A Comprehensive Review on Novel Pathways in Cancer Treatment: Clinical Applications and Future Prospects.

Cancer is a global health issue that requires ongoing therapeutic advances. This review provides an overview of recent treatment strategies focusing on novel pathways in cancer therapy. Emerging research has unveiled promising targets that go beyond traditional modalities, offering new avenues for precision medicine and improved patient outcomes. One key area of innovation lies in targeted therapies directed at specific molecular pathways implicated in cancer progression. The identification of novel biomarkers has paved the way for the development of precision medicines tailored to individual patient profiles. Immunotherapy has also revolutionised cancer treatment by using the immune system to identify and remove cancer cells. Moreover, advancements in epigenetic therapies and RNA-based interventions demonstrate unprecedented potential in modulating gene expression and disrupting cancer-specific signalling pathways. We have discussed the pathophysiology of cancer, different immune checkpoint inhibitors, and targeted therapies in signalling therapies. The epigenetic modulators, such as Histone deacetylase (HDACs) inhibitors and DNA methyltransferase (DNMT) inhibitors, were studied. Recent breakthroughs in cancer immunotherapy treatment (CAR-T) cell therapy showcase the potential to enhance the immune response against various cancers; thus, related information was incorporated. Further, RNA-based therapies like RNA interference and mRNA-based vaccines and therapies, combination therapies, and novel therapies were discussed in the present article.

Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes.

BACKGROUND: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. METHODS: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. RESULTS: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. CONCLUSIONS: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

Revisiting Post-ICU Admission Fluid Balance Across Pediatric Sepsis Mortality Risk Strata: A Secondary Analysis of a Prospective Observational Cohort Study.

OBJECTIVES: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (acute kidney injury), and use of continuous renal replacement therapy (CRRT) in pediatric septic shock. DESIGN: Ongoing multicenter prospective observational cohort. SETTING: Thirteen PICUs in the United States (2003-2023). PATIENTS: Six hundred and eighty-one children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cumulative percent PFB between days 1 and 7 (days 1-7 %PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of greater than or equal to two organ dysfunctions by day 7. Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II biomarkers were used to assign mortality probability and categorize patients into high mortality (n = 91), intermediate mortality (n = 134), and low mortality (n = 456) risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis-associated acute kidney injury on day 3, and use of CRRT, demonstrated that time-dependent variable days 1-7%PFB was independently associated with an increased hazard of complicated course. Risk-stratified analyses revealed that each 10% increase in days 1-7 %PFB was associated with increased hazard of complicated course only among patients with high mortality risk strata (adjusted hazard ratio 1.24 (95% CI, 1.08-1.43), p = 0.003). However, this association was not causally mediated by PERSEVERE-II biomarkers. CONCLUSIONS: Our data demonstrate the influence of cumulative %PFB on the risk of complicated course in pediatric septic shock. Contrary to our previous report, this risk was largely driven by patients categorized as having a high mortality risk based on PERSEVERE-II biomarkers. Incorporation of such prognostic enrichment tools in randomized trials of restrictive fluid management or early initiation of de-escalation strategies may inform targeted application of such interventions among at-risk patients.

Applications of artificial intelligence in prostate cancer histopathology.

The diagnosis of prostate cancer (PCa) depends on the evaluation of core needle biopsies by trained pathologists. Artificial intelligence (AI) derived models have been created to address the challenges posed by pathologists' increasing workload, workforce shortages, and variability in histopathology assessment. These models with histopathological parameters integrated into sophisticated neural networks demonstrate remarkable ability to identify, grade, and predict outcomes for PCa. Though the fully autonomous diagnosis of PCa remains elusive, recently published data suggests that AI has begun to serve as an initial screening tool, an assistant in the form of a real-time interactive interface during histological analysis, and as a second read system to detect false negative diagnoses. Our article aims to describe recent advances and future opportunities for AI in PCa histopathology.

SERUM HUMANIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE-ORGAN DYSFUNCTION SYNDROME.

