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The Gram-positive organism Corynebacterium diphtheriae, the cause of diphtheria in humans, expresses pili on its surface which it uses for adhesion and colonization of its host. These pili are covalent protein polymers composed of three types of pilin subunit that are assembled by specific sortase enzymes. A structural analysis of the major pilin SpaD, which forms the polymeric backbone of one of the three types of pilus expressed by C. diphtheriae, is reported. Mass-spectral and crystallographic analysis shows that SpaD contains three internal Lys-Asn isopeptide bonds. One of these, shown by mass spectrometry to be located in the N-terminal D1 domain of the protein, only forms slowly, implying an energy barrier to bond formation. Two crystal structures, of the full-length three-domain protein at 2.5 Å resolution and of a two-domain (D2-D3) construct at 1.87 Å resolution, show that each of the three Ig-like domains contains a single Lys-Asn isopeptide-bond cross-link, assumed to give mechanical stability as in other such pili. Additional stabilizing features include a disulfide bond in the D3 domain and a calcium-binding loop in D2. The N-terminal D1 domain is more flexible than the others and, by analogy with other major pilins of this type, the slow formation of its isopeptide bond can be attributed to its location adjacent to the lysine used in sortase-mediated polymerization during pilus assembly.

Background: Inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), serve as valuable prognostic indicators in various cancers. This multicenter, retrospective cohort study assessed the treatment outcomes of lenvatinib in 71 patients with radioactive iodine (RAI)-refractory thyroid cancer, considering the baseline inflammatory biomarkers. Methods: This study retrospectively included patients from five tertiary hospitals in Korea whose complete blood counts were available before lenvatinib treatment. Progression-free survival (PFS) and overall survival (OS) were evaluated based on the median value of inflammatory biomarkers. Results: No significant differences in baseline characteristics were observed among patients grouped according to the inflammatory biomarkers, except for older patients with a higher-than-median NLR (=2) compared to their counterparts with a lower NLR (P= 0.01). Patients with a higher-than-median NLR had significantly shorter PFS (P=0.02) and OS (P=0.017) than those with a lower NLR. In multivariate analysis, a higher-than-median NLR was significantly associated with poor OS (hazard ratio, 3.0; 95% confidence interval, 1.24 to 7.29; P=0.015). However, neither the LMR nor the PLR was associated with PFS. A higher-than-median LMR (≥3.9) was significantly associated with prolonged OS compared to a lower LMR (P≥0.036). In contrast, a higher-than-median PLR (≥142.1) was associated with shorter OS compared to a lower PLR (P=0.039). Conclusion: Baseline inflammatory biomarkers can serve as predictive indicators of PFS and OS in patients with RAI-refractory thyroid cancer treated with lenvatinib. [ABSTRACT FROM AUTHOR]

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres (100–300 nm in size) loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than non-specific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study reveals the potential for anti-cancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labeling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier allowing for the precise targeting of tumors. This combination has the potential to produce anti-tumor effects in the active targeted therapy of GBM. [ABSTRACT FROM AUTHOR]

This article shows that the Korean Extrinsic Plural Marker (EPM) may be acquired by children on the basis of very little evidence. The EPM marks distributivity, unlike the Instrinsic Plural Marker, which marks plurality. Thirty monolingual learners of Korean aged 5;03 to 6;09 (mean age 6;01) were tested using a series of Truth Value Judgment Tasks (Crain & Thornton 1998). The children were split into three groups: Experimental-1, Experimental-2, and Control. All children received a pretest, establishing that they are unaware of the properties of EPM. Children in the two experimental groups then received two interventions, each employing a single instance of a felicitous interaction between a child and a mother involving the EPM. One intervention presented positive evidence of the meaning of the EPM, and the other presented negative evidence. Each intervention was followed by an assessment of the effect of the intervention (using TVJT tests similar to the pretest). The experimental groups differed in the order of the interventions, and the control group received no interventions but otherwise received exactly the same regimen of tests as the experimental groups. The results show that fourteen of the twenty experimental children responded to the intervention that involved positive evidence; none responded to the intervention involving negative evidence; and none of the children in the control group acquired the meaning of the EPM. We conclude that inflectional patterns may be acquired on the basis of very little evidence, perhaps employing mechanisms of fast mapping akin to those found in the domain of the lexicon.

A prospective randomized controlled multicenter phase III trial was conducted to evaluate the effects of neoadjuvant chemotherapy with nimustine (ACNU)-cisplatin (CDDP) when used in conjunction with radiotherapy plus adjuvant temozolomide in patients with newly diagnosed glioblastoma. The study population was randomly assigned into one treatment and one control group. Both groups received radiotherapy followed by six cycles of adjuvant oral temozolomide (150-200 mg/m(2)) for 5 days every 28 days after surgery. Prior to radiotherapy, the treatment group also received two cycles, 6 weeks apart, of neoadjuvant chemotherapy with ACNU (40 mg/m(2)/day) and CDDP (40 mg/m(2)/day) infused continuously for 72 h. The primary end-point was median survival time. The study has closed after interim analysis with a total of 82 patients (48.8% of target number) due to unacceptable high frequency of toxicity profiles in spite of the promising actuarial survival outcome. Median survival time was 28.4 months [90% confidence interval (CI), 21.1 months to not available] in the treatment group and 18.9 months (90% CI, 17.1-27.4 months) in the control group (P = 0.2). The 2-year survival rate and progression-free survival time were 50.9% and 6.6 months (90% CI, 3.5-9.5 months) in the treatment group and 27.8% and 5.1 months (90% CI, 3.8-8.8 months) in the control group. Grade 3 or 4 toxicity was documented in 26 (68.4%) patients in the treatment group, including three neutropenic fever and one death from sepsis, while grade 3 or 4 toxicity occurred in 6 patients (15.8%) in the control group. The high frequency of serious hematological toxicity with ACNU-CDDP neoadjuvant chemotherapy followed by radiotherapy and adjuvant temozolomide limits its usage as primary treatment for glioblastoma. Future studies should aim to identify a subpopulation at reduced risk for ACNU-CDDP toxicity so that the potential of this protocol can be realized.