TNF-α can promote membrane invasion by activating the MAPK/MMP9 signaling pathway through autocrine in bone-invasive pituitary adenoma.

AIMS: A bone-invasive pituitary adenoma exhibits aggressive behavior, leading to a worse prognosis. We have found that TNF-α promotes bone invasion by facilitating the differentiation of osteoclasts, however, before bone-invasive pituitary adenoma invades bone tissue, it needs to penetrate the dura mater, and this mechanism is not yet clear. METHODS: We performed transcriptome microarrays on specimens of bone-invasive pituitary adenomas (BIPAs) and noninvasive pituitary adenomas (NIPAs) and conducted differential expressed gene analysis and enrichment analysis. We altered the expression of TNF-α through plasmids, then validated the effects of TNF-α on GH3 cells and verified the efficacy of the TNF-α inhibitor SPD304. Finally, the effects of TNF-α were validated in in vivo experiments. RESULTS: Pathway act work showed that the MAPK pathway was significantly implicated in the pathway network. The expression of TNF-α, MMP9, and p-p38 is higher in BIPAs than in NIPAs. Overexpression of TNF-α elevated the expression of MAPK pathway proteins and MMP9 in GH3 cells, as well as promoted proliferation, migration, and invasion of GH3 cells. Flow cytometry indicated that TNF-α overexpression increased the G2 phase ratio in GH3 cells and inhibited apoptosis. The expression of MMP9 was reduced after blocking the P38 MAPK pathway; overexpression of MMP9 promoted invasion of GH3 cells. In vivo experiments confirm that the TNF-α overexpression group has larger tumor volumes. SPD304 was able to suppress the effects caused by TNF-α overexpression. CONCLUSION: Bone-invasive pituitary adenoma secretes higher levels of TNF-α, which then acts on itself in an autocrine manner, activating the MAPK pathway and promoting the expression of MMP9, thereby accelerating the membrane invasion process. SPD304 significantly inhibits the effect of TNF-α and may be applied in the clinical treatment of bone-invasive pituitary adenoma.

Research on Surface Defect Detection of Strip Steel Based on Improved YOLOv7.

Surface defect detection of strip steel is an important guarantee for improving the production quality of strip steel. However, due to the diverse types, scales, and texture structures of surface defects on strip steel, as well as the irregular distribution of defects, it is difficult to achieve rapid and accurate detection of strip steel surface defects with existing methods. This article proposes a real-time and high-precision surface defect detection algorithm for strip steel based on YOLOv7. Firstly, Partial Conv is used to replace the conventional convolution blocks of the backbone network to reduce the size of the network model and improve the speed of detection; Secondly, The CA attention mechanism module is added to the ELAN module to enhance the ability of the network to extract detect features and improve the effectiveness of detect detection in complex environments; Finally, The SPD convolution module is introduced at the output end to improve the detection performance of small targets with surface defects on steel. The experimental results on the NEU-DET dataset indicate that the mean average accuracy (mAP@IoU = 0.5) is 80.4%, which is 4.0% higher than the baseline network. The number of parameters is reduced by 8.9%, and the computational load is reduced by 21.9% (GFLOPs). The detection speed reaches 90.9 FPS, which can well meet the requirements of real-time detection.

Immune checkpoint activity exacerbate renal interstitial fibrosis progression by enhancing PD-L1 expression in renal tubular epithelial cells.

