Targeting Breast Cancer Using 177 Lu-Labeled Trastuzumab and Trastuzumab Fragment : First-in-Human Clinical Experience.

PURPOSE: A monoclonal antibody, trastuzumab, is used for immunotherapy for HER2-expressing breast cancers. Large-sized antibodies demonstrate hepatobiliary clearance and slower pharmacokinetics. A trastuzumab fragment (Fab; 45 kDa) has been generated for theranostic use. PATIENTS AND METHODS: Fab was generated by papain digestion. Trastuzumab and Fab have been radiolabelled with 177 Lu after being conjugated with a bifunctional chelating. The affinity and target specificity were studied in vitro. The first-in-human study was performed. RESULTS: The bifunctional chelating agent conjugation of 1-2 molecules with trastuzumab and Fab was detected at the molar ratio 1:10 in bicarbonate buffer (0.5 M, pH 8) at 37°-40°C. However, 2-3 molecules of bifunctional chelating agent were conjugated when DMSO in PBS (0.1 M, pH 7) was used as a conjugation buffer at a molar ratio of 1:10. The radiolabelling yield of DOTA-conjugated Fab and trastuzumab at pH 5, 45°C to 50°C, with incubation time 2.5-3 hours was 80% and 41.67%, respectively. However, with DOTAGA-conjugated trastuzumab and Fab, the maximum radiolabelling yield at pH 5.5, 37°C, and at 2.5-3 hours was 80.83% and 83%, respectively. The calculated K d of DOTAGA Fab and trastuzumab with HER2-positive SKBR3 cells was 6.85 ± 0.24 × 10 -8 M and 1.71 ± 0.10 × 10 -8 M, respectively. DOTAGA-Fab and trastuzumab showed better radiolabelling yield at mild reaction conditions.177 Lu-DOTAGA-Fab demonstrated higher lesion uptake and lower liver retention as compared with 177 Lu-DOTAGA-trastuzumab. However, 177 Lu-DOTAGA-Fab as compared with 177 Lu-DOTAGA-trastuzumab showed a relatively early washout (5 days) from the lesion. CONCLUSIONS: 177 Lu-DOTAGA-Fab and trastuzumab are suitable for targeting the HER2 receptors.

177 Lu-Microspheres Selective Intra-arterial Radionuclide Therapy : A Facile and Biocompatible Permanent Micro-Seed Implants for Unresectable Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis. Surgical resection is limited. Selective intra-arterial radionuclide therapy (SIRT) emerged as a potential cure for intermediate HCC with portal vein thrombosis. We report a pilot study of a 48-year-old man with recurrent HCC who underwent 177 Lu-microsphere SIRT (2.2 GBq) in segment III. Posttherapy SPECT/CT images (24 hours to 3 months) demonstrated excellent localization and prolonged retention within the tumor. Pre- and 3-month post-SIRT CECT showed a notable decrease in arterial enhancement and tumor size. Time-activity curve of the standard and the lesion demonstrated similar decay pattern indicating that 177 Lu-microspheres act as permanent implant.

Estimation of absorbed dose to salivary glands in mCRPC patients undergoing 177 Lu- PSMA-617 radioligand therapy using quantitative SPECT-CT at single time point: a single-center feasibility study.

OBJECTIVE: 177 Lu-PSMA-617-radioligand therapy (RLT) has shown promising therapeutic role in patients with metastatic castration-resistant prostate cancer. However, off-target action in salivary glands often presents with xerostomia. Personalized dosimetry can help in optimizing the treatment, however, has so far been tedious due to multiple time-point imaging. In this prospective study, we intended to estimate the absorbed dose delivered to the salivary glands in patients undergoing 177 Lu-PSMA-617-RLT using quantitative SPECT/CT at a single time point. METHODS: Patients undergoing 177 Lu-PSMA-617 RLT were included in this prospective study. Post-therapy whole-body images and regional quantitative single time-point SPECT/CT were acquired at 24 h with high-energy collimator. The data was processed and analyzed using Q.Metrix software. A scaling factor, that is, the time-integrated activity conversion factor was applied for the image acquired at 24 h. Absorbed doses were computed using MIRD scheme and OLINDA software. RESULTS: A total of 21 patients (mean age: 66 ±â€…9 years) were included. The value of mean absorbed dose for the parotid glands was 1.90 ±â€…1.31Gy (range: 0.26-6.23) and that for the submandibular glands was 1.37 ±â€…0.94Gy (range: 0.16-3.65). The mean absorbed doses per administered activity for the parotid and submandibular glands were 0.26 ±â€…0.18 Gy/GBq and 0.19 ±â€…0.12 Gy/GBq, respectively. The absorbed doses were estimated for one cycle of therapy and were well within acceptable limits. None of the patients experienced dryness of mouth. CONCLUSION: Single time-point dosimetry with quantitative SPECT/CT is feasible and can be standardized to estimate the absorbed dose to salivary glands instead of multiple time-point acquisitions.

