Electrochemical Detection of a Breast Cancer Biomarker with an Amine-Functionalized Nanocomposite Pt-Fe3O4-MWCNTs-NH2 as a Signal-Amplifying Label.

We report an ultrasensitive sandwich-type electrochemical immunosensor to detect the breast cancer biomarker CA 15-3. Amine-functionalized composite of reduced graphene oxide and Fe3O4 nanoparticles (MRGO-NH2) was used as an electrochemical sensing platform material to modify the electrodes. The nanocomposite comprising Pt and Fe3O4 nanoparticles (NPs) anchored on multiwalled carbon nanotubes (Pt-Fe3O4-MWCNTs-NH2) was utilized as a pseudoenzymatic signal-amplifying label. Compared to reduced graphene oxide, the composite MRGO-NH2 platform material demonstrated a higher electrochemical signal. In the Pt-Fe3O4-MWCNTs-NH2 label, multiwalled carbon nanotubes provided the substratum to anchor abundant catalytic Pt and Fe3O4 NPs. The nanocomposites were thoroughly characterized using transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy. An electroanalytical study and prevalidation of the immunosensor was carried out. The immunosensor exhibited exceptional capabilities in detecting CA 15-3, offering a wider linear range of 0.0005-100 U mL-1 and a lower detection limit of 0.00008 U mL-1. Moreover, the designed immunosensor showed good specificity, reproducibility, and acceptable stability. The sensor was successfully applied to analyze samples from breast cancer patients, yielding reliable results.

Perfusion index to predict post spinal hypotension in lower segment caesarean section.

Background and Aims: It is important to predict and prevent post-spinal hypotension in lower segment cesarean section (LSCS). Peripheral vascular tone can be monitored as a perfusion index (PI) from a pulse oximeter. We aimed to study baseline PI as a predictor of post-spinal hypotension in LSCS. Material and Methods: Prospective observational study conducted in a tertiary care teaching public hospital on patients posted for elective LSCS under spinal anesthesia. Baseline PI and hypotension were compared. A receiver operating characteristic (ROC) curve was plotted and data were analyzed using SPSS version 20. Results: Among 90 females, 43 (47.8%) had a PI ≤3.5 and 47 (52.2%) had a PI >3.5. In the PI >3.5 group, 46 (97.9%) females had hypotension and required a high volume of IV fluids, and 29 (61.7%) required vasopressors, and the association with PI was statistically significant with Pearson's Chi-square values of 32.26 and 32.36, respectively (P = 0.001). In the ROC, the area under the curve (AUC) was 0.917, proving baseline PI >2.9 as an excellent classifier (P < 0.0001,95% confidence interval [CI] 0.840-0.965) and can predict hypotension with a sensitivity of 83.08% and specificity of 96.00%. Conclusion: Baseline PI >3.5 was associated with significant post-spinal hypotension and vasopressor administration in LSCS. We established baseline PI >2.9 can predict post-spinal hypotension with high sensitivity and specificity. PI is simple, quick, and non-invasive and can be used as a predictor for post-spinal hypotension in parturients undergoing LSCS so that prophylactic measures can be considered in at-risk patients for better maternal and fetal outcomes.

Regioselective Synthesis of the Tetrahydrocarbazole Core of Akuammiline Alkaloids via Palladium-Catalyzed Intramolecular Arylation Reaction.

Tetrahydrocarbazole is the central core for several biologically active alkaloids, and regioselective synthesis of this core is a challenging task. Herein, we report an efficient strategy for the synthesis of this core involving palladium-catalyzed intramolecular arylation reaction with excellent regioselectivity (>99%) starting from N-phenyl-bromoalkene without having any relocation of double bonds via competitive palladium-catalyzed isomerization reaction. Broad functional group tolerance and exclusive regioselectivity have been observed for meta-substituted halide substrates. Furthermore, this reaction can be scalable on the gram scale.

Self-Assembled Lanthanum Oxide Nanoflakes by Electrodeposition Technique for Resistive Switching Memory and Artificial Synaptic Devices.