Renal interstitial fibrosis (RIF) is often associated with inflammatory cell infiltration and no effective therapy. Programmed death cell-1 (PD-1) and its ligand PD-L1 were playing critical roles in T cell coinhibition and exhaustion, but the role in RIF is unclear. Here the data analyses of serum from 122 IgA nephrology (IgAN) patients showed that high level of soluble PD-1(sPD-1) was an independent risk factor for RIF and renal function progression. PD-L1 was also overexpressed in renal interstitial tissues from both IgAN patients with high level of sPD-1 and the unilateral ureteral obstruction (UUO) mouse. PD-L1 was significantly overexpressed in HK-2 cells with upregulated collagen and α-SMA when stimulated by inflammation or hypoxia in vitro. Additionally, matrix metalloproteinases (MMP-2) could increase the level of sPD-1 in culture supernatant when added in co-culture system of HK-2 and jurkat cells, which implied serum sPD-1 of IgAN might be cleaved by MMP-2 from T cells infiltrated into the tubulointerstitial inflammatory microenvironment. Crucially, injection of PD-L1 fusion protein, the blocker of sPD-1, could ameliorate kidney fibrosis in UUO mice by increasing T cell coinhibition and exhaustion, suggesting the therapeutic potential of PD-L1 fusion targeting for renal fibrosis. Take together, it reveals a novel causal role of sPD-1 in serum and PD-L1 of renal interstitial tissues in the development of renal fibrosis of IgAN, and targeting sPD-1 in serum by PD-L1 fusion protein is a potential therapeutic approach to prevent renal fibrosis of IgAN.

The impact of social and emotional support on serious psychological distress among people with functional disabilities and type 2 diabetes.

OBJECTIVES: To examine the impact of social and emotional support on serious psychological distress (SPD) in individuals with type 2 diabetes (T2DM) and functional disabilities after controlling for socio-demographic factors and health status. Findings provide information for healthcare providers to enhance patients' psychological well-being. METHODS: Data from 529 adults were obtained from the 2021 National Health Interview Survey, including those who had T2DM and also reported significant difficulty or inability to perform an activity in any of the following domains: seeing, hearing, walking or climbing stairs, communicating, remembering or concentrating, or practicing self-care. Descriptive analysis and a hierarchical regression model of SPD were used. RESULTS: The mean age of participants was 67.88 years old, and the mean duration of diabetes diagnosis was 16.88 years. Notably, 12.5% of individuals reported SPD. A decreased likelihood of reporting SPD occurrence was associated with older age (odds ratio (OR) = 0.95), a longer duration of T2DM diagnosis (OR = 0.97), having at least a high school education (OR = 0.54), and receiving social and emotional support. DISCUSSION: Social and emotional support likely mitigates psychological distress, suggesting that social and emotional support resources should be enhanced, especially among individuals who are younger and those more recently diagnosed with T2DM.

Lumbopelvic fixation in the treatment of spinopelvic dissociation: union, complications, and neurologic outcomes of a multicenter case series.

PURPOSE: To review outcomes of spinopelvic dissociation treated with open lumbopelvic fixation. METHODS: We reviewed all cases of spinopelvic dissociation treated at three Level-I trauma centers with open lumbopelvic fixation, including those with adjunctive percutaneous fixation. We collected demographic data, associated injuries, pre- and postoperative neurologic status, pre- and postoperative kyphosis, and Roy-Camille classification. Outcomes included presence of union, reoperation rates, and complications involving hardware or wound. RESULTS: From an initial cohort of 260 patients with spinopelvic dissociation, forty patients fulfilled inclusion criteria with a median follow-up of 351 days. Ten patients (25%) had a combination of percutaneous iliosacral and open lumbopelvic repair. Average pre- and postoperative kyphosis was 30 degrees and 26 degrees, respectively. Twenty patients (50%) had neurologic deficit preoperatively, and eight (20%) were unknown or unable to be assessed. All patients presenting with bowel or bladder dysfunction (n = 12) underwent laminectomy at time of surgery, with 3 patients (25%) having continued dysfunction at final follow-up. Surgical site infection occurred in four cases (10%) and wound complications in two (5%). All cases (100%) went on to union and five patients (13%) required hardware removal. CONCLUSION: Open lumbopelvic fixation resulted in a high union rate in the treatment of spinopelvic dissociation. Approximately 1 in 6 patients had a wound complication, the majority of which were surgical site infections. Bowel and bladder dysfunction at presentation were common with the majority of cases resolving by final follow-up when spinopelvic dissociation had been treated with decompression and stable fixation.

