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Introduction: Although primary care professionals often encounter difficulties when attending to patients in complex and challenging social situations (CCSS), little is known about how professionals cultivate an optimistic approach to caring for patients in CCSS. This study aims to recruit professionals who exhibit a passion for seeing patients in CCSS, to gain insights into their positive attitude., Methods: We conducted a qualitative study in Japan of 30 primary care professionals: 15 physicians and 15 non-physician professionals (nurses, medical social workers and medical clerks). We performed online in-depth interviews and employed a thematic analysis utilising the framework approach to identify how the participants felt a passion for seeing patients in CCSS., Results: Two themes emerged about the passion: (i) the joy derived from interacting with patients and (ii) the joy derived from professional growth or development. Participants expressed curiosity about their patients, found happiness in the journey with them and established irreplaceable relationships. Concurrently, participants noted professional growth as expert generalists, and their team developed collaboration and competency through accumulating experience and learning. These two domains of joy were intricately interconnected. In addition, several factors related to developing, maintaining and spreading the positive attitude were identified., Discussion: This study described the positive attitude of primary care professionals towards engaging with patients in CCSS. Despite the inherent challenges, these professionals demonstrated vibrancy and pleasure in their interactions with patients and their professional development. Workplace culture including team-based support and continuous learning is important in fostering and maintaining such an attitude., (© 2024 Association for the Study of Medical Education and John Wiley & Sons Ltd.)

The progress in artificial bone research is crucial for addressing fractures and bone defects in the aging population. However, challenges persist in terms of biocompatibility and structural complexity. Nanotechnology provides a promising avenue by which to overcome these challenges, with nano-ferrite particles (NFPs) exhibiting superparamagnetic properties. The ability to control cell positioning using a magnetic field opens up new possibilities for customizing artificial bones with specific shapes. This study explores the biological effects of NFPs on osteoblast-like cell lines (MC3T3-E1), including key analyses, such as cell viability, cellular uptake of NFPs, calcification processes, cell migration under external magnetic field conditions, and three-dimensional modeling. The results indicate that the impact of NFPs on cell proliferation is negligible. Fluorescence and transmission electron microscopy validated the cellular uptake of NFPs, demonstrating the potential for precise cell positioning through an external magnetic field. Under calcification-inducing conditions, the cells exhibited sustained calcification ability even in the presence of NFPs. The cell movement analysis observed the controlled movement of NFP-absorbing cells under an external magnetic field. Applying a magnetic field along the z-axis induced the three-dimensional shaping of cells incorporating NFPs, resulting in well-arranged z-axis directional patterns. In this study, NFPs demonstrated excellent biocompatibility and controllability under an external magnetic field, laying the foundation for innovative treatment strategies for customizing artificial bones.

Background: The specific dimensions of learners that have been impacted by educational programs related to social determinants of health (SDoH) remain unknown. This study aims to elucidate how learners are affected by postgraduate education (a single 90-min educational session) regarding tool-guided clinical assessment of patients' social backgrounds., Methods: A pretest-posttest design was utilized in which residents (postgraduate year (PGY) 1 or 2) and fellows in family medicine (PGY over 3) were recruited. Likert-type questions were developed based on previous qualitative findings. Participants answered these questions before, immediately after, and 1.5 months after the educational session on tool-guided clinical SDoH assessment. Paired-sample t -tests were used, and effect size was measured using Cohen's d ., Results: A total of 114 residents and fellows participated. After the session, participants expressed more interest in knowing their patients' social backgrounds when considering how to address their patients and were more open to embracing a pre-established assessment framework. Participants also considered clinical skills related to SDoH as learnable and improved their attitude toward patients. They reported that they did not perform specific interventions related to SDoH within 1.5 months after the session. Unlike previous qualitative findings, their concern about the implementation of SDoH-related practices did not increase significantly., Conclusion: An educational session on tool-guided SDoH assessment may have a positive impact on learners' attitudes related to addressing patients' social backgrounds without fostering concerns., Competing Interests: The author has stated explicitly that there are no conflicts of interest in connection with this article., (© 2024 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Introduction: There has been a growing recognition of the importance of incorporating a "social" perspective in primary care practice. However, the specific meaning of the term "social" in the context of primary care is often not clearly defined or explained in the literature. This study aims to explore the usage and interpretation of the term "social" in primary care discourse in Japan., Methods: We collected papers containing the term "social" ("shakai-teki" in Japanese) from 810 papers published between 2010 and 2022 in the Official Journal of the Japan Primary Care Association. Through abductive coding, we examined how the term was employed and the different meanings attributed to it., Results: The instances of using the term "social" were classified into five distinct categories: (i) non-medical, (ii) emphasizing the importance of topics, (iii) public as an object, (iv) connections with people who support health and well-being, and (v) structural inequities that are detrimental to health.  Conclusion: The analysis revealed that the term "social" in the context of primary care discourse was multifaceted and characterized by ambiguity. To ensure effective communication and clarity in discussions, it is crucial for primary care professionals to have a clear understanding of the intended meaning and implications of the term "social.", Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Mizumoto et al.)