ABSTRACT: Background: Multiple-organ dysfunction syndrome disproportionately contributes to pediatric sepsis morbidity. Humanin (HN) is a small peptide encoded by mitochondrial DNA and thought to exert cytoprotective effects in endothelial cells and platelets. We sought to test the association between serum HN (sHN) concentrations and multiple-organ dysfunction syndrome in a prospectively enrolled cohort of pediatric septic shock. Methods: Human MT-RNR2 ELISA was used to determine sHN concentrations on days 1 and 3. The primary outcome was thrombocytopenia-associated multiorgan failure (TAMOF). Secondary outcomes included individual organ dysfunctions on day 7. Associations across pediatric sepsis biomarker (PERSEVERE)-based mortality risk strata and correlation with platelet and markers of endothelial activation were tested. Results: One hundred forty subjects were included in this cohort, of whom 39 had TAMOF. The concentration of sHN was higher on day 1 relative to day 3 and among those with TAMOF phenotype in comparison to those without. However, the association between sHN and TAMOF phenotype was not significant after adjusting for age and illness severity in multivariate models. In secondary analyses, sHN was associated with presence of day 7 sepsis-associated acute kidney injury ( P = 0.049). Furthermore, sHN was higher among those with high PERSEVERE-mortality risk strata and correlated with platelet counts and several markers of endothelial activation. Conclusion: Future investigation is necessary to validate the association between sHN and sepsis-associated acute kidney injury among children with septic shock. Furthermore, mechanistic studies that elucidate the role of HN may lead to therapies that promote organ recovery through restoration of mitochondrial homeostasis among those critically ill.

Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort.

Background: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions. Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme. Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes. Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

External validation of the modified sepsis renal angina index for prediction of severe acute kidney injury in children with septic shock.

BACKGROUND: Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI). Here, we prospectively assess sRAI performance in a separate cohort. METHODS: A secondary analysis of a prospective, multicenter, observational study of children with septic shock admitted to the pediatric intensive care unit from 1/2019 to 12/2022. The primary outcome was severe AKI (≥ KDIGO Stage 2) on Day 3 (D3 severe AKI), and we compared predictive performance of the sRAI (calculated on Day 1) to the original RAI and serum creatinine elevation above baseline (D1 SCr > Baseline +). Original renal angina fulfillment (RAI +) was defined as RAI ≥ 8; sepsis renal angina fulfillment (sRAI +) was defined as RAI ≥ 20 or RAI 8 to < 20 with platelets < 150 × 103/µL. RESULTS: Among 363 patients, 79 (22%) developed D3 severe AKI. One hundred forty (39%) were sRAI + , 195 (54%) RAI + , and 253 (70%) D1 SCr > Baseline + . Compared to sRAI-, sRAI + had higher risk of D3 severe AKI (RR 8.9, 95%CI 5-16, p < 0.001), kidney replacement therapy (KRT) (RR 18, 95%CI 6.6-49, p < 0.001), and mortality (RR 2.5, 95%CI 1.2-5.5, p = 0.013). sRAI predicted D3 severe AKI with an AUROC of 0.86 (95%CI 0.82-0.90), with greater specificity (74%) than D1 SCr > Baseline (36%) and RAI + (58%). On multivariable regression, sRAI + retained associations with D3 severe AKI (aOR 4.5, 95%CI 2.0-10.2, p < 0.001) and need for KRT (aOR 5.6, 95%CI 1.5-21.5, p = 0.01). CONCLUSIONS: Prediction of severe AKI in pediatric septic shock is important to improve outcomes, allocate resources, and inform enrollment in clinical trials examining potential disease-modifying therapies. The sRAI affords more accurate and specific prediction than context-free SCr elevation or the original RAI in this population.

Application of thermoresponsive smart polymers based in situ gel as a novel carrier for tumor targeting.

The temperature-triggered in situ gelling system has been revolutionized by introducing an intelligent polymeric system. Temperature-triggered polymer solutions are initially in a sol state and then undergo a phase transition to form a gel at body temperature due to various parameters like pH, temperature, and so on. These smart polymers offer a number of advantages, including ease of administration, long duration of release of the drug, low administration frequency with good patient compliance, and targeted drug delivery with fewer adverse effects. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm), polyethylene glycol (PEG), poly (N, N'-diethyl acrylamide), and polyoxypropylene (PPO) have been briefly discussed. In addition to various novel Drug Delivery Systems (DDS), the smart temperature-triggered polymeric system has various applications in cancer therapy and many other disease conditions. This review focuses on the principals involved in situ gelling systems using various temperature-triggered polymers for chemotherapeutic purposes, using smart DDS, and their advanced application in cancer therapy, as well as available marketed formulations and recent advances in these thermoresponsive sol-gel transforming systems.

Revisiting post-ICU admission fluid balance across pediatric sepsis mortality risk strata: A secondary analyses from a prospective observational cohort study.

