A new genus of Phlugidini (Insecta, Orthoptera, Tettigoniidae, Meconematinae) from the Atlantic Forest.

In the Neotropical Region, Phlugidini is the most diverse tribe of Meconematinae, with 62 valid species in 10 genera, six of them recorded from Brazil. Brachyphlugis gen. nov. is described herein based on two new species, Brachyphlugis longicercalis sp. nov. (type species) and Brachyphlugis curvata sp. nov., collected in Parque Nacional do Itatiaia and Reserva Biológica do Tinguá, both in the Atlantic Forest of Rio de Janeiro State. The new genus is most similar to Neophlugis, but it can be distinguished from the latter and other neotropical Phlugidini by the following combination of characteristics: (1) mandibles symmetrical; (2) tegmen extending beyond metanotum; (3) pronotal disk posterior margin convex; (4) tenth tergite strongly projected and downcurved; (5) male cercus pronounced with a larger base and acuminate apex; (6) paraproct modified with developed spine; (7) male subgenital plate with two distolateral projections connected to a pair of styles; and (8) female subgenital plate wider than long, posterior margin with two projections. An up-to-date key to neotropical Phlugidini genera is also provided.

A Pooled Analysis of Trastuzumab Deruxtecan in Patients With HER2-Positive Metastatic Breast Cancer With Brain Metastases.

BACKGROUND: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with HER2-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. PATIENTS AND METHODS: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. Endpoints included intracranial objective response rate (ORR; complete or partial response in brain) per blinded independent central review (BICR) by RECIST v1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. RESULTS: 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those who were treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median (95% CI) intracranial DoR was 12.3 months (9.1-17.9 months), and for those with untreated/active BMs it was 17.5 months (13.6-31.6 months). The median (95% CI) CNS-PFS and OS was 12.3 months (11.1-13.8 months) and not reached (22.1 months-not estimable [NE]) in those with treated/stable BMs, and 18.5 months (13.6-23.3 months) and 30.2 months (21.3 months-NE) in those with untreated/active BMs, respectively. Drug-related TEAEs grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. CONCLUSIONS: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

Recent advances in microalgae encapsulation techniques for biomedical applications.

Microalgae are microorganisms that are rich in bioactive compounds, including pigments, proteins, lipids, and polysaccharides. These compounds can be utilized for a number of biomedical purposes, including drug delivery, wound healing, and tissue engineering. Nevertheless, encapsulating microalgae cells and microalgae bioactive metabolites is vital to protect them and prevent premature degradation. This also enables the development of intelligent controlled release strategies for the bioactive compounds. This review outlines the most employed encapsulation techniques for microalgae, with a particular focus on their biomedical applications. These include ionic gelation, oil-in-water emulsions, and spray drying. Such techniques have been widely explored, due to their ability to protect sensitive compounds from degradation, enhance their stability, extend their shelf life, mask undesirable tastes or odours, control the release of bioactive compounds, and enable targeted delivery to specific sites within the body or environment. Moreover, a patent landscape analysis is also provided, allowing an overview of the microalgae encapsulation technology development applied to a variety of fields, including pharmaceuticals, cosmetics, food, and agriculture.

Personalizing progressive changes to brain structure in Alzheimer's disease using normative modeling.

INTRODUCTION: Neuroanatomical normative modeling captures individual variability in Alzheimer's disease (AD). Here we used normative modeling to track individuals' disease progression in people with mild cognitive impairment (MCI) and patients with AD. METHODS: Cortical and subcortical normative models were generated using healthy controls (n ≈ 58k). These models were used to calculate regional z scores in 3233 T1-weighted magnetic resonance imaging time-series scans from 1181 participants. Regions with z scores < -1.96 were classified as outliers mapped on the brain and summarized by total outlier count (tOC). RESULTS: tOC increased in AD and in people with MCI who converted to AD and also correlated with multiple non-imaging markers. Moreover, a higher annual rate of change in tOC increased the risk of progression from MCI to AD. Brain outlier maps identified the hippocampus as having the highest rate of change. DISCUSSION: Individual patients' atrophy rates can be tracked by using regional outlier maps and tOC. HIGHLIGHTS: Neuroanatomical normative modeling was applied to serial Alzheimer's disease (AD) magnetic resonance imaging (MRI) data for the first time. Deviation from the norm (outliers) of cortical thickness or brain volume was computed in 3233 scans. The number of brain-structure outliers increased over time in people with AD. Patterns of change in outliers varied markedly between individual patients with AD. People with mild cognitive impairment whose outliers increased over time had a higher risk of progression from AD.

