Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor.

The lysosome-targeting chimera (LYTAC) approach has shown promise for the targeted degradation of secreted and membrane proteins via lysosomes. However, there have been challenges in design, development, and targeting. Here, we have designed a genetically engineered transferrin receptor (TfR)-mediated lysosome-targeting chimera (TfR-LYTAC) that is efficiently internalized via TfR-mediate endocytosis and targets PD-L1 for lysosomal degradation in cultured cells but not in vivo due to short half-life and poor tumor targeting. A delivery platform was developed by fusing TfR-LYTAC to the surface of bacterial outer membrane vesicles (OMVs). The engineered OMV-LYTAC combines PD-1/PD-L1 pathway inhibition with LYTAC and immune activation by bacterial OMVs. OMV-LYTAC significantly reduced tumor growth in vivo. We have provided a modular and simple genetic strategy for lysosomal degradation as well as a delivery platform for in vivo tumor targeting. The study paves the way for the targeting and degradation of extracellular proteins using the TfR-LYTAC system.

Efficacy and safety of endoscopic retrograde cholangiopancreatography in patients over 75 years of age.

Background: To investigate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in elderly choledocholithiasis patients compared with younger groups. Methods: This was a case-control study conducted from January 2018 to December 2020 at Fuyang People's Hospital, with 596 patients included. Patients who underwent ERCP were classified as two groups based on age stratification definitions from the National Institute of Health and the World Health Organisation: Patients <75 ages (n = 204) and patients ≥75 ages (n = 392). Demographic characteristics, details of endoscopic therapy, complications were retrospectively reviewed and compared between two groups. The subgroup was pre-formed to further explore the efficacy and safety of ERCP in the elderly population. Results: Between patients ≥75 ages and patients <75 ages, there were no significant differences in the complete stone removal rate and a second ERCP. Intubation difficulty (odds rate [OR]: 1.723, 95% confidence interval [CI]: 1.118-2.657) and longer ERCP operation time (ß = 4.314, 95% CI: 2.366-6.262) were observed in the elderly group at a higher frequency than the younger group. Elder patients were more likely to have intra-operative complications (χ2 = 18.158, P < 0.001), and post-operative complications (χ2 = 8.739, P = 0.003). In the subgroup group, ERCP was efficacious and safe in elderly patients with comorbidities. Conclusions: ERCP may be efficaciously performed on elderly patients. However, intra-operative and post-operative complications of ECRP should also be taken into consideration when selecting therapeutic options.

Photosensitizer-encapsulated amphiphilic chitosan derivative micelles: photoactivity and enhancement of phototoxicity against human pancreatic cancer cells.

Photosensitizer-encapsulated amphiphilic chitosan derivative (Photosan-DA-Chit) micelles with controlled photoactivity have been prepared using a simple self-assembly method in phosphate-buffered saline (pH 6.2). The fluorescence quantum yield and fluorescence lifetime of the Photosan-DA-Chit micelles were lower than those of free Photosan, which indicated that the micelles were suppressing the photoactivity of Photosan. However, upon incubation with human pancreatic cancer cells (i.e., Panc-1 cells), the Photosan-DA-Chit micelles showed higher fluorescence activity than free Photosan and generated higher levels of reactive oxygen species under laser illumination. The Photosan-DA-Chit micelles therefore exhibited strong phototoxicity, which led to significant levels of apoptosis in the Panc-1 cells. In the absence of light, however, the Photosan-DA-Chit micelles showed no cytotoxicity. These results indicated that they could be used as a potential photodynamic therapy in pancreatic cancer.

Neurological, functional, and biomechanical characteristics after high-velocity behind armor blunt trauma of the spine.

BACKGROUND: Behind armor blunt trauma (BABT) describes a nonpenetrating injury to the organs of an individual wearing body armor. The aim of this study was to investigate the neurologic and functional changes that occur in the central nervous system after high-velocity BABT of the spine as well as its biomechanical characteristics. METHODS: This study evaluated 28 healthy adult white pigs. Animals were randomly divided into three experimental groups: (1) 15 animals (9 in the exposed group and 6 in the control group) were tested for neurologic changes; (2) 10 animals (5 in the exposed group and 5 in the control group) were used for studies of cognitive function; (3) and 3 animals were used for examination of biomechanics. In the group tested for neurologic changes, 9 anesthetized pigs wearing body armor (including a ceramic plate and polyethylene body armor) on the back were shot on the eighth thoracic vertebrae (T8) with a 5.56-mm rifle bullet (velocity appropriately 910 m/s). As a control, six pigs were shot with blank ammunition. Ultrastructural changes of the spinal cord and brain tissue were observed with light and electron microscopy. Expression levels of myelin basic protein, neuron-specific enolase (NSE), and glial cytoplasmic protein (S-100B) were investigated in the serum and cerebrospinal fluid using enzyme-linked immunosorbent assays. Electroencephalograms (EEGs) were monitored before and 10 minutes after the shot. Pressures in the spine, common carotid artery, and brain were detected. Acceleration of the 10th vertebrae (T10) was tested. Finally, cognitive outcomes between exposed and control groups were compared. RESULTS: Neuronal degeneration and nerve fiber demyelination were seen in the spinal cord. The concentrations of neuron-specific enolase, myelin basic protein, and S-100B were significantly increased in the serum and cerebrospinal fluid 3 hours after trauma (p < 0.05). The electroencephalogram was suppressed within 3 to 6 minutes after trauma. The pressure detected in the brain was higher than that detected in the common carotid artery (p < 0.01). The trauma resulted in paralysis of two hind limbs and in cognitive dysfunction. CONCLUSION: The results from our animal model indicate that high-velocity BABT of the spine generates high pressure and acceleration in the spine, induces varying degrees of paralysis of hind limbs, and disturbs cerebral function. The neuronal degeneration caused by the pressure wave may be one of the important pathologic events involved in the development of trauma-related complications.