Relevant Markers Research Articles

Patterns of Hepatobiliary Pathologies and Their Relationship with Markers of Inflammation in COVID-19 Patients

Background: Altered hepatobiliary status has been reported in association with COVID-19 which has been linked, with limited evidence, to the exaggerated COVID-19-induced hyper-inflammatory response. Hence, the current study evaluated hepatocellular status and its association with indicators of inflammation among COVID-19 patients. Methods: This study was conducted among the RT-PCR-confirmed and treatment-naïve COVID-19 patients in Port Harcourt, South-south Nigeria. Pre-medical/surgical data were retrieved retrospectively from archived patients’ case notes, medical review charts, nurses’ vital signs/medication sheets, and laboratory records at the center using validated data acquisition templates. All retrieved data were analyzed using standard protocols. Results: Among the 396 studied, 16.7% (n=66) had hepatobiliary pathologies. The majority of those with hepatobiliary pathologies had severe COVID-19 (93.3%). Patients with severe COVID-19 and concurrent hepatobiliary pathologies were mostly males and of older age. Cholestatic-specific pathology was the most common pattern observed among the general cases with hepatobiliary pathologies and among those having specific mild, moderate, and severe COVID-19. Among those with severe COVID-19, significant positive relationships were observed between markers of inflammation (Proclacitonin/C-reactive protein/D-dimer) and cholestatic-specific hepatobiliary markers (ALP/G-GT/TBil/CBil) (p<0.05), but not with the hepatocellular-specific markers (ALT/AST) (p>0.05). In contrast, no significant relationship existed between the relevant markers of inflammation and all the cholestatic/hepatocellular markers among those with mild and moderate COVID-19 (p>0.05). Conclusion: Hepatobiliary pathologies, mostly of cholestatic patterns, are frequent among the studied COVID-19 patients which were associated with inflammatory markers among those with severe disease. Therefore, hepatobiliary evaluation should be prioritized, especially among those with severe COVID-19.

CSF Aβ42 and Aβ42/Aβ40 Ratio in Alzheimer's Disease and Frontotemporal Dementias.

Alzheimer's disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τT and τP-181), and amyloid beta with 42 and 40 amino acids (Aβ42 and Aβ40) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ42 to Aβ42/Aβ40 ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ42/Aβ40; τT/τP-181; τT/Aβ42; τP-181/Aβ42) and composite markers (t-tau: τT/(Aβ42/Aβ40); p-tau: τP-181/(Aβ42/Aβ40) were calculated. ROC curve analysis was performed to compare AUCs of Aβ42 and Aβ42/Aβ40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aβ42, and Aβ42/Aβ40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ42 and Aβ42/Aβ40; Results: Aβ42 did not differ from Aβ42/Aβ40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aβ42 ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ42/Aβ40 ratio was superior to Aβ42 in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses. Aβ42/Aβ40 ratio is superior to Aβ42 in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers.

HER2 as a potential therapeutic target on quiescent prostate cancer cells

Quiescent prostate cancer (PCa) cells are common in tumors but are often resistant to chemotherapy. Quiescent PCa cells are also enriched for a stem-like tumor initiating population, and can lead to recurrence after dormancy. Unfortunately, quiescent PCa cells are difficult to identify and / or target with treatment in part because the relevant markers are intracellular and regulated by protein stability. We addressed this problem by utilizing PCa cells expressing fluorescent markers for CDKN1B (p27) and CDT1, which can separate viable PCa cells into G0, G1, or combined S/G2/M populations. We used FACS to collect G1 and G0 PC3 PCa cells, isolated membrane proteins, and analyzed protein abundance in G0 vs G1 cells by gas chromatography mass spectrometry. Enrichment analysis identified nucleocytoplasmic transport as the most significantly different pathway. To identify cell surface proteins potentially identifying quiescent PCa cells for future patient samples or for antibody based therapeutic research, we focused on differentially abundant plasma membrane proteins, and identified ERBB2 (HER2) as a cell surface protein enriched on G0 PCa cells. High HER2 on the cell membrane is associated with quiescence in PCa cells and likely induced by the bone microenvironment. Using a drug conjugated anti-HER2 antibody (trastuzumab emtansine) in a mouse PCa xenograft model delayed metastatic tumor growth, suggesting approaches that target HER2-high cells may be beneficial in treating PCa. We propose that HER2 is deserving of further study in PCa as a target on quiescent cells to prevent recurrence, decrease chemotherapy resistance, or eradicate minimal residual disease.