Measles Virus-Based Vaccine Expressing Membrane-Anchored Spike of SARS-CoV-2 Inducing Efficacious Systemic and Mucosal Humoral Immunity in Hamsters.

As SARS-CoV-2 continues to evolve and COVID-19 cases rapidly increase among children and adults, there is an urgent need for a safe and effective vaccine that can elicit systemic and mucosal humoral immunity to limit the emergence of new variants. Using the Chinese Hu191 measles virus (MeV-hu191) vaccine strain as a backbone, we developed MeV chimeras stably expressing the prefusion forms of either membrane-anchored, full-length spike (rMeV-preFS), or its soluble secreted spike trimers with the help of the SP-D trimerization tag (rMeV-S+SPD) of SARS-CoV-2 Omicron BA.2. The two vaccine candidates were administrated in golden Syrian hamsters through the intranasal or subcutaneous routes to determine the optimal immunization route for challenge. The intranasal delivery of rMeV-S+SPD induced a more robust mucosal IgA antibody response than the subcutaneous route. The mucosal IgA antibody induced by rMeV-preFS through the intranasal routine was slightly higher than the subcutaneous route, but there was no significant difference. The rMeV-preFS vaccine stimulated higher mucosal IgA than the rMeV-S+SPD vaccine through intranasal or subcutaneous administration. In hamsters, intranasal administration of the rMeV-preFS vaccine elicited high levels of NAbs, protecting against the SARS-CoV-2 Omicron BA.2 variant challenge by reducing virus loads and diminishing pathological changes in vaccinated animals. Encouragingly, sera collected from the rMeV-preFS group consistently showed robust and significantly high neutralizing titers against the latest variant XBB.1.16. These data suggest that rMeV-preFS is a highly promising COVID-19 candidate vaccine that has great potential to be developed into bivalent vaccines (MeV/SARS-CoV-2).

Soluble programmed death ligand 1 as prognostic biomarker in non-small cell lung cancer patients receiving nivolumab, pembrolizumab or atezolizumab therapy.

Many studies have focused on the prognostic role of soluble programmed death ligand 1 (sPD-L1) in non-small cell lung cancer (NSCLC), but outcomes are ambiguous and further investigations are needed. We addressed the matter by studying sPD-L1 in baseline samples and in longitudinal samples taken prior to three subsequent cycles of anti-PD-1/anti-PD-L1 treatments. Eighty patients with NSCLC were enrolled. Median sPD-L1 level at baseline was 52 pg/mL [95% confidence interval (CI) 49-57]. In patients treated with pembrolizumab and nivolumab, the concentration of sPD-L1 remained rather stable throughout treatment. In contrast, sPD-L1 rose by 50-fold following the first cycle of atezolizumab therapy. We found the baseline level of sPD-L1 to be related to overall survival (OS) after two years of follow-up in simple Cox analysis (p = 0.006) and multiple Cox Regression, hazard ratio 1.02 (95% CI 1.00-1.03) (p = 0.033). There was no association between sPD-L1 and tissue PD-L1 expression, overall response rate, or progression free survival. In conclusion, sPD-L1 measured in baseline serum samples may be associated with OS in NSCLC patients receiving anti-PD1/anti-PD-L1 treatment. Importantly, the results signify that further research is warranted to explore the clinical utility of sPD-L1 in patients treated with anti-PD-L1.

Serum VEGF-A levels on admission in COVID-19 patients correlate with SP-D and neutrophils, reflecting disease severity: A prospective study.

