Identification of blood lipid markers of docetaxel treatment in prostate cancer patients.

Docetaxel is commonly used for treatment of castration-resistant prostate cancer. Unfortunately, many prostate cancer patients develop resistance to docetaxel. Clinical markers less invasive than biopsies, such as blood samples, would be ideal for monitoring and predicting patient treatment outcomes to docetaxel. Lipid alterations are often associated with the progression of many cancers, including prostate cancer. This study investigated the use of lipids from whole blood as clinical markers for docetaxel resistance in a small cohort of patients with prostate cancer. Qualitative lipidomics was performed by liquid chromatography-tandem mass spectrometry to assess the lipid composition of prostate cancer cells exposed to docetaxel as well as whole blood from prostate cancer patients before, during and after docetaxel treatment. Three patients had castration resistant prostate cancer, three had castration sensitive prostate cancer, and four had de novo prostate cancer during the extent of the study. Mean decrease accuracy and classical univariate receiving operating characteristic curve analyses were performed to identify potential biomarkers. In total, 245 and 221 altered lipids were identified from a second stage of mass spectrometry analysis of prostate cancer cells and clinical blood samples, respectively. Both models indicated that docetaxel treatment altered ether-linked phosphatidylcholines, lysophosphatidylcholine, diacylglycerols, ceramides, hexosylceramides, and sphingomyelins. The results also indicated several lipid changes were associated with sphingolipid signaling and metabolism, and glycerophospholipid metabolism. Collectively, these data suggest the potential usage of identified lipid species as indicators of docetaxel resistance in prostate cancer.

Interfacility Patient Transfers During COVID-19 Pandemic: Mixed-Methods Study.

Introduction: The United States lacks a national interfacility patient transfer coordination system. During the coronavirus 2019 (COVID-19) pandemic, many hospitals were overwhelmed and faced difficulties transferring sick patients, leading some states and cities to form transfer centers intended to assist sending facilities. In this study we aimed to explore clinician experiences with newly implemented transfer coordination centers. Methods: This mixed-methods study used a brief national survey along with in-depth interviews. The American College of Emergency Physicians Emergency Medicine Practice Research Network (EMPRN) administered the national survey in March 2021. From September-December 2021, semi-structured qualitative interviews were conducted with administrators and rural emergency clinicians in Arizona and New Mexico, two states that started transfer centers during COVID-19. Results: Among 141 respondents (of 765, 18.4% response rate) to the national EMPRN survey, only 30% reported implementation or expansion of a transfer coordination center during COVID-19. Those with new transfer centers reported no change in difficulty of patient transfers during COVID-19 while those without had increased difficulty. The 17 qualitative interviews expanded upon this, revealing four major themes: 1) limited resources for facilitating transfers even before COVID-19; 2) increased number of and distance to transfer partners during the COVID-19 pandemic; 3) generally positive impacts of transfer centers on workflow, and 4) the potential for continued use of centers to facilitate transfers. Conclusion: Transfer centers may have offset pandemic-related transfer challenges brought on by the COVID-19 pandemic. Clinicians who frequently need to transfer patients may particularly benefit from ongoing access to such transfer coordination services.

Citrullination, a novel post-translational modification of elastin, is involved in COPD Pathogenesis.

Elastin is an extracellular matrix protein (ECM) that supports elasticity of the lung, and in patients with chronic obstructive pulmonary disease (COPD) and emphysema, the structural changes that reduce the amount of elastic recoil, lead to loss of pulmonary function. We recently demonstrated that elastin is a target of peptidyl arginine deiminase (PAD) enzyme-induced citrullination, thereby leading to enhanced susceptibility of this ECM protein to proteolysis. The current study aimed to investigate the impact of PAD activity in vivo and furthermore assessed whether pharmacological inhibition of PAD activity protects against pulmonary emphysema. Using a Serpina1a-e knockout mouse model, previously shown to develop inflammation-mediated emphysema, we validated the involvement of PADs in airway disease. In line with emphysema development, intratracheal administration of lipopolysaccharide in combination with PADs provoked significant airspace enlargement (P < 0.001) and diminished lung function, including loss of lung tissue elastance (P = 0.0217) and increases in lung volumes (P = 0.0463). Intraperitoneal treatment of mice with the PAD inhibitor, BB-Cl-amidine, prevented PAD/LPS-mediated lung function decline and emphysema and reduced levels of citrullinated airway elastin (P = 0.0199). These results provide evidence for the impact of PADs on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.

Machine-learned molecular mechanics force fields from large-scale quantum chemical data.