Background: Although nurses are expected to address the social determinants of health (SDH) in clinical settings, the perspectives of front-line nurses on the integration of SDH into their clinical practice remain unclear. Understanding the dynamism of this integration and its outcomes can yield crucial insights into effective nursing care. This study aims to elucidate the integration and adoption of tool-based SDH assessment nursing programs and their impacts on daily nursing care., Methods: We conducted qualitative research at a small community-based hospital in Japan, where a tool-based program characterized by social background interviews and documentation was implemented. Nurses at the hospital were recruited via purposive and snowball sampling. After hypothesis generation, semi-constructed in-depth online interviews were conducted. Each interview lasted between 30 and 50 min. The data were analyzed via thematic analysis using the framework approach., Results: A total of 16 nurses participated. Participants' incorporation of the novel SDH assessment program was bolstered by prior learning and their recognition of its practical value. Institutional support and collaborative teamwork further facilitated the adoption of this innovation. Enhanced knowledge about the social contexts of their patients contributed to increased respect, empathy, and self-affirmation among participants, consequently enhancing the quality of nursing care., Conclusion: Through team-based learning, reflection, and support, nurses can integrate a tool-based SDH assessment program into their daily nursing practice. This program has the potential to empower nurses to deliver more holistic care and redefine their professional identity. Further research is warranted to assess patient-reported outcomes., Competing Interests: The author has stated explicitly that there are no conflicts of interest in connection with this article., (© 2023 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Background: Social trust in medical students is trust in the cluster of medical students and not individual medical students. Social trust in medical students seems critical in clinical practice since citizens often face unknown medical students for the first time. However, most previous research has focused on interpersonal trust in particular medical professions, and social trust in medical students has not been addressed sufficiently. In social science, the Salient Value Similarity model has demonstrated that the value similarity between professionals and citizens is associated with social trust. This research aimed to explore the relationship between social trust in medical students and the perception of value similarity. This study also aimed to determine whether the information of medical students strengthens social trust in them., Methods: We conducted a cross-sectional study to investigate how the perception of value similarity affects social trust. The participants answered the social trust questionnaires before and after reading a brief summary of the medical education curriculum and certification via the internet in Japan. The model structure of social trust in medical students, including the perception of value similarity, was investigated using SEM. A paired t-test was used to examine the effect of informing citizens about the knowledge, skills, and professionalism requirements of students attending medical school on social trust by reading the brief summary., Results: The study included 658 participants, who all answered a web questionnaire. Social trust in medical students was associated with the perception of ability and value similarity. Social trust in medical students, the perception of ability, and value similarity were improved by information about medical students., Conclusions: The perception of ability and value similarity seem to affect social trust in medical students. Information on medical education regarding the knowledge, skills, and professionalism of medical students may improve social trust in these students. Further research is required to sophisticate the model of social trust in medical students by exploring social trust in the medical students' supervisors in clinical settings., (© 2023. The Author(s).)

Background and Aims: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients., Methods: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients)., Results: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online., Conclusions: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country., Impact and Implications: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Vaccine administration skills are very important for physicians, especially in the era of global pandemics. However, medical students have reported that practical sessions to develop these skills are insufficient. Therefore, the aim of our study was to develop a vaccination training course for medical students. We also examined its educational effectiveness., Methods: 5th- and 6th-year medical students at the University of Tokyo were recruited to attend the vaccine administration training course in 2021. These students were our study participants. Our course consisted of an orientation part, which included a lecture on the indications, adverse events, and vaccination techniques of flu vaccines and practice on a simulator, and a main part in which the staff of the University of Tokyo Hospital were actually vaccinated. Before and after the main part of the course, study participants completed an online questionnaire that assessed their confidence in vaccine administration technique through a five-point Likert scale. We also surveyed their feedback about the course content and process. At the beginning and end of the main part, their technical competence in vaccination was assessed by two independent doctors. These doctors used a validated checklist scale (ranging from 16 to 80) and a global rating scale (ranging from 0 to 10). We used their mean scores for analysis. The quantitative data were analyzed through the Wilcoxon signed-rank test. For the qualitative data of the questionnaire, thematic analysis was conducted., Results: All 48 course participants participated in our study. Participants' confidence in vaccination technique (Z = -5.244, p < 0.05) and vaccination skill significantly improved (checklist rating: Z = -5.852, p < 0.05; global rating: Z = -5.868, p < 0.05). All participants rated the course as, "overall educational." Our thematic analysis identified four emerging themes: interest in medical procedures, efficacy of supervision and feedback, efficacy of "near-peer" learning, and very instructive course., Conclusions: In our study, we developed a vaccine administration course for medical students, assessed their vaccination techniques and confidence in those techniques, and investigated their perceptions of the course. Students' vaccination skills and confidence improved significantly after the course, and they positively evaluated the course based on a variety of factors. Our course will be effective in educating medical students about vaccination techniques., (© 2023. The Author(s).)

Introduction: The concept of social accountability in medical schools is globally accepted, but data regarding Japanese medical schools are lacking and unclear. This study aimed to elucidate the perception of social accountability of medical schools in Japan and compare this to global frameworks., Methods: A document on Japanese medical accreditation standards (Basic Medical Education: Japanese Specifications WFME Global Standards for Quality Improvement) was used for this study. We included 45 medical schools in a qualitative content analysis done via inductive category formation. The documents were also assessed using the social obligation scale., Results: Three main categories and 15 categories were identified. The three main categories were as follows: Issues in society, Quality assurance of medical school, and Improvement of individual quality. Most categories were common to those in global frameworks, but some were characteristic of the Japanese context. The distribution of schools on the social obligation scale in six elements varied mainly 'from responsibility to responsiveness' or equal unless the elements were promoted by national policy., Conclusions: The social accountability of Japanese medical schools is mostly common with the global frameworks. Our findings will help the social accountability of medical schools to become better understood and developed beyond contextual borders.