In recent years, many metal oxides have been rigorously studied to be employed as solid electrolytes for resistive switching (RS) devices. Among these solid electrolytes, lanthanum oxide (La2 O3 ) is comparatively less explored for RS applications. Given this, the present work focuses on the electrodeposition of La2 O3 switching layers and the investigation of their RS properties for memory and neuromorphic computing applications. Initially, the electrodeposited La2 O3 switching layers are thoroughly characterized by various analytical techniques. The electrochemical impedance spectroscopy (EIS) and Mott-Schottky techniques are probed to understand the in situ electrodeposition, RS mechanism, and n-type semiconducting nature of the fabricated La2 O3 switching layers. All the fabricated devices exhibit bipolar RS characteristics with excellent endurance and stable retention. Moreover, the device mimics the various bio-synaptic properties such as potentiation-depression, excitatory post-synaptic currents, and paired-pulse facilitation. It is demonstrated that the fabricated devices are non-ideal memristors based on double-valued charge-flux characteristics. The switching variation of the device is studied using the Weibull distribution technique and modeled and predicted by the time series analysis technique. Based on electrical and EIS results, a possible filamentary-based RS mechanism is suggested. The present results assert that La2 O3 is a promising solid electrolyte for memory and brain-inspired applications.

An Uncommon Presentation of Autoimmune Hepatitis in a Child With Thalassemia Trait.

Autoimmune hepatitis (AIH) is quite rare in children. AIH is classified into two types based on the presence of autoantibodies: type 1 and type 2. The presentation of AIH varies, ranging from asymptomatic to acute or chronic hepatitis and occasionally fulminant liver failure. It can present at any age. In 20% of AIH cases, other autoimmune disorders might be present, such as diabetes mellitus and arthritis. A high index of suspicion is required for the early diagnosis of this condition. Pediatricians should consider the possibility of AIH in patients with jaundice once common causes are ruled out. The diagnosis is done on the basis of the presence of typical autoantibody titer, liver biopsy findings, and response to immunosuppressive medications. Some AIH patients may not respond to immunosuppressive therapy and may need a liver transplant. We present a case of a 12-year-old male child with thalassemia trait who was diagnosed with AIH.

Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282.

Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.

Biosynthesized δ-Bi2O3 Nanoparticles from Crinum viviparum Flower Extract for Photocatalytic Dye Degradation and Molecular Docking.

Bioinspired delta-bismuth oxide nanoparticles (δ-Bi2O3 NPs) have been synthesized using a greener reducing agent and surfactant via co-precipitation method. The originality of this work is the use of Crinum viviparum flower extract for the first time for the fabrication of NPs, which were further calcined at 800 °C to obtain δ-Bi2O3 NPs. Physicochemical studies such as FTIR spectroscopy and XPS confirmed the formation of Bi2O3 NPs, whereas XRD and Raman verified the formation of the cubic delta (δ) phase of Bi2O3 NPs. However, HRTEM revealed the spherical shape with diameter 10-20 nm, while BET studies expose mesoporous nature with a surface area of 71 m2/gm. The band gap for δ-Bi2O3 NPs was estimated to be 3.45 eV, which ensured δ-Bi2O3 to be a promising photocatalyst under visible-light irradiation. Therefore, based on the results of physicochemical studies, the bioinspired δ-Bi2O3 NPs were explored as active photocatalysts for the degradation of toxic dyes, viz., Thymol blue (TB) and Congo red (CR) under visible-light irradiation. The study showed 98.26% degradation of TB in 40 min and 69.67% degradation of CR in 80 min by δ-Bi2O3 NPs. The photogenerated holes and electrons were found responsible for this enhancement. Furthermore, molecular docking investigations were also performed for δ-Bi2O3 NPs to understand its biological function as New Delhi metallo-ß-lactamase 1 (NDM-1) [PDB ID 5XP9] enzyme inhibitor, and studies revealed good interaction with various amino acid residues and found good hydrogen bonding with a fine pose energy of -3.851 kcal/mole.

Bioinspired NiO Nanospheres: Exploring In Vitro Toxicity Using Bm-17 and L. rohita Liver Cells, DNA Degradation, Docking, and Proposed Vacuolization Mechanism.

