Adverse Pathologies Research Articles

Synergistic Structural Inhibition of MMP-9 by Natural Flavonoids: A Natural Combinatorial Therapy against Cancer

Introduction: Cancer is the uncontrolled proliferation of cells leading to metastasis due to genetic alterations resulting in oncogenes activation and tumor suppressor genes deactivation. It is the 2nd leading cause of death across the world. MMP-9 or gelatinase B, plays an effective role in ECM degradation, normal tissue turnover, and tissue remodelling. Methods: Overexpression of MMP-9 has been studied in almost all types of cancers proving the effective role of MMP-9 in accelerating malignant conditions. Thus, targeting MMP-9 to treat cancer seems to be a potential strategy to deal with adverse pathologies of cancer. Methods: Chemotherapy and radiotherapy are frequently utilized for the treatment of cancer but are associated with diverse side effects. Flavonoids are natural compounds frequently found in plants and have been analyzed for the structural inhibition potential against MMP-9 by several researchers to develop natural treatments against cancer, but none of the flavonoids have landed into clinical use. In the present study, in-depth in-silico analysis to investigate the synergistic effects of flavonoids for structural inhibition of MMP-9 was done. The ADMET and bioactive properties analysis revealed effective drug-like properties of the considered flavonoids. Principal component analysis of ADMET and bioactive properties revealed high similarity in the chemical nature of luteolin and quercetin. Molecular docking analysis of MMP-9 with the considered flavonoids individually revealed the highest effective binding energy of luteolin. Results: Combination docking analysis of MMP-9 with different combinations of flavonoids led to the identification of two combinations including Quercetin with Genistein and Luteolin and Genistein revealing high negative binding energies of -15.48kcal/mol and -15.31kcal/mol which was significantly greater than the binding energies identified for respective ligands in individual dockings. Conclusion: Thus, the present study put forward synergistic natural flavonoid combinations against cancer via the MMP-9 inhibition approach that can be further evaluated to develop high-efficacy treatments.

Is it possible to detect cribriform adverse pathology in prostate cancer with magnetic resonance imaging machine learning-based radiomics?

Rationale and objectives: Cribriform patterns are accepted as aggressive variants of prostate cancer. These adverse pathologies are closely associated with early biochemical recurrence, metastasis, castration resistance, and poor disease-related survival. A few publications exist to diagnose these two adverse pathologies with multiparametric magnetic resonance imaging (mpMRI). Most of these publications are retrospective and are not studies that have made a difference in diagnosing adverse pathology. It is also known that fusion biopsies taken from lesions detected in mpMRI are insufficient to detect these adverse pathologies. Our study aims to diagnose this adverse pathology using machine learning-based radiomics data from MR images. Materials and methods: A total of 88 patients who had pathology results indicating the presence of cribriform pattern and prostate adenocarcinoma underwent preoperative MRI examinations and radical prostatectomy. Manual slice-by-slice 3D volumetric segmentation was performed on all axial images. Data processing and machine learning analysis were conducted using Python 3.9.12 (Jupyter Notebook, Pycaret Library). Results: Two radiologists, SE and MAG, with 7 and 8 years of post-graduate experience, respectively, evaluated the images using the 3D-Slicer software without knowledge of the histopathological findings. One hundred seventeen radiomic tissue features were extracted from T1 weighted (T1W) and apparent diffusion coefficient (ADC) sequences for each patient. The interobserver agreement for these features was analyzed using the intraclass correlation coefficient (ICC). Features with excellent interobserver agreement (ICC > 0.90) were further analyzed for collinearity between predictors using Pearson’s correlation. Variables showing a very high correlation (r ≥ ±0.80) were disregarded. The selected features for T1W and ADC images were First-order maximum, First-order skewness, First-order 10th percentile for ADC, and Gray level size zone matrix, Large area low gray level emphasis for T1W.As a result of the classification of PyCaret, the three best models were found. A single model was obtained by blending these three models. AUC, accuracy, recall, precision, and F1 scores were 0.79, 0.77, 0.85, 0.82, and 0.83, respectively. Conclusion: ML-based MRI radiomics of prostate cancer can predict the cribriform pattern. This prognostic factor cannot be determined through qualitative radiological evaluation and may be overlooked in preoperative histopathological specimens.

