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Background Patients with multicentric Castleman disease (MCD) who are negative for human immunodeficiency virus and human herpesvirus 8 are considered to have idiopathic MCD (iMCD). The clinical presentation of iMCD varies from mild constitutional symptoms to life-threatening symptoms or death. The treatment strategy varies from “watchful waiting” to high-dose chemotherapy. This diverse clinical presentation calls for a classification stratification system that takes into account the severity of the disease. Subjects, Materials, and Methods We analyzed the clinical, laboratory, and pathologic abnormalities and treatment outcomes of 176 patients with iMCD (median follow-up duration 12 years) from the U.S. and China to better understand the characteristics and prognostic factors of this disease. This discovery set of iMCD results was confirmed from the validation set composed of additional 197 patients with iMCD organized from The International Castleman Disease Consortium. Results Using these data, we proposed and validated the iMCD international prognostic index (iMCD-IPI), which includes parameters related to patient characteristics (age > 40 years), histopathologic features (plasma cell variant), and inflammatory consequences of iMCD (hepatomegaly and/or splenomegaly, hemoglobin Conclusion This study represents the largest series of studies on patients with iMCD in the field and proposed a novel risk-stratification model for iMCD-IPI that could be used to guide risk-stratified treatment strategies in patients with iMCD. Implications for Practice Patients with idiopathic multicentric Castleman disease (iMCD) can benefit from care based on clinical symptoms and disease severity. This study in 176 patients with iMCD constructed an iMCD-IPI score based on five clinical factors, including age >40 years, plasmacytic variant subtype, hepatomegaly and/or splenomegaly, hemoglobin

Development of novel activable dual-mode T1/T2-weighted magnetic resonance (MR) contrast agents with the same composition for dynamic precision imaging of tumors has been a challenging task. Here, we demonstrated a strategy to prepare clustered Fe3O4 nanoparticles (NPs) with redox-responsiveness to tumor microenvironment to achieve switchable T2/T1-weighted dual-mode MR imaging applications. In this study, we first synthesized ultrasmall Fe3O4 NPs with an average size of 3.3 nm and an r1 relaxivity of 4.3 mM-1 s-1, and then cross-linked the single Fe3O4 NPs using cystamine dihydrochloride (Cys) to form clustered Fe3O4/Cys NPs. The Fe3O4 nanoclusters (NCs) possess desirable colloidal stability, cytocompatibility, high r2 relaxivity (26.4 mM-1 s-1), and improved cellular uptake efficiency. Importantly, with the redox-responsiveness of the disulfide bond of Cys, the Fe3O4 NCs can be dissociated to form single particles under a reducing condition, hence displaying a switchable T2/T1-weighted MR imaging property that can be utilized for dynamic precision imaging of cancer cells in vitro and a subcutaneous tumor model in vivo due to the reductive intracellular environment of cancer cells and the tumor microenvironment. With the tumor reductive microenvironment-mediated switching of T2 to T1 MR effect and the ultrasmall size of the single particles that can pass through the kidney filter, the developed Fe3O4 NCs may be used as a promising switchable T2/T1 dual-mode MR contrast agent for precision imaging of different biosystems.

Alcohol drinking has been established as a major risk factor for esophageal diseases. Our previous study showed that ethanol exposure inhibited PAX9 expression in human esophageal squamous epithelial cells in vitro and in vivo. In this study, we aimed to investigate the molecular pathways through which alcohol drinking suppresses PAX9 in esophageal squamous epithelial cells. We first demonstrated the inhibition of NOTCH by ethanol exposure in vitro. NOTCH regulated PAX9 expression in KYSE510 and KYSE410 cells in vitro and in vivo. RBPJ and NOTCH intracellular domain (NIC) D1 ChIP-PCR confirmed Pax9 as a direct downstream target of NOTCH signaling in mouse esophagus. NOTCH inhibition by alcohol drinking was further validated in mouse esophagus and human tissue samples. In conclusion, ethanol exposure inhibited NOTCH signaling and thus suppressed PAX9 expression in esophageal squamous epithelial cells in vitro and in vivo. Our data support a novel mechanism of alcohol-induced esophageal injury through the inhibition of NOTCH-PAX9 signaling. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

