Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

Elucidating the Impact of Mg Substitution on the Properties of NASICON-Na3+yV2−yMgy(PO4)3 Cathodes

Vanadium multiredox-based NASICON-Na_zV_2−yM_y(PO₄)₃ (3 ≤ z ≤ 4; M = Al³⁺, Cr³⁺, and Mn²⁺) cathodes are particularly attractive for Na-ion battery applications due to their high Na insertion voltage (>3.5 V vs Na⁺/Na⁰), reversible storage capacity (≈150 mA h g⁻¹), and rate performance. However, their practical application is hindered by rapid capacity fade due to bulk structural rearrangements at high potentials involving complex redox and local structural changes. To decouple these factors, a series of Mg²⁺-substituted Na_3+yV_2−yMg_y(PO₄)₃ (0 ≤ y ≤ 1) cathodes is studied for which the only redox-active species is vanadium. While X-ray diffraction (XRD) confirms the formation of solid solutions between the y = 0 and 1 end members, X-ray absorption spectroscopy and solid-state nuclear magnetic resonance reveal a complex evolution of the local structure upon progressive Mg²⁺ substitution for V³⁺. Concurrently, the intercalation voltage rises from 3.35 to 3.45 V, due to increasingly more ionic V O bonds, and the sodium (de)intercalation mechanism transitions from a two-phase for y ≤ 0.5 to a solid solution process for y ≥ 0.5, as confirmed by in operando XRD, while Na-ion diffusion kinetics follow a nonlinear trend across the compositional series.     

Brain neurotoxicity of Penitrem A: electrophysiological, behavioral and histopathological study

The neurotoxicity of Penitrem A (PA) in rats was assessed against neurophysiological, behavioral and histopathological parameters. Animals were acutely given intracerebroventricular (22-45 mg) or intraperitoneal injections (0.5-1.5 mg/kg) of PA. A typical trembling syndrome associated with PA was always noted. Depending on the dose administered, animals may convulse and eventually die (1-1.5 mg/kg). PA-induced transient alterations of the EEG involving an increase in the frequency and voltage of electrical activity recorded from the cerebral cortex. Hippocampal activity was not modified and some pathologic activities may be recorded at the thalamus. Generally these EEG alterations disappeared at d 3 after the injection and the animals progressively recovered. However in the most severe cases, neuromotor disturbances were maintained at d 7 (rotarod test). Coronal sections of the brain at the striatal, thalamic, hippocampal and pons levels mainly revealed that PA was able to induce dose related injuries in the cerebellum with massive degeneration of Purkinje cells and a significant vacuolization within the molecular layer. The neurotoxic mechanism remains unclear. Action of the mycotoxin on the cerebello-thalamo-cortical tract is discussed.     

Sequence determination and molecular characterization of gigantin, a cytotoxic protein produced by the mould Aspergillus giganteus IFO 5818

To examine the ability of estrogens and anti-estrogens to induce cellular transformation and genetic effects, Syrian hamster embryo (SHE) cells were treated with estrogens, 17beta-estradiol (E2) or diethylstilbestrol (DES), or with anti-estrogens, tamoxifen (TAM), toremifene (TOR) or ICI 164,384. Treatment with each substance for 1-3 days suppressed cellular growth in a dose-dependent manner. Colony-forming efficiency (CFE) increased following treatment of cells with E2 or DES for 48 hr at 3 or 10 microM but decreased at 20 or 30 microM. In contrast, CFE was increased by treatment with TAM, TOR or ICI 164,348 over the concentration range examined (1-30 microM). Treatment with each chemical at 1-30 microM for 48 hr caused morphological transformation of SHE cells in a dose-related fashion. The highest frequency was exhibited in SHE cells treated with DES at 20 microM and was 2 times higher than that induced by treatment with benzo[alpha]pyrene (B[alpha]P) at 4 microM. Transformation frequencies induced by other substances (E2, TAM, TOR and ICI 164,348) did not exceed that induced by the B[alpha]P treatment. TOR showed a higher transforming ability over all concentrations examined when compared to the other anti-estrogens (TAM and ICI 164,348). No significant increases in the frequencies of chromosomal aberrations were observed in SHE cells that were treated with any of the chemicals. However, treatment of SHE cells with each chemical induced a dose-dependent increase of aneuploid cells in the near diploid range. Our results indicate that the ability of the estrogens and anti-estrogens to induce numerical chromosomal abnormality may be involved in their cell transformation activity and potential carcinogenicity.     

