Engineered Bacteriophage-Based In Situ Vaccine Remodels a Tumor Microenvironment and Elicits Potent Antitumor Immunity.

In situ vaccines (ISVs) utilize the localized delivery of chemotherapeutic agents or radiotherapy to stimulate the release of endogenous antigens from tumors, thereby eliciting systemic and persistent immune activation. Recently, a bioinspired ISV strategy has attracted tremendous attention due to its features such as an immune adjuvant effect and genetic plasticity. M13 bacteriophages are natural nanomaterials with intrinsic immunogenicity, genetic flexibility, and cost-effectiveness for large-scale production, demonstrating the potential for application in cancer vaccines. In this study, we propose an ISV based on the engineered M13 bacteriophage targeting CD40 (M13CD40) for dendritic cell (DC)-targeted immune stimulation, named H-GM-M13CD40. We induce immunogenic cell death and release tumor antigens through local delivery of (S)-10-hydroxycamptothecin (HCPT), followed by intratumoral injection of granulocyte-macrophage colony stimulating factor (GM-CSF) and M13CD40 to enhance DC recruitment and activation. We demonstrate that this ISV strategy can result in significant accumulation and activation of DCs at the tumor site, reversing the immunosuppressive tumor microenvironment. In addition, H-GM-M13CD40 can synergize with the PD-1 blockade and induce abscopal effects in cold tumor models. Overall, our study verifies the immunogenicity of the engineered M13CD40 bacteriophage and provides a proof of concept that the engineered M13CD40 phage can function as an adjuvant for ISVs.

SLC35A2 expression is associated with HER2 expression in breast cancer.

The role of SLC35A2 in breast cancer remains poorly understood, with limited available information on its significance. This study aimed to investigate the expression of SLC35A2 and clinicopathological variables in breast cancer patients. Immunohistochemical analysis of SLC35A2 protein was conductedon 40 adjacent non-neoplastic tissues and 320 breast cancer tissues. The study also assesed the association between SLC35A2 expression and breast cancer clinicopathological features of breast cancer, as well as its impact on overall survival. In comparison to adjacent non-neoplastic tissues, a significantly higher expression of SLC35A2 was observed in breast cancer tissues (P = 0.020), and this expression was found to be independently correlated with HER2 positivity (P = 0.001). Survival analysis indicated that patients with low SLC35A2 expression had a more favorable prognosis in HER2-positive subtype breast cancer (P = 0.017). These results suggest that SLC35A2 is overexpressed in breast cancer tissues compared to adjacent non-neoplastic tissues and may serve as a potential prognostic marker for HER2-positive subtype breast cancer. Furthermore, breast cancer patients with the HER2 positive subtype who exhibited decreased levels of SLC35A2 expression demonstrated improved long-term prognostic outcomes.

Receptor model-based sources and risk assessment of metals in sediment of the coastal construction-oriented aquatic system in Bangladesh.

Metal pollution in sediment from construction areas raises ecological and health concerns, yet source-based sediment pollution in Bangladesh remains understudied. Our investigation focused on fifteen locations in the Kohelia River and the coastal regions near the Matarbari projects (Matarbari Power Plant, Matarbari Deep Seaport), assessing metal concentrations' sources and impacts on ecology and human well-being. Sediment quality indices indicated high Cd and Cr contamination, with sites near Matarbari projects being the most polluted. The positive matrix factorization model identified three anthropogenic sources and mixed sources. Matarbari projects contributed significantly to As (67.9 %), Mn (50.25 %), Cd (48.35 %), and Cr (41.0 %), while ship-breaking yards contributed Fe (58.0 %), Zn (55.5 %), Pb (53.8 %), and Cu (36.1 %). Ecological indices showed different impacts on aquatic life from metal pollution, but cancer risk levels stayed below the threshold set by the US Environmental Protection Agency. These findings underscore the need for targeted measures to address metal pollution.

Temporal trends and barriers for inpatient palliative care referral in metastatic gynecologic cancer patients receiving specific critical care therapies.

