Leukemia in India: Insights Into Incidence, Prevalence, Mortality, and Disability-Adjusted Life Years.

OBJECTIVE: This study aimed to examine the impact of leukemia and other cancers in India and to observe any changes over time. METHODOLOGY: Detailed estimates of incidence, prevalence, mortality, and disability-adjusted life years (DALYs) for 30 types of cancers in India were analyzed for 29 years from 1990 to 2019 as part of the Global Burden of Diseases (GBD) study. Data from all available sources were used to gather information on the overall burden of disease in India. RESULTS: Cancer is a leading cause of death worldwide, with varying rates of incidence in India, making prevention and treatment a challenge. Because cancer is not a reportable disease in India, the overall burden estimate is still a work in progress. This study analyzed the impact of leukemia and other cancers in India, including trends in incidence, DALYs, and mortality related to all cancers and various malignancies. The causes of leukemia in India were also explored. CONCLUSIONS: The study found the trends of cancer types that account for the majority of leukemia-related and cancer-related DALYs, death, prevalence, and incidence in India. Among the four most frequent malignancies, such as leukemia, there was significant variation based on age. Over the last 29 years, mortality from chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) has decreased, while deaths from acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL) have increased steadily.

Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.

Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery-versus-nonsurgery trial as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT. Methods: The MIST-3 (third Multicenter Intrapleural Sepsis Trial) was a prospective multicenter RCT involving eight U.K. centers combining on-site and off-site surgical services. The study enrolled all patients with a confirmed diagnosis of pleural infection and randomized those with ongoing pleural sepsis after an initial period (as long as 24 h) of standard care to one of three treatment arms: continued standard care, early IET, or a surgical opinion with regard to early VATS. The primary outcome was feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 2 weeks of follow-up. The analysis was performed per intention to treat. Measurements and Main Results: Of 97 eligible patients, 60 (62%) were randomized, with 100% retained to discharge and 84% retained to 2 weeks. Baseline demographic, clinical, and microbiological characteristics of the patients were similar across groups. Median times to intervention were 1.0 and 3.5 days in the IET and surgery groups, respectively (P = 0.02). Despite the difference in time to intervention, length of stay (from randomization to discharge) was similar in both intervention arms (7 d) compared with standard care (10 d) (P = 0.70). There were no significant intergroup differences in 2-month readmission and further intervention, although the study was not adequately powered for this outcome. Compared with VATS, IET demonstrated a larger improvement in mean EuroQol five-dimension health utility index (five-level edition) from baseline (0.35) to 2 months (0.83) (P = 0.023). One serious adverse event was reported in the VATS arm. Conclusions: This is the first multicenter RCT of early IET versus early surgery in pleural infection. Despite the logistical challenges posed by the coronavirus disease (COVID-19) pandemic, the study met its predefined feasibility criteria, demonstrated potential shortening of length of stay with early surgery, and signals toward earlier resolution of pain and a shortened recovery with IET. The study findings suggest that a definitive phase III study is feasible but highlights important considerations and significant modifications to the design that would be required to adequately assess optimal initial management in pleural infection.The trial was registered on ISRCTN (number 18,192,121).

Methotrexate delivering microneedle patches for improved therapeutic efficacy in treatment of rheumatoid arthritis.

Arthritis is an inflammatory disorder that leads to degeneration and swelling in the joints thereby severely affecting mobility. Till date, a complete cure for this disorder remains elusive. Administration of disease modifying anti-rheumatic drugs has not proved effective owing to poor retention of drugs at the site of inflammation in the joints. In most cases, lack of adherence to the therapeutic regimen further aggravates the condition. Localized administration of the drugs through intra-articular injections is highly invasive and painful. A possible solution to overcome these issues will be to ensure sustained release of the anti-arthritic drug at the site of inflammation through a minimally invasive method. The present work focuses on the development of a microneedle patch for localized and minimally invasive delivery of methotrexate to arthritic joints in guinea pig model. The microneedle patch was found to elicit minimal immune response and ensured sustained release of the drug that was manifested through faster restoration of mobility and a distinct reduction in inflammatory and rheumatoid markers at the joints when compared to untreated and those treated through conventional hypodermic injections. Our results demonstrate the promise of microneedle-based platform for an effective arthritic therapy.

