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Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, a-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific CD8+ T cells in vivo. However, these CD8+ T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC-intrinsic PD-L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/ß-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment. [ABSTRACT FROM AUTHOR]

Terrestrial water storage change (TWSC) plays a crucial role in the hydrological cycle and climate system. To date, methods including 1) the terrestrial water balance method (PER), 2) the combined atmospheric and terrestrial water balance method (AT), and 3) the summation method (SS) have been developed to estimate TWSC, but the accuracy of these methods has not been systematically compared. This paper compares the spatial and temporal differences of the TWSC estimates by the three methods comprehensively with the GRACE data during the 2002-13 period. To avoid the impact of different inputs in the comparison, three advanced reanalysis datasets are used, namely 1) the National Centers for Environmental Prediction (NCEP)-Department of Energy (DOE) Reanalysis II (NCEP R2), 2) the ECMWF interim reanalysis (ERA-Interim), and 3) the Japanese 55-Year Reanalysis (JRA-55). The results show that all estimates with PER and AT considerably overestimate the long-term mean on a regional scale because the data assimilation in the reanalysis opens the water budget. The difficulty of atmospheric observation and simulation in arid and polar tundra regions is the documented reason for the failure of the AT method to represent the TWSC phase over 30% of the region found in this study. Although the SS result exhibited the best overall agreement with GRACE, the amplitude of TWSC based on SS differed substantially from that of GRACE and the similarity coefficient of the global distribution between the SS-derived estimate and GRACE is still not high. More detailed considerations of groundwater and human activities, for example, irrigation and reservoir impoundments, can help SS to achieve a higher accuracy. [ABSTRACT FROM AUTHOR]

This study aims to compare the anesthetic effects of remimazolam tosilate and propofol in patients undergoing radical mastectomy. The study group received remimazolam tosilate in combination with sufentanil and cisatracurium besilate for anesthesia induction, while the control group received propofol with sufentanil and cisatracurium besilate. In the study group, the eyelash reflex disappearance time was longer and the recovery time was shorter compared to the control group (p < 0.05). No significant differences were observed in Post-Anesthesia Care Unit (PACU) retention time and Visual Analogue Scale (VAS) scores at 24 hours post-operation between the groups (p > 0.05). Furthermore, the study group exhibited a lower decrease in Mean Arterial Pressure (MAP) at 1, 3 and 5 minutes after anesthesia induction (p<0.05). After losing consciousness, there was no statistically significant difference in HR decrease between both groups (p > 0.05). The study group also had higher respiratory rate (RR) and Tidal volume (VT) levels, with a lower incidence of apnea compared to the control group (p < 0.05). Thirty minutes before anesthesia, no significant differences were found in the five indicators between the groups (p>0.05). At 24 hours post-operation, the study group showed higher Cluster of Differentiation 3+ (CD3+), CD4+, natural killer (NK) cell levels and CD4+/CD8+ ratios compared to the control group (p < 0.05). However, at 72 hours post-operation, no statistically significant differences were observed in these five indicators between the groups (p > 0.05). Compared with propofol, remimazolam tosilate achieves rapid sedation, maintains adequate sedation, and reduces suppression of the respiratory and circulatory systems. [ABSTRACT FROM AUTHOR]

The plasmid-mediated transmission of antibiotic resistance genes has been reported to be involved in the development of antibiotic resistance in bacteria, and poses a serious threat for the success of bacterial infection treatment and human health worldwide. The present study used a 454 GS-FLX pyrosequencing system to determine the ~140 kb nucleotide sequence of plasmid pHS36-NDM, which was identified in a Salmonella Stanley isolate from the stool sample of an 11-month-old girl at Lishui Central Hospital, China, and which contains a New Delhi metallo-β-lactamase-1 (NDM-1) carbapenem resistance gene (blaNDM-1). The 181 open reading frames encode proteins with functions including replication, stable inheritance, antibiotic resistance and mobile genetic elements. Both horizontal transfer and passage stability-related genes were identified in pHS36-NDM, including a conserved type 4 secretion system and stbA (stable plasmid inheritance protein A). Two multidrug resistance gene islands were identified: The ISEcp1-blaCMY transposition unit which contains a CMY-6 β-lactamase gene (blaCMY-6) and a quaternary ammonium compound resistance gene (sugE); and the intI1-ISCR27 accessory region, which contained a trimethoprim resistance gene (dfrA12), two aminoglycoside resistance genes (aadA2 and rmtC), a truncated quaternary ammonium compound resistance gene (qacEπ1), a sulfonamide resistance gene (sul1), the blaNDM-1 carbapenemase and a bleomycin resistance gene (bleMBL). pHS36-NDM shared high homology with other blaNDM-1-containing plasmids reported in Sweden, Italy and Japan. However, no previous international travel history was documented for the patient and her family, even to neighboring cities. Furthermore, pHS36-NDM is of a different incompatibility group to other published blaNDM-1-carrying plasmids reported in China, with low homology in the surrounding structure of blaNDM-1. The present study will facilitate the understanding of the underlying resistance and dispersal mechanism of pHS36-NDM, and will deepen our recognition of the ongoing spread of the blaNDM-1-containing plasmids. [ABSTRACT FROM AUTHOR]

Akkermansia muciniphila (AKK) is a gut probiotic with great potential. It was only discovered in 2004 and has unique growth requirements. Therefore, comparing to other probiotics, AKK still needs to be explored. To understand the research status and development of AKK, the related literatures of AKK were excavated and sorted out. AKK is associated with metabolic and immune diseases. The current mainstream research is obesity and type 2 diabetes. In addition, AKK can also have a positive impact on autoimmune diseases, cancer, intestinal diseases, liver diseases, cardiovascular diseases, nervous system diseases, aging, periodontitis, and allergies. However, AKK may aggravate the development of diseases in some specific environments. People pay more and more attention to the influence of diet and drugs on the active AKK, and even put forward treatment programs such as pasteurized AKK (PAKK), AKK outer membrane protein Amuc_1100, and external vesicles, which greatly improves the security of AKK use. In the future, in addition to the treatment of diseases, the focus of AKK research will be expanded to areas such as safety assessment and optimization of cultivation conditions. [ABSTRACT FROM AUTHOR]

We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions but also contrast the previously published proposed binding mode. Compounds 4a and 6a significantly inhibited tumor growth in an A375 melanoma xenograft model and were accompanied by elevated levels of apoptosis and disruption of tumor vasculature. Finally, we demonstrated that compound 4a significantly overcame clinically relevant multidrug resistance in a paclitaxel resistant PC-3/TxR prostate cancer xenograft model. Collectively, these studies provide preclinical and structural proof of concept to support the continued development of this scaffold as a new generation of tubulin inhibitors. [ABSTRACT FROM AUTHOR]