Role of Alpha-Fetoprotein in the Pathogenesis of Cancer.

Alpha-fetoprotein (AFP) belongs to the albuminoid protein family and is considered as the fetal analog of serum albumin. This plasma protein is initially synthesized in the fetal liver and yolk sac and shows a maximum peak near the end of the first trimester. Later, concentrations begin to decline prenatally and drop precipitously after birth. This protein has three key ligand-binding pockets for interactions with various biomolecules. It contains multiple phosphorylation and acetylation sites for the regulation of physiological and pathophysiological states. High serum AFP titer is an established biomarker for yolk sac, embryonal and hepatocellular carcinoma. The present review critically analyzes the chemical nature, receptors, clinical implications, and therapeutic aspects of AFP, underpinning the development of different types of cancer.

Potential soil organic carbon sequestration vis-a-vis methane emission in lowland rice agroecosystem.

Mitigating the atmospheric greenhouse effect while enhancing the inherent soil quality and productive capacity is possible through soil carbon (C) sequestration, which has a significant potential to counteract the adverse effects of agroecosystem level C emission through natural and anthropogenic means. Although rice is the most important food in India, feeding more than 60% of the country's population, it is commonly blamed for significant methane (CH4) emissions that accelerate climate change. Higher initial soil organic matter concentrations would create more CH4 under the flooded soil conditions, as reducible soil C is a prerequisite for CH4 generation. In India, rice is generally cultivated in lowlands under continuous flooding. Less extensive organic matter breakdown in lowland rice agroecosystems often significantly impacts the dynamics of soil active and passive C pools. Change from conventional to conservation agriculture might trap a significant quantity of SOC. The study aims to investigate the potential of rice-based soils to sequester C and reduce the accelerated greenhouse effects through modified farming practices, such as crop residue retention, crop rotation, organic farming, varietal selection, conservation agriculture, integrated nutrient management, and water management. Overall, lowland rice agroecosystems can sequester significant amounts of SOC, but this potential must be balanced against the potential for CH4 emissions. Management practices that reduce CH4 emissions while increasing soil C sequestration should be promoted and adopted to maximize the sustainability of rice agroecosystems. This review is important for understanding the effectiveness of the balance between SOC sequestration and CH4 emissions in lowland rice agroecosystems for adopting sustainable agricultural practices in the context of climate change.

Atrial Fibrillation and Perioperative Inflammation (FIBRILLAMMED Study): A Retrospective Analysis of the Predictive Role of Preoperative Albumin-Adjusted Platelet-Leukocytic Indices in OPCABG.

Objective: New-onset atrial fibrillation (NOAF), an important postoperative complication, has pertinent inflammatory links. Motivated by the encouraging literature on the prognostic role of hypoalbuminemia, leukocytic indices [LIs: neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR)], systemic inflammation response index (SIRI=NLR×monocyte) and platelet-leukocytic indices [PLIs: platelet-to-lymphocyte ratio (PLR)], systemic immune inflammation index (SII=NLR×platelet), aggregate index of systemic inflammation (AISI=NLR×platelet×monocyte), we sought to investigate the NOAF-predictive value of preoperative albumin-adjusted indices (aa-LIs and aa-PLIs) in an off-pump coronary artery bypass grafting (OPCABG) setting. Methods: Of 899 patients, 151 patients (16.79%) developed the primary outcome i.e. NOAF that was analyzed further retrospectively for its predictors instead of the highlighted text perioperative data of 899 patients undergoing elective OPCABG, were retrospectively analyzed. The study participants were categorized into non-NOAF and NOAF groups (defined as new-onset atrial arrhythmia with irregular RR interval with indistinct P wave in the first week postoperatively). Results: One hundred and fifty-one patients (16.79%) developed NOAF. On univariate analysis: age, smoker status, The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, systemic hypertension, diabetes mellitus, prior congestive heart failure (CHF), and a higher preoperative NLR, PLR, SII, and albumin were significant predictors of NOAF. While age, CHF, and EuroSCORE II retained predictive significance in multivariate analysis, LI-PLIs and albumin did not emerge as independent NOAF predictors. Notably, aa-NLR, aa-PLR, and aa-SII independently predicted NOAF on the computation of model-estimates in the regression analysis (Odds ratio; 95% confidence interval: 31.05;15.75-70.61, 1.04;1.02-1.05, 1.12;1.10-1.14, respectively, P < 0.001). aa-NLR ≥1.32, aa-PLR ≥52.64, and aa-SII ≥344.38 predicted NOAF with the respective AUC;sensitivity;specificity of 0.66;63.6%;73.3%, 0.63;66.2%;59.0%, and 0.65;58.3%;78.2%. Preoperative aa-NLR, aa-PLR and aa-SII also positively correlated with CHA2DS2-VASc score (R=0.40, 0.45 and 0.42; P < 0.001). Conclusion: The independent NOAF predictive value of aa-NLR, aa-PLR, and aa-SII reiterates the inflammatory relationship of the arrhythmic complication following OPCABG.

