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1.
J Obstet Gynaecol Res ; 50(7): 1182-1191, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38697202

RESUMEN

AIM: Quality of care is important to reduce disease progression, and improve both survival and quality of life. The Japan Society of Gynecologic Oncology has published treatment guidelines to promote standardized high-quality care for ovarian cancer in Japan. We developed quality indicators based on the guideline recommendations and used them on large datasets of health service use to examine the quality of ovarian cancer care. METHODS: A panel of experts developed the indicators using a modified Delphi method. Adherence to each indicator was evaluated using data from a hospital-based cancer registry of patients diagnosed in 2018. All patients receiving first-line treatment at participating facilities were included. The adherence rates were returned to participating hospitals, and reasons for nonadherence were collected. A total of 580 hospitals participated, and the study examined the care received by 6611 patients with ovarian cancer and 1879 with borderline tumors using 11 measurable quality indicators. RESULTS: The adherence rate ranged from 22.6% for "Estrogen replacement within 6 months of operation" to 93.5% for "Bleomycin, etoposide, and cisplatin for germ cell tumor more than Stage II." Of 580 hospitals, 184 submitted the reasons for nonadherence. CONCLUSIONS: The quality of ovarian cancer care should be continuously assessed to encourage the use of best practices. These indicators may be a useful tool for this purpose.


Asunto(s)
Neoplasias Ováricas , Indicadores de Calidad de la Atención de Salud , Calidad de la Atención de Salud , Humanos , Femenino , Neoplasias Ováricas/terapia , Japón , Calidad de la Atención de Salud/normas , Adhesión a Directriz/estadística & datos numéricos
2.
J Cachexia Sarcopenia Muscle ; 15(3): 907-918, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38533539

RESUMEN

BACKGROUND: Recent studies have indicated the importance of muscle quality in addition to muscle quantity in sarcopenia pathophysiology. Intramuscular adipose tissue (IMAT), which originates from mesenchymal progenitors (MPs) in adult skeletal muscle, is a key factor affecting muscle quality in older adults, suggesting that controlling IMAT formation is a promising therapeutic strategy for sarcopenia. However, the molecular mechanism underlying IMAT formation in older adults has not been clarified. We recently found that the vitamin D receptor (VDR) is highly expressed in MPs in comparison to myotubes (P = 0.028, N = 3), indicating a potential role of vitamin D signalling in MPs. In this study, we aimed to clarify the role of vitamin D signalling in MP kinetics, with a focus on adipogenesis. METHODS: MPs isolated from mouse skeletal muscles were subjected to adipogenic differentiation conditions with or without vitamin D (1α,25(OH)2D3, 100 nM) for 7 days, and adipogenicity was evaluated based on adipogenic marker expression. For in vivo analysis, tamoxifen-inducible MP-specific VDR-deficient (VdrMPcKO) mice were newly developed to investigate whether lack of vitamin D signalling in MPs is involved in IMAT formation. To induce muscle atrophy, VdrMPcKO male mice were subjected to tenotomy of the gastrocnemius muscle, and then muscle weight, myofibre cross-sectional area, adipogenic marker expression, and fatty infiltration into the muscle were evaluated at 3 weeks after operation (N = 3-4). In addition, a vitamin D-deficient diet was provided to wild-type male mice (3 and 20 months of age, N = 5) for 3 months to investigate whether vitamin D deficiency causes IMAT formation. RESULTS: Vitamin D treatment nearly completely inhibited adipogenesis of MPs through Runx1-mediated transcriptional modifications of early adipogenic factors such as PPARγ (P = 0.0031) and C/EBPα (P = 0.0027), whereas VDR-deficient MPs derived from VdrMPcKO mice differentiated into adipocytes even in the presence of vitamin D (P = 0.0044, Oil-Red O+ area). In consistency with in-vitro findings, VdrMPcKO mice and mice fed a vitamin D-deficient diet exhibited fat deposition in atrophied (P = 0.0311) and aged (P = 0.0216) skeletal muscle, respectively. CONCLUSIONS: Vitamin D signalling is important to prevent fate decision of MPs towards the adipogenic lineage. As vitamin D levels decline with age, our data indicate that decreased vitamin D levels may be one of the causes of IMAT formation in older adults, and vitamin D signalling may be a novel therapeutic target for sarcopenia.