Pathology, target discovery, and the evolution of XO inhibitors from the first discovery to recent advances (2020-2023).

Hyperuricemia, a disease characterized by elevation of serum uric acid level beyond 6 mg/dL. This elevation led to appearance of symptoms from joint pain to gout and from gout to difficulty in mobility of the patient. So, in this review, we have summarized the pathology of hyperuricemia, discovery of target and discovery of first XO inhibitor. At last, this review provides in-sights about the recently discovered as natural XO inhibitors, followed by design, structure activity relationship and biological activity of synthetic compounds as XO inhibitors discovered between 2020 and 2023 years. At last, the pharmacophores generated in this study will guide new researchers to design and modify the structure of novel XO inhibitors.

Metamaterial based AMC backed archimedean spiral antenna for in-vitro microwave hyperthermia of skin cancer.

This research article presents a study that uses microwave frequencies (ISM band) for treatment of skin cancer by heating the malignant cells on skin with a Microwave Hyperthermia (MWHT) applicator. The proposed MWHT applicator has been designed as an Archimedean Spiral Microstrip Patch Antenna (AMSPA) of dimensions 38 × 38 × 1.64 mm3 backed with a Meshed-shaped AMC (48 × 48 × 3.27mm3) reflector, placed at an optimized distance of 12 mm from AMSPA. The proposed AMSPA is designed as a single spiral resonator and fabricated on FR-4 substrate, excited using a feed network. The proposed AMSPA shows a resonance at 2.5 GHz with an impedance BW of 260 MHz (2.37-2.63 GHz) and peak gain of 3.20 dB with a bidirectional radiation pattern. An AMC is placed at its backside that can be exploited as a phase-compensation surface to attain an in-phase profile for directive emission and improve the BW upto 470 MHz, peak gain to 6.8 dB and also enhance the front-to-back ratio of the radiating antenna with radiation efficiency of 80%. The simulated environment for hyperthermia analysis is set up using penne's Bio-Heat equations to deliver microwave energy to the bio-mimic, that leads to a rise in temperature over the designed bio-mimic in CST MWS in the range of 41-45°C. The validation of MWHT radiation properties and temperature rise inside the malignancy of phantom is carried out by fabricating the bio-mimic using gelatine, vegetable oils and glycerol. This set up enhances the penetration-depth of EM waves inside the tri-layered phantom up-to 29.5 mm with Effective Field Surface of 36 × 36 mm2 and SAR of 8 W/Kg.

This article discusses the design and development of a device designed to treat skin cancer, specifically melanoma. This device is called a Microwave Hyperthermia (MWHT) applicator. The applicator sends out focused waves of microwave energy but at a specific frequency of ISM band. These waves heat up a model of human skin, simulating what would happen if this is used on a real person with cancer. The goal is to heat the cancer to around 45°C, which can help treat it. The special thing about this applicator is that it's designed to be very compact and have good gain. It heats up the cancer without causing harm to the healthy tissues nearby. The researchers tested it extensively and found that it works well. It has a wide range of effectiveness for different tumor sizes and depths within the skin. To make sure it is safe and accurate, a model of a human forearm using materials like gelatin and water has been prepared. Then used the applicator on this model and measured the temperature increase. After about 40 minutes of exposure, there is a temperature rise of about 45 degrees Celsius. Thus this article is about a device that uses special waves to heat up and treat skin cancer. It's designed to be safe and effective, and the tests show it works on a model of human skin. This could be a useful tool for treating skin cancer in the future.