Revisiting the gonadotropic regulation of mammalian spermatogenesis: evolving lessons during the past decade.

Spermatogenesis is a multi-step process of male germ cell (Gc) division and differentiation which occurs in the seminiferous tubules of the testes under the regulation of gonadotropins - Follicle Stimulating Hormone (FSH) and Luteinising hormone (LH). It is a highly coordinated event regulated by the surrounding somatic testicular cells such as the Sertoli cells (Sc), Leydig cells (Lc), and Peritubular myoid cells (PTc). FSH targets Sc and supports the expansion and differentiation of pre-meiotic Gc, whereas, LH operates via Lc to produce Testosterone (T), the testicular androgen. T acts on all somatic cells e.g.- Lc, PTc and Sc, and promotes the blood-testis barrier (BTB) formation, completion of Gc meiosis, and spermiation. Studies with hypophysectomised or chemically ablated animal models and hypogonadal (hpg) mice supplemented with gonadotropins to genetically manipulated mouse models have revealed the selective and synergistic role(s) of hormones in regulating male fertility. We here have briefly summarized the present concept of hormonal control of spermatogenesis in rodents and primates. We also have highlighted some of the key critical questions yet to be answered in the field of male reproductive health which might have potential implications for infertility and contraceptive research in the future.

IDO1 and inflammatory neovascularization: bringing new blood to tumor-promoting inflammation.

In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the 'Hallmarks of Cancer', it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance to tumor antigens, thereby helping tumors evade adaptive immune control. Additionally, recent findings indicate that IDO1 also promotes tumor neovascularization by subverting local innate immunity. This newly recognized function for IDO1 is mediated by a unique myeloid cell population termed IDVCs (IDO1-dependent vascularizing cells). Initially identified in metastatic lesions, IDVCs may exert broader effects on pathologic neovascularization in various disease settings. Mechanistically, induction of IDO1 expression in IDVCs by the inflammatory cytokine IFNγ blocks the antagonistic effect of IFNγ on neovascularization by stimulating the expression of IL6, a powerful pro-angiogenic cytokine. By contributing to vascular access, this newly ascribed function for IDO1 aligns with its involvement in other cancer hallmark functionalities, (tumor-promoting inflammation, immune escape, altered cellular metabolism, metastasis), which may stem from an underlying role in normal physiological functions such as wound healing and pregnancy. Understanding the nuances of how IDO1 involvement in these cancer hallmark functionalities varies between different tumor settings will be crucial to the future development of successful IDO1-directed therapies.

N-WASP is competent for downstream signaling before full release from autoinhibition.

