Upregulation of Integrin beta-3 in astrocytes upon Alzheimer's disease progression in the 5xFAD mouse model.

Integrins are receptors that have been linked to various brain disorders, including Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. While Integrin beta-3 (ITGB3) is known to participate in multiple cellular processes such as adhesion, migration, and signaling, its specific role in AD remains poorly understood, particularly in astrocytes, the main glial cell type in the brain. In this study, we investigated alterations in ITGB3 gene and protein expression during aging in different brain regions of the 5xFAD mouse model of AD and assessed the interplay between ITGB3 and astrocytes. Primary cultures from adult mouse brains were used to gain further insight into the connection between ITGB3 and amyloid beta (Aß) in astrocytes. In vivo studies showed a correlation between ITGB3 and the astrocytic marker GFAP in the 5xFAD brains, indicating its association with reactive astrocytes. In vitro studies revealed increased gene expression of ITGB3 upon Aß treatment. Our findings underscore the potential significance of ITGB3 in astrocyte reactivity in the context of Alzheimer's disease.

Evaluation of margins during radical prostatectomy: confocal microscopy vs frozen section analysis.

OBJECTIVES: To test the performance of ex vivo fluorescence confocal microscopy (FCM; Vivascope 2500M-G4), as compared to intra-operative frozen section (IFS) analysis, to evaluate surgical margins during robot-assisted radical prostatectomy (RARP), with final pathology as the reference standard. METHODS: Overall, 54 margins in 45 patients treated with RARP were analysed with: (1) ex vivo FCM; (2) IFS analysis; and (3) final pathology. FCM margins were evaluated by two different pathologists (experienced [M.I.: 10 years] vs highly experienced [G.R.: >30 years]) as strongly negative, probably negative, doubtful, probably positive, or strongly positive. First, inter-observer agreement (Cohen's κ) between pathologists was tested. Second, we reported the sensitivity, specificity, positive predictive (PPV) and negative predictive value (NPV) of ex vivo FCM. Finally, agreement between ex vivo FCM and IFS analysis (Cohen's κ) was reported. For all analyses, four combinations of FCM results were evaluated. RESULTS: At ex vivo FCM, the inter-observer agreement between pathologists ranged from moderate (κ = 0.74) to almost perfect (κ = 0.90), according to the four categories of results. Indeed, at ex vivo FCM, the highly experienced pathologist reached the best balance between sensitivity (70.5%) specificity (91.8%), PPV (80.0%) and NPV (87.1%). Conversely, on IFS analysis, the sensitivity, specificity, PPV and NPV were, respectively, 88.2% vs 100% vs 100% vs 94.8%. The agreement between the ex vivo FCM and IFS analyses ranged from moderate (κ = 0.62) to strong (κ = 0.86), according to the four categories of results. CONCLUSION: Evaluation of prostate margins at ex vivo FCM appears to be feasible and reliable. The agreement between readers encourages its widespread use in daily practice. Nevertheless, as of today, the performance of FCM seems to be sub-par when compared to the established standard of care (IFS analysis).

Characterization of the immune environment in pregnancy-associated breast cancer.

Pregnancy-associated breast cancer (PrBC) is a rare and clinically challenging condition. Specific immune mechanisms and pathways are involved in maternal-fetal tolerance and tumor-host immunoediting. The comprehension of the molecular processes underpinning this immune synergy in PrBC is needed to improve patients' clinical management. Only a few studies focused on the immune biology of PrBC and attempted to identify bona fide biomarkers. Therefore, clinically actionable information remains extremely puzzling for these patients. In this review article, we discuss the current knowledge on the immune environment of PrBC, in comparison with pregnancy-unrelated breast cancer and in the context of maternal immune changes during pregnancy. A particular emphasis is given to the actual role of potential immune-related biomarkers for PrBC clinical management.

Pregnancy-associated breast cancer (PrBC) affects about 4% of women with breast cancer who are of childbearing age. Managing these tumors is difficult due to interactions between the mother, fetus and tumor. These interactions cause changes in the immune system of patients with PrBC. Understanding how the immune system responds to PrBC may lead to better ways of managing the disease. This review focuses on the current knowledge of the immune system in PrBC, including which components can be used as biomarkers to improve clinical management.

