Search Results (7,840)

Background: Skeletal-related events (SREs), including pathological fractures, spinal cord compression, radiotherapy to bone, and bone surgery, substantially worsen quality of life in breast cancer with bone metastases. Denosumab, a monoclonal antibody targeting RANKL, mechanistically differs from bisphosphonates and is not renally cleared, offering potential clinical advantages. In practice, an increasing number of patients transition from bisphosphonates to denosumab. However, the comparative effectiveness of sequential therapy versus initial denosumab remains unclear. Methods: We retrospectively analyzed 165 patients with breast cancer and radiologically confirmed bone metastases treated between 1 January 2019 and 30 April 2024 at a tertiary center in China. Patients were categorized into an initial denosumab group (n = 67) or a sequential bisphosphonate-to-denosumab group (n = 98). The primary endpoint was time to first on-treatment SRE; the 12-month first on-treatment SRE rate was also reported as a descriptive summary measure. Secondary endpoints included cumulative SRE incidence and safety. Kaplan–Meier and log-rank tests compared SRE-free survival; Cox regression explored prognostic factors. Results: The median age at bone-metastasis diagnosis was 54.7 years. Median time from diagnosis to bone-targeted agents (BTAs) initiation was 0.9 months in both groups; median follow-up was longer in the sequential group (22.5 vs. 11.3 months). At diagnosis, 46 of 165 patients (27.9%) presented with synchronous SREs, more frequent in the initial denosumab group (37.3% vs. 21.4%; p = 0.040). During follow-up, 31 patients (18.8%) developed SREs: 25 of 98 (25.5%) in the sequential group versus 6 of 67 (9.0%) in the initial denosumab group (p = 0.008). After BTA initiation, on-treatment SREs occurred in 28 of 165 patients (17.0%): 25 of 98 (25.5%) in the sequential group versus 3 of 67 (4.7%) in the initial denosumab group (p < 0.001). The 12-month first on-treatment SRE rate was 15.7% (95% CI 8.1–22.7) for sequential therapy and 5.9% (0–12.3) for initial denosumab. In Cox analysis, second-line systemic therapy increased SRE risk (HR = 2.651, p = 0.021). Safety outcomes were generally manageable and consistent with known class effects, with no clear exposure-adjusted safety advantage of one strategy over another. Conclusions: Initial denosumab was associated with fewer and delayed SREs compared with sequential bisphosphonate-to-denosumab therapy, supporting early denosumab initiation as a potentially preferable BTA strategy. Prospective studies are warranted to confirm these findings. Full article

Objectives: Acute peritonitis remains a critical condition with high mortality rates, further complicated by the rising antibiotic resistance. This study aimed to investigate the therapeutic potential of Chlorella vulgaris (CHL), both alone and in combination with standard antibiotic therapy (SFT), in a rat model of cecal ligation and puncture (CLP)-induced peritonitis. Methods: Seventy (70) male Wistar albino rats were divided into seven groups (n = 10): Control, Peritonitis Control, Low-dose CHL (CHL I) (150 mg/kg), High-dose CHL (CHL II) (300 mg/kg), the standard first-line therapy group (SFT) (Ceftriaxone + Metronidazole), SFT + CHL I, and SFT + CHL II. Following CLP-induced peritonitis, treatments were administered for 7 days. Peritoneal tissues were evaluated histopathologically and immunohistochemically for TNF-α, IL-1β, IL-10, and iNOS expression. Total Antioxidant Status (TAS) and Total Oxidant Stress (TOS) were measured to assess the oxidative stress. Results: Histopathological analysis showed that CLP-induced severe inflammatory damage was significantly reduced in all treatment groups, with the most prominent recovery observed in the SFT + CHL II group. CHL treatment led to a significant decrease in pro-inflammatory markers (TNF-α, IL-1β, iNOS) compared to the peritonitis control group (PC) (p < 0.05). Furthermore, CHL administration significantly improved the oxidative balance by increasing TAS and reducing TOS levels. Conclusions: Chlorella vulgaris exhibits significant anti-inflammatory, antioxidant, and immunomodulatory properties in experimental peritonitis. When used as an adjunct to standard antibiotic therapy, high-dose CHL provides synergistic effects that contribute to limiting tissue damage and controlling systemic inflammation. These findings suggest that CHL may be a promising supportive agent in the clinical management of acute peritonitis. Full article

