Emerging potential approaches in alkaline phosphatase (ALP) activatable cancer theranostics.

Alkaline phosphatase (ALP) is known as one of the most crucial members of the phosphatase family and encompasses the enormous ability to hydrolyze the phosphate group in various biomolecules; by this, it regulates several events in the pool of biological medium. Owing to its overexpression in various cancer cells, recently, its potential has evolved as a prominent biomarker in cancer research. In this article, we have underlined the recent advances (2019 onwards) of alkaline phosphatase in the arena of emerging cancer theranostics. Herein, we mainly focused on phosphate-locked molecular systems such as peptides, prodrugs, and aggregation-induced emission (AIE)-based molecules. When these theranostics encounter cancer cell-overexpressed ALP, it results in the hydrolysis of the phosphate group, which leads to the release of highly cytotoxic agents along with turn-on fluorophore/pre-existing fluorophore.

Comparative Evaluation of the Relationship Between Airway Inadequacy, Head Posture, and Craniofacial Morphology in Mouth-Breathing and Nasal-Breathing Patients: A Cephalometric Observational Study.

BACKGROUND: The process of respiration is the primary factor of the posture of the jaws and tongue. Thus, a changed respiratory form like mouth breathing can change the posture of the head, jaw, and tongue. This, in turn, could change the equilibrium of pressure on the jaws and teeth thus affecting jaw growth and teeth positions. The influence of nasorespiratory function on craniofacial growth has stimulated interest and debate for more than a century. Mouth breathing is the reason for numerous orthodontic glitches such as a mouth breather's face evolving aberrantly because of of functional disruptions triggered by chronic airway obstruction. The relationship between nasorespiratory function and dentofacial development remains controversial despite the long-standing clinical concern of orthodontists, so there was a need to evaluate and compare the relationship between head posture, airway inadequacy, and craniofacial morphology in mouth breathers and nasal breathers. METHODOLOGY: Forty patients were selected and divided equally into two groups: mouth breathers and nasal breathers. Patients were diagnosed as mouth breathers based on physical examination and a history of chronic allergic rhinitis, adenoid, and tonsil enlargement. Lateral cephalograms were taken for all patients in the natural head position (NHP) with the Planmeca Proline XC Dimax3 x-ray machine (Planmeca, Helsinki-Uusimaa, Finland). All lateral cephalograms were traced and analysis was done to check airway, head posture, and craniofacial morphology. Descriptive statistics were performed to obtain the means and standard deviation of all the sample sizes. Unpaired t test was performed between nasal breathers and mouth breathers to check and evaluate the relationship. RESULT: Mouth-breathing patients varied from nasal-breathing patients in airway adequacy and craniofacial morphology. A little, but not statistically significant, difference was seen in head posture between the two groups. CONCLUSIONS: Early interception of mouth breathing in patients could be very helpful, as the postural changes in the mouth-breathing patients, if continued for a longer period of time, could be the reason for severe skeletal deformities as well as dental malocclusion.

Ligand Dictated Photosensitization of Iridium(III) Dithiocarbamate Complexes for Photodynamic Therapy.

Organelle-targeted photosensitizers (PSs) for photodynamic therapy (PDT) are considered as an effective therapeutic strategy for the development of next generation PSs with the least side effects and high therapeutic efficacy. However, multiorganelle targeted PSs eliciting PDT via both type I and type II mechanisms are scarce. Herein, a series of cyclometalated iridium(III) complexes were formulated [Ir(C∧N)2(S∧S)] (C∧N = 2-phenylpyridine (ppy) and 2-(thiophen-2-yl)pyridine (thpy); S∧S = diethyldithiocarbamate (DEDTC), morpholine-N-dithiocarbamate (MORDTC) and methoxycarbonodithioate (MEDTC)) and the newly designed complexes Ir2@DEDTC and Ir1@MEDTC were characterized by single crystal X-ray crystallography. Complexes containing thpy as C∧N ligand exhibit excellent photophysical properties such as red-shifted emission, high singlet oxygen quantum yield (ϕΔ) and longer photoluminescence lifetime when compared with complexes containing ppy ligands. Ir2@DEDTC exhibits the highest Ï•Δ and photoluminescence lifetimes among the synthesized complexes. Therefore, Ir2@DEDTC was chosen to evaluate the photosensitizing ability to produce reactive oxygen species (ROS). Upon blue light irradiation (456 nm), it efficiently produces ROS, i.e., hydroxy radical (•OH) and singlet oxygen (1O2), which was confirmed by electron paramagnetic resonance (EPR) spectroscopy. In vitro photocytotoxicity toward HCT116, HeLa, and PC3 cell lines showed that out of all the synthesized complexes, Ir2@DEDTC has the highest photocytotoxic index (PI > 400) value. Ir2@DEDTC is efficiently taken up by the HCT116 cell line and accumulated mainly in the lysosome and mitochondria of the cells, and after PDT treatment, it elicits cell shrinkage, membrane blebbing, and DNA fragmentation. The phototherapeutic efficacy of Ir2@DEDTC has been investigated against 3D spheroids considering its ability to mimic some of the basic features of solid tumors. The morphology was drastically altered in the Ir2@DEDTC treated 3D spheroid after the light irradiation unleashed the potential of the Ir(III) dithiocarbamate complex as a superior PS for PDT. Hence, mitochondria and lysosome targeted photoactive cyclometalated Ir(III) dithiocarbamate complex exerting oxidative stress via both type I and type II PDT can be regarded as a dual-organelle targeted two-pronged approach for enhanced PDT.

