Znrf3 exon 2 deletion mice do not recapitulate congenital adrenal hypoplasia.

Wnt/ß-catenin signaling is essential for adrenocortical development. Zinc and ring finger 3 (ZNRF3), an E3 ubiquitin ligase that attenuates Wnt/ß-catenin signaling, is negatively regulated by R-spondin via an extracellular domain that is partially encoded by exon 2 of ZNRF3. We recently identified ZNRF3 exon 2 deletions in three individuals with congenital adrenal hypoplasia. ZNRF3 exon 2 deletion impairs R-spondin binding, thereby attenuating ß-catenin expression, eventually developing congenital adrenal hypoplasia. To elucidate the influence of ZNRF3/Znrf3 exon 2 deletion on adrenocortical development, we generated homozygous Znrf3 exon 2 deletion (Znrf3Δ2/Δ2) mice. The adrenal glands of Znrf3Δ2/Δ2 mice did not show gross morphological changes at birth but became enlarged with age. Moderate hyperplasia of the zona fasciculata (ZF), dispersed medulla arrangement, and a radially spreading zone comprised of cells with large nuclei between the ZF and medulla were observed at 6 weeks of age. Immunohistochemistry revealed low levels of 20α-hydroxysteroid dehydrogenase, a marker of the adrenal X-zone, in Znrf3Δ2/Δ2 mice. Plasma ACTH and serum corticosterone levels in Znrf3Δ2/Δ2 mice did not differ significantly from those in wild-type mice. Transcriptome analyses of the adrenal glands revealed substantial downregulation of X-zone markers but no significant changes in the expression of genes involved in the Wnt/ß-catenin signaling pathway. These results show that a species-specific difference in the effects of ZNRF3/Znrf3 exon 2 deletions in humans and mice; Znrf3Δ2/Δ2 mice do not develop congenital adrenal hypoplasia but instead exhibit moderate ZF hyperplasia, dispersed medulla arrangement, and X-zone dysplasia.

Studies on the potential risk of amyloidosis from exposure to cultured fibril from silk fibroin.

Amyloid A (AA) amyloidosis is induced by administering amyloid fibrils to animals under inflammatory conditions. Silk fibroin (SF), the main component of silk threads, forms amyloid-like fibrils and has been previously reported to induce AA amyloidosis in mice. In this study, SF was cultured in ethanol solution, and after confirming fibril formation through thioflavin T assay, Congo red assay, and observation under electron microscopy, cultured SF ethanol solutions were administered to mice via various routes to investigate the induction of target organs and amyloidosis. As a result, cultured SF ethanol solutions were confirmed to reach the lungs and spleen, but no amyloid deposition was observed. While SF forms amyloid-like fibril structures through cultivation in ethanol solution, its amyloid-enhancing factor (AEF) activity is considered low in mice.

Developing and evaluating a cancer communication picture book for children, families, and health care professionals: A mixed-methods feasibility study.

Objective: Effective communication about cancer with children is a significant challenge for healthcare professionals and families. This study aimed to create a picture book as a tool for facilitating communication about cancer and to assess its feasibility. It also demonstrated the use of mixed methods and convergent designs for intervention development. Methods: The study included healthcare professionals (n = 14), children without cancer (aged 4-8 years; n = 21) and their families (n = 18), as well as children with various types of cancer, undergoing maintenance therapy or follow-up (aged 4-12 years; n = 3) and their families (n = 3). Quantitative and qualitative data were separately analyzed, and meta-inferences were made using a joint display. The picture book was refined based on feedback from healthcare professionals, and a similar iterative process was carried out with children and their families. Results: Over 85% of the participants considered the picture book, along with a side book, feasible. The picture book was found to be helpful for discussing the topic of cancer with children. It also significantly improved the knowledge of children without cancer (P < 0.01). Most children expressed interest in reading it and believed it was useful for talking to others about cancer. However, some concerns were raised regarding the context and expressions in the picture book. Conclusions: This study successfully assessed the feasibility of the developed picture book using a mixed methods approach, offering valuable insights into its implementation and refinement. Further research is needed to evaluate the effectiveness of its use and gather user feedback.