Extending conducting channels in Fe-N-C by interfacial growth of CNTs with minimal metal loss for efficient ORR electrocatalysis.

Achieving a high electrocatalytic performance using a completely metal-free electrocatalyst, preferably based on only carbonaceous materials, remains a challenge. Alternatively, an efficient composite of a carbon nanostructure and a non-noble metal with minimum dependence on a metal holds immense potential. Although single-atom catalysis brings superior performance, its complex synthetic strategy limits its large-scale implementation. Previous investigation has shown that atomic dispersion (Fe-Nx-C) is accompanied by higher metal-loss compared to nanoparticle formation (Fe-NPs-N-C). Therefore, to achieve minimum metal loss, we first incorporated iron nanoparticles (Fe NPs) to N-doped carbon (N-C) and then exposed them to a cheap carbon source, melamine at high temperature, resulting in the growth of carbon nanotubes (CNTs) catalysed by those Fe NPs loaded on N-C (Fe-NPs-N-C). Thermogravimetric analysis showed that the metal-retention in the composite is higher than that in the bare carbon nanotube and even the atomically dispersed Fe-active sites on N-C. The composite material (Fe-NPs-N-C/CNT) shows a high half-wave potential (0.89 V vs. RHE) which is superior to that of commercial Pt/C towards the oxygen reduction reaction (ORR). The enhanced activity is attributed to the synergistic effect of high conductivity of CNTs and active Fe-sites as the composite exceeds the individual electrocatalytic performance shown by Fe-CNTs & Fe-NPs-N-C, and even that of atomically dispersed Fe-active sites on N-C.

Toxicity analysis of endocrine disrupting pesticides on non-target organisms: A critical analysis on toxicity mechanisms.

Endocrine disrupting compounds are the chemicals which mimics the natural endocrine hormones and bind to the receptors made for the hormones. Upon binding they activate the cascade of reaction which leads to permanent activating of the signalling cycle and ultimately leads to uncontrolled growth. Pesticides are one of the endocrine disrupting chemicals which cause cancer, congenital birth defects, and reproductive defects in non-target organisms. Non-target organisms are keen on exposing to these pesticides. Although several studies have reported about the pesticide toxicity. But a critical analysis of pesticide toxicity and its role as endocrine disruptor is lacking. Therefore, the presented review literature is an endeavour to understand the role of the pesticides as endocrine disruptors. In addition, it discusses about the endocrine disruption, neurological disruption, genotoxicity, and ROS induced pesticide toxicity. Moreover, biochemical mechanisms of pesticide toxicity on non-target organisms have been presented. An insight on the chlorpyrifos toxicity on non-target organisms along with species names have been presented.

Investigating the impact of fungicides and mungbean genotypes on the management of pod rot disease caused by Fusarium equiseti and Fusarium chlamydosporum.

Introduction: Mungbean is a vital pulse crop in India that can thrive in dry-land conditions and is grown in three seasons, with the added benefit of being used as green manure due to its ability to fix atmospheric nitrogen. Recently, pod rot disease has emerged as a serious threat to mungbean cultivation in India. Methods: In this study, morpho-molecular identification of associated pathogens and the bio-efficacy of systemic and non-systemic fungicides as well as genotype screening was performed during the years 2019 and 2020. The pathogens associated with this disease were confirmed on the basis of morphological and molecular characterization. For the molecular characterization, the translation elongation factor 1-alpha (tef-1) gene sequences were amplified by using primers (EF1 and EF2). Results: Under in vitro conditions, trifloxystrobin + tebuconazole 75% WG was found to be the most effective against Fusarium equiseti (ED50 2.39 µg ml-1) and Fusarium chlamydosporum (ED50 4.23 µg ml-1) causal agents of pod rot of mungbean. Under field conditions, three applications of trifloxystrobin + tebuconazole 75% WG at 0.07% as a foliar application at fortnightly intervals starting from the last week of July proved to be the most effective against pod rot disease on mungbean cultivars, i.e., ML 2056 and SML 668. To identify the potential resistance sources, 75 interspecific derivative and mutant lines of mungbean were screened for disease reaction to pod rot under natural epiphytotic conditions for the years 2019 and 2020. Genotypic differences were observed for resistance to pod rot disease. The study revealed that among the tested genotypes, ML 2524 exhibited resistance to pod rot disease, with a disease incidence of 15.62% and disease severity of 7.69%. In addition, 41 other genotypes were found to be moderately resistant (MR) to the disease. Conclusion: Altogether, the identified management options will offer an immediate solution to manage this disease under recent outbreak conditions and pave a path for futuristic disease management using identified resistant sources in breeding programs.

