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Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in one-carbon metabolism. The MTHFD2 gene is upregulated in various cancers but very low or undetectable in normal proliferating cells, and therefore a potential target for cancer treatment. In this study, we present the structure of MTHFD2 in complex with xanthine derivative 15, which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by 15. Allosteric inhibitors often provide good selectivity and, indeed, xanthine derivatives are highly selective for MTHFD2. Moreover, several conformational changes were observed upon the binding of 15, which impeded the binding of the cofactor and phosphate to MTHFD2. To the best of our knowledge, this is the first study to identify allosteric inhibitors targeting the MTHFD family and our results would provide insights on the inhibition mechanism of MTHFD proteins and the development of novel inhibitors.

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

Early integration of palliative care for terminally ill cancer and non-cancer patients improves quality of life. However, there are sparse data on results of palliative care consultation services (PCCS) between cancer and non-cancer patients. In this 9-year observational study, data were collected from the Hospice-Palliative Clinical Database (HPCD) of Taichung Veterans General Hospital (TCVGH). Terminally ill cancer and non-cancer patients who received PCCS during 2011 to 2019 were enrolled. Trend analysis was performed to evaluate differences in outcomes of PCCS, including duration of PCCS, the awareness of disease of patients and families before and after PCCS, status of PCCS termination, and DNR declaration before and after PCCS among cancer and non-cancer patients throughout study period. In total, 5223 cancer patients and 536 non-cancer patients received PCCS from 2011 to 2019. The number of people who received PCCS increased stably over the decade, both for cancer and non-cancer patients. The average duration of PCCS for cancer and non-cancer patients was 21.4 days and 18.4 days, respectively. Compared with non-cancer patients, cancer patients had longer duration of PCCS, less DNR declaration (82% vs. 98%, respectively), and more transfers to the palliative care unit (17% vs. 11%, respectively), or for palliative home care (12% vs.8%, respectively). Determinants of late referral to PCCS includes age (OR 0.992, 95% CI 0.987–0.996), DNR declaration after PCCS (OR 1.967, 95% CI 1.574–2.458), patients’ awareness after PCCS (OR 0.754, 95% CI 0.635–0.895), and status of PCCS termination. This 9-year observational study showed that the trend of PCCS among cancer and non-cancer patients had changed over the duration of the study, and early integration of PCCS to all patients is essential for both cancer and non-cancer patients.

Palliative care has the ability to relieve both physical discomfort and psychological distress in terminally ill patients. However, unexpected death may still occur in palliative care settings. This study aimed to utilize Palliative Care Outcomes Collaboration (PCOC) data to better determine any associated factors which may surround unexpected death in palliative care settings. Data were extracted from the PCOC database by the palliative care team within Taichung Veterans General Hospital (TCVGH). Data of deceased patients were extracted during the period from January 2021 to December 2021 from multiple palliative care settings. The deaths of patients whose last recorded palliative phase was 1–3 were defined as unexpected. A total of 280 deceased patients were included, with mean age at death being 67.73, 61% being male, and 83.2% cancer patients. We discovered that shortness of breath, as assessed by the Symptom Assessment Scale (SAS), decreased risk of unexpected death (OR: 0.91, 95% CI: 0.84–0.98), while impending death discharge (OR: 3.93, 95% CI: 1.20–12.94) and a higher Australia-modified Karnofsky performance status (AKPS) score (OR: 1.15, 95% CI: 1.10–1.21) were associated with unexpected death. Thus, medical staff must inform the family of patients early on regarding any risk factors surrounding unexpected death to help everyone involved be prepared in advance.

Backgrounds Early integration of palliative care for terminally ill non-cancer patients improves quality of life. However, there are scanty data on Palliative Care Consultation Service (PCCS) among non-cancer patients. Methods In this 9-year observational study Data were collected from the Hospice-Palliative Clinical Database (HPCD) of Taichung Veterans General Hospital (TCVGH). Terminally ill non-cancer patients with 9 categories of diagnoses who received PCCS during 2011 to 2019 were enrolled. Trend analysis was performed to evaluate differences in categories of diagnosis throughout study period, duration of PCCS, patient outcomes, DNR declaration, awareness of disease by patients and families before and after PCCS. Results In total, 536 non-cancer patients received PCCS from 2011 to 2019 with an average age of 70.7 years. The average duration of PCCS was 18.4 days. The distributions of age, gender, patient outcomes, family’s awareness of disease before PCCS, and patient’s awareness of disease after PCCS were significantly different among the diagnoses. Organic brain disease and Chronic kidney disease (CKD) were the most prevalent diagnoses in patients receiving PCCS in 2019. For DNR declaration, the percentage of patients signing DNR before PCCS remained high throughout the study period (92.8% in 2019). Patient outcomes varied according to the disease diagnoses. Conclusion This 9-year observational study showed that the trend of PCCS among non-cancer patients had changed over the duration of the study. An increasing number of terminally ill non-cancer patients received PCCS during late life, thereby increasing the awareness of disease for both patients and families, which would tend to better prepare terminally ill patients for end-of-life as they may consider DNR consent. Early integration of PCCS into ordinary care for terminally non-cancer patients is essential for better quality of life.

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.

The purpose of this study is to determine the possible correlation between the do-not-resuscitate (DNR) status and the prescribed use of systemic strong opioid analgesics (SSOA) among patients with terminal cancer in Taiwan. This retrospective cross-sectional study used data from a single tertiary care medical center. We identified patients with terminal cancer who died after signing a DNR order between 2008 and 2016. Subsequently, we reviewed their clinical characteristics, DNR consent type, survival time after DNR declaration, and SSOA dose. Of the 4123 patients enrolled for this study, 1380 (33.5%) had received SSOA before DNR and 2742 (66.5%) had received SSOA after DNR (p

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 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.

Background: Some patients who receive hospice home care still end up dying in hospital. The significance of the variables possibly affecting the place of death in patients with terminal cancer who received hospice home care was examined. Methods: Retrospective study. Results: Four hundred and thirty-nine patients were enrolled in this study. In all, 60.8% of the patients died at home and 39.2% of the patients died in hospital. Multiple logistic regression analysis revealed that preferred place of death was the prior factor associated with home death, followed by average days of rehospitalization, education level, distance between home and hospital, and age. Conclusions: For a better hospice care service, it is essential to inquire patients or their relatives on preferred place of death while concerning the influences of other factors.