BACKGROUND AND OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity and mortality. This study aimed to investigate the clinical significance of serum vascular endothelial growth factor A (VEGF-A) in COVID-19 patients and its association with disease severity and pulmonary injury. METHODS: We prospectively collected data from 71 hospitalized COVID-19 patients between June 2020 and January 2021. Patients were classified as either mild or severe based on their oxygen requirements during hospitalization. Serum VEGF-A levels were measured using an ELISA kit. RESULTS: In comparison to mild cases, significantly elevated serum VEGF-A levels were observed in severe COVID-19 patients. Furthermore, VEGF-A levels exhibited a positive correlation with white blood cell count, neutrophil count, and lymphocyte count. Notably, serum surfactant protein-D (SP-D), an indicator of alveolar epithelial cell damage, was significantly higher in patients with elevated VEGF-A levels. CONCLUSION: These results suggest that elevated serum VEGF-A levels could serve as a prognostic biomarker for COVID-19 as it is indicative of alveolar epithelial cell injury caused by SARS-CoV-2 infection. Additionally, we observed a correlation between VEGF-A and neutrophil activation, which plays a role in the immune response during endothelial cell injury, indicating a potential involvement of angiogenesis in disease progression. Further research is needed to elucidate the underlying mechanisms of VEGF-A elevation in COVID-19.

Seguimiento farmacoterapéutico a pacientes polimedicados / Pharmaceutical care to polimedicated patients

Los servicios profesionales farmacéuticos asistenciales contribuyen a un mejor control de los problemas de salud, sobre todo en pacientes polimedicados, y a una optimización de los recursos sanitarios, lo cual conlleva una menor prescripción de medicamentos y un menor número de visitas a los centros sanitarios. Formaron parte de este estudio 78 pacientes, siendo el sexo femenino el más prevalente, con una edad media 72,49 ± 13,92 años; de ellos, 60 pacientes eran mayores de 65 años y, por tanto, considerados pacientes geriátricos. Fueron incluidos en un servicio de sistemas personalizados de dosificación y, posteriormente, se realizó un seguimiento farmacoterapéutico. Se detectaron 450 problemas relacionados con los medicamentos siendo los más frecuentes los asociados al paciente: falta de conocimiento de uso, mala adherencia terapéutica, errores en la administración…, siendo la probabilidad de presentarlos mayor en el sexo masculino. Asociados a estos problemas con los medicamentos se detectaron 160 resultados negativos asociados a la medicación; solo 5 de ellos no fueron resueltos durante la fase estudio, los más frecuentes fueron los de inefectividad no cuantitativa, es decir, aquellos que no se resuelven con una modificación de la dosis farmacológica sino incluyendo o eliminando otros principios activos. En conclusión, el servicio de sistema personalizado de dosificación precisa de una revisión de la medicación como, por ejemplo, el seguimiento farmacoterapéutico, ya que ambos permiten optimizar el tratamiento de los pacientes polimedicados, así como, un aumento del control de los problemas de salud.(AU)

Professional pharmaceutical care services contribute to better health problem control, especially in polymedicated patients, and to the optimization of health resources, which leads to less medication prescription and fewer visits to healthcare centers. This study included 78 patients, with the female sex being the most prevalent, with an average age of 72.49 ± 13.92 years; of these, 60 patients were over 65 years of age and, herefore, considered geriatric patients. They were included in a personalized medication dispensing service and, subsequently, a pharmacotherapeutic follow-up was carried out. 450 medication-related problems were detected, the most frequent of which were associated with the patient: lack of knowledge of use, poor therapeutic adherence, administration errors, etc., with the probability of presenting them being higher in the male sex. Associated with these medication problems, 160 negative medication-related results were detected; only 5 of them were not resolved during the study phase, the most frequent being those of non-quantitative ineffectiveness, that is, those that are not resolved with a modification of the pharmacological dose but by including or eliminating other active ingredients. In conclusion, the personalized medication dispensing service requires a medication review, such as pharmacotherapeutic follow-up, as both allow the optimization of the treatment of polymedicated patients, as well as an increase in the control of health problems.(AU)

SlWRKY81 regulates Spd synthesis and Na+ /K+ homeostasis through interaction with SlJAZ1 mediated JA pathway to improve tomato saline-alkali resistance.