Dissecting Heterogeneity in Functional Network Connectivity Aberrations in Antipsychotic Medication-Naïve First Episode Psychosis Patients - A Normative Modeling Study.

Importance: While there is a general consensus that functional connectome pathology is a key mechanism underlying psychosis spectrum disorders, the literature is plagued with inconsistencies and translation into clinical practice is non-existent. This is perhaps because group-level findings may not be accurate reflections of pathology at the individual patient level. Objective: To characterize inter-individual heterogeneity in functional networks and investigate if normative values can be leveraged to identify biologically less heterogeneous subgroups of patients. Design Setting and Participants: We used data collected in a case-control study conducted at the University of Alabama at Birmingham (UAB). We recruited antipsychotic medication-naïve first-episode psychosis patients from UAB outpatient, inpatient, and emergency room settings. Main Outcomes and Measures: Individual-level patterns of deviations from a normative reference range in resting-state functional networks using the Yeo-17 atlas for parcellations. Results: Statistical analyses included 108 medication-naïve first-episode psychosis patients. We found that there is a high level of inter-individual heterogeneity in resting-state network connectivity deviations from the normative reference range. Interestingly 48% of patients did not have any functional connectivity deviations, and no more than 11.1% of patients shared functional deviations between the same regions of interest. In a post hoc analysis, we grouped patients based on deviations into four theoretically possible groups. We discovered that all four groups do exist in our experimental data and showed that subgroups based on deviation profiles were significantly less heterogeneous compared to the overall group (positive deviation group: z= -2.88, p = 0.002; negative deviation group: z= -3.36, p<0.001). Conclusions and Relevance: Our findings experimentally demonstrate that there is a high level of inter-individual heterogeneity in resting-state network pathology in first-episode psychosis patients which support the idea that group-level findings are not accurate reflections of pathology at the individual level. We also demonstrated that normative functional connectivity deviations may have utility for identifying biologically less heterogeneous subgroups of patients, even though they are not distinguishable clinically. Our findings constitute a significant step towards making precision psychiatry a reality, where patients are selected for treatments based on their individual biological characteristics. KEY POINTS: Question: How heterogeneous is individual-level resting-state functional network pathology in patients suffering from a first psychotic episode? Can normative reference values in functional network connectivity be leveraged to identify biologically more homogenous subgroups of patients?Findings: We report that functional network pathology is highly heterogeneous, with no more than 11% of patients sharing functional deviations between the same regions of interest.Meaning: Normative modeling is a tool that can map individual neurobiological differences and enables the classification of a clinically heterogenous patient group into subgroups that are neurobiologically less heterogenous.

Co-administration of PEGylated Apohemoglobin and Haptoglobin can Limit Vascular Dysfunction in the Microcirculation and Prevent Acute Inflammation.

Unfortunately, during pathological conditions resulting in chronic hemolysis cell-free hemoglobin (Hb) is released into the circulation which releases free heme, resulting in several complications. One approach to prevent these toxicities is administration of supplemental scavenger proteins, haptoglobin (Hp) and hemopexin (Hpx). The goal of this body of work is to objectively measure levels of vascular reactivity and inflammatory profiles after an infusion of acellular hemoglobin in animals that were given a co-administration of PEGylated human apohemoglobin (PEG-apoHb), a hemopexin (Hpx)-mimetic that can scavenge free heme from hemoglobin, together with human plasma-derived Hp that can scavenge dimerized Hb. Utilizing intravital microscopy, Golden Syrian hamsters instrumented with a dorsal window chamber were used to evaluate the in vivo effects of 4 experimental groups that were then challenged with a hypovolemic injection (10% of the animal's blood volume) of human Hb (hHb, 5 g/dL). The four experimental groups consisted of: 1) lactated Ringer's (control), 2) PEG-apoHb only, 3) Hp only, and 4) PEG-apoHb + Hp. The microvascular hemodynamics (diameter and flow) in arterioles and venules were recorded at baseline, 20 minutes after treatment, and 20 minutes after hHb challenge. Systemic parameters (blood pressure and heart rate), blood gases (pH, pCO2, and pO2), blood parameters (Hb concentration and hematocrit), and multiorgan functionality/ inflammation were also measured. Our results suggest that co-administration of PEG-apoHb + Hp as a booster prior to the infusion of acellular hemoglobin significantly prevented vasoconstriction in the microcirculation, significantly increased the number of functional capillaries, and significantly reduced inflammation.