Bioengineering of biowaste to recover bioproducts and bioenergy: A circular economy approach towards sustainable zero-waste environment.

The inevitable need for waste valorisation and management has revolutionized the way in which the waste is visualised as a potential biorefinery for various product development rather than offensive trash. Biowaste has emerged as a potential feedstock to produce several value-added products. Bioenergy generation is one of the potential applications originating from the valorisation of biowaste. Bioenergy production requires analysis and optimization of various parameters such as biowaste composition and conversion potential to develop innovative and sustainable technologies for most effective utilization of biowaste with enhanced bioenergy production. In this context, feedstocks, such as food, agriculture, beverage, and municipal solid waste act as promising resources to produce renewable energy. Similarly, the concept of microbial fuel cells employing biowaste has clearly gained research focus in the past few decades. Despite of these potential benefits, the area of bioenergy generation still is in infancy and requires more interdisciplinary research to be sustainable alternatives. This review is aimed at analysing the bioconversion potential of biowaste to renewable energy. The possibility of valorising underutilized biowaste substrates is elaborately presented. In addition, the application and efficiency of microbial fuel cells in utilizing biowaste are described in detail taking into consideration of its great scope. Furthermore, the review addresses the significance bioreactor development for energy production along with major challenges and future prospects in bioenergy production. Based on this review it can be concluded that bioenergy production utilizing biowaste can clearly open new avenues in the field of waste valorisation and energy research. Systematic and strategic developments considering the techno economic feasibilities of this excellent energy generation process will make them a true sustainable alternative for conventional energy sources.

Increased PSMA Expression in 177 Lu-PSMA-617 Scan in Metastatic Castrate-Resistant Prostate Cancer Patient Treated With PSMA Radioligand Therapy and Enzalutamide : A Potential Game-Changer.

ABSTRACT: Androgen deprivation therapy plays an integral role in the treatment algorithm of advanced prostate cancer. Enzalutamide has shown great benefit in castrate-sensitive as well as resistant prostate cancer. Few studies have shown that enzalutamide can potentially increase the PSMA expression on 68 Ga-PSMA-11 PET/CT imaging in patients with metastatic castrate-resistant prostate cancer. We present an interesting case where addition of short course of enzalutamide resulted in increased localization of 177 Lu-PSMA-617 in metastatic lesions on posttherapy scan pointing to the added benefit of PSMA RLT.

Neuroprotective Effects of Carbonic Anhydrase Inhibition and Cyclic Adenosine Monophosphate Activation in Mouse Model of Transient Global Cerebral Ischemia and Reperfusion.

Cerebral ischemia is the primary basis of stroke, both sharing common pathogenic origins leading to irreversible brain damage if blood supply is not restored promptly. Existing evidence indicates that carbonic anhydrase (CA) inhibitors (CAIs) may impart therapeutic benefits against ischemia-reperfusion (I/R) pathology via the adenylyl cyclase-cyclic adenosine monophosphate (cAMP) pathway. We hypothesize that CAI and cAMP activation may enhance the therapeutic outcome against I/R conditions. In this investigation, the potential of dichlorphenamide (CAI) and the role of cAMP against ischemia-reperfusion injury were evaluated using a transient global cerebral I/R (tGCI/R) model. Swiss albino mice were subjected to bilateral common carotid artery occlusion (BCCAo) for 20 min and reperfusion (R) or sham surgery on day 1. Dichlorphenamide (DCPA, 20 mg/kg) and/or forskolin (cAMP agonist, 3 mg/kg) was administered intraperitoneally (i.p.) after BCCAo/R for 14 days. Results showed that tGCI/R impaired neurocognitive functions and lowered brain levels of cAMP and protein kinase A (PKA) that were ameliorated by DCPA and/or forskolin (FSK). DCPA and/or FSK attenuated tGCI/R-induced brain edema, blood-brain barrier dysfunction, oxidative-nitrosative stress, pro-inflammatory cytokines, acetylcholinesterase activity, cell death, and neurotransmitter imbalance (e.g., glutamate, γ-aminobutyric acid). The study showed that DCPA improved neurological and biochemical parameters against tGCI/R injury via cAMP-PKA-mediated activation of protective mechanisms. However, DCPA and FSK in combination showed much enhanced therapeutic outcomes against tGCI/R. Therefore, CA and cAMP present novel targets that may retard the progress of a transient ischemic attack to a full-blown stroke.

