Unilateral Administration of Surface-Modified G1 and G4 PAMAM Dendrimers in Healthy Mice to Assess Dendrimer Migration in the Brain.

Polyamidoamine (PAMAM) dendrimers are nanoparticles that have a wide scope in the field of biomedicine. Previous evidence shows that the generation 4 (G4) dendrimers with a 100% amine surface (G4-NH2) are highly toxic to cells in vitro and in vivo due to their positively charged amine groups. To reduce the toxicity, we modified the surface of the dendrimers to have more neutral functional groups, with 10% of the surface covered with -NH2 and 90% of the surface covered with hydroxyl groups (-OH; G4-90/10). Our previous in vitro data show that these modified dendrimers are taken up by cells, neurons, and different types of stem cells in vitro and neurons and glial cells in vivo. The toxicity assay shows that these modified dendrimers are less toxic compared with G4-NH2 dendrimers. Moreover, prolonged dendrimer exposure (G1-90/10 and G4-90/10), up to 3 weeks following unilateral intrastriatal injections into the striatum of mice, showed that dendrimers have the tendency to migrate within the brain via corpus callosum at different rates depending on their size. We also found that there is a difference in migration between the G1 and G4 dendrimers based on their size differences. The G4 dendrimers migrate in the anterior and posterior directions as well as more laterally from the site of injection in the striatum compared to the G1 dendrimers. Moreover, the G4 dendrimers have unique projections from the site of injection to the cortical areas.

Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities.

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.

Efficient anode material derived from nutshells for bio-energy production in microbial fuel cell.

Biochar is a carbonaceous solid that is prepared through thermo-chemical decomposition of biomass under an inert atmosphere. The present study compares the performance of biochar prepared from Peanut shell, coconut shell and walnut shell in dual chamber microbial fuel cell. The physicochemical and electrochemical analysis of biochar reveals that prepared biochar is macroporous, amorphous, biocompatible, and electrochemically conductive. Polarization studies show that Peanut shell biochar (PSB) exhibited a maximum power density of 165 mW/m2 followed by Coconut shell biochar (CSB) Activated Charcoal (AC) and Walnut shell biochar (WSB). Enhanced power density of PSB was attributed to its surface area and suitable pore size distribution which proved conducive for biofilm formation. Furthermore, the high electrical capacitance of PSB improved the electron transfer between microbes and anode.

Investigating the potential of delignified rice husk as a carbon-rich resource for extracting glucose and its utilization in biocement production through fungal isolates.

Burning rice straw is now a significant issue faced by different regions in India, as its burning releases harmful gases, mainly carbon dioxide. Various techniques are now in trend to utilize the rice straw, e.g., producing compressed natural gas using rice straw, bioethanol, etc., as a substrate for various microorganisms. A high quantity of non-utilized rice husk generates more ideas for its proper utilization. The cellulose, hemicellulose, and lignin found in rice straws can be a fungi growth medium. In this research, the delignification of rice husk is done by acid (2% and 4% H2SO4) and alkali (2% and 4% NaOH) at 121 °C at 103 kPa for 1 h to obtain crude carbon source which is further utilized for biomineralization. The glucose is subjected to qualitative and quantitative analysis using Molisch's and Dinitro salicylic tests. The delignification process showed a positive outcome when 2% H2SO4 is utilized maximum yield of 5.9 ug/ml free sugar concentration. Representing the highest glucose yield compared to the experiment's other acid and base substances used. Various techniques such as field emission-scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and Fourier transformed infra-red (FTIR) spectroscopy are employed to examine surface and chemical alterations. The 2% H2SO4 pretreated rice husk is utilized for microbial-induced calcite precipitation using fungal isolates S1 (3), S1 (18), and S4 (1). The calcite and vaterite produced by biomineralization are confirmed using XRD for fungal isolates namely, S1 (3), S1 (18), and S4 (1) having percentage crystallinity of 59%, 46.428%, and 62.69% percentage crystallinity respectively.

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

The dark side of circular RNA, a new driver of genome instability.

Circular RNAs (circRNAs) are covalently closed RNA molecules whose functions are still largely uncharacterized. In the July issue of Cancer Cell, Conn et al.1 demonstrate that circRNA can bind cognate DNA loci, forming circRNA-DNA hybrids (circR loops), driving genetic rearrangements of MLL/KMT2A, which are associated with the most aggressive acute leukemias.

ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer.

Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial.

PURPOSE: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. PATIENTS AND METHODS: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. RESULTS: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. CONCLUSIONS: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.

Emerging waste-to-wealth applications of fly ash for environmental remediation: A review.

