Standardized intrapulmonary lymph node dissection in lung cancer specimens: A national Colombian analysis.

Objective: In patients with non-small cell lung cancer, lymph node assessment is essential for appropriate staging. The intrapulmonary lymph nodes (IPLNs) should be considered when assigning the N stage but are infrequently evaluated in Colombian centers, resulting in understaging that may hinder optimal treatment. Methods: We conducted a prospective study of IPLN dissection in patients with clinical stage I or II non-small cell lung cancer who underwent surgical resection at 9 institutions in Colombia between 2021 and 2023. IPLN dissection was performed by trained surgeons who collected lymph nodes from fresh specimens after resection and before formalin fixation. Results: One hundred patients were eligible for the analysis. Their mean age was 67 ± 10.9 years, and 76% were women. Most (74%) had adenocarcinoma, 20% had neuroendocrine tumors, and 6% had squamous cell carcinoma. Successful sampling and histopathologic analysis of at least one IPLN station was obtained in 85% of patients, 9% had upstaging due to positive N2 lymph nodes, and 5% had upstaging due to positive N1 lymph nodes. Among the patients with pN0 or pN1 disease, 3.2% (3 out of 91) were upstaged exclusively due to positive IPLNs. Conclusions: Fresh-specimen dissection to collect IPLNs is appropriate and feasible to achieve more accurate pathological staging in Colombian lung cancer patients. In clinical N0 patients, IPLN dissection maximizes selection for adjuvant therapy.

Diffuse pulmonary lymphangiomatosis as a differential diagnosis of anterior mediastinal mass.

Diffuse pulmonary lymphangiomatosis (DLP) is an extremely rare silent disease, characterized by proliferation and thickening of abnormal pulmonary, pleural, and mediastinal soft tissue lymphatic channels. Its clinical presentation is nonspecific symptoms such as cough, dyspnea, and hemoptysis. Tomographic findings for DLP include thickening of the interlobular septa and peribronchovascular interstitium and ground glass opacities. Nevertheless, the anterior mediastinal mass, associated with thickening of interlobular septa and peribronchovascular interstitial, ground glass opacities, pleural effusion, diffuse infiltration of the mediastinum and pleural thickening in a patient with lymphangiomas, DLP should be suspected as a differential diagnosis.

Quiste Dermoide presacro en un adulto. Reporte de un caso / Presacral dermoid cyst in an adult. Report of a case

Introducción: Durante el desarrollo embriológico, el espacio retrorrectal o presacro está ocupado por células pluripotenciales y, por tanto, puede contener un grupo heterogéneo de tumores. El quiste dermoide es una entidad muy rara dentro de este grupo de tumores. Descripción de caso: femenina de 36 años de edad, con sensación de pesadez en hipogastrio, dolor en sedestación, y cambios en patrón evacuatorio; se realizó palpación abdominal, tacto rectal positivo para masa blanda dolorosa; eco endoanal y resonancia evidenciaron lesión ocupante de espacio presacro. Se realizó exéresis completa vía abdominal, con diagnóstico histopatológico definitivo de quiste dermoide. Discusión: un tumor presacro involucra un reto diagnóstico y terapéutico debido a la gran variedad de diagnósticos diferenciales. En el presente caso se diagnosticó un quiste dermoide, tumor benigno, fuera de su localización habitual. Conclusión: los tumores retrorrectales son lesiones poco habituales, es necesaria la exéresis completa y su posterior estudio histopatológico, para establecer su naturaleza. (AU)

Introduction: During embryological development, the retrorectal or presacral space is occupiedby pluripotent cells and, therefore, may contain a heterogeneous group of tumors. The dermoid cyst is a very rare entity within this group of tumors. Materials and methods: We present a case of a 36-year-old female patient with a sensation of heaviness inthe hypogastrium. Magnetic resonance imaging was performed in which presacral tumor was evident. Results: complete abdominal excision was performed, with a definitive histopathological diagnosis of dermoid cyst. Discussion: a presacral tumor involves a diagnostic and therapeutic challenge due to the great variety of differential diagnoses. The present case was diagnosed with a dermoid cyst, a benign tumor, outside its usual location. Conclusion: Retrorectal tumors are rare tumors, in which complete excision and histopathological report are necessary. (AU)

Pulmonary matrix-derived hydrogels from patients with idiopathic pulmonary fibrosis induce a proinflammatory state in lung fibroblasts in vitro.