Quinoline derivatives volunteering against antimicrobial resistance: rational approaches, design strategies, structure activity relationship and mechanistic insights.

Emergence of antimicrobial resistance has become a great threat to human species as there is shortage of development of new antimicrobial agents. So, its mandatary to combat AMR by initiating research and developing new novel antimicrobial agents. Among phytoconstituents, Quinoline (nitrogen containing heterocyclic) have played a wide role in providing new bioactive molecules. So, this review provides rational approaches, design strategies, structure activity relationship and mechanistic insights of newly developed quinoline derivatives as antimicrobial agents.

Tibial Intramedullary Nailing by Suprapatellar Approach: Is It Quicker and Safer?

Background With the increasingly accepted method of suprapatellar tibial nailing for tibial shaft fractures, we aimed to compare intraoperative and postoperative outcomes of infrapatellar (IP) vs suprapatellar (SP) tibial nails. Methods This is a retrospective cohort analysis of 34 SP tibial nails over three years vs 24 IP tibial nails over a similar time frame. We compared total radiation dose (TRD), patient positioning time (PPT), fracture healing and follow up time. Knee pain in the SP group was evaluated utilising the Hospital for Special Surgery (HSS) Knee Injury and Osteoarthritis Outcome Score (KOOS). Results Fifty-eight patients with a mean age of 43 years were included. Mean intraoperative radiation dose for SP nails was 61.78 cGy (range: 11.60-156.01 cGy) vs 121.09 cGy (range: 58.01-18.03 cGy) for IP nails (p < 0.05). Mean PPT for SP nails was 10 minutes vs 18 minutes for IP nails (p < 0.05). All fractures united in the SP group vs one non-union in the IP group. Mean follow up was 5.5 months vs 11 months in the IP and SP groups, respectively. Mean KOOS was 7 (range: 0-22) at six months for the SP group. Conclusion The semi-extended position (SP group) leads to reduced TRD because of ease of imaging. Patients showed improved outcomes with shorter follow up and fracture union in all patients (SP group). The KOOS revealed that SP nail patients had minimal pain and good knee function. This study establishes a management and patient-reported outcome measures (PROMs) baseline for ongoing evaluation of SP nails.

3-Hydroxy-3-alkylindolin-2-ones: regioselective synthesis, molecular docking and nematicidal studies against Meloidogyne incognita.

Regioselective nucleophilic addition of unsubstituted isatin (1) was carried out for the synthesis of pharmaceutically and to be agrochemically important 3-hydroxy-3-akylindolin-2-ones (3a-f) using discrete nucleophiles via generation of Grignard reagent. The synthesized derivatives were characterized by spectral techniques and were evaluated for nematicidal activity against Meloidogyne incognita. The nematicidal assay revealed that 1-ethyl-3-hydroxyindolin-2-one (3a) exhibited potent nematicidal activity against M. incognita. The most active member (3a) exhibited reasonably good ovicidal (LC50 = 0.077 mg/mL) and larvicidal activity (LC50 = 0.058 mg/mL), respectively. In support of the nematicidal activity, molecular docking of isatin (1) and its derivatives (3a-f) was performed using three parasitic proteins viz., carboxylic ester hydrolase, cytochrome c oxidase and aspartyl protease which revealed maximum interaction with amino acid residues Tyr 356, Tyr 170, Glu 238, Glu 327, Arg 271, Arg 112, Ser 29, Ser 31, Ser 368, Asn 115, Leu 326 and His 51 which act as supporting factors for compounds to curb the parasite.

Comparison of Dermoscopic Findings in Female Androgenetic Alopecia and Telogen Effluvium and Female Controls in a Tertiary Care Center.