Circulating tumour DNA testing in metastatic breast cancer: Integration with tissue testing.

Breast cancer biomarker profiling predominantly relies on tissue testing (surgical and/or biopsy samples). However, the field of liquid biopsy, particularly the analysis of circulating tumour DNA (ctDNA), has witnessed remarkable progress and continues to evolve rapidly. The incorporation of ctDNA-based testing into clinical practice is creating new opportunities for patients with metastatic breast cancer (MBC). ctDNA offers advantages over conventional tissue analyses, as it reflects tumour heterogeneity and enables multiple serial biopsies in a minimally invasive manner. Thus, it serves as a valuable complement to standard tumour tissues and, in certain instances, may even present a potential alternative approach. In the context of MBC, ctDNA testing proves highly informative in the detection of disease progression, monitoring treatment response, assessing actionable biomarkers, and identifying mechanisms of resistance. Nevertheless, ctDNA does exhibit inherent limitations, including its generally low abundance, necessitating timely blood samplings and rigorous management of the pre-analytical phase. The development of highly sensitive assays and robust bioinformatic tools has paved the way for reliable ctDNA analyses. The time has now come to establish how ctDNA and tissue analyses can be effectively integrated into the diagnostic workflow of MBC to provide patients with the most comprehensive and accurate profiling. In this manuscript, we comprehensively analyse the current methodologies employed in ctDNA analysis and explore the potential benefits arising from the integration of tissue and ctDNA testing for patients diagnosed with MBC.

Unusual Square Pyramidal Chalcogenide Mo5 Cluster with Bridging Pyrazolate-Ligands.

The family of chalcogenide molybdenum clusters is well presented in the literature by a series of compounds of nuclearity ranging from binuclear to multinuclear articulating octahedral fragments. Clusters actively studied in the last decades were shown to be promising as components of superconducting, magnetic, and catalytic systems. Here, we report the synthesis and detailed characterization of new and unusual representatives of chalcogenide clusters: square pyramidal complexes [{Mo5(µ3-Se)i4(µ4-Se)i(µ-pz)i4}(pzH)t5]1+/2+ (pzH = pyrazole, i = inner, t = terminal). Individually obtained oxidized (2+) and reduced (1+) forms have very close geometry (proven by single-crystal X-ray diffraction analysis) and are able to reversibly transform into each other, which was confirmed by cyclic voltammetry. Comprehensive characterization of the complexes, both in solid and in solution, confirms the different charge state of molybdenum in clusters (XPS), magnetic properties (EPR), and so on. DFT calculations complement the diverse study of new complexes, expanding the chemistry of molybdenum chalcogenide clusters.

Spatially Resolved Molecular Approaches for the Characterisation of Non-Invasive Follicular Tumours with Papillary-like Features (NIFTPs).

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are low-risk thyroid lesions most often characterised by RAS-type mutations. The histological diagnosis may be challenging, and even immunohistochemistry and molecular approaches have not yet provided conclusive solutions. This study characterises a set of NIFTPs by Matrix-Assisted Laser Desorption/Ionisation (MALDI)-Mass Spectrometry Imaging (MSI) to highlight the proteomic signatures capable of overcoming histological challenges. Archived formalin-fixed paraffin-embedded samples from 10 NIFTPs (n = 6 RAS-mutated and n = 4 RAS-wild type) were trypsin-digested and analysed by MALDI-MSI, comparing their profiles to normal tissue and synchronous benign nodules. This allowed the definition of a four-peptide signature able to distinguish RAS-mutant from wild-type cases, the latter showing proteomic similarities to hyperplastic nodules. Moreover, among the differentially expressed signals, Peptidylprolyl Isomerase A (PPIA, 1505.8 m/z), which has already demonstrated a role in the development of cancer, was found overexpressed in NIFTP RAS-mutated nodules compared to wild-type lesions. These results underlined that high-throughput proteomic approaches may add a further level of biological comprehension for NIFTPs. In the future, thanks to the powerful single-cell detail achieved by new instruments, the complementary NGS-MALDI imaging sequence might be the correct methodological approach to confirm that the current NIFTP definition encompasses heterogeneous lesions that must be further characterised.

