Peptide and peptidomimetic ligands for CXC chemokine receptor 4 (CXCR4).

The development of novel peptide and peptidomimetic ligands for the CXC chemokine receptor 4 (CXCR4) as therapeutic agents for HIV-1 infection, cancer, and immune system diseases has grown over the last decade. In this perspective article, the design of CXCR4 agonists and antagonists from endogenous stromal cell-derived factor-1 (SDF-1)/CXCL12 and horseshoe crab-derived antimicrobial peptides and their therapeutic and diagnostic applications are described

Synthesis of IB-01212 by multiple N-methylations of peptide bonds.

There are many natural peptides with multiple N-methylamino acids that exhibit potent attractive biological activities. N-methylation of a peptide bond(s) is also one of the standard approaches in medicinal chemistry of bioactive peptides, to improve the potency and physicochemical properties, especially membrane permeability. In this study, we investigated a facile synthesis process of N-methylated peptides via simultaneous N-methylation of several peptide bonds in the presence of peptide bonds that were not to be methylated. As a model study, we investigated the synthesis of the antiproliferative depsipeptide, IB-01212. We used a pseudoproline to protect the non-methylated peptide bond during a simultaneous N-methylation with MeI-Ag[2]O. Using further manipulations including a dimerization/cyclization process, IB-01212 and its derivatives were successfully synthesized. A preliminary structure-activity relationship study demonstrated that the symmetric structure contributed to the potent cytotoxic activity of IB-01212

Stereoisomer-dependent conversion of dinaphthothienothiophene precursor films

Soluble precursor materials of organic semiconductors are employed for fabricating solution-processable thin film devices. While the so-called precursor approach has already been tried for various organic electronic devices such as transistors and solar cells, understanding of the conversion process in the film lags far behind. Here, we report that molecular aggregation of the precursor compound significantly influences the thermal conversion reaction in the film. For this study, two stereoisomers of a dinaphthothienothiophene (DNTT) precursor that are the endo- and exo-DNTT-phenylmaleimide monoadducts are focused on. The structural change during the thermal conversion process has been investigated by a combination of infrared spectroscopy and X-ray diffraction techniques. The results show that the endo-isomer is readily converted to DNTT in the film by heating, whereas the exo-isomer exhibits no reaction at all. This reaction suppression is found to be due to the self-aggregation property of the exo-isomer accompanying the intermolecular C–H⋯O interactions. This finding shows a new direction of controlling the on-surface reaction, as well as the importance of analyzing the film structure at the initial stage of the reaction

Design and synthesis of biotin- or alkyne-conjugated photoaffinity probes for studying the target molecules of PD 404182.

To investigate the mechanism of action of the potent antiviral compound PD 404182, three novel photoaffinity probes equipped with a biotin or alkyne indicator were designed and synthesized based on previous structure-activity relationship studies. These probes retained the potent anti-HIV activity of the original pyrimidobenzothiazine derivatives. In photoaffinity labeling studies using HIV-1-infected H9 cells (H9IIIB), eight potential proteins were observed to bind PD 404182

The metastasis suppressor KISS1 lacks antimetastatic activity in the C8161.9 xenograft model of melanoma.

The objective of this study was to use the established xenograft model of human melanoma (C8161.9) to test a pharmacological approach to the effect of the metastasis suppressor KISS1. A KISS1 analog was used to inhibit the metastatic development of C8161.9 cells in nude mice. Further experiments were performed to test the validity of the C8161.9 model and test the connection between KISS1 expression and loss of metastatic potential. New clones of C8161.9 cells were obtained, with or without KISS1 expression, and were tested for metastasis formation. The absence of benefit in survival with the KISS1 analog compared with PBS prompted us to revisit the C8161.9 model. We found that the cells expressing KISS1, used in the previous study and obtained by transfection and single-cell cloning, were defective for both formation of orthotopic tumors and metastases. In mixing experiments, these cells could not suppress orthotopic tumor growth of KISS1-negative C8161.9 cells, suggesting that the suppression of metastasis by C8161.9-KISS1 cells may be intrinsic to the selected clone rather than related to KISS1 expression. Isolation of clones from parental C8161.9 cells in soft agar yielded cell populations that phenotypically and genotypically mimicked the KISS1-positive clone. In addition, new clones expressing KISS1 did not show any decrease in metastatic growth. These data demonstrate the heterogeneity of cell types in the C8161.9 cell line and the high risk of artifact linked to single-cell selection. A different xenograft model will be necessary to evaluate the use of KISS1 analogs as antimetastatic therapy

Stargazer: Long-Term and Multiregional Measurement of Timing/ Geolocation-Based Cloaking

