The Impact of Continuous Use of Home Health Care Resources on End-of-Life Care at Home in Older Patients with Cancer: A Retrospective Cohort Study in Fukuoka, Japan.

This study aimed at examining the effect of continued use of home health care resources on end-of-life care at home in older patients with cancer. This retrospective cohort study was conducted using medical and long-term care claims data of 6435 older patients with cancer who died between April 2016 and March 2019 in Fukuoka Prefecture. The main explanatory variables were enhanced home care support clinics and hospitals (HCSCs), enhanced HCSCs with beds, conventional HCSCs, other HCSCs, and home visit nursing care. The covariates were sex, age, required level of care, and the Charlson Comorbidity Index. A logistic regression model was used. The results of the multilevel logistic regression analysis showed that the following were significantly associated with end-of-life care at home: use of enhanced HCSCs with beds (odds ratio, OR: 8.66; 95% confidence interval, CI: [4.31-17.40]), conventional HCSCs (OR: 5.78; 95% CI: [1.86-17.94]), enhanced HCSCs (OR: 4.44; 95% CI: [1.47-13.42]), home-visit nursing care (OR: 1.86; 95% CI: [1.42-2.44]), and a severe need for care (OR: 3.89; 95% CI: [2.92-5.18]). The results suggest that the continued use of home health care resources in older patients with cancer who require out-of-hospital care may lead to increased end-of-life care at home. Particularly, use of enhanced HCSCs with beds is most strongly associated with end-of-life care at home.

Acupuncture for cancer patients with nausea and vomiting: A protocol for systematic review and meta-analysis.

BACKGROUND: Nausea and vomiting are among the most common adverse effects experienced by cancer patients undergoing treatment worldwide. Their treatment with pharmacologic therapy can often be complicated by medication interactions and other unwanted side effects. The aim of this systematic review and meta-analysis protocol is to assess the effectiveness and safety of acupuncture therapy for treating nausea and vomiting in patients with cancer. METHODS: Three electronic databases and 2 clinical registry platforms will be searched from inception to May 2022: the MEDLINE via PubMed, Embase via Ovid, the Cochrane Central Register of Controlled Trials via the Cochrane Library, the World Health Organisation International Clinical Trials Registry Platform, and National Institutes of Health Clinical trials.gov. Search terms will include nausea, vomiting, cancer, and acupuncture. Two researchers will independently select studies, extract data and assess the risk of bias. The primary outcome will be the incidence of nausea and/or vomiting or other validated outcome measures. Meta-analysis will be carried out using RevMan V.5.4. The quality of evidence from randomized clinical trials will be evaluated with the Grading of Recommendations Assessment, Development and Evaluation System tool. RESULTS: The results will provide a high-quality synthesis of evidence for clinicians in the field of oncology. CONCLUSION: The conclusion is expected to provide evidence to determine whether acupuncture is an effective and safe treatment for cancer patients with nausea and vomiting.

Entelon® (Vitis vinifera Seed Extract) Prevents Cancer Metastasis via the Downregulation of Interleukin-1 Alpha in Triple-Negative Breast Cancer Cells.

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.

Quantifying Regional and Health Care Variations to Identify Ways to Improve Hemodialysis Service Quality and Survival Outcomes.

The authors examined variations in hemodialysis care and quantified the effect of these variations on all-cause mortality. Insurance claims data from April 1, 2017 to March 30, 2018 were reviewed. In total, 2895 hospital patients were identified, among whom 398 died from various causes. Controlling effects of the facility and secondary medical care areas, all-cause mortality was associated with older age, heart failure, malignancy, cerebral stroke, severe comorbidity, and the first and ninth centile of physician density. Multilevel analyses indicated a significant variation at facility level (σ22 0.27, 95% confidence interval: 0.09-0.49). Inclusion of all covariates in the final model significantly reduced facility-level variance. Physician density emerged as an important factor affecting survival outcome; thus, a review of workforce and resource allocation policies is needed. Better clinical management and standardized work processes are necessary to attenuate differences in hospital practice patterns.

Elucidating variations in outcomes among older end-stage renal disease patients on hemodialysis in Fukuoka Prefecture, Japan.

