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Although cancer immunotherapy using immune checkpoint inhibitors (ICIs) has been recognized as one of the major treatment modalities for malignant diseases, the clinical outcome is not uniform in all cancer patients. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells that possess various strong immunosuppressive activities involving multiple immunocompetent cells that are significantly accumulated in patients who did not respond well to cancer immunotherapies. We reviewed the perspective of MDSCs with emerging evidence in this review. Many studies on MDSCs were performed in malignant diseases. Substantial studies on the participation of MDSCs on non-malignant diseases such as chronic infection and autoimmune diseases, and physiological roles in obesity, aging, pregnancy and neonates have yet to be reported. With the growing understanding of the roles of MDSCs, variable therapeutic strategies and agents targeting MDSCs are being investigated, some of which have been used in clinical trials. More studies are required in order to develop more effective strategies against MDSCs.

Supplemental Table 4. Nine cohorts of stage I, lung squamous cell carcinoma patients

Progression-free survival of responders (R) and non-responders (NR) in all subjects (combined test and validation cohorts).

Clinicopathological characteristics of study populations.

Supplemental Figure 1. Nomogram to predict 5-year survival rates for stage IA (A) or stage IB (B) lung adenocarcinoma separately. Each clinical variable (4-gene score, sex and age) is assigned a point value. The sum of those points can then be used to estimate probability of survival for 5-years.

Supplementary Figure Legends

Supplemental Table 1. Datasets considered for inclusion in the meta-analysis and the rationale for inclusion or exclusion.

Supplemental Table 2. Selected probes for each platform

Purpose: To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC).Experimental Design: The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR–based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis.Results: A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power.Conclusion: The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence. Clin Cancer Res; 20(18); 4784–93. ©2014 AACR.

Supplemental Table 3. Univariable and Multivariable Cox regression of a linear score for the 4-coding gene classifier in the combined cohorta of Stage I, adenocarcinoma patients

Supplementary Data. This excel file contains all of the data on stage I lung adenocarcinoma that was used for this manuscript. The second worksheet contains a description of the columns

Supplementary Figure 1 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

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Supplementary Figure 4 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

Supplementary Figure 3 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

Supplementary Table 1 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

Supplementary Figure 7 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

PDF file - 836K, Supplemental Figure 1: Overview of the study design for the identification of candidate coding genes, development and validation of the four coding gene classifier using five independent datasets. Supplemental Figure 2: Technical validation of the microarray experiments showing Pearson�s correlation between microarray expression values and qRT-PCR expression values for each gene across all tumors that were examined.Supplemental Figure 3: Kaplan-Meier survival curves according to tertiles of the four coding gene classifier in AJCC 6th edition stage I-II lung adenocarcinoma from five independent cohorts, including the Japan (n=199, relapse-free survival), US/Norway (n=92, cancer specific mortality), Directors� (n=378, overall survival), Bhattacharjee (n=100, overall survival) and Tomida (n=92, overall survival) cohorts. P-values were estimated by log-rank test for trend. Supplemental Figure 4: For survival analysis, miR-21 expression values as measured by nCounter miRNA assays were normalized to the average of the 5 most highly expressed microRNAs in tumor tissue, excluding miR-21 itself. Supplemental Figure 5: In the Japan cohort, the four coding gene classifier and the non-coding miR-21 classifier are each significantly associated with relapse-free survival.Supplemental Figure 6: In the US/Norway cohort, the four coding gene classifier and the non-coding miR-21 classifier are each significantly associated with relapse-free survival. Supplemental Figure 7: Estimation of miR-21 copies per cell in lung adenocarcinoma tissue by PCR-based absolute quantification. Supplemental Figure 8: Total RNA content per lung tumor cell was estimated at approximately 20pg per cell based on a series of total RNA extraction from serially diluted cultured lung adenocarcinoma cell lines A549 and NCI-H23. Supplemental Figure 9: Prognostic significance of BRCA1 expression in multiple cancer types. Supplemental Table 1. Characteristics of study populations of patients from public database. Supplemental Table 2. Univariate Cox regression analysis in the Japan cohort using microarray data (AJCC TNM 6th, Stage I, n=148). Supplemental Table 3. Univariate Cox Regression analysis of the expression of six genes.

