Abstract Hepatocellular carcinoma (HCC) is recognized as a highly malignant tumor. Targeted combination immunotherapy, the initially approved regimen, is compromised by adverse side effects and low response rates during clinical treatment. Traditional Chinese medicine and its derived natural compounds, known for their anticancer effects, offer advantages of low toxicity and cost. In this study, we performed high-throughput phenotypic screening in vitro to identify promising anti-HCC drugs. Among 1,444 bioactive compounds, digoxigenin (DIG) was found to significantly impede HCC cell progression. We validated DIG’s therapeutic effects through assays such as cell counting by CCK8, lactate dehydrogenase, and colony formation. Analyses including transmission electron microscopy, western blotting, and immunofluorescence demonstrated that DIG inhibits HCC cell proliferation via autophagy. Network pharmacology and molecular docking studies suggest that DIG targets the PI3K/AKT/mTOR signaling pathway. Comparative treatments of Hep3B and Huh7 cells with DIG or mTOR inhibitors revealed similar inhibitory impacts, indicating that DIG induces autophagy by inhibiting the PI3K/AKT/mTOR pathway. In vivo studies confirmed that DIG halts the growth of subcutaneous xenograft tumors. In conclusion, DIG represents a potential HCC treatment by modulating the PI3K/AKT/mTOR pathway to induce autophagy. This research, via phenotypic screening, accelerates drug discovery and the development of novel therapies targeting the underlying mechanisms of liver cancer.
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cytology
Claudia Fredolini, Tea Dodig-Crnković, Annika Bendes
et al.
Abstract Background Self-sampling of dried blood spots (DBS) offers new routes to gather valuable health-related information from the general population. Yet, the utility of using deep proteome profiling from home-sampled DBS to obtain clinically relevant insights about SARS-CoV-2 infections remains largely unexplored. Methods Our study involved 228 individuals from the general Swedish population who used a volumetric DBS sampling device and completed questionnaires at home during spring 2020 and summer 2021. Using multi-analyte COVID-19 serology, we stratified the donors by their response phenotypes, divided them into three study sets, and analyzed 276 proteins by proximity extension assays (PEA). After normalizing the data to account for variances in layman-collected samples, we investigated the association of DBS proteomes with serology and self-reported information. Results Our three studies display highly consistent variance of protein levels and share associations of proteins with sex (e.g., MMP3) and age (e.g., GDF-15). Studying seropositive (IgG+) and seronegative (IgG-) donors from the first pandemic wave reveals a network of proteins reflecting immunity, inflammation, coagulation, and stress response. A comparison of the early-infection phase (IgM+IgG-) with the post-infection phase (IgM-IgG+) indicates several proteins from the respiratory system. In DBS from the later pandemic wave, we find that levels of a virus receptor on B-cells differ between seropositive (IgG+) and seronegative (IgG-) donors. Conclusions Proteome analysis of volumetric self-sampled DBS facilitates precise analysis of clinically relevant proteins, including those secreted into the circulation or found on blood cells, augmenting previous COVID-19 reports with clinical blood collections. Our population surveys support the usefulness of DBS, underscoring the role of timing the sample collection to complement clinical and precision health monitoring initiatives.
Shintaro Shiba, Takahiro Shimo, Masashi Yamanaka
et al.
Abstract Thermal neutrons generated in the body during proton beam therapy (PBT) can be used to cause boron neutron capture reactions and have recently been proposed as neutron capture enhanced PBT (NCEPBT). However, the cell killing effect of NCEPBT remains underexplored. Here, we show an increase in the cell killing effect of NCEPBT. Using Monte Carlo simulations, we showed that neutrons generated by proton beam irradiation are uniformly spread on tissue culture plates. Human salivary gland tumor cell line (HSG), human osteosarcoma cell line (MG63), human tongue squamous cell carcinoma cell line (SAS), and human malignant melanoma cell line (G-361) were irradiated with X-rays, proton beams, and proton beams with 10B-enriched boronophenylalanine (boron concentration of 20 and 80 ppm). The relative biological effectiveness (RBE) values of proton beams alone, proton beams with 20 ppm boron, and proton beams with 80 ppm boron for HSG, MG63, SAS, and G-361 were 1.02, 1.07, and 1.23; 1.01, 1.08, and 1.44; 1.05, 1.09, and 1.46; and 1.04, 1.13, and 1.63, respectively. NCEPBT with high boron concentration showed high RBE and a high sensitizing effect. Our results confirm an increase in the cell killing effect of NCEPBT, should aid in its clinical use, and warrant its further investigation.
