Delivery of a STING Agonist Using Lipid Nanoparticles Inhibits Pancreatic Cancer Growth.

Introduction: The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a large number of cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. STING agonists have demonstrated the ability to inflame the TME, reduce tumor burden, and confer anti-tumor activity in mouse models. 2'3' cyclic guanosine monophosphate adenosine monophosphate (2'3'-cGAMP) is a high-affinity endogenous ligand of STING. However, delivering cGAMP to antigen-presenting cells and tumor cells within the cytosol remains challenging due to membrane impermeability and poor stability. Methods: In this study, we encapsulated 2'3'-cGAMP in a lipid nanoparticle (cGAMP-LNP) designed for efficient cellular delivery. We assessed the properties of the nanoparticles using a series of in-vitro studies designed to evaluate their cellular uptake, cytosolic release, and minimal cytotoxicity. Furthermore, we examined the nanoparticle's anti-tumor effect in a syngeneic mouse model of pancreatic cancer. Results: The lipid platform significantly increased the cellular uptake of 2'3'-cGAMP. cGAMP-LNP exhibited promising antitumor activity in the syngeneic mouse model of pancreatic cancer. Discussion: The LNP platform shows promise for delivering exogenous 2'3'-cGAMP or its derivatives in cancer therapy.

Establishment of a Rat Model of Alcoholic Liver Fibrosis with Simulated Human Drinking Patterns and Low-Dose Chemical Stimulation.

Although alcohol is a well-known causal factor associated with liver diseases, challenges remain in inducing liver fibrosis in experimental rodent models. These challenges include rodents' natural aversion to high concentrations of alcohol, rapid alcohol metabolism, the need for a prolonged duration of alcohol administration, and technical difficulties. Therefore, it is crucial to establish an experimental model that can replicate the features of alcoholic liver fibrosis. The objective of this study was to develop a feasible rat model of alcoholic liver fibrosis that emulates human drinking patterns and combines low-dose chemicals within a relatively short time frame. We successfully developed an 8-week rat model of alcoholic liver fibrosis that mimics chronic and heavy drinking patterns. Rats were fed with a control liquid diet, an alcohol liquid diet, or alcohol liquid diet combined with multiple binges via oral gavage. To accelerate the progression of alcoholic liver fibrosis, we introduced low-dose carbon tetrachloride (CCl4) through intraperitoneal injection. This model allows researchers to efficiently evaluate potential therapeutics in preclinical studies of alcoholic liver fibrosis within a reasonable time frame.

"Papillary Adenoma-like" Renal Tumor with TFE3 Gene Rearrangement, A Potential Precursor to or Early Event in the Development of TFE3 Translocation Renal Cell Carcinoma.

MiT family translocation renal cell carcinomas harbor gene fusion involving members of MiT family of transcription factors. Their precursor lesions have not been identified. Herein, we report the first case of small papillary tumors morphologically resembling papillary adenomas but harboring TFE3 gene alteration. The patient was a 23-year old man with multiple small papillary tumors in the right kidney discovered following a gunshot wound injury. These lesions were < 5 mm, well-circumscribed but not encapsulated tubulopapillary proliferation lined with a single layer of cuboidal cells with WHO/ISUP grade 1 or 2 nuclei. The tumor cells were immunoreactive to PAX8, AMACR, high molecular weight cytokeratin, and keratin 7 and negative for CD10, CA9, TTF1, and cathepsin K. Morphologically and immunohistochemically, these lesions were diagnosed as papillary adenomas. TFE3 gene rearrangement was confirmed by fluorescence in-situ hybridization (FISH) using a TFE3 break-apart probe. We term these tumors "papillary adenoma-like" renal tumor with TFE3 gene rearrangement. These tumors are likely a precursor to or represent an early event in the development of TFE3 translocation renal cell carcinomas. An understanding of such tumors to translocation renal cell carcinoma progression can provide insight into the pathogenic mechanism, and ultimately aid the diagnosis and management of translocation renal cell carcinoma.

Discovery of Small Anti-ACE2 Peptides to Inhibit SARS-CoV-2 Infectivity.

COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects host cells by binding its viral spike protein receptor-binding domain (RBD) to the angiotensin converting enzyme 2 (ACE2) on host cells. Blocking the SARS-CoV-2-RBD/ACE2 interaction is, therefore, a potential strategy to inhibit viral infections. Using a novel biopanning strategy, a small anti-ACE2 peptide is discovered, which shows high affinity and specificity to human ACE2. It blocks not only the SARS-CoV-2-RBD/ACE2 interaction but also the SARS-CoV-1-RBD/ACE2 interaction. Moreover, it inhibits SARS-CoV-2 infection in Vero-E6 cells. The peptide shows negligible cytotoxicity in Vero-E6 cells and Huh7 cells. In vivo short-term lung toxicity study also demonstrates a good safety of the peptide after intratracheal administration. The anti-ACE2 peptide can be potentially used as a prophylactic or therapeutic agent for SARS-CoV-2 or other ACE2-mediated viruses. The strategy used in this study also provides a fast-track platform to discover other antiviral peptides, which will prepare the world for future pandemics.

Mammary analogue secretory carcinoma of salivary gland diagnosed on submandibular gland cytology: A case report and review of the literature.

Mammary analogue secretory carcinoma of the salivary glands has morphological shares molecular similarities to secretory carcinoma of the breast. Here, we report a 46-year-old woman who presented with a right submandibular gland mass. Fine needle aspiration differential diagnosis included oncocytosis, oncocytoma, acinic cell carcinoma and mammary analogue secretory carcinoma. We also review the current literature regarding clinical presentation and diagnostic workup of this entity.

Preferred retinal locus--hand coordination in a maze-tracing task.

PURPOSE: Fine manual tasks require coordination of vision, eye movements, and motor control. Macular scotomas from age-related macular degeneration (AMD) may adversely affect this coordination. The purpose of this research was to find whether the preferred retina locus for fixation (fPRL) also guided the hand in performing fine manual tasks and how the fingers, fPRL, and scotomas interacted in task performance. METHODS: Subjects with bilateral macular scotomas from AMD and normally sighted controls traced an irregular "maze" line pattern with the index finger while viewing their hand and the maze in a scanning laser ophthalmoscope (SLO). Video images from the SLO showing the fingers and maze on the retina during the task were analyzed to produce retinal maps showing the scotoma and bivariate ellipses of fPRL and fingertip retinal positions. RESULTS: Fingertip retinal ellipses surrounded and were approximately centered on the fPRL ellipses. Fingertip retinal bivariate area was positively correlated with fPRL bivariate area and the percent time the fPRL was on the maze was correlated with visual acuity. Maze-tracing accuracy was positively correlated with saccade rate for scotoma subjects. CONCLUSIONS: Concentric overlap of fPRL and fingertip retinal ellipses indicates that it is the fPRL that guides the hand in the maze-tracing visuomotor task, just as the fovea guides the fingertip for visually normal subjects. It is likely that factors other than fPRL and scotoma characteristics contribute to poorer maze-tracing performance by scotoma subjects in comparison with controls.

Effect of bilateral macular scotomas from age-related macular degeneration on reach-to-grasp hand movement.

PURPOSE: Vision plays a critical role in reaching and grasping objects. Consequently, bilateral macular scotomas from age-related macular degeneration (AMD) may affect reach-to-grasp movements. The purpose of this work was to investigate changes in reach-to-grasp movement dynamics and to relate those changes to the characteristics of subjects' preferred retinal loci (PRL), scotomas, and visual acuities. METHODS: Three-dimensional positions of the index finger and thumb were recorded while subjects with bilateral scotomas and subjects with normal vision reached for and grasped blocks of three widths at two distances under binocular and monocular viewing conditions. Reach-dynamic parameters and the grip aperture (thumb-index finger distance) were calculated. Retinal locations and sizes of subjects' scotomas and PRLs were mapped with a scanning laser ophthalmoscope. RESULTS: Scotoma subjects' hand trajectories had longer movement durations, lower maximum velocities, and longer visual reaction times than those of control subjects. With monocular viewing, maximum grip aperture (MGA) increased as a function of block width at a significantly higher rate for scotoma subjects than for control subjects. MGA decreased with increasing PRL bivariate normal ellipse area, and visual reaction time increased with decreasing acuity of the eye tested. CONCLUSIONS: Compared with normally sighted subjects, subjects with bilateral macular scotomas from AMD have reach-to-grasp movements with longer trajectories, longer visual reaction times, lower velocities, and altered MGA-block width scaling. Visual reaction time and MGA are directly related to PRL characteristics. Deficits in reach-to-grasp movement caused by macular scotomas are greater in degree than those reported by others for real or artificial peripheral scotomas.