Variations in health care outcomes and services potentially indicate resource allocation inefficiency. Therefore, this study was conducted to examine variations in mortality and hospitalization cases among end-stage renal disease (ESRD) patients receiving hemodialysis (HD) care from medical facilities located in 13 secondary medical care areas (SMAs) of Fukuoka prefecture, Japan. The research was designed as a retrospective, cross-sectional study using insurance claims data. The subjects of the study were older patients (over 65 years old) insured by the Fukuoka prefecture's Latter-Stage Elderly Healthcare Insurance. Using an electronic claims database, we identified patients with chronic kidney disease (CKD) who had received HD care from April 1, 2017 to March 31, 2018. The CKD status was identified using International Classification of Disease, 10th revision code, and HD maintenance status was ascertained using specific insurance procedure codes. A total of 5,243 patients met our inclusion criteria and their records were subsequently reviewed. About 73% (n = 3,809) of patients had admission records during the period studied. Thus, the data regarding hospital length of stay (LOS) and admission costs were analyzed separately. Significant differences in terms of increased risks in hospitalization were evident in a number of SMAs. An increase in mortality risk due to heart failure and malignancy was observed in two separate SMAs. Also, analyzed LOS, total hospitalization cost, and cost per day according to SMAs showed statistically significant variations. The findings highlight the magnitude of the burden of CKD and ESRD in the community. The high prevalence of ESRD, associated mortality, and hospitalized HD patients signal the need for clinicians to assume broader roles in measures against chronic kidney disease through involvement in community awareness programs. To improve patient outcomes, improvement of regional health care provision, the level of medical care, and the development of existing human resources are needed.

Inhibition of platelet-derived growth factor receptor synergistically increases the pharmacological effect of tamoxifen in estrogen receptor α positive breast cancer.

The platelet-derived growth factor (PDGF) family, a complex and imperative group of proangiogenic factors, acts as strong cell growth chemokines and is essential for the progression of malignancy in humans. In the present study, it was observed that aberrant PDGFB expression is associated with survival rates in patients with estrogen receptor-positive (ER+) breast cancer unlike other subtypes, including PDGFA, PDGFC and PDGFD. Accordingly, the effect of specific PDGF receptor (PDGFR) inhibitors on ER-α+ breast cancer cells was investigated. To block the PDGF-BB signaling pathway, PDGFR inhibitors (sunitinib or ponatinib) were employed. Sunitinib and ponatinib were found to arrest the cell cycle at the G0-G1 phase. In addition, the two PDGFR inhibitors were revealed to significantly inhibit cell growth and decrease the expression of matrix metalloproteinase-1, which is one of the metastasis-related genes. Finally, the combined effects of the two PDGFR inhibitors with tamoxifen were investigated. The results demonstrated that the combination of two PDGFR inhibitors with tamoxifen inhibited the growth of cells more consistently, compared with the effect mediated by tamoxifen alone. Therefore, it is proposed that PDGFR inhibitors, including sunitinib and ponatinib, should be applied effectively to treat ER-α+ breast cancer.

Inhibition of platelet-derived growth factor C and their receptors additionally increases doxorubicin effects in triple-negative breast cancer cells.

Complex of platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of various cell types. Herein, it was found that aberrant PDGFC expression is closely associated with survival rates in triple-negative breast cancer (TNBC) patients. In addition, PDGFC expression was identified to be significantly increased in TNBC cells unlike other subtypes such as PDGFA, PDGFB, and PDGFD. Apparently, the effects of specific PDGF receptor (PDGFR) inhibitors such as sunitinib and ponatinib on HCC1806 and Hs578T TNBC cells were investigated. Both inhibitors decreased cell viability in a dose-dependent manner. In addition, the inhibitors completely inhibited cell growth in both the cell lines and decreased the expression of matrix metalloproteinase-1 (MMP-1), one of the metastasis-related genes. Cell migration was also decreased by the inhibitors. Finally, the combined effects of the inhibitors with doxorubicin (DOX) were investigated. The results showed that the combination of two PDGFR inhibitors with DOX inhibited the growth of cells and enhanced the apoptotic cell death more uniformly than DOX. Consequently, it is demonstrated that PDGFR inhibitors, sunitinib and ponatinib hold the potential for effective treatment of TNBC.