Introduction: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (AKI), and use of renal replacement therapy (CRRT) in pediatric septic shock. Design: Ongoing multi-center prospective observational cohort. Setting: Thirteen pediatric ICUs in the United States (2003-2023). Patients: Six hundred and eighty-one children with septic shock. Interventions: None. Measurements and Main Results: Cumulative percent positive fluid balance between day 1-7 (Day 1-7%PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of ≥ 2 organ dysfunctions by day 7. PERSEVERE-II biomarkers were used to assign mortality probability and categorize patients into high (n = 91), intermediate (n = 134), and low (n = 456) mortality risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis associated acute kidney injury (SA-AKI) on Day 3, and any use of CRRT, demonstrated that time-dependent variable Day 1-7%PFB was independently associated with increased hazard of complicated course in the cohort. Risk stratified analyses revealed that each 10% increase in Day 1-7%PFB was independently associated with increased hazard of complicated course among patients with high mortality risk strata (adj HR of 1.24 (95%CI: 1.08-1.42), p = 0.002), but not among those categorized as intermediate- or low- mortality risk. Conclusions: Our data demonstrate the independent influence of cumulative %PFB on the risk of complicated course. Contrary to our previous report, this risk was largely driven by patients categorized as having a high-mortality risk based on PERSEVERE-II biomarkers. Further research is necessary to determine whether this subset of patients may benefit from targeted deployment of restrictive fluid management or early initiation of de-escalation therapies upon resolution of shock.

Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock.

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI. METHODS: Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of ≥ Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI among prespecified subgroups based on PERSEVERE-II risk. RESULTS: A total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr. CONCLUSIONS: Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children.

SERUM SOLUBLE ENDOGLIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE ORGAN DYSFUNCTION SYNDROME.

ABSTRACT: Background: Endothelial activation is a key driver of multiple organ dysfunction syndrome (MODS). Soluble endoglin (sENG) is expressed by mature and progenitor endothelial cells and thought to have angiogenic properties. We sought to determine the association between sENG and pediatric sepsis-associated MODS. Methods: Prospective observational study of pediatric septic shock. Primary outcome of interest was complicated course-a composite of death by (or) MODS on day 7 of illness. Secondary outcomes included individual organ dysfunctions. Endothelial biomarkers including sENG were measured using multiplex Luminex assays among patients with existing data on the Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) data. Multivariable regression was used to test the independent association between sENG and clinical outcomes. Serum sENG concentrations across PERSEVERE-II mortality risk strata and correlations with established markers of endothelial dysfunction were determined. Results: Three hundred six critically ill children with septic shock were included. Serum sENG concentrations were higher among those with primary and secondary outcomes of interest, with the exception of acute neurological dysfunction. Soluble endoglin was independently associated with increased odds of complicated course (adjusted odds ratio, 1.53; 95% confidence interval, 1.02-2.27; P = 0.038) and acute renal dysfunction (adjusted odds ratio, 1.84; 95% confidence interval, 1.18-2.876; P = 0.006). Soluble endoglin demonstrated graded responses across PERSEVERE-II risk strata and was positively correlated with endothelial biomarkers, except angiopoietin-1. Conclusions: Serum sENG is independently associated with complicated course and acute renal dysfunction in pediatric septic shock. Future studies are required to validate our observational data, and mechanistic studies are necessary to elucidate whether endoglin plays an organ-specific role in the development or resolution of acute renal dysfunction in sepsis.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

BACKGROUND: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction. METHODS: Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified. RESULTS: A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype. CONCLUSIONS: We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies.

Multicenter Evaluation of Pre-operative Feeding in Infants with Ductal Dependent Circulation.

Enteral feeds are often withheld from neonates with ductal dependent cardiac lesions who are receiving prostaglandins. This is despite positive benefits of enteral feeding. We describe a multicenter cohort of these neonates who were fed pre-operatively. We also give a granular description of vital sign measurements and other risk factors prior to feeding. A retrospective chart review was performed at seven centers. Inclusion criteria were full-term neonates under one month of age with ductal dependent lesions receiving prostaglandins. These neonates were fed for at least 24 h during the pre-operative period. Premature neonates were excluded. Using the inclusion criteria, 127 neonates were identified. While being fed, 20.5% of the neonates were intubated, 10.2% were on inotropes, and 55.9% had an umbilical arterial catheter in place. Median oxygen saturations in the six hours prior to feeding were 92.5% in patients with cyanotic lesions, median diastolic blood pressure was 38 mmHg and median somatic NIRS were 66.5%. The median peak daily feeding volume reached was 29 ml/kg/day (IQ range 15.5-96.8 ml/kg/day). One patient developed suspected necrotizing enterocolitis (NEC) in this cohort. Only one adverse event occurred, which was an aspiration thought to be related to feeding, but did not result in intubation or cessation of feeds. NEC was rare among neonates with ductal dependent lesions while receiving enteral nutrition pre-operatively. Umbilical arterial catheters were in place in the majority of these patients. Hemodynamic measures demonstrated a high median oxygen saturation prior to initiation of feeds.