Replenishment in the Family of Rhenium Chalcobromides; Synthesis and Structure of Molecular {Re4S4}Br8(TeBr2)4, Dimeric [{Re4S4}Br8(TeBr2)3]2, and Polymeric {Re4S4}Br8 Compounds Based on the {Re4S4}8+ Tetrahedral Cluster Core.

We have obtained three new rhenium(IV) chalcobromides belonging to the homologous series {Re4S4}Br8(TeBr2)n (n = 0, 3, 4): a molecular complex {Re4S4}Br8(TeBr2)4 (1), a dimeric complex [{Re4S4}(TeBr2)3Br7(µ-Br)]2 (2), and a two-dimensional (2D) polymeric compound {Re4S4}Br8 (3). Compound 1 is isotypic to the already known {Re4Te4}(TeBr2)4Br8, while 2 and 3 exhibit a new type of binding of tetrahedral clusters via µ-Br bridges. Compounds were characterized by X-ray single-crystal diffraction, X-ray powder diffraction, and thermal and elemental analyses. In compound 2, two tetrahedral cluster cores {Re4S4}8+ are linked together forming a dimer through two Re-µ-Br-Re bridges. Calculations of the electron localization function (ELF) showed that there is no covalent interaction between rhenium atoms of neighboring clusters. In compound 3, each rhenium atom of the {Re4S4}8+ core is coordinated by three Br ligands: one terminal Br and two bridging µ-Br ligands. As a result, eight bridging bromine atoms link {Re4S4}8+ cluster cores into goffered layers. {Re4S4}Br8 is the new stable rhenium(IV) thiobromide, the first discovered in the Re-S-Br system, along with the already known octahedral rhenium(III) thiobromides Re6S4+xBr10-2x (x = 0-4).

PATHOMORPHOLOGICAL CHARACTERISTICS OF IMMUNOCOMPLEX RENAL DISEASE IN PATIENTS WITH IMMUNODEFICIENCY VIRUS AND HEPATITIS C VIRUS, RECEIVING ANTIRETROVIRAL THERAPY.

OBJECTIVE: The aim is to verify and describe the morphological substrate of renal impairment in HIV/HCV co-infection among patients receiving ART to assess and predict the morphogenesis of immunocomplex lesions. PATIENTS AND METHODS: Materials and methods: To assess and predict the morphogenesis of immunocomplex renal disease, we examined retrospectively the kidney tissue samples of 15 patients, who died with HIV/HCV co-infection and received ART. Histological, histochemical and immunohistochemical research methods were used. RESULTS: Results: Segmental and diffuse mesangial proliferation with extracellular matrix expansion with glomerular damage ≥50% in 9 (60%) cases, and involving <50% of glomeruli in 5 (33%), with CD68 expression as single cells were detected. In 12 (80%) cases, there was uneven swelling and focal proliferation of endothelial cells with the involvement of 20-50% of the glomeruli, as well as the presence of cellular infiltrates in the lumen of capillary loops in 3 (20%) cases with monomorphic intensity in "+". Sclerotic changes were present in various degrees of severity - from cases of complete glomerulosclerosis with obliteration of the Bowman's lumen to focal and microfocal depressions 8 (55%), sclerosis 10 (66%), hyalinosis 1 (6%), uneven thickening, focal cleft 8 (55%) and perihilar focal sclerosis. These areas were positive for IgG and C1q complement fractions within the "+", "++" intensity. Among the study group, no case of HIV-associated nephropathy was found that coincided with the predicted spectrum of kidney damage for patients in this sample. The described morphological changes were mainly verified as immuno-mediated by HCV. CONCLUSION: Conclusions: A comprehensive morphological study revealed the morphological substrate of kidney damage and its morphogenesis in patients with HIV/HCV co-infection, receiving ART.

Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer's disease.

BACKGROUND: Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer's disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state. METHODS: Male 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (Aß) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice. RESULTS: Long-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, Aß plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from Aß plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95. CONCLUSIONS: Voluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.

Hexamolybdenum Clusters Supported on Exfoliated h-BN Nanosheets for Photocatalytic Water Purification.