Allosteric regulation of intrinsically disordered proteins (IDPs) is still vastly understudied compared to the counterpart of structured proteins. Here, we used molecular dynamics simulations to characterize the regulation of the IDP N-WASP by the binding of its basic region with inter- and intramolecular ligands (PIP2 and an acidic motif, respectively). The intramolecular interactions keep N-WASP in an autoinhibited state; PIP2 binding frees the acidic motif for interacting with Arp2/3 and thereby initiating actin polymerization. We show that PIP2 and the acidic motif compete in binding with the basic region. However, even when PIP2 is present at 30% in the membrane, the acidic motif is free of contact with the basic region ("open" state) in only 8.5% of the population. The very C-terminal three residues of the A motif are crucial for Arp2/3 binding; conformations where only the A tail is free are present at a much higher population than the open state (40- to 6-fold, depending on the PIP2 level). Thus, N-WASP is competent for Arp2/3 binding before it is fully freed from autoinhibition.

Why Does Synergistic Activation of WASP, but Not N-WASP, by Cdc42 and PIP2 Require Cdc42 Prenylation?

Human WASP and N-WASP are homologous proteins that require the binding of multiple regulators, including the acidic lipid PIP2 and the small GTPase Cdc42, to relieve autoinhibition before they can stimulate the initiation of actin polymerization. Autoinhibition involves intramolecular binding of the C-terminal acidic and central motifs to an upstream basic region and GTPase binding domain. Little is known about how a single intrinsically disordered protein, WASP or N-WASP, binds multiple regulators to achieve full activation. Here we used molecular dynamics simulations to characterize the binding of WASP and N-WASP with PIP2 and Cdc42. In the absence of Cdc42, both WASP and N-WASP strongly associate with PIP2-containing membranes, through their basic region and also possibly through a tail portion of the N-terminal WH1 domain. The basic region also participates in Cdc42 binding, especially for WASP; consequently Cdc42 binding significantly compromises the ability of the basic region in WASP, but not N-WASP, to bind PIP2. PIP2 binding to the WASP basic region is restored only when Cdc42 is prenylated at the C-terminus and tethered to the membrane. This distinction in the activation of WASP and N-WASP may contribute to their different functional roles.

An Arg/Ala-rich helix in the N-terminal region of M. tuberculosis FtsQ is a potential membrane anchor of the Z-ring.

Mtb infects a quarter of the worldwide population. Most drugs for treating tuberculosis target cell growth and division. With rising drug resistance, it becomes ever more urgent to better understand Mtb cell division. This process begins with the formation of the Z-ring via polymerization of FtsZ and anchoring of the Z-ring to the inner membrane. Here we show that the transmembrane protein FtsQ is a potential membrane anchor of the Mtb Z-ring. In the otherwise disordered cytoplasmic region of FtsQ, a 29-residue, Arg/Ala-rich α-helix is formed that interacts with upstream acidic residues in solution and with acidic lipids at the membrane surface. This helix also binds to the GTPase domain of FtsZ, with implications for drug binding and Z-ring formation.

Metallic micro-ring device for highly efficient large cargo delivery in mammalian cells using infrared light pulses.

Uniform transfection of biomolecules into live cells with high delivery efficiency and cell viability is an immensely important area of biological research and has many biomedical applications. In the present study, we report highly efficient, uniform parallel intracellular delivery of small to very large biomolecules into diverse cell types using a titanium micro-ring (TMR) device activated by infrared (IR) light pulse. A TMR array device (2 cm × 2 cm) consists of a 10 µm outer diameter and 3 µm inner diameter for each micro-ring, and 10 µm interspacing between two micro-rings. Upon IR (1050 nm) pulse laser irradiation on the TMR device, photothermal cavitation bubbles are generated, disrupting the cell plasma membrane, and biomolecules are gently delivered into the cells by a simple diffusion process. This TMR device successfully delivered diverse types of small to very large biomolecules such as propidium iodide (PI; 668.4 Da) dye, dextran (3 kDa), small interfering RNA (13.3 kDa), enhanced green fluorescent protein expression plasmid DNA (6.2 kb), and ß-galactosidase enzyme (465 kDa) into human cervical (SiHa), mouse fibroblast (L929), and mouse neural crest-derived (N2a) cancer cells. For smaller molecules (PI dye), delivery efficiency and cell viability were achieved at ∼96% and ∼97%, respectively, with a laser fluence of 21 mJ cm-2 for 250 pulses. In contrast, ∼85% transfection efficiency and ∼90% cell viability were achieved for plasmid DNA with 45 mJ cm-2 laser fluence for 250 pulses in SiHa cells. Moreover, the intracellular delivery of ß-galactosidase enzyme was confirmed with confocal microscopy and flow cytometry analysis resulting in ∼83% co-staining of ß-galactosidase enzyme and calcein AM. Based on these efficient deliveries of diverse types of biomolecules in different cell types, the device has the potential for cellular diagnostic and therapeutic applications.