Background: Several organisations have called for primary care professionals to address social determinants of health (SDoH) in clinical settings. For primary care physicians to fulfill their community health responsibilities, the implications of the SDoH recommendations need to be clarified., Aim: To describe primary care physicians' views about being asked to address SDoH in clinical settings, from both positive and negative perspectives., Design & Setting: A qualitative study in Japan. Twenty-one physicians were purposively recruited., Method: 'Love and breakup letter' methodology was used to collect qualitative data that contained both positive and negative feelings. Participants wrote love and breakup letters about being asked to address SDoH in a clinical setting, then undertook an in-depth online interview. Data were analysed via thematic analysis using the framework approach., Results: The following themes were identified: (i) primary care physicians take pride in being expected to address SDoH; (ii) primary care physicians rely on the recommendations as a partner, even in difficult situations; (iii) primary care physicians consider the recommendations to be bothersome, with unreasonable demands and challenges, especially when supportive surroundings are lacking; and (iv) primary care physicians reconstruct the recommendations on the basis of their experience., Conclusion: Primary care physicians felt both sympathy and antipathy towards recommendations asking them to address SDoH in their clinical practice. The recommendations were not followed literally, instead contributing to physicians' clinical mindlines. Professional organisations that plan to develop and publish recommendations about SDoH should consider how their recommendations might be perceived by their target audience., (Copyright © 2023, The Authors.)

Background and Objective: In the Japanese primary care setting, a set of questions to screen patients' social circumstances has never been developed in a scientific manner. This project aimed to reach a consensus among diverse experts to develop a set of such questions, to meet the need for assessing patients' health-related social circumstances., Methods: We used a Delphi technique to generate expert consensus. The expert panel was composed of various clinical professionals, medical trainees, researchers, support members for marginalized people, and patients. We conducted multiple rounds of communication online. In round 1, the participants provided their opinions about what health care professionals should ask to assess patients' social circumstances in primary care settings. These data were analyzed into several themes. In round 2, all themes were confirmed by consensus., Results: Sixty-one people participated in the panel. All participants completed the rounds. Six themes were generated and confirmed: economic condition and employment, access to health care and other services, living in everyday life and leisure time, total physiological needs, tools and technology, and history of the patient's life. In addition, the panelists emphasized the importance of respecting the patient's preferences and values., Conclusion: A questionnaire, abbreviated by the acronym of HEALTH+P, was developed. Further research about its clinical feasibility and impact on patient outcomes is warranted., (© 2023 by the Society of Teachers of Family Medicine.)

With the advent of nanotechnology, the use of nanoparticles as drug delivery system (DDS) has attracted great interest. We aimed to apply carbon nanohorns (CNHs) as DDS in the development of new treatments for bone diseases. We evaluated the in vitro and in vivo cellular responses of CNHs in bone-related cells compared with carbon blacks (CBs), which are similar in particle size but differ in surface and structural morphologies. Although in vitro experiments revealed that both CNHs and CBs were incorporated into the lysosomes of RAW264-induced osteoclast-like cells (OCs) and MC3T3-E1 osteoblast-like cells (OBs), no severe cytotoxicity was observed. CNHs reduced the tartrate-resistant acid phosphatase activity and expression of the differentiation marker genes in OCs at noncytotoxic concentrations, whereas the alkaline phosphatase activity and differentiation of OBs increased. Under calcification of OBs, CNHs increased the number of calcified nodules and were intra- and extracellularly incorporated into calcified vesicles to form crystal nuclei. The in vivo experiments showed significant promotion of bone regeneration in the CNH group alone, with localized CNHs being found in the bone matrix and lacunae. The suppression of OCs and promotion of OBs suggested that CNHs may be effective against bone diseases and could be applied as DDS.

Introduction: An understanding of social determinants of health (SDH) and patients' social circumstances is recommended to deliver contextualised care. However, the processes of patient care related to SDH in clinical settings have not been described in detail. Observable practice activities (OPAs) are a collection of learning objectives and activities that must be observed in daily practice and can be used to describe the precise processes for professionals to follow in specific situations (process OPA.) METHODS: We used a modified Delphi technique to generate expert consensus about the process OPA for patient care related to SDH in primary care settings. To reflect the opinions of various stakeholders, the expert panel comprised clinical professionals (physicians, nurses, public health nurses, social workers, pharmacists and medical clerks), residents, medical students, researchers (medical education, health care, sociology of marginalised people), support members for marginalised people and patients. The Delphi rounds were conducted online. In Round 1, a list of potentially important steps in the processes of care was distributed to panellists. The list was modified, and one new step was added. In Round 2, all steps were acknowledged with few modifications., Results: Of 63 experts recruited, 61 participated, and all participants completed the Delphi rounds. A total of 14 observable steps were identified, which were divided into four components: communication, practice, maintenance and advocacy. The importance of ongoing patient-physician relationships and collaboration with professionals and stakeholders was emphasised for the whole process of care., Discussion: This study presents the consensus of a variety of experts on the process OPA for patient care related to SDHs. Further research is warranted to investigate how this Communication-Practice-Maintenance-Advocacy framework could affect medical education, quality of patient care, and patient outcomes., (© 2022 Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Objective Vaccination technique is a crucial skill for medical trainees to learn, especially in the current coronavirus disease 2019 pandemic. To this end, validated assessment tools are essential in teaching appropriate techniques. However, valid instruments for assessing vaccine administration skills have not yet been developed. We therefore explored the development and validation of an assessment tool for vaccination techniques based on expert consensus. Methods We implemented a modified Delphi process to develop a vaccination technique assessment tool. We then conducted a validation study to establish the reliability and validity of the tool. Results Two rounds of the modified Delphi process were performed to generate a 19-item, vaccination performance assessment checklist. In the validation study, the linear weighted kappa value for inter-rater reliability of the overall checklist score was 0.725. Spearman's correlation coefficient between the mean checklist score and the global rating was 0.98 (p<0.01). Conclusions This is a pioneering study examining the development and validation of an assessment tool for vaccine administration techniques. The tool will be widely used in vaccination-related education.