Nowadays, the development of new effective photocatalytic materials for the purification of real wastewaters and model systems containing organic molecules constitutes an important challenge. Here we present a preparation strategy for composite materials based on hexamolybdenum cluster complexes and exfoliated hexagonal boron nitride (h-BN) nanosheets. Cluster deposition on the nanosheet surface was achieved by impregnation of the matrix by a (Bu4N)2[{Mo6I8}(NO3)6]/acetone solution. Successful cluster immobilization and chemical composition of the samples were verified by inductively coupled plasma atomic emission spectroscopy, transmission electron microscopy with elemental mapping (TEM/EDS), X-ray photoelectron spectroscopy (XPS), and optical diffuse-reflectance spectroscopy. A small amount of water in acetone initiates the hydrolysis of a molybdenum cluster precursor with labile NO3- ligands, which are absent in the final composite, according to the XPS data. Intermediate hydrolyzed cluster forms anchor to the surface of h-BN nanosheets and promote growth of the insoluble compound [{Mo6I8}(H2O)2(OH)4]·yH2O as the final hydrolysis product. TEM/EDS proves that the cluster exists at the nanosheet surface in the form of an X-ray diffraction amorphous thin film. The samples obtained show high photocatalytic activity in the degradation of a model pollutant rhodamine B under UV- and visible-light irradiation. The materials retain their initial photocatalytic efficacy during at least six cycles without the need for recovery.

Detecting Proteomic Indicators to Distinguish Diabetic Nephropathy from Hypertensive Nephrosclerosis by Integrating Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging with High-Mass Accuracy Mass Spectrometry.

INTRODUCTION: Diabetic nephropathy (DN) and hypertensive nephrosclerosis (HN) represent the most common causes of chronic kidney disease (CKD) and many patients progress to -end-stage renal disease. Patients are treated primarily through the management of cardiovas-cular risk factors and hypertension; however patients with HN have a more favorable outcome. A noninvasive clinical approach to separate these two entities, especially in hypertensive patients who also have diabetes, would allow for targeted treatment and more appropriate resource allocation to those patients at the highest risk of CKD progression. Meth-ods: In this preliminary study, high-spatial-resolution matrix-assisted laser desorption/ion-ization (MALDI) mass spectrometry imaging (MSI) was integrated with high-mass accuracy MALDI-FTICR-MS and nLC-ESI-MS/MS analysis in order to detect tissue proteins within kidney biopsies to discriminate cases of DN (n = 9) from cases of HN (n = 9). RESULTS: Differences in the tryptic peptide profiles of the 2 groups could clearly be detected, with these becoming even more evident in the more severe histological classes, even if this was not evident with routine histology. In particular, 4 putative proteins were detected and had a higher signal intensity within regions of DN tissue with extensive sclerosis or fibrosis. Among these, 2 proteins (PGRMC1 and CO3) had a signal intensity that increased at the latter stages of the disease and may be associated with progression. DISCUSSION/CONCLUSION: This preliminary study represents a valuable starting point for a future study employing a larger cohort of patients to develop sensitive and specific protein biomarkers that could reliably differentiate between diabetic and hypertensive causes of CKD to allow for improved diagnosis, fewer biopsy procedures, and refined treatment approaches for clinicians.

Early Coaching to Increase Water Intake in CKD.