Digital mining has become a tangible reality in recent years and the digital revolution enables and requires data exchange for autonomous machines and operational flow management. LoRa technology and its underground propagation behavior can make an important contribution to this digitalization. This paper presents a Data Mule approach that enabled progress in digitalization at refueling stations in active underground mining areas of a mine near Werra, Germany, operated by the K+S Group. This demonstration aimed to automate manual data collection at fuel gauges by using a dynamic LoRa network. We used specially developed LoRa Data Mule modules for operations over many square kilometers. LoRa was chosen for its industrial functionality and long-range capabilities, particularly in underground environments. The Data Mule modules used were in-house-designed units with underground mining-rated casing and connectors, as well as commercial LoRa boards and custom communication protocols. Connectivity between all systems was realized at travel speeds of 20 to 40 km/h, with connection data successfully relayed for 180 to 770 m, despite 90° turns and no line of sight. It was shown that the LoRa Data Mule approach can be used in a network of remote but active data generation points. Full article

Inflammation is associated with metabolic alterations that can lead to the release of volatile organic compounds (VOCs) reflecting cellular biochemical activity. Profiling these volatile metabolites may provide insight into cellular responses to inflammatory stimuli, although their characterization in skin-derived cells remains limited. In this exploratory proof-of-concept study, we investigated the volatile metabolite profiles of human skin fibroblasts exposed to different inflammatory stimuli. Fibroblast cell lines were stimulated with polyinosinic:polycytidylic acid (Poly I:C), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharide (LPS) to model viral-, cytokine-, and bacterial-associated stress conditions. Headspace solid-phase microextraction coupled with comprehensive two-dimensional gas chromatography and time-of-flight mass spectrometry (HS-SPME-GC×GC-TOFMS) was applied to analyze volatile metabolites released from the cell cultures, enabling exploratory profiling of the fibroblast volatilome. A data-processing workflow including pairwise comparisons between experimental groups and statistical filtering was implemented to identify volatile features associated with the different conditions. Several VOCs were tentatively identified, mainly belonging to alcohol, ester, and hydrocarbon classes, and showed differential abundance patterns between stimulated and control samples. Multivariate analysis indicated a separation between stimulated and non-stimulated groups, suggesting stimulus-associated differences in the volatile profiles of fibroblast cultures. While these observations may reflect metabolic responses occurring under inflammatory stimulation, the chemical identity and biochemical origins of several detected features remain to be confirmed. All in all, this study demonstrates the feasibility of applying HS-SPME-GC×GC-TOFMS-based volatilome profiling to investigate stimulus-associated changes in fibroblast cultures. The detected VOC patterns should therefore be considered preliminary observations requiring further chemical characterization and independent validation. Future studies including larger sample numbers, complementary biological verification of the inflammatory response, and more physiologically relevant experimental models will be necessary to further assess the robustness and potential relevance of these volatile signatures in the context of inflammatory processes. Full article

Vitamin D plays an important role in bone metabolism and may influence postoperative healing processes. This study evaluated the association between preoperative serum vitamin D levels and recovery after mandibular third molar extraction. This secondary exploratory analysis included 122 healthy patients undergoing surgical extraction of an impacted mandibular third molar, of whom 98 had complete datasets for clinical and radiographic evaluation. Postoperative outcomes included pain intensity, facial swelling, trismus, early soft tissue healing assessed with the Wachtel Early Healing Index, and bone regeneration evaluated four months after surgery using CBCT-based fractal dimension analysis. Serum vitamin D levels were not significantly associated with postoperative pain, trismus, or early soft tissue healing. A weak correlation was observed between lower vitamin D levels and greater swelling along the tragus–pogonion line on postoperative day 1 (ρ = −0.21, p = 0.035), with no significant associations at later time points. Fractal dimension analysis did not demonstrate significant differences between groups. Within the limitations of this secondary exploratory analysis, vitamin D levels showed limited and inconsistent associations with postoperative outcomes, and their clinical relevance remains uncertain. Full article