Objective: Existing evidence suggests that palliative care (PC) is highly underutilized in metastatic gynecologic cancer (mGCa). This study aims to explore temporal trends and predictors for inpatient PC referral in mGCa patients who received specific critical care therapies (CCT). Methods: The National Inpatient Sample from 2003 to 2015 was used to identify mGCa patients receiving CCT. Basic characteristics were compared between patients with and without PC. Annual percentage change (APC) was estimated to reflect the temporal trend in the entire cohort and subgroups. Multivariable logistic regression was employed to explore potential predictors of inpatient PC referral. Results: In total, 122,981 mGCa patients were identified, of whom 10,380 received CCT. Among these, 1,208 (11.64%) received inpatient PC. Overall, the rate of PC referral increased from 1.81% in 2003 to 26.30% in 2015 (APC: 29.08%). A higher increase in PC usage was found in white patients (APC: 30.81%), medium-sized hospitals (APC: 31.43%), the Midwest region (APC: 33.84%), and among patients with ovarian cancer (APC: 31.35%). Multivariable analysis suggested that medium bedsize, large bedsize, Midwest region, West region, uterine cancer and cervical cancer were related to increased PC use, while metastatic sites from lymph nodes and genital organs were related to lower PC referral. Conclusion: Further studies are warranted to better illustrate the barriers for PC and finally improve the delivery of optimal end-of-life care for mGCa patients who receive inpatient CCT, especially for those diagnosed with ovarian cancer or admitted to small scale and Northeast hospitals.

ICOSL expressed in triple-negative breast cancer can induce Foxp3+ Treg cell differentiation and reverse p38 pathway activation.

Inducible costimulator ligand (ICOSL) expressed on cancer cells has immunoregulatory functions in various malignancies. However, the role of ICOSL in triple-negative breast cancer (TNBC) remains unclear. In this study, the role and expression of ICOSL in TNBC were analyzed using the cBioPortal and GEPIA databases. Then the role of ICOSL in Foxp3+ Treg cell differentiation, reversal of p38 pathway activation and cell proliferation, migration and apoptosis was determined in vitro. Finally, the effect of ICOSL expression on TNBC progression was verified in a nude mouse model of TNBC. We here observed that ICOSL expression in TNBC was found to be related to relapse-free survival, and Treg abundance was positively correlated with ICOSL expression, as demonstrated by database analyses. In vitro experiments showed that ICOSL overexpression (OE) in MDA-MB-231 cells induced cocultured T cells to differentiate into Foxp3+ Treg cells and promoted secretion of the tumor-promoting factors IL-10 and IL-4. Furthermore, in vitro experiments showed that ICOSL reversed p38 phosphorylation and promoted the proliferation, invasion, and metastasis of MDA-MB-231 ICOSL-OE cells. Finally, tumor progression was found to be promoted by ICOSL expression in a TNBC nude mouse model. Together, ICOSL expression can enhance tumor cell growth by inducing Foxp3+ Treg cell differentiation and reversing p38 pathway activation in TNBC.

Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy.

Retinal endothelial cells (RECs) are the primary target cells for diabetes-induced vascular damage. The P2X7/NLRP3 pathway plays an essential role in amplifying inflammation via an ATP feedback loop, promoting the inflammatory response, pyroptosis, and apoptosis of RECs in the early stages of diabetic retinopathy induced by hyperglycemia and inflammation. 3TC, a type of nucleoside reverse transcriptase inhibitor, is effective against inflammation, as it can targeting formation of the P2X7 large pore formation. Hence, our aim was to evaluated the anti-inflammatory effects and potential mechanisms of action of 3TC in vitro in retinal microvascular endothelial cells treated with high-glucose (HG) and lipopolysaccharide (LPS), as well as in vivo in the retinas of C57BL/6J male mice with streptozotocin-induced diabetes. The expression of inflammasome-related proteins P2X7 and NLRP3, and apoptosis in the retinas of 3TC-treated diabetic mice were compared to those of untreated diabetic mice. Furthermore, the anti-inflammatory, anti-apoptotic, and anti-pyroptotic effects of 3TC were evaluated in vitro in cultured mice retinal endothelial cells. Co-application of HG and LPS significantly increased the secretion of IL-6, IL-1ß, and TNF-α, and ATP levels, whereas 3TC decreased cell inflammation, apoptosis, and pyroptosis. Inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury. 3TC prevented cytokine and ATP release following co-application of HG and LPS/BzATP. Our findings provide new insights regarding the mechanisms of action of 3TC in diabetic environment-induced retinal injury, including apoptosis and pyroptosis.