The Role of Multiparametric MRI (mpMRI) in the Prediction of Adverse Prostate Cancer Pathology in Radical Prostatectomy Specimen.

Prostate cancer (PCa) risk stratification is essential in guiding therapeutic decision. Multiparametric magnetic resonance tomography (mpMRI) holds promise in the prediction of adverse pathologies (AP) after prostatectomy (RP). This study aims to identify clinical and imaging markers in the prediction of adverse pathology. Patients with PCa, diagnosed by targeted biopsy after mpMRI and undergoing RP, were included. The predictive accuracy of mpMRI for extraprostatic extension (ECE), seminal vesicle infiltration (SVI), and lymph node positivity was calculated from the final histopathology. 846 patients were involved. Independent risk parameters include imaging findings such as ECE (OR 3.12), SVI (OR 2.55), and PI-RADS scoring (4: OR 2.01 and 5: OR 4.34). mpMRI parameters such as ECE, SVI, and lymph node metastases showed a high prognostic accuracy (73.28% vs. 95.35% vs. 93.38%) with moderate sensitivity compared to the final histopathology. The ROC analysis of our combined scoring system (D'Amico classification, PSA density, and MRI risk factors) improves the prediction of adverse pathology (AUC: 0.73 vs. 0.69). Our study supports the use of mpMRI for comprehensive pretreatment risk assessment in PCa. Due to the high accuracy of factors like ECE, SVI, and PI-RADS scoring, utilizing mpMRI data enabled accurate prediction of unfavorable pathology after RP.

Chronic jet lag reduces motivation and affects other mood-related behaviors in male mice.

Introduction: The circadian system regulates various physiological processes such as sleep-wake cycles, hormone secretion, metabolism, and the reaction to both natural and drug-based rewards. Chronic disruption of the circadian system caused by unsteady synchronization with light-dark (LD) schedules, such as advancing chronic jet lag (CJL), leads to adverse physiological effects and pathologies, and is linked with changes in mood and depressive behaviors in humans and rodent models. Methods: C57BL/6J male mice were subjected to circadian disruption through phase advances of 6h every 2days (CJL +6/2). Mice under 12:12-h LD cycle were used as controls. After 8weeks under these conditions, a battery of behavioral tests was performed to assess if mood-related behaviors were affected. Results: Compared to controls under 24h LD cycles, mice under CJL presented desynchronization of activity-rest rhythms that led to several behavioral impairments, including a decrease in motivation for food reward, and an increase in anxiety, anhedonia, and depressive-like behavior. Conclusion: Chronic circadian disruption, caused by an experimental CJL protocol, affects mood-related and reward-related behaviors in mice. Understanding the importance of the circadian system and its potential role for disruption due to CJL is important for maintaining good health and well-being.

DNA Methylation of Genes Involved in the HPA Axis in Presence of Suicide Behavior: A Systematic Review

DNA methylation in genes of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with suicide behavior. Through a systematic review, we aimed to evaluate DNA methylation levels of the genes involved in the HPA pathway and their association with suicide behavior. A search of articles was performed using PubMed and Science Direct, EBSCO. The terms included were "DNA methylation", "suicide", "epigenetics", "HPA axis" and "suicide behavior". This systematic review was performed by the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. Six studies comprising 743 cases and 761 controls were included in this systematic review. The studies included individuals with suicide ideation, suicide attempts or completed suicide and childhood trauma, post-traumatic stress disorder (PTSD), or depression. One study reported hypermethylation in GR in childhood trauma, while two studies found hypermethylation of NR3C1 in childhood trauma and major depressive disorder (MDD). Only one study reported hypermethylation in BNDF in people with MDD. FKBP5 was found to be hypermethylated in people with MDD. Another study reported hypermethylation in CRHBP. SKA2 was reported to be hypermethylated in one study and another study found hypomethylated both in populations with PTSD. CRHR1 was found to be hypermethylated in people with MDD, and the last study found hypomethylation in CRH. Our result showed that patients with suicidal behavior showed a DNA methylation state of genes of the HPA axis in association with psychiatric comorbidity and with adverse events. Genes of the HPA axis could play a role in suicidal behavior associated with adverse events and pathologies. As a result, DNA methylation levels, proteins, and genes involved in the HPA axis could be considered for the search for biomarkers for the prevention of suicidal behavior in future studies.