Asunto(s)
Células Madre Mesenquimatosas , Músculo Esquelético , Receptores de Calcitriol , Transducción de Señal , Vitamina D , Animales , Ratones , Vitamina D/metabolismo , Vitamina D/farmacología , Células Madre Mesenquimatosas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Masculino , Receptores de Calcitriol/metabolismo , Tejido Adiposo/metabolismo , Adipogénesis , Modelos Animales de Enfermedad , Diferenciación Celular
3.
Yonago Acta Med ; 67(1): 9-21, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38371280

RESUMEN

Background: Clinical nursing competence includes ethics, cooperation with other professionals, and management, in addition to nursing abilities and responding per situation. Therefore, it may vary depending on one's experience and the work environment. However, there is a lack of studies exploring the competence for different experience levels. Therefore, this study aimed to clarify the association between clinical nursing competence and the work environment by experience groups. Methods: Anonymous self-administered questionnaire surveys were conducted on 717 nurses in regional core hospitals from December 2017 to March 2018. Clinical nursing competence was measured using the Clinical Nursing Competence Self-Assessment Scale (CNCSS). Association of CNCSS with experience and work environment was examined. Results: Responses from 231 nurses with 1-10 years of experience were analyzed. Compared with those in the 2-year experience group, those in the 3-5- and 6-10-year experience groups assessed their "planned development of nursing care" and "assessment of care" competencies to be higher. Additionally, compared with those in the 2-year experience group, those in the 6-10-year experience group assessed their "clinical judgment" and "care coordination" competencies to be higher. Nurses with 1 year of experience showed significant positive correlations between clinical nursing competence and "good interpersonal relationship," "clarity about the organization's vision," and "ease of taking time off"; and those with 6-10 years of experience showed significant positive correlations between clinical nursing competence and "support from superiors and senior coworkers" and "established and easily accessible support system for taking time off for childcare and caregiving." Conclusion: The relationship between clinical nursing competence and the work environment differed according to years of experience. Interventions to improve clinical nursing competence should be developed for each experience group considering the associations.

4.
Life Sci Alliance ; 6(11)2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37673445

RESUMEN

Vitamin D receptor (VDR) is essential for hair follicle homeostasis as its deficiency induces hair loss, although the mechanism involved remains unknown. Our research shows that, in Vdr-knockout mice, the hair cycle is halted during the catagen stage, preceding alopecia. In addition, in Vdr-knockout hair follicles, epithelial strands that normally regress during the catagen phase persist as "surviving epithelial strands." Single-cell RNA sequencing analysis suggests that these surviving epithelial strands are formed by cells in the lower part of the hair follicle. These findings emphasize the importance of the regression phase in hair follicle regeneration and establish VDR as a regulator of the catagen stage.


Asunto(s)
Folículo Piloso , Receptores de Calcitriol , Animales , Ratones , Muerte Celular , Homeostasis , Ratones Noqueados , Receptores de Calcitriol/genética
5.
J Gastroenterol Hepatol ; 38(7): 1107-1115, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37278369

RESUMEN

BACKGROUND: Vedolizumab (VDZ) is a humanized monoclonal antibody that binds to α4ß7 integrin expressed in T-lymphocytes and is gut selective. Few studies have evaluated the safety and efficacy of VDZ in pediatric ulcerative colitis (UC) patients, especially from Asia. METHODS: A longitudinal multicenter retrospective study was conducted at 10 Japanese tertiary medical institutions. Patients aged ≤18 years old who received VDZ for UC between January 2019 and July 2021 were enrolled. Information on the clinical characteristics, prior/concomitant treatment, and safety during the observation period was collected. RESULTS: The data obtained from 48 patients (males, n = 30; females, n = 18) were analyzed. The median age at VDZ induction was 14 (range 4-18) years old. VDZ was indicated in 73% of patients as switching from previous biologics due to primary failure, loss of response, and adverse events (AEs) and was the first biologic in 27%. Remission was achieved or maintained at weeks 14, 30, and 54 in 79.2%, 75.0%, and 65.8% of patients, respectively. There were no significant differences between the number of previous biologics exposures and VDZ effectiveness. The hematocrit, serum albumin concentrations, and erythrocyte sedimentation rate (ESR) at baseline differed significantly by VDZ effectiveness. Nine AEs, including infusion reaction, were noted in seven (14.3%) patients. There were no severe AEs related to VDZ administration. CONCLUSIONS: VDZ was safe and effective in children with UC. The hematocrit, albumin, and ESR at VDZ initiation might be predictors for VDZ effectiveness. VDZ may be an important option for pediatric patients and can be used as an alternative to immunomodulators.


