Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly ...improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.
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•Histamine binding of HRH1 on macrophages induces an immunosuppressive phenotype•H1-antihistamine treatment enhances immunotherapy response•Allergic reaction promotes immune evasion and resistance to immunotherapy•High histamine and HRH1 levels correlate with poor immunotherapy response in patients
Li et al. investigate how cancer cells evade immune attack and resist immunotherapies. Cancer cell-derived or allergy-released histamine binds to HRH1 on tumor-associated macrophages that suppress CD8+ T cell function, accelerate tumor growth, and confer immunotherapy resistance. H1-antihistamines counteract histamine-mediated immunosuppression, reinforce antitumor immunity, and significantly enhance immunotherapy response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Black phosphorus (BP) nanostructures such as nanosheets and nanoparticles have attracted considerable attention in recent years due to their unique properties and great potential in various ...physical, chemical, and biological fields. In this article, water-soluble and biocompatible PEGylated BP nanoparticles with a high yield were prepared by one-pot solventless high energy mechanical milling technique. The resultant BP nanoparticles can efficiently convert near infrared (NIR) light into heat, and exhibit excellent photostability, which makes them suitable as a novel nanotheranostic agent for photoacoustic (PA) imaging and photothermal therapy of cancer. The in-vitro results demonstrate the excellent biocompatibility of PEGylated BP nanoparticles, which can be used for photothermal ablation of cancer cells under irradiation with NIR light. The in-vivo PA images demonstrate that these BP nanoparticles can be efficiently accumulated in tumors through the enhanced permeability retention effect. The resultant BP nanoparticles can be further utilized for photothermal ablation of tumors by irradiation with NIR light. The tumor-bearing mice were completely recovered after photothermal treatment with BP nanoparticles, in comparison with mice from control groups. Our research highlights the great potential of PEGylated BP nanoparticles in detection and treatment of cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This study aims to build a radiological model based on standard MR sequences for detecting methylguanine methyltransferase (MGMT) methylation in gliomas using texture analysis. A retrospective ...cross‐sectional study was undertaken in a cohort of 53 glioma patients who underwent standard preoperative magnetic resonance (MR) imaging. Conventional visual radiographic features and clinical factors were compared between MGMT promoter methylated and unmethylated groups. Texture analysis extracted the top five most powerful texture features of MR images in each sequence quantitatively for detecting the MGMT promoter methylation status. The radiomic signature (Radscore) was generated by a linear combination of the five features and estimates in each sequence. The combined model based on each Radscore was established using multivariate logistic regression analysis. A receiver operating characteristic (ROC) curve, nomogram, calibration, and decision curve analysis (DCA) were used to evaluate the performance of the model. No significant differences were observed in any of the visual radiographic features or clinical factors between different MGMT methylated statuses. The top five most powerful features were selected from a total of 396 texture features of T1, contrast‐enhanced T1, T2, and T2 FLAIR. Each sequence’s Radscore can distinguish MGMT methylated status. A combined model based on Radscores showed differentiation between methylated MGMT and unmethylated MGMT both in the glioblastoma (GBM) dataset as well as the dataset for all other gliomas. The area under the ROC curve values for the combined model was 0.818, with 90.5% sensitivity and 72.7% specificity, in the GBM dataset, and 0.833, with 70.2% sensitivity and 90.6% specificity, in the overall gliomas dataset. Nomogram, calibration, and DCA also validated the performance of the combined model. The combined model based on texture features could be considered as a noninvasive imaging marker for detecting MGMT methylation status in glioma.
