A review on the transformation of birnessite in the environment: Implication for the stabilization of heavy metals.

Birnessite is ubiquitous in the natural environment where heavy metals are retained and easily transformed. The surface properties and structure of birnessite change with the changes in external environmental conditions, which also affects the fate of heavy metals. Clarifying the effect and mechanism of the birnessite phase transition process on heavy metals is the key to taking effective measures to prevent and control heavy metal pollution. Therefore, the four transformation pathways of birnessite are summarized first in this review. Second, the relationship between transformation pathways and environmental conditions is proposed. These relevant environmental conditions include abiotic (e.g., co-existing ions, pH, oxygen pressure, temperature, electric field, light, aging, pressure) and biotic factors (e.g., microorganisms, biomolecules). The phase transformation is achieved by the key intermediate of Mn(III) through interlayer-condensation, folding, neutralization-disproportionation, and dissolution-recrystallization mechanisms. The AOS (average oxidation state) of Mn and interlayer spacing are closely correlated with the phase transformation of birnessite. Last but not least, the mechanisms of heavy metals immobilization in the transformation process of birnessite are summed up. They involve isomorphous substitution, redox, complexation, hydration/dehydration, etc. The transformation of birnessite and its implication on heavy metals will be helpful for understanding and predicting the behavior of heavy metals and the crucial phase of manganese oxides/hydroxides in natural and engineered environments.

Intracranial Solitary Fibrous Tumor Mimicking Meningioma.

Solitary fibrous tumor (SFT) is a clinically rare tumor derived from mesenchymal spindle cells. Central nervous system SFT represents only 0.09% of tumors occurring on the meninges, while intracranial solitary fibrous tumors (ISFT) are even more rare. Due to the similar genetic characteristics it shares with hemangiopericytoma, in 2016, the World Health Organization (WHO) classified it as a single disease called solitary fibrous tumor (SFT)/hemangiopericytoma. We reported a case of a 60-year-old female with an intracranial solitary fibrous tumor (ISFT). The patient's magnetic resonance imaging showed a mass adhering extensively to the dura mater, with adjacent thickening of the meninges and evidence of a meningeal tail sign. These radiologic findings suggested a meningioma. The tumor was surgically removed and sent for pathologic examination, which confirmed that the tumor was consistent with a solitary fibrous tumor(WHO III). Due to its rarity and similarities with meningioma, ISFT is often misdiagnosed as other types of brain tumors. ISFT is poorly understood and poses a diagnostic challenge. Our case report presents several features suggestive of meningioma, but histopathological examination after surgery confirmed the diagnosis of SFT. Knowledge of these tumors is crucial for neurosurgeons to include them in preoperative differential diagnosis.

Treatment of a Patient With Meningioma With Complicated Blood Supply.

Meningiomas account for ~30% of primary intracranial tumors, making them the second most common type of brain tumor. Most meningiomas are benign, and surgical resection is curative. By utilizing 3-dimensional slicer technology for multimodal image fusion, a wealth of 3-dimensional anatomic information can be obtained, enabling more effective treatment of meningiomas with complex tumor locations and surrounding structures. Guided by the 3-dimensional structural models, we conducted detailed preoperative planning for 1 case of highly vascularized meningioma and utilized combined surgery for complete tumor removal, effectively avoiding intraoperative bleeding and postoperative complications.

Capture gaseous arsenic in flue gas by amorphous iron manganese oxides with high SO2 resistance.

In non-ferrous metal smelting, the problem of gaseous arsenic in high-sulfur flue gas is difficult to solve. Now we have developed oxygen-enriched amorphous iron manganese oxide (AFMBO) based on the unique superiority of iron-manganese oxide for arsenic capture to realize the effective control of gaseous arsenic in the non-ferrous smelting flue gas. The experimental results show that the arsenic adsorption capacity of AFMBO is up to 102.7 mg/g, which has surpassed most of the current adsorbents. In particular, AFMBO can effectively capture gaseous arsenic even at 12% v/v SO2 concentrations (88.45 mg/g). Moreover, the spent AFMBO possesses pronounced magnetic characteristics that make it easier to separate from dust, which is conducive to reducing the secondary environmental risk of arsenic. In terms of mechanism study, various characterization methods are used to explain the important role of lattice oxygen and adsorbed oxygen in the capture process of gaseous arsenic. Moreover, the reason for the efficient arsenic removal performance of AFMBO is also reasonably explained at the microscopic level. This study provides ideas and implications for gaseous arsenic pollution control research.

Slit Ventricle Syndrome.

Slit ventricle syndrome (SVS) is a complication after ventriculoperitoneal shunt (VPS) or cystoperitoneal shunt(CPS), mostly due to excessive drainage of cerebrospinal. The disease is most often seen in children and has a complex pathogenesis. Clinical manifestations are mainly intermittent headache, slow refilling of the shunt reservoir, and slit-like ventricles on imaging. Surgery is the main treatment. We present a 22-year-old female patient with a previous 14-year history of CPS. The patient recently presented with typical symptoms but her ventricular morphology was normal. We performed VPS after diagnosis of SVS. After the surgery, the patient's symptoms improved and her condition was stable.

Intracranial Neuro-Enteric Cyst.