Idiopathic pulmonary fibrosis (IPF), one of the most common forms of interstitial lung disease, is a poorly understood, chronic, and often fatal fibroproliferative condition with only two FDA-approved medications. Understanding the pathobiology of the fibroblast in IPF is critical to evaluating and discovering novel therapeutics. Using a decellularized lung matrix derived from patients with IPF, we generate three-dimensional hydrogels as in vitro models of lung physiology and characterize the phenotype of fibroblasts seeded into the hydrogels. When cultured in IPF extracellular matrix hydrogels, IPF fibroblasts display differential contractility compared with their normal counterparts, lose the classical myofibroblast marker α-smooth muscle actin, and increase expression of proinflammatory cytokines compared with fibroblasts seeded two-dimensionally on tissue culture dishes. We validate this proinflammatory state in fibroblast-conditioned media studies with monocytes and monocyte-derived macrophages. These findings add to a growing understanding of the lung microenvironment effect on fibroblast phenotypes, shed light on the potential role of fibroblasts as immune signaling hubs during lung fibrosis, and suggest intervention in fibroblast-immune cell cross-talk as a possible novel therapeutic avenue.

Challenging assumptions: "unveiling meritocracy's reality in neurosurgery".

Introduction: Meritocracy, a concept revered as the cornerstone of fairness and equal opportunity, is critically examined in the context of neurosurgery. This article challenges the notion that success in this demanding field is solely determined by individual abilities and effort. It reveals that factors such as background, gender, and socioeconomic status significantly influence one's career trajectory. By investigating how these systemic barriers impact admissions to neurosurgical training programs and professional advancement, the paper underscores the complexity of meritocracy in neurosurgery, suggesting that the meritocratic ideal is more nuanced and influenced by external variables than commonly believed. Results: Certain universities deemed elite offer a curriculum divergent from that of their counterparts in low and middle-income countries. Students at these "elite" institutions gain exposure to new technologies and research incentives, which brings us to the realm of research. Remarkably, 75% of articles originating from developed nations account for just 25% of traumatic brain injury cases. This disparity highlights a significant research imbalance, and the common refrain underscores the need to bolster research capabilities in low-income countries. For neurosurgeons in the developing world, engaging in research often becomes a luxury due to multifaceted challenges. Financial barriers, including publication costs and paywalls for accessing articles, pose significant hurdles. Comparing salaries between countries underscores the glaring divide according to "Neurosurgeon Salary" in 2024. Neurosurgeons in the United States receive a median salary of $412,000 dollars per year, compared to $13,200 dollars in Latin America, as of June 2023. Given such incongruities, the prospect of even attending conferences or workshops abroad remains difficult for neurosurgeons from developing nations. Research isn't cast aside due to a lack of interest but due to resource limitations. The present landscape demands reconsideration. Conclusion: We underscore the journey towards a more inclusive and equitable future in neurosurgery as not just a goal, but a dynamic process fuelled by resilience, collaboration, and a commitment to diversity. The narrative promotes a collective endeavour to dismantle barriers and embrace innovation, emphasizing the importance of mentorship, cross-institutional collaboration, and the amplification of underrepresented voices.