Much research, both pathophysiological and clinical, has been produced about septic shock during the last 20 years. Nevertheless, many aspects of treatment are still controversial, among these the approach to the administration of fluids and vasopressors. After the first clinical trial on Early goal-directed therapy (EGDT) was published, a liberal approach to the use of fluids and conservative use of vasopressors prevailed, but in recent years a more restrictive use of fluids and an earlier introduction of vasopressors seem to be preferred. Although both treatments are based on sound pathophysiological knowledge, clinical evidence is still inadequate and somehow controversial. In this non-systematic review, recent research on the hemodynamics of septic shock and its treatment with fluids and inotropes is discussed. As a conclusion, general indications are proposed for a practical approach to patients in septic shock.
Odontogenic phlegmons of maxillofacial localization are a common problem of modern medicine. According to the literature data, it was established that odontogenic phlegmons of maxillofacial localization make up from 2.7% to 3.4% of all visits to the dentist. Unfortunately, these pathological processes do not have a tendency to decrease their prevalence among the population, which is due to the general low level of dental rehabilitation of patients, as well as reluctance to seek medical help and hope for the effectiveness of selftreatment.
The aim of this work. The analysis of methods of treatment of odontogenic phlegmons of maxillofacial localization, substantiation of factors affecting the effectiveness of treatment of purulent-inflammatory diseases have been carried out.
Materials and methods: The analysis of literary sources of Ukrainian and foreign authors regarding the course, treatment and complications of maxillofacial localization over the past 10 years has been conducted.
Research results and their discussion. Although the treatment of odontogenic infections has been improved over the past decades, further improvements are needed in this area.
The main factors that contributed to the development of odontogenic phlegmons of maxillofacial localization are unsatisfactory oral hygiene (76%), smoking (41%) and alcohol consumption (19%).
To optimize the treatment of patients with purulent odontogenic processes of maxillofacial localization, it is necessary to perform a thorough history and clinical examination, which are important for determining the severity of any infection.
The concept of "physiological reserve" is a significant driver of outcomes in patients fighting infection. Age is a significant factor that is inversely proportional to physiological reserve; that is, a decrease in respiratory, cardiovascular and metabolic reserve.
Early and adequate intervention is essential to prevent avoidable deterioration of the condition with invasion of corrected anatomic spaces and symptoms of sepsis.
Conclusions. According to the results of the study, it was established that the treatment of patients with odontogenic phlegmon of maxillofacial localization should have a comprehensive approach, failure to comply with which can lead to the development of severe complications of both local and general nature.
Abstract Background Sepia officinalis ink is a bioactive secondary metabolite rich in melanin granules, which has a wide range of nutritional and therapeutic values and also has been used to prevent various gastrointestinal disorders. Gastric ulcer, the most common gastrointestinal disease, is characterized by severe gastric mucosa damage, and its prevention is currently one of the main goals of clinical and experimental studies. Thus, the present study was focused on evaluating the potential gastroprotective efficacy of Sepia officinalis ink extract (SOIE) against ethanol-induced gastric ulcer in rats. Results The current results revealed that SOIE administration at the two selected doses improved significantly gastric mucosa integrity as indicated by the significant (P < 0.05) amelioration in gastric secretion indices (pH and volume) and the marked decrease in the ulcer index. Moreover, SOIE could counteract the gastric oxidative stress induced by ethanol via a marked decline in malondialdehyde content as well as a significant (P < 0.05) increment in glutathione content and antioxidant enzymes activities (catalase and glutathione-s-transferase). Additionally, SOIE treatment caused a significant (P < 0.05) reduction in gastric nitric oxide content. Respecting morphological and histopathological studies, SOIE treatment at 200 mg/kg body weight caused marked healing of gastric lesions as indicated by no hemorrhagic bands or injuries observed as well as significantly reduced severity score of ulcer. Conclusions SOIE could be used as a promising alternative antiulcerogenic compound to treat severe gastric lesions.