The rheology of ultra-high molecular weight poly(ethylene oxide) dispersed in a low molecular weight carrier.

Gel spinning is the industrial method of choice for combining hydrophilic ultra-high molecular weight (UHMW) polymer resins with a hydrophobic support polymer to produce composite filaments for cytapheresis. Cytapheresis is a medical technique for removal of leukocytes from blood. Gel spinning is used to avoid high melt viscosity and thermal sensitivity of UHMW resins and the high melt temperature of the substrate resin but requires the recovery of toxic solvents. The UHMW resin is used because it forms a stable gel phase in the presence of water; a lower molecular weight resin (LMW) simply dissolves. UHMW and LMW resins were both poly(ethylene oxide) (PEO) and the substrate was polyarylsulfone (PAS). The literature indicated PEO undergoes non-oxidative thermal degradation above 200 °C and PAS is processed up to 350 °C. Dynamic oscillatory shear rheometry was used to study 0, 25, 40, 50, 60, and 75 wt. % UHMW PEO in LMW PEO to take advantage of the sensitivity of viscosity to changes in molecular weight and material configuration, indicating degradation. Samples were exposed to 220 °C, 230 °C, 240 °C, 250 °C, 275 °C, and 300 °C temperatures for 5 min to explore conditions that could result in sample degradation. The viscosity decreased less with increasing UHMW PEO content for samples exposed to the same temperature and the viscosity decreased more with increasing exposure temperature for samples with the same UHMW PEO content. Parameters were regressed from observed data to predict the change in molecular weight via empiricisms relating the viscosity to molecular weight, shear rate, temperature, and time.

Dual targeting micelles loaded with paclitaxel and lapatinib for combinational therapy of brain metastases from breast cancer.

Due to the presence of the blood-brain barrier (BBB), the delivery of general drugs into the brain tissue remains to be a tricky problem. For patients with brain metastases from breast cancer, drug delivery systems must overcome this physical barrier. Targeted nano vehicles arise as a promising alternative to deliver drugs to brain tissues successively. Herein, a dual targeting micelle drug delivery system loaded with paclitaxel (PTX) and lapatinib (LPTN) was developed for combinational therapy of brain metastases. In our study, it was shown the micelles modified with Angiopep-2 had high loading efficiency of paclitaxel and lapatinib (Ang-MIC-PTX/LP). In addition, Ang-MIC-PTX/LP could transport across the in vitro BBB model and accumulate in breast cancer cells. After intravenous injection, Ang-MIC significantly accumulated in the brain metastasis. Ang-MIC-PTX/LP could also extend the life span of brain metastasis mouse models. Overall, this study provided a promising method for treatment of brain metastases from breast cancer.

Uranium-thorium dating of coral mortality and community shift in a highly disturbed inshore reef (Weizhou Island, northern South China Sea).

Inshore coral habitats are at high risk of loss due to a combination of climate warming and regional-scale human impacts. As a result, they have undergone significant declines. Direct evidence of acute and chronic disturbance on most inshore coral assemblages is limited. Long-term, periodical surveys and historical baseline data essential for effective management are lacking. Using high-precision uranium-thorium (UTh) dating, we reconstruct a ~100-year-long history of extensive coral loss, changes in coral community structure, and a shifting baseline. The data were collected at Weizhou Island, northern South China Sea (SCS), which has highly disturbed inshore coral habitats that are typical globally. According to our UTh dates, major coral mortalities around Weizhou Island have occurred since the 1950s, with increasing frequency and severity since the 1980s. The extensive loss of branching Acropora and collapse of coral communities with peaks around 1960, 1984, and 1998 are accompanied by a shift toward low coral cover and noncoral-dominated assemblages. Prior to this collapse, the local coral community structure sustained remarkable long-term stability over millennia. The timing of the Acropora loss and massive coral mortalities coincides with multiple acute and chronic, natural and anthropogenic disturbance events. We suggest that priority should be given to directly addressing the causes of degradation and effectively controlling chronic disturbances before attempting to restore reef ecosystems. This is probably the only way to solve the "wicked problem" of sustaining the key functions and ecosystem services of inshore coral habitats such as those of Weizhou Island, northern SCS.