ESMO Recommendations on clinical reporting of genomic test results for solid cancers.

BACKGROUND: Genomic tumour profiling has a crucial role in the management of patients with solid cancers, as it helps selecting and prioritising therapeutic interventions based on prognostic and predictive biomarkers, as well as identifying markers of hereditary cancers. Harmonised approaches to interpret the results of genomic testing are needed to support physicians in their decision making, prevent inequalities in precision medicine and maximise patient benefit from available cancer management options. METHODS: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group assembled a group of international experts to propose recommendations for preparing clinical genomic reports for solid cancers. These recommendations aim to foster best practices in integrating genomic testing within clinical settings. After review of available evidence, several rounds of surveys and focused discussions were conducted to reach consensus on the recommendation statements. Only consensus recommendations were reported. Recommendation statements were graded in two tiers based on their clinical importance: level A (required to maintain common standards in reporting) and level B (optional but necessary to achieve ideal practice). RESULTS: Genomics reports should present key information in a front page(s) followed by supplementary information in one or more appendices. Reports should be structured into sections: (i) patient and sample details; (ii) assay and data analysis characteristics; (iii) sample-specific assay performance and quality control; (iv) genomic alterations and their functional annotation; (v) clinical actionability assessment and matching to potential therapy indications; and (vi) summary of the main findings. Specific recommendations to prepare each of these sections are made. CONCLUSIONS: We present a set of recommendations aimed at structuring genomics reports to enhance physician comprehension of genomic profiling results for solid cancers. Communication between ordering physicians and professionals reporting genomic data is key to minimise uncertainties and to optimise the impact of genomic tests in patient care.

Exploring Recent Changes to the New Urology Residency Match.

INTRODUCTION: This study assesses the effects of the recent changes to the urology residency match process. METHODS: We emailed an anonymous, multiple-choice survey to each candidate who applied to any of our 3 urology programs for the 2024 Urology Residency Match. RESULTS: Of the 433 candidates invited, 146 (33.7%) completed the survey. Of the 133 respondents who matched, 38.3% matched where they did an away subinternship (sub-I), 20.3% matched with their home program, and 91.0% matched with a program where they sent a preference signal (PS); only 8 respondents (6.0%) matched with a program where they did not complete a sub-I or send a PS. Of the 4 candidates who did not take Step 2 before submitting their application, only 1 matched. The 126 applicants who completed 3 or more sub-Is, including the home sub-I, had a higher match rate (95.2%) than the 20 applicants who completed 1 or 2 (65.0%, P < .0005). Disclosing any geographic preferences was associated with a decreased probability of matching (relative risk = 0.89, P < .05). CONCLUSIONS: Taking Step 2 before submitting applications and completing 3 or more sub-Is were both correlated with a higher match rate. Geographic signaling was correlated with a lower match rate. There was little benefit to applying to programs outside of those where the applicant had completed a sub-I or sent a PS. Future candidates should consider these findings early in the application process. These findings should be taken into consideration when making future changes to the application process.

Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis.