A retrospective cross‐sectional study was undertaken in a cohort of 53 glioma patients who underwent standard preoperative magnetic resonance (MR) imaging. Conventional visual radiographic features and clinical factors were compared between methylguanine methyltransferase (MGMT) promoter methylated and unmethylated groups. Texture analysis extracted the top five most powerful texture features of MR images in each sequence quantitatively for detecting the MGMT promoter methylation status.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Copper and zinc are essential micronutrients, whose imbalance may be involved in the development and progression of cancer. However, the role of copper and/or zinc imbalance in the prognosis of ...hepatocellular carcinoma (HCC) is currently unclear. Our objective was to investigate the association between serum levels of copper, zinc and their ratio (copper/zinc) at diagnosis with HCC survival. We included 989 patients with incident HCC in this prospective cohort study, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study within 30 days of diagnosis between September 2013 and February 2017. Serum copper and zinc were measured using inductively coupled plasma mass spectrometry. Primary outcomes were liver cancer‐specific survival (LCSS) and overall survival (OS). Cox proportional hazards models were used to calculate the multivariable hazard ratios (HRs) and 95% confidence interval (CI). Higher serum copper levels were strongly associated with worse LCSS (Q4 vs. Q1: HR = 1.87, 95% CI: 1.22–2.86; p < 0.01 for trend) and OS (Q4 vs. Q1: HR = 2.06, 95% CI: 1.36–3.11; p < 0.01 for trend). The calculated copper/zinc ratio was positively associated with LCSS (Q4 vs. Q1: HR = 1.31, 95% CI: 0.89–1.92; P = 0.04 for trend) and OS (Q4 vs. Q1: HR = 1.43, 95% CI: 0.99–2.08; P = 0.01 for trend). No overall associations were observed between serum zinc levels and LCSS or OS in the entire cohort. The results suggest that higher serum copper and copper in relation to zinc levels (i.e., higher copper/zinc ratio) may be associated with worse HCC survival, but serum zinc levels may be not associated with HCC survival.
What's new?
Copper and zinc are essential micronutrients whose imbalance may be involved in development and progression of cancer. Currently, the role of copper and/or zinc imbalance in the prognosis of hepatocellular carcinoma (HCC) however remains unclear. The authors examine for the first time whether serum levels of copper, zinc, and their ratios are associated with survival in a large prospective cohort of newly diagnosed patients. The findings suggest that higher copper levels and copper/zinc ratios are associated with worse survival, but serum zinc levels are not associated with HCC survival. The results may have important implications for the prognosis of HCC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The expression of gp350 facilitates the recognition of EBV by the human immune system and initiates the complement pathway and antibody-dependent cell-mediated cytotoxicity (ADCC) to eliminate the EB ...virus. 11 Excessive inflammatory reactions, especially in a microenvironment that results from nonresolving inflammation, may lead to DNA breakage, increase the probability of mutation and induce cell proliferation, which may eventually lead to carcinogenesis. 2 Moreover, through the downregulation of the expression of c-Jun (AP1 transcription factor), LTF can inhibit the transcriptional activation of c-Jun by the AKT pathway kinase PDK1, which downregulates the activity of the AKT pathway and inhibits the growth of NPC cells through downstream AKT signaling. 15 LTF can also inhibit PDK1 and then inhibit AKT phosphorylation and membrane translocation, which leads to the inhibition of tumor cell proliferation, invasion and metastasis through the PDK1/AKT pathway.
N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m6A ...in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m6A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m6A modification has fundamental and broad functions in mammalian cells.