Mimicking the Natural World with Nanoarchitectonics for Self-Assembled Superstructures.

Scientists are often inspired by nature, where naturally occurring morphologies, such as those that resemble animals and plants, can be created in the lab. In this review, we have provided an overview on complex superstructures of animals, plants and some similar shapes from the natural world. We begin this review with a discussion about the formation of various animal-like shapes from small organic molecules and polymers, and then move onto plants and other selected shapes. Literature surveys reveal that most of the polymers studied tend to form micellar structures, with some exceptions. Nevertheless, small organic molecules tend to form not only micellar structures but also other animal shapes such as worms and caterpillars. These superstructures tend to have high surface areas and variable surface morphology, making them very useful material for applications in various field such as catalysis, solar cells, and biomedicine, amongst others.

Structure-based pharmacophore mapping and virtual screening of natural products to identify polypharmacological inhibitor against c-MET/EGFR/VEGFR-2.

Three receptor tyrosine kinases (RTKs), c-MET, EGFR, and VEGFR-2 have been identified as potential oncogenic targets involved in tumor development, metastasis, and invasion. Designing inhibitors that can simultaneously interact with multiple targets is a promising approach, therefore, inhibiting these three RTKs with a single chemical component might give an effective chemotherapeutic strategy for addressing the disease while limiting adverse effects. The in-silico methods have been developed to identify the polypharmacological inhibitors particularly for drug repurposing and multitarget drug design. Here, to find a viable inhibitor from natural source against these three RTKs, structure-based pharmacophore mapping and virtual screening of SN-II database were carried out. The filtered compound SN00020821, identified as Cedeodarin, from different computational approaches, demonstrated good interactions with all the three targets, c-MET/EGFR/VEGFR-2, with interaction energies of -42.35 kcal/mol, -49.32 kcal/mol and -44.83 kcal/mol, respectively. SN00020821displayed stable key interactions with critical amino acids of all the three receptors' kinase catalytic domains including "DFG motif" explored through the MD simulations. Furthermore, it also met the ADMET requirements and was determined to be drug-like as predicted from the Lipinski's rule of five and Veber's rule. Finally, SN00020821 provides a novel molecular scaffold that could be investigated further as a polypharmacological anticancer therapeutic candidate that targets the three RTKs.Communicated by Ramaswamy H. Sarma.

The Biological Role of Pleural Fluid PAI-1 and Sonographic Septations in Pleural Infection: Analysis of a Prospectively Collected Clinical Outcome Study.

Rationale: Sonographic septations are assumed to be important clinical predictors of outcome in pleural infection, but the evidence for this is sparse. The inflammatory and fibrinolysis-associated intrapleural pathway(s) leading to septation formation have not been studied in a large cohort of pleural fluid (PF) samples with confirmed pleural infection matched with ultrasound and clinical outcome data. Objectives: To assess the presence and severity of septations against baseline PF PAI-1 (Plasminogen-Activator Inhibitor-1) and other inflammatory and fibrinolysis-associated proteins as well as to correlate these with clinically important outcomes. Methods: We analyzed 214 pleural fluid samples from PILOT (Pleural Infection Longitudinal Outcome Study), a prospective observational pleural infection study, for inflammatory and fibrinolysis-associated proteins using the Luminex platform. Multivariate regression analyses were used to assess the association of pleural biological markers with septation presence and severity (on ultrasound) and clinical outcomes. Measurements and Main Results: PF PAI-1 was the only protein independently associated with septation presence (P < 0.001) and septation severity (P = 0.003). PF PAI-1 concentrations were associated with increased length of stay (P = 0.048) and increased 12-month mortality (P = 0.003). Sonographic septations alone had no relation to clinical outcomes. Conclusions: In a large and well-characterized cohort, this is the first study to associate pleural biological parameters with a validated sonographic septation outcome in pleural infection. PF PAI-1 is the first biomarker to demonstrate an independent association with mortality. Although PF PAI-1 plays an integral role in driving septation formation, septations themselves are not associated with clinically important outcomes. These novel findings now require prospective validation.