Malicious hosts have come to play a significant and varied role in today's cyber attacks. Some of these hosts are equipped with a technique called cloaking, which discriminates between access from potential victims and others and then returns malicious content only to potential victims. This is a serious threat because it can evade detection by security vendors and researchers and cause serious damage. As such, cloaking is being extensively investigated, especially for phishing sites. We are currently engaged in a long-term cloaking study of a broader range of threats. In the present study, we implemented Stargazer, which actively monitors malicious hosts and detects geographic and temporal cloaking, and collected 30,359,410 observations between November 2019 and February 2022 for 18,397 targets from 13 sites where our sensors are installed. Our analysis confirmed that cloaking techniques are widely abused, i.e., not only in the context of specific threats such as phishing. This includes geographic and time-based cloaking, which is difficult to detect with single-site or one-shot observations. Furthermore, we found that malicious hosts that perform cloaking include those that survive for relatively long periods of time, and those whose contents are not present in VirusTotal. This suggests that it is not easy to observe and analyze the cloaking malicious hosts with existing technologies. The results of this study have deepened our understanding of various types of cloaking, including geographic and temporal ones, and will help in the development of future cloaking detection methods

Design and synthesis of amidine-type peptide bond isosteres: application of nitrile oxide derivatives as active ester equivalents in peptide and peptidomimetics synthesis.

Amidine-type peptide bond isosteres were designed based on the substitution of the peptide bond carbonyl (C=O) group with an imino (C=NH) group. The positively-charged property of the isosteric part resembles a reduced amide-type peptidomimetic. The peptidyl amidine units were synthesized by the reduction of a key amidoxime (N-hydroxyamidine) precursor, which was prepared from nitrile oxide components as an aminoacyl or peptidyl equivalent. This nitrile oxide-mediated C-N bond formation was also used for peptide macrocyclization, in which the amidoxime group was converted to peptide bonds under mild acidic conditions. Syntheses of the cyclic RGD peptide and a peptidomimetic using both approaches, and their inhibitory activity against integrin-mediated cell attachment, are presented

Preoperative chemoradiotherapy for locally advanced low rectal cancer using intensity-modulated radiotherapy to spare the intestines: a single-institutional pilot trial

The irradiated volume of intestines is associated with gastrointestinal toxicity in preoperative chemoradiotherapy for rectal cancer. The current trial prospectively explored how much of the irradiated volume of intestines was reduced by intensity-modulated radiotherapy (IMRT) compared with 3-dimensional conformal radiotherapy (3DCRT) and whether IMRT might alleviate the acute gastrointestinal toxicity in this population. The treatment protocol encompassed preoperative chemoradiotherapy using IMRT plus surgery for patients with clinical T3–4, N0–2 low rectal cancer. IMRT delivered 45 Gy per 25 fractions for gross tumors, mesorectal and lateral lymph nodal regions, and tried to reduce the volume of intestines receiving 15 Gy (V₁₅ Gy) < 120 cc and V₄₅ Gy ≤ 0 cc, respectively, while keeping target coverage. S-1 and irinotecan were concurrently administered. Acute gastrointestinal toxicity, rates of clinical downstaging, sphincter preservation, local regional control (LRC) and overall survival (OS) were evaluated. Twelve enrolled patients completed the chemoradiotherapy protocol. The volumes of intestines receiving medium to high doses were reduced by the current IMRT protocol compared to 3DCRT; however, the predefined constraint of V15 Gy was met only in three patients. The rate of ≥ grade 2 gastrointestinal toxicity excluding anorectal symptoms was 17%. The rates of clinical downstaging, sphincter preservation, three-year LRC and OS were 75%, 92%, 92% and 92%, respectively. In conclusion, preoperative chemoradiotherapy using IMRT for this population might alleviate acute gastrointestinal toxicity, achieving high LRC and sphincter preservation; although further advancement is required to reduce the irradiated volume of intestines, especially those receiving low doses

Reducing variability among treatment machines using knowledge‐based planning for head and neck, pancreatic, and rectal cancer

PURPOSE: This study aimed to assess dosimetric indices of RapidPlan model-based plans for different energies (6, 8, 10, and 15 MV; 6- and 10-MV flattening filter-free), multileaf collimator (MLC) types (Millennium 120, High Definition 120, dual-layer MLC), and disease sites (head and neck, pancreatic, and rectal cancer) and compare these parameters with those of clinical plans. METHODS: RapidPlan models in the Eclipse version 15.6 were used with the data of 28, 42, and 20 patients with head and neck, pancreatic, and rectal cancer, respectively. RapidPlan models of head and neck, pancreatic, and rectal cancer were created for TrueBeam STx (High Definition 120) with 6 MV, TrueBeam STx with 10-MV flattening filter-free, and Clinac iX (Millennium 120) with 15 MV, respectively. The models were used to create volumetric-modulated arc therapy plans for a 10-patient test dataset using all energy and MLC types at all disease sites. The Holm test was used to compare multiple dosimetric indices in different treatment machines and energy types. RESULTS: The dosimetric indices for planning target volume and organs at risk in RapidPlan model-based plans were comparable to those in the clinical plan. Furthermore, no dose difference was observed among the RapidPlan models. The variability among RapidPlan models was consistent regardless of the treatment machines, MLC types, and energy. CONCLUSIONS: Dosimetric indices of RapidPlan model-based plans appear to be comparable to the ones based on clinical plans regardless of energies, MLC types, and disease sites. The results suggest that the RapidPlan model can generate treatment plans independent of the type of treatment machine