INTRODUCTION: In observational studies, increased water intake improves kidney function but not in adults with CKD stage 3 and more. CKD WIT trial has shown a nonsignificant gradual decline in kidney function after 1 year of coaching to increase water intake (CIWI) [1]. We propose that CIWI may benefit in CKD stage 1-2 (G1 and G2) and depends on functional renal functional reserve (RFR) [2, 3]. OBJECTIVE: Parallel-group randomized trial was aimed to determinate the effectiveness of CIWI dependence of estimated glomerular filtration rate (eGFR) stage and RFR in adults with CKD 1-2 stages. METHODS: CKD WIT trial was taken as the basis for prospective multicenter randomized trial named "Early Coaching to Increase Water Intake in CKD (ECIWIC)." The primary outcome was the change in kidney function by eGFR from baseline to 12 months. Secondary outcomes included 1-year change in urine albumin/Cr ratio, and patient-reported overall quality of health (QH) ranged from 0 (worst possible) to 10 (best possible). CIWI aimed to have the diuresis being 1.7-2 L. There were 4 groups with nondiet sodium restriction which consisted of 31 patients each: 2 groups with CKD G1 and CKD G2, undergoing CIWI and 2 others with CKD G1 and CKD G2 without CIWI (Fig. 1a). Overall checks were made at 0, 6, and 12 months. RFR evaluation was performed using 0.45% sodium chloride oral solution. RESULTS: Of our randomized 124 patients (mean age 53.2 years; men 83 [67%], 0 died), mean change in 24-h urine volume was 0.6 L per day in G1 with CIWI group and 0.5 L in G2. No statistically significant data on eGFR depending CIWI were obtained (Fig. 1b). However, the trend suggests that CIWI improves eGFR in CKD G1 (from 95 to 96 mL/min/1.73 m2) and preserves eGFR decline in CKD G2 (78-78). The QH values were also preserved (from 7 to 7 in G1 and G2 groups). Although coaching to maintain the same water intake did not preserve physiological and pathological eGFR decreasing in CKD G1-2 (G1 from 96 to 93, G2 from 76 to 73; t = 0.6, p = 0.29, and p ≤ 0.05 in all groups) and the QH was declined (from 7 to 6 in both groups). An individual analysis of the RFR has shown that patients with RFR more than 50% (G1 19 patients, 61%, and G2 13 patients, 42%) had reliable preservation of eGFR with its increase of 1.5 mL/min on CIWI, while patients with low functional renal reserve had a drop of eGFR at 1.1 mL/min/m2 within 12 months. Patients with low normal serum sodium levels have shown worse results on CIWI. CONCLUSIONS: With CKD G1, the CIWI leads to the preservation of the renal function with its increase of GFR per 1 mL/min/m2/per year in comparison with the same water intake. In CKD G2, the CIWI prevents physiological and pathological loss of renal function, and RFR above 50% aids restoration of eGFR both in CKD G1-2. ECIWIC trial demonstrates benefit of CIWI in patients with CKD 1-2 and preserved RFR.

Theoretical and experimental comparative study of the stability and phase transformations of sesquichalcogenides M2Q3 (M = Nb, Mo; Q = S, Se).

The extensive family of transition metal chalcogenides has been comprehensively investigated owing to their diverse useful properties. However, even among them, there are ones that have received comparatively less attention; in particular, these are molybdenum and niobium sulfides and selenides with the composition of M : Q = 2 : 3 (M = Mo, Nb; Q = S, Se). Mo or Nb chalcogenides with this stoichiometry may adopt one of two structures: (i) sesquichalcogenides M2Q3, where important structural elements are infinite metal chains, or (ii) self-intercalated compounds M1.33Q2, in which extra M atoms are inserted between MQ2 layers. Depending on the M-Q combination, in practice, either none, one, or both of them may exist. The reasons for chemical dissimilarity in the series of seemingly related compounds haven't been addressed until the present work. Here, we present the first generalized comparative study of these chalcogenides by quantum-chemical computations verified by laboratory experiments. High-temperature phases of Mo2S3 and Nb2Se3 may be stably isolated at room temperature, while "Nb2S3" and "Mo2Se3" had not been obtained, nor were they expected to exist from DFT data. The structure-determining motifs of sesquichalcogenides M2Q3 are metallic chains, and thus, apparently, if metal's electron deficiency (or excess) prevents the formation of M-M chains, then the M2Q3-type structure cannot form. If the metal has an adequate electron density and the structure does form at high temperature (as it happens for Mo2S3 and Nb2Se3), then it can be kinetically stabilized by quenching, and stored under laboratory conditions for long times. However, if Nb2Se3 is left to cool down slowly, it undergoes phase transition to iso-stoichiometric intercalate Nb1.333Se2, in good agreement with DFT predictions of the close values of their free energies. Isostructural intercalate Nb1.333S2 is found to be the only experimental product in the Nb-S system, in full accordance with DFT prediction. Effective stabilization of self-intercalated phases is provided by significant charge transfer from intercalated Nb atoms to the NbQ2 layers, as confirmed by DFT. The obtained data may serve to get insight into polymorphism of some less-studied transition metal chalcogenides and to promote their use for future functional materials.