Caspase-9-mediated cleavage of vimentin attenuates the aggressiveness of leukemic NB4 cells.

Vimentin is a main type 3 intermediate filament protein. It seems that abnormal expression of vimentin is contributed to the appearance of the aggressive feature of cancer cells. So that it has been reported that malignancy and epithelial-mesenchymal transition in solid tumors, and poor clinical outcomes in patients with lymphocytic leukemia and acute myelocytic leukemia have been associated with the high expression of vimentin. Vimentin is a non-caspase substrate of caspase-9 although its cleavage by caspase-9 in biological processes has not been reported. In the present study, we sought to understand whether vimentin cleavage mediated by caspase-9 could reverse the malignancy in leukemic cells. Herein, to address the issue, we investigated vimentin changes in differentiation and took advantage of the inducible caspase-9 (iC9)/AP1903 system in human leukemic NB4 cells. Following the transfection and treatment of the cells using the iC9/AP1903 system, vimentin expression, cleavage, and subsequently, the cell invasion and the relevant markers such as CD44 and MMP-9 were evaluated. Our results revealed the downregulation and cleavage of vimentin which attenuates the malignant phenotype of the NB4 cells. Considering the favorable effect of this strategy in keeping down the malignant features of the leukemic cells, the effect of the iC9/AP1903 system in combination with all-trans-retinoic acid (ATRA) treatment was evaluated. The obtained data prove that iC9/AP1903 significantly makes the leukemic cells more sensitive to ATRA.

SAkuraBONSAI: Protocol design of a novel, prospective study to explore clinical, imaging, and biomarker outcomes in patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorder receiving open-label satralizumab.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune disease of the central nervous system that produces acute, unpredictable relapses causing cumulative neurological disability. Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced NMOSD relapse risk vs. placebo in two Phase 3 trials: SAkuraSky (satralizumab ± immunosuppressive therapy; NCT02028884) and SAkuraStar (satralizumab monotherapy; NCT02073279). Satralizumab is approved to treat aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD. SAkuraBONSAI (NCT05269667) will explore fluid and imaging biomarkers to better understand the mechanism of action of satralizumab and the neuronal and immunological changes following treatment in AQP4-IgG+ NMOSD. SAkuraBONSAI will evaluate clinical disease activity measures, patient-reported outcomes (PROs), pharmacokinetics, and safety of satralizumab in AQP4-IgG+ NMOSD. Correlations between imaging markers (magnetic resonance imaging [MRI] and optical coherence tomography [OCT]) and blood and cerebrospinal fluid (CSF) biomarkers will be investigated. SAkuraBONSAI is a prospective, open-label, multicenter, international, Phase 4 study that will enroll approximately 100 adults (18-74 years) with AQP4-IgG+ NMOSD. This study includes two patient cohorts: newly diagnosed, treatment-naïve patients (Cohort 1; n = 60); and inadequate responders to recent (<6 months) rituximab infusion (Cohort 2; n = 40). Satralizumab monotherapy (120 mg) will be administered subcutaneously at Weeks 0, 2, 4, and Q4W thereafter for a total of 92 weeks. Disease activity related to relapses (proportion relapse-free, annualized relapse rate, time to relapse, and relapse severity), disability progression (Expanded Disability Status Scale), cognition (Symbol Digit Modalities Test), and ophthalmological changes (visual acuity; National Eye Institute Visual Function Questionnaire-25) will all be assessed. Peri-papillary retinal nerve fiber layer and ganglion cell complex thickness will be monitored using advanced OCT (retinal nerve fiber layer and ganglion cell plus inner plexiform layer thickness). Lesion activity and atrophy will be monitored by MRI. Pharmacokinetics, PROs, and blood and CSF mechanistic biomarkers will be assessed regularly. Safety outcomes include the incidence and severity of adverse events. SAkuraBONSAI will incorporate comprehensive imaging, fluid biomarker, and clinical assessments in patients with AQP4-IgG+ NMOSD. SAkuraBONSAI will provide new insights into the mechanism of action of satralizumab in NMOSD, while offering the opportunity to identify clinically relevant neurological, immunological, and imaging markers.