Saline-alkali stress is an important abiotic stress factor affecting tomato (Solanum lycopersicum L.) plant growth. Although the involvement of the tomato SlWRKY gene family in responses to saline-alkali stress has been well established, the mechanism underlying resistance to saline-alkali stress remains unclear. In this study, we investigated the role of SlWRKY81 in conferring saline-alkali stress resistance by using overexpression and knockout tomato seedlings obtained via genetic modification. We demonstrated that SlWRKY81 improves the ability of tomato to withstand saline-alkali stress by enhancing antioxidant capacity, root activity, and proline content while reducing malondialdehyde levels. Saline-alkali stress induces an increase in jasmonic acid (JA) content in tomato seedlings, and the SlWRKY81 promoter responds to JA signaling, leading to an increase in SlWRKY81 expression. Furthermore, the interaction between SlJAZ1 and SlWRKY81 represses the expression of SlWRKY81. SlWRKY81 binds to W-box motifs in the promoter regions of SlSPDS2 and SlNHX4, thereby positively regulating their expression. This regulation results in increased spermidine (Spd) content and enhanced potassium (K+ ) absorption and sodium (Na+ ) efflux, which contribute to the resistance of tomato to saline-alkali stress. However, JA and SlJAZ1 exhibit antagonistic effects. Elevated JA content reduces the inhibitory effect of SlJAZ1 on SlWRKY81, leading to the release of additional SlWRKY81 protein and further augmenting the resistance of tomato to saline-alkali stress. In summary, the modulation of Spd synthesis and Na+ /K+ homeostasis mediated by the interaction between SlWRKY81 and SlJAZ1 represents a novel pathway underlying tomato response to saline-alkali stress.

An algorithm to detect dicrotic notch in arterial blood pressure and photoplethysmography waveforms using the iterative envelope mean method.

Background and Objective: Detection of the dicrotic notch (DN) within a cardiac cycle is essential for assessment of cardiac output, calculation of pulse wave velocity, estimation of left ventricular ejection time, and supporting feature-based machine learning models for noninvasive blood pressure estimation, and hypotension, or hypertension prediction. In this study, we present a new algorithm based on the iterative envelope mean (IEM) method to detect automatically the DN in arterial blood pressure (ABP) and photoplethysmography (PPG) waveforms. Methods: The algorithm was evaluated on both ABP and PPG waveforms from a large perioperative dataset (MLORD dataset) comprising 17,327 patients. The analysis involved a total of 1,171,288 cardiac cycles for ABP waveforms and 3,424,975 cardiac cycles for PPG waveforms. To evaluate the algorithm's performance, the systolic phase duration (SPD) was employed, which represents the duration from the onset of the systolic phase to the DN in the cardiac cycle. Correlation plots and regression analysis were used to compare the algorithm with an established DN detection technique (second derivative). The marking of the DN temporal location was carried out by an experienced researcher using the help of the 'find_peaks' function from the scipy PYTHON package, serving as a reference for the evaluation. The marking was visually validated by both an engineer and an anesthesiologist. The robustness of the algorithm was evaluated as the DN was made less visually distinct across signal-to-noise ratios (SNRs) ranging from -30 dB to -5 dB in both ABP and PPG waveforms. Results: The correlation between SPD estimated by the algorithm and that marked by the researcher is strong for both ABP (R2(87343) =.99, p<.001) and PPG (R2(86764) =.98, p<.001) waveforms. The algorithm had a lower mean error of dicrotic notch detection (s): 0.0047 (0.0029) for ABP waveforms and 0.0046 (0.0029) for PPG waveforms, compared to 0.0693 (0.0770) for ABP and 0.0968 (0.0909) for PPG waveforms for the established 2nd derivative method. The algorithm has high accuracy of DN detection for SNR of >= -9 dB for ABP waveforms and >= -12 dB for PPG waveforms indicating robust performance in detecting the DN when it is less visibly distinct. Conclusion: Our proposed IEM- based algorithm can detect DN in both ABP and PPG waveforms with low computational cost, even in cases where it is not distinctly defined within a cardiac cycle of the waveform ('DN-less signals'). The algorithm can potentially serve as a valuable, fast, and reliable tool for extracting features from ABP and PPG waveforms. It can be especially beneficial in medical applications where DN-based features, such as SPD, diastolic phase duration, and DN amplitude, play a significant role.

sPD-L1 and sPD-L2 in plasma of patients with lung cancer and their clinical significance.

