Search Results (69)

Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. Escherichia coli expressing long-form cytidine deaminase (CDD_L) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDD_S) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: Aggregatibacter actinomycetemcomitans carrying CDD_L, Enterococcus faecalis, Streptococcus mutans, Porphyromonas gingivalis, all carrying CDD_S, and Fusobacterium nucleatum lacking CDD. The selected microbes, along with wild-type and CDD-deficient E. coli, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. A. actinomycetemcomitans fully degraded gemcitabine and induced resistance. Surprisingly, CDD_S-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDD_L or CDD_S in CDD-deficient E. coli resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment. Full article

Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype. Methods: We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival. Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes. Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents. Full article

Hyperattenuating contents detected in the gastrointestinal (GI) tract on CT scans are commonly seen and are almost always due to the purposeful ingestion of an oral contrast agent, usually barium- or iodine-based, used for evaluating the GI tract. Occasionally, other ingested material such as antacids or other medications, foreign objects, and medical devices can also be hyperattenuating. While these are usually correctly identified, these materials can potentially be misdiagnosed as a pathologic condition. Lokelma (sodium zirconium cyclosilicate (SZC)) is an increasingly used agent to treat hyperkalemia and has a hyperattenuating appearance on CT due to the presence of zirconium. However, this is not well known to the radiologic community. Here, we describe a case where SZC was seen in the GI tract on CT and misinterpreted as an acute GI bleed. A 72-year-old woman underwent single (portal venous) phase intravenous contrast-enhanced abdominal and pelvic CT after presenting to the ED with a lower GI bleed. The CT showed intraluminal hyperattenuation within the cecum, which was diagnosed prospectively as an active GI bleed. A CT angiogram of the abdomen and pelvis performed the following day for follow-up showed the hyperattenuating contents to be present on the non-IV contrast-enhanced series of the study, thereby proving that it was not due to active bleeding. Further investigation of the patient’s medical record showed that the patient was being treated with SZC for hyperkalemia, accounting for the hyperattenuating cecal contents. Awareness of the hyperattenuating appearance of SZC on CT by radiologists and clinical staff can help avoid confusion and misdiagnosis. Full article

Background: Within the past few years, many new therapies have emerged for psoriasis and psoriatic arthritis (PsA). Current topical therapies—including corticosteroids, vitamin D analogs, tapinarof, and roflumilast—remain the mainstay for mild disease, while oral systemic and biologic options are for moderate to severe cases. Biologics—such as Tumor necrosis factor-alpha (TNF-alpha), Interleukin 12/23 (IL-12/23), Interleukin-17 (IL-17), and Interleukin-23 (IL-23)—have revolutionized care by providing highly effective and safer alternatives. Oral small molecules, including Janus kinase (JAK) and tyrosine kinase 2 (TYK2) inhibitors, further expand the therapeutic options. Objectives: The goal for this review article was to examine current and latest treatments for psoriasis and PsA and discuss whether these emerging therapeutic options address the unmet needs of current treatments. Methods: The search for this review article included PubMed, Google Scholar, and ClinicalTrials.gov for relevant articles and current clinical trials using keywords. Results: A wide range of novel psoriatic and PsA therapies are currently undergoing clinical trials. These include selective JAK inhibitors, TYK2 inhibitors, retinoic acid-related orphan receptor (RORγT) inhibitors, oral IL-23 receptor inhibitors, oral IL-17A inhibitors, nanobody products, sphingosine-1-phosphate (S1P1R) antagonists, A3 adenosine receptor (A3AR) agonists, heat shock protein (HSP) 90 inhibitors, and rho-associated protein kinases (ROCK-2) inhibitors. Conclusions: These different mechanisms of action not only expand treatment options but may offer potential solutions for patients who do not achieve adequate response with existing therapies. However, the safety and contraindications of these newer agents remain an important consideration to ensure appropriate patient selection and minimize potential risks. Certain mechanisms may pose increased risks for infection, cardiovascular manifestations, malignancy, or other immune-related adverse events, necessitating careful monitoring and individualized treatment decisions. Ongoing clinical research aims to address unmet needs for patients who do not respond to previous agents to achieve sustained remission, monitor long-term safety outcomes, and assess patient preferences for delivery, including a preference for oral delivery. Oral IL-23 inhibitors hold potential due to their robust safety profiles. In contrast, oral IL-17 inhibitors and TYK-2 inhibitors are effective but may present side effects that could impact their acceptability. It is essential to balance efficacy, safety, and patient preferences to guide the selection of appropriate therapies. Full article