Hepatocellular Carcinoma in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Importance: In the US, hepatocellular carcinoma (HCC) has been the most rapidly increasing cancer since 1980, and metabolic dysfunction-associated steatotic liver disease (MASLD) is expected to soon become the leading cause of HCC. Objective: To develop a prediction model for HCC incidence in a cohort of patients with MASLD. Design, Setting, and Participants: This prognostic study was conducted among patients aged at least 18 years with MASLD, identified using diagnosis of MASLD using International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes; natural language processing of radiology imaging report text, which identified patients who had imaging evidence of MASLD but had not been formally diagnosed; or the Dallas Steatosis Index, a risk equation that identifies individuals likely to have MASLD with good precision. Patients were enrolled from Kaiser Permanente Northern California, an integrated health delivery system with more than 4.6 million members, with study entry between January 2009 and December 2018, and follow-up until HCC development, death, or study termination on September 30, 2021. Statistical analysis was performed during February 2023 and January 2024. Exposure: Data were extracted from the electronic health record and included 18 routinely measured factors associated with MASLD. Main Outcome and Measures: The cohort was split (70:30) into derivation and internal validation sets; extreme gradient boosting was used to model HCC incidence. HCC risk was divided into 3 categories, with the cumulative estimated probability of HCC 0.05% or less classified as low risk; 0.05% to 0.09%, medium risk; and 0.1% or greater, high risk. Results: A total of 1 811 461 patients (median age [IQR] at baseline, 52 [41-63] years; 982 300 [54.2%] female) participated in the study. During a median (range) follow-up of 9.3 (5.8-12.4) years, 946 patients developed HCC, for an incidence rate of 0.065 per 1000 person-years. The model achieved an area under the curve of 0.899 (95% CI, 0.882-0.916) in the validation set. At the medium-risk threshold, the model had a sensitivity of 87.5%, specificity of 81.4%, and a number needed to screen of 406. At the high-risk threshold, the model had a sensitivity of 78.4%, a specificity of 90.1%, and a number needed to screen of 241. Conclusions and Relevance: This prognostic study of more than 1.8 million patients with MASLD used electronic health record data to develop a prediction model to discriminate between individuals with and without incident HCC with good precision. This model could serve as a starting point to identify patients with MASLD who may need intervention and/or HCC surveillance.

ABBV-319: a CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

ABSTRACT: Glucocorticoids are key components of the standard-of-care treatment regimens for B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in a phase 1 clinical trial.

Dysregulation of Glypicans and Notum in Osteoarthritis: Plasma Levels, Bone Marrow Mesenchymal Stromal Cells and Osteoblasts.

In this study of the alterations of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts in Osteoarthritis (OA), the levels of GPCs and Notum in the plasma of 25 patients and 24 healthy subjects were measured. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured over a period of 21 days using both a culture medium and an osteogenic medium. Protein and gene expression levels of GPCs and Notum were determined using ELISA and qPCR at 0, 7, 14 and 21 days. GPC5 and Notum levels decreased in the plasma of OA patients, while the BM-MSCs of OA patients showed downexpression of GPC6 and upregulation of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPCs 2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in patients with OA. Furthermore, the protein levels of GPC2, GPC5 and Notum decreased, while the levels of GPC3 increased. Glypicans and Notum were altered in BM-MSCs and during osteogenic differentiation from patients with OA. The alterations found point to GPC5 and Notum as new candidate biomarkers of OA pathology.

The hormonal profile in women using combined monophasic oral contraceptive pills varies across the pill cycle: a temporal analysis of serum endogenous and exogenous hormones using liquid chromatography with tandem mass spectroscopy.

Oral contraceptive pills, of all types, are used by approximately 151 million women worldwide; however, a clear understanding of the concentrations of endogenous and exogenous hormones across a 28-day combination monophasic oral contraceptive pill pack is not well described. In our study of 14 female participants taking various combination monophasic oral contraceptive pills, we found significant fluctuations in endogenous and exogenous hormone levels throughout the pill cycle. Our analysis revealed significantly greater levels of ethinyl estradiol on the 20th and 21st days of active pill ingestion, compared with days 1-2 (active) and days 27-28 (inactive pill ingestion). Conversely, estradiol concentrations decreased during active pill consumption, while progestin and progesterone levels remained stable. During the 7 days of inactive pill ingestion, estradiol levels rose sharply and were significantly higher at days 27-28 compared with the mid and late active phase time points, while ethinyl estradiol declined and progestin did not change. These findings challenge the previous assumption that endogenous and exogenous hormones are stable throughout the 28-day pill cycle.NEW & NOTEWORTHY The results from this study have wide-ranging implications for research and treatment in women's health including considerations in research design and interpretation for studies including women taking oral contraceptives, the potential for more precise and personalized methods of dosing to reduce unwanted side effects and adverse events, and the potential treatment of a variety of disorders ranging from musculoskeletal to neurological with exogenous hormones.

Reliability of magnetic resonance for temporomandibular joint disc perforation: A 12 years retrospective study.