Keratinic amyloid deposition in canine hair follicle tumors.

Keratinic primary localized cutaneous amyloidosis is a disease in humans; however, no similar condition has been reported in animals. This study aimed to investigate cutaneous keratinic amyloid deposition in dogs and elucidate its etiology. Canine hair follicle tumor tissues were histopathologically analyzed. Immunohistochemistry and mass spectrometry-based proteomic analyses were performed to identify precursor protein candidates. Structural prediction and in vitro fibrillization analyses were conducted to determine the amyloidogenic region and gene sequencing analysis was performed to assess mutations. Of the 266 samples, 16 had amyloid deposition. Amyloid deposits were found in the stroma of tumors and in the margins of keratin debris and around normal hair follicles. Cytokeratin 5 (CK5) was identified as a precursor protein candidate. C-terminal truncation of CK5 was observed in amyloid deposits, and the truncation sites varied depending on the deposition pattern. There was a significantly higher incidence of amyloid deposition in Shiba dogs, and CK5 amino acid polymorphisms were identified in these dogs. A part of the C-terminal region of both canine and human CK5 exhibited highly amyloidogenic properties in vitro. This study revealed the existence of cutaneous keratinic amyloid deposition in animals and identified CK5 as an amyloid precursor protein, providing novel insights into understanding the etiology of cutaneous amyloidosis.

Experiences with the end-of-life decision-making process in children with cancer, their parents, and healthcare professionals: A systematic review and meta-ethnography.

BACKGROUND: Decision-making during the end-of-life (EOL) phase for children with cancer is extremely difficult for parents. We synthesized the qualitative experiences of children with cancer, parents, and healthcare professionals (HCPs), and their social interactions during the EOL decision-making process in the pediatric oncology setting. METHODS: Meta-ethnography was used to conduct a systematic review and meta-synthesis. We searched four online databases to identify original studies published in English and Japanese and examined 21 relevant studies. Two Japanese reviewers discussed the differences/relationships and included studies that synthesized the translated qualitative findings. A conceptual model of social interactions was created. RESULTS: We identified four themes regarding children's, parents', and HCPs' experiences: hope and confrontation with the child's death, guidance and support during uncertainty, awareness of being protected and having hope, and mutual unspoken integration of values. CONCLUSIONS: These themes evince the experiences of children, parents, and HCPs during the EOL decision-making process and suggests a complex three-way social interaction model. While considering such distinctive social interactions during a child's EOL, this study revealed the sharing of prudent information and psychosocial support by HCPs. The findings indicate that hope and uncertainty are key elements for effectively understanding the experiences of children and parents and that EOL decision-making should not be rushed but should be supported by leaving room for uncertainty and acknowledging parents' emotional needs and fostering new hope. Further research into how hope can be further supported in situations that are rife with uncertainty is needed.

Factors related to employment in childhood cancer survivors in Japan: A preliminary study.

Purpose: Previous research has revealed vocational and academic difficulties in childhood cancer survivors, and explored impact of survivors' medical history and physical function on vocational and academic status. However, we often encounter survivors with similar diagnoses and late effects but different academic or employment statuses. This raises the question of what affects academic attainment and employment other than treatment or late effects. This study aimed to explore factors associated with childhood cancer survivors' employment status and academic achievement. Methods: Comprehensive health check-up and questionnaire survey were conducted for 69 survivors who were over the age of 18 and participated in St. Luke's Lifetime cohort study. We obtained survivors' biological function using comprehensive health check-up, neurocognitive states, quality of life, transition readiness, and family function. We conducted univariate analysis (Mann-Whitney U tests or chi-square tests) to compare the differences between the regular workers/students and non-regular workers/unemployed groups. The variables with p-values <0.1 were used as independent variables multivariate logistic regression to explore predictors of employment status and academic attainment. Results: Result of the univariate analysis, intelligence quotient, SF-8 PCS, transition readiness, family function were used for multivariate logistic regression as independent variables. The stepwise likelihood method was conducted; intelligence quotient (odds ratio [OR] = 1.100; 95% confidence interval [CI] 1.015-1.193; p = 0.021), transition readiness (OR = 0.612; 95% CI 0.396-0.974; p = 0.038), and family function (OR = 2.337; 95% CI 1.175-4.645; p = 0.015) were found to be associated with survivors' regular workers/students in the final regression model. Conclusion: Long-term follow-up of pediatric cancer survivors requires the provision of total care, which supports physical, psychological, and social functions to improve health, readiness for transition to self-management, and family functioning.