New-onset nontuberculous mycobacterial pulmonary disease in bronchiectasis: tracking the clinical and radiographic changes.

BACKGROUND: The close association between bronchiectasis and nontuberculous mycobacterial pulmonary disease (NTM-PD) is well-known. However, the clinical impact of subsequent new-onset NTM-PD in bronchiectasis patients has not been elucidated. The aim of this study is to investigate the clinical courses and radiographic changes of patients with bronchiectasis in whom NTM-PD subsequently developed. METHODS: A total of 221 patients with bronchiectasis who had participated in a non-NTM bronchiectasis cohort between July 1st 2011 and August 31st 2019 at Seoul National University Hospital were included in this study. The data of patients in whom NTM-PD developed during this observation period were analyzed; specifically, changes in the Bronchiectasis Severity Index (BSI) and lesions on computerized tomography (CT) scan of the chest arising during the observation period. RESULTS: During the observation period, NTM was isolated from 35 patients. A total of 31 patients (14.0%) satisfied the diagnostic criteria of NTM-PD. The median time from enrollment in the cohort to the development of subsequent NTM-PD was 37 months (Interquartile range [IQR], 18-78 months). Mycobacterium avium complex was the most common pathogen (80.6%). Twelve patients underwent antibiotic treatment for NTM-PD with a median interval of 20 months (IQR, 13-30) from the time of NTM-PD diagnosis. When NTM-PD developed, the severity and extent of bronchiectasis, cellular bronchiolitis, and the extent of nodules worsened on CT scans, while BSI did not change. CONCLUSIONS: NTM-PD can develop in previously negative bronchiectasis patients. It is associated with worsening radiographic lesions. Active screening of non-NTM bronchiectasis patients for new-onset NTM infection should be considered, especially if radiographic findings worsen. The BSI is not a reliable predictor of new-onset NTM-PD. TRIAL REGISTRATION: This study was performed at Seoul National University Hospital ( NCT01616745 ).

WNT5A augments cell invasiveness by inducing CXCL8 in HER2-positive breast cancer cells.

WNT5A is abnormally increased in a variety of cancers including breast cancer and has an adverse effect on the prognosis. However, the biological function of WNT5A is not fully known in HER2-positive (HER2+) breast cancer. Using public clinical data, we analyzed disease-free survival (DFS) and distant metastasis-free survival (DMFS). Here, we found that abnormal WNT5A induction is a correlation with the poor prognosis of HER2+ breast cancer. WNT5A expression was also decreased by pan-HER inhibitor neratinib but not by trastuzumab. In addition, WNT5A augmented cell invasiveness of HER2+ breast-cancer cells. To find WNT5A-induced metastatic-related factors, we did a human cytokine array. The levels of GM-CSF and CXCL8 were significantly increased by WNT5A. CXCL8 also accelerated cell invasiveness in HCC1954 breast-cancer cells. The expression of CXCL8 induced by WNT5A has been significantly reduced by MEK inhibitor, binimetinib. Finally, we studied the effect of CXCR2 antagonist, SB225002, to verify the relevance of CXCL8 in WNT5A-induced cell invasion. As expected, we found that WNT5A-induced cell invasion is completely inhibited by SB225002. Taken together, we have demonstrated that WNT5A directly mediates cell invasion through the induction of CXCL8 and ultimately affects the survival rate of HER2+ breast cancer.

Cur2004-8, a synthetic curcumin derivative, extends lifespan and modulates age-related physiological changes in Caenorhabditis elegans.