The development of reliable and extensible molecular mechanics (MM) force fields-fast, empirical models characterizing the potential energy surface of molecular systems-is indispensable for biomolecular simulation and computer-aided drug design. Here, we introduce a generalized and extensible machine-learned MM force field, espaloma-0.3, and an end-to-end differentiable framework using graph neural networks to overcome the limitations of traditional rule-based methods. Trained in a single GPU-day to fit a large and diverse quantum chemical dataset of over 1.1 M energy and force calculations, espaloma-0.3 reproduces quantum chemical energetic properties of chemical domains highly relevant to drug discovery, including small molecules, peptides, and nucleic acids. Moreover, this force field maintains the quantum chemical energy-minimized geometries of small molecules and preserves the condensed phase properties of peptides and folded proteins, self-consistently parametrizing proteins and ligands to produce stable simulations leading to highly accurate predictions of binding free energies. This methodology demonstrates significant promise as a path forward for systematically building more accurate force fields that are easily extensible to new chemical domains of interest.

The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype.

Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin (also known as Cdh1) and upregulation of mesenchymal markers such as N-cadherin (Cdh2) and vimentin (Vim). Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines 4T07, 168FARN and 67NR. We found that 4T1 cells display a hybrid epithelial/mesenchymal phenotype with co-expression of epithelial and mesenchymal markers, whereas 4T07, 168FARN, and 67NR cells display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid epithelial/mesenchymal phenotype that promotes invasion and metastasis.

The impact of the COVID-19 pandemic on the performance of the Rapid Access Lung Cancer Clinic.

BACKGROUND: The Rapid Access Lung Cancer Clinic (RALC) experienced fewer referrals during the COVID-19 pandemic in Ireland. AIMS: Our aim was to determine the impact of the pandemic on the key performance indicators (KPIs) of the Cork University Hospital (CUH) RALC, using a retrospective chart review of the referrals and attendances. METHODS: The medical charts of patients referred to CUH-RALC from 03/2019 to 02/2020 (period I), and from 03/2020 to 02/2021 (period II) were reviewed. Performance of the RALC was determined based on average wait time from referral to 1] acquisition of the first CT scan, 2] consultation, and 3] receiving a cancer diagnosis, and compared between periods I and II. RESULTS: Average monthly referrals (57.3 vs 42.1, p = 0.0078) and RALC reviews (24.3 vs 22, p = 0.0310) were lower in period II compared to period I. However, no difference was seen in the length of time from referral to review at RALC or time to receive cancer diagnosis. There were shorter wait times from referral to CT scan (11.2 vs. 8.7 days, p = 0.0011) and to surgery (109.0 vs 79.3 days, p = 0.0236) in period II. CONCLUSIONS: The COVID-19 pandemic had minimal impact on the performance of RALC at our institution. Fewer referrals to RALC in period II may relate to hesitancy in attending general practitioner (GP) and/or GPs raising the thresholds for referrals to RALC during the early lockdown period of the pandemic. A national evaluation will be required to fully determine the impact of this pandemic on lung cancer in Ireland.

An MITF- and mTOR-dependent FLCN pathway suppresses TFE3-driven metastasis in melanoma.

Cancer cells have remarkable plasticity allowing them to acquire many biological states. Melanoma cells have the ability to switch from a proliferative melanocytic state to an invasive mesenchymal state and back again resulting in intratumoral heterogeneity. While microphthalmia-associated transcription factor (MITF) promotes the melanocytic phenotype, it is unclear what transcription factors drive the mesenchymal phenotype, and what mechanisms regulate the switch from the proliferative state to the mesenchymal state. We show that nuclear localization of the MITF paralog TFE3 correlates positively with metastatic potential in melanoma cell lines and tumors, and that deletion of TFE3 in MITF-low melanoma cell lines eliminates migration and metastatic ability. Further, we find that MITF suppresses the mesenchymal phenotype by activating expression of FNIP2, which encodes a component of an mTORC1-stimulated pathway promoting cytoplasmic retention and lysosomal degradation of TFE3. These findings point to the mTOR pathway and TFE3 as key regulators of melanoma plasticity.

Label-free liquid chromatography-mass spectrometry comparison of the breast muscle proteome profiles in two fast-growing broilers.