Significance of active screening for detection of health problems in childhood cancer survivors.

Background: Childhood cancer survivors (CCSs) have a lifelong increased risk of chronic health problems, most of which are associated with the curative therapies. Recent studies have suggested that prospective active screening using comprehensive assessments for CCSs is superior in identifying undiagnosed chronic health problems. Methods: To assess the significance of active screening using comprehensive medical examinations for detecting chronic health problems in multiple organ systems in CCSs, we retrospectively compared the frequency and severity of health problems between two different cohorts of CCSs in a single institution: 110 CCSs who visited the outpatient clinic for regular follow-ups between December 2010 and December 2015 (regular follow-up group) vs. 58 CCSs who underwent comprehensive medical examinations between February 2016 and September 2019 (active screening group). CCSs were defined as patients aged ≥ 18 years who had been diagnosed as having childhood cancer ≥ 10 years before and had survived without cancer for ≥ 5 years. Results: Patient characteristics were similar between the two groups except for primary diagnosis (more brain tumors and embryonal tumors in the active screening group) and treatment history (more alkylating agents used and surgical interventions performed in the active screening group). The prevalence and the median number of health problems were significantly higher in the active screening group than in the regular follow-up group: 93% vs. 67% and 1.0 [0.0-8.0] vs. 2.0 [0.0-7.0] respectively. In term of organ-specific health problems, pulmonary dysfunction, neurocognitive impairment, ocular abnormalities, and dental abnormalities were identified more in the active screening group, partly because these problems had not been assessed in the regular follow-up group. Nevertheless, the prevalence of grade 3-5 health problems was similar between the two groups, except for pulmonary dysfunction. Conclusion: Active screening using comprehensive medical examinations was effective for identifying health problems in CCSs. Although the prevalence of severe problems identified by both approaches was similar, comprehensive medical examinations could detect overlooked problems such as severe pulmonary dysfunction, dental maldevelopment, and borderline intellectual functioning, which might have an impact on quality of life in CCSs.

Information needs of children with leukemia and their parents' perspectives of their information needs: a qualitative study.

BACKGROUND: Despite the potential benefits of effective communication, telling a child that they have a life-threatening condition is one of the most daunting challenges. This study aimed to explore the information needs of children with leukemia from the perspectives of children and their parents at the time of diagnosis. METHODS: We conducted an exploratory qualitative study using semi-structured individual interviews with children diagnosed with leukemia between seven and 13 years old (n = 7) and their parents (n = 9). Children and parents' interview data were analyzed using thematic analysis. RESULTS: We identified three themes for the information needs of children with leukemia, 1) beginning to cope, 2) avoiding disclosure - protecting child, and 3) informational support. The children and their parents needed to receive understandable information at the best time to cope with cancer. However, the children and parents expressed different views about children's information needs. The children needed clear information about the disease, treatment, hospitalization, and the benefits of hospitalization from the time of diagnosis. In contrast, the parents felt they should not tell their children about the disease if they were in shock by their child's cancer diagnosis. Moreover, the parents believed that information that would be incomprehensible to the child and distress should be avoided to protect their children. CONCLUSIONS: While the information needs of children with leukemia are varied, children and their parents need the information to cope with cancer. However, if the parents believe that the information would be distressful, they might manage communication with their children. Healthcare professionals should explore the motivations behind parents' attitudes against communication with children and confront conflict. Healthcare professionals also should communicate with the children and their parents to understand their information needs and respect children's views.

Reliability and Validity of the Japanese Pediatric Version of Memorial Symptom Assessment Scale.