Standardized pathology report for HER2 testing in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

Since the release of the DESTINY-Breast04 (DB-04) trial findings in June 2022, the field of pathology has seen a renaissance of HER2 as a predictive biomarker in breast cancer. The trial focused on patients with metastatic breast cancer who were classified as "HER2-low," i.e., those with immunohistochemistry (IHC) HER2 1 + or 2 + and negative in situ hybridization (ISH) results. The study revealed that treating these patients with trastuzumab deruxtecan (T-DXd) instead of the oncologist's chosen chemotherapy led to outstanding improvements in survival. This has challenged the existing binary HER2 pathological classification system, which categorized tumors as either positive (overexpression/amplification) or negative, as per the ASCO/CAP 2018 guideline reaffirmed by ASCO/CAP 2023 guideline update. Given that DB-04 excluded patients with HER2 IHC score 0 status, the results of the ongoing DB-06 trial may shed further light on the potential benefits of T-DXd therapy for these patients. Roughly half of all breast cancers are estimated to belong to the HER2-low category, which does not represent a distinct or specific subtype of cancer. Instead, it encompasses a diverse group of tumors that exhibit clinical, morphological, immunohistochemical, and molecular variations. However, HER2-low offers a distinctive biomarker status that identifies a specific therapeutic regimen (i.e., T-DXd) linked to a favorable prognosis in breast cancer. This unique association emphasizes the importance of accurately identifying these tumors. Differentiating between a HER2 IHC score 0 and score 1 + has not been clinically significant until now. To ensure accurate classification and avoid misdiagnosis, it is necessary to adopt standardized procedures, guidelines, and specialized training for pathologists in interpreting HER2 expression in the lower spectrum. Additionally, the utilization of artificial intelligence holds promise in supporting this endeavor. Here, we address the current state of the art and unresolved issues in assessing HER2-low status, with a particular emphasis on the score 0. We explore the dilemma surrounding the exclusion of HER2-zero patients from potentially beneficial therapy based on traditional HER2 testing. Additionally, we examine the clinical context, considering that DB-04 primarily involved heavily pretreated late-stage metastatic breast cancers. We also delve into emerging evidence suggesting that extrapolating HER2-low status from the original diagnosis may lead to misleading results. Finally, we provide recommendations for conducting high-quality testing and propose a standardized pathology report in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.

Early Breast Cancer Risk Assessment: Integrating Histopathology with Artificial Intelligence.

Effective risk assessment in early breast cancer is essential for informed clinical decision-making, yet consensus on defining risk categories remains challenging. This paper explores evolving approaches in risk stratification, encompassing histopathological, immunohistochemical, and molecular biomarkers alongside cutting-edge artificial intelligence (AI) techniques. Leveraging machine learning, deep learning, and convolutional neural networks, AI is reshaping predictive algorithms for recurrence risk, thereby revolutionizing diagnostic accuracy and treatment planning. Beyond detection, AI applications extend to histological subtyping, grading, lymph node assessment, and molecular feature identification, fostering personalized therapy decisions. With rising cancer rates, it is crucial to implement AI to accelerate breakthroughs in clinical practice, benefiting both patients and healthcare providers. However, it is important to recognize that while AI offers powerful automation and analysis tools, it lacks the nuanced understanding, clinical context, and ethical considerations inherent to human pathologists in patient care. Hence, the successful integration of AI into clinical practice demands collaborative efforts between medical experts and computational pathologists to optimize patient outcomes.

PD-L1 testing in metastatic triple-negative breast cancer: Interobserver and interplatform reproducibility of CE-IVD assays for CPS and IC scores.