Supplementary Figure 5 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

Supplementary Figure 2 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

Supplementary Figure 6 from Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence

Objective: The number of elderly people with coronavirus disease 2019 (COVID-19) is increasing. To reduce the risk of progression of COVID-19, Molnupiravir, an oral small molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2, was administered. The targets of administration were 29 elderly people aged over 80 years old (median 87 years old, range 80-100). We evaluated the efficacy and safety of treatment with Molnupiravir; oral administration was started within 24 hours after the onset of signs or symptoms in hospitalized elderly patients with at least one confirmed risk factor for severe COVID-19.Molnupiravir (800 mg) was administered twice daily for 5 days. Results: There were no deaths within 28 days, and the treatment was effective. Adverse events occurred in only 55% of the target patients within 7 days after oral administration, but only nausea was observed, and no serious side effects were observed; thus, the drug could be safely administered to elderly patients. Early treatment with Molnupiravir reduced the risk of death in elderly individuals at risk for COVID-19. TRN: ISRCTN79981540, Registration date: 15/07/2022

Objective: The number of elderly people with coronavirus disease 2019 (Covid-19) is increasing. In order to reduce the risk of progress of Covid-19, Molnupiravir, an oral small molecule antiviral prodrug active against severe acute respiratory syndrome coronavirus 2, was administered. The targets of administration were 29 elderly people over 80 years old (median 87 years old, range 80-100). We evaluated the efficacy and safety of treatment with Molnupiravir, which we had started oral administration within 24 hours after the onset of signs or symptoms in hospitalized elderly with at least one risk factor for Covid-19 disease confirmed in the laboratory. Molnupiravir 800 mg was administered twice daily for 5 days. Results: There was no death within 30 days and it was effective. Adverse events occurred only in 55% of target patients within 7 days after internal administration, but only nausea was observed, no serious side effects were observed, and thus the drug could be safely administered to the elderly. Early treatment with Molnupiravir reduced the risk of death in the elderly at risk for Covid-19.

Background Over 30% of the population of Okinawa Prefecture have a high body mass index. The incidence of hypertension and dyslipidaemia has also increased in recent years. We found that Ooitabi (Ficus pumila L.), a plant native to Okinawa, was useful for hypertension. During ancient times, the extracts of Ooitabi leaves were used for making Ishimaki tea in some areas of Okinawa Prefecture. The plants in Okinawa are rich in antioxidants, and four flavonoid glycosides, including rutin, have been identified in Ooitabi. Methods In the present study, we conducted clinical verification tests on the effects of drinking Ishimaki tea on outpatients with hypertension and dyslipidaemia. Of 3814 Japanese patients who underwent medical check‐ups in Okinawa, 38 individuals with high blood pressure, dyslipidaemia, liver dysfunction and gout visited our hospital as outpatients and were asked to drink Ishimaki tea. Results After 3 months, there were significant reductions in body mass index, systolic and diastolic blood pressure, total cholesterol, low‐density lipoprotein cholesterol, γ‐glutamyltrans peptidase, uric acid and ratio of blood vessel insulin resistance. Conclusions Ooitabi extract can lower blood pressure and improve lipid abnormalities and has likely contributed to the well‐known health and longevity of the population in Okinawa., Shisa is Okinawan lion (or lion dog) statue placed as talisman against evil at entrances, on roofs and on stone walls. Shisa holds Ooitabi leaves in its mouth (Fig. 2a).