CONTEXT: Few instruments in Japanese assess health-related quality of life in pediatric cancer patients. OBJECTIVES: To translate the Memorial Symptom Assessment Scale (MSAS) into Japanese pediatric and proxy versions (MSAS-J 7-12, MSAS-J 13-18, and MSAS-J-Proxy) and assess validity and reliability. METHODS: Phase I comprised forward-backward translation and pilot testing in 13 children and 16 guardians. Phase II consisted of psychometric testing of the three MSAS-J versions in 162 children and 238 guardians. Internal consistency, test-retest reliability, and construct and known-group validity of the MSAS-J were assessed. RESULTS: Cronbach's alpha coefficients for the total and subscale scores were over 0.70, excluding the psychological symptom (PSYCH) subscale score of the MSAS-J 7-12. Most MSAS-J scores significantly inversely correlated with two versions of the Pediatric Quality of Life Inventory. A strong child-guardian correlation was shown in the total and subscale scores (ICC range 0.66-0.83). Kappa estimates showed acceptable child-guardian symptom agreement. MSAS-J 7-12 and proxy differentiated patients according to clinical status. CONCLUSION: MSAS-J is a reliable and valid instrument to assess symptoms among Japanese children with cancer.

Changes of cancer diagnosis disclosure to children in Japan in the last 20 years.

BACKGROUND: The practice of cancer diagnosis disclosure to children has been changed with the times. The regulations of clinical trials in the 2000s might change the practice in Japan. However, the perspective of this topic among children and adults has not been investigated in detail. METHODS: We studied changes in the practice of information sharing with children with cancer at pediatric cancer centers and the perspective of cancer diagnosis disclosure to children among school children, their parents and pediatric oncologists in the last 20 years by comparing the results of questionnaire surveys conducted in 1998, 2008 and 2018. RESULTS: This study revealed that the performing rate has increased with the times, but the institutions actively performing for children aged 7-9 years were 36.4% even in the 2018 survey. More than 70% of children wished diagnosis disclosure if they suffer from cancer in the series of surveys, while the ratio of parents who tell cancer diagnosis to their children hovered at 34.5 to 53.7% (p < 0.001 in all surveys). The ratio of pediatric oncologists having the policy to perform diagnosis disclosure proactively increased from 9.3 to 60.0%, while that of parents having the same policy stayed at 5.3% even in 2018. CONCLUSIONS: The performing rate of information sharing with children with cancer was significantly changed in the last 20 years. The opinion gaps were observed between parents and children and between parents and pediatric oncologists.

Systemic amyloidosis derived from EFEMP1 in a captive Tsushima leopard cat.

In animals, most cases of systemic amyloidosis are of amyloid A type, and the other types of systemic amyloidoses are rare. This study analyzed systemic amyloidosis in a 15-year-old female Tsushima leopard cat. Amyloid deposits strongly positive for Congo red staining were observed in the arterial walls as well as the interstitium in multiple organs. Mass spectrometry-based proteomic analysis with laser microdissection of amyloid deposits identified epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) as a prime amyloidogenic protein candidate. Immunohistochemistry showed that the amyloid deposits were positive for the N-terminal region of EFEMP1. From these results, the present case was diagnosed as EFEMP1-derived amyloidosis. It is the first such case in an animal. EFEMP1-derived amyloidosis in humans has recently been reported as a systemic amyloidosis, and it is known as an age-related venous amyloidosis. The present case showed different characteristics from human EFEMP1-derived amyloidosis, including the amyloid deposition sites and the amyloidogenic region of the EFEMP1 protein, suggesting a different pathogenesis between Tsushima leopard cat and human EFEMP1-derived amyloidosis.

Species-barrier on the cross-species oral transmission of bovine AA amyloidosis in mice.