The present work demonstrated a novel Cleome simplicifolia-mediated green fabrication of nickel oxide nanoparticles (NiO NPs) to explore in vitro toxicity in Bm-17 and Labeo rohita liver cells. As-fabricated bioinspired NiO NPs were characterized by several analytical techniques. X-ray diffraction (XRD) revealed a crystalline face-centered-cubic structure. Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible diffuse reflectance spectroscopy (UV-DRS), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS) confirmed NiO formation. The chemical composition was confirmed by energy-dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy. Brunauer-Emmett-Teller (BET) revealed the mesoporous nature. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed the formation of 97 nm diameter nanospheres formed due to the congregation of 10 nm size particles. Atomic force microscopy (AFM) revealed the nearly isotropic behavior of NiO NPs. Further, a molecular docking study was performed to explore their toxicity by binding with genetic molecules, and it was found that the docking energy was about -9.65284 kcal/mol. On evaluating the in vitro toxicity of NiO NPs for Bm-17 cells, the study showed that when cells were treated with a high concentration of NPs, cells were affected severely by toxicity, while at a lower concentration, cells were affected slightly. Further, on using 50 µg/mL, quick deaths of cells were observed due to the formation of more vacuoles in the cells. The DNA degradation study revealed that NiO NPs are significantly responsible for DNA degradation. For further confirmation, trypan blue assay was observed for cell viability, and morphological assessment was performed using inverted tissue culture microscopy. Further, the cytotoxicity of NiO NPs in L. rohita liver cells was studied. No toxicity was observed at 1 mg/L of NiO NPs; however, when the concentration was 30 and 90 mg/L, dark and shrank hepatic parenchyma was observed. Hence, the main cause of cell lysis is the increased vacuolization in the cells. Thus, the present study suggests that the cytotoxicity induced by NiO NPs could be used in anticancer drugs.

Drug Repositioning: A Unique Approach to Refurbish Drug Discovery.

For a decade, it has been observed that there is a remarkable decrease in the quantum of novel clinically approved drugs, in spite of modernization in the research and development process. We have highlighted repositioning of drugs as a methodology that has found new therapeutic implications for clinically approved drugs but with different indications. This can be considered as an upbringing strategy to deliver timely and cost-effective solutions, which still need exploration for getting over the shortage of novel drugs reaching the market. This review focuses on an activity-based drug repositioning approach, which is used to explore new uses of known drugs that are already approved for specific indications and are now being used for other indications on the basis that a single drug interacts with multiple targets. It also includes current research trends related to drug repositioning, which depends on strong knowledge of medicinal chemistry and involves elucidation of mechanisms of action and validation of novel targets. The review highlights the importance of computational tools and databases of various forms for drug repositioning purposes, which have enhanced the ability to pose reasonable and testable hypotheses. The critical nature of this aspect is obvious in cases where data gathered from in vitro, or animal models do not confirm in subsequent clinical trials. Hence, considering the positive outcomes of drug repositioning, it can be surmised that this approach can serve as a promising one that can develop into a robust drug discovery strategy.

Micropsalliota pileocystidiata (Agaricaceae), a new species from Maharashtra, India.

A new species of Micropsalliota is described from tropical region of Maharashtra, India. The species is recognized on the basis of morphological details and its phylogenetic placement is determined by using of nrITS and nrLSU sequence data analyses. Micropsalliota pileocystidiata is characterised by its robust basidiomes covered by reddish brown appressed fibrillose squamules, ellipsoid to amygdaliform basidiospores, pyriform pileocystidia and clavate, utriform to broadly utriform or sometimes ellipsoid cheilo- and pleurocystidia.

Microwave prompted solvent-free synthesis of new series of heterocyclic tagged 7-arylidene indanone hybrids and their computational, antifungal, antioxidant, and cytotoxicity study.

In this study, we report the expeditious synthesis of ten new antifungal and antioxidant agents containing heterocyclic linked 7-arylidene indanone moiety. The solvent-free microwave technique, ample substrate scope, superfast synthesis, and very simple operation are noteworthy features of this protocol. Antifungal activities of the newly synthesized compounds were evaluated against four fungal strains namely Rhizophus oryzae, Mucor mucido, Aspergillus niger, and Candida albicans. Most of the compounds were shown strong inhibition of the investigated fungal agents. In vitro, antioxidant potential against DPPH and OH radicals affirmed that the synthesized compounds are good to excellent radicals scavenging agents. The cytotoxicity data of the synthesized compounds towards HL-60 cells uncovered that the synthesized compounds display very low to negligible cytotoxicity. The structural and quantum chemical parameters of the synthesized compounds were explored by employing density functional theory (DFT) at B3LYP functional using 6-311G(d,p) basis set. The compound 3a is discussed in detail for the theoretical and experimental correlation. Time-dependent density functional theory (TD-DFT) at CAM-B3LYP functional with 6-311G(d,p) basis set was used for the electronic absorption study in the gas phase and indichloromethane and benzene solvents. The UV-Visible absorption peaks and fundamental vibrational wavenumbers were computed and a good agreement between observed and theoretical results has been achieved. From the DFT and antifungal activity correlation, it has been found that the 7-heteroarylidene indanones with more stabilized LUMO energy levels display good antifungal potential.