Use of Critical View of Safety and Proctored Preceptorship in Preventing Bile Duct Injury During Laparoscopic Cholecystectomy-Experience of 3726 Cases From a Tertiary Care Teaching Institute.

INTRODUCTION: Bile duct injury (BDI) continues to occur despite technological advances and improvements in surgical training over the past 2 decades. This study was conducted to audit our data on laparoscopic cholecystectomies performed over the past 2 decades to determine the role of Critical View of Safety (CVS) and proctored preceptorship in preventing BDI and postoperative complications. MATERIALS AND METHODS: All patients undergoing elective laparoscopic cholecystectomy were analyzed retrospectively. The data were obtained from a prospectively maintained database from January 2004 to December 2019. Proctored preceptorship was used in all cases. Intraoperative details included the number of patients where CVS was defined, number of BDI and conversions. Postoperative outcomes, including hospital stay, morbidity, and bile duct stricture, were noted. RESULTS: Three thousand seven hundred twenty-six patients were included in the final analysis. Trainee surgeons performed 31.6% of surgeries and 9.5% of these surgeries were taken over by the senior surgeon. A CVS could be delineated in 96.6% of patients. The major BDI rate was only 0.05%. CONCLUSION: This study reiterates the fact that following the basic tenets of safe laparoscopic cholecystectomy, defining and confirming CVS, and following proctored preceptorship are critical in preventing major BDI.

Retrospective Evaluation of Platelet-Leukocyte Indices and Cardiac Surgical Outcomes in Acyanotic Heart Disease Patients with Pulmonary Hypertension (REPLICA-PH)

Abstract Introduction: Acyanotic congenital heart disease (ACHD) patients with pulmonary hypertension (PH) are prone to postoperative complications, and characterization of the risk profile continues to fail in identifying inflammatory predilection. Our objective is to investigate the role of platelet-leukocyte indices (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII] [neutrophil × platelet/lymphocyte]) in predicting poor outcomes following cardiac surgery in ACHD cohort with preoperative PH. Methods: This single-center, retrospective risk-predictive study included ACHD patients undergoing surgical correction at our tertiary cardiac center between January 2015 and December 2019. Standard institutional perioperative management protocol was followed, and poor postoperative outcome was defined as ≥ 1 of: low cardiac output syndrome, new-onset renal failure, prolonged mechanical ventilation (MV > 24 hours), stroke, sepsis, and/or death. Results: One hundred eighty patients out of 1,040 (17.3%) presented poor outcome. On univariate analysis, preoperative factors including right ventricular systolic pressure (RVSP) (PH-severity marker), congestive heart failure, albumin, NLR, PLR, SII, and aortic cross-clamping (ACC) and cardiopulmonary bypass (CPB) times predicted poor outcome. However, on multivariate analysis, RVSP, NLR, SII, and ACC and CPB times emerged as independent predictors. An NLR, SII prognostic cutoff of 3.33 and 860.6×103/mm3 was derived (sensitivity: 77.8%, 78.9%; specificity: 91.7%, 82.2%; area under the curve: 0.871, 0.833). NLR and SII values significantly correlated with postoperative MV duration, mean vasoactive-inotropic scores, and length of intensive care unit and hospital stay (P<0.001). Conclusion: Novel parsimonious, reproducible plateletleukocyte indices present the potential of stratifying the risk in congenital cardiac surgical patients with pre-existing PH.

