Immunogenic Treatment of Metastatic Breast Cancer Using Targeted Carbon Nanotube Mediated Photothermal Therapy in Combination with Anti-Programmed Cell Death Protein-1.

The high prevalence of breast cancer is a global health concern, compounded by the lack of safe or effective treatments for its advanced stages. These facts urge the development of novel treatment strategies. Annexin A5 (ANXA5) is a natural human protein that binds with high specificity to phosphatidylserine, a phospholipid tightly maintained in the inner leaflet of the cell membrane on most healthy cells but externalized in tumor cells and the tumor vasculature. Here, we have developed a targeted photosensitizer for photothermal therapy (PTT) of solid tumors through the functionalization of single-walled carbon nanotubes (SWCNTs) to ANXA5-the SWCNT-ANXA5 conjugate. The ablation of tumors through the SWCNT-ANXA5-mediated PTT synergizes with checkpoint inhibition, creating a systemic anticancer immune response. In vitro ablation of cells incubated with the conjugate promoted cell death in a dose-dependent and targeted manner. This treatment strategy was tested in vivo with the orthotopic EMT6 breast tumor model in female balb/cJ mice. Enhanced therapeutic effects were achieved by using intratumoral injection of the conjugate and treating tumors at a lower PTT temperature (45°C). Intratumoral injection prevented the accumulation of the SWCNTs in major clearance organs. When combined with checkpoint inhibition of anti-programmed cell death protein-1, SWCNT-ANXA5-mediated PTT increased survival and 80% of the mice survived for 100 days. Evidence of immune system activation by flow cytometry of splenic cells strengthens the hypothesis of an abscopal effect as a mechanism of prolonged survival. SIGNIFICANCE STATEMENT: This study demonstrated a relatively high survival rate (80% at 100 days) of mice with aggressive breast cancer when treated with photothermal therapy using the SWCNT-ANXA5 conjugate injected intratumorally and combined with immune stimulation using the anti-programmed cell death protein-1 checkpoint inhibitor. Photothermal therapy was accomplished by maintaining the tumor temperature at a relatively low level of 45°C and avoiding accumulation of the nanotubes in the clearance organs by using intratumoral administration.

Unveiling autonomic failure in synucleinopathies: Significance in diagnosis and treatment.

Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic failure (PAF). Cardiovascular autonomic failure affects quality of life and can be life threatening due to the risk of falls and the increased incidence of myocardial infarction, stroke, and heart failure. In PD and PAF, pathogenic involvement is mainly post-ganglionic, while in MSA, the involvement is mainly pre-ganglionic. Cardiovascular tests exploring the autonomic nervous system (ANS) are based on the analysis of continuous, non-invasive recordings of heart rate and digital blood pressure (BP). They assess facets of sympathetic and parasympathetic activities and provide indications on the integrity of the baroreflex arc. The tilt test is widely used in clinical practice. It can be combined with catecholamine level measurement and analysis of baroreflex activity and cardiac variability for a detailed analysis of cardiovascular damage. MIBG myocardial scintigraphy is the most sensitive test for early detection of autonomic dysfunction. It provides a useful measure of post-ganglionic sympathetic fiber integrity and function and is therefore an effective tool for distinguishing PD from other parkinsonian syndromes such as MSA. Autonomic cardiovascular investigations differentiate between certain parkinsonian syndromes that would otherwise be difficult to segregate, particularly in the early stages of the disease. Exploring autonomic failure by gathering information about residual sympathetic tone, low plasma norepinephrine levels, and supine hypertension can guide therapeutic management of orthostatic hypotension (OH).

Spinocerebellar ataxia 27B (SCA27B), a frequent late-onset cerebellar ataxia.

Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.

Microbialite Accretion and Growth: Lessons from Shark Bay and the Bahamas.

Microbialites provide geological evidence of one of Earth's oldest ecosystems, potentially recording long-standing interactions between coevolving life and the environment. Here, we focus on microbialite accretion and growth and consider how environmental and microbial forces that characterize living ecosystems in Shark Bay and the Bahamas interact to form an initial microbialite architecture, which in turn establishes distinct evolutionary pathways. A conceptual three-dimensional model is developed for microbialite accretion that emphasizes the importance of a dynamic balance between extrinsic and intrinsic factors in determining the initial architecture. We then explore how early taphonomic and diagenetic processes modify the initial architecture, culminating in various styles of preservation in the rock record. The timing of lithification of microbial products is critical in determining growth patterns and preservation potential. Study results have shown that all microbialites are not created equal; the unique evolutionary history of an individual microbialite matters.