Peculiarities of the sunflower breeding for resistance to broomrape (orobanche cumana wallr.)

Purpose and Objectives. Our purpose was to find available information on the sunflower breeding for resistance to the broomrape. To achieve this purpose, we solved following tasks: to review publications covering the history and current state of research into the subject; find out the specifics of such studies; and to highlight the main unresolved issues for the organization of further work.&#x0D; Materials and Methods. Publications of Ukrainian and foreign scientists became the material for the study: articles in journals and conference abstracts.&#x0D; Results and Discussion. In the article, publications covering domestic and foreign studies of the peculiarities of sunflower breeding for resistance to the parasitic plant Orobanche cumana Wallr. are collected and reviewed. The changes in the race composition of the parasite since the beginning of the 19th century, which have accelerated in recent years, are described. Experiments and breeding for resistance to the broomrape began in 1909-1913, when there was only one (the first) broomrape race A. Currently, the existence of the seventh race (G) and the broomrape biotypes affecting race G-resistant sunflower accessions has been recognized in the world. During the last 20 years, the appearance of new broomrape races was observed in the countries where sunflowers are grown with violations of crop rotation requirements.&#x0D; Marking resistance genes of domestic plants and determining the molecular polymorphism of both host and parasitic plants are important problems of genetics, solving of which is aimed at the improvement of sunflowers in terms of resistance to the broomrape. The identification of genes of resistance to the broomrape and the development of methods for their marking are discussed. Studies in the genetics of resistance to O. cumana are limited by few relevant molecular markers. Scientists announced that they had onstructed a molecular genetic map of linkage groups with the Or7 gene of resistance to race G. Genetic studies of the broomrape as a plant are mainly focused on the structure and genetic diversity of parasite populations. The broomrape aggressiveness depends on weather and climate, so an increase in temperatures and lack of precipitation can lead to the broomrape spread over large areas. Scientists adapt the phytotron test for resistance to the broomrape to modern equipment, developing certain methodological subtleties. In addition, new methods of evaluation are developed: histological and molecular genetic assessments&#x0D; Conclusions. The sunflower broomrape is one of the main biotic factors that harm the crop fields. The peculiarity of the breeding for resistance is associated with continuous formation of new races of the parasite. Studies by scientists from different countries on the formation of new physiological races of the broomrape indicate the annually growing threat from the parasite, the need for constant monitoring of broomrape populations and the continuous development of research in this direction. Several genes of resistance to the broomrape have been identified; methods of their marking have been developed; this ensures success in improving the existing and developing new progressive approaches in the sunflower breeding for resistance to the parasite. The specificity of control of resistance to the broomrape, which is determined by genetic factors, was established. Thus, genetic methods are the best ones to fight against the broomrape. However, inheritance patterns of resistance to new, virulent, widespread in Ukraine broomrape races are not described in the literature, though it is important for the creation of commercial hybrids. The relationships between resistance to new virulent broomrape races, which are common in Ukraine, and valuable economic characteristics in F1 hybrids should be also studied. Taking into account the recent climatic changes, in particular a rise in air temperatures and consequences of this global process, one can predict an increase in the intensity of damage to sunflowers by the parasite, which prompts breeders of the crop to combine resistance to adverse abiotic factors and resistance to the broomrape

Cell morphology as a biological fingerprint of chondrocyte phenotype in control and inflammatory conditions.