Despite the tremendous impact that a good constitutive relation for the response of arterial tissues can have with regard to advances in cardiovascular science and medicine, and notwithstanding the intense effort to put a felicitous constitutive relation into place, no reliable constitutive relation is available in the literature. In this review article, we provide a brief survey and assessment of the evolution of constitutive relations that have been developed to describe the response of arterial tissues, their inadequacies, and the various quintessential aspects of the response that need to be taken into consideration. We then fashion a nonlinear constitutive relation to describe an inhomogeneous anisotropic compressible viscoelastic solid, which while being grossly inadequate to describe the tissue in its entirety, makes it evident that what one ought to strive for is not in capturing the complexity of tissues, but rather the development of a simple global measure that can be a reliable predictor of the onset of tissue disease, and tissue damage and failure.
Pituitary apoplexy (PA) is an acute and potentially vision-threatening clinical condition caused by hemorrhage or infarction of the pituitary gland. PA usually occurs in a pre-existing pituitary tumor. Severe headache is almost universal and is often accompanied by hormonal deficiencies that require immediate empiric treatment. Magnetic resonance imaging is the recommended diagnostic imaging modality. Patients without acute neurological decline can be managed conservatively.
Resumen: Introducción: de los preceptos claves de la enseñanza centrada en el estudiante es tomar en cuenta sus necesidades, las formas de aprender y de gestionar la información. Los actuales estudiantes de la carrera de médico cirujano pertenecen a una generación que prefieren obtener información por medios digitales. Entre estos medios se encuentran los videos alojados en YouTube. Material y método: Se realizó un diseño de investigación mixta de tipo secuencial explicatorio. Se inició con la fase de producción del material audiovisual para posteriormente seguir a las cuantitativas y cualitativas. La parte cuantitativa consistió en un diseño de grupo control no equivalente con pretest y postest en la que 30 estudiantes participaron en una estación tipo «evaluación clínica objetiva estructurada» donde realizaron una exploración de nervios craneales. En la fase cualitativa los mismos estudiantes contestaron una serie de preguntas abiertas sobre la experiencia educativa. Resultados: A pesar de que en este estudio existió poca diferencia estadística entre el grupo experimental y el de control, este último logró en general puntajes más altos. La investigación cualitativa permitió identificar que los estudiantes prefieren complementar texto y video, atribuyendo a cada uno distintos tipos de aprendizaje. Conclusión: Se propone brindar al estudiante de medicina material textual que se acompañe de material audiovisual educativo debidamente producido, al momento de buscar desarrollar habilidades clínicas. Abstract: Introduction: One of the key precepts of student-centered teaching is to consider their needs, forms of learning and manage information. Current medical surgeon career students belong to a generation that prefer to get it by digital means. These media include videos hosted on YouTube. Materials and method: A mixed research design was implemented. It began with the production of an audiovisual material. The quantitative phase consisted of a not equivalent control group with pretest and posttest. 30 students participated in a station type «Objective Structured Clinical Examination». In the qualitative phase the same students answered a series of open questions about the educational experience. Results: Little statistically significant differences were found between the control group and experimental, although the last one, attained high scores in general. The qualitative research identified that students prefer to supplement text and video, attributing to each, different types of learning. Conclusions: It is proposed to provide the medical student with textual material that is accompanied by educational audiovisual material duly produced, when seeking to develop clinical skills.
Luca Barni, María Ruiz-Muñoz, Manuel Gonzalez-Sanchez
et al.