In AA amyloidosis, cross-species oral transmission has been demonstrated in several animal models. While it is known that the transmission efficiency of AA amyloidosis between different species is lower than that among the same species, the mechanism of this species-barrier is unclear. In this study, we found at first that mice orally given a large amount of bovine AA simultaneously with inflammatory stimulation did not develop AA amyloidosis. Therefore, we hypothesized that the low efficiency of the cross-species oral transmission of AA amyloidosis might be due to the low absorption rate in Peyer's patches. To evaluate the hypothesis, we next investigated whether bovine AA was taken up by Peyer's patches and translocated to other organs in vivo and ex vivo models. The direct absorption of bovine AA by Peyer's patches was not observed. Besides, translocation of bovine AA to the mesenteric lymph nodes, spleen, liver, or kidney was not observed except the mesenteric lymph node of a single mouse. Thus, absorption of bovine AA by Peyer's patches occurred much less efficiently in mouse models of cross-species oral transmission of AA amyloidosis. The present study suggests that the less efficient amyloid uptake by Peyer's patches may be involved in the species-barrier of oral transmission of AA amyloidosis.

A new hexenoic acid glycoside with cytotoxic activity from the leaves of Psychotria luzoniensis.

A new hexenoic acid glycoside (1) together with known compounds, flavonol glycosides (2-4), iridoid glycoside (5), megastigmane glycoside (6), and amino acid (7) were isolated from the leaves of P. luzoniensis by resin column chromatography and preparative HPLC. Their structures were determined based on spectroscopic analysis, including HRFABMS and NMR (1H and 13C, 1H-1H COSY, HMQC, and HMBC) data. All compounds tested for cytotoxicity were active (IC50 < 50 µM) with IC50 values ranging from 1.97 to 32.85 µM against human colon adenocarcinoma cell line, compared to etoposide (IC50 1.19 µM).

Comparison of steroid hormone hydroxylation mediated by cytochrome P450 3A subfamilies.

Hydroxylation activity at the 6ß-position of steroid hormones (testosterone, progesterone, and cortisol) by human cytochromes P450 (CYP) 3A4, polymorphic CYP3A5, and fetal CYP3A7 were compared to understand the catalytic properties of the major forms of human CYP3A subfamily. Testosterone, progesterone, and cortisol 6ß-hydroxylation activities of recombinant CYP3A4, CYP3A5, and CYP3A7 were determined by liquid chromatography. Michaelis constants (Km) for CYP3A7-mediated 6ß-hydroxylation of testosterone, progesterone, and cortisol were similar to those of CYP3A4 and CYP3A5. The maximal velocity (kcat) and kcat/Km values for CYP3A4 were the highest, followed by CYP3A5 and those for CYP3A7 were the lowest among three CYP3A subfamily members. A decrease in Km values for progesterone 6ß-hydroxylation by CYP3A4, CYP3A5, and CYP3A7 in the presence of testosterone was observed, and the kcat values for CYP3A5 gradually increased with increasing testosterone. This indicated that testosterone stimulated progesterone 6ß-hydroxylation by all three CYP3A subfamily members. However, progesterone inhibited testosterone 6ß-hydroxylation mediated by CYP3A4, CYP3A5, and CYP3A7. In conclusion, the kcat values, rather than Km values, for 6ß-hydroxylation of three steroid hormones mediated by CYP3A7 were different from those for CYP3A4 and CYP3A5. In addition, the inhibitory/stimulatory pattern of steroid-steroid interactions would be different among CYP3A subfamily members.

Indirubin promotes adipocyte differentiation and reduces lipid accumulation in 3T3­L1 cells via peroxisome proliferator­activated receptor γ activation.

The peroxisome proliferator­activated receptor Î³ (PPARγ) plays an important role in insulin sensitivity and adipocyte differentiation. It is known as ligand­receptor that improves insulin sensitivity in type 2 diabetes mellitus. Several kinds of indigo plant have been already used to treat diabetes in oriental traditional medicine, but its mechanism has not been clarified yet. To investigate the effect of indirubin, which is a component of Polygonum tinctorium on the cell differentiation and adipprocess in 3T3­L1 cells, 3T3­L1 cells were cultured to determine the effect of cell differentiation and glucose uptake with indirubin. As a result, Indirubin compound enhanced adipocyte differentiation in 3T3­L1 cells similar to rosiglitazone. This effect was terminated by cotreatment with GW9662, a PPARγ antagonist. In mature 3T3­L1 adipocytes, the lipid droplet size and accumulation were reduced by this compound. The basal and insulin­stimulated glucose uptakes were also significantly increased. In addition, indirubin treatment significantly enhanced estrogen level by 1.64­fold with mature adipocytes which can be attributed to its aromatase activity. Conclutionaly, this finding suggested that indirubin is a potential anti­diabetic compound for type 2 diabetes mellitus by promoting adipocyte differentiation and glucose uptake via PPARγ.