Inborn errors of immunity (IEIs) encompass a heterogeneous group of more than 550 genetic conditions with variable ages of onset. A significant proportion of IEI arises from genetic variants that may not yet be fully elucidated or recorded in existing genomic databases. Molecular diagnoses are achieved in approximately 15–35% of IEI cases, yet in only 9–20% of individuals with predominant antibody deficiencies, particularly in adult cohorts. We aimed to evaluate whole genome sequencing (WGS) diagnostic yield in adults suspected to have IEI. Clinical assessments of the patients were carried out at tertiary medical institutions in Timisoara and Bucharest, Romania. The study cohort included a consecutive series of 21 adult patients (aged 19–60 years) with IEI phenotype, who underwent genetic analysis, using WGS as the first diagnostic approach. A definitive molecular diagnosis was confirmed in only 9.5% (2/21) of the participants, in LRBA and BTK genes. Variants of uncertain significance (VUS) were detected in three patients (13.6%) in TNFRSF13B, COPA, GATA2 genes. For about half of the cohort the onset of the disease was noted in childhood. WGS as a first-line diagnostic strategy in a cohort of adults with IEI yielded a low diagnostic rate. There were significant delays in genetic diagnosis, as half of the cohort experienced childhood-onset symptoms. Results suggest that adult IEI diagnosis remains challenging, necessitating functional studies and longitudinal re-evaluation of genomic data. Full article

This paper presents a deterministic embedded control architecture for an industrial electroplating line. The validated system includes two autonomous trolleys, 18 station-aligned process positions, shared-track motion, and redundant grouped baths. The proposed controller addresses the limitations of rigid sequential automation by combining asynchronous finite-state trolley execution, runtime allocation of equivalent technological stations, dwell-time-preserving retrieval, distributed thermal supervision, and layered fail-safe protection within a single ATmega2560-based implementation. The core contribution is the integration of virtual process groups and temporal FIFO logic into a compact plant-side embedded controller. This enables adaptive bath selection and process-completion-based retrieval without reliance on a real-time operating system or a computationally heavy supervisory runtime. The architecture also incorporates predictive pre-start validation, runtime software arbitration, hardware-wired interlocks, binary-coded trolley positioning, and a distributed 1-Wire thermal measurement network. Validation was performed in a controller-centered hardware-in-the-loop representation of an 18-station zinc electroplating line. Over a 100-batch horizon, the proposed architecture reduced makespan from 1642 min to 1244 min, corresponding to a 24.2% throughput improvement. Average trolley idle time decreased from 18.4 min/batch to 4.1 min/batch. Grouped-bath utilization increased from 64% to 91%, while tracked bottleneck incidents decreased from 18 to 2. These results show that adaptive, resource-aware, and safety-layered electroplating control can be realized effectively on a compact embedded platform in an industry-representative HIL setting, while preserving dwell-time integrity and controller-level safety invariants. Full article