Single step fabrication of hollow microneedles and an experimental package for controlled drug delivery.

Hollow microneedle arrays (HMNs) are an excellent choice for managing chronic diseases requiring the administration of multiple drug doses over a prolonged duration. However, HMNs have gained partial success due to limitations in their manufacturing capabilities, and cumbersome processes. In the present study, polymeric HMNs were fabricated using a novel single-step drop-casting process without needing cleanroom facilities, and sophisticated instrumentation. When drop casted on the pyramidal tip stainless steel needles, the optimized polymer solution allowed the reproducible formation of desired height HMMs on a detachable acrylic base. To enable broader applications, the base with HMNs was integrated into an experimental package built to deliver a dose of âˆ¼ 5 µL per 30° clockwise rotation of the actuator, allowing multiple metered drug dose administrations. The fabricated HMNs were optically imaged, and tested for mechanical integrity and stability. The working and functional utility of the HMNs package in delivering metered drug doses was demonstrated by delivering vitamin B12 (ex vivo) and insulin (in vivo), respectively. The optimized process can be used for the large-scale manufacturing of HMNs and the experimental package shows the potential to be further developed into a wearable device.

A New 'Off-On' System Based on Core-Substituted Naphthalene Diimide with Dimethylamine for Reversible Acid-Base Sensing.

A new 'Off-On' system designed and synthesised by functionalisation of a naphthalene diimide (NDI) core with dimethylamine produces 4,9-bis(dimethylamino)-2,7-dioctylbenzo[lmn][3,8]-phenanthroline-1,3,6,8-(2H,7H)-tetraone, abbreviated as DDPT (1). DDPT 1 was synthesised using a simple strategy, namely aromatic nucleophilic substitution using Br2 -NDI with dimethylamine at 110 °C. DDPT was characterized by 1 H and 13 C NMR spectroscopy, ESI mass spectrometry and elemental analysis. DDPT 1 was then used for optical studies through protonation of its dimethylamine core with trifluoroacetic acid (TFA), blue-shifting the absorption band from 600 nm to 545 nm in solution. Interestingly, the fluorescence of DDPT 1 is weak in solution with a quantum yield Φ=0.09, which is significantly enhanced to Φ=0.78 upon addition of TFA. The limit of detection (LOD) was determined to 2.77 nm. Furthermore, DDPT 1 can be used for naked eyed detection not only under UV light (365 nm) but also using visible light, as clear changes can be clearly seen upon addition of TFA. The binding constant of DDPT was calculated to 2.1×10-3  m-1 . Importantly, DDPT 1 showed reversible switching by alternative addition of acid (TFA) and base (triethylamine) without loss of activity. Immobilised on paper, DDPT 1 can be used for strip-test sensing in which the colour changes from blue to reddish when expose to TFA vapours and reverse in the presence of triethylamine vapours.

Preliminary evaluation of serum zonulin in canine chronic enteropathies.