The considerable increase in world energy consumption owing to rising global population, intercontinental transportation and industrialization has posed numerous environmental concerns. Particularly, in order to meet the required electricity supply, thermal power plants for electricity generation are widely used in many countries. However, an annually excessive quantity of waste fly ash up to 1 billion tones was globally discarded from the combustion of various carbon-containing feedstocks in thermoelectricity plants. About half of the industrially generated fly ash is dumped into landfills and hence causing soil and water contamination. Nonetheless, fly ash still contains many valuable components and possesses outstanding physicochemical properties. Utilizing waste fly ash for producing value-added products has gained significant interests. Therefore, in this work, we reviewed the current implementation of fly ash-derived materials, namely, zeolite and geopolymer as efficient adsorbents for the environmental treatment of flue gas and polluted water. Additionally, the usage of fly ash as a catalyst support for the photodegradation of organic pollutants and reforming processes for the corresponding wastewater remediation and H2 energy generation is thoroughly covered. In comparison with conventional carbon-based adsorbents, fly ash-derived geopolymer and zeolite materials reportedly exhibited greater heavy metal ions removal and reached the maximum adsorption capacity of about 150 mg g-1. As a support for biogas reforming process, fly ash could enhance the activity of Ni catalyst with 96% and 97% of CO2 and CH4 conversions, respectively.

Quantification of protein enrichment at site-specific DNA double-strand breaks by chromatin immunoprecipitation in cultured human cells.

Here, we present a chromatin-immunoprecipitation-based protocol to quantify the recruitment of proteins adjacent to site-specific DNA double-strand breaks (DSBs), such as proteins involved in DSB repair. We describe steps to induce DSBs in U2OS osteosarcoma cells stably expressing the restriction endonucleases FokI or AsiSI. We then detail the procedures of chromatin isolation and immunoprecipitation, followed by protein elution and quantitative-PCR-based quantification of DNA. This protocol cannot be used on DSBs generated at random loci by DNA damaging agents. For complete details on the use and execution of this protocol, please refer to Fitieh et al. (2022).1.

Role of Tyrosine Kinases and their Inhibitors in Cancer Therapy: A Comprehensive Review.

BACKGROUND: Cancer has been recognized as one of the non-communicable diseases with an increasing number of new cases, higher morbidity, and higher mortality rates at the global level. Thus, there is non-stop search for novel targets and small molecules to improve the chemotherapeutic outcomes concerning potency, selectivity, efficiency, affinity, ADMET, etc. Among anticancer therapeutic targets, tyrosine kinase has been documented well and approved as an important target with the development of various clinically used drugs. There are several structurally diverse small molecules in different preclinical and clinical stages of development that act by affecting tyrosine kinases in cancerous cells. Here, we have summarized different potent molecules acting against tyrosine kinases that can be considered as anticancer agents. OBJECTIVE: The current review focused on structural aspects of different chemical agents for inhibition of tyrosine kinases as anticancer agents. METHODS: The present study provides a summarized review of published information on tyrosine kinase inhibitors, their binding pattern, potencies, and structure-activity relationships. The review also highlighted the structural aspects of the interaction between inhibitors and amino acid residues of tyrosine kinases. Moreover, it also provided a summary of different types of cancers and the currently available options for treatment. RESULTS: Several studies are being conducted for the inhibition of different tyrosine kinases using small molecules for the treatment of cancer. Tyrosine kinases have been reported involving in routine cellular functions, growth, and division of cells through different pathways which depend on phosphorylation. The overexpression and uncontrolled activity of tyrosine kinases have been identified as an important feature of cancerous cells. Thus, various small molecules have been reported which inhibit tyrosine kinases to block the growth and division of cancer cells. Here, more than 30 highly potent inhibitors of tyrosine kinases are summarised, which consist of pyrimidine, pyrazole, triazine, quinazoline, quinoline, pyrazine, chromene, etc. rings as a basic skeleton with different substituents. CONCLUSION: Inhibition of tyrosine kinases by different small molecules is an approved strategy for the development of novel anticancer agents. Several published reports have mentioned the characteristics of the different binding sites and crucial residues in tyrosine kinases for the design of novel molecular inhibitors. However, selectivity is an important criterion for the development of chemotherapeutic agents due to the existence of approximately 30 families of tyrosine kinases.

Recent Developments in the Synthesis and Anticancer Activity of Indole and Its Derivatives.