Background: Female androgenetic alopecia (FAGA) is a patterned hair loss caused by progressive miniaturization of hair follicles. This leads to reduction in the number and thickness of hairs, especially in the central, frontal, and parietal scalp regions. Telogen effluvium (TE) is characterized by diffuse hair loss within months of a significant systemic stressor because of premature follicular transition from the anagen to the telogen. Objective: This article aims to highlight the dermoscopic differences between TE and FAGA compared to healthy female controls. Methods: A total of 124 female patients, which included 31 women with clinical diagnosis of FAGA, 33 with TE, and 60 controls, were enrolled. Two dermatologists independently assessed each patient clinically as well as with dermoscope, recorded the history and examination findings on a proforma, and made a diagnosis. These dermoscopic images were later revised in photographs on the computer. Results: There was a statistically significant difference in hair diameter diversity (HDD) between patients with FAGA versus TE and FAGA versus controls (p<0.0001). The difference in the mean percentage of single PSU in both frontal and occipital areas in FAGA versus controls and FAGA versus TE patients was statistically significant. The vellus hair were significantly higher in the FAGA patients than TE and control. Conclusion: Dermoscopic features of FAGA and TE will help in early detection on the basis of increased proportion of thin and vellus hairs, HDD, perifollicular discoloration, and the presence of a variable number of yellow dots.

Tc-99m-tamoxifen: A novel diagnostic imaging agent for estrogen receptor-expressing breast cancer patients.

PURPOSE The aim of the study was to radiolabel, characterize, and perform in vitro and in vivo assessment of Technetium-99m (Tc-99m) tamoxifen for screening ER expressing lesions in breast cancer patients. METHODS In this study, tamoxifen has been radiolabeled with Tc-99m via Tc-99m-tricarbonyl core. The characterization and quality control tests of Tc-99m-tamoxifen were performed. In vitro recep- tor binding and blocking studies were performed in both positive control (MCF-7) and negative control cell lines (MDA-MB-231). Normal biodistribution studies were performed in female Wistar albino rats. The pilot clinical studies were performed in 4 ER-expressing breast cancer patients. Of the 4 patients, 1 was on tamoxifen therapy. All 4 patients had also undergone Fluorine-18 fluorodeoxyglucose (F-18-FDG) positron emission tomography/computed tomography. RESULTS Tamoxifen was radiolabeled with Tc-99m via Tc-99m-tricarbonyl core with more than 95% radio- chemical yield. Mass spectra showed a peak corresponding to the molecular weight of Tc-99m- tricarbonyl and Tc-99m-tamoxifen. The site of binding of Tc-99m-tricarbonyl with tamoxifen was determined by proton nuclear magnetic resonance. The Tc-99m-tamoxifen showed 30% binding with MCF-7 and only 1%-2% receptor binding with MDA-MB-231 cell lines. Also, the percentage of receptor binding was drastically reduced (up to 72%) when ER was saturated with 50 times the excess molar ratio of unlabeled tamoxifen. In a pilot patient study, Tc-99m-tamoxifen uptake was observed in primary and metastatic lesions. However, no uptake was observed in a patient who was on tamoxifen therapy. The uptake of F-18-FDG was noted in all the patients. CONCLUSION Tamoxifen was radiolabeled with an in-house-synthesized Tc-99m-tricarbonyl core. The radio- labeled complex has been characterized and evaluated for receptor specificity in in vitro and in vivo studies. Also, this is the first clinical study using Tc-99m-tamoxifen for imaging ER. More patients need to be evaluated to further explore the role of Tc-99m-tamoxifen in ER-expressing lesions.

Design, synthesis, and biological evaluation of isatin-indole-3-carboxaldehyde hybrids as a new class of xanthine oxidase inhibitors.

A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.

Ultrathin Twisty PdNi Alloy Nanowires as Highly Active ORR Electrocatalysts Exhibiting Morphology-Induced Durability over 200 K Cycles.

