized by orbital inflammation, tissue remodeling, and potential visual morbidity. Conventional therapies, particularly systemic glucocorticoids, offer only partial symptomatic relief, failing to reverse chronic structural changes such as proptosis and diplopia, and are associated with substantial adverse effects. This review aims to synthesize recent developments in understandings of TED pathogenesis and to critically evaluate emerging therapeutic strategies. Methods: A systematic literature review was conducted using MEDLINE, Embase, and international clinical trial registries focusing on pivotal clinical trials and investigational therapies targeting core molecular pathways involved in TED. Results: Current evidence suggests that TED pathogenesis is primarily driven by the autoimmune activation of orbital fibroblasts (OFs) through thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) signaling. Teprotumumab, a monoclonal IGF-1R inhibitor and the first therapy approved by the U.S. Food and Drug Administration for TED, has demonstrated substantial clinical benefit, including improvements in proptosis, diplopia, and quality of life. However, concerns remain regarding relapse rates and treatment-associated adverse events, particularly hearing impairment. Investigational therapies, including next-generation IGF-1R inhibitors, small-molecule antagonists, TSH-R inhibitors, neonatal Fc receptor (FcRn) blockers, cytokine-targeting agents, and gene-based interventions, are under development. These novel approaches aim to address both inflammatory and fibrotic components of TED. Conclusions: Teprotumumab has changed TED management but sustained control and toxicity reduction remain challenges. Future therapies should focus on targeted, mechanism-based, personalized approaches to improve long-term outcomes and patient quality of life. Full article

Background: Fear of falling (FOF) is a significant concern among older adults, especially after total knee arthroplasty (TKA). FOF can limit daily activities, reduce quality of life, and hinder recovery. This study aimed to investigate the prevalence, severity, and impacts of FOF in patients undergoing TKA and identify factors contributing to increased FOF. Methods: A prospective observational study was conducted at King Abdulaziz Medical City in Riyadh, Saudi Arabia, from April 2024 to December 2024. This study included 52 participants aged 20 to 75 years who had undergone primary TKA. Data were collected at two time points: after TKA and at three months post-surgery. The Short Falls Efficacy Scale-International (SFES-I) was used to assess the severity of FOF, and the Short Form 36 (SF-36) was used to measure the quality of life. Descriptive statistics, t-tests, and logistic regression were used for analysis. Results: This study included 52 participants (mean age: 63.77 ± 6.65 years; 82.7% female). Post-TKA, all participants exhibited high FOF (mean SFES-I score: 56.75 ± 8.30). After three months, the mean SFES-I score decreased significantly to 49.04 ± 12.45 (t = 4.408, p < 0.05). Post-TKA, SF-36 showed significant improvements in the physical function, role of physical limitations, bodily pain, vitality, social function, role of emotional limitations, and mental health subdomains. Bilateral total knee arthroplasty, body mass index, and some SF-36 subcomponents—such as general health, vitality, and role of emotional limitations—were identified as factors leading to increased FOF. Conclusions: FOF remains prevalent and severe in TKA patients, even at three months post-surgery, affecting rehabilitation outcomes. Early identification and tailored interventions for FOF should be considered essential components of comprehensive TKA recovery programs. Full article

The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase (TPMT) was initially the primary focus, the discovery of nudix hydrolase 15 (NUDT15) appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of NUDT15 pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of NUDT15 in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated NUDT15 variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that NUDT15 genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, NUDT15 pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines. Full article

(1) Background: People living with spinal cord injury (SCI) face numerous challenges in their lives in terms of health conditions, everyday activity, and participation in society, which are not fully recognized. To address such issues, a community survey with 125 questions for people living with SCI was conducted and the response rates, population characteristics, health and functioning problems are reported. (2) Methods: The survey questionnaire comprised 125 questions on SCI characteristics, health conditions, activities, participation, and environmental and personal factors. The survey response rates were calculated, and demographics and health and functioning characteristics were analyzed. (3) Results: A total of 890 individuals responded to the survey. The median age of the participants was 48 years (interquartile range (IQR), 39–56), and 76% of the population were males. Paraplegia (60%) and complete injury (58%) were the most common injury type, and the cause was mostly traumatic (92%). More health problems and lower quality of life were more frequent with older age and in patients without paid work. (4) Conclusions: The Ko-InSCI study provides valuable information in terms of health needs and service gaps for people with SCI in the community. Full article