OBJECTIVE: To evaluate the comparative effectiveness and acceptability of oral monotherapy using psychedelics and escitalopram in patients with depressive symptoms, considering the potential for overestimated effectiveness due to unsuccessful blinding. DESIGN: Systematic review and Bayesian network meta-analysis. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, ClinicalTrial.gov, and World Health Organization's International Clinical Trials Registry Platform from database inception to 12 October 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials on psychedelics or escitalopram in adults with depressive symptoms. Eligible randomised controlled trials of psychedelics (3,4-methylenedioxymethamphetamine (known as MDMA), lysergic acid diethylamide (known as LSD), psilocybin, or ayahuasca) required oral monotherapy with no concomitant use of antidepressants. DATA EXTRACTION AND SYNTHESIS: The primary outcome was change in depression, measured by the 17-item Hamilton depression rating scale. The secondary outcomes were all cause discontinuation and severe adverse events. Severe adverse events were those resulting in any of a list of negative health outcomes including, death, admission to hospital, significant or persistent incapacity, congenital birth defect or abnormality, and suicide attempt. Data were pooled using a random effects model within a Bayesian framework. To avoid estimation bias, placebo responses were distinguished between psychedelic and antidepressant trials. RESULTS: Placebo response in psychedelic trials was lower than that in antidepression trials of escitalopram (mean difference -3.90 (95% credible interval -7.10 to -0.96)). Although most psychedelics were better than placebo in psychedelic trials, only high dose psilocybin was better than placebo in antidepression trials of escitalopram (mean difference 6.45 (3.19 to 9.41)). However, the effect size (standardised mean difference) of high dose psilocybin decreased from large (0.88) to small (0.31) when the reference arm changed from placebo response in the psychedelic trials to antidepressant trials. The relative effect of high dose psilocybin was larger than escitalopram at 10 mg (4.66 (95% credible interval 1.36 to 7.74)) and 20 mg (4.69 (1.64 to 7.54)). None of the interventions was associated with higher all cause discontinuation or severe adverse events than the placebo. CONCLUSIONS: Of the available psychedelic treatments for depressive symptoms, patients treated with high dose psilocybin showed better responses than those treated with placebo in the antidepressant trials, but the effect size was small. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023469014.

Zika virus capsid protein closed structure modulates binding to host lipid systems.

Zika virus (ZIKV), a mosquito-borne Flavivirus of international concern, causes congenital microcephaly in newborns and Guillain-Barré syndrome in adults. ZIKV capsid (C) protein, one of three key structural proteins, is essential for viral assembly and encapsidation. In dengue virus, a closely related flavivirus, the homologous C protein interacts with host lipid systems, namely intracellular lipid droplets, for successful viral replication. Here, we investigate ZIKV C interaction with host lipid systems, showing that it binds host lipid droplets but, contrary to expected, in an unspecific manner. Contrasting with other flaviviruses, ZIKV C also does not bind very-low density-lipoproteins. Comparing with other Flavivirus, capsid proteins show that ZIKV C structure is particularly thermostable and seems to be locked into an auto-inhibitory conformation due to a disordered N-terminal, hence blocking specific interactions and supporting the experimental differences observed. Such distinct structural features must be considered when targeting capsid proteins in drug development.

Multiscale heterogeneity of white matter morphometry in psychiatric disorders.

Background: Inter-individual variability in neurobiological and clinical characteristics in mental illness is often overlooked by classical group-mean case-control studies. Studies using normative modelling to infer person-specific deviations of grey matter volume have indicated that group means are not representative of most individuals. The extent to which this variability is present in white matter morphometry, which is integral to brain function, remains unclear. Methods: We applied Warped Bayesian Linear Regression normative models to T1-weighted magnetic resonance imaging data and mapped inter-individual variability in person-specific white matter volume deviations in 1,294 cases (58% male) diagnosed with one of six disorders (attention-deficit/hyperactivity, autism, bipolar, major depressive, obsessive-compulsive and schizophrenia) and 1,465 matched controls (54% male) recruited across 25 scan sites. We developed a framework to characterize deviation heterogeneity at multiple spatial scales, from individual voxels, through inter-regional connections, specific brain regions, and spatially extended brain networks. Results: The specific locations of white matter volume deviations were highly heterogeneous across participants, affecting the same voxel in fewer than 8% of individuals with the same diagnosis. For autism and schizophrenia, negative deviations (i.e., areas where volume is lower than normative expectations) aggregated into common tracts, regions and large-scale networks in up to 35% of individuals. Conclusions: The prevalence of white matter volume deviations was lower than previously observed in grey matter, and the specific location of these deviations was highly heterogeneous when considering voxel-wise spatial resolution. Evidence of aggregation within common pathways and networks was apparent in schizophrenia and autism but not other disorders.

Social Cognition and Functional Connectivity in Early and Chronic Schizophrenia.