Background: Electronic cigarettes (ECIGs) have grown in popularity, particularly among adolescents and young adults. Flavored ECIG-liquids (E-liquids) are aerosolized by these ECIGs and inhaled into the respiratory system. Several studies have shown detrimental effects of E-liquids in airway tissues, revealing that flavoring agents may be the most irritating component. However, research on the effects of E-liquids on biological processes of the oral cavity, which is the first site of aerosol contact, is limited. Hence, this study focuses on the effects of E-liquid flavors on oral epithelial cells using the OKF6/TERT-2 cell line model. Methodology: E-liquid was prepared with and without flavors (tobacco, menthol, cinnamon, and strawberry). OKF6/TERT-2 oral epithelial cells, cultured at 37 °C and 5% CO₂, were exposed to 1% E-liquid ± flavors for 24 h. Outcomes determined include cell morphology, media pH, wound healing capability, oxidative stress, expression of mucin and tight junction genes, glycoprotein release, and levels of inflammatory cytokines (TNFα, IL-6, and IL-8). Results: Exposure to 1% flavored E-liquids negatively affect cellular confluency, adherence, and morphology. E-liquids ± flavors, particularly cinnamon, increase oxidative stress and production of IL-8, curtail wound healing recovery, and decrease glycoprotein release. Gene expression of muc5b is downregulated after exposure to E-liquids. In contrast, E-liquids upregulate occludin and claudin-1. Conclusions: This study suggests that ECIG use is not without risk. Flavored E-liquids, particularly cinnamon, result in pathophysiological responses of OKF6/TERT-2 cells. The dysregulation of inflammatory responses and cellular biology induced by E-liquids may contribute to various oral pathologies. Full article

Drug-induced gingival overgrowth is associated with various systemic diseases, including epilepsy. Among antiepileptic medications, phenytoin is commonly reported to cause this condition. In contrast, sodium valproate (VPA), another widely used antiepileptic drug, rarely induces gingival overgrowth. This difference in side effects highlights the variability in drug-induced oral complications among different antiepileptic medications. This case study presents a patient who developed significant gingival overgrowth after using VPA for over 10 years. The study aims to identify VPA as the causative agent and observe changes during long-term administration and after dose reduction. Our findings demonstrate that even long-standing gingival overgrowth can improve rapidly following discontinuation of the causative medication, providing valuable insights for managing similar cases in the future. Full article

Background/Objectives: This single-center analysis evaluated the number of potential candidates for endocrine-based oral maintenance therapy in a real-world setting, focusing on three therapeutic agents, namely, olaparib, abemaciclib, and ribociclib, for patients with hormone receptor-positive HER2-negative early breast cancer. Methods: All breast cancer cases from the past 10 years (n = 3230) that underwent treatment at the certified Breast Cancer Center of the Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Lübeck Campus, were analyzed. Results: Of a total of 2038 patients with HR+ HER2− eBC, 685 patients (33.6%) qualified for one or more of the three agents—olaparib, abemaciclib, and ribociclib. Of these 685 patients, 523 patients (76.4%) had node-positive and 162 (23.6%) node-negative disease. Moreover, 368 patients (18.1% of a total of 2038 patients with HR+ HER2− eBC) were eligible exclusively for ribociclib, including all node-negative patients. A total of 141 patients (6.9%) met the criteria for all three agents. In contrast, 1353 patients (66.4%) had no indication for combined endocrine therapy. Conclusions: To our knowledge, this is the largest analysis addressing all three therapeutic strategies for combined endocrine therapy. The broad indication criteria of the NATALEE study may increase clinic workloads due to more frequent physician/patient interactions. It also remains unclear how therapy recommendations will influence actual treatment, as increased visits and potential side effects could affect patient compliance and adherence. Full article