Abstract Introduction There is no systematic review that analyzes the psychometric properties of questionnaires in Italian. Previous studies have analyzed the psychometric characteristics of instruments for the measurement of pathologies of upper limbs and their joints in different languages. The aim of the present study was to analyze the psychometric properties of the questionnaires published in Italian for the evaluation of the entire upper limb or some of its specific regions and related dysfunctions. Evidence acquisition For the development of this systematic review, the following databases were used: PubMed, Scopus, Cochrane, Dialnet, Cinahl, Embase and PEDro. The selection criteria used in this study were: studies of transcultural adaptation to Italian of questionnaires oriented to the evaluation of upper limbs or any of their structures (specifically shoulder, elbow and wrist/hand), and contribution of psychometric variables of the questionnaire in its Italian version. Evidence synthesis After reading the titles and applying the inclusion and exclusion criteria to the complete documents, 16 documents were selected: 3 for the upper limb, 8 for the shoulder, 1 for the elbow and 4 for the wrist and hand. The cross-sectional psychometric variables show levels between good and excellent in all the questionnaires. Longitudinal psychometric variables had not been calculated in the vast majority of the analyzed questionnaires. Conclusions Italian versions of the questionnaires show good basic structural and psychometric characteristics for the evaluation of patients with musculoskeletal disorders of the upper limb and its joints (shoulder, elbow and wrist/hand).
Computer applications to medicine. Medical informatics
Natalia Buda, Agnieszka Skoczylas, Marcello Demi
et al.
Background: This study concerns the application of lung ultrasound (LUS) for the evaluation of the significance of vertical artifact changes with frequency and pleural line abnormalities in differentiating pulmonary edema from pulmonary fibrosis. Study Design and Methods: The study was designed as a diagnostic test. Having qualified patients for the study, an ultrasound examination was performed, consistent with a predetermined protocol, and employing convex and linear transducers. We investigated the possibility of B-line artifact conversion depending on the set frequency (2 MHz and 6 MHz), and examined pleural line abnormalities. Results: The study group comprised 32 patients with interstitial lung disease (ILD) (and fibrosis) and 30 patients with pulmonary edema. In total, 1941 cineloops were obtained from both groups and analyzed. The employment of both types of transducers (linear and convex) was most effective (specificity 91%, specificity 97%, positive predictive value (PPV) 97%, negative predictive value (NPV) 91%, LR(+) 27,19, LR(−) 0.097, area under curve (AUC) = 0.936, <i>p</i> = 7 × 10<sup>−6</sup>). Interpretation: The best accuracy in differentiating the etiology of B-line artifacts was obtained with the use of both types of transducers (linear and convex), complemented with the observation of the conversion of B-line artifacts to Z-line.
Mehdi Kargar, Leila Ghahremani, Mohammad Hosein Kaveh
et al.
Abstract: Background: Nurses have insufficient physical activity due to occupational conditions. This study investigated occupational factors affecting their physical activity based on PRECEDE-PROCEED Model. Methods: This is a cross-sectional study conducted among 161 nurses working at Shiraz University of Medical Sciences. The data were collected by simple randomization. Researcher-made tools included demographic, attitude, and PRECEDE-PROCEED constructs questionnaires. Self-Efficacy for Exercise (SEE) Scale, General Health Questionnaire(GHQ), and Beck Physical Activity questionnaire were standard tools used in the present investigation. Data were analyzed by Linear Regression and descriptive analysis. Results: The findings showed that attitude score of 96.4% of the studied nurses and self-efficacy scores of 50.9% of these nurses were higher than the overall mean scores. But they achieved scores lower than the overall mean scores in Enabling (44.1%), Reinforcing (44.7%) and Management-Organizational (29.2%) factors.Less than half of the nurses could attain scores higher than the overall mean scores of physical activity (49.1%) and general health (48.4%) .There were no any significant correlations between attitude(.922), self-efficacy(.134), Enabling factors (.224), Reinforcing factors (.950), and Management-Organizational factor (.627) with their physical activity level. But direct correlations were found among Enabling, Reinforcing, and Management-organizational factors. Conclusion: Although nurses owned enough Predisposing factors, insufficient Enabling, Reinforcing and Management-Organizational factors led them to do insufficient physical activity. Consequently, occupational factors should be provided in the workplace for nurses.