VASOplegia is Predicted by Preoperative Platelet-LEucocyte conGlomerate Indices in Cardiac Surgery (VASOPLEGICS): A retrospective single-center study.

Background: Post-cardiotomy vasoplegia syndrome (VS) is often linked to an exaggerated inflammatory response to cardiopulmonary bypass (CPB). At the same time, the prognostic role of platelet-leucocyte indices (PLIs) and leucocyte indices (LIs), (platelet-lymphocyte ratio [PLR], systemic immune-inflammation index [SII = platelet × neutrophil/lymphocyte], aggregate index of systemic inflammation [AISI = platelet × monocyte × neutrophil/lymphocyte], and neutrophil-lymphocyte ratio [NLR], systemic inflammation response index [SIRI = monocyte × neutrophil/lymphocyte), respectively] has been recently described in diverse inflammatory settings. Methods: The retrospective study was conducted to evaluate the VS predictive performance of PLIs and LIs in 1,045 adult patients undergoing elective cardiac surgery at a tertiary care center. VS was defined by mean blood pressure <60 mmHg, low systemic vascular resistance (SVRI <1,500 dynes.s/cm 5/m2), a normal or high CI (>2.5 L/min/m2), and a normal or reduced central filling pressure despite high-dose vasopressors. Results: About 205 (19.61%) patients developed VS postoperatively. On univariate analysis, age, diabetes, dialysis-dependent renal failure, preoperative congestive heart failure (CHF), the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, ejection fraction, NLR, PLR, SII, SIRI, AISI, CPB, and aortic cross clamp (ACC) duration, packed red blood cell (PRBC) transfusion, and time-weighted average blood glucose predicted VS. Subsequent to the multivariate analysis, the predictive performance of EuroSCORE II (OR: 3.236; 95% CI: 2.345-4.468; P < 0.001), CHF (OR: 1.04; 95% CI: 1.02-1.06; P = 0.011), SII (OR: 1.09; 95% CI: 1.02-1.18; P = 0.001), AISI (OR: 1.11; 95% CI: 1.05-1.17; P < 0.001), PRBC (OR: 4.747; 95% CI: 2.443-9.223; P < 0.001), ACC time (OR: 1.003; 95% CI: 1.001-1.005; P = 0.004), and CPB time (OR: 1.016; 95% CI: 1.004-1.028; P = 0.001) remained significant. VS predictive cut-offs of SII and AISI were 1,045 1045×109 /mm3 and 137532×109/mm3, respectively. AISI positively correlated with the postoperative vasoactive-inotropic score (R = 0.718), lactate (R = 0.655), mechanical ventilation duration (R = 0.837), and ICU stay (R = 0.757). Conclusions: Preoperative elevated SII and AISI emerged as independent predictors of post-cardiotomy VS.

Sequence-Dependent Backbone Dynamics of Intrinsically Disordered Proteins.

For intrinsically disordered proteins (IDPs), a pressing question is how sequence codes for function. Dynamics serves as a crucial link, reminiscent of the role of structure in sequence-function relations of structured proteins. To define general rules governing sequence-dependent backbone dynamics, we carried out long molecular dynamics simulations of eight IDPs. Blocks of residues exhibiting large amplitudes in slow dynamics are rigidified by local inter-residue interactions or secondary structures. A long region or an entire IDP can be slowed down by long-range contacts or secondary-structure packing. On the other hand, glycines promote fast dynamics and either demarcate rigid blocks or facilitate multiple modes of local and long-range inter-residue interactions. The sequence-dependent backbone dynamics endows IDPs with versatile response to binding partners, with some blocks recalcitrant while others readily adapting to intermolecular interactions.

Membrane Tethering of SepF, a Membrane Anchor for the Mycobacterium tuberculosis Z-ring.