The Intersection Between Malaria Treatment and Chemoprophylaxis and Their Potential Adverse Dermatologic Manifestations: A Narrative Review.

Malaria is a life-threatening parasitic disease caused by various forms of the protozoa Plasmodium and is transmitted by the female Anopheles mosquito. The parasitic infection is endemic in 90 countries, with approximately 500 million cases reported annually and an estimated annual mortality of 1.5-2.7 million individuals. Historically, the use of antimalarial drugs has been promising for the chemoprophylaxis and treatment of malaria, mitigating the annual mortality rate. Notably, these antimalarial drugs have been associated with various adverse effects, including gastrointestinal upset and headaches. However, the adverse cutaneous manifestations these antimalarial drugs may lead to are poorly documented and understood. We aim to describe the lesser-studied adverse cutaneous pathologies of malaria treatment to better educate physicians on the proper treatment of their patients. Our narrative review describes the skin manifestations associated with specific antimalarial treatments and their associated prognoses and treatments. The cutaneous pathologies discussed include aquagenic pruritus (AP), palmoplantar exfoliation, Steven-Johnson syndrome, toxic epidermal necrolysis, cutaneous vasculitis, psoriasis, ecchymosis, and tropical lichenoid dermatitis.Further studies and vigilant documentation of the cutaneous adverse events of antimalarial drugs need to be performed and emphasized to prevent potential life-threatening adverse outcomes.

Re: Sensitivity of Multiparametric MRI and Targeted Biopsy for Detection of Adverse Pathologies (Cribriform Gleason Pattern 4 and Intraductal Carcinoma): Correlation of Detected and Missed Prostate Cancer Foci with Whole Mount Histopathology

Re: Sensitivity of Multiparametric MRI and Targeted Biopsy for Detection of Adverse Pathologies (Cribriform Gleason Pattern 4 and Intraductal Carcinoma): Correlation of Detected and Missed Prostate Cancer Foci with Whole Mount Histopathology

An Overview of Laboratory Testing for Antiphospholipid Antibodies.

Antiphospholipid antibodies (aPL) represent a group of autoantibodies directed against phospholipids. These antibodies may arise in a number of autoimmune conditions, of which the antiphospholipid (antibody) syndrome (APS) is best recognized. aPL can be detected by various laboratory assays, essentially comprising both solid-phase (immunological) assays and "liquid-phase" clotting assays identifying so-called lupus anticoagulants (LA). aPL are associated with various adverse pathologies, including thrombosis and placental/fetal morbidity and mortality. The type of aPL present, as well as the pattern of reactivity, is variously associated with the severity of the pathology. Thus, laboratory testing for aPL is indicated to help assess the future risk of such events, as well as representing certain "classification" criteria for APS, also used as surrogates for diagnostic criteria. The current chapter overviews the laboratory tests available to measure aPL and their potential clinical utility.

Association of cannabis use disorder with cardiovascular diseases: A two-sample Mendelian randomization study.

BackgroundThe use of cannabis has increased globally due to more regions decriminalizing marijuana use for therapeutic and recreational aims. Several observational studies have revealed that cannabis use is associated with an increased risk of adverse cardiovascular pathologies and diseases. Nevertheless, the causal associations between cannabis use and cardiovascular diseases remain unclear. Hence, we performed single-variable and multivariable Mendelian randomization (MR) to evaluate the association between cannabis use disorder and various cardiovascular diseases.Materials and methodsSummary statistics were collected from the largest-to-date genome-wide association studies (GWAS) of cannabis use disorder. The 12 SNPs for cannabis use disorder were used as instrumental variables in this study. MR estimates were pooled using a random-effects inverse-variance weighted (IVW) method. Simple median and weighted median methods were conducted as sensitivity analyses.ResultsThe genetic liability to cannabis use disorder was associated with an augmented risk of coronary artery disease, myocardial infarction, atrial fibrillation, heart failure, deep venous thrombosis, pulmonary embolism, and stroke. Except for stroke, the results were inconsistent in the sensitivity analyses. The overall patterns for the associations of cannabis use disorder with atrial fibrillation, heart failure, pulmonary embolism and stroke remained in multivariable MR analyses adjusting for potential mediators, including smoking, alcohol, body mass index, blood lipid, type 2 diabetes, hypertension, and depression. However, the association with coronary artery disease, myocardial infarction, and deep venous thrombosis did not persist in multivariable MR analyses. Mediation analysis demonstrated that smoking, body mass index, low-density lipoprotein, hypertension, and depression have more significant mediation effects, which suggests that these factors partly mediate the link from cannabis use disorder to coronary artery disease, myocardial infarction, and deep venous thrombosis.ConclusionThe genetic liability to cannabis use disorder was associated with a higher risk of atrial fibrillation, heart failure, pulmonary embolism, and stroke. The evidence for the association between cannabis use disorder, coronary artery disease, myocardial infarction, and deep venous thrombosis was weak. Hence, future use of cannabis for therapeutic and recreational aims should consider its potential impact on cardiovascular diseases.