BACKGROUND: Individuals with schizophrenia (SZ) experience impairments in social cognition that contribute to poor functional outcomes. However, mechanisms of social cognitive dysfunction in SZ remain poorly understood, which impedes the design of novel interventions to improve outcomes. This pre-registered project (https://doi.org/10.17605/OSF.IO/JH5FC) examines the representation of social cognition in the brain's functional architecture across early and chronic SZ. METHODS: The study contains two parts: a confirmatory and an exploratory portion. In the confirmatory portion, we identified resting-state connectivity disruptions evident in early and chronic SZ. We performed a connectivity analysis using regions associated with social cognitive dysfunction in early and chronic SZ to test whether aberrant connectivity observed in chronic SZ (N=47; HC=52) was also present in early SZ (N=71, HC=47). In the exploratory portion, we assessed the out-of-sample generalizability and precision of predictive models of social cognition. We used machine learning to predict social cognition and established generalizability with out-of-sample testing and confound control. RESULTS: Results reveal decreases between left inferior frontal gyrus and intraparietal sulcus in early and chronic SZ, which are significantly associated with social and general cognition and global functioning in chronic SZ and with general cognition and global functioning in early SZ. Predictive modeling reveals the importance of out-of-sample evaluation and confound control. CONCLUSION: This work provides insights into the functional architecture in early and chronic SZ and suggests that IFG-IPS connectivity could be a prognostic biomarker of social impairments and a target for future interventions (e.g. neuromodulation) focused on improved social functioning.

Integrative Transcriptomic and Single-Cell Protein Characterization of Colorectal Carcinoma Delineates Distinct Tumor Immune Microenvironments Associated with Overall Survival.

Colorectal carcinoma (CRC) is a heterogeneous group of tumors with varying therapeutic response and prognosis, and evidence suggests the tumor immune microenvironment (TIME) plays a pivotal role. Using advanced molecular and spatial biology technologies, we aimed to evaluate the TIME in patients with CRC to determine whether specific alterations in the immune composition correlated with prognosis. We identified primary and metastatic tumor samples from 31 consented patients, which were profiled with whole-exome sequencing and bulk RNA-seq. Immune cell deconvolution followed by gene set enrichment analysis and unsupervised clustering was performed. A subset of tumors underwent in situ analysis of the TIME spatial composition at single-cell resolution through Imaging Mass Mass Cytometry. Gene set enrichment analysis revealed two distinct groups of advanced CRC, one with an immune activated phenotype and the other with a suppressed immune microenvironment. The activated TIME phenotype contained increased Th1 cells, activated dendritic cells, tertiary lymphoid structures, and higher counts of CD8+ T cells whereas the inactive or suppressed TIME contained increased macrophages and a higher M2/M1 ratio. Our findings were further supported by RNA-seq data analysis from the TCGA CRC database, in which unsupervised clustering also identified two separate groups. The immunosuppressed CRC TIME had a lower overall survival probability (HR 1.66, p=0.007). This study supports the pertinent role of the CRC immune microenvironment in tumor progression and patient prognosis. We characterized the immune cell composition to better understand the complexity and vital role that immune activity states of the TIME play in determining patient outcome.

A bio-behavioral model of systemic inflammation at breast cancer diagnosis and fatigue of clinical importance 2 years later.

BACKGROUND: We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance 2 years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation. PATIENTS AND METHODS: Women with stage I-III hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance [European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 ≥40/100] 2 years after diagnosis (year 2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers [interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, interferon γ, IL-1 receptor antagonist, tumor necrosis factor-α, and C-reactive protein], and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling. RESULTS: Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year 2. High pre-treatment levels of IL-6 (quartile 4 versus 1) were associated with global CRF at year 2 [adjusted odds ratio (aOR): 2.06 (95% confidence interval [CI] 1.40-3.03); P = 0.0002; area under the receiver operating characteristic curve = 0.74]. Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese [62.4%; mean body mass index 28.0 (standard deviation 6.3 kg/m2)] and physically inactive (53.5% did not meet World Health Organization recommendations). Clinical and behavioral associations with CRF at year 2 included pre-treatment CRF [aOR versus no pre-treatment CRF: 3.99 (95% CI 2.81-5.66)], younger age [aOR per 1-year decrement: 1.02 (95% CI 1.01-1.03)], current tobacco smoking [aOR versus never: 1.81 (95% CI 1.26-2.58)], and worse insomnia or pain [aOR per 10-unit increment: 1.08 (95% CI 1.04-1.13), and 1.12 (95% CI 1.04-1.21), respectively]. Secondary analyses indicated additional associations of IL-2 [aOR per log-unit increment: 1.32 (95% CI 1.03-1.70)] and IL-10 [0.73 (95% CI 0.57-0.93)] with global CRF and of C-reactive protein [1.42 (95% CI 1.13-1.78)] with cognitive CRF at year 2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF. CONCLUSIONS: This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance 2 years later among a large prospective sample of survivors of breast cancer.