Asunto(s)
Productos Biológicos , Colitis Ulcerosa , Masculino , Femenino , Humanos , Niño , Preescolar , Adolescente , Colitis Ulcerosa/tratamiento farmacológico , Estudios Retrospectivos , Japón , Fármacos Gastrointestinales/efectos adversos , Factores Biológicos/uso terapéutico , Productos Biológicos/uso terapéutico , Resultado del Tratamiento
6.
Lung Cancer ; 182: 107278, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37321075

RESUMEN

OBJECTIVES: Limited treatment options are available for non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD). The rationale for immunotherapy and its adverse events for NSCLC with ILD remains unclear. In this study, we examined T cell profiles and functions in the lung tissues of NSCLC patients with or without ILD to provide evidence for the potential mechanism of immune checkpoint inhibitor (ICI)-related pneumonitis in NSCLC patients with ILD. MATERIAL AND METHODS: We investigated T cell immunity in the lung tissues of NSCLC patients with ILD to support the application of immunotherapy for these patients. We analyzed T cell profiles and functions in surgically resected lung tissues from NSCLC patients with and without ILD. The T cell profiles of infiltrating cells in lung tissues were analyzed by flow cytometry. T cell functions were measured based on cytokine production by T cells stimulated with phorbol 12-myristate 13-acetate and ionomycin. RESULTS: The percentages of CD4+ T cells expressing immune checkpoint molecules (Tim-3, ICOS, and 4-1BB), CD103+CD8+ T cells, and regulatory T (Treg) cells were higher in NSCLC patients with than in those without ILD. A functional analysis of T cells in lung tissues indicated that CD103+CD8+ T cells positively correlated with IFNγ production, whereas Treg cells negatively correlated with IFNγ and TNFα production. Cytokine production by CD4+ and CD8+ T cells did not significantly differ between NSCLC patients with and without ILD, except for TNFα production by CD4+ T cells being lower in the former than in the latter. CONCLUSION: In NSCLC patients with ILD stable for surgery, T cells were active participants and balanced in part by Treg cells in lung tissues, suggesting the potential development of ICI-related pneumonitis in NSCLC patients with ILD.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Enfermedades Pulmonares Intersticiales , Neoplasias Pulmonares , Neumonía , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Linfocitos T CD8-positivos , Factor de Necrosis Tumoral alfa , Estudios Retrospectivos
7.
BMC Cancer ; 23(1): 450, 2023 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-37198556

RESUMEN

BACKGROUND: Total neoadjuvant therapy (TNT) is a novel treatment strategy that is an alternative to preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). However, an optimal protocol for TNT has not yet been established. The present study will be an open-label, single-arm, single-center trial to develop a new protocol. METHODS: Thirty LARC patients at high risk of distant metastasis will receive CRT consisting of long-course radiation, concurrent with tegafur/uracil, oral leucovorin, irinotecan (TEGAFIRI), followed by mFOLFOX-6 or CAPOX before undergoing surgery. DISCUSSION: Since previous findings showed a high percentage of grade 3-4 adverse events with the TEGAFIRI regimen for CRT and TNT, the primary outcome of this study will be safety and feasibility. Our regimen for CRT consists of the biweekly administration of irinotecan for good patient compliance. The novel combination approach of this treatment may improve the long-term outcomes of LARC. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031210660.