The expression of APE1 in triple-negative breast cancer and its effect on drug sensitivity of olaparib.

Triple-negative breast cancer is a kind of breast cancer with poor prognosis and special biological behavior, which lacked endocrine therapy and targeted therapy. We investigate the effect of human APE1 (apurinic/apyrimidyl endonuclease 1), a rate-limiting enzyme of base excision repair, on the prognosis in triple-negative breast cancer and drug sensitivity of olaparib. The expression of APE1 was detected by immunohistochemistry in the triple-negative breast cancer tissues and its effect on survival of triple-negative breast cancer patients was followed. To find whether APE1 effect the drug sensitivity in triple-negative breast cancer cells, the APE1-knockout HCC1937 cell line (triple-negative breast cancer cell line) was established by CRISPR/Cas9 system. Then, we use the wild-type and knockout one to test the drug sensitivity of olaparib. The expression of APE1 in triple-negative breast cancer tissues was significantly higher than that in the adjacent tissues (85.6% vs 14.4%) and its expression was related to tumor size (p < 0.05). We also found that it is an independent prognostic factor in patients with triple-negative breast cancer (overall survival, p = 0.01). In vitro assay, the half maximal inhibitory concentration of olaparib in HCC1937-APE1-KO was significantly increased (17.22 vs 91.85 µM) compared to the wild type. The growth curve showed that olaparib had a stronger lethality on HCC1937 compared to HCC1937- APE1-KO (p < 0.05 on day 3). HCC1937 resulted in more mitotic G2/M arrest and increased apoptosis rate after treatment with 40 µM of olaparib, while HCC1937-APE1-KO did not change significantly. When HCC1937 was treated with different concentrations of olaparib, it was found that APE1 expression decreased more significantly at 15 µM of olaparib was. In HCC1937-APE1-KO, the expression of endogenous poly (ADP-ribose) polymerase 1 was also less than that of HCC1937. These results suggested that the expression of APE1 was an important basis for the maintenance of poly (ADP-ribose) polymerase 1, and the deletion of APE1 may be related to the resistance of olaparib.

Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells.

To investigate TRAIL resistance mechanisms in hepatocellular carcinoma (HCC), we isolated a stable TRAIL-resistant sub-population of the HCC cell line LH86, designated LH86-TR. Differential activation of AKT was not responsible for acquisition of TRAIL resistance. Cells with both congenital and acquired resistance to TRAIL exhibited increased Msi1 expression, which conferred TRAIL resistance by activating ERK. Forced expression of Msi1 decreased the sensitivity of HCC cells to TRAIL both in vitro and in vivo. Conversely, shRNA-mediated depletion of Msi1 enhanced TRAIL efficacy. SiRNA-mediated depletion of ERK overcame TRAIL resistance. Hence, we conclude that Msi1 is a mediator of TRAIL resistance in HCC cells.

ISG12a mediates cell response to Newcastle disease viral infection.

Newcastle disease virus (NDV) oncolysis is believed to be facilitated by a defective Type I interferon (IFN) response. We compared hepatocellular carcinoma (HCC)-derived cell lines and found that TRAIL-resistant cells were more susceptible to NDV oncolysis than were TRAIL-sensitive cells. In examining the IFN response, we found that basal expression of the IFN-stimulated gene (ISG)-12a was low in TRAIL-resistant but high in TRAIL-sensitive cells, and ISG12a over-expression or silencing enhanced or reduced their TRAIL sensitivities, respectively. Moreover, ISG12a over-expression in TRAIL-resistant cells decreased NDV replication but surprisingly increased oncolysis while ISG12a silencing had the opposite effect on TRAIL-sensitive cells. Finally, RIG-I and Noxa appear to also contribute to NDV oncolysis. Together, these results suggest that high basal ISG12a may inhibit NDV replication and oncolysis, while low basal ISG12a may allow sufficient NDV replication for induction of ISG12a, and other factors required for NDV oncolysis, with implications for future therapeutics.