Alkaline phosphatase (ALP) activatable small molecule-based prodrugs for cancer theranostics.

Highly water-soluble small molecule-based prodrugs (5-FUPD and SAHAPD) are formulated. They comprise a phosphate group to lock the active drug payload (5-fluorouracil and SAHA) along with a turn-on fluorophore consisting of a glutathione (GSH) depletory feature. Installation of the phosphate group along with purification of final product has been accomplished in an operationally facile manner. Activation of the prodrugs is facilitated by alkaline phosphatase (ALP)-mediated hydrolysis of the phosphate group followed by 1,8-elimination. The prodrugs were found to be highly effective against ALP flared human cervical cancer (HeLa) and liver cancer (HepG2) cell lines. Most notably, they were found to be innocuous to normal liver cells (WRL-68).

Managing healthcare supply chain through artificial intelligence (AI): A study of critical success factors.

Healthcare is one of the most critical sectors due to its importance in handling public health. With the outbreak of various diseases, more recently during Covid-19, this sector has gained further attention. The pandemic has exposed vulnerabilities in the healthcare supply chain (HSC). Recent advancements like the adoption of various advanced technologies viz. AI and Industry 4.0 in the healthcare supply chain are turning out to be game-changers. This study focuses on identifying critical success factors (CSFs) for AI adoption in HSC in the emerging economy context. Rough SWARA is used for ranking CSFs of AI adoption in HSC. Results indicate that technological (TEC) factors are the most influential factor that impacts the adoption of AI in HSC in the context of emerging economies, followed by institutional or environmental (INT), human (HUM), and organizational (ORG) dimensions.

Location of organ procurement and distribution organisation decisions and their impact on kidney allocations: a developing country perspective.

Managing organ transplant networks is a complex task. It intertwines between locating the organ procurement and distribution organization (OPDO) (long-term decision) and allocating organs to the suitable destination (short-term decision). The literature lacks deliberation on the effect of those long-term decisions on short-term ones under the influence of clinical and non-clinical factors. This paper addresses this gap using a k-sum model for locational choice, and a discrete simulation approach for the allocation procedure for a real-life case study from a developing economy perspective. The study explores the trade-off between efficiency (distance-centric models) and equity (the result of time-centric allocation models). Our analysis of the efficiency of locational models and equity of the allocation policies reveal strong inter-dependence of both these decisions, a significant finding of this research. These findings offer an integrated model for high-level decision-makers, which can be used during the locational planning stage and provide input to design standard operating procedures for transplantation schemes.

Managing the retail operations in the COVID-19 pandemic: Evidence from Morocco.

Novel coronavirus disease (COVID-19) and resulting lockdowns have contributed to major retail operational disturbances around the globe, forcing retail organizations to manage their operations effectively. The impact can be measured as a black swan event (BSE). Therefore, to understand its impact on retail operations and enhance operational performance, the study attempts to evaluate retail operations and develop a decision-making model for disruptive events in Morocco. The study develops a three-phase evaluation approach. The approach involves fuzzy logic (to measure the current performance of retail operations), graph theory (to develop an exit strategy for retail operations based on different scenarios), and ANN and random forest-based prediction model with K-cross validation (to predict customer retention for retail operations). This methodology is preferred to develop a unique decision-making model for BSE. From the analysis, the current retail performance index has been computed as "Average" level and the graph-theoretic approach highlighted the critical attributes of retail operations. Further, the study identified triggering attributes for customer retention using machine learning-based prediction models (MLBPM) and develops a contactless payment system for customers' safety and hygiene. The framework can be used on a periodic basis to help retail managers to improve their operational performance level for disruptive events.