Biogenic Synthesis of Metal/Metal Oxide Nanostructured Materials.

Nanotechnology is an emerging outlet of nanoscience in which the atoms are encompassed in nanoscale dimensions and become more receptive compared with their distinctive counterparts. Recently, the utilization of synthetic designs and physicochemical approaches has received special attention; nevertheless, the generation of noxious impressions on the eco-system has raised serious concerns of the scientific community worldwide. Presently, environment-friendly green synthesis routes are promising venues for the arrangement of Metal/Metal Oxide (M/MO) nanostructured materials by using plants and their corresponding alliances. This revolution is predominantly recompensing as far as the reduction of toxic emissions and wastes is concerned. Accordingly, material scientists have adopted various renewable naturally-occurring eco-friendly materials, and biogenic processes to fabricate the functional M/MO nanostructured materials. The current review article recapitulates and assimilates the present state of knowledge on different strategies for biogenic fabrication of M/MO nanostructured materials.

LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization.

α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Induction Heating Analysis of Surface-Functionalized Nanoscale CoFe2O4 for Magnetic Fluid Hyperthermia toward Noninvasive Cancer Treatment.

Oleic acid-coated cobalt ferrite nanoparticles were synthesized using the chemical co-precipitation route and characterized by standard techniques for structure, morphology, and magnetic properties analysis. The Rietveld refined X-ray diffraction (XRD) pattern of CoFe2O4 nanoparticles indicated the formation of a cubic-spinel single-phase structure with the Fd3̅m space group. The average crystallite size (∼12 nm) confirmed the nanocrystalline appearance of the prepared CoFe2O4 nanoparticles. Transmission electron microscopy (TEM) images revealed the spherical nature of both (CoFe2O4) and (OA-CoFe2O4) samples. The absorption bands in the Fourier transform infrared (FT-IR) spectrum at ∼3418, 3026, 1628, 1404, 1068, 845, 544, and 363 cm-1 affirmed the spinel ferrite formation and OA attachment. The M-H curve recorded at room temperature showed the superparamagnetic nature of the CoFe2O4 nanoparticles with moderate saturation magnetization (∼78 emu/gm). The blocking temperature of the prepared CoFe2O4 nanoparticles obtained from the field-cooled and zero-field-cooled (FC-ZFC) curve was estimated to be 144 K. Further, the characterized surface-modified CoFe2O4 was then added in ethylene glycol/water with various concentrations and characterized by the induction heating technique for the evaluation of their self-heating characteristics. A series of temperature versus time measurements were made by varying the ethylene glycol/water proportion for better understanding of the self-heating characteristics of the prepared CoFe2O4 nanoparticles. All of the findings display the applicability of the surface-modified CoFe2O4 nanoparticles in magnetic fluid hyperthermia toward noninvasive cancer treatment and other bio-applications.

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

Tumor budding in invasive breast cancer - An indispensable budding touchstone.

BACKGROUND: Tumor budding denotes a phenomenon in which the tumor cells, singly or in small aggregates, become detached from the neoplastic glands at the invasive front of adenocarcinoma. Tumors with budding cells have a significantly more aggressive clinical course. Significance of tumor budding has mainly been examined in the field of colorectal cancer. AIMS: To document the number tumor buds at the invasive front of invasive breast cancer. To correlate the number of tumor buds with other histopathological parameters, and available clinical details. SETTING AND STUDY DESIGN: Analytical study at a rural tertiary care referral institute. MATERIALS AND METHODS: It was a retrospective study of invasive breast cancer cases from January 2012 to April 2015. Tumor buds were counted in H and E stained sections in 10 High Power Fields (HPFs). Association of tumor budding with histological parameters and available clinical details were analyzed statistically. STATISTICAL ANALYSIS USED: Frequencies, Chi-Square Test and Crosstabs were used for calculation. RESULTS: 50 cases of invasive breast carcinoma were analyzed. Invasive ductal carcinoma constituted predominant histological type (92%). Low tumor budding (tumor buds ≤20/10HPFs) constituted 20 cases. High tumor budding (tumor buds >20/10HPFs) constituted 30 cases. Association of high tumor budding with lympho-vascular invasion, lymph node metastasis, primary tumor staging, regional lymph node staging, necrosis and Monckeberg medial sclerosis was statistically significant. CONCLUSION: Tumor budding may be incorporated as a new parameter in reporting protocols. Tumor budding serves as an indispensable touchstone in evaluating cases of invasive breast cancer.