INTRODUCTION: Lung cancer is the leading cause of cancer death worldwide. We aim here to determine the soluble programmed death ligand-1 (sPD-L1) and soluble programmed death ligand-2 (sPD-L2) levels in the plasma of patients with lung cancer and evaluate the clinical significance. METHODS: Plasma samples from 95 lung cancer patients and 55 healthy donors were collected, and the sPD-L1 and sPD-L2 levels were measured using the enzyme-linked immunosorbent assay. The correlations of the plasma sPD-L1 and sPD-L2 levels with clinicopathological status and survival of the patients were analyzed. RESULTS: The sPD-L1 and sPD-L2 levels in plasma of lung cancer patients were 713.8 (240.6-3815) pg/ mL and 3233(1122-13955) pg/ mL, respectively, which were significantly higher than those of the health donors 618.6 (189.1-1149) pg/ mL and 2182 (1133-3471) pg/ mL, and the plasma levels of sPD-L1 are correlated with sPD-L2. ROC results showed that both sPD-L1 and sPD-L2 were potential biomarker for lung cancer, and with a higher accuracy level when combined with CEA. Patients with Higher plasma sPD-L1 level (>713.75 pg/ mL) are associated with poor overall survival in advanced lung cancer patients (197 days vs 643 days). CONCLUSIONS: The combination of sPD-L1 and sPD-L2 could be used as adjunctive diagnostic, High level of plasma sPD-L1 rather than sPD-L2 is associated with poor prognosis in lung cancer patients.

Multiple serum biomarkers associate with mortality and interstitial lung disease progression in systemic sclerosis.

OBJECTIVES: To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups. METHODS: Participants with sera, high-resolution computed tomography, and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. 27 of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc. RESULTS: 407 participants were identified, 252 (61.9%) with SSc-ILD. The median follow up after biomarker measurement was 6.31 (3.11-9.22) years. 16 biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality (HR 3.55; 95%CI 2.37-5.33; p< 0.001). Five additional biomarkers had a HR > 2: SP-D (2.28, 1.57-3.31; p< 0.001), E-selectin (2.19; 1.53-3.14; p< 0.001), IL-6 (2.15 1.50-3.09; p< 0.001), MMP3 (1.42-2.95; p< 0.001) and ET-1 (2.03, 1.40-2.92; p< 0.001). 11 biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at one year follow up: CXCL4 (OR 2.67, 1.46-4.88; p= 0.001), MMP-1 (2.56, 1.43-4.59; p= 0.002) and ET-1 (2.18, 1.24-3.83; p= 0.007). CONCLUSION: Multiple biomarkers, especially VCAM-1, E-Selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc.

Forensic application of three interstitial pneumonia markers: search for new pneumonia markers in dead bodies.

In forensic cases, detailed identification of pneumonia is important. Our objective was to statistically determine the applicability of three interstitial lung disease (ILD) markers for forensic diagnosis using serum collected from dead bodies with various postmortem intervals (PMIs). We retrospectively analyzed the levels of postmortem serum Krebs von den Lungen-6 (KL-6) and pulmonary surfactant-associated proteins A and D (SP-A and SP-D) using 221 samples obtained during forensic autopsy at our facility from 2019 to 2023. We evaluated the diagnostic efficacy of ILD markers for various pneumonias against the pathological diagnosis, and examined the assessment of the severity of ILD. When comparing the ILD group with bacterial pneumonia (BP) versus the control group, there was a significant increase in KL-6 in the ILD group. When comparing the severe ILD (SILD) group with the mild ILD (MILD) group, there was a significant increase in KL-6 and SP-D in the SILD group. The optimal cutoff values for differentiating SILD were 607.0 U/mL for KL-6, 55.5 ng/mL for SP-A, and 160.0 ng/mL for SP-D, and the sensitivity/specificity (%) of KL-6, SP-A, and SP-D for SILD were 84.1/95.2, 55.6/85.7, and 66.7/74.6, respectively. This is the first study to examine KL-6 in postmortem serum in forensic medicine. By analyzing dead bodies with various PMIs, our results confirmed statistically that postmortem serum KL-6 specifically detects ILD, postmortem serum SP-A has high sensitivity to lung injury, and postmortem serum SP-D is potentially useful in assessing the severity of ILD.