Many human diseases ranging from cancer to hereditary disorders are caused by single-nucleotide mutations in critical genes. Repairing these mutations would significantly improve the quality of life for patients with hereditary diseases. However, current procedures for repairing deleterious single-nucleotide mutations are not straightforward, requiring multiple steps and taking several months to complete. In the current study, we aimed to repair pathogenic allele-specific single-nucleotide mutations using a single round of genome editing. Using high-fidelity, site-specific nuclease AsCas12a/Cpf1, we attempted to repair pathogenic single-nucleotide variants (SNVs) in disease-specific induced pluripotent stem cells. As a result, we achieved repair of the Met918Thr SNV in human oncogene RET with the inclusion of a single-nucleotide marker, followed by absolute markerless, scarless repair of the RET SNV with no detected off-target effects. The markerless method was then confirmed in human type VII collagen-encoding gene COL7A1. Thus, using this One-SHOT method, we successfully reduced the number of genetic manipulations required for genome repair from two consecutive events to one, resulting in allele-specific repair that can be completed within 3 weeks, with or without a single-nucleotide marker. Our findings suggest that One-SHOT can be used to repair other types of mutations, with potential beyond human medicine.

Ovarian cancer is the most common malignant disease leading to death among women. IL (interleukin)-17A is the most well-studied member of the IL-17 family, and has been demonstrated to play a critical role in host defenses against various microbial pathogens, as well as against tissue inflammation. T-helper (Th)17 cells that produce interleukin (IL)-17A are of particular importance, because IL-17A exerts a wide variety of biological functions, particularly related to inflammation and the resultant carcinogenesis, as well as immune suppression in patients with cancer, and IL-17A-targeted therapy has been proven to be effective in the treatment of some autoimmune diseases. The pathogenic features of Th17 and IL-17A cells in cancer are still controversial, and Th17 cells appear to promote disease progression, as well as be present in the vicinity of many types of malignant diseases. In cancer patients, MDSC (myeloid-derived suppressor cells), one of the major immunosuppressive immature cells, and VEGF (vascular endothelial growth factor) are reported to correlate each other and strongly connected to IL-17-driven inflammation and malnutrition. In the present review, the latest advances are presented about the basic features of IL-17A and Th17. The function of IL-17A has not been clarified especially in ovarian cancer. This review overview the basic features of IL-17A and the functions in ovarian cancer as well as in other malignant and non-malignant diseases. Increasing our understanding of the interactions between IL-17A and ovarian cancer could lead to new therapeutic strategies in oncology.

Human T-cell leukemia virus type 1 was isolated as the retrovirus to be identified in humans. Here, we focused on Ficus pumila L. as a factor that be effective against human T-cell leukemia virus type 1. The significant and novel findings is that symptoms of patients with drinking Ficus pumila L. extracts did not worsen despite a lack of aggressive pharmacotherapy against adult T-cell leukemia, a human T-cell leukemia virus type 1-associated myelopathy, or T-cell leukemia virus type 1 uveitis. Twenty-eight of the 194 inpatients who underwent showed high levels of human T-cell leukemia virus type 1.Among human T-cell leukemia virus type 1-infected patients, those who were administered Ficus pumila L. extracts had no human T-cell leukemia virus type 1-related symptoms, while those who were not administered Ficus pumila L. extracts had human T-cell leukemia virus type 1-related diseases and a significantly poorer prognosis. This suggests that the Ficus pumila L. extracts may show some utility against virus infection.

Body weight (BW) is regulated in age-dependent manner; it continues to increase during growth period, and reaches a plateau once reaching adulthood. However, its underlying mechanism remains unknown. Regarding such mechanisms in the brain, we here report that neural circuits from the hypothalamus (paraventricular nucleus: PVN) to the brainstem (dorsal vagal complex: DVC) suppress late-onset BW gain without affecting food intake. The genetic suppression of the PVN-DVC circuit induced BW increase only in aged rats, indicating that this circuit contributes to suppress the BW at a fixed level after reaching adulthood. PVN neurons in the hypothalamus were inactive in younger rats but active in aged rats. The density of neuropeptide Y (NPY) terminal/fiber is reduced in the aged rat PVN area. The differences in neuronal activity, including oxytocin neurons in the PVN, were affected by the application of NPY or its receptor inhibitor, indicating that NPY is a possible regulator of this pathway. Our data provide new insights into understanding age-dependent BW regulation.