Background Obstetric Medicine is an area of expertise within General Internal Medicine (GIM) in Canada. Essential content for clinical rotations for GIM residents was identified by subject-matter experts (N=204 items). However, this work did not address the perspective of curriculum stakeholders. Methods Members of the Canadian GIM Specialty Committee (GIMSC) were surveyed to obtain their perspective on essential content that GIM residents should acquire in Obstetric Medicine. Results GIMSC members (N=14) selected “core content” which reduced the initial content blueprint by 72%. Some sections of the blueprint were left largely unchanged (e.g., hypertensive disorders of pregnancy), whereas others were removed entirely (e.g., transplant medicine). Interpretation GIMSC were more selective than Canadian Obstetric Internists in choosing the essential content for GIM residents, with a moderate overall agreement of 78% ( kappa coefficient of 0.53). Comparison of perspectives and content mapping may provide useful validity evidence for further work.
In the UK all surgeons need to have leadership skills as, despite the increasing importance of team management, the consultant surgeon still has overall responsibility for the patient under their care. Poor care is evident when clinical leadership fails. The UK hospital system is non-hierarchical within the consultant body. The clinical surgical manager in a hospital may not be the most senior clinician and the role will often rotate. The manager may or may not have the characteristics of a leader, and very often surgical leaders in a hospital may have no formal role. They are, however, essential to the functioning of the service. Nationally the roles in which professional leadership may reside are numerous. The country has multiple Surgical Royal Colleges and innumerable specialty associations and sub specialty associations all of which have councils and presidents and the multiple specialty and sub-specialty associations normally will have an annual meeting. In the long term this is probably unsustainable and although consolidation is desirable it is hard to achieve. In summary, good surgical leadership is found in many settings in the UK, some in formal roles within hospitals, some in the colleges and specialty associations and sometimes in individuals with no formal role but the capacity to make things happen.
The main direction of improving the quality of grain is the cultivation of new varieties genetically predisposed to form high quality grain. At the same time, the genetic potential of varieties can only be realized under specific weather conditions and the application of cultivation techniques that favourably affect the growth and development of plants. In these studies, various conditions were created by changing plant nutritional regimes in order to determine the possibilities of varieties to form a grain crop with a high protein content. The purpose of the work was to evaluate and highlight varieties of winter wheat that can realize the potential of grain quality at various levels of intensification of mineral nutrition. To achieve the goal, a two-factor field experiment was carried out. Factor A – winter wheat varieties, factor B – levels of mineral nutrition. As a result, it was established that varieties of winter wheat were characterized by unequal properties to accumulate protein in grain. Variety Claudia 2 was characterized by high activity to accumulate protein when fertilizing. Bezenchukskaya 380, Moskovskaya 56 were characterized by medium activity and Nemchinovskaya 57, Scepter and Fatigna – by low. The application of mineral fertilizers at the rate of N16 P16 K16 during sowing in fall and N68 for top dressing in spring contributed to the formation of grain with a higher protein content in all varieties of winter wheat.
Víctor Manuel Medina Pérez, Yoannis George Gómez, Diana Laura Medina Pérez
Señor Editor:
El cáncer ha entrado al siglo XXI con una incidencia global aproximada de 12,7 millones de casos nuevos diagnosticados cada año; más de la mitad de estos pacientes viven en países en vías de desarrollo. Según señala la Agencia Internacional para la Investigación sobre el cáncer, estrechamente vinculada a la Organización Mundial de la Salud, solo en el año 2012 esta enfermedad tuvo una incidencia global de 14 millones de casos y, de forma probabilística, se espera que aumente a 22 millones, aproximadamente un 70 % en los próximos 20 años, lo que supondrá un incremento en las defunciones por esta causa de 8,2 millones hasta 13 millones al año.
Claire M Gillan, Michal Kosinski, Robert Whelan
et al.