Role of myocardial microRNAs in the long-term ventricular remodelling of patients with aortic stenosis.

Aims: We hypothesize that miRs are key players in the dynamics of the hypertrophy phenotype in aortic stenosis (AS) patients. In our study, we aimed to identify the transcriptional patterns (protein-coding transcripts and miRs) from myocardial sample biopsies that could be associated with the absence of left ventricular (LV) mass regression after aortic valve replacement (AVR) in patients with severe AS and LV hypertrophy. Methods and results: We prospectively included 40 patients with severe AS, LV hypertrophy, and preserved ejection fraction undergoing AVR. Myocardial biopsies obtained during surgery were analysed for transcriptomic analysis performed by next-generation sequencing. At a 1-year follow-up, no hypertrophy reversal was observed in about half of the patients in the absence of patient-prosthesis mismatch and prosthesis dysfunction of uncontrolled hypertension. Predictors of mass regression were assessed from clinical, echocardiographic, and biochemical variables as well as from 300 miRs obtained from myocardial specimens, allowing the identification 29 differentially expressed. miR-4709-3p was found as a positive independent predictor of hypertrophy regression together with high-sensitivity troponin T (cTNT-hs) as a negative predictor. Gene transcripts RFX1, SIX5, MAPK8IF3, and PKD1 were predicted as simultaneous targets of five upregulated miRs suggesting its importance in LV hypertrophy. Conclusion: In our cohort, tissue miR-4709-3p and cTNT-hs were independent predictors of hypertrophy regression. The hypertrophy reversal process will likely depend from a complex network where miRNAs may have an important role, allowing a potential opportunity for therapy.

The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development.

BACKGROUND: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. METHODS: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. RESULTS: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. CONCLUSION: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted.

Degree of PEGylatation of Lumbricus terrestris Hemoglobin Improves Microcirculatory Blood Flow but Increases the Rate of Auto-Oxidation.

INTRODUCTION: The demand for red blood cells (RBCs) is on the rise due to the increasing diagnosis of chronic diseases such as sickle cell anemia, malaria, and thalassemia. Despite many commercial attempts, there are no U.S. FDA-approved artificial RBCs for use in humans. Existing RBC substitutes have employed various strategies to transport oxygen, extend the circulation time, and reduce organ toxicity, but none have replicated the natural protective mechanisms of RBCs, which prevent hemoglobin (Hb) dimerization and heme iron oxidation. Lumbricus terrestris (earthworm) erythrocruorin (LtEc) is a naturally occurring extracellular hemoglobin (Hb) with promising attributes: large molecular diameter (30 nm), high molecular weight (3.6 MDa), low auto-oxidation rate, and limited nitric oxide-scavenging properties. These characteristics make LtEc an ideal candidate as an RBC substitute. However, LtEc has a significant drawback, its short circulatory half-life. To address this issue, we explored thiol-mediated surface PEGylation of LtEc (PEG-LtEc) at varying polyethylene glycol (PEG) surface coverages. Increasing PEG surface coverage beyond 40% destabilizes LtEc into smaller subunits that are 1/12th the size of LtEc. Therefore, we evaluated two PEG surface coverage options: PEG-LtEc-0.2 (20% PEGylation) and PEG-LtEc-1.0 (100% PEGylation). METHODS: We conducted experiments using golden Syrian hamsters with dorsal window chambers and catheters to assess the efficacy of these solutions. We measured microvascular parameters, organ function, cerebral blood flow, circulation time, mean arterial pressure, heart rate, and blood gases and performed histology to screen for toxicity. CONCLUSION: Our findings indicate that both PEG-LtEc molecules offer significant benefits in restoring microvascular parameters, organ function, cerebral blood flow, and circulation time compared to LtEc alone. Notably, PEG-LtEc-1.0 showed superior microvascular perfusion, although it exhibited a higher rate of auto-oxidation compared to PEG-LtEc-0.2. These results underscore the advantages of PEGylation in terms of tissue perfusion and organ health while highlighting its limitations.