Continuous blood pressure monitoring is essential in the management of patients in critical conditions, as well as those under anesthesia. However, continuous blood pressure monitoring requires insertion of a catheter into the radial artery. Thus, continuous noninvasive arterial blood pressure monitoring would be ideal.We designed and built a continuous noninvasive arterial blood pressure monitoring device with a pressure sensor diaphragm using microelectromechanical system technology, a square with 4 mm sides that were 0.4 mm thick. Comparisons between a continuous noninvasive arterial blood pressure monitoring device and a sphygmomanometer were carried out on 92 volunteers, and comparisons between noninvasive and invasive blood pressure monitoring were performed on three patients perioperatively at Fukushima Medical University Hospital.In the comparisons of arterial blood pressure measurements between a sphygmomanometer and our device, the differences became gradually greater over time after starting continuous monitoring in conscious participants. In the comparisons of arterial blood pressure measurements between the invasive and noninvasive methods in unconscious subjects under general anesthesia, the results of noninvasive monitoring were consistent with those of invasive arterial blood pressure monitoring.Continuous noninvasive arterial monitoring with a pressure sensor diaphragm using microelectromechanical system technology is a possible alternative to conventional invasive arterial pressure monitoring by an arterial catheter.

Background: It has been hypothesized that flavonoid ingestion stimulates immunity, promotes health, and prevents human illness. The aim of this analysis was to evaluate the association of the levels of immunoglobulin A (IgA) with the prevention of influenza infections and with the polyphenols contained in Okinawan vegetables. Methods: IgA, immunoglobulin G (IgG), immunoglobulin M (IgM), and soluble interleukin-2 receptor (sIL-2R) levels were measured in 44 outpatients who regularly ingested vegetables grown on Okinawa Island (200–300 g/day for ≥ 300 days/year) with no history of influenza infection and in 73 patients who ingested the vegetables irregularly or not at all with a history of influenza infection. Results: The patients who regularly ate Okinawan vegetables had higher IgA, IgG, and IgM levels than those who did not. On the other hand, patients who did not consume Okinawan vegetables and had influenza had lower IgA, IgG, and IgM levels. In addition, the IgA and IgG levels showed significant positive correlations with the sIL-2R levels in both groups. Conclusions: It may be beneficial to eat vegetables abundant in polyphenols every day. Secretory IgA antibodies are an important part of the immune defense against viral diseases. People who ingest Okinawan vegetables have high IgA levels and might be more likely to develop immunity against influenza RNA viruses.

Endochondral bone formation is fundamental for skeletal development. During this process, chondrocytes undergo multiple steps of differentiation and coordinated transition from a proliferating to a hypertrophic stage, which is critical to advance skeletal development. Here, we identified the transcription factor Dmrt2 (double-sex and mab-3 related transcription factor 2) as a Sox9-inducible gene that promotes chondrocyte hypertrophy in pre-hypertrophic chondrocytes. Epigenetic analysis further demonstrated that Sox9 regulates Dmrt2 expression through an active enhancer located 18 kb upstream of the Dmrt2 gene and that this enhancer’s chromatin status is progressively activated through chondrocyte differentiation. Dmrt2-knockout mice exhibited a dwarf phenotype with delayed initiation of chondrocyte hypertrophy. Dmrt2 augmented hypertrophic chondrocyte gene expression including Ihh through physical and functional interaction with Runx2. Furthermore, Dmrt2 deficiency reduced Runx2-dependent Ihh expression. Our findings suggest that Dmrt2 is critical for sequential chondrocyte differentiation during endochondral bone formation and coordinates the transcriptional network between Sox9 and Runx2., Koichiro Ono et al. report that Dmrt2 is a critical transcription factor for chondrocyte maturation during endochondral ossification. The study shows that Dmrt2 is the direct target of Sox9 and acts as a transcriptional coactivator of Runx2 providing novel insights into the transcription factor network during skeletal development.