The aim of this study was to evaluate the reliability of magnetic resonance imaging (MRI) in detecting disc perforations in the temporomandibular joint (TMJ), and to establish diagnostic criteria for this purpose. The retrospective analysis included patients who had undergone preoperative MRI and TMJ arthroscopy at the same hospital. Direct and indirect signs of disc abnormalities on MRI were compared with arthroscopic findings of disc perforation. Out of 355 joints evaluated in 185 patients, arthroscopy confirmed disc perforations in 14.7% of cases. Several MRI findings were significantly associated with disc perforation, including anterior disc displacement without reduction (ADDwoR), signal alterations in the mid-disc area, disc deformity (SAMD), retrocondylar disc fragments, osteophytes, condylar bone marrow degeneration (CBMD), and joint effusion in both joint spaces (ESJS-EIJS). Regression analysis revealed that SAMD, osteophytes, and CBDM were strongly associated with disc perforation. The ROC curve showed that MRI had an AUC = 0.791, with a sensitivity of 88.5% and a specificity of 61.5%. Two diagnostic methods, one based on three findings (osteophytes, ADDwoR, and SAMD) and one based on two direct signs (ADDwoR and SAMD), yielded high sensitivity and specificity values of 80.4% and 69.8%, and 84.3% and 62.5%, respectively. In conclusion, MRI demonstrated acceptable accuracy in the detection of TMJ disc perforations, with specific diagnostic criteria offering high sensitivity and specificity. Significant MRI indicators of disc perforation included SAMD, osteophytes, and CBDM. This study provides valuable information on the use of MRI as a diagnostic tool for TMJ disc perforations.

Microplastics and plastisphere at surface waters in the Southwestern Caribbean sea.

Pollution generated by plastic waste has brought an environmental problem characterized by the omnipresence of smaller pieces of this material known as microplastics (MP). This issue was addresses by collecting samples with 250 µm pore size nets in two marine-coastal sectors of Southwestern Caribbean Sea during two contrasting seasons. Higher concentrations were found in rainy season than in dry season, reaching respectively 1.72 MP/m3 and 0.22 MP/m3. Within each sector, there were differences caused firstly by localities of higher concentrations of semi-closed water bodies localities during rainy season (Ciénaga Grande de Santa Marta and La Caimanera marsh), and secondly by lower concentrations of localities with less influenced of flow rates during dry season (Salamanca and Isla Fuerte). Moreover, the lowest concentration in dry season corresponding to La Caimanera marsh reflects how the community environmental management might decrease MP pollution. In both sectors and seasons, the particles of 0.3 mm (0.3-1.4 mm) size class dominated over those of 1.4 mm (1.4-5.0 mm) (reaching each respectively 1.33 MP/m3 and 0.39 MP/m3), with a dominance of fibers, except in the rainy season in Magdalena, where they were films. Using the FTIR technique, polypropylene was identified as the most abundant polymer in both sectors. The composition of the assemblage of microorganisms attached to microplastics presented higher richness and differed from that of free-living planktonic microbes. The most abundant members of the plastisphere were proteobacteria whose major representation was the pathogenic genus Vibrio, while the cyanobacteria dominated in seawater samples.

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism in four European countries.

BACKGROUND: The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. METHODS: Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. RESULTS: Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9-63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. CONCLUSIONS: This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials.

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

17ß-Estradiol Effects in Skeletal Muscle: A 31P MR Spectroscopic Imaging (MRSI) Study of Young Females during Early Follicular (EF) and Peri-Ovulation (PO) Phases.

The natural variation in estrogen secretion throughout the female menstrual cycle impacts various organs, including estrogen receptor (ER)-expressed skeletal muscle. Many women commonly experience increased fatigue or reduced energy levels in the days leading up to and during menstruation, when blood estrogen levels decline. Yet, it remains unclear whether endogenous 17ß-estradiol, a major estrogen component, directly affects the energy metabolism in skeletal muscle due to the intricate and fluctuating nature of female hormones. In this study, we employed 2D 31P FID-MRSI at 7T to investigate phosphoryl metabolites in the soleus muscle of a cohort of young females (average age: 28 ± 6 years, n = 7) during the early follicular (EF) and peri-ovulation (PO) phases, when their blood 17ß-estradiol levels differ significantly (EF: 28 ± 18 pg/mL vs. PO: 71 ± 30 pg/mL, p < 0.05), while the levels of other potentially interfering hormones remain relatively invariant. Our findings reveal a reduction in ATP-referenced phosphocreatine (PCr) levels in the EF phase compared to the PO phase for all participants (5.4 ± 4.3%). Furthermore, we observe a linear correlation between muscle PCr levels and blood 17ß-estradiol concentrations (r = 0.64, p = 0.014). Conversely, inorganic phosphate Pi and phospholipid metabolite GPC levels remain independent of 17ß-estradiol but display a high correlation between the EF and PO phases (p = 0.015 for Pi and p = 0.0008 for GPC). The robust association we have identified between ATP-referenced PCr and 17ß-estradiol suggests that 17ß-estradiol plays a modulatory role in the energy metabolism of skeletal muscle.

