Bone morphogenetic protein signaling is a possible therapeutic target in gynecologic cancer.

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor ß (TGFß) superfamily. BMPs play crucial roles in embryogenesis and bone remodeling. Recently, BMP signaling has been found to have diverse effects on different types of tumors. In this review, we summarized the effects of BMP signaling on gynecologic cancer. BMP signaling has tumor-promoting effects on ovarian cancer (OC) and endometrial cancer (EC), whereas it has tumor-suppressing effects on uterine cervical cancer (UCC). Interestingly, EC has frequent gain-of-function mutations in ACVR1, encoding one of the type I BMP receptors, which are also observed in fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Little is known about the relationship between BMP signaling and other gynecologic cancers. Tumor-promoting effects of BMP signaling in OC and EC are dependent on the promotion of cancer stemness and epithelial-mesenchymal transition (EMT). In accordance, BMP receptor kinase inhibitors suppress the cell growth and migration of OC and EC. Since both cancer stemness and EMT are associated with chemoresistance, BMP signaling activation might also be an important mechanism by which OC and EC patients acquire chemoresistance. Therefore, BMP inhibitors are promising for OC and EC patients even if they become resistant to standard chemotherapy. In contrast, BMP signaling inhibits UCC growth in vitro. However, the in vivo effects of BMP signaling have not been elucidated in UCC. In conclusion, BMP signaling has a variety of functions, depending on the types of gynecologic cancer. Therefore, targeting BMP signaling should improve the treatment of patients with gynecologic cancer.

Association between Maternal Characteristics and Immune Factors TGF-ß1, TGF-ß2, and IgA in Colostrum: An Exploratory Study in Japan.

Colostrum is the first food for newborns and it contains various crucial immune factors. The concentrations of immune factors in breast milk may change depending on maternal characteristics such as body mass index, collection day, and age at first pregnancy. In this exploratory study, we investigated the association between TGF-ß1, TGF-ß2, and IgA in colostrum and rarely studied factors that affect breast milk components, including the use of labor-inducing medication, colostrum secretion, sex of newborns, breast or nipple problems, and nipple care. Breast milk samples were collected from 42 mothers and analyzed for TGF-ß1, TGF-ß2, and IgA. The results suggest that parity and mode of delivery may be correlated with the concentrations of immune factors in colostrum. However, we found no association between the immune factors in colostrum and the use of labor-inducing medications, colostrum secretion, sex of newborns, breast or nipple problems, and nipple care. These findings have some implications for further analysis of the effects of immune factors in breast milk on the prognosis of allergies in children.

Differences in energy source storage in eye stalks between two species of stalk-eyed flies, Sphyracephala detrahens and Cyrtodiopsis dalmanni.

Some diopsid flies have sexually dimorphic eye stalks that are assumed to require considerable nutrition for growth but are advantageous in competition and courtship. According to the handicap theory, the eye span in some dimorphic species serves as a reliable signal of individual quality to an opponent. However, it is not well understood how well eye span represents energy source storage. In this study, we focused on two species: Sphyracephala detrahens, which has weak dimorphism, and Cyrtodiopsis dalmanni, which has moderate dimorphism. We found that the eye stalks of the former species contained more fat bodies than those of the latter species. When the flies were starved, the fat body cells in the eye stalks underwent autophagy. A strong positive correlation was consistently found between eye span and starvation tolerance for S. detrahens, while a weak correlation was found for C. dalmanni. Furthermore, starvation decreased the contest winning rate between S. detrahens pairs with similar eye spans. These findings suggest that the presentation of resource holding potential may be larger than the actual storage ability and that the fidelity of nutritional storage signaling varies; the signal presented by S. detrahens is more reliable than that presented by C. dalmanni.

Diagnostic utility of the basophil activation test in natto-induced hypersensitivity.

BACKGROUND: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. METHODS: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. RESULTS: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. CONCLUSIONS: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.

BMP2-induction of FN14 promotes protumorigenic signaling in gynecologic cancer cells.

We previously reported that bone morphogenetic protein (BMP) signaling promotes tumorigenesis in gynecologic cancer cells. BMP2 enhances proliferation of ovarian and endometrial cancer cells via c-KIT induction, and triggers epithelial-mesenchymal transition (EMT) by SNAIL and/or SLUG induction, leading to increased cell migration. However, the downstream effectors of BMP signaling in gynecological cancer cells have not been clearly elucidated. In this study, we performed RNA-sequencing of Ishikawa endometrial and SKOV3 ovarian cancer cells after BMP2 stimulation, and identified TNFRSF12A, encoding fibroblast growth factor-inducible 14 (FN14) as a common BMP2-induced gene. FN14 knockdown suppressed BMP2-induced cell proliferation and migration, confirmed by MTS and scratch assays, respectively. In addition, FN14 silencing augmented chemosensitivity of SKOV3 cells. As a downstream effector of BMP signaling, FN14 modulated both c-KIT and SNAIL expression, which are important for growth and migration of ovarian and endometrial cancer cells. These results support the notion that the tumor promoting effects of BMP signaling in gynecological cancers are partially attributed to FN14 induction.