This study aimed to optimize CT esophagography by identifying effective oral contrast dilution ratios and exploring the advantages of dual-energy CT (DECT) over conventional CT for improving image quality. Ex vivo experiments using iodine contrast agents (320–400 mgI/mL) at 21 dilution ratios were scanned at three voltages, with additional dual-energy scans generating various reconstruction images. Image quality was assessed both objectively and subjectively. The study found significant variability in image quality across different dilution ratios. Specific dilution ratios that produced image quality comparable to the control group (a commercial oral contrast agent) and those meeting the standards for clinical diagnosis and high-quality images were identified based on image quality assessments. Recommendations for preparing 100 mL of oral contrast solution were provided, such as for achieving high-quality images at a scanning voltage of 100 kVp: the optimal dilution ratios are 1:6 to 1:19 for 320 mgI/mL, and 1:8 to 1:19 for 350 to 400 mgI/mL. Additionally, beam-hardening artifacts were significantly reduced in DECT images. These findings provide valuable guidance for improving CT esophagography protocols. Full article

Background: Hypertension affects 32% of adults worldwide, leading to a significant global consumption of cardiovascular medications. Atenolol, a β-adrenergic receptor blocker, is widely prescribed for cardiovascular diseases such as hypertension, angina pectoris, and myocardial infarction. According to the Biopharmaceutics Classification System (BCS), atenolol belongs to Class III, characterized by high solubility but low permeability. Currently, atenolol is commercially available in oral formulations. Increasing attention is being directed towards developing cost-effective transdermal delivery systems, due to their ease of use and better patient compliance. Eutectogels represent next-generation systems that are attracting great interest in the scientific community. Typically obtained from deep eutectic solvents (DESs) combined with gelling agents, these systems exhibit unique properties due to the intrinsic characteristics of DESs. Methods: In this study, a DES based on choline chloride as a hydrogen bond acceptor (HBA) and propylene glycol as a hydrogen bond donor (HBD) was explored to enhance the topical delivery of atenolol. The solubility of atenolol in the DES was evaluated using spectroscopic and thermodynamic measurements which confirmed the formation of hydrogen bonds between the drug and DES components. Additionally, the safety of the DES was assessed in a cell viability assay. Subsequently, we formulated eutectogels with different concentrations using animal gelatin and Tego Carbomer 140, and characterized these formulations through rheological measurements, swelling percentage, and permeation studies with Franz cells. Results: These novel eutectogels exhibit superior performance over conventional hydrogels, with a release rate of approximately 86% and 51% for Carbomer- and gelatin-based eutectogels, respectively. In contrast, comparable hydrogels released only about 27% and 35%. Conclusions: These findings underscore the promising potential of eutectogels for the transdermal delivery of atenolol. Full article

Objectives: To assess the efficacy of magnetic resonance (MR) lymphography with gadobutrol contrast for sentinel lymph node (SLN) mapping in early-stage oral squamous cell carcinoma (OSCC). Methods: This pilot study compared the identification of SLNs by MR lymphography using a gadolinium-based contrast agent (gadobutrol) to conventional [^99mTc]Tc-nanocolloid lymphoscintigraphy (including single-photon emission computed tomography/computed tomography (SPECT/CT)) in 10 early-stage OSCC patients undergoing SLN biopsy. The patients initially underwent conventional lymphoscintigraphy following the peritumoral administration of indocyanine green [^99mTc]Tc-nanocolloid (120 megabecquerel; ~0.5 mL). Subsequently, 0.5–1.0 mL gadobutrol was peritumorally injected, and MR imaging was acquired for 30 min. The following day, the identified SLNs were harvested and subjected to a histopathological assessment. The MR lymphography and [^99mTc]Tc-nanocolloid lymphoscintigraphy results were evaluated and compared with respect to those of the SLN identification. The reference standard consisted of a histopathological evaluation of the harvested SLNs, complementary neck dissection specimens, and follow-up data. Results: The MR lymphography detected 16 out of 27 SLNs identified by [^99mTc]Tc-nanocolloid lymphoscintigraphy, revealing an additional SLN that did not harbor metastasis. MR lymphography failed to identify any SLNs in one patient. Of the seven histopathologically positive SLNs detected by [^99mTc]Tc-nanocolloid lymphoscintigraphy, three were identified by MR lymphography. All patients remained disease-free after a median follow-up of 16 months. Compared to [^99mTc]Tc-nanocolloid lymphoscintigraphy, MR lymphography using gadobutrol achieved an SLN identification rate of 59%, a sensitivity of 75%, and a negative predictive value of 86%. Conclusions: MR lymphography using gadobutrol demonstrates limited reliability for SLN mapping in early-stage OSCC. Full article

Anticoagulants can complicate the interpretation of routine and specialised coagulation assays. Several methodologies have been developed to minimise or eliminate anticoagulant-associated interferences; however, no ‘universal methodology’ that encompasses different anticoagulant classes is currently available. Ciraparantag is a promising reversal agent that can bind both direct oral anticoagulants (DOACs) and heparin-like anticoagulants. As such, we aimed to investigate whether ciraparantag could be employed as a ‘universal’ anticoagulant chelator in vitro. Human plasma was spiked with ascending concentrations of ciraparantag, with or without DOACs or heparin, and assayed for routine coagulation parameters. Ciraparantag had minimal effects on coagulation testing when added to human plasma at concentrations similar to pharmacokinetic maxima; however, ciraparantag did not remove DOAC- or heparin-associated activities in vitro, which was likely due to the preferential chelation of anionic substances in the coagulation reagents. In contrast, DOAC-Stop™, a commercial activated charcoal-based adsorbent, efficiently removed both DOAC- and ciraparantag-associated interferences. In conclusion, although ciraparantag is not effective as a ‘universal’ anticoagulant chelator in vitro, we report that activated charcoal-based adsorbents may be clinically useful in situations where laboratory investigations are complicated by the presence of DOACs and/or ciraparantag. Full article

The primary objective of this study was to investigate the pulmonary damage resulting from isolated or combined exposure to inhaled toluene (300 ppm) and noise 85 dB (A), with a focus on evaluating the potential protective effects of Olea europaea L. leaf extract (OLE). Forty-eight male Wistar rats were divided into eight groups: control (C), OLE treatment (O), noise exposure (N), noise exposure with OLE treatment (N+OLE), toluene exposure (T), toluene exposure with OLE treatment (T + OLE), co-exposure to toluene and noise (NT), and co-exposure with OLE treatment (NT + OLE). OLE (40 mg/kg/day) was administered daily for six weeks via oral gavage. Exposure to toluene and noise resulted in significant disruption of the pulmonary tissue structure, accompanied by oxidative stress, as evidenced by increased lipid peroxidation, diminished catalase and superoxide dismutase activities, and elevated pro-inflammatory cytokines IL6, IL-β, and TNF-α. Notably, the administration of OLE effectively mitigated oxidative stress and inflammation and preserved pulmonary histology. In conclusion, exposure to toluene and its combination with noise significantly elevated oxidative stress, inflammatory responses, and histological disruptions in the lung tissue. In contrast, noise exposure alone is characterized by minimal effects, although it is still associated with an inflammatory response. Notably, Olea europaea L. leaf extract (OLE) exhibits a substantial protective role, effectively mitigating the adverse effects of combined exposure and highlighting its potential as a therapeutic agent for lung health. Full article

Ceratonia siliqua L. is a medicinal plant that has long been used in traditional Moroccan medicine to treat many diseases. This study aimed to assess the impact of the stages of the immature phase of carob pulp (M1, M2, M3, M4, and M5) on phytochemical composition, antioxidant activity, and antidiabetic activity of Ceratonia siliqua L. The identification of the phenolic profile by HPLC-UV/MS-MS and the study of the antidiabetic effect by in silico, in vitro, and in vivo studies were carried out for extracts with high contents of phenolic compounds from immature wild carob pulp from the communes of Timoulit (TM), Bin Elouidane (AW), and Ouaouizerth (TG) in the province of Azilal in the Béni Mellal-Khénifra region. The results revealed a gradual increase in total sugar content over the pulp’s ripening period, reaching a value of 2134 ± 56.23 mg GE/100 g fresh weight (FW) for TG. The three locations showed peak values for total polyphenol content (TPC), total flavonoid content (TFC), and total condensed tannin (TCT) at the M2 stage. AW had the highest concentrations of TPC (3819 ± 226.4 mg GAE/100 g FM), TFC (1034 ± 57.08 mg QE/100 g FM), and TCT (1472 ± 28.46 mg CE/100 g FM). The DPPH assay (7892 ± 296.1 mg TE/100 g FM) and the FRAP assay (278.2 ± 7.85 mg TE/100 g FM) both demonstrated that the TG zone is a highly potent antioxidant zone. In contrast, the AW site exhibited a markedly elevated value of 725.4 ± 103.6 mg TE/100 g FM in the ABTS assay. HPLC-UV-MS/MS analysis showed that the methanolic extracts of immature carob pulp (MEICP) from the three areas contained several different chemical compounds. The most prevalent were 3-O-p-coumaroyl-5-O-caffeoylquinic acid, quercetin 3-methyl ether, gallic acid, and galloylquinic acid. Immature carob pulp extract (ICPE) from AW showed the strongest in vitro inhibition of pancreatic α-amylase (IC₅₀ = 0.405 µg/mL) and TG extracts were most potent against intestinal α-glucosidase (IC₅₀ = 0.063 µg/mL). In vivo, AW, TG, and TM extracts significantly reduced postprandial glycemia in rats, with AW having the greatest effect. These results highlight the antidiabetic potential of ICPE. The 3-O-p-Coumaroyl-5-O-caffeoylquinic acid showed better affinity for α-amylase compared to acarbose and interacted significantly with several amino acid residues of the enzyme. Similarly, this molecule and 3,4-Dicaffeoylquinic acid demonstrated a strong affinity for α-glucosidase, suggesting their potential as natural inhibitors of enzymes involved in carbohydrate metabolism. Most of the compounds are not substrates of P-glycoprotein and exhibited high intestinal absorption. Furthermore, the majority of these compounds did not act as inhibitors or substrates of CYP450 enzymes, reinforcing their suitability for development as oral medications. These results underscore the potential of immature carob pulp as a promising antidiabetic agent. Full article

In this research, resorbable phosphate-based glass (PBG) compositions were developed using varying modifier oxides including iron (Fe₂O₃), copper (CuO), and manganese (MnO₂), and then processed via a rapid single-stage flame spheroidisation process to manufacture dense (i.e., solid) and highly porous microspheres. Solid (63–200 µm) and porous (100–200 µm) microspheres were produced and characterised via SEM, XRD, and EDX to investigate their surface topography, structural properties, and elemental distribution. Complementary NMR investigations revealed the formation of Q², Q¹, and Q⁰ phosphate species within the porous and solid microspheres, and degradation studies performed to evaluate mass loss, particle size, and pH changes over 28 days showed no significant differences among the microspheres (63–71 µm) investigated. The microspheres produced were then investigated using clinical (1.5 T) and preclinical (7 T) MRI systems to determine the R₁ and R₂ relaxation rates. Among the compositions investigated, manganese-based porous and solid microspheres revealed enhanced levels of R₂ (9.7–10.5 s⁻¹ for 1.5 T; 17.1–18.9 s⁻¹ for 7 T) and R₁ (3.4–3.9 s⁻¹ for 1.5 T; 2.2–2.3 s⁻¹ for 7 T) when compared to the copper and iron-based microsphere samples. This was suggested to be due to paramagnetic ions present in the Mn-based microspheres. It is also suggested that the porosity in the resorbable PBG porous microspheres could be further explored for loading with drugs or other biologics. This would further advance these materials as MRI theranostic agents and generate new opportunities for MRI contrast-enhancement oral-delivery applications. Full article

Bitter taste receptors (TAS2Rs) are not only responsible for taste perception in the oral cavity, but are spread throughout the body, generating a widespread chemosensory system. In humans, 25 subtypes have been identified and are differentially expressed in tissues and organs, including in the immune system. In fact, several TAS2R subtypes have been detected in neutrophils, lymphocytes, B and T cells, NK cells, and monocytes/macrophages, in which they regulate various protective functions of the innate immune system. Given its recognized anti-inflammatory and antioxidant activity, and the generally protective role of bitter taste receptors, in this work, we studied TAS2R46’s potential in the protection of human monocyte/macrophage DNA from stress-induced damage. Through both direct and indirect assays and a single-cell gel electrophoresis assay, we demonstrated that absinthin, a specific TAS2R46 agonist, counteracts the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and reduces DNA damage in both cell types. Even though the release of ROS from monocytes/macrophages is fundamental for contrast pathogen agents, supraphysiological ROS production impairs their function, finally leading to cell death. Our results highlight TAS2R46 as a novel player involved in the protection of monocytes and macrophages from oxidative stress damage, while simultaneously supporting their antimicrobial activity. Full article