Background: Coronavirus disease 2019 (COVID-19) has substantially affected the health and lives of medical professionals. However, the experiences of nurses engaged in primary care remain unclear. We explored how nurses working in primary care were psychologically and socially affected by the COVID-19 disaster and how they overcame the difficulties experienced., Methods: We conducted a qualitative study of seven Japanese nurses working in primary care. Data collection was performed before, during, and after a workshop based on the Tojisha-Kenkyu (user-led research) framework to explore how the COVID-19 disaster affected the nurses and how they coped. Data were analyzed using inductive thematic analysis., Results: Three themes emerged from the analysis: effects of the COVID-19 disaster on nurses, nurses' newly found strength during the pandemic, and their changes and achievements through the Tojisha-Kenkyu framework. The first theme comprised four subthemes: fear of the unknown; difficulty in adaptation; dysfunction in patient care; and defilement and oppression. The second theme involved feeling in control and professionalism. The third theme, which was based on participants' discovery of "same and different" fellowships, showed work reconstruction and self-understanding, which alleviated their difficulties., Conclusions: The effect of the pandemic on nurses working in primary care ranges from work-related frustration to daily life issues. The Tojisha-Kenkyu method can help nurses to alleviate difficulties. Further research should be conducted to elucidate the constant burden on primary care professionals and establish appropriate occupational and daily life support during pandemics., Competing Interests: The author has stated explicitly that there are no conflicts of interest in connection with this article., (© 2022 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Background: The COVID-19 pandemic has affected the mental health of health care workers. This study aimed to investigate the stress factors that cause burnout in Japanese physicians and their coping methods during the COVID-19 pandemic., Methods: We conducted a sequential explanatory mixed-method study to investigate the psychological responses of physicians in the early stages of the pandemic. A cross-sectional, web-based, anonymous survey was conducted among members of the American College of Physicians Japan Chapter to quantitatively investigate the stress factors and prevalence of burnout. An open-ended questionnaire with questions about stress factors and coping methods was additionally administered. The qualitative data were analyzed using qualitative content analysis., Results: Among the 1173 physicians surveyed, 214 (18.2%) responded. Among the participants, 107 (50.0%) responded "yes" to the question "I feel or have felt very stressed at work during the COVID-19 pandemic," and 68 (31.8%) reported burnout symptoms. Those who reported feeling stress (117 respondents) were asked to select 12 items of the stress factors related to COVID-19. The most significant stress factor related to COVID-19 was "Perceived risk of spreading COVID-19 to family members" ( n  = 47). Content analysis identified 12 categories for the stress factors and 7 for stress-coping methods corresponding to COVID-19 (Cohen's kappa = 0.84 and 0.95, respectively)., Conclusion: Several distinct stressors existed during the COVID-19 pandemic, which might be related to burnout among physicians. Practicing stress-coping strategies, as identified in the present study, may help reduce work-related stress and prevent burnout., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2022 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Background: Educating healthcare professionals about the social determinants of health is important in improving health outcomes of marginalized patients. Residents' experience of learning about the social determinants of health and a clinical assessment tool remains unclear., Methods: Residents participated in an online session about the social determinants of health and the assessment tool. Using the New World Kirkpatrick Model, we obtained data about participants' experience from various perspectives. The data were analyzed using a concurrent triangulation mixed-methods design., Results: The study included 20 out of 30 residents. Their response was good, and self-reported learning scores were increased by the session. They learned when to ask about patients' social conditions, what to ask, and how to coordinate medical care appropriately. Participants reported reflecting on their role as medical professionals and implementing new practices based on their learning, as well as concerns about addressing patients' social conditions., Conclusion: Through learning about the social determinants of health, and assessment tools, residents both acquired knowledge and skills, and reflected on their previous practice, accepted patients as they are, understood difficult patients better, and developed interprofessional collaboration. Medical education about the social determinants of health can trigger changes in residents' views., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 2022 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Nanomaterials show great promise as bone regeneration materials. They can be used as fillers to strengthen bone regeneration scaffolds, or employed in their natural form as carriers for drug delivery systems. A variety of experiments have been conducted to evaluate the osteogenic potential of bone regeneration materials. In vivo, such materials are commonly tested in animal bone defect models to assess their bone regeneration potential. From an ethical standpoint, however, animal experiments should be minimized. A standardized in vitro strategy for this purpose is desirable, but at present, the results of studies conducted under a wide variety of conditions have all been evaluated equally. This review will first briefly introduce several bone regeneration reports on nanomaterials and the nanosize-derived caveats of evaluations in such studies. Then, experimental techniques (in vivo and in vitro), types of cells, culture media, fetal bovine serum, and additives will be described, with specific examples of the risks of various culture conditions leading to erroneous conclusions in biomaterial analysis. We hope that this review will create a better understanding of the evaluation of biomaterials, including nanomaterials for bone regeneration, and lead to the development of versatile assessment methods that can be widely used in biomaterial development.