PD-L1 test is recommended in different types of tumors to select patients eligible for immune checkpoint inhibitors (ICI) therapy. Several factors make this test challenging in metastatic triple-negative breast cancer (mTNBC). Different assays and platforms are available, each associated with distinct scoring systems and threshold values specific to the ICI compound used, i.e. CPS≥10 for pembrolizumab and IC ≥ 1 % for atezolizumab. Our objective was to assess the consistency of PD-L1 testing in mTNBC by examining interobserver and interassay reproducibility. We assessed n = 60 mTNBC samples for PD-L1 testing using 22C3 pharmDx assay on a Dako Autostainer Link 48 and VENTANA PD-L1 (SP263) on a Ventana BenchMark Ultra. Additionally, a subset of n = 19 samples was tested using the SP142 assay, also on the Ventana BenchMark Ultra. CPS with both 22C3 and SP263 was independently evaluated by five pathologists, all certified PD-L1 trainers. The IC with SP142 was assessed by three of these pathologists, who have particular expertise in breast pathology. Following the computation of the intraclass correlation coefficient (ICC) for each assay and their respective thresholds, we assessed the agreement between different raters and assays using Fleiss's κ, with a 95 % confidence interval (CI). Overall, we observed a significant (p < 0.001) ICC with both CPS assays [22C3 = 0.939 (CI:0.913-0.96); SP263 = 0.972 (CI:0.96-0.982); combined 22C3-SP263 = 0.909 (CI:0.874-0.938)]. Fleiss's κ confirmed an almost perfect agreement among pathologists and assays: 22C3 = 0.938 (CI:0.857-1.018); SP263 = 0.972 (CI:0.890-1.052); combined 22C3-SP263 = 0.907 (CI:0.869-0.945). Perfect inter-rater agreement was reached considering IC. This study establishes the reliability of assessing CPS in mTNBC using either the 22C3 pharmDx, as employed in the KEYNOTE studies, or the VENTANA SP263 assay. Each assay must be used on its designated platform, namely the Dako for 22C3 pharmDx and the Ventana for VENTANA SP263. It is important to remark that CPS and IC identify different patient cohorts and, therefore, are not interchangeable.

Proteomic insights into mental health status: plasma markers in young adults.

Global emphasis on enhancing prevention and treatment strategies necessitates an increased understanding of the biological mechanisms of psychopathology. Plasma proteomics is a powerful tool that has been applied in the context of specific mental disorders for biomarker identification. The p-factor, also known as the "general psychopathology factor", is a concept in psychopathology suggesting that there is a common underlying factor that contributes to the development of various forms of mental disorders. It has been proposed that the p-factor can be used to understand the overall mental health status of an individual. Here, we aimed to discover plasma proteins associated with the p-factor in 775 young adults in the FinnTwin12 cohort. Using liquid chromatography-tandem mass spectrometry, 13 proteins with a significant connection with the p-factor were identified, 8 of which were linked to epidermal growth factor receptor (EGFR) signaling. This exploratory study provides new insight into biological alterations associated with mental health status in young adults.

A Phase 3 Prospective Randomized Trial to Evaluate the Impact of Augmented Reality During Robot-assisted Radical Prostatectomy on the Rates of Postoperative Surgical Margins: A Clinical Trial Protocol.

We designed a phase 3, prospective, randomized trial to evaluate the impact of augmented reality and augmented reality frozen section analysis in reducing the rates of positive surgical margins after robot-assisted radical prostatectomy.

Malignancies in Patients with Celiac Disease: Diagnostic Challenges and Molecular Advances.

Celiac disease (CD) is a multiorgan autoimmune disorder of the chronic intestinal disease group characterized by duodenal inflammation in genetically predisposed individuals, precipitated by gluten ingestion. The pathogenesis of celiac disease is now widely studied, overcoming the limits of the purely autoimmune concept and explaining its hereditability. The genomic profiling of this condition has led to the discovery of numerous genes involved in interleukin signaling and immune-related pathways. The spectrum of disease manifestations is not limited to the gastrointestinal tract, and a significant number of studies have considered the possible association between CD and neoplasms. Patients with CD are found to be at increased risk of developing malignancies, with a particular predisposition of certain types of intestinal cancer, lymphomas, and oropharyngeal cancers. This can be partially explained by common cancer hallmarks present in these patients. The study of gut microbiota, microRNAs, and DNA methylation is evolving to find the any possible missing links between CD and cancer incidence in these patients. However, the literature is extremely mixed and, therefore, our understanding of the biological interplay between CD and cancer remains limited, with significant implications in terms of clinical management and screening protocols. In this review article, we seek to provide a comprehensive overview of the genomics, epigenomics, and transcriptomics data on CD and its relation to the most frequent types of neoplasms that may occur in these patients.