Sensitivity of multiparametric MRI and targeted biopsy for detection of adverse pathologies (Cribriform gleason pattern 4 and intraductal carcinoma): Correlation of detected and missed prostate cancer foci with whole mount histopathology.

Accurate preoperative detection of prostate cancer (PCa) exhibiting "cribriform" morphology (intraductal carcinoma [IDC-P] or cribriform Gleason pattern 4 [CrP4]) is important as it is independently associated with a variety of adverse clinical outcomes. The sensitivity of multiparametric magnetic resonance imaging (mpMRI) in the detection of PCa exhibiting "cribriform" morphology remains controversial. A total of 117 eligible men with prospectively reported mpMRI who underwent in-bore MRI targeted biopsy followed by whole-mount radical prostatectomy (RP) were analyzed for lesion-level imaging-pathology correlation. Of the 206 PCa foci at RP (117 index and 89 non-index), 74% (152/206) were detected by mpMRI. Of the 54 tumors missed by mpMRI, most were non-index (98%, 53/54), grade group (GG) 1 (68%, 37/54) or GG 2 (26%, 14/54), with a median size of 1.0 cm (range, 0.7-1.5 cm), and non-cribriform morphology (96%, 52/54). Cribriform morphology was detected in 26% (53/206) of all tumors, and although targeted biopsies identified 96% (51/53) of these cancers, the cribriform component was depicted in only 45% (24/53). Of these, mpMRI detected all (100%, 44/44) index and 78% (7/9) of the non-index tumors. At univariable analysis, tumor size greater than 5 mm, % pattern 4 > 5%, cribriform morphology, zone (transition versus peripheral zone), and region (apex versus mid/base) were significantly associated with tumor visibility at mpMRI. At multivariable analysis, only tumor size, presence of any pattern 4, and peripheral zone remained significant predictors for visibility by mpMRI. At a lesion level, mpMRI offers high sensitivity for the detection of cribriform morphologies, however, the cribriform component is frequently missed by targeted biopsies. The MRI visibility is significantly associated with larger tumor size, presence of Gleason pattern 4, and peripheral zone location.

When Problems Only Get Bigger: The Impact of Adverse Childhood Experience on Adult Health.

Introduction: Previous studies have shown that adverse childhood experiences negatively impact child development, with consequences throughout the lifespan. Some of these consequences include the exacerbation or onset of several pathologies and risk behaviors.Materials and Methods: A convenience sample of 398 individuals aged 20 years or older from the Porto metropolitan area, with quotas, was collected. The evaluation was conducted using an anonymous questionnaire that included sociodemographic questions about exposure to adverse childhood experiences, a list of current health conditions, questions about risk behaviors, the AUDIT-C test, the Fagerström test and the Childhood Trauma Questionnaire–brief form. Variables were quantified to measure adverse childhood experiences, pathologies, and risk behaviors in adult individuals for comparison purposes.Results: Individuals with different forms of adverse childhood experiences present higher rates of smoking dependence, self-harm behaviors, victimization of/aggression toward intimate partners, early onset of sexual life, sexually transmitted infections, multiple sexual partners, abortions, anxiety, depression, diabetes, arthritis, high cholesterol, hypertension, and stroke. Different associations are analyzed and presented.Discussion and Conclusions: The results show that individuals with adverse childhood experiences have higher total scores for more risk behaviors and health conditions than individuals without traumatic backgrounds. These results are relevant for health purposes and indicate the need for further research to promote preventive and protective measures.