Poultry meat-production is increasing worldwide; leading to the selection of chickens for meat-production that show a fast growth. A label-free quantitative proteomic-approach and Western-blot were applied to investigate the dynamics of muscle protein under rapid growth conditions in two common fast-growing broiler genetic-lines (Ross 508 and AZ Extra Heavy Red-chicken). Muscle exudate from chicken Pectoralis major was used as substrate to unveil the proteome of these genetic-lines. Six-hundred forty-five proteins were identified in total from all samples, and after statistical-analysis 172 proteins were found to be differentially-expressed, clearly distinguishing the two chicken genetic-lines. Several of these differentially-expressed proteins were involved with the proteasome and glycolysis/gluconeogenesis-pathways. Changes in meat-quality traits were also observed, which were reflected in the proteomic-profile. Proteins involved in the ubiquitin-proteasome system were associated with the bigger muscle mass of Ross 508, while phosphoglucomutase 1 was associated with a possible higher capability of AZ Extra Heavy Red-chickens to cope with stressors. This pilot proteomic-approach applied on muscle exudate samples provided key evidence about the pathways and processes underlying these two chicken genetic-lines and their meat-quality parameters. We also identified potential biomarkers that could determine the peculiar production potentials (e.g. breast-growth) of these broilers-lines, which arise from differences in their genetic-backgrounds.

Changing the definition of treatment success alters treatment outcomes in periprosthetic joint infection: a systematic review and meta-analysis.

Background: Variability in the definition of treatment success poses difficulty when assessing the reported efficacy of treatments for hip and knee periprosthetic joint infection (PJI). To address this problem, we determined how definitions of PJI treatment success have changed over time and how this has affected published rates of success after one-stage and two-stage treatments for hip and knee PJI. Methods: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted to identify one-stage and two-stage revision hip and knee PJI publications in major databases (2006-2021). Definition of treatment success, based on Musculoskeletal Infection Society tier criteria, was identified for each study. Publication year, number of patients, minimum follow-up, and study quality were also recorded. The association of success definitions and treatment success rate was measured using multi-variable meta-regression. Results: Study quality remained unchanged in the 245 publications included. Over time, no antibiotics (tier 1) and no further surgery (tier 3) (40.7 % and 54.5 %, respectively) became the two dominant criteria. After controlling for type of surgery, study quality, study design, follow-up, and year of publication, studies with less strict success definitions (tier 3) reported slightly higher odds ratios of 1.05 [1.01, 1.10] ( p = 0.009 ) in terms of treatment success rates compared to tier 1. Conclusions: PJI researchers have gravitated towards tier-1 and tier-3 definitions of treatment success. While studies with stricter definitions had lower PJI treatment success, the clinical significance of this is unclear. Study quality, reflected in the methodological index for non-randomized studies (MINORS) score, did not improve. We advocate for improving PJI study quality, including clarification of the definition of treatment success.

The influence of threat on visuospatial perception, affordances, and protective behaviour: A systematic review and meta-analysis.

Perception has been conceptualised as an active and adaptive process, based upon incoming sensory inputs, which are modified by top-down factors such as cognitions. Visuospatial perception is thought to be scaled based on threat, with highly threatening objects or contexts visually inflated to promote escape or avoidance behaviours. This meta-analytical systematic review quantified the effect and evidence quality of threat-evoked visuospatial scaling, as well as how visuospatial scaling relates to affordances (perceived action capabilities) and behavioural avoidance/escape outcomes. Databases and grey literature were systematically searched inclusive to 10/04/24. Studies were assessed with a customised Risk of Bias form and meta-analysis was performed using a random-effects model. 12,354 records were identified. Of these, 49 experiments (n = 3027) were included in the review. There was consistent evidence that threat the of height influenced contextual perception (g = 0.66, 95% CI: 0.45, 0.88) and affordances (g = -0.43, 95% CI: -0.84, -0.03). Threatening objects were viewed as larger (g = 0.76, 95% CI: 0.26, 1.26) and as closer (g = 0.30, 95% CI: 0.17, 0.42). Bodily threat (pain) yielded conflicting effects on visuospatial perception/affordances. We conclude that threat may influence visuospatial perception and affordances. However, since behavioural measures were poorly reported, their relationship with visuospatial perception/affordances remains elusive.

Proteomic reference map for sarcopenia research: mass spectrometric identification of key muscle proteins of organelles, cellular signaling, bioenergetic metabolism and molecular chaperoning.