Tumor Promoting Effect of BMP Signaling in Endometrial Cancer.

The effects of bone morphogenetic proteins (BMPs), members of the transforming growth factor-ß (TGF-ß) family, in endometrial cancer (EC) have yet to be determined. In this study, we analyzed the TCGA and MSK-IMPACT datasets and investigated the effects of BMP2 and of TWSG1, a BMP antagonist, on Ishikawa EC cells. Frequent ACVR1 mutations and high mRNA expressions of BMP ligands and receptors were observed in EC patients of the TCGA and MSK-IMPACT datasets. Ishikawa cells secreted higher amounts of BMP2 compared with ovarian cancer cell lines. Exogenous BMP2 stimulation enhanced EC cell sphere formation via c-KIT induction. BMP2 also induced EMT of EC cells, and promoted migration by induction of SLUG. The BMP receptor kinase inhibitor LDN193189 augmented the growth inhibitory effects of carboplatin. Analyses of mRNAs of several BMP antagonists revealed that TWSG1 mRNA was abundantly expressed in Ishikawa cells. TWSG1 suppressed BMP7-induced, but not BMP2-induced, EC cell sphere formation and migration. Our results suggest that BMP signaling promotes EC tumorigenesis, and that TWSG1 antagonizes BMP7 in EC. BMP signaling inhibitors, in combination with chemotherapy, might be useful in the treatment of EC patients.

BMP signaling is a therapeutic target in ovarian cancer.

BMP signaling has been found to have tumor-promoting as well as tumor-suppressing effects in different types of tumors. In this study, we investigated the effects of BMP signaling and of BMP inhibitors on ovarian cancer (OC) cells in vitro and in vivo. High expression of BMP receptor 2 (BMPR2) correlated with poor overall survival of OC patients in the TCGA dataset. Both BMP2 and BMPR2 enhanced OC cell proliferation, whereas BMP receptor kinase inhibitors inhibited OC cell growth in cell culture as well as in a mouse model. BMP2 also augmented sphere formation, migration, and invasion of OC cells, and induced EMT. High BMP2 expression was observed after chemotherapy of OC patients in the GSE109934 dataset. In accordance, carboplatin, used for the treatment of OC patients, increased BMP2 secretion from OC cells, and induced EMT partially via activation of BMP signaling. Our data suggest that BMP signaling has tumor-promoting effects in OC, and that BMP inhibitors might be useful therapeutic agents for OC patients. Considering that carboplatin treatment augmented BMP2 secretion, the possibility to use a combination of BMP inhibitors and carboplatin in the treatment of OC patients, would be worth exploring.

Development of an electronic medical record-based algorithm to identify patients with Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), severe drug reactions, are often misdiagnosed due to their rarity and lack of information on differential diagnosis. The objective of the study was to develop an electronic medical record (EMR)-based algorithm to identify patients with SJS/TEN for future application in database studies. From the EMRs of a university hospital, two dermatologists identified all 13 patients with SJS/TEN seen at the Department of Dermatology as the case group. Another 1472 patients who visited the Department of Dermatology were identified using the ICD-10 codes for diseases requiring differentiation from SJS/TEN. One hundred of these patients were then randomly sampled as controls. Based on clinical guidelines for SJS/TEN and the experience of the dermatologists, we tested 128 algorithms based on the use of ICD-10 codes, clinical courses for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) of each algorithm were calculated, and the optimal algorithm was defined as that with high PPV and maximal sensitivity and specificity. One algorithm, consisting of a combination of clinical course for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus, but not ICD-10 codes, showed a sensitivity of 76.9%, specificity of 99.0%, PPV of 40.5%, NPV of 99.8%, and DOR of 330.00. We developed a potentially optimized algorithm for identifying SJS/TEN based on clinical practice records. The almost perfect specificity of this algorithm will prevent bias in estimating relative risks of SJS/TEN in database studies. Considering the small sample size, this algorithm should be further tested in different settings.

Issues experienced while administering care to patients with dementia in acute care hospitals: a study based on focus group interviews.

OBJECTIVE: Dementia is a major public health problem. More and more patients with dementia are being admitted to acute care hospitals for treatment of comorbidities. Issues associated with care of patients with dementia in acute care hospitals have not been adequately clarified. This study aimed to explore the challenges nurses face in providing care to patients with dementia in acute care hospitals in Japan. METHODS: This was a qualitative study using focus group interviews (FGIs). The setting was six acute hospitals with surgical and medical wards in the western region of Japan. Participants were nurses in surgical and internal medicine wards, excluding intensive care units. Nurses with less than 3 years working experience, those without experience in dementia patient care in their currently assigned ward, and head nurses were excluded from participation. FGIs were used to collect data from February to December 2008. Interviews were scheduled for 1-1.5 h. The qualitative synthesis method was used for data analysis. RESULTS: In total, 50 nurses with an average experience of 9.8 years participated. Eight focus groups were formed. Issues in administering care to patients with dementia at acute care hospitals were divided into seven groups. Three of these groups, that is, problematic patient behaviors, recurrent problem, and problems affecting many people equally, interact to result in a burdensome cycle. This cycle is exacerbated by lack of nursing experience and lack of organization in hospitals. In coping with this cycle, the nurses develop protection plans for themselves and for the hospital. CONCLUSIONS: The two main issues experienced by nurses while administering care to patients with dementia in acute care hospitals were as follows: (a) the various problems and difficulties faced by nurses were interactive and caused a burdensome cycle, and (b) nurses do their best to adapt to these conditions despite feeling conflicted.