Objective To evaluate the change in the prevalence of burnout during the COVID-19 pandemic among internists and primary care physicians in Japan, and to identify factors associated with the exacerbation of burnout among these populations during this period. Methods This was a cross-sectional study based on two web-based surveys conducted in January 2020 (before the declaration of the COVID-19 pandemic) and June 2020 (during the pandemic). The participants were internists and primary care physicians of the Japanese Chapter of the American College of Physicians. The main outcome was the change in the prevalence of burnout between before and during the "first wave" of the pandemic. We also examined factors associated with the exacerbation of burnout during this period. Results Among the 283 respondents in the first survey and 322 in the second survey, 98 (34.6%) and 111 (34.5%) reported symptoms of burnout, respectively. In June 2020, 82 respondents (25.5%) reported that their level of burnout exacerbated compared to January 2020. Only the experience of self-quarantine was associated with the exacerbation of burnout [odds ratio (OR) 3.12; 95% confidence interval (CI) 1.49-6.50; p=0.002], while being a woman, being a resident physician, and an experience of having worked in a prefecture under a state of emergency were not. Conclusions No marked change in the prevalence of burnout among internists and primary care physicians in Japan was observed during the COVID-19 pandemic as a whole. However, self-quarantine was associated with the exacerbation of the burnout level.

Objective The Mini-Z 2.0 is a new, simple, and nonproprietary tool for assessing physician well-being and burnout. To date, a non-English version of the Mini-Z 2.0 survey has not been validated. Therefore, we aimed to develop a Japanese version of the Mini-Z 2.0 and to evaluate its validity and reliability using survey data from physicians affiliated with an internal medicine academic society. Methods The Mini-Z 2.0 survey was translated into Japanese using a forward-backward translation method. The participants belonged to the American College of Physicians' Japan Chapter. The translated version of the Mini-Z 2.0 survey was distributed to participants using an electronic mailing list. Convergent validity was assessed between burnout and other items using Pearson's product-moment statistic. Structural validity was evaluated using an exploratory factor analysis and confirmatory factor analysis, and reliability was assessed using internal consistency. Results Of the 1,255 physicians and medical residents contacted, 283 responded (22.5%). Burnout was present in 34.6% of the participants, with 48.8% reporting high stress levels. Convergent validity was demonstrated, with satisfactory correlations between burnout and satisfaction, value alignment, work control, and stress. An exploratory factor analysis identified two factors (i.e., Well-Being and Relationships and Work-Related Stressors); however, the three models evaluated using the confirmatory factor analysis revealed a poor fit. Cronbach's alpha for the sample was 0.80. Conclusion The Japanese version of the Mini-Z 2.0 demonstrated good internal consistency and convergent validity. Despite its inadequate structural validity, it can be used to measure physician well-being and related workplace conditions in Japan.

Many biomaterials have been evaluated using cultured cells. In particular, osteoblast-like cells are often used to evaluate the osteocompatibility, hard-tissue-regeneration, osteoconductive, and osteoinductive characteristics of biomaterials. However, the evaluation of biomaterial osteogenesis-inducing capacity using osteoblast-like cells is not standardized; instead, it is performed under laboratory-specific culture conditions with different culture media. However, the effect of different media conditions on bone formation has not been investigated. Here, we aimed to evaluate the osteogenesis of MC3T3-E1 cells, one of the most commonly used osteoblast-like cell lines for osteogenesis evaluation, and assayed cell proliferation, alkaline phosphatase activity, expression of osteoblast markers, and calcification under varying culture media conditions. Furthermore, the various media conditions were tested in uncoated plates and plates coated with collagen type I and poly-L-lysine, highly biocompatible molecules commonly used as pseudobiomaterials. We found that the type of base medium, the presence or absence of vitamin C, and the freshness of the medium may affect biomaterial regeneration. We posit that an in vitro model that recapitulates in vivo bone formation should be established before evaluating biomaterials.

Background and Aims: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy., Methods: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively., Results: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m 2 ) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51-4.25) and 2.56 (95% CI: 1.14-5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61-2.33)., Conclusions: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR., Competing Interests: Kazuhiko Koike has received research funding from Merck Sharp & Dohme, Chugai Pharmaceutical Co., Ltd, Bristol-Meyers Squibb, Gilead Sciences, AbbVie GK, Janssen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma Corporation. Ryosuke Tateishi has received lecture fee from Merck Sharp & Dohme, Chugai Pharmaceutical Co., Ltd, Bristol-Meyers Squibb, Gilead Sciences, AbbVie GK, and Mitsubishi Tanabe Pharma Corporation. Tatsuya Minami has received lecture fee from Merck Sharp & Dohme, Gilead Sciences, and AbbVie GK. Hiroshi Yotsuyanagi has received lecture fee from Merck Sharp & Dohme, Bristol-Meyers Squibb, Gilead Sciences, and AbbVie GK. Naoya Kato has received research funding and lecture fee from Merck Sharp & Dohme, Chugai Pharmaceutical Co., Ltd, Bristol-Meyers Squibb, Gilead Sciences, AbbVie GK, Jansen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma Corporation. Atsushi Tanaka has received lecture fee from Gilead Sciences and AbbVie GK. Yoshinari Asaoka has received lecture fee from Merck Sharp & Dohme, Gilead Sciences, and AbbVie GK. Kazuaki Inoue has received research funding from Chugai Pharmaceutical K.K, Bristol-Myers Squibb, AbbVie GK, and Merck Sharp & Dohme and has received lecture fee from AbbVie GK, Bristol-Myers Squibb, Merck Sharp & Dohme, and Gilead Sciences. Yasuo Tanaka has received research funding from Gilead Sciences. Hayato Nakagawa has received lecture fee from Merck Sharp & Dohme and Gilead Sciences. Takamasa Ohki has received lecture fee from Bayer Yakuhin Ltd and Eisai Co., Ltd., (Copyright © 2021 by S. Karger AG, Basel.)