miR-942 decreases TRAIL-induced apoptosis through ISG12a downregulation and is regulated by AKT.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive death ligand in targeted cancer therapy. Many cancer cells are refractory to TRAIL-induced cell death and the mechanisms underlying resistance are unclear. The molecular mechanisms of HCC and gastric cancer cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. In vivo experiments were conducted to study the effect of interferon stimulated gene 12a (ISG12a) on human liver cancer xenografts in mice. ISG12a decreases in TRAIL-resistant cancer cells. ISG12a regulates the sensitivity of cancer cells to TRAIL in vitro and in vivo. MicroRNA-942 (miR-942) is inversely correlated with ISG12a expression in cancer cells and tissues. Forced expression of miR-942 in TRAIL-sensitive cells significantly reduces endogenous ISG12a level and changes the TRAIL sensitive phenotype to a resistant one. Knockdown of miR-942 expression in TRAIL-resistant cells restores the expression of ISG12a and sensitizes the cells to TRAIL treatment. AKT control TRAIL resistance of cancer cells through downregulation of ISG12a by miR-942. Downregulation of ISG12a by miR-942 is needed to maintain the TRAIL-resistant phenotype of cancer cells and favors cancer cell survival. MiR-942 may offer a novel drug response marker with important implications in designing new therapeutics for TRAIL resistant tumors.

Anomalous Ba/Ca signals associated with low temperature stresses in Porites corals from Daya Bay, northern South China Sea.

Barium to calcium (Ba/Ca) ratio in corals has been considered as a useful geochemical proxy for upwelling, river flood and other oceanic processes. However, recent studies indicated that additional environmental or biological factors can influence the incorporation of Ba into coral skeletons. In this study, Ba/Ca ratios of two Porites corals collected from Daya Bay, northern South China Sea were analyzed. Ba/Ca signals in the two corals were 'anomalous' in comparison with Ba behaviors seen in other near-shore corals influenced by upwelling or riverine runoff. Our Ba/Ca profiles displayed similar and remarkable patterns characterized by low and randomly fluctuating background signals periodically interrupted by sharp and large synchronous peaks, clearly indicating an environmental forcing. Further analysis indicated that the Ba/Ca profiles were not correlated with previously claimed environmental factors such as precipitation, coastal upwelling, anthropogenic activities or phytoplankton blooms in other areas. The maxima of Ba/Ca appeared to occur in the period of Sr/Ca maxima, coinciding with the winter minimum temperatures, which suggests that the anomalous high Ba/Ca signals were related to winter-time low sea surface temperature. We speculated that the Ba/Ca peaks in corals of the Daya Bay were most likely the results of enrichment of Ba-rich particles in their skeletons when coral polyps retracted under the stresses of anomalous winter low temperatures. In this case, Ba/Ca ratio in relatively high-latitude corals can be a potential proxy for tracing the low temperature stress.

[Low water temperature tolerance and responding mode of scleractinian corals in Sanya Bay].

In an experimental temperature-regulated mesocosm, the low water temperature tolerance of five dominant scleractinian coral species Pavona decussate, Acropora pulchra, Acropora florida, Acropora valida, and Porites lutea in Sanya Bay was investigated, and their responding modes to the cold water stress were analyzed. The tolerance of test corals to low water temperature was closely related to their morphologies, with the branching corals being the most vulnerable to bleaching and death by separating the symbiotic polyps from their skeletons. The lethal low water temperature for branching Acropora corals was 14 degrees C lasting for 3 days, and that for foliose P. decussate was 12 degrees C lasting for 10 days. Massive P. lutea corals responded to low water temperature by forming mucus membrane, which helped to prevent the further losing of symbiotic algae. The corals showing strong tolerance to high water temperature also had strong tolerance to low water temperature, and had similar responding modes to both high and low water temperature, i.e., the corals didn't extend their tentacle first, followed by the continuous release of mucus and the discharge of symbiotic zooxanthellae, and finally, bleached and died.