Little is known how inflammatory processes quantitatively affect chondrocyte morphology and how single cell morphometric data could be used as a biological fingerprint of phenotype. We investigated whether trainable high-throughput quantitative single cell morphology profiling combined with population-based gene expression analysis can be used to identify biological fingerprints that are discriminatory of control vs. inflammatory phenotypes. The shape of a large number of chondrocytes isolated from bovine healthy and human osteoarthritic (OA) cartilages was quantified under control and inflammatory (IL-1β) conditions using a trainable image analysis technique measuring a panel of cell shape descriptors (area, length, width, circularity, aspect ratio, roundness, solidity). The expression profiles of phenotypically relevant markers were quantified by ddPCR. Statistical analysis, multivariate data exploration, and projection-based modelling were used for identifying specific morphological fingerprints indicative of phenotype. Cell morphology was sensitive to both cell density and IL-1β. In both cell types, all shape descriptors correlated with expression of extracellular matrix (ECM)- and inflammatory-regulating genes. A hierarchical clustered image map revealed that individual samples sometimes responded differently in control or IL-1β conditions than the overall population. Despite these variances, discriminative projection-based modeling revealed distinct morphological fingerprints that discriminated between control and inflammatory chondrocyte phenotypes: the most essential morphological characteristics attributable to non-treated control cells was a higher cell aspect ratio in healthy bovine chondrocytes and roundness in OA human chondrocytes. In contrast, a higher circularity and width in healthy bovine chondrocytes and length and area in OA human chondrocytes indicated an inflammatory (IL-1β) phenotype. When comparing the two species/health conditions, bovine healthy and human OA chondrocytes exhibited comparable IL-1β-induced morphologies in roundness, a widely recognized marker of chondrocyte phenotype, and aspect ratio. Overall, cell morphology can be used as a biological fingerprint for describing chondrocyte phenotype. Quantitative single cell morphometry in conjunction with advanced methods for multivariate data analysis allows identifying morphological fingerprints that can discriminate between control and inflammatory chondrocyte phenotypes. This approach could be used to assess how culture conditions, inflammatory mediators, and therapeutic modulators regulate cell phenotype and function.

Evolution of hematocrit in burn patients as a marker of early fluid management during acute phase

ObjectiveTo evaluate the value of hematocrit for monitoring fluid resuscitation of burn patients in the acute phase of their care. MethodWe conducted a single-center retrospective study focused on patients admitted with a burn surface of more than 20 % of the total body surface area (TBSA) from 2014 to 2021. We investigated the relationship between the change in hematocrit and the volume administered for patient resuscitation. The change in hematocrit is the difference between an admission hematocrit and a second one taken between the eighth and twenty-fourth hour. ResultsWe included 230 patients with an average burn size of 39.1 ± 20.3 % TBSA, in 94.4 % by a thermal mechanism. The management seems to be in accordance with the current recommendations, with a volume administered during the first 24 h of 4.3 ± 2.5 ml/kg/ % BSA, allowing to obtain an hourly diuresis of 0.9 ± 0.7 ml/kg/h. We did not find any correlation between the pre-hospital volume administration and the hematocrit at admission (p = 0.36). Hematocrit decreased on average to −4.5 ± 8.1 % between admission and a control performed after the 8th hour. This decrease was weakly correlated with the volumes infused between the two samples (r2 =0.13, p < 0.001). A resuscitation above 5.2 ml/kg/ % Burn surface area is an independent factor for excess mortality. ConclusionHematocrit or its variations in our limited data base appears to not reliably detect over-resuscitation, therefore it is possible that it may not be a relevant marker. These conclusions should be clarified in a multi-institutional prospective or real-world analysis to validate the findings and null hypothesis.

Utility of comet assay of DNA damage in the detection of malignant transformation of chronic liver cirrhosis

Early detection of hepatocellular carcinoma (HCC) remains a great challenge in laboratory medicine. This study aimed to assess the ability to use the degree of DNA damage (using the comet assay) for the early detection of malignant transformation of liver cirrhosis (LC) to HCC. We used alkaline comet assay for measuring DNA damage in peripheral blood lymphocytes in 50 patients with chronic LC and 50 patients with HCC. Fifty healthy individuals served as a control group. We compared the results of comet assay parameters with alpha fetoprotein as a relevant traditional marker. The HCC group was associated with a significantly higher tail intensity (p=.004), tail moment (p=.016), total area (p=.003), total intensity (p=.010), width (p=.005), and a significantly lower head intensity (.004) when compared to the LC group. Good areas under the curve (AUCs) were found for total area (0.890), head intensity (0.880) and tail intensity (0.880), making it useful for discrimination between HCC and LC groups. Lower head intensity, higher tail intensity, tail moment, total area and width were found to be independent risk factors for HCC on top of LC. Measuring DNA damage using the Alkaline comet assay technique can be considered a sensitive and reliable diagnostic tool for early neoplastic transformation of advanced LC.

Atypical anorexia nervosa: Implications of clinical features and BMI cutoffs.