Epithelial cells in the biliary system can develop refractory types of cancers, which are often associated with inflammation caused by viruses, parasites, stones, and chemicals. Genomic studies have revealed recurrent genetic changes and deregulated signaling pathways in biliary tract cancer (BTC). The causal roles have been at least partly clarified using various genetically engineered mice. Technical advances in Cre-LoxP technology, together with hydrodynamic tail injection, CRISPR/Cas9 technology, in vivo electroporation, and organoid culture have enabled more precise modeling of BTC. Organoid-based genetic modeling, combined with implantation in mice, has recently drawn attention as a means to accelerate the development of BTC models. Although each model may not perfectly mimic the disease, they can complement one another, or two different approaches can be integrated to establish a novel model. In addition, a comparison of the outcomes among these models with the same genotype provides mechanistic insights into the interplay between genetic alterations and the microenvironment in the pathogenesis of BTCs. Here, we review the current status of genetic models of BTCs in mice to provide information that facilitates the wise selection of models and to inform the future development of ideal disease models.

One of the greatest challenges to overcome in the pursuit of the medical application of carbon nanomaterials (CNMs) is safety. Particularly, when considering the use of CNMs in drug delivery systems (DDSs), evaluation of safety at the accumulation site is an essential step. In this study, we evaluated the toxicity of carbon nanohorns (CNHs), which are potential DDSs, using human lymph node endothelial cells that have been reported to accumulate CNMs, as a comparison to fibrous, multi-walled carbon nanotubes (MWCNTs) and particulate carbon black (CB). The effect of different surface characteristics was also evaluated using two types of CNHs (untreated and oxidized). In the fibrous MWCNT, cell growth suppression, as well as expression of inflammatory cytokine genes was observed, as in previous reports. In contrast, no significant toxicity was observed for particulate CB and CNHs, which was different from the report of CB cytotoxicity in vascular endothelial cells. These results show that (1) lymph endothelial cells need to be tested separately from other endothelial cells for safety evaluation of nanomaterials, and (2) the potential of CNHs as DDSs.

The organoid culture technique has been recently applied to modeling carcinogenesis in several organs. To further explore its potential and gain novel insights into tumorigenesis, we here investigated whether pancreatic ductal adenocarcinoma (PDA) could be generated as subcutaneous tumors in immunocompromised nude mice, by genetic engineering of normal organoids. As expected, acute induction of KrasG12Din vitro occasionally led to development of tiny nodules compatible with early lesions known as pancreatic intraepithelial neoplasia (PanIN). KrasG12D-expressing cells were enriched after inoculation in the subcutis, yet proved rather declined during culture, suggesting that its advantage might depend on surrounding environments. Depletion of growth factors or concurrent Trp53 deletion resulted in its robust enrichment, invariably leading to development of PanIN or large high-grade adenocarcinoma, respectively, consistent with in vivo mouse studies for the same genotype. Progression from PanIN was also recapitulated by subsequent knockdown of common tumor suppressors, whereas the impact of Tgfbr2 deletion was only partially recapitulated, illustrating genotype-dependent requirement of the pancreatic niche for tumorigenesis. Intriguingly, analysis of tumor-derived organoids revealed that KrasG12D-expressing cells with spontaneous deletion of wild-type Kras were positively selected and exhibited an aging-related mutation signature in nude mice, mirroring the pathogenesis of human PDA, and that the sphere-forming potential and orthotopic tumorigenicity in syngenic mice were significantly augmented. These observations highlighted the relevance of the subcutis of nude mice in promoting PDA development despite its ectopic nature. Taken together, pancreatic carcinogenesis could be considerably recapitulated with organoids, which would probably serve as a novel disease model., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cancers arising from the biliary tract are refractory to conventional therapies, requiring the development of novel therapeutics. However, only a limited number of genetically engineered mouse models have been created, partly because of time-consuming work required. Besides, liver-specific gene manipulation mostly resulted in concurrent development of hepatocellular carcinoma, another type of liver cancer, and gallbladder-restricted gene targeting is still not feasible. Consequently, establishment of cancer type-specific disease modeling remains a technical challenge. To address this issue, we took an alternative cell-based approach to quickly induce tumorigenesis ex vivo. Specifically, murine primary organoids from liver and gallbladder were transduced with lentiviral vectors to reconstitute genetic alterations common in biliary tract cancers, followed by inoculation in immunodeficient mice. Although any single genetic alteration did not induce tumors, mutant Kras and repression of major tumor suppressors cooperated for tumor development within 2 months. Induced lesions varied among normal, dysplastic and papillary lesions to adenocarcinoma, recapitulating multistep tumorigenesis even in a heterotopic situation. We further demonstrated that two putative oncogenes in intrahepatic cholangiocellular carcinoma, mutant Pik3ca and FGFR2-AHCYL1 fusion, were rather modest drivers for liver-derived organoids, probably requiring additional mutations or hepatic niche to robustly induce full-blown tumors. Thus, we showed that cancer cells could be readily generated from primary cells in the biliary tract, at least in cases where genetic factors play dominant roles. Collectively, this study will likely contribute to gaining mechanistic insights into biliary carcinogenesis and providing valuable resources for drug discovery., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole-exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage-matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A-to-C nucleotide change in the context of "AAG" was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such "LM-associated" genes were overrepresented for extracellular matrix-receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1-substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Dysplasia represents a preneoplastic status in multistep colon carcinogenesis. Whereas laborious preparation of thin sections is required for its diagnosis, we here show that newly defined aberrant crypt foci (ACF) simply mark the majority of the dysplasia on the whole colon. Specifically, decoloring of the azoxymethane-treated rat colon after scoring classical ACF (cACF) resulted in visualization of a subset of aberrant crypts that remained densely stained. They were morphologically classified into three subtypes, of which two with compressed luminal openings proved highly correlated with dysplasia. Accordingly, we designated those foci harboring either of the two crypt subtypes as dysplasia-associated ACF (dACF). By serially applying different detection methods for known preneoplastic lesions to the same colon, we showed that most dACF had already been identified as cACF, and a few newly identified dACF contained an entire population of more advanced lesions, such as flat ACF and mucin-depleted foci. Consequently, integrative scoring of cACF and dACF enabled capture of all early lesions of the colon. Furthermore, 94% of the dACF showed dysplasia and 90% of the dysplastic lesions proved to be dACF. Thus, dACF is a promising marker for dysplasia, likely facilitating precise identification of the early stages of colon carcinogenesis., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Purpose: Exosomal microRNAs (miRNAs) have been attracting major interest as potential diagnostic biomarkers of cancer. The aim of this study was to characterize the miRNA profiles of serum exosomes and to identify those that are altered in colorectal cancer (CRC). To evaluate their use as diagnostic biomarkers, the relationship between specific exosomal miRNA levels and pathological changes of patients, including disease stage and tumor resection, was examined., Experimental Design: Microarray analyses of miRNAs in exosome-enriched fractions of serum samples from 88 primary CRC patients and 11 healthy controls were performed. The expression levels of miRNAs in the culture medium of five colon cancer cell lines were also compared with those in the culture medium of a normal colon-derived cell line. The expression profiles of miRNAs that were differentially expressed between CRC and control sample sets were verified using 29 paired samples from post-tumor resection patients. The sensitivities of selected miRNAs as biomarkers of CRC were evaluated and compared with those of known tumor markers (CA19-9 and CEA) using a receiver operating characteristic analysis. The expression levels of selected miRNAs were also validated by quantitative real-time RT-PCR analyses of an independent set of 13 CRC patients., Results: The serum exosomal levels of seven miRNAs (let-7a, miR-1229, miR-1246, miR-150, miR-21, miR-223, and miR-23a) were significantly higher in primary CRC patients, even those with early stage disease, than in healthy controls, and were significantly down-regulated after surgical resection of tumors. These miRNAs were also secreted at significantly higher levels by colon cancer cell lines than by a normal colon-derived cell line. The high sensitivities of the seven selected exosomal miRNAs were confirmed by a receiver operating characteristic analysis., Conclusion: Exosomal miRNA signatures appear to mirror pathological changes of CRC patients and several miRNAs are promising biomarkers for non-invasive diagnosis of the disease.