Characteristics of caregiver perceptions of end-of-life caregiving experiences in cancer survivorship: in-depth interview study.

OBJECTIVE: Little is known about caregiver experiences during the end-of-life period. Our objective was to characterize caregiver perceptions of their experiences in cancer survivorship with special reference to the end-of-life stage considering depression in bereavement. METHODS: Qualitative research using in-depth interviews of 34 caregivers from two palliative care units in Japan. Data were analyzed inductively using framework analysis. Depression and personality traits were measured using the Center for Epidemiological Studies Depression (CES-D) and Sense of Coherence (SOC) scales, respectively. RESULTS: Caregiver perceptions were characterized along two axes. One axis involved four caregiver-cancer patient relationships: strengthening, reconstruction, intimacy-maintained, and estrangement-maintained. The core concept was transformation of relationships: caregivers reappraised aspects of caregiver-patient interactions through caregiving. The other axis involved subjective caregiving experiences divided into five concepts: spontaneity of care, discussing death, sympathy for patient emotions, impressions on first witnessing death, and introspective reflections in bereavement. Strengthening and reconstruction relationships appeared similar among the four relationship types, but only the former tended to overcompensate by sacrificing private time. Although median CES-D scores in each relationship type were under the cutoff for possible depression, four of eight caregivers suspected to have depressive tendencies belonged to the strengthening type. The mean SOC score for all caregivers was intermediate relative to scores previously reported in Japanese studies. CONCLUSIONS: While caregivers' subjective experiences can be classified, their relationship to depression in bereavement needs future research. The present findings indicate that caregivers should also be considered in clinicians' views of cancer survivorship.

Effectiveness of simplified chest compression-only CPR training program with or without preparatory self-learning video: a randomized controlled trial.

OBJECTIVES: To evaluate the effectiveness of 1-h practical chest compression-only cardiopulmonary resuscitation (CPR) training with or without a preparatory self-learning video. METHODS: Participants were randomly assigned to either a control group or a video group who received a self-learning video before attending the 1-h chest compression-only CPR training program. The primary outcome measure was the total number of chest compressions during a 2-min test period. RESULTS: 214 participants were enrolled, 183 of whom completed this study. In a simulation test just before practical training began, 88 (92.6%) of the video group attempted chest compressions, while only 58 (64.4%) of the control group (p<0.001) did so. The total number of chest compressions was significantly greater in the video group than in the control group (100.5+/-61.5 versus 74.4+/-55.5, p=0.012). The proportion of those who attempted to use an automated external defibrillator (AED) was significantly greater in the video group (74.7% versus 28.7%, p<0.001). After the 1-h practical training, the number of total chest compressions markedly increased regardless of the type of CPR training program and inter-group differences had almost disappeared (161.0+/-31.8 in the video group and 159.0+/-35.7 in the control group, p=0.628). CONCLUSIONS: 1-h chest compression-only CPR training makes it possible for the general public to perform satisfactory chest compressions. Although a self-learning video encouraged people to perform CPR, their performance levels were not sufficient, confirming that practical training as well is essential. (UMIN000001046).

Barriers to vaccination among Japanese medical students: focus group interviews.

BACKGROUND: To date, medical schools and clinical training hospitals in Japan that require students to show immunity for measles, mumps, rubella, varicella (chickenpox), and hepatitis B prior to the commencement of residency are limited. METHODS: This qualitative study used focus group interviews to elucidate why medical students do not undergo vaccination. A total of three groups were identified and interviewed: group A (two men, three women), group B (two men, two women), group C (three men, two women). All recorded interviews were transcribed verbatim and analyzed according to the constant comparative method with a series of codes and categories. RESULTS: Findings elucidated that vaccination for medical students is not mandatory in Japan. Analysis found that the factors that influence willingness to be vaccinated can be divided into three dimensions (individual level, university/regional hospital level, governmental level) and two primary categories (cost of vaccination, awareness of vaccination) consisting of 10 codes. These factors did not exist in isolation, but have mutually overlapping areas. CONCLUSIONS: Vaccination against vaccine-preventable diseases is essential to a hospital's infectious-disease countermeasures and cannot continue to be overlooked by physicians (at the individual level), by universities and residency programs (at the community level) nor by the government (at the national level).