ObjectiveTo identify risk factors associated with surgical site infection (SSI) after major oral oncological surgery.MethodsThis retrospective study reviewed data from patients that underwent major surgery for oral cancer at a tertiary referral hospital in China between January 2005 and July 2016. SSI was diagnosed within 30 days. Demographic, cancer-related, preoperative, perioperative and postoperative data were analysed using descriptive statistics and univariate and multivariate analyses of the risk factors for SSI.ResultsA total of 786 patients were enrolled, of whom 125 had SSI (15.9%), which were all incisional. Independent risk factors for SSI, identified by multivariate analysis, were diabetes mellitus (odds ratio [OR] 2.147, 95% confidence interval [CI] 1.240, 3.642), prior radiotherapy (OR 4.595, 95% CI 1.293, 17.317) and oral–neck communication (OR 2.838, 95% CI 1.263, 7.604); and factors reflecting large extent resections were tracheostomy (OR 2.235, 95% CI 1.435, 3.525), anterolateral thigh flap (OR 1.971, 95% CI 1.103, 3.448) and latissimus dorsi flap (OR 4.178, 95% CI 1.325, 13.189).ConclusionsMultiple risk factors were associated with SSI after major oral oncological surgery. To minimize SSI risk, surgeons managing oral cancer patients should have a better understanding of the risk factors, including diabetes mellitus, prior radiotherapy, tracheostomy, oral–neck communication and flap reconstruction.

Booming graphitic carbon nitride (g-C3N4) photocatalyzed water splitting increases crisis of aquatic contamination. However, a controversial understanding regarding effect of g-C3N4 on growth of microalgae still exists. Accordingly, Chlorella vulgaris were cultured in 0–250 mg/L of g-C3N4 with biomass named as C-0, C-50, C-100, C-150, C-200, and C-250, respectively. g-C3N4 below 200 mg/L was beneficial to short-term cultivation of microalgae, while it was harmful to long-time cultivation. Protein factions of C-0, C-100, and C-250 were 41.4, 42.3, and 36.4 wt%, while their lipid factions varied from 21.5, 16.9, to 17.8 wt%, respectively. In short-term cultivation, superoxide dismutase’s activity of C-0, C-150, and C-250 increased dramatically, while accumulated H2O2 led to increased activity of catalase. However, it started to decrease once antioxidant enzymes were per-oxidized, leading to increase of malondialdehyde content. In long-term cultivation, activities of superoxide dismutase, catalase and malondialdehyde content decreased dramatically owning to peroxidation of algae. Scavenger tests with tertiary butanol and triethanolamine implied that·OH was dominate parameter affecting growth of microalgae. This work indicates that g-C3N4 below 200 mg/L is propitious to short-term cultivation of microalgae, while it is bad to long-time cultivation of microalgae, revealing dual rules of g-C3N4 in Chlorella vulgaris cultivation.

The calculation of improper integral is of great importance. In this paper, we consider a kind of real improper integral using the method of complex analysis and prove the equation ∫ 0 ∞ x α ( 1 + x β ) x d x = π β sin α π β . Firstly we give the condition for the convergence of the improper integral ∫ 0 ∞ x α ( 1 + x β ) x d x when 0 < α < β , so we can see the integrand as a complex function. This function is defined on a simply connected set not containing zero to ensure that the function is holomorphic. We use three methods to prove the equation. In the first method, we choose a certain closed path as the boundary of the simply connected set, compute the integral along the path by the Residue Formula according to Cauchy’s Theorem, and obtain the value of the real improper integral. In the second method, we use Mellin transform, while the idea is similar to that of the Residue Formula. In the third method, we find that the path we choose becomes simpler by a variable substitution. The function that is integrated along the new path does not have the problem of multivaluedness, so we do not have to define it on a simply connect set. Moreover, using the method of complex analysis, we prove that the equation holds when α, β are complex numbers, and the condition is about the real parts of α and β, i.e., 0 < ℜ α < ℜ β . The real improper integral is just a particular case where α, β are real numbers. We compute the value of such kind of complex improper integral by some calculation and simplification, which is exactly π β sin α π β . We find the relationship between this integral and gamma function. The equation can prove a property of gamma function. We prove that the equation holds when α, β are complex numbers, and the condition becomes 0 < ℜ α < ℜ β . We hope that this can be used in the research of more properties of the gamma function. The proof of the equation reminds us of a way of calculating such kinds of real improper integrals.