We conducted a retrospective study of the efficacy of a polyethylene glycol purge before colonoscopic examination in 110 patients with colonic diverticular bleeding. The patients' data were assessed for the timing of colonoscopy and the methods used to stop bleeding. The rate at which bleeding diverticula were identified was markedly higher when a purge was used than when it was not (28.2% vs. 12.0%, p=0.11). In addition, the identification rate was significantly higher when colonoscopic examination was performed within 18 hours of the final hematochezia than when it was performed after 18 hours (40.5% vs. 10.5%, p<0.01). These findings suggest that patients with diverticular bleeding should undergo colonoscopy following an orally administered colonic purge, providing their condition permits. Furthermore, colonoscopy should be performed within 18 hours of the final hematochezia in order to improve identification of the bleeding diverticulum.

A 42-year-old man was admitted to our hospital with a lower extremity rash, general fatigue, and abdominal discomfort. Laboratory findings revealed elevated serum transaminases as well as positivity for the hepatitis B surface antigen and the immunoglobulin M type anti-hepatitis B core antibody. He was diagnosed with a rash typical of Gianotti-Crosti syndrome due to acute infection with hepatitis B virus, genotype A. After admission, the rash gradually decreased; however, serum transaminases and jaundice increased. Entecavir therapy was initiated on day 11 of admission, and his liver function subsequently improved over two weeks. Gianotti-Crosti syndrome is rarely seen in adult patients. It may be important to pay attention to the typical rash of Gianotti-Crosti syndrome because it may provide an important clue to an otherwise asymptomatic acute hepatitis B infection.

Background: Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer., Methods: Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry., Results: Six out of the 7 gastric cancer cell lines overexpressed Mcl-1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44-positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44-positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations., Conclusion: These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells.

Background: Although previous studies indicate that gastrointestinal (GI) cancer may originate from cells recruited from bone marrow (BM) in mice, whether similar phenomena occur in humans is controversial. In the current study, we evaluated two female patients who developed colonic adenocarcinoma more than 10 years after gender-mismatched BM transplantation, and followingly underwent successful endoscopic mucosal resection., Materials and Methods: Fluorescent in situ hybridization (FISH) analysis was used to determine whether the tumours contained donor-derived BM cells., Results: Approximately 1.2% of the tumour cells contained Y-chromosome-positive signals, and a comparable percentage of normal colonic epithelial cells close to the tumour also contained Y-chromosome-positive signals., Conclusion: These results do not support the concept that GI cancer can originate from BM-derived cells.

Background: The aim of this study was to evaluate whether apoptosis-resistant cancer cells have cancer stem cell (CSC)-like properties., Materials and Methods: Panc-1 pancreatic cancer cells were incubated in the presence of 5-fluorouracil (5-FU) for 24 h, and further incubated without 5-FU for 28 days. To assess the capacity of self-renewal, surviving cells were planted for sphere-forming assay. Epithelial-to-mesenchymal transition (EMT) was induced with TGF-β, then mRNA expression was evaluated by real-time PCR for E-cadherin, SNAIL, and vimentin. The E-Cadherin protein levels were also examined by immunoblot analysis. The Local invasion ability was analyzed by Matrigel invasion assay., Results: The frequency of cells that were capable of initiating spheres was higher in 5-FU-pre treated cells, which also overexpressed stem cell marker genes, OCT4 and NANOG. Matrigel invasion activity of apoptosis-resistant Panc-1 cells was greater than that of control Panc-1 cells., Conclusion: Apoptosis-resistant cancer cells have CSC-like properties, i.e., able to initiate sphere formation, express stem cell genes, and respond to EMT stimulation.