Epicatechin an incredible tool to dissociate MDM2-p53 interaction for treatment of glioblastomas: a molecular docking and molecular dynamics simulation approach

Glioblastomas, aggressive tumors that arise from malignant transformation of astrocytes, account for 60% brain cancer cases. Current treatments including radiation and chemotherapy accompanied by surgeries result in an average survival increment of 15 months. New therapeutics based on molecular pathology and pathways demonstrate great scope. p53, a tumor-suppressor protein is downregulated by MDM2. In malignant conditions, MDM2 levels increase immensely due to genetic mutations, causing excessive p53 downregulation, thereby enhancing malignancy to extremities. Inhibition of MDM-2 to p53 interaction by potent inhibitors can be a potent therapy but the use of synthetic inhibitors poses many side effects. Natural dietary flavonoids like epicatechin possess high antioxidant and anti-carcinogenic properties. Molecular docking and MD simulation approaches were used to reveal the effectiveness of epicatechin in this regard, a high negative binding energy of -9.619 kcal/mol with Ki value of 82.34 nM and 6 hydrogen bonds with the leading residues responsible for MDM2 p53 interaction were noticed. MD simulation of 100 ns revealed that epicatechin continues to interact with the vital residues of MDM2 and p53 and occupies the hydrophobic p53-binding cleft in MDM2. Significant structural modifications in MDM2-p53 complex due to epicatechin interactions were observed. The increase in RMSD and Rg values of MDM2-p53 complex in presence of epicatechin provides evidence for the destabilization of complex. The extreme increase in RMSF values of p53 in turn indicates towards its reduced interaction with MDM2. Hence, epicatechin can promisingly treat adverse glioblastoma pathologies by inhibiting MDM2-p53 interactions, therefore exhaustive research is urgently demanded.

Glutaredoxin-2 and Sirtuin-3 deficiencies impair cardiac mitochondrial energetics but their effects are not additive

Altered redox biology and oxidative stress have been implicated in the progression of heart failure. Glutaredoxin-2 (GRX2) is a glutathione-dependent oxidoreductase and catalyzes the reversible deglutathionylation of mitochondrial proteins. Sirtuin-3 (SIRT3) is a class III histone deacetylase and regulates lysine acetylation in mitochondria. Both GRX2 and SIRT3 are considered as key in the protection against oxidative damage in the myocardium. Knockout of either contributes to adverse heart pathologies including hypertrophy, hypertension, and cardiac dysfunction. Here, we created and characterized a GRX2 and SIRT3 double-knockout mouse model, hypothesizing that their deletions would have an additive effect on oxidative stress, and exacerbate mitochondrial function and myocardial structural remodeling. Wildtype, single-gene knockout (Sirt3−/−, Grx2−/−), and double-knockout mice (Grx2−/−/Sirt3−/−) were compared in heart weight, histology, mitochondrial respiration and H2O2 production. Overall, the hearts from Grx2−/−/Sirt3−/− mice displayed increased fibrosis and hypertrophy versus wildtype. In the Grx2−/− and the Sirt3−/− we observed changes in mitochondrial oxidative capacity, however this was associated with elevated H2O2 emission only in the Sirt3−/−. Similar changes were observed but not worsened in hearts from Grx2−/−/Sirt3−/− mice, suggesting that these changes were not additive. In human myocardium, using genetic and histopathological data from the human Genotype-Tissue Expression consortium, we confirmed that SIRT3 expression correlates inversely with heart pathology. Altogether, GRX2 and SIRT3 are important in the control of cardiac mitochondrial redox and oxidative processes, but their combined absence does not exacerbate effects, consistent with the overall conclusion that they function together in the complex redox and antioxidant systems in the heart.