Prominent theories suggest that compulsive behaviors, characteristic of obsessive-compulsive disorder and addiction, are driven by shared deficits in goal-directed control, which confers vulnerability for developing rigid habits. However, recent studies have shown that deficient goal-directed control accompanies several disorders, including those without an obvious compulsive element. Reasoning that this lack of clinical specificity might reflect broader issues with psychiatric diagnostic categories, we investigated whether a dimensional approach would better delineate the clinical manifestations of goal-directed deficits. Using large-scale online assessment of psychiatric symptoms and neurocognitive performance in two independent general-population samples, we found that deficits in goal-directed control were most strongly associated with a symptom dimension comprising compulsive behavior and intrusive thought. This association was highly specific when compared to other non-compulsive aspects of psychopathology. These data showcase a powerful new methodology and highlight the potential of a dimensional, biologically-grounded approach to psychiatry research.
Objective: To scrutinize patterns of multi-drug-resistant uropathogenic Escherichia coli (UPEC) strains and particularly of fluoroquinolone-resistance this is an alternative choice for the treatment of urinary tract infections.
Methods: Bacterial samples (n = 250) were collected from out-patients from August 2012 to August 2014 Islamabad. Antibiotic susceptibility profiling and determination of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations were performed according to the guidelines of Clinical and Laboratory Standards Institute (CLSI, 2012). Genes, qnrA, qnrB and qnrS were identified by DNA amplification and sequencing.
Results: The highest percentage of UPEC isolates were resistant to co-trimoxazole (82%) followed by cephalothin (80%), 2nd Gen, 3rd Gen and 4th Gen cephalosporins, respectively. Resistance against gentamicin, amikacin remained 29% and 4%. For other drugs including nitrofurantoin, tetracycline, carbapenem and beta-lactam inhibitors remained below 10%. Altogether, 59% of the isolates were resistant to at least three antibiotics including one fluoroquinolone. Overall, MICs for ciprofloxacin remained (MIC ≥ 256 μg/mL) and for levofloxacin (MIC ≥ 16 μg/mL and 32 μg/mL). No significant differences were observed regarding MIC values of extended spectrum β-lactamase (ESBL) and non-ESBL producers. For qnrS and qnrB positive isolates MICs remained above 32 μg/mL. Prevalence of UPEC was significantly higher among females and 40% of the isolates were ESBL producers.
Conclusions: Higher percentages of ESBL producing UPEC were associated with urinary tract infections. Moreover, the majority of these isolates were multi-drug resistant and fluoroquinolone-resistant.
Four cycles of chemotherapy are required to assess responses of multiple myeloma (MM) patients. We investigated whether circulating endothelial progenitor cells (cEPCs) could be a biomarker for predicting patient response in the first cycle of chemotherapy with bortezomib and dexamethasone, so patients might avoid ineffective and costly treatments and reduce exposure to unwanted side effects. We measured cEPCs and stromal cell-derived factor-1α (SDF-1α) in 46 MM patients in the first cycle of treatment with bortezomib and dexamethasone, and investigated clinical relevance based on patient response after four 21-day cycles. The mononuclear cell fraction was analyzed for cEPC by FACS analysis, and SDF-1α was analyzed by ELISA. The study population was divided into 3 groups according to the response to chemotherapy: good responders (n=16), common responders (n=12), and non-responders (n=18). There were no significant differences among these groups at baseline day 1 (P>0.05). cEPC levels decreased slightly at day 21 (8.2±3.3 cEPCs/μL) vs day 1 (8.4±2.9 cEPCs/μL) in good responders (P>0.05). In contrast, cEPC levels increased significantly in the other two groups (P<0.05). SDF-1α changes were closely related to changes in cEPCs. These findings indicate that change in cEPCs at day 21 in the first cycle might be considered a noninvasive biomarker for predicting a later response, and extent of change could help decide whether to continue this costly chemotherapy. cEPCs and the SDF-1α/CXCR4 axis are potential therapeutic targets for improved response and outcomes in MM patients.