Development of a novel Bruton's tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells.

Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton's tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents.

Carbamylation of Integrin α IIb ß 3: The Mechanistic Link to Platelet Dysfunction in ESKD.

BACKGROUND: Bleeding diatheses, common among patients with ESKD, can lead to serious complications, particularly during invasive procedures. Chronic urea overload significantly increases cyanate concentrations in patients with ESKD, leading to carbamylation, an irreversible modification of proteins and peptides. METHODS: To investigate carbamylation as a potential mechanistic link between uremia and platelet dysfunction in ESKD, we used liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to quantify total homocitrulline, and biotin-conjugated phenylglyoxal labeling and Western blot to detect carbamylated integrin α IIb ß 3 (a receptor required for platelet aggregation). Flow cytometry was used to study activation of isolated platelets and platelet-rich plasma. In a transient transfection system, we tested activity and fibrinogen binding of different mutated forms of the receptor. We assessed platelet adhesion and aggregation in microplate assays. RESULTS: Carbamylation inhibited platelet activation, adhesion, and aggregation. Patients on hemodialysis exhibited significantly reduced activation of α IIb ß 3 compared with healthy controls. We found significant carbamylation of both subunits of α IIb ß 3 on platelets from patients receiving hemodialysis versus only minor modification in controls. In the transient transfection system, modification of lysine 185 in the ß 3 subunit was associated with loss of receptor activity and fibrinogen binding. Supplementation of free amino acids, which was shown to protect plasma proteins from carbamylation-induced damage in patients on hemodialysis, prevented loss of α IIb ß 3 activity in vitro. CONCLUSIONS: Carbamylation of α IIb ß 3-specifically modification of the K185 residue-might represent a mechanistic link between uremia and dysfunctional primary hemostasis in patients on hemodialysis. The observation that free amino acids prevented the carbamylation-induced loss of α IIb ß 3 activity suggests amino acid administration during dialysis may help to normalize platelet function.

Dynamic collaborative optimization for disaster relief supply chains under information ambiguity.

Large-scale disasters occur worldwide, with a continuing surge in the frequency and severity of disruptive events. Researchers have developed several optimization models to address the critical challenges of disaster relief supply chains (e.g., emergency material reserving and scheduling inefficiencies). However, most developed algorithms are proven to have low fault tolerance, which makes it difficult for disaster relief supply chain managers to obtain optimal solutions and meet the emergency distribution requirements within a limited time frame. Considering the uncertainty and ambiguity of disaster relief information and using Interval Type-2 Fuzzy Set (IT2TFS), this paper presents a collaborative optimization model based on an integrative emergency material supplier evaluation framework. The optimal emergency material suppliers are first selected using a multi-attribute group decision-making ranking method. Multi-objective fuzzy optimization is then run in three emergency phases: early -, mid-, and late-disaster relief stages. Focusing on a massive flash flood disaster event in Yunnan Province as a case study, a comprehensive numerical analysis tests and validates the developed model. The results revealed that the proposed optimization method can optimize emergency material planning while ensuring that reserve material safety inventory is always maintained at a reasonable level. The presented method suggests a fuzzy interval to prevent emergency materials' safety inventory shortage and minimize continuous life/property losses in disaster-affected areas.

Reconfiguration of food grain supply network amidst COVID-19 outbreak: an emerging economy perspective.