Curcumin, a compound found in Indian yellow curry, is known to possess various biological activities, including anti-oxidant, anti-inflammatory, and anti-cancer activities. Cur2004-8 is a synthetic curcumin derivative having symmetrical bis-alkynyl pyridines that shows a strong anti-angiogenic activity. In the present study, we examined the effect of dietary supplementation with Cur2004-8 on response to environmental stresses and aging using Caenorhabditis elegans as a model system. Dietary intervention with Cur2004-8 significantly increased resistance of C. elegans to oxidative stress. Its anti-oxidative-stress effect was greater than curcumin. However, response of C. elegans to heat stress or ultraviolet irradiation was not significantly affected by Cur2004-8. Next, we examined the effect of Cur2004-8 on aging. Cur2004-8 significantly extended both mean and maximum lifespan, accompanying a shift in time-course distribution of progeny production. Age-related decline in motility was also delayed by supplementation with Cur2004-8. In addition, Cur2004-8 prevented amyloid-beta-induced toxicity in Alzheimer's disease model animals which required a forkhead box (FOXO) transcription factor DAF-16. Dietary supplementation with Cur2004-8 also reversed the increase of mortality observed in worms treated with high-glucose-diet. These results suggest that Cur2004-8 has higher anti-oxidant and anti-aging activities than curcumin. It can be used for the development of novel anti-aging product.

Nontuberculous mycobacterial pulmonary disease diagnosed by two methods: a prospective cohort study.

BACKGROUND: Microbiological criteria for diagnosing nontuberculous mycobacterial pulmonary disease (NTM-PD) include positive culture results from at least two separately expectorated sputum specimens or one bronchial washing or lavage. However, the clinical similarities and differences between patients diagnosed by these two methods remain unclear. We compared clinical features and prognoses of patients with NTM-PD diagnosed from both specimen types. METHODS: We analysed data from patients who participated in the Seoul National University Hospital NTM-PD cohort ( ClinicalTrials.gov identifier: NCT01616745). Baseline demographics, symptoms, radiographic findings, disease progression, and treatment responses were summarized and compared between patients diagnosed from sputum specimens and patients diagnosed from bronchoscopic specimens. RESULTS: Three hundred forty-seven patients were included in the analyses. Of these, 279 (80.4%) were diagnosed from two separately expectorated sputum specimens, and 68 (19.6%) were diagnosed from bronchoscopic specimens. Patients diagnosed from sputum specimens had more frequent and severe cough, sputum, postnasal drip, and high St. George's Respiratory Questionnaire scores. However, the extent and severity of the radiographic lesions, disease progression, and treatment responses were similar for both groups. Further analysis based on the following three groups (sputum culture positive, sputum culture negative/bronchoscopy, and scanty sputum/bronchoscopy groups) suggested that the scanty sputum/bronchoscopy group appeared to have the worst prognosis in terms of both time to progression and time to culture conversion. CONCLUSIONS: Although some symptoms and quality of life were worse in patients with NTM-PD diagnosed from sputum specimens, their prognoses were similar to those of patients diagnosed by bronchoscopic specimen. We recommend bronchoscopic sampling for patients in whom NTM-PD is suspected clinically or radiographically, especially those who have no or scanty sputum.

1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of C. elegans by down-regulating PAK1 at nM levels.

PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic/ageing kinase, and its dysfunction extends the healthy lifespan of C. elegans by activating HSP16 gene. 15K is a highly cell-permeable 1,2,3-triazolyl ester of ketorolac that down-regulates both PAK1 and its down-stream COX-2 in R- and S-forms, respectively. 15K is 500-5,000 times more potent than ketorolac, an old pain-killer, inhibiting the growth of cancer cell lines with IC50 ranging 5-24 nM. Scores of natural and synthetic PAK1-blockers have been shown to extend the lifespan of small animals such as C. elegans, but none of them has been effective at nM levels. Thus, we examined in vivo effect of 15K at nM levels on the survival rate of C. elegans with or without heat-shock. Like the PAK1-deficient mutant, 15K (at 50 nM)-treated worm significantly lives longer, is far more heat-resistant and less productive (fertile) than the non-treated counterpart, with an increased expression of HSP16 gene. 15K has been proven to be among the most potent anti-cancerous and longevity-promoting PAK1-blockers, and therefore has a potential to treat a variety of solid tumours without severe side effect.

Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes.