The design of pH-sensitive supramolecular drug delivery systems for efficient antineoplastic drug delivery remains a huge challenge. Herein, we describe the development of pH-responsive core–shell tecto dendrimers (CSTDs) formed using benzimidazole (BM)-modified generation 3 (G3) poly(amidoamine) (PAMAM) dendrimers (G3.NHAc-BM) as a shell and β-cyclodextrin (CD)-modified G5 PAMAM dendrimers (G5.NHAc-CD) as a core. By virtue of the host–guest recognition and pH-responsiveness of BM/β-CD assembly, the pH-sensitive supramolecular CSTDs of G5.NHAc-CD/BM-G3.NHAc were formed and adopted to encapsulate the anticancer drug doxorubicin (DOX) via hydrophobic interactions for pH-responsive drug delivery applications. The synthesis of dendrimer derivatives and the loading of the DOX were well characterized via different methods. We show that the encapsulated DOX can be released in a sustained manner with a rapid release speed under a slightly acidic pH condition (pH < 6), which is similar to acidic tumor microenvironment. The enhanced intracellular release of DOX and improved anticancer activity of the drug-loaded pH-responsive CSTDs were demonstrated and compared with the control CSTDs formed without pH-responsiveness through flow cytometry and viability assays of cancer cells. Furthermore, the pH-sensitive CSTDs also showed efficient drug penetration and growth inhibition of three-dimensional tumor spheroids owing to the faster DOX release in an acidic pH environment. The pH-sensitive G5.NHAc-CD/BM-G3.NHAc CSTDs may be employed as a valuable intelligent delivery system for various anticancer drugs.

International audience; The development of a powerful nanoplatform to realize the simultaneous therapy and diagnosis of cancer using a similar element for theranostics remains a critical challenge. Herein, we report such a theranostic nanoplatform based on pyridine (Pyr)-functionalized generation 5 (G5) poly(amidoamine) dendrimers complexed with copper(II) (Cu(II)) for radiotherapy-enhanced T1-weighted magnetic resonance (MR) imaging and the synergistic radio-chemotherapy of both tumors and tumor metastasis. In this study, amine-terminated G5 dendrimers were covalently linked with 2-pyridinecarboxylic acid, acetylated to neutralize their remaining terminal amines, and complexed with Cu(II) through both the internal tertiary amines and the surface Pyr groups to form the G5.NHAc-Pyr/Cu(II) complexes. We show that the complexes are able to inhibit the proliferation of different cancer cell lines with half-maximal inhibitory concentrations ranging from 4 to 10 μM and induce significant cancer cell apoptosis. Due to the presence of Cu(II), the G5.NHAc-Pyr/Cu(II) complexes display an r1 relaxivity of 0.7024 mM–1 s–1, enabling effective in vivo MR imaging of tumor xenografts and lung metastatic nodules. Further, under radiotherapy (RT) conditions, the tumor MR imaging sensitivity can be significantly enhanced, and the G5.NHAc-Pyr/Cu(II) complexes enable the enhanced chemotherapy of both a xenografted tumor model and a blood-vessel metastasis model. With the demonstrated theranostic potential of the dendrimer-Cu(II) nanocomplexes without additional agents or elements for RT-enhanced MR imaging and chemotherapy of tumor and tumor metastasis, this novel Cu(II)-based nanohybrids may hold great promise for the theranostics of different cancer types and metastases.