Cytokine and soluble programmed death-ligand 1 levels in serum and plasma of cancer patients treated with immunotherapy: Preanalytical and analytical considerations.

AIM: To evaluate cytokine and soluble programmed death ligand-1 (sPD-L1) levels in the serum and plasma of cancer patients treated with immunotherapy, and to test different assays. METHODS: Three Luminex xMAP assays and two ELLA microfluidic cartridges were used to screen 28 immune-related biomarkers in 38 paired serum and citrate-theophylline-adenosine-dipyridamole (CTAD) plasma samples collected from 10 advanced melanoma or non-small cell lung cancer (NSCLC) patients at different time points during immunotherapy. RESULTS: Twenty-three of 28 biomarkers were detected both in serum and plasma by at least one of the assays, including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, GM-CSF, IFN-γ, TNF-α, VEGF, IP-10, MCP-1, eotaxin, fractalkine, G-CSF, IFN-α, IL-1RA, IL-13, IL-17A, MIP-1ß and sPD-L1. Conversely, FGF-2 and IL-1α were not detected in both matrices; GRO-α factor and EGF were detected only in serum and MIP-1α only in plasma. sPD-L1, MCP-1, IFN-γ, IL-8, MIP-1ß and VEGF were, respectively, 1.15-, 1.44-, 1.83-, 2.43-, 2.82-, 6.72-fold higher in serum, whereas IL-10, IL-4, IL-2 and IL-5 were 1.05-, 1.19-, 1.92- and 2.17-fold higher, respectively, in plasma. IP-10 levels were higher in plasma but, as well as for VEGF, the bias serum versus plasma varied depending on the assay used (IP-10: -5.7% to -145%; VEGF: 115% to 165%). No significant differences were found for the remaining nine analyzed cytokines. CONCLUSION: The cytokine and sPD-L1 levels may differ between serum and plasma samples collected from cancer patients treated with immunotherapy, and the results obtained can be influenced by the different characteristics of the tested assays. The standardization of pre-analytical and analytical procedures is therefore needed for the future implementation of these circulating biomarkers in clinical practice.

WIV, a protein domain found in a wide number of arthropod viruses, which probably facilitates infection.

The most powerful approach to detect distant homologues of a protein is based on structure prediction and comparison. Yet this approach is still inapplicable to many viral proteins. Therefore, we applied a powerful sequence-based procedure to identify distant homologues of viral proteins. It relies on three principles: (1) traces of sequence similarity can persist beyond the significance cutoff of homology detection programmes; (2) candidate homologues can be identified among proteins with weak sequence similarity to the query by using 'contextual' information, e.g. taxonomy or type of host infected; (3) these candidate homologues can be validated using highly sensitive profile-profile comparison. As a test case, this approach was applied to a protein without known homologues, encoded by ORF4 of Lake Sinai viruses (which infect bees). We discovered that the ORF4 protein contains a domain that has homologues in proteins from >20 taxa of viruses infecting arthropods. We called this domain 'widespread, intriguing, versatile' (WIV), because it is found in proteins with a wide variety of functions and within varied domain contexts. For example, WIV is found in the NSs protein of tospoviruses, a global threat to food security, which infect plants as well as their arthropod vectors; in the RNA2 ORF1-encoded protein of chronic bee paralysis virus, a widespread virus of bees; and in various proteins of cypoviruses, which infect the silkworm Bombyx mori. Structural modelling with AlphaFold indicated that the WIV domain has a previously unknown fold, and bibliographical evidence suggests that it facilitates infection of arthropods.