Asunto(s)
Neoplasias del Recto , Tegafur , Humanos , Irinotecán/uso terapéutico , Oxaliplatino , Leucovorina , Terapia Neoadyuvante/métodos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/patología , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/métodos , Fluorouracilo/uso terapéutico , Estadificación de Neoplasias , Ensayos Clínicos Fase II como Asunto
8.
Microorganisms ; 11(2)2023 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-36838436

RESUMEN

Severe cases of COVID-19 continue to put pressure on medical operations by prolonging hospitalization, occupying intensive care beds, and forcing medical personnel to undergo harsh labor. The eradication of SARS-CoV-2 through vaccine development has yet to be achieved, mainly due to the appearance of multiple mutant-incorporating strains. The present study explored the utility of human intravenous immunoglobulin (IVIG) preparations in suppressing the aggravation of any COVID-19 infection using a SARS-CoV-2 pseudovirus assay. Our study revealed the existence of IgG antibodies in human IVIG preparations, which recognized the spike protein of SARS-CoV-2. Remarkably, the pretreatment of ACE2/TMPRSS2-expressing host cells (HEK293T cells) with IVIG preparations (10 mg/mL) inhibited approximately 40% entry of SARS-CoV-2 pseudovirus even at extremely low concentrations of IgG (0.16-1.25 mg/mL). In contrast, the antibody-dependent enhancement of viral entry was confirmed when SARS-CoV-2 pseudovirus was treated with some products at an IgG concentration of 10 mg/mL. Our data suggest that IVIG may contribute to therapy for COVID-19, including for cases caused by SARS-CoV-2 variants, since IVIG binds not only to the spike proteins of the virus, but also to human ACE2/TMPRSS2. An even better preventive effect can be expected with blood collected after the start of the COVID-19 pandemic.

9.
Cancer Med ; 12(7): 8476-8489, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36691316

RESUMEN

BACKGROUND: Small cell carcinoma of the uterine cervix (SCCC) is a rare and highly malignant human papillomavirus (HPV)-associated cancer in which human genes related to the integration site can serve as a target for precision medicine. The aim of our study was to establish a workflow for precision medicine of HPV-associated cancer using patient-derived organoid. METHODS: Organoid was established from the biopsy of a patient diagnosed with HPV18-positive SCCC. Therapeutic targets were identified by whole exome sequencing (WES) and RNA-seq analysis. Drug sensitivity testing was performed using organoids and organoid-derived mouse xenograft model. RESULTS: WES revealed that both the original tumor and organoid had 19 somatic variants in common, including the KRAS p.G12D pathogenic variant. Meanwhile, RNA-seq revealed that HPV18 was integrated into chromosome 8 at 8q24.21 with increased expression of the proto-oncogene MYC. Drug sensitivity testing revealed that a KRAS pathway inhibitor exerted strong anti-cancer effects on the SCCC organoid compared to a MYC inhibitor, which were also confirmed in the xenograft model. CONCLUSION: In this study, we confirmed two strategies for identifying therapeutic targets of HPV-derived SCCC, WES for identifying pathogenic variants and RNA sequencing for identifying HPV integration sites. Organoid culture is an effective tool for unveiling the oncogenic process of rare tumors and can be a breakthrough for the development of precision medicine for patients with HPV-positive SCCC.


Asunto(s)
Carcinoma de Células Pequeñas , Neoplasias Pulmonares , Infecciones por Papillomavirus , Carcinoma Pulmonar de Células Pequeñas , Neoplasias del Cuello Uterino , Femenino , Humanos , Animales , Ratones , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Papillomavirus Humano 18/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/tratamiento farmacológico , Infecciones por Papillomavirus/patología , Medicina de Precisión , Proteínas Proto-Oncogénicas p21(ras)/genética
10.
J Cachexia Sarcopenia Muscle ; 13(6): 2961-2973, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36237134

RESUMEN

BACKGROUND: Vitamin D is an essential nutrient in musculoskeletal function; however, its relationship to sarcopenia remains ambiguous, and the mechanisms and targets of vitamin D activity have not been elucidated. This study aimed to clarify the role of vitamin D in mature skeletal muscle and its relationship with sarcopenia. METHODS: This epidemiological study included 1653 community residents who participated in both the fifth and seventh waves of the National Institute for Longevity Sciences, Longitudinal Study of Aging and had complete background data. Participants were classified into two groups: vitamin D-deficient (serum 25-hydroxyvitamin D < 20 ng/mL) and non-deficient (serum 25-hydroxyvitamin D ≥ 20 ng/mL); they underwent propensity-score matching for background factors (age, sex, height, weight, comorbidities, smoker, alcohol intake, energy intake, vitamin D intake, steps, activity, season and sarcopenia). Changes in muscle strength and mass over the 4-year period were compared. For basic analysis, we generated Myf6CreERT2 Vitamin D Receptor (VDR)-floxed (VdrmcKO ) mice with mature muscle fibre-specific vitamin D receptor knockout, injected tamoxifen into 8-week-old mice and analysed various phenotypes at 16 weeks of age. RESULTS: Grip strength reduction was significantly greater in the deficient group (-1.55 ± 2.47 kg) than in the non-deficient group (-1.13 ± 2.47 kg; P = 0.019). Appendicular skeletal muscle mass reduction did not differ significantly between deficient (-0.05 ± 0.79 kg) and non-deficient (-0.01 ± 0.74 kg) groups (P = 0.423). The incidence of new cases of sarcopenia was significantly higher in the deficient group (15 vs. 5 cases; P = 0.039). Skeletal muscle phenotyping of VdrmcKO mice showed no significant differences in muscle weight, myofibre percentage or myofibre cross-sectional area; however, both forelimb and four-limb muscle strength were significantly lower in VdrmcKO mice (males: forelimb, P = 0.048; four-limb, P = 0.029; females: forelimb, P < 0.001; four-limb, P < 0.001). Expression profiling revealed a significant decrease in expression of sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA) 1 (P = 0.019) and SERCA2a (P = 0.049) genes in the VdrmcKO mice. In contrast, expression of non-muscle SERCA2b and myoregulin genes showed no changes. CONCLUSIONS: Vitamin D deficiency affects muscle strength and may contribute to the onset of sarcopenia. Vitamin D-VDR signalling has minimal influence on the regulation of muscle mass in mature myofibres but has a significant influence on muscle strength.


Asunto(s)
Sarcopenia , Deficiencia de Vitamina D , Masculino , Femenino , Humanos , Ratones , Animales , Receptores de Calcitriol , Ratones Noqueados , Estudios Longitudinales , Sarcopenia/genética , Sarcopenia/epidemiología , Vitamina D , Vitaminas , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/metabolismo
12.
Plant Cell Environ ; 45(8): 2337-2350, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35672880

RESUMEN

Guard-cell-type aluminium-activated malate transporters (ALMTs) are involved in stomatal closure by exporting anions from guard cells. However, their physiological and electrophysiological functions are yet to be explored. Here, we analysed the physiological and electrophysiological properties of the ALMT channels in Arabidopsis and tomato (Solanum lycopersicum). SlALMT11 was specifically expressed in tomato guard cells. External malate-induced stomatal closure was impaired in ALMT-suppressed lines of tomato and Arabidopsis, although abscisic acid did not influence the stomatal response in SlALMT11-knock-down tomato lines. Electrophysiological analyses in Xenopus oocytes showed that SlALMT11 and AtALMT12/QUAC1 exhibited characteristic bell-shaped current-voltage patterns dependent on extracellular malate, fumarate, and citrate. Both ALMTs could transport malate, fumarate, and succinate, but not citrate, suggesting that the guard-cell-type ALMTs are dicarboxylic anion channels activated by extracellular organic acids. The truncation of acidic amino acids, Asp or Glu, from the C-terminal end of SlALMT11 or AtALMT12/QUAC1 led to the disappearance of the bell-shaped current-voltage patterns. Our findings establish that malate-activated stomatal closure is mediated by guard-cell-type ALMT channels that require an acidic amino acid in the C-terminus as a candidate voltage sensor in both tomato and Arabidopsis.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Transportadores de Anión Orgánico , Solanum lycopersicum , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacología , Aluminio/metabolismo , Aluminio/toxicidad , Aniones/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Fumaratos/metabolismo , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Malatos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Estomas de Plantas/fisiología
13.
Biol Pharm Bull ; 45(4): 429-437, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35370267

RESUMEN

Cancer immunotherapies are powerful therapeutic options for cancer patients. To enhance the therapeutic effects of cancer immunotherapies, we plan to develop novel immunostimulatory drugs for use in combination with cancer immunotherapy. In the present study, we focused on tetracyclines, the effects of which are controversial for immunotherapy. We examined the effects of tetracyclines on human T cells in the peripheral blood of healthy donors and the tumor tissues of non-small cell lung cancer (NSCLC) patients. By using bispecific T-cell engager technology to assess the cytotoxicity of peripheral T cells against tumor cells, we showed that tetracyclines (minocycline, tetracycline, doxycycline, meclocycline, chlortetracycline, and demeclocycline) enhanced T-cell cytotoxicity through granzyme B expression and CD4+ and CD8+ T-cell proliferation. In analyses of the peripheral blood mononuclear cells (PBMCs) and lung tumor-infiltrated cells of NSCLC patients, we found that demeclocycline enhanced T-cell cytotoxicity not only in PBMCs, but also in lung tumor tissues. These results support the further application of tetracyclines to combination cancer immunotherapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Leucocitos Mononucleares , Neoplasias Pulmonares/tratamiento farmacológico , Minociclina , Linfocitos T
14.
Sci Rep ; 12(1): 5377, 2022 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-35354899

RESUMEN

Regulatory T cells (Tregs) suppress the host immune response and maintain immune homeostasis. Tregs also promote cancer progression and are involved in resistance to immune checkpoint inhibitor treatments. Recent studies identified selective CCR8 expression on tumor-infiltrating Tregs; CCR8+ Tregs have been indicated as a possible new target of cancer immunotherapy. Here, we investigated the features of CCR8+ Tregs in lung cancer patients. CCR8+ Tregs were highly activated and infiltration of CCR8+ Tregs in tumors was associated with poor prognosis in lung cancer patients. We also investigated their immune suppressive function, especially the influence on cytotoxic T lymphocyte cell function. The Cancer Genome Atlas analysis revealed that CD8 T cell activities were suppressed in high CCR8-expressing tumors. Additionally, depletion of CCR8+ cells enhanced CD8 T cell function in an ex vivo culture of lung tumor-infiltrating cells. Moreover, CCR8+ Tregs, but not CCR8- Tregs, induced from human PBMCs markedly suppressed CD8 T cell cytotoxicity. Finally, we demonstrated the therapeutic effect of targeting CCR8 in a murine model of lung cancer. These findings reveal the significance of CCR8+ Tregs for immunosuppression in lung cancer, especially via cytotoxic T lymphocyte cell suppression, and suggest the potential value of CCR8-targeted therapy for cancer treatment.


Asunto(s)
Neoplasias Pulmonares , Linfocitos T Reguladores , Animales , Humanos , Tolerancia Inmunológica , Inmunoterapia , Neoplasias Pulmonares/patología , Ratones , Receptores CCR8/metabolismo , Linfocitos T Citotóxicos
15.
Cancer Med ; 11(18): 3457-3470, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35343095

RESUMEN

Postoperative recurrence of colorectal cancer (CRC) eventually leads to therapeutic failure; therefore, treatment strategies based on accurate prediction of recurrence are urgently required. To identify biomarkers that can predict treatment outcomes, we compared the mutational profiles of surgically resected specimens from patients with recurrent cancer with those from patients with non-recurrent cancer. Target sequencing, whole-exome sequencing (WES), or whole-genome sequencing (WGS) was performed on 89 and 58 tumors from recurrent and non-recurrent cases, respectively. WGS revealed the driver mutations that were not detected with target sequencing or WES, including the structural variations affecting ZFP36L2. Loss of function of ZFP36L2 was frequently observed in primary tumors from recurrent cases. Furthermore, the recurrence-free survival of patients with loss of function of ZFP36L2 was significantly shorter relative to patients with no loss of ZFP36L2 function. In summary, the study demonstrated that detailed genomic analysis could help improve precision medicine for CRC.


Asunto(s)
Neoplasias Colorrectales , Recurrencia Local de Neoplasia , Biomarcadores , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Genómica , Humanos , Mutación , Recurrencia Local de Neoplasia/genética , Secuenciación del Exoma
16.
Gastroenterology ; 162(3): 799-812, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34687740

RESUMEN

BACKGROUND & AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability-high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Genes MHC Clase I/genética , Escape del Tumor/genética , Escape del Tumor/inmunología , Microglobulina beta-2/genética , Alelos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Metilación de ADN , Epigénesis Genética , Expresión Génica , Antígenos HLA-A/genética , Antígenos HLA-A/metabolismo , Humanos , Inmunogenética , Linfocitos Infiltrantes de Tumor , Inestabilidad de Microsatélites , Complejo de la Endopetidasa Proteasomal/genética , Factores de Transcripción del Factor Regulador X/genética , Tasa de Supervivencia , Microglobulina beta-2/metabolismo
17.
J Clin Neurosci ; 94: 244-249, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34863446

RESUMEN

The prevalence of chronic subdural hematoma (CSDH) associated with dural metastasis is uncertain, and appropriate treatment strategies have not been established. This study aimed to investigate the characteristics of and appropriate treatment strategies for CSDH associated with dural metastasis. We retrospectively reviewed the charts of 214 patients who underwent surgery for CSDH. The patients were divided into the dural metastasis group (DMG; n = 5, 2.3%) and no dural metastasis group (No-DMG; n = 209, 97.3%). Patient characteristics, treatment, and outcomes were compared between the two groups. Active cancer was detected in 31 out of 214 patients, 5 of whom (16.1%) had dural metastasis. In-hospital death (80.0% vs. 0%; p < 0.001) and recurrence within 14 days (80.0% vs. 2.9%; p < 0.001) and 60 days (80.0% vs. 13.9%; p = 0.002) were significantly prevalent in the DMG. All patients in the DMG developed subdural hematoma re-accumulation requiring emergent surgery because of brain herniation, and patients in the DMG had significantly worse recurrence-free survival (p < 0.001). This relationship remained significant (p < 0.001) even when the analysis was limited to the active cancer cohort (n = 31). CSDH associated with dural metastasis leads to early recurrence and death because of the difficulty in controlling subdural hematoma re-accumulation by common drainage procedures. Depending on the primary cancer status, withdrawal of active treatment and change to palliative care should be discussed after diagnosing CSDH associated with dural metastasis.


Asunto(s)
Hematoma Subdural Crónico , Neoplasias , Estudios de Cohortes , Hematoma Subdural Crónico/diagnóstico por imagen , Hematoma Subdural Crónico/etiología , Hematoma Subdural Crónico/cirugía , Mortalidad Hospitalaria , Humanos , Recurrencia , Estudios Retrospectivos
19.
Artículo en Inglés | MEDLINE | ID: mdl-34574371

RESUMEN

Reports on the expenditure of cancer treatments per patient using comprehensive data remain unavailable in Japan. This study aimed to use Japan's cancer registry data and health service utilization data for evaluating the disease-specific, per-patient costs of five major cancers-stomach, lung, colorectal, liver, and breast cancers. We used a database linking the 2017 data from a hospital-based cancer registry and the health service utilization data from the Diagnosis Procedure Combination survey. All patients who started their first treatment course at each hospital were included. The costs were calculated using the total volume of the health services provided and the unit fee information included in the data. We analyzed 304,698 patients. Lung cancer had the highest healthcare cost per-patient for the first year of diagnosis and the longest median hospitalization duration. Conversely, breast cancer showed the lowest cost and the shortest median hospitalization duration. However, in the first month after diagnosis, colorectal cancer showed the highest cost. Subsequently, the gaps between the costs of the five common cancers drastically diminished. The cancer type having the longest hospitalization duration had the highest overall healthcare resource utilization costs. This information is essential for care planning and research studies.


Asunto(s)
Neoplasias de la Mama , Costos de la Atención en Salud , Femenino , Gastos en Salud , Hospitalización , Humanos , Japón/epidemiología , Estudios Retrospectivos
20.
Surg Neurol Int ; 12: 347, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34345487

RESUMEN

BACKGROUND: The treatment of internal carotid artery (ICA) - posterior communicating artery aneurysms (ICPC aneurysms) is challenging when a fetal posterior cerebral artery (PCA) arises from the saccular neck. This complex angioarchitecture renders endovascular approaches difficult. Giant thrombosed IC-PC aneurysms are also hard to treat by endovascular coiling because its flow-diversion effect is insufficient. CASE DESCRIPTION: We report the first case of a ruptured giant thrombosed IC-PC aneurysm associated with a fetal PCA that was successfully treated by coil embolization with retrograde overlap horizontal stenting using low-profile stents introduced through the contralateral ICA. The aneurysm was completely occluded and follow-up MRI scans demonstrated the reduction of the aneurysmal size. CONCLUSION: Our technique is advantageous because low-profile stents can be used to treat lesions not accessible with flow-diverter stents due their presence in complex angioarchitectures, and overlap stenting may have flow-diversion effects that can result in the complete occlusion of giant thrombosed aneurysms.

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