It is found that the speckle structure of the photoinduced light scattering indicatrix of the LiNbO₃:Y³⁺(0.46 wt%) crystal and its behavior with the time of crystal irradiation with a laser undergo an atypical behavior caused by the features of the dissipation processes of laser-induced defects in the crystal. In the frequency range of 100–4000 cm⁻¹, the Raman spectra of the LiNbO₃:Y³⁺(0.46 wt%) single crystal were recorded upon excitation by visible (532 nm) and near-IR (785 nm) laser radiation. Five second-order Raman scattering lines were detected in the frequency range of 1000–2100 cm⁻¹, with the frequencies of two of them (of about 1790 and 1940 cm⁻¹) somewhat exceeding the doubled value of the frequencies of fundamental vibrations of the 4A₁(z)LO (longitudinal optical) and 9E(x,y) symmetry types, which allows us to attribute these lines to the overtones of the fundamental vibrations of 4A₁(z)LO and 9E(x,y). It is found that only one Raman scattering line is observed in the region of stretching vibrations of OH-groups (3200–3800 cm⁻¹). The frequency of this line is found to depend on the scattering geometry, varied within 3431–3438 cm⁻¹, and to be shifted to the low-frequency region by about 30–50 cm⁻¹ relative to the frequencies in the IR absorption spectrum. This finding may be due to the alternative prohibition rule due to the presence of the center of symmetry of the oxygen octahedra O₆ of the crystal structure. Full article

Pyrrolo[2,3-d]pyrimidine is a privileged fused heterocyclic scaffold that has attracted considerable attention in medicinal chemistry due to its diverse biological activities. Herein, we report an efficient synthesis strategy for the preparation of the pyrrolo[2,3-d]pyrimidine-based natural toyocamycin aglycone and pyrrolo[2,3-d]pyrimidine derivatives. The synthesis of toyocamycin aglycone features a key benzylamine nucleophilic substitution followed by a palladium-catalyzed cyanation reaction. From a key intermediate derived from this route, nineteen new pyrrolo[2,3-d]pyrimidine derivatives were rapidly synthesized via key Suzuki–Miyaura coupling and amine nucleophilic substitution reactions. Their cytotoxic activities were evaluated against Huh-7 and HepG liver cancer cell lines. Most derivatives were inactive after 24 h. However, 28a–28c, 28e and 28f exhibited moderate cytotoxicity with IC₅₀ values ranging from 5.7 to 62.6 μM. Among them, compound 28e displayed the highest potency against HepG cells, with IC₅₀ values of 5.7 μM. Compared with normal HEK293 cells, it showed a selectivity index (SI) of 3.60 against HepG cells. Preliminary structure-activity relationship analysis suggested that incorporation of a cyclopropyl group further improves antitumor activity. Full article

Background: Recent research has highlighted the potential of postbiotics for addressing obesity and associated metabolic disorders. In this randomized, double-blind clinical trial, the efficacy of a postbiotic product in managing overweight and associated parameters was assessed. Methods: Sixty individuals were randomized into two groups: one group (n = 30) received the Postbiotic (heat-killed L. fermentum strain K8-Lb1) and the other (n = 30) a Placebo control. Body weight, waist circumference, body composition, vital signs, blood biomarkers and questionnaires for quality of life, eating behavior, eating control and gastrointestinal symptoms were assessed. Results: After a 12-week intervention, body fat mass (primary parameter) was significantly (p = 0.016) reduced in the Postbiotic group (98.15 ± 3.32% of baseline) compared to the Placebo group (100.41 ± 3.39%). In line with this, body weight (p = 0.047) and waist circumference (p = 0.034) were significantly reduced and visceral fat tended to be reduced (p = 0.053). Accordingly, the Postbiotic group tended (p = 0.066) to feel more in control of their body weight. Despite weight loss, muscle mass tended (p = 0.062) to increase. ALT, AST and GGT tended to be reduced, which may indicate an improvement in liver steatosis. Estimated average glucose (eAG) differed significantly between the groups in individuals with normal fasting glucose levels. The ability to concentrate significantly (p = 0.014) improved. Conclusions: Under an ad libitum diet, the postbiotic L. fermentum strain K8-Lb1 reduced body fat mass, body weight, and waist circumference, improved the ability to concentrate, and showed a trend towards an increase in muscle mass. The results of this pilot trial need confirmation by a pivotal trial. Full article