Preventive effects of "ovalbumin-conjugated celastrol-loaded nanomicelles'' in a mouse model of ovalbumin-induced allergic airway inflammation

Allergies affect a significant proportion of the world's population, and existing vaccination strategies to restrict their adverse pathologies often render side-effects. The aim of this study was to design a new vaccine for allergen-specific immunotherapy (SIT), and to investigate its preventive effects during allergic inflammation. We constructed ovalbumin (OVA)-conjugated celastrol-loaded nanomicelles (OVA-NMs-celastrol), wherein celastrol (a bioactive anti-inflammatory compound) was loaded into carboxyl-functioned polymeric nanomicelles using a thin-film hydration method. OVA was used as a model allergen and conjugated on nanomicelles. The OVA-NMs-celastrol obtained were characterized based on particle size, morphology, drug encapsulation efficiency, and drug loading percentage. Further, the preventive effect of OVA-NMs-celastrol was evaluated in a mouse model of allergic asthma. Our results showed that OVA-NMs-celastrol possessed valuable characteristics such as small particle size (50.72 ± 0.98 nm) and spherical-like shape, with celastrol encapsulation efficiency of 99.89 ± 0.85% and a drug loading percentage of 4.76 ± 0.03%. Further, in vivo results showed that treatment with OVA-NMs-celastrol could decrease OVA specific IgE and histamine levels, Th2 cytokine (IL-4, IL-5) levels, and inflammatory cell infiltration in the lung tissues. Moreover, it could enhance the OVA specific IgG1 and IgG2a levels and decrease the IgE / IgG2a ratio. These results demonstrate the successful construction of OVA-NMs-celastrol as a potential vaccine candidate for use in SIT for allergic inflammation.

Nanoparticle contrast-enhanced micro-CT: A preclinical tool for the 3D imaging of liver and spleen in longitudinal mouse studies

In drug discovery and development, X-ray micro-computed tomography (micro-CT) has gained increasing importance over the past decades. In recent years, micro-CT imaging of soft tissues has become popular due to the introduction of a variety of radiopaque contrast agents. More recently, nanoparticle-based ExiTron nano 12,000 has become commercially available for the nonclinical micro-CT imaging of soft tissues in rodents. Phagocytosis and accumulation of the contrast agent by Kupffer cells in the liver, as well as macrophages in the spleen, increase the soft tissue X-ray attenuation for up to 6 months. Therefore, it is essential to understand the potential toxicity of this nanomaterial in micro-CT imaging prior to its application in pharmacology and/or toxicology studies. Herein, we describe the time-course and distribution of the contrast in the liver, spleen and blood after a single intravenous injection (IV) of this nanoparticle contrast agent at 0.1 ml/mouse. Thoracic images of male adult C57BL/6 mice were acquired using a Bruker SkyScan 1276 micro-CT over a period of 29 days. The stability of X-ray attenuation enhancement in the above tissues was also tested after a single dose of Kupffer cell toxicant gadolinium chloride (GdCl3) at 15 mg/kg on day 2. The liver, spleen and kidney were examined microscopically on days 15 and 29 post treatment. Serum and liver cytokines (IL-1β, IL-2, IL-6, IL-10, IL-12p70, IFN-γ, IP-10, MIP1-α, MIP1-β and TNF-α) were quantified on days 15 and 29 as indicators of a pro-inflammatory response to treatment. This study determined that there was an accumulation of amphophilic granular material in the cells of the mononuclear phagocyte system in the liver and spleen following a single dose of ExiTron nano 12,000 and a second dose of GdCl3 or its vehicle. However, ExiTron nano12000 contrast administration did not cause any hepatotoxicity in the liver, nor did pro-inflammatory cytokines release in the liver or serum. Similarly, there were no adverse pathologies in the spleen or kidneys. In summary, ExiTron nano12000 contrast agent-enhanced micro-CT could be used as a safe method in up to 29-day longitudinal efficacy and toxicology mouse studies for the non-invasive assessment of the liver and spleen.

GRÖMeR: A Pipeline for Geodesic Refinement of Mesh Registration.

The electrical signals produced by the heart can be used to assess cardiac health and diagnose adverse pathologies. Experiments on large mammals provide essential sources of these signals through measurements of up to 1000 simultaneous, distributed locations throughout the heart and torso. To perform accurate spatial analysis of the resulting electrical recordings, researchers must register the locations of each electrode, typically by defining correspondence points from post-experiment, three-dimensional imaging, and directly measured surface electrodes. Often, due to the practical limitations of the experimental situation, only a subset of the electrode locations can be measured, from which the rest must be estimated. We have developed a pipeline, GRÖMeR, that can perform registration of cardiac surface electrode arrays given a limited correspondence point set. This pipeline accounts for global deformations and uses a modified iterative closest points algorithm followed by a geodesically constrained radial basis deformation to calculate a smooth, correspondence-driven registration. To assess the performance of this pipeline, we generated a series of target geometries and limited correspondence patterns based on experimental scenarios. We found that the best performing correspondence pattern required only 20, approximately uniformly distributed points over the epicardial surface of the heart. This study demonstrated the GRÖMeR pipeline to be an accurate and effective way to register cardiac sock electrode arrays from limited correspondence points.