The procurement of food grains from farmers is one of the biggest challenges under the COVID-19 outbreak due to country-wise lockdowns. The present study aims to reconfigure the existing food grain supply chain network. The study advances the extant literature by proposing a novel mathematical model that considers the government guidelines issued to procure food grains from farmers under the COVID-19 situation. The model includes personal distancing, a key parameter relevant in the COVID-19 crisis, and has remained unaddressed in the existing literature. The proposed model is tested in India. The effect of different parameters like personal distancing cost, carbon emission cost, fixed cost, and transportation cost is also investigated under a given set of procurement centers. Finally, the procurement schedule for each procurement center is generated, which is especially useful for managing its activities and is also helpful to farmers to streamline the process. Results indicate that the proposed model is highly effective under pandemic emergencies like the current COVID-19 crisis. Policymakers and the government will find this model helpful in drafting relevant policies regarding food grain procurement under emergencies such as the COVID-19 outbreak. The distribution segment of the supply chain network is not part of the present research work. In future studies, this part could be then added to the whole of the procurement process, and both procurement and distribution can be assessed together again.

Frailty, Disability, and Mortality in a Rural Community-Dwelling Elderly Cohort from Northern India.

INTRODUCTION: With increasing proportion of the elderly in the world, detecting and preventing frailty assumes importance to improve the quality of life and health. The study aimed to estimate the prevalence of frailty, disability and its determinants and their relation with mortality among community dwelling elderly cohort. MATERIALS AND METHODS: The study was conducted in a cohort in rural Haryana, India, and was followed till October 2018. Frailty was assessed using the Edmonton Frailty Scale and disability was assessed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) scale by trained physicians. RESULTS: The prevalence of frailty was found to be 47.3% (95% confidence interval [CI]: 44.0-50.8). The median WHODAS-2 score was found to be 10.4 (2.1-29.2). Those who were older (odds ratio [OR] - 2.5; 95% CI: 1.8-3.4), women (OR - 3.3; 95% CI: 2.2-4.9) and those with chronic disease (OR 2.3; 95% CI: 1.7-3.1) had higher rates of frailty. The adjusted hazard ratio of death among frail people was 4.7 (2.3-9.7). CONCLUSION: In this study we found the frailty is associated with the mortality among community dwelling elderly. Thus early identification of the frailty and its determinants may help us to reduce the mortality related to this.

Immunomodulatory Effects of a Concoction of Natural Bioactive Compounds-Mechanistic Insights.

Natural bioactive compounds derived from plant-based products are known for their biological immunomodulatory activities. They possess systemic pleiotropic effects, minimal side effects, and very low toxicities. Plant-based bioactive compounds have tremendous potential as natural therapeutic entities against various disease conditions and act as anti-inflammatory, antioxidant, anti-mutagenic, anti-microbial, anti-viral, anti-tumour, anti-allergic, neuroprotective, and cardioprotective agents. A herbal formulation extract including five biologically active compounds: Apigenin, Quercetin, Betulinic acid, Oleanolic acid, and ß-Sitosterol can impart several immunomodulatory effects. In this review, we systematically present the impact of these compounds on important molecular signaling pathways, including inflammation, immunity, redox metabolism, neuroinflammation, neutropenia, cell growth, apoptosis, and cell cycle. The review corroborates the beneficial effect of these compounds and shows considerable potential to be used as a safer, more cost-effective treatment for several diseases by affecting the major nodal points of various stimulatory pathways.

AIE material for photodynamic therapy.

Photodynamic therapy (PDT) is emerging as an excellent strategy to treat different types of cancers. The advantages of using PDT over other cancer treatment modalities are owing to its non-invasive nature, spatiotemporal precession, controllable photoactivity, and least side effects. The photosensitization ability of traditional photosensitizers (PSs) are severely curtailed by aggregation-induced quenching (ACQ). On the contrary, aggregation induced emission (AIE) molecules/fluorogens (AIEgens) show enhanced fluorescence emission and high reactive oxygen species (ROS)/singlet oxygen (1O2) production capability in the aggregated state. These unique characteristics of AIEgens make them potential AIE-PSs for fluorescence/luminescence image-guided combination PDT. In this chapter, we discussed the strategies that are developed to synthesize small molecule-based AIE-PSs, metal complex-based AIE-PSs, and AIE-PSs with two-photon absorbance (TPA) properties, polymer-based AIE-PSs, and nanoparticles based AIE-PSs for PDT. We have also discussed the rational design of targeting peptide conjugated AIE-PSs to selective target cancer cells over normal cells. Furthermore, recent findings on nanoparticle-based combination AIE-PSs are also discussed, where the combination AIE-PSs show synergistically improved anticancer activity and overcome the drug resistance. Finally, we shed light on the recent development, ongoing challenges, and future directions for designing better AIE-PS for PDT.