Self-assembly and hydrogelation of a potential bioactive peptide derived from quinoa proteins.

In this work the identification of peptides derived from quinoa proteins which could potentially self-assemble, and form hydrogels was carried out with TANGO, a statistical mechanical based algorithm that predicts ß-aggregate propensity of peptides. Peptides with the highest aggregate propensity were subjected to gelling screening experiments from which the most promising bioactive peptide with sequence KIVLDSDDPLFGGF was selected. The self-assembling and hydrogelation properties of the C-terminal amidated peptide (KIVLDSDDPLFGGF-NH2) were studied. The effect of concentration, pH, and temperature on the secondary structure of the peptide were probed by circular dichroism (CD), while its nanostructure was studied by transmission electron microscopy (TEM) and small-angle neutron scattering (SANS). Results revealed the existence of random coil, α-helix, twisted ß-sheet, and well-defined ß-sheet secondary structures, with a range of nanostructures including elongated fibrils and bundles, whose proportion was dependant on the peptide concentration, pH, or temperature. The self-assembly of the peptide is demonstrated to follow established models of amyloid formation, which describe the unfolded peptide transiting from an α-helix-containing intermediate into ß-sheet-rich protofibrils. The self-assembly is promoted at high concentrations, elevated temperatures, and pH values close to the peptide isoelectric point, and presumably mediated by hydrogen bond, hydrophobic and electrostatic interactions, and π-π interactions (from the F residue). At 15 mg/mL and pH 3.5, the peptide self-assembled and formed a self-supporting hydrogel exhibiting viscoelastic behaviour with G' (1 Hz) ~2300 Pa as determined by oscillatory rheology measurements. The study describes a straightforward method to monitor the self-assembly of plant protein derived peptides; further studies are needed to demonstrate the potential application of the formed hydrogels in food and biomedicine.

PD-L1 expression complements CALGB prognostic scoring system in malignant pleural mesothelioma.

Background: Programmed death ligand-1 (PD-L1) expression is a predictive biomarker in patients with lung cancer, but its role in malignant pleural mesothelioma (MPM) remains unclear. Evidence suggests that higher PD-L1 expression is correlated with worse survival. CALGB is the main scoring system used to predict the benefit of chemotherapy treatment. This study aimed to determine the prognostic value of PD-L1 expression and its addition to CALGB scoring system in patients with MPM. Methods: In this retrospective analysis, we evaluated samples with confirmed locally advanced or metastatic MPM. PD-L1 Tumor Proportional Score (TPS) was determined by immunohistochemistry at diagnosis. Results: 73 patients were included in this study. A cutoff value of 15 was set for a high or low PD-L1 TPS. In total, 71.2% (n=52) and 28.8% (n=21) of individuals harbored low or high PD-L1 expression, respectively. PD-L1High was associated with worse median progression-free Survival (mPFS) [4.9 vs. 10.8 months; HR 2.724, 95% CI (1.44-5.14); p = 0.002] and Overall Survival (OS) [6.0 vs. 20.9 months; HR 6.87, 95% CI (3.4-8.7); p<0.001] compared to patients with PD-L1Low. Multivariate analysis confirmed that PD-L1 expression was an independent factor for PFS and OS in patients with MPM and CALGB score of 5-6. Conclusion: PD-L1 addition to CALGB scale improves its prognostic estimation of MPM survival and should be considered in future research.

PGF2α signaling drives fibrotic remodeling and fibroblast population dynamics in mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-ß1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen-treated IER-SftpcI73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr-null (FPr-/-) line showed attenuated weight loss and gene dosage-dependent rescue of mortality compared with FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.