Heterocyclic compounds are a class of compounds that is deeply intertwined with biological processes and is found in about 90% of commercially available medicines. They serve a critical function in medicinal chemistry and are focused in the field of medication development for their intensive research due to their broad variety of biological effects because of their intriguing molecular architecture, such as indoles are good candidates for drug development. It is a bicyclic structure consisting of a six-membered benzene ring fused to a five-membered pyrrole ring with several pharmacophores that yield a library of different lead compounds. Human cancer cells have been demonstrated to be inhibited by indoles in the development of new anticancer medicines. This is the first comprehensive review to focus on current methodologies for incorporating indole moiety, with their mechanistic targets as anticancer drugs, in order to shed light on the logical development of indole-based anticancer treatment options with high efficacy. This compiled data may serve as a benchmark for modifying existing ligands in order to design novel potent molecules through excellent yield synthesis techniques.

Tetrazole: A privileged scaffold for the discovery of anticancer agents.

Carcinoma, characterized by abnormal growth of cells and tissue, is a ubiquitously leading cause of mortality across the globe due to some carcinogenic factors. Currently, several anticancer agents are commercially available in the global market. However, due to their resistance and cost, researchers are gaining more interest in developing newer novel potential anticancer agents. In the search for new drugs for clinical use, the tetrazole ring system has emerged as an exciting prospect in the optimization studies of promising lead molecules. Among the various heterocyclic agents, tetrazole-containing compounds have shown significant promise in the treatment of a wide range of diseases, particularly cancer. Here, in this review, we focused on several synthetic approaches for the synthesis of tetrazole analogs, their targets for treating cancer along with the biological activity of some of the recently reported tetrazole-containing anticancer agents.

Gold nanoparticle-decorated earth-abundant clay nanotubes as catalyst for the degradation of phenothiazine dyes and reduction of 4-(4-nitrophenyl)morpholine.

In the present work, halloysite nanotubes modified with gold nanoparticles (AuNPs-HNT) are successfully prepared by wet chemical method for the catalytic degradation of phenothiazine dyes (azure B (AZB) and toluidine blue O (TBO)) and also cleaner reduction of 4-(4-nitrophenyl)morpholine (4NM) in the sodium borohydride (NaBH4) media. The catalyst is formulated by modifying the HNT support with a 0.964% metal loading using the HNT supports modified with 3-aminopropyl-trimethoxysilane (APTMS) coupling agent to facilitate the anchoring sites to trap the AuNPs and to prevent their agglomeration/aggregation. The AuNPs-HNT catalyst is investigated for structural and morphological characterization to get insights about the formation of the catalyst for the effective catalytic reduction of dyes and 4NM. The microscopic studies demonstrate that AuNPs (2.75 nm) are decorated on the outer surface of HNT. The as-prepared AuNPs-HNT catalyst demonstrates AZB and TBO dye degradation efficiency up to 96% in 10 and 11 min, respectively, and catalytic reduction of 4NM to 4-morpholinoaniline (MAN) is achieved up to 97% in 11 min, in the presence of NaBH4 without the formation of any by-products. The pseudo-first-order rate constant (K1) value of the AuNPs-HNT catalyst for AZB, TBO, and 4NM were calculated to be 0.0078, 0.0055, and 0.0066 s-1, respectively. Moreover, the synthesized catalyst shows an excellent reusability with stable catalytic reduction for 7 successive cycles for both the dyes and 4NM. A plausible mechanism for the catalytic dye degradation and reduction of 4NM by AuNPs-HNT catalyst is proposed as well. The obtained results clearly indicate the potential of AuNPs-HNT as an efficient catalyst for the removal of dye contaminants from the aquatic environments and cleaner reduction of 4NM to MAN, insinuating future pharmaceutical applications.

Nanoparticle-based toxicity in perishable vegetable crops: Molecular insights, impact on human health and mitigation strategies for sustainable cultivation.

With the advancement of nanotechnology, the use of nanoparticles (NPs) and nanomaterials (NMs) in agriculture including perishable vegetable crops cultivation has been increased significantly. NPs/NMs positively affect plant growth and development, seed germination, plant stress management, and postharvest handling of fruits and vegetables. However, these NPs sometimes cause toxicity in plants by oxidative stress and excess reactive oxygen species production that affect cellular biomolecules resulting in imbalanced biological and metabolic processes in plants. Therefore, information about the mechanism underlying interactions of NPs with plants is important for the understanding of various physiological and biochemical responses of plants, evaluating phytotoxicity, and developing mitigation strategies for vegetable crops cultivation. To address this, recent morpho-physiological, biochemical and molecular insights of nanotoxicity in the vegetable crops have been discussed in this review. Further, factors affecting the nanotoxicity in vegetables and mitigation strategies for sustainable cultivation have been reviewed. Moreover, the bioaccumulation and biomagnification of NPs and associated phytotoxicity can cause serious effects on human health which has also been summarized. The review also highlights the use of advanced omics approaches and interdisciplinary tools for understanding the nanotoxicity and their possible use for mitigating phytotoxicity.

BMI-1 regulates DNA end resection and homologous recombination repair.

BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but the exact mechanism of how BMI-1 participates in the process is unclear. Here, we establish a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection. Mechanistically, BMI-1 mediates DNA end resection by facilitating the recruitment of CtIP, thus allowing RPA and RAD51 accumulation at DNA damage sites. Interestingly, treatment with transcription inhibitors rescues the DNA end resection defects of BMI-1-depleted cells, suggesting BMI-1-dependent transcriptional silencing mediates DNA end resection. Moreover, we find that H2A ubiquitylation at K119 (H2AK119ub) promotes end resection. Taken together, our results identify BMI-1-mediated transcriptional silencing and promotion of H2AK119ub deposition as essential regulators of DNA end resection and thus the progression of HR.

Prospects of MXenes in energy storage applications.

The transition metal carbides/nitrides referred to as MXenes has emerged as a wonder material presenting newer opportunities owing to their unique properties such as high thermal and electrical conductivity, high negative zeta-potential and mechanical properties similar to the parent transition metal carbides/nitrides. These properties of MXenes can be utilized in various societal applications including for energy storage and energy conversion. In this focused review, we provide a ready glance into the evolutionary development of the MXene family and various efforts that are made globally towards property improvement and performance enhancement. Particular attention in this review is made to direct the attention of readers to the bright prospects of MXene in the energy storage and energy conversion process - which is extremely timely to tackle the current concern on climate change. The review concludes by offering fresh insights into the future research needs and challenges that need to be addressed to develop resilient energy solutions.

An overview of MXene-Based nanomaterials and their potential applications towards hazardous pollutant adsorption.

With the massive development of industrialization, multiple ecological contaminants in gaseous, liquid, and solid forms are vented into habitats, which is currently at the forefront of worldwide attention. Because of the possible damage to public health and eco-diversity, high-efficiency clearance of these environmental contaminants is a serious concern. Improved nanomaterials (NMs) could perform a significant part in the exclusion of contaminants from the atmosphere. MXenes, a class of two-dimensional (2D) compounds that have got tremendous consideration from researchers for a broad array of applications in a variety of industries and are viewed as a potential route for innovative solutions to identify and prevent a variety of obstreperous hazardous pollutants from environmental compartments due to their exceptional innate physicochemical and mechanical features, including high specific surface area, physiological interoperability, sturdy electrodynamics, and elevated wettability. This paper discusses the recent progress in MXene-based nanomaterials' applications such as environmental remediation, with a focus on their adsorption-reduction characteristics. The removal of heavy metals, dyes, and radionuclides by MXenes and MXene-based nanomaterials is depicted in detail, with the adsorption mechanism and regeneration potential highlighted. Finally, suggestions for future research are provided to ensure that MXenes and MXene-based nanomaterials are synthesized and applied more effectively.

Applicability of bio-synthesized nanoparticles in fungal secondary metabolites products and plant extracts for eliminating antibiotic-resistant bacteria risks in non-clinical environments.

The abundance of antibiotic-resistant bacteria in the prawn pond effluents can substantially impact the natural environment. The settlement ponds, which are the most common treatment method for farms wastewater, might effectively reduce the suspended solids and organic matter. However, the method is insufficient for bacterial inactivation. The current paper seeks to highlight the environmental issue associated with the distribution of antibiotic resistant bacteria (ARB) from prawn farm wastewater and their impact on the microbial complex community in the surface water which receiving these wastes. The inactivation of antibiotic-resistant bacteria in prawn wastewater is strongly recommended because the presence of antibiotic-resistant bacteria in the environment causes water pollution and public health issues. The nanoparticles are more efficient for bacterial inactivation. They are widely accepted due to their high chemical and mechanical stability, broad spectrum of radiation absorption, high catalytic activity, and high antimicrobial activity. Many studies have examined the use of fungi or plants extract to synthesis zinc oxide nanoparticles (ZnO NPs). It is evident from recent papers in the literature that green synthesized ZnO NPs from microbes and plant extracts are non-toxic and effective. ZnO NPs inactivate the bacterial cells as a function for releasing reactive oxygen species (ROS) and zinc ions. The inactivation of antibiotic-resistant bacteria tends to be more than 90% which exhibit strong antimicrobial behavior against bacterial species.