A series of 6-azaindole pyridinium derivatives were synthesized, structurally characterized, and evaluated for their antimicrobial (against Staphylococcus aureus, Escherichia coli, and Candida albicans) and anticancer properties (against NCI 60 panel). Hemocompatibility was evaluated using the hemolytic index, while ADME properties were estimated using in silico methods. Structure–activity relationship analysis indicated that para-substitution of the phenyl ring, particularly with halogen or methoxy groups, influences antimicrobial activity, selectivity toward Gram-positive bacteria, and hemocompatibility. Compounds 2b and 2c showed the most notable antimicrobial effects, including inhibition of microbial adhesion at hemocompatible concentrations. Compound 2b exhibited growth inhibition against cancer cells, showing 57% percent growth inhibition (PGI) against the MDA-MB-468 breast cancer cell line at 10 mM. Overall, these results highlight 6-azaindole pyridinium salts as a promising class of compounds for further investigation. Full article

Munronia pinnata (Meliaceae), a medicinal plant used in Zhuang traditional medicine, is recognized as a rich source of structurally diverse limonoids. In our continuing investigation of bioactive constituents from Guangxi medicinal plants, four new prieurianin-type limonoids, munropins G–J (1–4), were isolated from their aerial parts. Their structures were determined through comprehensive spectroscopic analysis, including nuclear magnetic resonance and high-resolution mass spectrometry, and further supported by quantum chemical calculations for electronic circular dichroism and statistical probability analysis. Munropins G (1) and H (2) feature an unprecedented C-12 β-D-glucosylated α-methyl-2′-hydroxypentanoate side chain and a C-17 β-substituted furan ring, with 1 being the 7-O-acetyl derivative of 2. Munropins I (3) and J (4) possess a formyl group at C-11, a 3-methyl-2-hydroxypentanoate ester at C-12, and a C-17 γ-hydroxy-α,β-unsaturated γ-lactone unit (21-hydroxy for 3, 23-hydroxy for 4), each existing as an equilibrating mixture of C-21 epimers—a phenomenon observed for the first time within a prieurianin-type framework. The absolute configurations of 1 and 2 were established by quantum chemical electronic circular dichroism calculations, while those of 3 and 4 remain to be assigned. All compounds were evaluated for cytotoxicity against human lung (A549), liver (HepG2), breast (MCF-7), and colon (HCT116) cancer cell lines and for anti-inflammatory activity in lipopolysaccharide-induced RAW 264.7 murine macrophages, but none exhibited significant effects at a concentration of 80 μM. This study expands the chemical diversity of Munronia limonoids and provides new molecular scaffolds for future structure–activity relationship investigations and chemotaxonomic markers for the Meliaceae family. Full article

Background: Fine-needle aspiration biopsy (FNAB) is the standard initial diagnostic procedure for thyroid nodules; however, a considerable proportion of results are non-diagnostic or indeterminate, often requiring repeat procedures and delaying management. Core needle biopsy (CNB) has been proposed as a second-line option. This study evaluated the frequency of non-conclusive FNAB and CNB results and assessed the diagnostic contribution of CNB in nodules with initially non-conclusive FNAB findings. Methods: A retrospective–prospective study was conducted between 2019 and 2025 at a tertiary referral center, including 434 thyroid nodules. Ultrasound risk stratification followed ACR TI-RADS criteria. FNAB was performed in 430 nodules, and CNB in 85 nodules, including 82 evaluated by both methods. Biopsy results were classified according to the Bethesda system as conclusive or non-conclusive. Paired comparisons were analyzed using the McNemar test, and associations with ultrasound risk were assessed. Results: FNAB produced non-conclusive results in 56.5% of cases, compared with 23.5% for CNB. In paired analysis, 53.7% of nodules with non-conclusive FNAB were reclassified as conclusive after CNB (p < 0.001). CNB significantly distinguished benign from malignant lesions, unlike FNAB. Hypoechogenicity, irregular margins, and punctate echogenic foci were independent predictors of malignancy. Minor complications were more frequent after CNB, while major complications were rare in both groups. Conclusions: CNB improves diagnostic yield when used as a second-line procedure in nodules with non-conclusive FNAB findings. Selective use in higher-risk nodules may reduce repeat procedures and facilitate more structured clinical management. Full article