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► ALKBH5 is a mammalian m6A RNA demethylase ► RNA demethylation affects mRNA export and RNA metabolism ► RNA demethylation is important for mouse fertility ► Reversible mammalian messenger RNA methylation affects gene expression
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dopamine D1 receptor (D1DR) and D2 receptor (D2DR) are closely associated with pain modulation, but their exact effects on neuropathic pain and the underlying mechanisms remain to be identified. Our ...research revealed that intrathecal administration of D1DR and D2DR antagonists inhibited D1-D2DR complex formation and ameliorated mechanical and thermal hypersensitivity in chronic constriction injury (CCI) rats. The D1-D2DR complex was formed in the rat spinal cord, and the antinociceptive effects of D1DR and D2DR antagonists could be reversed by D1DR, D2DR, and D1-D2DR agonists. Gαq, PLC, and IP3 inhibitors also alleviated CCI-induced neuropathic pain. D1DR, D2DR, and D1-D2DR complex agonists all increased the intracellular calcium concentration in primary cultured spinal neurons, and this increase could be reversed by D1DR, D2DR antagonists and Gαq, IP3, PLC inhibitors. D1DR and D2DR antagonists significantly reduced the expression of p-PKC γ, p-CaMKII, p-CREB, and p-MAPKs. Levo-corydalmine (l-CDL), a monomeric compound in Corydalis yanhusuo W.T. Wang, was found to obviously suppress the formation of the spinal D1-D2DR complex to alleviate neuropathic pain in CCI rats and to decrease the intracellular calcium concentration in spinal neurons. l-CDL-induced inhibition of p-PKC γ, p-MAPKs, p-CREB, and p-CaMKII was also reversed by D1DR, D2DR, and D1-D2DR complex agonists. In conclusion, these results indicate that D1DR and D2DR form a complex and in turn couple with the Gαq protein to increase neuronal excitability via PKC γ, CaMKII, MAPK, and CREB signaling in the spinal cords of CCI rats; thus, they may serve as potential drug targets for neuropathic pain therapy.
Background and Aims
Free and bioavailable 25‐hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to ...hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival.
Approach and Results
We included 1,031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum‐free 25OHD levels were measured using a two‐step enzyme‐linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer–specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow‐up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C‐reactive protein, Barcelona Clinic Liver Cancer stage, and cancer treatment. The multivariable‐adjusted HRs in the highest versus lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend = 0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend = 0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS.
Conclusions
Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population‐based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever in East Asia caused by SFTS virus (SFTSV), a newly discovered phlebovirus. The Haemaphysalis longicornis tick has ...been suspected to be the vector of SFTSV. To determine whether SFTSV can be transmitted among ticks, from ticks to animals, and from animals to ticks, we conducted transmission studies between developmental stages of H. longicornis ticks and between ticks and mice. Using reverse transcription PCR, we also analyzed the prevalence of SFTSV infection among H. longicornis ticks collected from vegetation in Shandong Province, China. Our results showed a low prevalence of SFTSV among collected ticks (0.2%, 8/3,300 ticks), and we showed that ticks fed on SFTSV-infected mice could acquire the virus and transstadially and transovarially transmit it to other developmental stages of ticks. Furthermore, SFTSV-infected ticks could transmit the virus to mice during feeding. Our findings indicate ticks could serve as a vector and reservoir of SFTSV.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction: Interstitial nephritis related to novel oral anticoagulants was only reported in sporadic case reports and none was accompanied by anticoagulants related nephropathy (ARN).
Case Report: ...We presented here a case of biopsy-proven subacute interstitial nephritis (SubAIN) accompanied by ARN after oral dabigatran to alarm clinicians. This case manifested with gross hematuria, acute kidney injury, slightly prolonged thrombin time, moderate anemia, moderate proteinuria, a large quantity of intratubular hemoglobin casts confirmed by hemoglobin antibody immunohistochemical staining which presumed to occur around 1 week after dabigatran and subacute interstitial nephritis accompanied by focal proliferative glomerulonephritis. Serum creatinine level did not continue to elevate after discontinuation of the oral anticoagulant. With the subsequent supportive therapy, it decreased to some extent then reduced to normal with the help of prednisone (half of the full dose).
Conclusions: When we came across a patient who manifested as hematuria or acute kidney injury with a history of anticoagulants usage, we should think of ARN and pay more attention on history collection. Secondly, subacute interstitial nephritis may coexist with ARN. Thirdly, hemoglobin immunohistochemical staining may be helpful to make it clear whether the intra-tubular protein casts came from red blood cells. In addition, for those patients who may have decreased kidney function, anticoagulants dose should be reduced to prevent the occurrence of ARN.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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