OBJECTIVES: In humans, serum zonulin, a biomarker of intestinal permeability, correlates with underlying enteropathies and has potential application as a therapeutic target. The aim of this study was to evaluate serum zonulin as a biomarker for canine chronic enteropathy. MATERIALS AND METHODS: Prospective enrolment of twenty-one client-owned dogs with at least 1 of the following gastrointestinal (GI) signs for at least 3 weeks duration: anorexia, hyporexia, dysrexia, vomiting, weight loss or diarrhea. 21 control dogs, age and breed matched, were also enrolled. Dogs with gastrointestinal signs were diagnosed with chronic enteropathy based on a complete blood count, serum chemistry, specific canine pancreatic lipase, cobalamin, resting cortisol, abdominal ultrasound and gastrointestinal endoscopy with histopathology. Enrolled control dogs had an unremarkable physical examination, complete blood count, serum chemistry and no clinical signs of gastrointestinal disease. Dogs were ineligible if antibiotics or immunosuppressive medications were administered within 1 month of enrolment. Blood samples were analysed using a commercial canine serum zonulin quantitative ELISA. RESULTS: Dogs with chronic enteropathies had median serum zonulin values of 0.28 ng/mL (interquartile range: 0.04-2.59), while control dogs of 0.27 ng/mL (0.05-3.67). There was no significant difference in canine serum zonulin levels between these populations. The estimated difference in the median concentrations was -0.01 ng/mL (95% CI: -0.23 to 0.89). CLINICAL SIGNIFICANCE: In this study, using a commercial canine zonulin ELISA, serum zonulin levels did not differentiate between dogs with chronic enteropathies and control dogs.

Tetraphenylethene Derivatives Modulate the RNA Hairpin-G-Quadruplex Conformational Equilibria in Proto-oncogenes.

RNA G-quadruplex (GQs) sequences in 5'-UTRs of certain proto-oncogenes co-localize with hairpin (Hp) forming sequences resulting in intramolecular Hp-GQ conformational equilibria, which is suggested to regulate cancer development and progression. Thus, regulation of Hp-GQ equilibria with small molecules is an attractive but less explored therapeutic approach. Herein, two tetraphenylethene (TPE) derivatives, TPE-Py and TPE-MePy, were synthesized and their effect on Hp-GQ equilibrium was explored. FRET, CD and molecular docking experiments suggest that cationic TPE-MePy shifts the Hp-GQ equilibrium significantly towards the GQ conformer mainly through π-π stacking and van der Waals interactions. In the presence of TPE-MePy, the observed rate constant values for first and second folding steps were increased up to 14.6 and 2.6-fold, respectively. The FRET melting assay showed a strong stabilizing ability of TPE-MePy (ΔTm=4.36 °C). Notably, the unmethylated derivative TPE-Py did not alter the Hp-GQ equilibrium. Subsequently, luciferase assay analysis demonstrated that the TPE-MePy derivatives suppressed the translation efficiency by ∼5.7-fold by shifting the Hp-GQ equilibrium toward GQ conformers in the 5'-UTR of TRF2. Our data suggests that HpGQ equilibria could be selectively targeted with small molecules to modulate translation for therapy.

Polyanionic Cyclodextrin-Induced Supramolecular Assembly of a Cationic Tetraphenylethylene Derivative with Aggregation-Induced Emission.

The combination of supramolecular chemistry and aggregation-induced emission-based luminogens (AIEgens) has recently attracted tremendous attention because of its ability to offer large emission enhancement even in substantially dilute solutions. In this work, a new aggregation-induced emission (AIE)-based supramolecular assembly has been reported, which consists of a polyanionic cyclodextrin derivative and a tetracationic tetraphenylethylene (TPE) derivative. Ionic cyclodextrins have attracted significant attention in host-guest supramolecular chemistry and pharmaceutical industry. However, ionic derivatives of ß-cyclodextrins have not been explored to establish noncovalent interactions-based aggregation assembly of the most popular class of AIEgens, i.e., tetraphenylethylene derivatives. The current report demonstrates AIE of a tetracationic methyl pyridinium derivative of tetraphenylethylene (TPy-TPE) induced by a polyanionic sulfated ß-cyclodextrin (S-ßCD). The AIE-based supramolecular assembly has been thoroughly investigated using steady-state fluorescence, ground-state absorbance, and time-resolved fluorescence measurements. Further, the response of the supramolecular assembly towards external stimuli, such as, ionic strength, pH, and temperature, has been investigated. In addition, the complexation behavior of the TPE derivative has also been compared with the native neutral ß-cyclodextrin derivative, which delineates the important role of the negatively charged portal of S-ßCD in inducing aggregation of the TPy-TPE. The stoichiometry of the complex has been found to be 3:1 for TPy-TPE:S-ßCD, using Job's plot analysis. Finally, to get insights into the underlying interactions between the supramolecular assembly components, molecular docking calculations have been performed.