Atypical anorexia nervosa (atypical AN) appears to be a heterogeneous disorder under the current diagnostic system. Though the body mass index (BMI) cutoff point of 18.5kg/m2 is a criterion that distinguishes atypical AN from AN, the cutoff may not be universally applicable as the norms for BMI vary and can be affected by several factors, including cross-country differences and social determinants. It is unfortunate that we do not yet have reliable or widely available criteria other than BMI for the diagnosis of atypical AN. Additional relevant markers of atypical AN are needed in future diagnostic systems.

Alkaline phosphatase in clinical practice in childhood: Focus on rickets.

Serum alkaline phosphatase (ALP) and its isoenzymes reflect bone metabolism: ALP increases the ratio of inorganic phosphate to pyrophosphate systemically and facilitates mineralization as well as reduces extracellular pyrophosphate concentration, an inhibitor of mineral formation. On the contrary, low ALP activity is associated with reduction of bone turnover. ALP includes four isoenzymes depending on the site of tissue expression: intestinal ALP, placental ALP, germ cell ALP and tissue nonspecific ALP or liver/bone/kidney ALP. The bone isoenzyme (B-ALP) is involved in bone calcification and is a marker of bone turnover as a result of osteoblastic activity. ALP and its isoenzymes are crucial in the diagnostic process of all the forms of rickets.The most common cause of rickets is vitamin D nutritional deficiency. The aim of this review is to update on the role played by ALP serum concentrations as a relevant marker in thediagnosis and treatment of rickets. Indeed, the diagnosis of rickets is based on its clinical, radiological and laboratory characteristics. An elevated ALP level is one of the markers for the diagnosis of rickets in children, though it is also associated with bone formation process. ALP is also useful for the differentiation between rickets and other disorders that can mimic rickets because of their clinical and laboratory characteristics, and, together with other biochemical markers, is crucial for the differential diagnosis of the different forms of rickets. Age, severity and duration of rickets may also modulate ALP elevation. Finally, ALP measurements are useful in clinical and therapeutic follow-up.

A quality assurance review of penile cancer diagnostic delays and stage at presentation during the COVID-19 pandemic.

Penile carcinomas represent a rare malignancy associated with significant psychosocial impacts that deter afflicted individuals from seeking medical attention, thus, worsening prognosis. Following the dramatic shift in healthcare delivery to virtual platforms, it is suspected that prevalent psychosocial impacts have been further compounded by the COVID-19 pandemic, resulting in several late-stage presentations and engendering poorer outcomes. A retrospective chart review of surgically managed cases of penile cancer was conducted from January 2019 to June 2022 to identify patients that may have been unduly impacted by the COVID-19 pandemic. Included cases were analyzed in quantifying diagnostic and treatment delays, along with patient outcomes. Relevant epidemiological and pathological markers were also examined. Ten patients met the inclusion criteria. Average time delay from first complaint of a penile lesion to surgical management was 75 days, with 60% of patients experiencing a time delay of two months or more. The average delay from first complaint to diagnosis was 62 days in 2020 and 18 days in 2021. Advanced-stage disease was present in n=6 (60%) of individuals at presentation, while n=4 (40%) of patients perished during the study period. In cases of concern for penile malignancy, virtual care cannot replace the necessity of physical exams in preventing diagnostic and treatment delays. The present study further highlights the necessity of initial physical examination of penile abnormalities in preventing fatal outcomes for those afflicted. Such consideration warrants urgent examination of referred males with genital abnormalities to prevent further exacerbation of delays.

Cadmium treatment induces endoplasmic reticulum stress and unfolded protein response in Arabidopsisthaliana

We report about the response of Arabidopsis thaliana to chronic and temporary Cd2+ stress, and the Cd2+ induced activation of ER stress and unfolded protein response (UPR). Cd2+-induced UPR proceeds mainly through the bZIP60 arm, which in turn activates relevant ER stress marker genes such as BiP3, CNX, PDI5 and ERdj3B in a concentration- (chronic stress) or time- (temporary stress) dependent manner. A more severe Cd-stress triggers programmed cell death (PCD) through the activation of the NAC089 transcription factor. Toxic effects of Cd2+ exposure are reduced in the Atbzip28/bzip60 double mutant in terms of primary root length and fresh shoot weight, likely due to reduced UPR and PCD activation. We also hypothesised that the enhanced Cd2+ tolerance of the Atbzip28/bzip60 double mutant is due to an increase in brassinosteroids signaling, since the amount of the brassinosteroid insensitive1 receptor (BRI1) protein decreases under Cd2+ stress only in Wt plants. These data highlight the complexity of the UPR pathway, since the ER stress response is strictly related to the type of the treatment applied and the multifaceted connections of ER signaling. The reduced sensing of Cd2+ stress in plants with UPR defects can be used as a novel strategy for phytoremediation.