Predicting Response of Triple-Negative Breast Cancer to Neoadjuvant Chemotherapy Using a Deep Convolutional Neural Network-Based Artificial Intelligence Tool.

PURPOSE: Achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved patient outcomes in triple-negative breast cancer (TNBC). Currently, there are no validated predictive biomarkers for the response to NAC in TNBC. We developed and validated a deep convolutional neural network-based artificial intelligence (AI) model to predict the response of TNBC to NAC. MATERIALS AND METHODS: Whole-slide images (WSIs) of hematoxylin and eosin-stained core biopsies from 165 (pCR in 60 and non-pCR in 105) and 78 (pCR in 31 and non-pCR in 47) patients with TNBC were used to train and validate the model. The model extracts morphometric features from WSIs in an unsupervised manner, thereby generating clusters of morphologically similar patterns. Downstream ranking of clusters provided regions of interest and morphometric scores; a low score close to zero and a high score close to one represented a high or low probability of response to NAC. RESULTS: The predictive ability of AI score for the entire cohort of 78 patients with TNBC ascertained by receiver operating characteristic analysis demonstrated an area under the curve (AUC) of 0.75. The AUC for stages I, II, and III disease were 0.88, 0.73, and 0.74, respectively. Using a cutoff value of 0.35, the positive predictive value of the AI score for pCR was 73.7%, and the negative predictive value was 76.2% for non-pCR patients. CONCLUSION: To our knowledge, this study is the first to demonstrate the use of an AI tool on digitized hematoxylin and eosin-stained tissue images to predict the response to NAC in patients with TNBC with high accuracy. If validated in subsequent studies, these results may serve as an ancillary aid for individualized therapeutic decisions in patients with TNBC.

Serum renin and prorenin concentrations predict severe persistent acute kidney injury and mortality in pediatric septic shock.

BACKGROUND: Studies in critically ill adults demonstrate associations between serum renin concentrations (a proposed surrogate for renin-angiotensin-aldosterone system dysregulation) and poor outcomes, but data in critically ill children are lacking. We assessed serum renin + prorenin concentrations in children with septic shock to determine their predictive ability for acute kidney injury (AKI) and mortality. METHODS: We conducted a secondary analysis of a multicenter observational study of children aged 1 week to 18 years admitted to 14 pediatric intensive care units (PICUs) with septic shock and residual serum available for renin + prorenin measurement. Primary outcomes were development of severe persistent AKI (≥ KDIGO stage 2 for ≥ 48 h) in the first week and 28-day mortality. RESULTS: Among 233 patients, day 1 median renin + prorenin concentration was 3436 pg/ml (IQR 1452-6567). Forty-two (18%) developed severe persistent AKI and 32 (14%) died. Day 1 serum renin + prorenin predicted severe persistent AKI with an AUROC of 0.75 (95% CI 0.66-0.84, p < 0.0001; optimal cutoff 6769 pg/ml) and mortality with an AUROC of 0.79 (95% CI 0.69-0.89, p < 0.0001; optimal cutoff 6521 pg/ml). Day 3/day 1 (D3:D1) renin + prorenin ratio had an AUROC of 0.73 (95% CI 0.63-0.84, p < 0.001) for mortality. On multivariable regression, day 1 renin + prorenin > optimal cutoff retained associations with severe persistent AKI (aOR 6.8, 95% CI 3.0-15.8, p < 0.001) and mortality (aOR 6.9, 95% CI 2.2-20.9, p < 0.001). Similarly, D3:D1 renin + prorenin > optimal cutoff was associated with mortality (aOR 7.6, 95% CI 2.5-23.4, p < 0.001). CONCLUSIONS: Children with septic shock have very elevated serum renin + prorenin concentrations on PICU admission, and these concentrations, as well as their trend over the first 72 h, predict severe persistent AKI and mortality. A higher resolution version of the Graphical abstract is available as Supplementary information.

Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1.