Bacterial cell division begins with the formation of the Z-ring via polymerization of FtsZ and the localization of Z-ring beneath the inner membrane through membrane anchors. In Mycobacterium tuberculosis (Mtb), SepF is one such membrane anchor, but our understanding of the underlying mechanism is very limited. Here we used molecular dynamics simulations to characterize how SepF itself, a water-soluble protein, tethers to acidic membranes that mimic the Mtb inner membrane. In addition to an amphipathic helix (residues 1-12) at the N-terminus, membrane binding also occurs through two stretches of positively charged residues (Arg27-Arg37 and Arg95-Arg107) in the long linker preceding the FtsZ-binding core domain (residues 128-218). The additional interactions via the disordered linker stabilize the membrane tethering of SepF, and keep the core domain of SepF and hence the attached Z-ring close to the membrane. The resulting membrane proximity of the Z-ring in turn enables its interactions with and thus recruitment of two membrane proteins, FtsW and CrgA, at the late stage of cell division.

ReSMAP: Web Server for Predicting Residue-Specific Membrane-Association Propensities of Intrinsically Disordered Proteins.

The functional processes of many proteins involve the association of their intrinsically disordered regions (IDRs) with acidic membranes. We have identified the membrane-association characteristics of IDRs using extensive molecular dynamics (MD) simulations and validated them with NMR spectroscopy. These studies have led to not only deep insight into functional mechanisms of IDRs but also to intimate knowledge regarding the sequence determinants of membrane-association propensities. Here we turned this knowledge into a web server called ReSMAP, for predicting the residue-specific membrane-association propensities from IDR sequences. The membrane-association propensities are calculated from a sequence-based partition function, trained on the MD simulation results of seven IDRs. Robustness of the prediction is demonstrated by leaving one IDR out of the training set. We anticipate there will be many applications for the ReSMAP web server, including rapid screening of IDR sequences for membrane association.

COVID-19 Positive Cohort Undergoing Cardiac Surgery: A Possible Un(3H)oly Trinity of Hypoxia-Hemolysis-Hyperinflammation

Abstract While the fraternity continues to ponder on the mechanisms by which coronavirus disease (COVID-19) positivity affects the outcome of cardiac surgical subset, we put forth a 3H (Hypoxia-Hemolysis-Hyperinflammation) trilogy aimed at elucidating the liaison between cardiopulmonary bypass (commonly employed for cardiac surgical conduct) and COVID-19 infection. A sound comprehension of the same can doubtlessly assist the perioperative team in staging a well-directed pathophysiology-driven management approach.

Artificial intelligence guided conformational mining of intrinsically disordered proteins.

Artificial intelligence recently achieved the breakthrough of predicting the three-dimensional structures of proteins. The next frontier is presented by intrinsically disordered proteins (IDPs), which, representing 30% to 50% of proteomes, readily access vast conformational space. Molecular dynamics (MD) simulations are promising in sampling IDP conformations, but only at extremely high computational cost. Here, we developed generative autoencoders that learn from short MD simulations and generate full conformational ensembles. An encoder represents IDP conformations as vectors in a reduced-dimensional latent space. The mean vector and covariance matrix of the training dataset are calculated to define a multivariate Gaussian distribution, from which vectors are sampled and fed to a decoder to generate new conformations. The ensembles of generated conformations cover those sampled by long MD simulations and are validated by small-angle X-ray scattering profile and NMR chemical shifts. This work illustrates the vast potential of artificial intelligence in conformational mining of IDPs.

In Silico Integration of Transcriptome and Interactome Predicts an ETP-ALL-Specific Transcriptional Footprint that Decodes its Developmental Propensity.