Even though the anion exchange membrane fuel cells have many advantages, the stability of their electrocatalysts for oxygen reduction reaction (ORR) has remained remarkably poor. We report here on the ultrathin twisty PdNi-alloy nanowires (NWs) exhibiting a very low reaction overpotential with an E1/2 ∼ 0.95 V versus RHE in alkaline media maintained over 200 K cycles, the highest ever recorded for an electrocatalyst. The mass activity of the used NWs is >10 times higher than fresh commercial Pt/C. Therein, Ni improves the Pd d-band center for a more efficient ORR, and its leaching continuously regenerates the surface active sites. The twisty nanowire morphology imparts multiple anchor points on the electrode surface to arrest their detachment or coalescence and extra stability from self-entanglement. The significance of the NW morphology was further confirmed from the high-temperature durability studies. The study demonstrates that tailoring the number of contact points to the electrode-surface may help realize commercial-grade stability in the highly active electrocatalysts.

Dimension switchable auto-fluorescent peptide-based 1D and 2D nano-assemblies and their self-influence on intracellular fate and drug delivery.

The production of dynamic, environment-responsive shape-tunable biomaterials marks a significant step forward in the construction of synthetic materials that can easily rival their natural counterparts. Significant progress has been made in the self-assembly of bio-materials. However, the self-assembly of a peptide into morphologically distinct auto-fluorescent nanostructures, without the incorporation of any external moiety is still in its infancy. Hence, in this study, we have developed peptide-based self-assembled auto-fluorescent nanostructures that can shuttle between 1D and 2D morphologies. Different morphological nanostructures are well known to have varied cellular internalization efficiencies. Taking advantage of our morphologically different particles emanating from the same peptide monomer, we further explored the intracellular fate of our nanostructures. We observed that the nanostructures' cellular internalization is a complex process that gets influenced by particle morphology and this might further affect their intracellular drug delivery potential. Overall, this study provides initial cues for the preparation of environment-responsive shape-shifting peptide-nano assemblies. Efforts have also been made to understand their shape driven cellular uptake behaviour, along with establishing them as nanocarriers for the cellular delivery of therapeutic molecules.

Clinical and Molecular Attributes of Patients With BCR/ABL1-negative Myeloproliferative Neoplasms in India: Real-world Data and Challenges.

INTRODUCTION: Classic BCR/ABL1-negative myeloproliferative neoplasms (MPNs) are characterized by clinical and genetic heterogeneity and include 4 distinct constituents. Very little data on clinical presentation and epidemiology of the same is available from the Indian setting. PATIENTS AND METHODS: Patients referred to Hematology-Oncology from January 2018 to August 2020 with suspected MPNs were included in the analysis and prospectively followed-up. All patients were initially screened, and only those meeting the updated World Health Organization 2016 criteria were included in the analysis. Epidemiologic, clinical, and molecular characteristics were documented, and patients were followed-up prospectively. RESULTS: A total of 233 patients were referred for evaluation of MPN, of which 63 were included in the analysis, including 39 males and 24 females. The median age at diagnosis was 57 years (range, 28-82 years), and 38% patients were younger than 50 years of age. The most common presentations were incidental detection in 35 (55.5%), abdominal symptoms in 13 (20%), fatiguability in 7 (11%), and recent vascular events in 6 (9.5%) patients. Final diagnosis was polycythemia vera in 27, essential thrombocytosis (ET) in 21, prefibrotic myelofibrosis in 9, and myelofibrosis in 6 patients. The frequency of driver mutations in polycythemia vera included JAK2 in 75%; in ET, JAK2 in 33%, CALR in 33%, and MPL in 4%; and in prefibrotic myelofibrosis, JAK2 in 66% and CALR in 33%. Aspirin was used for all patients along with risk-adapted cytoreduction with hydroxyurea. Ruxolitinib was reserved for symptoms refractory to hydroxyurea. After a median follow-up of 15 months (interquartile range, 10-28 months) from diagnosis, disease progression was noted in 4 patients. Two patients died at the end of the follow-up period, including 1 with secondary acute myeloid leukemia post myelofibrosis and one with ET and coexistent oral malignancy. The remaining 61 patients are alive and on regular treatment. RESULTS: This is one of the first systematic descriptions and prospective follow-up of patients with BCR/ABL-negative MPNs from India. Our study indicates a younger median age of presentation and higher proportion of JAK2-unmutated disease across all subtypes. The primary role of bone marrow morphology and supportive role of somatic mutations in differentiating MPN subtypes is indicated. CONCLUSIONS: This study sets the stage for a collaborative registry for defining epidemiologic data and long-term outcomes with MPN in India.