Genetic polymorphisms and vincristine-induced peripheral neuropathy in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy.

Vincristine (VCR)-induced peripheral neuropathy (VIPN) is a common and life-long toxicity in lymphoma patients receiving current standard chemotherapy. The association between VIPN and genetic polymorphisms is largely unknown in adult lymphoma patients. To examine the possible relationship between known genetic polymorphisms in patients with pediatric acute lymphoblastic leukemia and incidence of VIPN in adult patients with B cell lymphoma, we examined CEP72 rs924607, ETAA1 rs17032980, MTNR1B rs12786200, CYP3A5 rs776746, rs7963521, and rs1045644 genetic polymorphisms in samples from 56 adult patients with B-cell lymphoma who received rituximab, cyclophosphamide, doxorubicin, VCR, and prednisone (R-CHOP) chemotherapy. Mutation analysis was performed by direct sequencing. The median age was 65 years (range 30-79). The median cumulative dose of VCR was 12 mg (range 2-16). VIPN was documented in 42 patients (75%), and 9 (16%) had grade 2-4 VIPN. Age, impaired glucose tolerance, number of cycles of R-CHOP, and VCR cumulative dose were not associated with incidence of VIPN. There was no association between the incidence of grade 2-4 or any grade VIPN and these six genetic polymorphisms. These results indicate that CEP72, MTNR1B, ETAA1, CYP3A5, rs7963521, and rs1045644 genetic polymorphisms are not associated with VIPN in patients with B-cell lymphoma who received R-CHOP.

[A Case of Extrahepatic Bile Duct Carcinoid Tumor Involving Diagnostic Difficulties].

A patient in his 60s had undergone laparoscopic anterior resection for the treatment of carcinoma of the rectum in February 2016. Histopathologic examination revealed the lesion as a pT2(MP)n(-)M0, fStage Ⅰrectal cancer. One year post-surgery, contrast-enhanced computed tomography(CT)revealed enhancement of parts of the intrapancreatic distal bile ducts. Magnetic resonance cholangiopancreatography(MRCP)showed filling defects at the same site. Magnetic resonance imaging( MRI)with an endorectal coil(ERC)was then performed to identify reproducible bile duct filling defects. Neither cytology nor biopsy yielded any findings that definitely indicated malignancy. Intraductal ultrasonography(IDUS)led to the suspicion of a nonepithelial tumor or an enlarged lymph node. Repeated biopsies via ERC were performed based on the absence of evidence of malignancy and revealed the presence of some atypical cells within the lesions. Although no definitive diagnosis could be made, the patient was scheduled for surgery in June 2017 after obtaining his consent. Upon taping of the common bile duct during surgery, a tumor was palpable on the dorsal aspect of the pancreas. The bile duct tumor was completely excised and submitted for intraoperative diagnosis; the pancreatic dorsal aspect appeared to be totally split. There was no evidence of atypia in the neoplasm, which was therefore considered to be benign; however, malignancy could not be completely ruled out because the patient had presented with elevated serum levels of carbohydrate antigen(CA)19-9 once before the operation. After intraoperative consultation with the patient's family members, who were reluctant to provide consent for pancreaticoduodenectomy, we completed the operation with resection of the bile duct tumor, followed by choledochojejunostomy. The tumor was found to be chromogranin A(+), cluster of differentiation(CD)56(+/-), CA19-9(+, solely ductal structure), carcinoembryonic antigen(CEA)(+, solely ductal structure), and intranuclear p53(-), with an MIB- 1 index of<2%. With regard to neuroendocrine markers, a region that could potentially have been a carcinoid tumor, based on the findings on hematoxylin and eosin(HE)staining, and a lumenized superficial region showed positivity in toto. Therefore, the lesion as a whole was diagnosed as a G1 carcinoid neuroendocrine tumor(NET). However, the superficial lumenized layer was positive for both CA19-9 and CEA; therefore, the tumor was thought to concurrently have epithelial characteristics. The lateral stumpwas negative, while the status of the ablated region remained unclear. After discussing the histopathologic examination results with the patient and his family members, the patient's follow-upwas decided to consist of periodic checkups without any further surgical intervention. The patient has since remained free of recurrence. Carcinoid tumor of the bile duct is extremely rare but should be considered in cases involving bile duct tumors that show enhancement on imaging prior to surgery and for which no definitive diagnosis can be established despite repeated biopsy explorations.