Objectives: Colistin is frequently used as a last-line treatment option for periprosthetic joint infections (PJIs) caused by multidrug-resistant (MDR) Gram-negative pathogens, and mortality rates are high in this patient group. This study aimed to evaluate 90-day mortality and its associated clinical factors in MDR Gram-negative PJI cases treated with colistin, with particular attention to the American Society of Anesthesiologists (ASA) score and changes in renal function during therapy. Methods: Patients diagnosed with MDR Gram-negative PJI and treated with intravenous colistin at a single center between 2010 and 2024 were retrospectively reviewed. Demographic data, infection localization, comorbidities, American Society of Anesthesiologists (ASA) score, causative pathogens, presence of sepsis, intensive care unit (ICU) admission, duration of colistin therapy, pre- and post-treatment renal function parameters, and mortality were all recorded. Survivors and non-survivors were compared using univariate analysis. Results: The cohort included 44 patients with a mean age of 72 years (23 women and 21 men). Infections involved the hip in 33 patients (75.0%) and the knee in 11 (25.0%). Twenty-two patients (50.0%) were in the high-ASA group (ASA ≥ III group). Within 90 days of initiating colistin therapy, 25 patients died and 19 survived. A high ASA score was significantly more common among non-survivors than among survivors (18/25 (72.0%) vs. 4/19 (21.1%); p < 0.001), and dialysis requirement was also more common among non-survivors [20/25 (80.0%) vs. 8/19 (42.1%); p = 0.013]. End-of-treatment renal parameters were significantly worse among non-survivors, including urea [71.2 (50.9–78.8) vs. 38.5 (34.8–42.5) mg/dL; p = 0.003], creatinine [2.29 (1.75–2.64) vs. 0.93 (0.72–1.60) mg/dL; p = 0.003], urea delta [42.8 (38.0–48.6) vs. −5.4 (−7.9 to −2.0) mg/dL; p = 0.006], and creatinine delta [0.78 (0.33–1.57) vs. 0.16 (0.10–0.57) mg/dL; p = 0.008] levels. In contrast, age, sepsis, ICU admission, and colistin treatment duration were not significantly associated with 90-day survival. Conclusions: In this high-risk cohort of patients with MDR Gram-negative PJI treated with colistin, the 90-day mortality rate was high and was associated with higher American Society of Anesthesiologists scores, dialysis requirements, and worsening renal function during treatment. No significant association was observed between treatment duration and response in this cohort. These findings should be interpreted cautiously, given the retrospective design and the limited sample size. Full article

Rumination time is considered a sensitive behavioral indicator of physiological and metabolic status in dairy cows, yet its relationships with biochemical and milk quality parameters under commercial robotic milking conditions remain insufficiently described. This study combined precision monitoring technologies, serum biochemical profiling, and in-line milk analysis to evaluate physiological differences among early-lactation Holstein cows according to rumination time. A total of 88 cows were classified into three rumination time categories (>527, 412–527, and <412 min/day). Milk production traits, milk quality indicators, and blood biochemical parameters were compared among groups, and univariable regression analysis was performed to identify variables associated with rumination time. Cows in the low rumination group showed higher milk temperature, electrical conductivity, and somatic cell count, as well as lower milk protein percentage. They also showed higher concentrations of total protein, urea, gamma-glutamyl transferase, and lactate dehydrogenase, while triglyceride concentrations were lower. Regression analysis identified electrical milk conductivity, creatinine, magnesium, potassium, and chloride as variables associated with rumination time. These findings indicate that reduced rumination time is associated with changes in milk quality and biochemical parameters in early-lactation dairy cows, suggesting that rumination monitoring may provide useful information for identifying cows experiencing physiological and metabolic challenges under commercial farming conditions. Full article