Early T precursor acute lymphoblastic leukemia (ETP-ALL) exhibits poor clinical outcomes and high relapse rates following conventional chemotherapeutic protocols. Extensive developmental flexibility of the multipotent ETP-ALL blasts with considerable intra-population heterogeneity in terms of immunophenotype and prognostic parameters might be a target for novel therapeutic interventions. Using a public gene expression dataset (GSE28703) from NCBI GEO DataSets with 12 ETP-ALL and 40 non-ETP-ALL samples, such heterogeneity was found to be reflected in their transcriptome as well. Hub genes were identified from the STRING-derived functional interaction network of genes showing differential expression between ETP-ALL and non-ETP-ALL as well as variable expression across ETP-ALL. Nine genes (KIT, HGF, NT5E, PROM1, CD33, ANPEP, CDH2, IL1B, and CXCL2) among the hubs were further validated as possible diagnostic ETP-ALL markers using another gene expression dataset (GSE78132) with 17 ETP-ALL and 27 non-ETP-ALL samples. Linear dimensionality reduction analysis with the expression levels of the hub genes in ETP-ALL revealed their divergent inclinations towards different hematopoietic lineages, proposing them as novel indicators of lineage specification in the incompletely differentiated ETP-ALL blasts. This further led to the formulation of a personalized lineage score calculation algorithm, which uncovered a considerable B-lineage-bias in a substantial fraction of ETP-ALL subjects from the GSE28703 and GSE78132 cohorts. In addition, STRING-derived physical interactome of the potential biomarkers displayed complete segregation of the B-lineage-skewed markers from other lineage-associated factors, highlighting their distinct functionality and possible druggability in ETP-ALL. A panel of these biomarkers might be useful in pinpointing the dominant lineage specification programmes in the ETP-ALL blasts on a personalized level, urging the development of novel lineage-directed precision therapies as well as repurposing of existing therapies against leukemia of different hematopoietic lineages; which might overcome the drawbacks of conventional chemotherapy.

COVID-19 Positive Cohort Undergoing Cardiac Surgery: A Possible Un(3H)oly Trinity of Hypoxia-Hemolysis-Hyperinflammation.

While the fraternity continues to ponder on the mechanisms by which coronavirus disease (COVID-19) positivity affects the outcome of cardiac surgical subset, we put forth a 3H (Hypoxia-Hemolysis-Hyperinflammation) trilogy aimed at elucidating the liaison between cardiopulmonary bypass (commonly employed for cardiac surgical conduct) and COVID-19 infection. A sound comprehension of the same can doubtlessly assist the perioperative team in staging a well-directed pathophysiology-driven management approach.

Retrospective Evaluation of Platelet-Leukocyte Indices and Cardiac Surgical Outcomes in Acyanotic Heart Disease Patients with Pulmonary Hypertension (REPLICA-PH).

INTRODUCTION: Acyanotic congenital heart disease (ACHD) patients with pulmonary hypertension (PH) are prone to postoperative complications, and characterization of the risk profile continues to fail in identifying inflammatory predilection. Our objective is to investigate the role of platelet-leukocyte indices (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII] [neutrophil × platelet/lymphocyte]) in predicting poor outcomes following cardiac surgery in ACHD cohort with preoperative PH. METHODS: This single-center, retrospective risk-predictive study included ACHD patients undergoing surgical correction at our tertiary cardiac center between January 2015 and December 2019. Standard institutional perioperative management protocol was followed, and poor postoperative outcome was defined as ≥ 1 of: low cardiac output syndrome, new-onset renal failure, prolonged mechanical ventilation (MV > 24 hours), stroke, sepsis, and/or death. RESULTS: One hundred eighty patients out of 1,040 (17.3%) presented poor outcome. On univariate analysis, preoperative factors including right ventricular systolic pressure (RVSP) (PH-severity marker), congestive heart failure, albumin, NLR, PLR, SII, and aortic cross-clamping (ACC) and cardiopulmonary bypass (CPB) times predicted poor outcome. However, on multivariate analysis, RVSP, NLR, SII, and ACC and CPB times emerged as independent predictors. An NLR, SII prognostic cutoff of 3.33 and 860.6×103/mm3 was derived (sensitivity: 77.8%, 78.9%; specificity: 91.7%, 82.2%; area under the curve: 0.871, 0.833). NLR and SII values significantly correlated with postoperative MV duration, mean vasoactive-inotropic scores, and length of intensive care unit and hospital stay (P<0.001). CONCLUSION: Novel parsimonious, reproducible plateletleukocyte indices present the potential of stratifying the risk in congenital cardiac surgical patients with pre-existing PH.