[Pathological Complete Response Following Chemotherapy for Sigmoid Colon Cancer with Para-Aortic Lymph Node Metastasis-A Case Report].

A man in his 50s visitedour hospital with complaints of frequent urination, painful micturition, macrohematuria, and weight loss. On examination, he was diagnosed with RAS-wild-type sigmoid colon cancer invading the urinary bladder, ureter, andexternal iliac artery, with para-aortic lymph node metastasis(T4b, NX, M1a, Stage ⅣA according to the Union for International Cancer Control 8th edition guidelines)andsigmoid -vesical fistula. Thus, sigmoidcolostomy was performed. Postoperatively, S-1 plus oxaliplatin was administered. After 3 courses of chemotherapy, the primary tumor and para-aortic lymph node metastases shrunk. Moreover, after 8 courses of chemotherapy, further shrinkage of the primary tumor and paraaortic lymph node metastases was confirmed; however, tumor markers in the blood increased. Therefore, the patient received 3 additional courses of S-1 plus oxaliplatin plus cetuximab, which resultedin complete response. Sigmoidectomy, partial cystectomy, ureterectomy, resection of the external iliac artery, andreconstruction using a prosthetic vascular graft were performed. Subsequent pathological examination revealed no viable cancer cells(pathological response), achieving R0 resection. The patient has been followedup for 2.5 years after the curative resection, with no recurrence.

Astragalus root induces ovarian ß­oxidation and suppresses estrogen­dependent uterine proliferation.

Continuous estrogen stimulation in the uterus has been known to cause excess proliferation of the functional layer of endometrium, resulting in endometrial hyperplasia and leading to infertility. Estrogens can modulate other nuclear receptor signaling pathways, such as peroxisome proliferator­activated receptors (PPARs). Astragalus root (AsR) has exhibited strong PPARα agonistic activity. Female Imprinting Control Region mice were fed a powder diet that included 5% AsR hot water extract or 0.1% bezafibrate as a positive control for 56 days to investigate AsR effects on the reproductive tract, ovary and uterus. AsR resulted in upregulation of the expression of uterine and ovarian PPARα mRNA by 2.5­fold, and 1.5­fold, respectively, compared with controls. AsR significantly increased ovarian expression levels of mitochondrial 2,4­dienoyl­CoA reductase (mDECR), an auxiliary enzyme involved in ß­oxidation. AsR­fed mice also exhibited a significant increase in blood estradiol levels and tended to have higher ovary weight. AsR resulted in significantly decreased uterine weight and mDECR expression levels. It has been reported that a PPARα agonist suppresses the development of estrogen­dependent endometrial hyperplasia. These findings raise the possibility that AsR suppresses estrogen­dependent endometrial hyperplasia and ovarian dysfunction leading to infertility.

Bortezomib alters sour taste sensitivity in mice.

Chemotherapy-induced taste disorder is one of the critical issues in cancer therapy. Bortezomib, a proteasome inhibitor, is a key agent in multiple myeloma therapy, but it induces a taste disorder. In this study, we investigated the characteristics of bortezomib-induced taste disorder and the underlying mechanism in mice. Among the five basic tastes, the sour taste sensitivity of mice was significantly increased by bortezomib administration. In bortezomib-administered mice, protein expression of PKD2L1 was increased. The increased sour taste sensitivity induced by bortezomib returned to the control level on cessation of its administration. These results suggest that an increase in protein expression of PKD2L1 enhances the sour taste sensitivity in bortezomib-administered mice, and this alteration is reversed on cessation of its administration.