P278 Endoscopic scoring system utilization for Inflammatory Bowel Disease activity assessment: a multicenter real-world evidence study from Argentina (DARE study)

Abstract Background The use of scores for the assessment of endoscopic activity in inflammatory bowel disease (IBD) patients is crucial for accurate and reproducible evaluation of mucosal healing, which is a relevant marker of prognosis. Frequency and patterns of their use in a real-life setting are not known. We aimed to describe the prevalence of adequate use of endoscopic scores in IBD patients who underwent colonoscopy in a real-life setting. Methods A multicenter observational study comprising six community hospitals in Argentina was undertaken. Patients with a diagnosis of Crohn’s disease or ulcerative colitis who underwent colonoscopy for endoscopic activity assessment between July 2018 and July 2022 were included. Colonoscopy reports of included subjects were manually reviewed to determine the proportion of colonoscopies that included an endoscopic score report. We compared the endoscopic findings to determine if there were differences in the score reported and the inflammatory activity described. Finally, we determined the proportion of colonoscopy reports that included all of the IBD colonoscopy report quality elements proposed by BRIDGe group. Endoscopist’s specialty, years of experience as well as expertise in IBD were assessed. Chi square test was used for the comparison of categorical variables; Student t test for the comparison of numerical variables. A multivariate analysis was performed using a logistic regression model. A p value of less than 0.05 was considered to be statistically significant. Results A total of 1206 patients were included for analysis (32.25% patients with Crohn’s disease). Mean age was 45.48±15.6. Endoscopic score reporting was found in only 34.45% of Crohn’s disease colonoscopies and in 52.87% of ulcerative colitis colonoscopies. Most frequently used scores were Mayo endoscopic score (90.56%) and SES-CD (56.03%). We found discrepancies between the score reported and the findings described in colonoscopies in 10.92% of cases; only 26% of reports included all recommendations proposed by BRIDGe group. On multivariate analysis, surgeons as operators [OR 0.08 (0.03-0.18)], &amp;gt;15 years of endoscopist experience [OR 0.24 (0.07-0.37)], IBD expertise [OR 2.86 (1.86-4.41)] and compliance of quality elements of reporting [OR 2.48 (1.24-3.76)] were significantly associated with endoscopic score reporting. Conclusion We identified a low prevalence of endoscopic activity score reporting in IBD patients’ colonoscopies. This finding is associated with operator-dependent characteristics. Educational interventions can be introduced to increase adequate score reporting.

Cancer Registration, Molecular Marker Status, and Adherence to the WHO 2016 Classification of Pathology Reports for Glioma Diagnosed during 2017–2019 in Belgium

Introduction: The objective of this study was to cross-check and, if necessary, adjust registered ICD-O-3 topography and morphology codes with the findings in pathology reports available at the Belgian Cancer Registry (BCR) for glioma patients. Additionally, integration of molecular markers in the pathological diagnosis and concordance with WHO 2016 classification is investigated. Methods: Since information regarding molecular tests and corresponding conclusions are not available as structured data at population level, a manual screening of all pseudonymized pathology reports available at the BCR for registered glioma patients (2017–2019) was conducted. ICD-O-3 morphology and topography codes from the BCR database (based on information as provided by hospital oncological care programmes and pathology laboratories), were, at tumour level, cross-checked with the data from the pathology reports and, if needed, specified or corrected. Relevant molecular markers (IDH1/2, 1p19q codeletion, promoter region of the MGMT gene [MGMTp]) were manually extracted from the pathology reports. Results: In 95.3% of gliomas, the ICD-O-3 morphology code was correct. Non-specific topography codes were specified in 9.3%, while 3.3% of specific codes were corrected. The IDH status was known in 75.2% of astrocytic tumours. The rate of correct integrated diagnoses varied from 47.6% to 56.4% among different gliomas. MGMTp methylation status was available in 32.2% of glioblastomas. Conclusion: Both the integration of molecular markers in the conclusion of the pathology reports and the delivery of those reports to the BCR can be improved. The availability of distinct ICD-O-3 codes for each molecularly defined tumour entity within the WHO classification would increase the consistency of cancer registration, facilitate population level research and international benchmarking.