The role of SERPIN citrullination in thrombosis.

Aberrant protein citrullination is associated with many pathologies; however, the specific effects of this modification remain unknown. We have previously demonstrated that serine protease inhibitors (SERPINs) are highly citrullinated in rheumatoid arthritis (RA) patients. These citrullinated SERPINs include antithrombin, antiplasmin, and t-PAI, which regulate the coagulation and fibrinolysis cascades. Notably, citrullination eliminates their inhibitory activity. Here, we demonstrate that citrullination of antithrombin and t-PAI impairs their binding to their cognate proteases. By contrast, citrullination converts antiplasmin into a substrate. We recapitulate the effects of SERPIN citrullination using in vitro plasma clotting and fibrinolysis assays. Moreover, we show that citrullinated antithrombin and antiplasmin are increased and decreased in a deep vein thrombosis (DVT) model, accounting for how SERPIN citrullination shifts the equilibrium toward thrombus formation. These data provide a direct link between increased citrullination and the risk of thrombosis in autoimmunity and indicate that aberrant SERPIN citrullination promotes pathological thrombus formation.

Progesterone stimulates histone citrullination to increase IGFBP1 expression in uterine cells.

Peptidylarginine deiminases (PAD) enzymes were initially characterized in uteri, but since then little research has examined their function in this tissue. PADs post-translationally convert arginine residues in target proteins to citrulline and are highly expressed in ovine caruncle epithelia and ovine uterine luminal epithelial (OLE)-derived cell line. Progesterone (P4) not only maintains the uterine epithelia but also regulates the expression of endometrial genes that code for proteins that comprise the histotroph and are critical during early pregnancy. Given this, we tested whether P4 stimulates PAD-catalyzed histone citrullination to epigenetically regulate expression of the histotroph gene insulin-like growth factor binding protein 1 (IGFBP1) in OLE cells. 100 nM P4 significantly increases IGFBP1 mRNA expression; however, this increase is attenuated by pre-treating OLE cells with 100 nM progesterone receptor antagonist RU486 or 2 µM of a pan-PAD inhibitor. P4 treatment of OLE cells also stimulates citrullination of histone H3 arginine residues 2, 8, and 17 leading to enrichment of the ovine IGFBP1 gene promoter. Since PAD2 nuclear translocation and catalytic activity require calcium, we next investigated whether P4 triggers calcium influx in OLE cells. OLE cells were pre-treated with 10 nM nicardipine, an L-type calcium channel blocker, followed by stimulation with P4. Using fura2-AM imaging, we found that P4 initiates a rapid calcium influx through L-type calcium channels in OLE cells. Furthermore, this influx is necessary for PAD2 nuclear translocation and resulting citrullination of histone H3 arginine residues 2, 8, and 17. Our work suggests that P4 stimulates rapid calcium influx through L-type calcium channels initiating PAD-catalyzed histone citrullination and an increase in IGFBP1 expression.

Role of Antizyme Inhibitor Proteins in Cancers and Beyond.

Polyamines are multivalent organic cations essential for many cellular functions, including cell growth, differentiation, and proliferation. However, elevated polyamine levels are associated with a slew of pathological conditions, including multiple cancers. Intracellular polyamine levels are primarily controlled by the autoregulatory circuit comprising two different protein types, Antizymes (OAZ) and Antizyme Inhibitors (AZIN), which regulate the activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC). While OAZ functions to decrease the intracellular polyamine levels by inhibiting ODC activity and exerting a negative control of polyamine uptake, AZIN operates to increase intracellular polyamine levels by binding and sequestering OAZ to relieve ODC inhibition and to increase polyamine uptake. Interestingly, OAZ and AZIN exhibit autoregulatory functions on polyamine independent pathways as well. A growing body of evidence demonstrates the dysregulation of AZIN expression in multiple cancers. Additionally, RNA editing of the Azin1 transcript results in a "gain-of-function" phenotype, which is shown to drive aggressive tumor types. This review will discuss the recent advances in AZIN's role in cancers via aberrant polyamine upregulation and its polyamine-independent protein regulation. This report will also highlight AZIN interaction with proteins outside the polyamine biosynthetic pathway and its potential implication to cancer pathogenesis. Finally, this review will reveal the protein interaction network of AZIN isoforms by analyzing three different interactome databases.

Succination inactivates gasdermin D and blocks pyroptosis.

Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.