Background: Sepsis is associated with significant mortality, yet there are no efficacious therapies beyond antibiotics and supportive care. In adult sepsis studies, PCSK9 loss-of-function (LOF) and inhibition has shown therapeutic promise, likely through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance. In contrast, we previously demonstrated higher mortality in septic juvenile hosts with PCSK9 LOF. In addition to direct influence on serum lipoprotein levels, PCSK9 likely exerts pleiotropic effects on vascular endothelium. Both mechanisms may influence sepsis outcomes. We sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction in pediatric sepsis. Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. Single nucleotide polymorphisms of PCSK9 and LDLR genes were assessed. Serum PCSK9, lipoprotein, and endothelial marker concentrations were measured. Multivariable linear regression tested the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses assessed impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified. Results: 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of patients homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 levels did not correlate with endothelial dysfunction. PCSK9 LOF significantly influenced concentrations of Angiopoietin-1 (Angpt-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). However, upon adjusting for LDL and HDL, PCSK9 LOF remained significantly associated with low Angpt-1 alone. Causal Mediation Analysis demonstrated that the effect of PCSK9 LOF on mortality was partially mediated by Angpt-1 (p=0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype. Conclusions: PCSK9 LOF independently influences serum Angpt-1 levels in pediatric septic shock. Angpt-1 likely contributes mechanistically to the effect of PCSK9 LOF on mortality in juvenile hosts. Mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of novel pediatric-specific sepsis therapies.

Design and Characterization of Silver Nanoparticles of Different Species of Curcuma in the Treatment of Cancer Using Human Colon Cancer Cell Line (HT-29).

BACKGROUND: Cancer is a deadly disease responsible for worldwide mortality; usually, middle- and low-income countries have been more affected by cancer and are responsible for 70% of deaths. The present study was performed with the aim to design silver nanoparticles using three species of Curcuma, i.e., Curcuma longa, Curcuma aromatica, and Curcuma caesia. METHODS: The rhizomes of different plants were extracted with ethanol. The rhizome extracts were used to prepare silver nanoparticles. It was optimized at different pH, silver ion concentrations, and concentrations of plant extracts. The anticancer activity of prepared nanoparticles of C. longa, C. aromatica, and C. caesia was evaluated on a human colon cancer cell line (HT-29) using sulforhodamine B (SRB) assay. RESULTS: The percentage yield of C. longa, C. aromatica, and C. caesia was 11.34 g, 15.45 g, and 12.67 g, respectively. The results exhibited that the prepared nanoparticles were smooth and spherical. All the nanoparticles of rhizome extracts rescued the viability of HT-29 cells in a different extent. HT-29 cells were sensitive to prepared nanoparticles that induce more cytotoxicity towards cancer cells. CONCLUSION: Thus, the prepared silver nanoparticle of Curcuma species through green synthesis may help treat cancer with low toxicity.

Clinical manifestations of human monkeypox infection and implications for outbreak strategy.

Monkeypox is an orthopoxvirus-based zoonotic illness that causes symptoms similar to smallpox in humans. Health care workers around the world are making it a priority to educate themselves on the many clinical manifestations and treatment options for this virus as public health agencies strive to stop the current outbreak. The infected do not have access to any treatment at this time. However, information obtained from the smallpox pandemic has led researchers to examine vaccinia immune globulin (IVG), tecovirimat, and cidofovir as viable treatments for monkeypox. Moreover, medication like tecovirimat may be given in extreme circumstances, and supportive therapy can help with symptom relief. The European Medicines Agency (EMA) certified tecovirimat as safe and effective against monkeypox in 2022, per the World Health Organization (WHO). As there are now no established guidelines for alleviating these symptoms, the efficacy of these treatments is highly questionable. Some high-profile cases in recent years have cast doubt on the long-held belief that this illness is rare and always resolves itself without treatment. We aimed to conduct this review to get a deeper comprehension of the evolving epidemiology of monkeypox by analysing such factors as the number of confirmed, probable, and potential cases, the median age at presentation, the mortality rate, and the geographic distribution of the disease. This study offers an updated review of monkeypox and the clinical treatments that are currently available as a result of the worldwide epidemics.

Genomics and Pediatric Sepsis.

Sepsis is a clinical syndrome manifested by a dysregulation of the immune system triggered by an infection. The severity of illness is variable, which can include mild symptoms with no organ dysfunction to severe symptoms and multiorgan failure, eventually leading to death. Advances in bioinformatics have elucidated distinct sepsis endotypes and have allowed for a better understanding of the pathophysiologic mechanisms. As we learn more about these sepsis endotypes, more precise therapies will emerge for use as adjuncts to antibiotics. [Pediatr Ann. 2022;51(10):e387-e389.].

Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study.

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock. METHODS: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter. RESULTS: Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables-ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1-contributed to the models' predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively. CONCLUSIONS: The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.