During the natural aging process, frailty is often associated with abnormal muscular performance. Although inter-individual differences exit, in most elderly the tissue mass and physiological functionality of voluntary muscles drastically decreases. In order to study age-related contractile decline, animal model research is of central importance in the field of biogerontology. Here we have analyzed wild type mouse muscle to establish a proteomic map of crude tissue extracts. Proteomics is an advanced and large-scale biochemical method that attempts to identify all accessible proteins in a given biological sample. It is a technology-driven approach that uses mass spectrometry for the characterization of individual protein species. Total protein extracts were used in this study in order to minimize the potential introduction of artefacts due to excess subcellular fractionation procedures. In this report, the proteomic survey of aged muscles has focused on organellar marker proteins, as well as proteins that are involved in cellular signaling, the regulation of ion homeostasis, bioenergetic metabolism and molecular chaperoning. Hence, this study has establish a proteomic reference map of a highly suitable model system for future aging research.

Proteomic reference map for sarcopenia research: mass spectrometric identification of key muscle proteins located in the sarcomere, cytoskeleton and the extracellular matrix.

Sarcopenia of old age is characterized by the progressive loss of skeletal muscle mass and concomitant decrease in contractile strength. Age-related skeletal muscle dysfunctions play a key pathophysiological role in the frailty syndrome and can result in a drastically diminished quality of life in the elderly. Here we have used mass spectrometric analysis of the mouse hindlimb musculature to establish the muscle protein constellation at advanced age of a widely used sarcopenic animal model. Proteomic results were further analyzed by systems bioinformatics of voluntary muscles. In this report, the proteomic survey of aged muscles has focused on the expression patterns of proteins involved in the contraction-relaxation cycle, membrane cytoskeletal maintenance and the formation of the extracellular matrix. This includes proteomic markers of the fast versus slow phenotypes of myosin-containing thick filaments and actin-containing thin filaments, as well as proteins that are associated with the non-sarcomeric cytoskeleton and various matrisomal layers. The bioanalytical usefulness of the newly established reference map was demonstrated by the comparative screening of normal versus dystrophic muscles of old age, and findings were verified by immunoblot analysis.

Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Infection After Lower-Limb Osseointegration: A Single-Center Retrospective Evaluation of Pathogens, Management, and Outcomes.

PURPOSE: Osseointegration (OI) is a novel alternative to traditional socket-suspended prostheses for lower-limb amputees, eliminating the socket-skin interface and allowing for weight bearing directly on the skeletal system. However, the stoma through which the implant attaches to the external prosthesis creates an ingress route for bacteria, and infection rates as high as 66% have been reported. The aims of this study are to classify infection management and long-term outcomes in this patient population to maximize implant salvage. METHODS: An institutional review board-approved retrospective analysis was performed on all patients who underwent lower-limb OI at our institution between 2017 and 2022. Demographic, operative, and outcome data were collected for all patients. Patients were stratified by the presence and severity of infection. Chi-square and t tests were performed on categorical and continuous data, respectively, using an alpha of 0.05. RESULTS: One hundred two patients met our study criteria; 62 had transfemoral OI and 40 had transtibial OI. Patients were followed for 23.8 months on average (range, 3.5-63.7). Osteomyelitis was more likely than soft tissue infection to be polymicrobial in nature (71% vs 23%, P < 0.05). Infections at the stoma were mostly (96%) managed with oral antibiotics alone, whereas deeper soft tissue infections also required intravenous antibiotics (75%) or operative washout (19%). Osteomyelitis was managed with intravenous antibiotics and required operative attention; 5 (71%) underwent washout and 2 (29%) underwent explantation. Both implants were replaced an average of 3.5 months after explantation. There was no correlation between history of soft tissue infection and development of osteomyelitis (P > 0.05). The overall implant salvage rate after infection was 96%. CONCLUSIONS: This study describes our institution's experience managing infection after OI and soft tissue reconstruction. Although infections do occur, they are easily treatable and rarely require operative intervention. Explantation due to infection is rare and can be followed up with reimplantation, reaffirming that OI is a safe and effective treatment modality.

Real-world treatment patterns and outcomes in patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab.