Phase retrieval algorithm using edge point referencing.

In the past few decades, extensive research and efforts have been made for developing a phase retrieval iterative algorithm (PRA) for reconstructing a complex object from far-field intensity equivalently from the object autocorrelation. Since most of the existing PRA techniques employ a random initial guess, the reconstruction output sometimes changes in different trials leading to a non-deterministic output. Additionally, the output of such algorithm occasionally either shows non-convergence, needs a longer time to converge, or shows the twin-image problem. Due to these problems, PRA methods are unsuitable for cases where consecutive reconstructed outputs need to be compared. In this Letter, a novel, to the best of our knowledge, method is developed and discussed using edge point referencing (EPR). In the EPR scheme, in addition to illuminating a region of interest (ROI) of the complex object, a small area near the periphery of the complex object within the ROI is illuminated with an additional beam. Such illumination creates an imbalance in the autocorrelation that can be used to improve the initial guess for achieving unique deterministic output free from the aforementioned problems. Furthermore, by introducing the EPR, one can also achieve faster convergence. To support our theory, derivation, simulations, and experiment are performed and presented.

Parapneumonic Effusion and Empyema.

The rising incidence and high morbidity of pleural infection remain a significant challenge to health care systems worldwide. With distinct microbiology and treatment paradigms from pneumonia, pleural infection is an area in which the evidence base has been rapidly evolving. Progress in recent years has revolved around characterizing the microbiome of pleural infection and the addition of new strategies such as intrapleural enzyme therapy to the established treatment pathway of drainage and antibiotics. The future of improving outcomes lies with personalizing treatment, establishing optimal timing of intrapleural agents and surgery, alongside wider use of risk stratification to guide treatment.

Aggregation-Induced Emission-Based Material for Selective and Sensitive Recognition of Cyanide Anions in Solution and Biological Assays.

Cyanide is one of the highly poisonous pollutants to our environment and toxic to human health. It is important to develop the widely applicable methods for their recognition to secure safe uses for people coming into contact and handling cyanide and their derivatives. In this regard, the aggregation-induced emission materials possess high potential for the development of simple, fast, and convenient methods for cyanide detection through either "turn-off" or "turn-on". Among the AIE-based materials, tetraphenylethylene is a promising sensor for various sensing applications. In this paper, we have designed and synthesized a TPE-based chemosensor, which shows high sensitivity and displays good selectivity for cyanide (CN-) over others in the presence of interfering Cl-, I-, F-, Br-, HSO4 -, H2PO4 -, NO3 -, HCO3 -, and ClO4 - anions employed. The naked-eye, UV-vis, and fluorescence methods are employed to evaluate the performance of probe 1 toward CN- detection. From these experiments, CN- ions can be detected with a limit of detection as low as 67 nM, which is comparatively lower than that of the World Health Organization (WHO) permissible limit of the cyanide anion, that is, 1.9 µM. From the Job's plot, the 1:1 stoichiometric complexation reaction between probe 1 and CN- was found. The probe was efficiently applied for the detection of CN- ions using a paper strip method. The probe 1 also showed the potential of detecting CN- ions in various food items and in the cell line.

Aggregation Induced Emissive Luminogens for Sensing of Toxic Elements.

The major findings in the growing field of aggregation induced emissive (AIE) active materials for the detection of environmental toxic pollutants have been summarized and discussed in this Review article. Owing to the underlying photophysical phenomenon, fluorescent AIE active molecules show more impact on sensing applications. The major focus in current research efforts is on the development of AIE active materials such as TPE based organic fluorescent molecules, metal organic framework, and polymers that can be employed for the detection of toxic pollutants such as CN- , NO2- , Hg2+ , Cd2+ , As3+ , As5+ , F- , Pb2+ , Sb3+ ions.