Replication fork maintenance pathways preserve chromosomes, but their faulty application at nonallelic repeats could generate rearrangements causing cancer, genomic disorders and speciation. Potential causal mechanisms are homologous recombination and error-free postreplication repair (EF-PRR). Homologous recombination repairs damage-induced DNA double-strand breaks (DSBs) and single-ended DSBs within replication. To facilitate homologous recombination, the recombinase RAD51 and mediator BRCA2 form a filament on the 3' DNA strand at a break to enable annealing to the complementary sister chromatid while the RecQ helicase, BLM (Bloom syndrome mutated) suppresses crossing over to prevent recombination. Homologous recombination also stabilizes and restarts replication forks without a DSB. EF-PRR bypasses DNA incongruities that impede replication by ubiquitinating PCNA (proliferating cell nuclear antigen) using the RAD6-RAD18 and UBC13-MMS2-RAD5 ubiquitin ligase complexes. Some components are common to both homologous recombination and EF-PRR such as RAD51 and RAD18. Here we delineate two pathways that spontaneously fuse inverted repeats to generate unstable chromosomal rearrangements in wild-type mouse embryonic stem (ES) cells. Gamma-radiation induced a BLM-regulated pathway that selectively fused identical, but not mismatched, repeats. By contrast, ultraviolet light induced a RAD18-dependent pathway that efficiently fused mismatched repeats. Furthermore, TREX2 (a 3'→5' exonuclease) suppressed identical repeat fusion but enhanced mismatched repeat fusion, clearly separating these pathways. TREX2 associated with UBC13 and enhanced PCNA ubiquitination in response to ultraviolet light, consistent with it being a novel member of EF-PRR. RAD18 and TREX2 also suppressed replication fork stalling in response to nucleotide depletion. Interestingly, replication fork stalling induced fusion for identical and mismatched repeats, implicating faulty replication as a causal mechanism for both pathways.

RAD51 mutants cause replication defects and chromosomal instability.

RAD51 is important for restarting stalled replication forks and for repairing DNA double-strand breaks (DSBs) through a pathway called homology-directed repair (HDR). However, analysis of the consequences of specific RAD51 mutants has been difficult since they are toxic. Here we report on the dominant effects of two human RAD51 mutants defective for ATP binding (K133A) or ATP hydrolysis (K133R) expressed in mouse embryonic stem (ES) cells that also expressed normal mouse RAD51 from the other chromosome. These cells were defective for restarting stalled replication forks and repairing breaks. They were also hypersensitive to camptothecin, a genotoxin that generates breaks specifically at the replication fork. In addition, these cells exhibited a wide range of structural chromosomal changes that included multiple breakpoints within the same chromosome. Thus, ATP binding and hydrolysis are essential for chromosomal maintenance. Fusion of RAD51 to a fluorescent tag (enhanced green fluorescent protein [eGFP]) allowed visualization of these proteins at sites of replication and repair. We found very low levels of mutant protein present at these sites compared to normal protein, suggesting that low levels of mutant protein were sufficient for disruption of RAD51 activity and generation of chromosomal rearrangements.

Molecular cloning and characterization of chicken orphan nuclear receptor cTR2.

Orphan nuclear receptors belong to the nuclear receptor superfamily of liganded transcription factors, whose ligands either do not exist or remain to be identified. We report here the cloning and characterization of the chicken orphan nuclear receptor, cTR2 (chicken testicular receptor 2). The cTR2 gene encodes a protein of 569 amino acids which shows approximately 72% overall identity with TR2 (NR2C1) and 95% identity in the DNA-binding domain (DBD). The cTR2 gene is expressed in almost all adult tissues and embryonic stages examined unlike its mammalian relative TR2, which is specifically expressed in testis. Electrophoretic mobility shift assays demonstrate that cTR2 binds the canonical direct repeat DNA recognition sequences spaced by one, four, and five nucleotides (DR1, DR4, and DR5), and in consistence with the results with canonical DNA-binding sequences, cTR2 forms specific DNA-protein complex with chicken phenobarbital response elements containing DR4 motifs. Both in vitro and in vivo interaction studies demonstrate that cTR2 forms homodimer. Moreover, transient transfection studies reveal its capability to transactivate canonical DR1, DR4, and DR5 sequences and the constitutive activity of cTR2 is mapped to the N-terminal region of this orphan receptor. Finally, cTR2 represses transactivation of estrogen receptor in a dose-dependent manner.