High-Resolution Analysis of Mononuclear Phagocytes Reveals GPNMB as a Prognostic Marker in Human Colorectal Liver Metastasis.

Patients with colorectal liver metastasis (CLM) present with heterogenous clinical outcomes and improved classification is needed to ameliorate the therapeutic output. Macrophages (Mϕ) hold promise as prognostic classifiers and therapeutic targets. Here, stemming from a single-cell analysis of mononuclear phagocytes infiltrating human CLM, we identified two Mϕ markers associated with distinct populations with opposite clinical relevance. The invasive margin of CLM was enriched in pro-inflammatory monocyte-derived Mϕ (MoMϕ) expressing the monocytic marker SERPINB2, and a more differentiated population, tumor-associated Mϕ (TAM), expressing glycoprotein nonmetastatic melanoma protein B (GPNMB). SERPINB2+ MoMϕ had an early inflammatory profile, whereas GPNMB+ TAMs were enriched in pathways of matrix degradation, angiogenesis, and lipid metabolism and were found closer to the tumor margin, as confirmed by spatial transcriptomics on CLM specimens. In a cohort of patients, a high infiltration of SERPINB2+ cells independently associated with longer disease-free survival (DFS; P = 0.033), whereas a high density of GPNMB+ cells correlated with shorter DFS (P = 0.012) and overall survival (P = 0.002). Cell-cell interaction analysis defined opposing roles for MoMϕ and TAMs, suggesting that SERPINB2+ and GPNMB+ cells are discrete populations of Mϕ and may be exploited for further translation to an immune-based stratification tool. This study provides evidence of how multi-omics approaches can identify nonredundant, clinically relevant markers for further translation to immune-based patient stratification tools and therapeutic targets. GPNMB has been shown to set Mϕ in an immunosuppressive mode. Our high dimensional analyses provide further evidence that GPNMB is a negative prognostic indicator and a potential player in the protumor function of Mϕ populations.

A High MCM6 Proliferative Index in Atypical Meningioma Is Associated with Shorter Progression Free and Overall Survivals.

The aim of this study was to evaluate the prognostic value of MCM6, in comparison with Ki-67, in two series of grade 1 and 2 meningiomas, and to evaluate its correlation with methylation classes. The first cohort included 100 benign (grade 1, World Health Organization 2021) meningiomas, and the second 69 atypical meningiomas (grade 2). Immunohistochemical Ki-67 and MCM6 labeling indices (LI) were evaluated independently by two observers. Among the atypical meningiomas, 33 cases were also studied by genome-wide DNA methylation. In grade 2 meningiomas, but not grade 1, both Ki-67 and MCM6 LIs were correlated with PFS (p = 0.004 and p = 0.005, respectively; Cox univariate analyses). Additionally, MCM6 was correlated with overall survival only in univariate analysis. In a multivariate model, including mitotic index, Ki-67, MCM6, age, sex, and the quality of surgical resection, only MCM6 was correlated with PFS (p = 0.046). Additionally, we found a significant correlation between PTEN loss and high MCM6 or Ki-67 LIs. Although no correlation was found with the methylation classes and subtypes returned by the meningioma algorithm MNGv2.4., MCM6 LI was significantly correlated with the methylation of 2 MCM6 gene body loci. In conclusion, MCM6 is a relevant prognostic marker in atypical meningiomas. This reproducible and easy-to-use marker allows the identification of a highly aggressive subtype of proliferative meningiomas, characterized notably by frequent PTEN losses, which was previously reported to be sensitive to histone deacetylase inhibitors.