Adherencia al tratamiento en paciente polimedicado con sistemas personalizados de dosificación (SPD) y su impacto en salud / Adherence to treatment in polymedicated patients using Monitored Dosage Systems (MDS) and their impact on health

Los Sistemas Personalizados de Dosificación (SPD) son una herramienta eficaz, segura y homologada para el reacondicionamiento de fármacos en farmacia comunitaria. Estos implican la revisión del uso del medicamento (RUM) y la colaboración con el médico de atención primaria (MAP). En el presente artículo se describe el caso de una paciente de 57 años intervenida de lumbociatalgia en 2021 y 2022, con dolor crónico mal controlado y aturdimiento derivado del olvido y/o duplicidad de las tomas. Durante la dispensación habitual se detectan estos problemas relacionados con el medicamento (PRM) y se deriva a la paciente al servicio SPD. Tras la implantación del mismo, la paciente mejora a nivel cognitivo, eliminando el aturdimiento y controlando el dolor, lo que supuso un aumento en su calidad de vida. En conclusión, se destaca la importancia de los diferentes servicios disponibles en la farmacia para mejorar la calidad de vida del paciente, la adherencia al tratamiento y la detección de PRM. (AU)

Monitored Dosage Systems (MDS) are an efficient, reliable and approved device for drug reconditioning in pharmacy. These systems imply a review on proper drug use and the collaboration between primary health care and pharmacists. The case study describes a female patient with a surgical intervention due to lumbosciatica in 2021 and 2022. Patient describes uncontrolled chronic pain and confusion related to improper drug use. During regular dispensing of her medication, these medicine-related problems (MRP) were detected and the patient was referred to the MDS service. After its implementation, the patient’s confusion was eliminated and pain management was achieved, increasing her quality of life. As a conclusion, the different health services provided by the pharmacy can improve a patient’s quality of life, treatment adherence and MRP detection. (AU)

Clinicopathological characteristics of everolimus-associated interstitial lung disease: A single-center consecutive analysis.

BACKGROUND: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD. METHODS: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases. RESULTS: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings. CONCLUSIONS: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke.

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

Different Prognostic Role of Soluble PD-L1 in the Course of Severe and Non-Severe COVID-19.

Understanding the link between COVID-19 and patient immune characteristics is crucial. We previously demonstrated that high levels of the soluble Programmed Death-Ligand1 (sPD-L1) at the beginning of the infection correlated with low lymphocyte number and high C-reactive protein (CRP), longer length of stay (LOS), and death. This study investigated whether sPD-L1 can be a prognosis biomarker during COVID-19. Severe and non-severe COVID-19 patients were enrolled at the University Hospital of Salerno. During hospitalization, at admission, and after 12-14 days, patients' data were collected, and sPD-L1 levels were measured by enzyme-linked immunosorbent assay. The peripheral lymphocyte number negatively correlated with the time of negativization (p = 0.006), length of stay (LOS) (p = 0.032), and CRP (p = 0.004), while sPD-L1 positively correlated with LOS (p = 0.015). Patients with increased sPD-L1 and lymphocyte number showed a shorter LOS than those with decreased sPD-L1 and lymphocyte number (p = 0.038) and those with increased sPD-L1 and decreased lymphocyte number (p = 0.025). Moreover, patients with increased sPD-L1 and decreased CRP had a shorter LOS than those with increased sPD-L1 and CRP (p = 0.034) and those with decreased sPD-L1 and CRP (p = 0.048). In conclusion, while at an early phase of COVID-19, sPD-L1 promotes an immune escape, later, it might act to dampen an excessive immune response, proving its role in COVID-19 prognosis.