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon gamma, is approved in the United States to treat primary HLH (pHLH) in patients with refractory, recurrent, or progressive disease, or intolerance with conventional HLH treatments. REAL-HLH, a retrospective study, conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with ≥1 dose of emapalumab between 20 November 2018 and 31 October 2021. In total, 46 patients met the pHLH classification criteria. Median age at diagnosis was 1.0 year (range, 0.3-21.0). Emapalumab was initiated for treating refractory (19/46), recurrent (14/46), or progressive (7/46) pHLH. At initiation, 15 of 46 patients were in the intensive care unit, and 35 of 46 had received prior HLH-related therapies. Emapalumab treatment resulted in normalization of key laboratory parameters, including chemokine ligand 9 (24/33, 72.7%), ferritin (20/45, 44.4%), fibrinogen (37/38, 97.4%), platelets (39/46, 84.8%), and absolute neutrophil count (40/45, 88.9%). Forty-two (91.3%) patients were considered eligible for transplant. Pretransplant survival was 38 of 42 (90.5%). Thirty-one (73.8%) transplant-eligible patients proceeded to transplant, and 23 of 31 (74.2%) of those who received transplant were alive at the end of the follow-up period. Twelve-month survival probability from emapalumab initiation for the entire cohort (N = 46) was 73.1%. There were no discontinuations because of adverse events. In conclusion, results from the REAL-HLH study, which describes treatment patterns, effectiveness, and outcomes in patients with pHLH treated with emapalumab in real-world settings, are consistent with the emapalumab pivotal phase 2/3 pHLH trial.

Label-Free Quantitative Analysis of Pig Liver Proteome after Hepatitis E Virus Infection.

Hepatitis E represents an emerging zoonotic disease caused by the Hepatitis E virus (HEV), for which the main route of transmission is foodborne. In particular, infection in humans has been associated with the consumption of contaminated undercooked meat of pig origin. The aim of this study was to apply comparative proteomics to determine if porcine liver protein profiles could be used to distinguish between pigs seropositive and seronegative for HEV. Preliminarily, an ELISA was used to evaluate the presence of anti-HEV antibodies in the blood serum of 136 animals sent to slaughter. Among the analyzed samples, a seroprevalence of 72.8% was estimated, and it was also possible to identify 10 animals, 5 positive and 5 negative, coming from the same farm. This condition created the basis for the quantitative proteomics comparison between homogeneous animals, in which only the contact with HEV should represent the discriminating factor. The analysis of the proteome in all samples of liver exudate led to the identification of 554 proteins differentially expressed between the two experimental groups, with 293 proteins having greater abundance in positive samples and 261 more represented in negative exudates. The pathway enrichment analysis allowed us to highlight the effect of the interaction between HEV and the host biological system in inducing the potential enrichment of 69 pathways. Among these, carbon metabolism stands out with the involvement of 41 proteins, which were subjected to interactomic analysis. This approach allowed us to focus our attention on three enzymes involved in glycolysis: glucose-6-phosphate isomerase (GPI), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and fructose-bisphosphate aldolase A (ALDOA). It therefore appears that infection with HEV induced a strengthening of the process, which involves the breakdown of glucose to obtain energy and carbon residues useful for the virus's survival. In conclusion, the label-free LC-MS/MS approach showed effectiveness in highlighting the main differences induced on the porcine liver proteome by the interaction with HEV, providing crucial information in identifying a viral signature on the host metabolism.

International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Kartograf: A Geometrically Accurate Atom Mapper for Hybrid-Topology Relative Free Energy Calculations.

Relative binding free energy (RBFE) calculations have emerged as a powerful tool that supports ligand optimization in drug discovery. Despite many successes, the use of RBFEs can often be limited by automation problems, in particular, the setup of such calculations. Atom mapping algorithms are an essential component in setting up automatic large-scale hybrid-topology RBFE calculation campaigns. Traditional algorithms typically employ a 2D subgraph isomorphism solver (SIS) in order to estimate the maximum common substructure. SIS-based approaches can be limited by time-intensive operations and issues with capturing geometry-linked chemical properties, potentially leading to suboptimal solutions. To overcome these limitations, we have developed Kartograf, a geometric-graph-based algorithm that uses primarily the 3D coordinates of atoms to find a mapping between two ligands. In free energy approaches, the ligand conformations are usually derived from docking or other previous modeling approaches, giving the coordinates a certain importance. By considering the spatial relationships between atoms related to the molecule coordinates, our algorithm bypasses the computationally complex subgraph matching of SIS-based approaches and reduces the problem to a much simpler bipartite graph matching problem. Moreover, Kartograf effectively circumvents typical mapping issues induced by molecule symmetry and stereoisomerism, making it a more robust approach for atom mapping from a geometric perspective. To validate our method, we calculated mappings with our novel approach using a diverse set of small molecules and used the mappings in relative hydration and binding free energy calculations. The comparison with two SIS-based algorithms showed that Kartograf offers a fast alternative approach. The code for Kartograf is freely available on GitHub (https://github.com/OpenFreeEnergy/kartograf). While developed for the OpenFE ecosystem, Kartograf can also be utilized as a standalone Python package.