Exercise during pregnancy has a preventative effect on excessive maternal weight gain and gestational diabetes. A randomized controlled trial

BackgroundExcessive gestational weight gain is associated with several adverse events and pathologies during pregnancy. ObjectiveThe purpose of this study was to examine the effects of an exercise program throughout pregnancy on maternal weight gain and prevalence of gestational diabetes. MethodA randomized controlled trial was designed that included an exercise intervention group (EG) and standard care control group (CG). The exercise intervention included moderate aerobic exercise performed three days per week (50–55minutes per session) for 8–10 weeks to 38–39 weeks gestation. Results594 pregnant women were assessed for eligibility and 456 were included (EG n=234; CG n=222). The results showed a higher percentage of pregnant women gained excessive weight in the CG than in the EG (30.2% vs 20.5% respectively; odds ratio, 0.597; 95% confidence interval, 0.389–0.916; p=0.018). Similarly, the prevalence of gestational diabetes was significantly higher in the CG than the EG (6.8% vs 2.6% respectively; odds ratio, 0.363; 95% confidence interval, 0.138–0.953; p=0.033). ConclusionThe results of this trial indicate that exercise throughout pregnancy can reduce the risk of excessive maternal weight gain and gestational diabetes.

Clinical Proof-of-concept of a Novel Platform Utilizing Biopsy-derived Live Single Cells, Phenotypic Biomarkers, and Machine Learning Toward a Precision Risk Stratification Test for Prostate Cancer Grade Groups 1 and 2 (Gleason 3 + 3 and 3 + 4)

ObjectiveTo examine the ability of a novel live primary-cell phenotypic (LPCP) test to predict postsurgical adverse pathology (P-SAP) features and risk stratify patients based on SAP features in a blinded study utilizing radical prostatectomy (RP) surgical specimens. MethodsTwo hundred fifty-one men undergoing RP were enrolled in a prospective, multicenter (10), and proof-of-concept study in the United States. Fresh prostate samples were taken from known areas of cancer in the operating room immediately after RP. Samples were shipped and tested at a central laboratory. Utilizing the LPCP test, a suite of phenotypic biomarkers was analyzed and quantified using objective machine vision software. Biomarkers were objectively ranked via machine learning-derived statistical algorithms (MLDSA) to predict postsurgical adverse pathological features. Sensitivity and specificity were determined by comparing blinded predictions and unblinded RP surgical pathology reports, training MLDSAs on 70% of biopsy cells and testing MLDSAs on the remaining 30% of biopsy cells across the tested patient population. ResultsThe LPCP test predicted adverse pathologies post-RP with area under the curve (AUC) via receiver operating characteristics analysis of greater than 0.80 and distinguished between Prostate Cancer Grade Groups 1, 2, and 3/Gleason Scores 3 + 3, 3 + 4, and 4 + 3. Further, LPCP derived-biomarker scores predicted Gleason pattern, stage, and adverse pathology with high precision—AUCs>0.80. ConclusionUsing MLDSA-derived phenotypic biomarker scores, the LPCP test successfully risk stratified Prostate Cancer Grade Groups 1, 2, and 3 (Gleason 3 + 3 and 7) into distinct subgroups predicted to have surgical adverse pathologies or not with high performance (>0.85 AUC).

Consistent Biopsy Quality and Gleason Grading Within the Global Active Surveillance Global Action Plan 3 Initiative: A Prerequisite for Future Studies

Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15000 patients worldwide, was created.Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group ≥2 (Gleason score ≥7) in 15% showed 89% concordance at review with moderate agreement (κ=0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses—without correction—toward uniform global AS guidelines for men with low-risk PCa. Patient summaryMovember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers.

Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules.

Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ.