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Summary: Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-α-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1+ dendritic cells to enhance CD8+ T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade. : Tsuchiya et al. demonstrate that local administration of iPSC-derived myeloid cells producing interferon-α suppresses local, as well as distant, tumors. The efficacy depends on the tumor-reactive T cell response mediated by the activation of host XCR1+ dendritic cells. The concomitant use of a PD-1/PD-L1 inhibitor yields a superior antitumor effect. Keywords: cancer immunotherapy, induced pluripotent stem cells, type I interferon, XCR1, dendritic cells, cross-presentation, checkpoint blockade, PD-1, STING, CXCR3

We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor”.

Abstract Background Randomized controlled trial (RCT) data have important implications in drug development. However, the feasibility and cost of conducting RCTs lower the motivation for drug development, especially for rare diseases. We investigated the potential factors associated with the need for RCTs in the clinical data package for new drug applications for rare diseases in the United States (US). This study focused on 233 drugs with orphan drug designations approved in the US between April 2001 and March 2021. Univariable and multivariable logistic regression analyses were conducted to investigate the association between the presence or absence of RCTs in the clinical data package for new drug applications. Results Multivariable logistic regression analysis showed that the severity of the disease outcome (odds ratio [OR] 5.63, 95% confidence interval [CI] 2.64–12.00), type of drug usage (odds ratio [OR] 2.95, 95% confidence interval [CI] 1.80–18.57), and type of primary endpoint (OR 5.57, 95% CI 2.57–12.06) were associated with the presence or absence of RCTs. Conclusions Our results indicated that the presence or absence of RCT data in the clinical data package for successful new drug application in the US was associated with three factors: severity of disease outcome, type of drug usage, and type of primary endpoint. These results highlight the importance of selecting target diseases and potential efficacy variables to optimize orphan drug development.

From the viewpoint of the stability of biped walking, the stability for both anteroposterior, lateral, and diagonal directions should be considered owing to the frequent occurrence of turning and curving motions in the daily environment. In this study, a measure called the all-round margin of stability (MoS) is proposed to evaluate the kinematic balance of the all-round direction. A curving experiment was performed to analyze the characteristics of the all-round MoS. The curving gait was recorded with and without the restriction of hip rotation. The all-round MoS of trials were classified using cluster analysis, and the characteristics of curving motion were extracted from gait parameters using factor analysis. By comparing the characteristics of the all-round MoS and factor scores, the features of the all-round MoS were discussed. The results suggest that the effect of the parameters on the MoS, such as the velocity of the center of gravity and step width, matched the characteristics of the all-round MoS. Thus, the effect of the range of motion of hip rotation on curving gait was analyzed using an all-round MoS. The all-round MoS helps visualize the anisotropy of balance, which then enables estimation of the direction with high fall risk. Furthermore, the all-round MoS enables to evaluate and improve the performance of gait assist devices such as exoskeletons. This study proposes the concept of all-round MoS as the method to evaluate balance in diagonal direction especially for complex gait.

The article presents a study which examined the possibility of using the AT-rich domain-containing protein 3B (ARID3B) as a cancer stem cells (CSC) marker of melanoma. The variables include a comparison of ARID3B expression in CD271+ and CD271-cells, tissue samples of melanoma, nevus and normal skin, and ARID3B mRNA transcripts. The role of the ARID3B in embryonic development and progression of melanoma malignancy is described.

We report a case of a 74-year-old man with a cluster of differentiation (CD) 7-positive diffuse large B-cell lymphoma (DLBCL) in the right nasal cavity. Flow cytometry analyses showed CD7 and CD20 positivity in tumor cells. The patient received 6 cycles of R-CHOP plus local radiation therapy because positron emission tomography-computed tomography after R-CHOP revealed an intranasal lesion. The patient achieved complete remission (CR) after radiation therapy. The frequency of CD7-positive DLBCL is rare, and only 11 cases with follow-up of clinical course have been reported thus far. CR or partial response was noted in 8 of 11 cases after receiving rituximab combined with chemotherapy. In total, 9 of 12 cases involved the development of extranodal lesions, which occurred as an intranasal tumor in 3 cases. It is important to examine the clinical features by accumulation of further cases.

Abstract Background Major depressive disorder (MDD) is a common and often chronic problem. Patients with chronic MDD often have negative impacts on the health of their families. Family psychoeducation is recognized as part of the optimal treatment for patients with psychotic disorder, and has been shown to reduce the rate of relapse in individuals with schizophrenia and to reduce the burden on their caregivers. Thus, we predict that family psychoeducation has the potential to reduce the burden on the caregivers of patients with chronic MDD. In the present study, we aimed to investigate the effects of brief multifamily psychoeducation (BMP) on the mental health status of family members of patients with chronic MDD. Methods We conducted a clinical trial consisting of 49 chronic MDD patients and their families. Each family was randomly assigned to either the BMP intervention group or the control group. The intervention group received four BMP sessions, once every two weeks for eight weeks. The control group received one counseling session administered by a nurse. All patients received standard treatment administered by physicians. The primary outcome measurement was the Kessler Screening Scale for Psychological Distress (K6) score of family members at 16- weeks after the first BMP session. Secondary outcomes were depressive symptoms of both family members and patients at multiple time points, as well as family functioning as evaluated by the patients. Intention-to-treat analyses were conducted. Results There was no statistically significant effect of BMP on K6 scores at 16- weeks (mean difference 1.17, 95% confidence interval: − 0.63 to 2.98, P = 0.19). Exploratory analyses revealed that BMP reduced depressive symptoms in family members at 8- weeks (difference = − 3.37, 95%CI -6.32 to − 0.43, P = 0.02) and improved family functioning at multiple time points (Role; 8 W, difference = − 0.13, 95%CI -0.26 to − 0.00, P = 0.04, Affective Responsiveness; 8 W, difference = − 0.24, 95%CI -0.43 to − 0.05, P = 0.01, 32 W, difference = − 0.22, 95%CI -0.41 to − 0.03, P = 0.02, Behavior Control; 16 W, difference = − 0.17, 95%CI -0.34 to − 0.00, P = 0.04). Conclusions Four BMP sessions did not significantly reduce the psychological distress of family members of patients with chronic MDD. Trial registration Clinical Trials. gov NCT01734291, retrospectively registered (Registration date: November 21, 2012).

Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians' perceptions of patients' decision-making incapacity.Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated.Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision-making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen's kappa -0.54).Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity.