Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2. Pembrolizumab, a programmed death 1-blocking antibody, demonstrated a high overall response rate (ORR) in patients with relapsed or refractory classic Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 ( ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of pembrolizumab in three cohorts of patients with rrHL, defined on the basis of lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without BV after transplantation. Patients received pembrolizumab 200 mg once every 3 weeks. Response was assessed every 12 weeks. The primary end points were ORR by central review and safety. Results A total of 210 patients were enrolled and treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). At the time of analysis, patients received a median of 13 treatment cycles. Per central review, the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was 22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2% for cohort 2, and 70.0% for cohort 3. Thirty-one patients had a response ≥ 6 months. The safety profile was largely consistent with previous pembrolizumab studies. Conclusion Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease.

The treatment difficulties of venous thrombosis include short half-life, low utilization, and poor penetration of drugs at thrombus site. Here, we develop one kind of mesoporous/macroporous silica/platinum nanomotors with platelet membrane (PM) modification (MMNM/PM) for sequentially targeting delivery of thrombolytic and anticoagulant drugs for thrombus treatment. Regulated by the special proteins on PM, the nanomotors target the thrombus site and then PM can be ruptured under near-infrared (NIR) irradiation to achieve desirable sequential drug release, including rapid release of thrombolytic urokinase (3 hours) and slow release of anticoagulant heparin (>20 days). Meantime, the motion ability of nanomotors under NIR irradiation can effectively promote them to penetrate deeply in thrombus site to enhance retention ratio. The in vitro and in vivo evaluation results confirm that the synergistic effect of targeting ability from PM and motion ability from nanomotors can notably enhance the thrombolysis effect in both static/dynamic thrombus and rat model.

Homeostasis of the endoplasmic reticulum (ER) is essential for normal cellular functions. Disturbance of this homeostasis causes ER stress and activates the Unfolded Protein Response (UPR). The Ufm1 conjugation system is a novel Ubiquitin-like (Ubl) system whose physiological target(s) and biological functions remain largely undefined. Genetic study has demonstrated that the Ufm1-activating enzyme Uba5 is indispensible for erythroid differentiation in mice, highlighting the importance of this novel system in animal development. In this report we present the evidence for involvement of RCAD/Ufl1, a putative Ufm1-specific E3 ligase, and its binding partner C53/LZAP protein in ufmylation of endogenous Ufm1 targets. Moreover, we found that the Ufm1 system was transcriptionally up-regulated by disturbance of the ER homeostasis and inhibition of vesicle trafficking. Using luciferase reporter and ChIP assays, we dissected the Ufm1 promoter and found that Ufm1 was a potential target of Xbp-1, one of crucial transcription factors in UPR. We further examined the effect of Xbp-1 deficiency on the expression of the Ufm1 components. Interestingly, the expression of Ufm1, Uba5, RCAD/Ufl1 and C53/LZAP in wild-type mouse embryonic fibroblasts (MEFs) was significantly induced by inhibition of vesicle trafficking, but the induction was negated by Xbp-1 deficiency. Finally, we found that knockdown of the Ufm1 system in U2OS cells triggered UPR and amplification of the ER network. Taken together, our study provided critical insight into the regulatory mechanism of the Ufm1 system and established a direct link between this novel Ubl system and the ER network.

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The serine protease autotransporters of Enterobacteriaceae (SPATEs) represent a large family of virulence factors. The prevailing model for autotransporter secretion comprises entry to the periplasm via the Sec apparatus, followed by an obscure series of steps in which the C terminus of the periplasmic species inserts into the outer membrane as a ␤-barrel protein, accompanied by translocation of the passenger domain to the bacterial cell surface. Little is known about the fate of the autotransporter proteins in the periplasm, including whether accessory periplasmic proteins are involved in translocation to the external milieu. Here we studied the role of the major periplasmic chaperones in the biogenesis of EspP, a prototype SPATE protein produced by Escherichia coli O157:H7. The yeast two-hybrid approach, secretion analysis of chaperone mutant strains, and surface plasmon resonance analysis (SPR) revealed direct protein-protein interactions between the periplasmic SurA and DegP chaperones and either the EspP-␤ or EspP passenger domains. The secretion of EspP was moderately reduced in the surA and skp mutant strains but severely impaired in the degP background. Site-directed mutagenesis of highly conserved aromatic amino acid residues in the SPATE family resulted in ϳ80% reduction of EspP secretion. Synthetic peptides containing aromatic residues derived from the EspP passenger domain blocked DegP and SurA binding to the passenger domain. SPR suggested direct proteinprotein interaction between periplasmic chaperones and the unfolded EspP passenger domain. Our data suggest that translocation of AT proteins may require accessory factors, calling into question the moniker "autotransporter."Secretion of proteins to the surface of gram-negative bacteria requires passage through the inner membrane (IM), the periplasm, and the outer membrane (OM). This formidable series of obstacles can be overcome only by complex biological processes. The autotransporter (AT) system, probably the most common gram-negative secretion mechanism (13), is characterized by formation of an OM ␤-barrel comprised of the C terminus of the periplasmic species. The precise events required for AT translocation across the OM, however, are controversial. The original model for OM translocation comprised targeting to the periplasm via the Sec apparatus, followed by formation of an OM ␤-barrel, which mediates passage of an unfolded or partially folded N-terminal passenger domain to the extracellular milieu (30). Three models of AT translocation have gained some acceptance (3, 16). According to the hairpin model, translocation of the passenger domain is initiated with the C-terminal end of the passenger forming a hairpin structure inside the AT ␤-barrel, followed by movement of the rest of the passenger through the barrel's pore in a C-to-N direction. Under the Omp85 model, the pore-forming Omp85 (YaeT in Escherichia coli) OM protein (OMP) facilitates insertion of the AT translocator domain into the OM, whereupon the AT passenger domain translocates th...

A series of hypercrosslinked microporous organic copolymer networks was synthesized via Friedel–Crafts alkylation of tetraphenylethylene (TPE) and/or 1,1,2,2-tetraphenylethane-1,2-diol (TPD) promoted by anhydrous FeCl3.

Parent-reported, high-quality family-centeredness and a high level of realized access to primary care were associated with decreased subsequent nonurgent emergency department visits for children. Parent reports of health care quality in these domains provide important complementary information on health care quality.

Combined chemo/chemodynamic therapy is a promising strategy to achieve an improved anticancer effect. However, the hypoxic microenvironment and limited amount of H2O2 in most solid tumors severely restrict the efficacy of this treatment. Herein, the construction of a nanocatalytic medicine, CaO2@DOX@ZIF‐67, via a bottom‐up approach is described. CaO2@DOX@ZIF‐67 simultaneously supplies O2 and H2O2 to achieve improved chemo/chemodynamic therapy. In the weakly acidic environment within tumors, CaO2@DOX@ZIF‐67 is broken down to rapidly release the Fenton‐like catalyst Co2+ and the chemotherapy drug doxorubicin (DOX). The unprotected CaO2 reacts with H2O to generate both O2 and H2O2. The generated O2 relieves the hypoxia in the tumor and further improve the efficacy of DOX. Meanwhile, the generated H2O2 reacts with Co2+ ions to produce highly toxic •OH through a Fenton‐like reaction, resulting in improved chemodynamic therapy.