Liver metastasis is a major lethal complication associated with colon cancer, and post-intravasation steps of the metastasis are important for its clinical intervention. In order to identify inhibitory microRNAs (miRNAs) for these steps, we performed 'dropout' screens of a miRNA library in a mouse model of liver metastasis. Functional analyses showed that miR-493 and to a lesser extent miR-493(*) were capable of inhibiting liver metastasis. miR-493 inhibited retention of metastasized cells in liver parenchyma and induced their cell death. IGF1R was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects. High levels of miR-493 and miR-493(*), but not pri-miR-493, in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. We propose that, in a subset of colon cancer, upregulation of miR-493 during carcinogenesis prevents liver metastasis via the induction of cell death of metastasized cells.

A 41-year-old man was admitted to our hospital with gastrointestinal bleeding. Esophagogastroduodenoscopy revealed a submucosal protrusion with erosion in the duodenal bulb which was thought to be the bleeding source. Dynamic CT scan, ultrasonography and angiography of the abdomen revealed a hepatic artery aneurysm and a dilated celiac artery that dissected from its origin. Although we considered percutaneous transcatheter arterial embolization with metallic coils, we chose surgical resection and vascular reconstruction to prevent hepatic ischemia resulting from interruption of collateral circulation. On the 8(th) day, hepatic artery aneurysmectomy and revascularization with a great saphenous vein was carried out without any severe complication. The pathological specimen demonstrated segmental arterial mediolysis.

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

MicroRNA (miRNA), non-coding RNA of approximately 22 nucleotides, post-transcriptionally represses expression of its target genes. miRNA regulates a variety of biological processes such as cell proliferation, cell death, development, stemness and genomic stability, not only in physiological conditions but also in various pathological conditions such as cancers. More than 1000 mature miRNA have been experimentally identified in humans and mice, yet the functions of a vast majority of miRNA remain to be elucidated. Identification of novel cancer-associated miRNA seems promising considering their possible application in the development of novel cancer therapies and biomarkers. Currently, there are two major approaches to identify miRNA that are associated with cancer: expression profiling study and functional screening assay. The former approach is widely used, and a large number of studies have shown aberrant miRNA expression profiles in cancer tissues compared with their non-cancer counterparts. Although aberrantly expressed miRNA are potentially good biomarkers, in most cases a majority of them do not play causal roles in cancers when functional assays are performed. In contrast, the latter approach allows screening of 'driver' miRNA with cancer-associated phenotypes, such as cell proliferation and cell invasion. Thus, this approach might be suitable in finding crucial targets of novel cancer therapy. The combination of both types of approaches will contribute to further elucidation of the cancer pathophysiology and to the development of a novel class of cancer therapies and biomarkers., (© 2011 Japanese Cancer Association.)

A 57-year-old man with advanced gallbladder cancer and accompanying hepatic, colonic and duodenal invasion and para-aortic lymph node metastasis was referred to our hospital. Gemcitabine plus S-1 administration was chosen. Gemcitabine was administered intravenously at a dose of 1000 mg/m(2) on days 1 and 15, and repeated every 4 weeks. S-1 was administered orally at a dose of 40 mg/m(2) b.i.d. on days 1-14. Chemotherapy was effective for the primary gallbladder tumor and lymph node metastasis. The primary tumor and metastatic lymph nodes were shown to have disappeared by a FDG-PET CT study after 10 courses of chemotherapy. Informed consent was obtained prior to performing surgery of the primary lesion. Pathological examination showed fibrosis and a small focus of residual cancer in the resected gallbladder. Complete resection was achieved as all the margins were negative. The findings suggest that gemcitabine plus S-1 treatment may be effective against advanced gallbladder cancer.

A 64-year-old male presented with discomfort in the chest. His endoscopic examination and CT scan showed esophageal cancer with multiple liver metastases. A total of ten courses of systemic chemotherapy by 5-fluorouracil (5-FU) (800 mg for five days) and cisplatin (CDDP) (80 mg/day on the first day of the week for four weeks) were performed, and liver and lymph node metastases disappeared. The primary lesion was the only site detected positive by PET scan. After a concurrent chemoradiation therapy, salvage endoscopic mucosal resection (EMR) was performed on the remainder of the primary site and the patient gained a complete response (CR). We report this case because, although the mean survival time of advanced esophageal cancer is less than one year, this patient responded to chemotherapy and gained complete response by salvage EMR. This patient has had no recurrence for four years since his initial diagnosis.

Selective activation of p53 target genes in response to various cellular stresses is a critical step in determining the ability to induce cell-cycle arrest or apoptosis. Here we report the identification of the microRNA miR-22 as a p53 target gene that selectively determines the induction of p53-dependent apoptosis by repressing p21. Combinatorial analyses of the AGO2 immunocomplex and gene expression profiles identified p21 as a direct target of miR-22. Induction of p21 was inhibited by miR-22 after exposure to the genotoxic agent Adriamycin (doxorubicin; Bedford Laboratories), sensitizing cells to p53-dependent apoptosis. Interestingly, the activation of miR-22 depended on the intensity of the stresses that induced cells to undergo apoptosis in the presence of p21 suppression. Our findings define an intrinsic molecular switch that determines p53-dependent cellular fate through post-transcriptional regulation of p21., (©2011 AACR.)