An intracranial nerve-enteric cyst is a relatively rare benign disease, and the main clinical manifestations are related to the location and size of the cyst. The main symptoms are caused by cyst compression. When the cyst is small without compression, it may have no obvious symptoms, and when the cyst increases to a certain degree, it may cause corresponding clinical manifestations. The diagnosis of this disease is mainly based on clinical manifestations, imaging examinations, and pathological examinations. The authors present a 47-year-old woman who was admitted to the hospital with "dizziness". Imaging was performed and revealed a small round lesion in the posterior cranial fossa in front of the brainstem. It was surgically removed and the postoperative pathology revealed an intracranial neuro-enteric cyst. The patient's dizziness disappeared after surgery and was reviewed 1 year later without recurrence.

Deep eutectic solvent for spent lithium-ion battery recycling: comparison with inorganic acid leaching.

Deep eutectic solvents (DESs) as novel green solvents are potential options to replace inorganic acids for hydrometallurgy. Compared with inorganic acids, the physicochemical properties of DESs and their applications in recycling of spent lithium-ion batteries were summarized. The viscosity, metal solubility, toxicological properties and biodegradation of DESs depend on the hydrogen bond donor (HBD) and acceptor (HBA). The viscosity of ChCl-based DESs increased according to the HBD in the following order: alcohols < carboxylic acids < sugars < inorganic salts. The strongly coordinating HBDs increased the solubility of metal oxide via surface complexation reactions followed by ligand exchange for chloride in the bulk solvent. Interestingly, the safety and degradability of DESs reported in the literature are superior to those of inorganic acids. Both DESs and inorganic acids have excellent metal leaching efficiencies (>99%). However, the reaction kinetics of DESs are 2-3 orders of magnitude slower than those of inorganic acids. A significant advantage of DESs is that they can be regenerated and recycled multiple times after recovering metals by electrochemical deposition or precipitation. In the future, the development of efficient and selective DESs still requires a lot of attention.

Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase γ (PI3Kγ).

Phosphoinositide-3-kinase γ (PI3Kγ) is highly expressed in immune cells and promotes the production and migration of inflammatory mediators. The inhibition of PI3Kγ has been shown to repolarize the tumor immune microenvironment to a more inflammatory phenotype, thereby controlling immune suppression in cancer. Herein, we report the structure-based optimization of an early lead series of pyrazolopyrimidine isoindolinones, which culminated in the discovery of highly potent and isoform-selective PI3Kγ inhibitors with favorable drug-like properties. X-ray cocrystal structure analysis, molecular docking studies, and detailed structure-activity relationship investigations resulted in the identification of the optimal amide and isoindolinone substituents to achieve a desirable combination of potency, selectivity, and metabolic stability. Preliminary in vitro studies indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory cytokine gene expression in M1 macrophages.

Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3Kγ Inhibitors.

The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.

Discovery of Potent and Selective PI3Kγ Inhibitors.

The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the "selectivity" and "alkyl-induced" pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 µM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.

Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.

CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.

Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633).

Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.

Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).

The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.

Graphitic Carbon Nitride-Based Heterojunction Photoactive Nanocomposites: Applications and Mechanism Insight.

The design of heterojunction with superior performance of light absorption and appropriate conduction band and valence band potentials is a promising approach for the applications in efficient environmental remediation and the solar energy storage. In recent years, many studies have been devoted to the applications of graphitic carbon nitride (g-C3N4)-based heterojunction photoactive nanomaterials under visible light irradiation due to its excellent physical, optical, and electrical properties, which inspired us to compile this review. Although many reviews demonstrated about the syntheses and applications of g-C3N4 composites, a targeted review on the systematic application and photocatalytic mechanisms of g-C3N4-based heterojunction, in which components are in intimate linkage with each other rather than a physical mixture, is still absent. In this review, the applications of g-C3N4-based heterojunction photoactive nanomaterials in environmental remediation and solar energy storage, such as photocatalytic treatment of persistent organic pollutants, heavy-metal-ion redox, oxidative decomposition of pathogens, water splitting for H2 evolution, and CO2 reduction, are systematically discussed. In addition, some emerging applications, such as solar cells and biosensors, are also introduced. Meanwhile, a comprehensive assessment on the basis of first-principles calculations and the thermodynamics and kinetics of surface catalytic reaction for the electronic structure and photocatalytic properties of g-C3N4-based heterojunction are valued by this review. In the end, a brief summary and perspectives in designing practical heterojunction photoactive nanomaterials also showed the bright future of g-C3N4-based heterojunction. Altogether, this review systematically complements the information that previous reviews have frequently ignored and points out the future development trends of g-C3N4-based heterojunction, which expected to provide important references and right directions for the development and practical applications of g-C3N4-based heterojunction photoactive nanomaterials.

Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4.

In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.

Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation.

1. AMG 232 is a novel inhibitor of the p53-MDM2 protein-protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data. 2. AMG 232 exhibited low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%). 3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered (14)C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species. 4. The in vitro-in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.

Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction.

Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.

Synthesis, in Vitro Covalent Binding Evaluation, and Metabolism of (14)C-Labeled Inhibitors of 11ß-HSD1.

In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11ß-HSD1 inhibitors labeled with (14)C: AMG 456 (1), AM-6949 (2), and AM-7715 (3). We evaluated the covalent protein binding of the labeled inhibitors in human liver microsomes in vitro and assessed their potential bioactivation risk in humans. We then studied the in vitro mechanism of 2 in human hepatocytes and the formation of reactive intermediates. Our study results suggest that 1 and 3 have low potential for metabolic bioactivation in humans, while 2 has relatively high risk.

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.