Trends in Structure and Ethylene Polymerization Reactivity of Transition-Metal Permethylindenyl-phenoxy (PHENI*) Complexes.

A family of ansa-permethylindenyl-phenoxy (PHENI*) transition-metal chloride complexes has been synthesized and characterized (1-7; {(η5-C9Me6)Me(R″)Si(2-R-4-R'-C6H2O)}MCl2; R,R' = Me, tBu, Cumyl (CMe2Ph); R″ = Me, nPr, Ph; M = Ti, Zr, Hf). The ancillary chloride ligands could readily be exchanged with halides, alkyls, alkoxides, aryloxides, or amides to form PHENI* complexes [L]TiX2 (8-17; X = Br, I, Me, CH2SiMe3, CH2Ph, NMe2, OEt, ODipp). The solid-state crystal structures of these PHENI* complexes indicate that one of two conformations may be preferred, parametrized by a characteristic torsion angle (TA'), in which the η5 system is either disposed away from the metal center or toward it. Compared to indenyl PHENICS complexes, the permethylindenyl (I*) ligand appears to favor a conformation in which the metal center is more accessible. When heterogenized on solid polymethylaluminoxane (sMAO), titanium PHENI* complexes exhibit exceptional catalytic activity toward the polymerization of ethylene. Substantially greater activities are reported than for comparable PHENICS catalysts, along with the formation of ultrahigh-molecular-weight polyethylenes (UHMWPE). Catalyst-cocatalyst ion pairing effects are observed in cationization experiments and found to be significant in homogeneous catalytic regimes; these effects are also related to the influence of the ancillary ligand leaving groups in slurry-phase polymerizations. Catalytic efficiency and polyethylene molecular weight are found to increase with pressure, and PHENI* catalysts can be categorized as being among the most active for the controlled synthesis of UHMWPE.

Prognostic and Therapeutic Implications of Cell Division Cycle 20 Homolog in Breast Cancer.

Cell division cycle 20 homolog (CDC20) is a well-known regulator of cell cycle progression. Abnormal expression of CDC20 leads to mitotic defects, which play a significant role in cancer development. In breast cancer (BC), CDC20 has been identified as a biomarker that has been linked to poor patient outcomes. In this study, we investigated the association of CDC20 with BC prognosis and immune cell infiltration by using multiple online databases, including UALCAN, KM plotter, TIMER2.0, HPA, TNM-plot, bc-GenExMiner, LinkedOmics, STRING, and GEPIA. The results demonstrate that BC patients have an elevated CDC20 expression in tumor tissues compared with the adjacent normal tissue. In addition, BC patients with overexpressed CDC20 had a median survival of 63.6 months compared to 169.2 months in patients with low CDC20 expression. Prognostic analysis of the examined data indicated that elevated expression of CDC20 was associated with poor prognosis and a reduction of overall survival in BC patients. These findings were even more prevalent in chemoresistance triple-negative breast cancer (TNBC) patients. Furthermore, the Gene Set Enrichment Analysis tool indicated that CDC20 regulates BC cells' cell cycle and apoptosis. CDC20 also significantly correlates with increased infiltrating B cells, CD4+ T cells, neutrophils, and dendritic cells in BC. In conclusion, the findings of this study suggest that CDC20 may be involved in immunomodulating the tumor microenvironment and provide evidence that CDC20 inhibition may serve as a potential therapeutic approach for the treatment of BC patients. In addition, the data indicates that CDC20 can be a reliable prognostic biomarker for BC.

Towards designer polyolefins: highly tuneable olefin copolymerisation using a single permethylindenyl post-metallocene catalyst.

Using a highly active permethylindenyl-phenoxy (PHENI*) titanium catalyst, high to ultra-high molecular weight ethylene-linear-α-olefin (E/LAO) copolymers are prepared in high yields under mild conditions (2 bar, 30-90 °C). Controllable, efficient, and predictable comonomer enchainment provides access to a continuum of copolymer compositions and a vast range of material properties using a single monomer-agnostic catalyst. Multivariate statistical tools are employed that combine the tuneability of this system with the analytical and predictive power of data-derived models, this enables the targeting of polyolefins with designer properties directly through predictive alteration of reaction conditions.