ClonoCluster: A method for using clonal origin to inform transcriptome clustering

Clustering cells based on their high-dimensional profiles is an important data reduction process by which researchers infer distinct cellular states. The advent of cellular barcoding, however, provides an alternative means by which to group cells: by their clonal origin. We developed ClonoCluster, a computational method that combines both clone and transcriptome information to create hybrid clusters that weight both kinds of data with a tunable parameter. We generated hybrid clusters across six independent datasets and found that ClonoCluster generated qualitatively different clusters in all cases. The markers of these hybrid clusters were different but had equivalent fidelity to transcriptome-only clusters. The genes most strongly associated with the rearrangements in hybrid clusters were ribosomal function and extracellular matrix genes. We also developed the complementary tool Warp Factor that incorporates clone information in popular 2D visualization techniques like UMAP. Integrating ClonoCluster and Warp Factor revealed biologically relevant markers of cell identity.

Updates in pathology and molecular diagnostics to inform the evolving landscape of thoracic surgery and oncology.

The pathologic assessment of lung cancers provides essential guidance to the surgeon and oncologist who are considering the best treatment strategies for patients with both early and advanced-stage disease. The management of patients with lung cancer is predicated first and foremost on access to an accurate diagnosis, even when the sample size is limited, as is often the case with use of modern, minimally invasive sampling techniques. Once the diagnosis and disease stage are established, predictive biomarker testing may be essential, particularly for those patients with nonsmall cell lung carcinoma (NSCLC) being considered for immunotherapy or genomic biomarker-driven targeted therapy. This review will discuss the best practices for the diagnosis of NSCLC using morphology and immunohistochemistry, thus providing the surgeon with needed information to understand and critically evaluate pathology reports. Controversial and evolving topics including tumor spread through airspaces,evaluation of multiple tumors, and staging based on invasive tumor size will be addressed. Clinical genomic profiling in NSCLC is driven by published guidelines and reflects evidence based on clinical trials and regulatory approvals. In this fast-moving space, surgeons should be aware of the critical immunohistochemical and genomic biomarkers that drive systemic therapy decisions and anticipate when such testing will be required, both to ensure adequate sampling and to advise the pathologist when tumor material will be required for biomarker analysis. The basic approaches to and sample requirements for molecular biomarker testing will be addressed. As biomarker testing moves exclusively from advanced-stage patients into earlier stage disease, the surgeon should be aware of the relevant markers and work with the pathologist and oncologist to ensure that this information is available to facilitate timely access to therapies not just in the advanced setting, but in consideration of neoadjuvant and adjuvant care.

The naturally occurring GIP(1-30)NH2 is a GIP receptor agonist in humans

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) is an important regulator of glucose and bone metabolism. In rodents, the naturally occurring GIP variant, GIP(1-30)NH2, has shown similar effects as full-length GIP (GIP(1-42)), but its effects in humans are unsettled. Here, we investigated the actions of GIP(1-30)NH2 compared to GIP(1-42) on glucose and bone metabolism in healthy men and in isolated human pancreatic islets. Nine healthy men completed three separate three-step glucose clamps (0-60 minutes at fasting plasma glucose (FPG) level, 60-120 minutes at 1.5× FPG, and 120-180 minutes at 2× FPG) with infusion of GIP(1-42) (4 pmol/kg/min), GIP(1-30)NH2 (4 pmol/kg/min), and saline (9 mg/mL) in randomised order. Blood was sampled for measurement of relevant hormones and bone turnover markers. Human islets were incubated with low (2 mmol/L) or high (20 mmol/L) d-glucose with or without GIP(1-42) or GIP(1-30)NH2 in three different concentrations for 30 minutes, and secreted insulin and glucagon were measured. Plasma glucose (PG) levels at FPG, 1.5× FPG, and 2× FPG were obtained by infusion of 1.45 g/kg, 0.97 g/kg, and 0.6 g/kg of glucose during GIP(1-42), GIP(1-30)NH2, and saline, respectively (P = .18), and were similar on the three experimental days. Compared to placebo, GIP(1-30)NH2 resulted in similar glucagonotropic, insulinotropic, and carboxy-terminal type 1 collagen crosslinks-suppressing effects as GIP(1-42). In vitro experiments on human islets showed similar insulinotropic and glucagonotropic effects of the two GIP variants. GIP(1-30)NH2 has similar effects on glucose and bone metabolism in healthy individuals and in human islets in vitro as GIP(1-42).