Differential thermoluminescence (DTL) -a new instrument for measurement of thermoluminescence with suppression of blackbody radiation

A new instrumental technique for the determination of thermoluminescent glow curves, especially useful for investigation at high temperatures, is described. Two samples, identical in all respects except that one is preheated, are simultaneously heated. The light outputs from the samples are individually modulated at two different frequencies, fed to a single photomultiplier tube the output of which is amplified by two lock-in amplifiers. The selectively amplified signals are further fed to a differential amplifier which cancels out the undesirable blackbody radiation to give a signal due only to the luminophor. This technique conveniently extends the temperature range of thermoluminescence and further allows high-temperature investigation of emissions in the red region of the spectrum.     

Hydrogen-Bonding Organocatalysis Enabled Photocatalytic Intramolecular [2+2]-Cycloaddition Reaction

The combination of organocatalytic activation and photocatalysis for enabling the intramolecular [2+2]-cycloaddition of enone-ene substrates bearing one Lewis base binding site is reported. While in a variety of solvents a poor conversion or no reaction takes place in the absence of a hydrogen bonding catalyst, the corresponding ring-fused cyclobutane products could be built in moderate to good yields using a synergistic dual iridium-urea co-catalytic system. Control and mechanistic studies supported the postulated interaction between the organocatalyst and the substrate, which proved essential for an efficient energy transfer from the photosensitizer.     

Microfibril-microvessel connections in the rabbit eye: Correlative confocal and electron microscopy

The connections between elastic tissue and microvessels (arterioles, capillaries, and venules) in the rabbit eye were examined by light and electron microscopy. In particular, confocal scanning laser microscopy of tissue stained with orcein and examined by fluorescence using a rhodamine filter was correlated with electron microscopic observations. The goal was an analysis of the way in which elastic tissue of the uvea (i.e., choroid, ciliary body, and iris) and the optic nerve of the eye connect to the microvessels in these structures. Confocal microscopy revealed these connections advantageously and showed how they link the elastic tissue meshwork in the perivascular tissue spaces with the wall of the blood vessels. Electron microscopy showed that the connections consist of bundles of 10–12 nm diameter microfilaments that insert into vascular basement membranes. These connections may contribute to the vascular response to changes in blood pressure or intraocular pressure in the eye.     

Enhanced Performance of Zn/Br Flow Battery Using N-Methyl-N-Propylmorpholinium Bromide as Complexing Agent

Redox flow batteries (RFB) are one of the most interesting technologies in the field of energy storage, since they allow the decoupling of power and capacity. Zinc–bromine flow batteries (ZBFB) are a type of hybrid RFB, as the capacity depends on the effective area of the negative electrode (anode), on which metallic zinc is deposited during the charging process. Gaseous bromine is generated at the positive electrode (cathode) during the charging process, so the use of bromine complexing agents (BCA) is very important. These BCAs are quaternary amines capable of complexation with bromine and generating an organic phase, immiscible with the aqueous electrolyte. One of the most commonly used BCAs in RFB technology is 4-methylethylmorpholinium bromide (MEM-Br). In this work, an alternative quaternary amine 4-methylpropylmorpholinium bromide (MPM-Br) was studied. MPM-Br was integrated into the electrolyte, and 200 charge–discharge cycles were performed on the resulting ZBFBs. The obtained results were compared with those when MEM-Br was used, and it was observed that the electrolyte with MPM-Br displays a higher resistance in voltage and higher energy efficiency, making it a promising alternative to MEM-Br.     

Catalytic transmetalation from group 6 Fischer carbene complexes: an emerging powerful tool in organic synthesis

The chemistry of metal carbene complexes has experienced an enormous development in the past decades. Despite this fact, the use of transition metals as catalysts in reactions involving group 6 Fischer carbene complexes was virtually neglected. Here, we describe how the reactivity of these compounds can be enhanced or modified in the presence of catalytic amounts of a transition metal, leading to new forms of reactivity and others offering clear advantages in terms of efficiency over the uncatalyzed reactions. The key step for these reactions is the transmetalation from the stoichiometric metal carbene reagent to the catalyst. This process generates a new metal-carbene complex that leads to enhanced reactivity of new reaction modes. Two examples of Fischer carbene complexes obtained by transmetalation to Pd and Cu have been isolated during the last 2 years, showing the flexibility if the mechanistic hypothesis for these reactions. The work presented in this Account shows how an area, which was practically unexplored 5 years ago, has emerged as a new and powerful field of research.