Dissecting task-based fMRI activity using normative modelling: an application to the Emotional Face Matching Task.

Functional neuroimaging has contributed substantially to understanding brain function but is dominated by group analyses that index only a fraction of the variation in these data. It is increasingly clear that parsing the underlying heterogeneity is crucial to understand individual differences and the impact of different task manipulations. We estimate large-scale (N = 7728) normative models of task-evoked activation during the Emotional Face Matching Task, which enables us to bind heterogeneous datasets to a common reference and dissect heterogeneity underlying group-level analyses. We apply this model to a heterogenous patient cohort, to map individual differences between patients with one or more mental health diagnoses relative to the reference cohort and determine multivariate associations with transdiagnostic symptom domains. For the face>shapes contrast, patients have a higher frequency of extreme deviations which are spatially heterogeneous. In contrast, normative models for faces>baseline have greater predictive value for individuals' transdiagnostic functioning. Taken together, we demonstrate that normative modelling of fMRI task-activation can be used to illustrate the influence of different task choices and map replicable individual differences, and we encourage its application to other neuroimaging tasks in future studies.

Tangential flow filtration facilitated fractionation of polymerized human serum albumin: Insights into the effects of molecular size on biophysical properties.

Human serum albumin (HSA) is currently used as a plasma expander (PE) to increase blood volume during hypovolemic conditions, such as blood loss. However, its effectiveness is suboptimal in septic shock and burn patients due to their enhanced endothelial permeability, resulting in HSA extravasation into the tissue space leading to edema, and deposition of toxic HSA-bound metabolites. Hence, to expand HSA's applicability toward treating patients with compromised endothelial permeability, HSA has been previously polymerized to increase its molecular size thus compartmentalizing the polymerized HSA (PolyHSA) molecules in the vascular space. Previous studies bracketed PolyHSA between 100 kDa and 0.2 µm. In this research, PolyHSA was synthesized at two cross-link densities 43:1 and 60:1 (i.e., molar ratios of glutaraldehyde to HSA) and subsequently fractionated via tangential flow filtration (TFF) into two narrower brackets: bracket A (500 kDa and 0.2 µm) and bracket B (50-500 kDa). PolyHSA within the same size bracket at different cross-link densities exhibited similar solution viscosity, zeta potential, and osmolality but differed in hydrodynamic diameter. At the same cross-link density, the PolyHSA A bracket showed higher viscosity, lowered zeta potential, and a larger hydrodynamic diameter compared with the PolyHSA B bracket while maintaining osmolality. Interestingly, PolyHSA 43:1 B, PolyHSA 60:1 A, and PolyHSA 60:1 B brackets exhibited colloid osmotic pressure similar to HSA, indicating their potential to serve as PEs.

Tangential flow filtration-facilitated purification of human red blood cell membrane fragments and its preferential use in removing unencapsulated material from resealed red blood cell ghosts compared to centrifugation.

The biodistribution of many therapeutics is controlled by the immune system. In addition, some molecules are cytotoxic when not encapsulated inside of larger cellular structures, such as hemoglobin (Hb) encapsulation inside of red blood cells (RBCs). To counter immune system recognition and cytotoxicity, drug delivery systems based on red blood cell membrane fragments (RBCMFs) have been proposed as a strategy for creating immunoprivileged therapeutics. However, the use of RBCMFs for drug delivery applications requires purification of RBCMFs at large scale from lysed RBCs free of their intracellular components. In this study, we were able to successfully use tangential flow filtration (TFF) to remove >99% of cell-free Hb from lysed RBCs at high concentrations (30%-40% v/v), producing RBCMFs that were 2.68 ± 0.17 µm in diameter. We were also able to characterize the RBCMFs more thoroughly than prior work, including measurement of particle zeta potential, along with individual TFF diacycle data on the cell-free Hb concentration in solution and time per diacycle, as well as concentration and size of the RBCMFs. In addition to purifying RBCMFs from lysed RBCs, we utilized a hypertonic solution to reseal purified RBCMFs encapsulating a model protein (Hb) to yield resealed Hb-encapsulated RBC ghosts (Hb-RBCGs). TFF was then compared against centrifugation as an alternative method for removing unencapsulated Hb from Hb-RBCGs, and the effects that each washing method on the resulting Hb-RBCG biophysical properties was assessed.