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Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.

Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor

The study aims to explore how 18 M.A. TESOL students, who are prospective or experienced ESL/EFL teachers, perceive poetry writing in a second language. A qualitative interview-based design was utilized. Following Iida’s (2012a) analytical framework in examining EFL students’ perceptions toward writing haiku in English, this current study investigates 18 prospective ESL/EFL teachers’ perspectives through the lens of difficulty, value, emotion, and attitude. In order to validate the coding of the interviews, the intraclass correlation coefficient (ICC) test was computed among three interview coders including the primary researcher, which yields a great agreement rate at .86. The results indicate that while these prospective ESL/EFL teachers understand writing poetry in a second language involves various difficulties, they acknowledge the values of utilizing poetry writing in second language classrooms. The results also show that writing poetry in a second language contains both positive and negative emotions, but positive ones are more frequently addressed. Most importantly, the data suggests that writing poetry in a second language is considered as an applicable practice in ESL/EFL language classrooms.

Aim Elderly nursing home residents are often malnourished or at risk of malnutrition. Family members often visit residents during mealtimes, which might be an ideal opportunity for interventions targeted at improving the nutritional status of older residents. Therefore, this study aimed to explore motivations behind family member visits with nursing home residents during mealtime in Taiwan. Methods This phenomenological study was conducted with family members of residents from four nursing homes in Taiwan. Participants were purposively sampled. Data were collected with individual face-to-face interviews from 18 family members. Data from transcribed audio-recorded interviews were analyzed using the approach of van Manen. Results Analysis of the interview data identified the essence of motivations underlying family members' visits to nursing home residents during mealtimes, which we termed "tailoring homely meals." This referred to providing food tailored to residents' needs, providing a comforting family atmosphere, assisting residents during mealtime, and monitoring food consumption. Conclusions The motivations of family members to visit during mealtime could guide healthcare professionals working with East Asian populations in developing interventions to reduce the possibility of malnutrition, while also improving their quality of life. We recommend providing the following for nursing home residents: a nutritious and balanced diet, supporting their independence and ability to feed themselves, and encouraging involvement of family members during mealtimes.

A structure-based virtual screening strategy, comprising homology modeling, ligand-support binding site optimization, virtual screening, and structure clustering analysis, was developed and used to identify novel tryptophan 2,3-dioxygenase (TDO) inhibitors. Compound 1 (IC50 = 711 nM), selected by virtual screening, showed inhibitory activity toward TDO and was subjected to structural modifications and molecular docking studies. This resulted in the identification of a potent TDO selective inhibitor (11e, IC50 = 30 nM), making it a potential compound for further investigation as a cancer therapeutic and other TDO-related targeted therapy.

Indoleamine 2,3-dioxygenase is a heme-containing enzyme implicated in the down regulation of the anti-tumor immune response, and considered a promising anti-cancer drug target. Several pharmaceutical companies, including Pfizer, Merck, and Bristol-Myers Squibb, are known to be in pursuit of IDO inhibitors, and Incyte recently reported good results in the phase II clinical trial of the IDO inhibitor Epacadostat. In previous work, we developed a series of IDO inhibitors based on a sulfonylhydrazide core structure, and explored how they could serve as potent IDO inhibitors with good drug profiles. Herein, we disclose the development of the 4-bromophenylhydrazinyl benzenesulfonylphenylurea 5k, a potent IDO inhibitor which demonstrated 25% tumor growth inhibition in a murine CT26 syngeneic model on day 18 with 100 mg/kg oral administration twice daily, and a 30% reduction in tumor weight. Pharmacodynamic testing of 5k found it to cause a 25% and 21% reduction in kyn/trp ratio at the plasma and tumor, respectively. In the CT26 tumor model, 5k was found to slightly increase the percentage of CD3+ T cells and lymphocyte responsiveness, indicating that 5k may have potential in modulating anti-tumor immunity. These data suggest 5k to be worthy of further investigation in the development of anti-tumor drugs.

The San Diego Biodiversity Project introduces undergraduate students at four different 2- and 4-year schools to a short-term research experience (SRE) that was implemented as a module in the last third of a traditional laboratory course. The study assesses the qualities of this SRE for students using three different methods. Twenty-one participants were interviewed about their experiences in the traditional and research components of their course. In a repeated-measures design, 124 participants took the Persistence in the Sciences (PITS) survey immediately before and after their participation in the SRE. Finally, using a propensity score matching technique, PITS survey results for SRE students were compared with those for students in a course-based research experience (CRE). Student perceptions of the traditional lab and the SRE are different—students appreciate learning basic processes and procedures in the traditional lab, but they express having personal investment in and a sense of participating in science in the SRE. Significant increases were found for the variable of Project Ownership in the SRE condition over the traditional lab, but SRE outcomes were lower than CRE outcomes. Although the SRE may not provide the benefits of a CRE, it is a serious option for expanding access to authentic research.

Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.

Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.

Radical cyclizations of acylsilanes with radicalphilic pendant introduced on silicon proceeded in a tandem fashion to give spiro products containing a cyclic silyl ether skeleton. Because the alkoxysilyl group can be replaced with a hydroxy group through oxidation, the spiro silyl ethers can be converted into diols. In the case with a radical intermediate carrying 2-oxa-3-sila-6-heptenyl skeleton, products derived from 1,7-endo cyclization were obtained in good yields.