Background/objectives: Chronic kidney disease (CKD) affects up to 15% of the global population and is driven by vascular and interstitial damage, and is most prevalent in persons with hypertension and diabetes. Vitamin K, a necessary cofactor for activation of vitamin K-dependent proteins may modulate these processes. It is well established that vitamin K deficiency is associated with CKD, but the therapeutic effects of supplementation on kidney function are still uncertain. We aimed to review the current evidence on the effect of vitamin K deficiency and supplementation on any marker of renal function and kidney disease, across general adult populations and CKD patient populations. Methods: A search was conducted in PubMed, targeting terms related to vitamin K status and CKD. Studies were included if they reported data on vitamin K status or supplementation in relation to kidney function outcomes. Results: A total of 16 studies were included. Nine interventional studies were included and confirmed that vitamin K supplementation improves biomarkers of vitamin K status but showed no consistent beneficial effects on renal function. Seven observational studies across populations found significant associations between vitamin K status and decline in kidney function; however, associations were often attenuated after adjustments. Conclusions: No clear effect of supplementation was observed on the reported kidney markers in patient populations. A clear association between low vitamin K status and impaired kidney function was confirmed. Studying heterogeneity makes the comparability and generalizability of the results difficult. Our review highlights the need for more cohort studies and clinical trials in general or patient populations. Full article

Lung cancer remains one of the most prevalent and lethal malignancies worldwide. Although conventional treatments such as surgery, chemotherapy, and radiotherapy have modestly improved patient survival, their overall efficacy remains limited, and the prognosis is generally poor. In recent years, immunotherapy, particularly immune checkpoint inhibitors, has revolutionized cancer treatment. Nevertheless, the immunosuppressive tumor microenvironment, tumor heterogeneity, and immune escape mechanisms significantly restrict the clinical benefit, which falls short of expectations. Within this context, cancer vaccines have emerged as a promising immunotherapeutic strategy. By activating the host immune system to eliminate tumor cells, cancer vaccines offer high specificity, low toxicity, and the potential to induce long-lasting immune memory. These advantages have positioned them as a focal point in cancer immunotherapy research. This paper provides a comprehensive overview of recent clinical advances in lung cancer vaccines, discusses the major challenges impeding their clinical application, and explores potential strategies to overcome these barriers. Full article

Acromegaly is caused by an excessive secretion of growth hormone and the secondary elevation of IGF-1 levels, leading to progressive changes in multiple body systems, including the craniofacial region and oral cavity. Dental manifestations such as mandibular overgrowth, macroglossia, malocclusion, periodontal disease, and prosthetic difficulties represent not only a clinical component of the disease but also a significant therapeutic and diagnostic challenge. The aim of this review is to present the current state of knowledge on the relationship between acromegaly and oral health and to analyze the role of interdisciplinary collaboration between endocrinologists and dentists in patient care. For this narrative review, a literature search was conducted in the PubMed, Scopus, and Web of Science databases covering the period from 2000 to 2025. Sixty-two peer-reviewed publications meeting the methodological and thematic criteria were included in the analysis, including original studies, meta-analyses, systematic reviews, and case reports. The results indicate significant correlations between disease activity and the severity of periodontal and microbiological changes, while effective endocrine treatment only results in the partial regression of morphological changes. Particular attention was given to the role of the dentist in recognizing the early symptoms of the disease, planning prosthetic and surgical treatment, and monitoring therapy-related complications. Interdisciplinary collaboration models, including integrated clinics and co-managed care, were also described as optimal systemic solutions for improving treatment quality. The conclusion drawn from the analysis are as follows: there is a need for the permanent integration of dentistry into the standard of interdisciplinary care for patients with acromegaly, in both diagnostic and therapeutic dimensions. Increasing awareness among dentists and developing integrated collaboration models may reduce the time to diagnosis, improve patients’ quality of life, and enable the more effective management of craniofacial complications in the course of this rare disease. Full article

Background: In recent years, there has been increasing interest in the application of repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct-Current Stimulation (tDCS) to enhance and rehabilitate the language abilities in individuals with neurodegenerative diseases. Objective: The aim of this narrative literature review is to investigate the usefulness of rTMS and tDCS to improve language abilities in people with Primary Progressive Aphasia (PPA). Methods: This narrative literature review was conducted through a search of the PubMed online database to identify studies investigating the effects of multiple sessions of rTMS or tDCS on language abilities in PPA patients, applied either as stand-alone interventions or in combination with language treatment. Results: Thirty-three studies fulfilled the inclusion criteria; five studies employed rTMS without language treatment; two studies applied tDCS as stand-alone intervention; twenty-two studies combined tDCS with language treatment; and four studies assessed the effects of tDCS during verbal task without language treatment. Conclusions: rTMS and tDCS applied with or without concomitant language treatment appear to be promising interventions for enhancing language abilities in PPA, with sustained effects reported over time. Further research is necessary to optimise stimulation protocols and to improve our understanding of their long-term effects. Moreover, randomised controlled trials (RCTs) with larger sample sizes are critically needed to clarify the true impact of brain stimulation in PPA, with a focus on changes in cognitive and functional performance, neural activity, and potential molecular correlates. Full article