Working conditions contribute to fertility-related quality of life: a cross-sectional study in Japan.

RESEARCH QUESTION: Is there an association between employment conditions and fertility-related quality of life among women undergoing fertility care? DESIGN: The study was a cross-sectional survey of 721 women in Japan recruited via an online social research panel. Participants included women aged 25-44 years with paid employment who were undergoing fertility diagnosis or treatment. They completed online questionnaires to assess fertility quality of life (FertiQoL) and job stress based on the demand-control-support model (Brief Job Stress Questionnaire). Information was also collected on individual and partner employment conditions (e.g. working hours per week, access to time off) and partner support of fertility treatment. RESULTS: The mean FertiQoL scores were low, ranging from 42 (emotional) to 65 (relational). A multivariable linear regression model showed that the total FertiQoL score was significantly associated with several work-related variables, including the participants' self-employment status (ß = 0.11), job demand (ß = -0.18), co-worker support (ß = 0.14) and access to time off (ß = 0.22), as well as their partner's access to time off (ß = 0.11), number of working hours (ß = -0.11) and level of cooperation (ß = 0.18), after adjusting for clinical and socioeconomic factors, including age (ß = 0.10), diagnosis of male infertility (ß = -0.07), long duration of treatment (ß = -0.12) and frequent clinic visits (ß = -0.10) (all Ps < 0.05, adjusted R2 = 0.27). CONCLUSIONS: Fertility-related quality of life is significantly associated with certain employment conditions among both women and their partners. Easy access to time off, lighter workloads and supportive co-workers could contribute to higher fertility-related quality of life by helping employees effectively manage their work and fertility treatments.

[PAX5-positive plasma cell leukemia presenting as lymphocytosis].

An 82-year-old Japanese male patient was initially diagnosed with lymphocytosis. His complete blood count revealed a white blood cell count of 30.9×109/l with 81% abnormal lymphocytes. The abnormal lymphocytes included monoclonal clones of CD38+ and CD138+cytoplasmic κ+ and IgG-κ M-protein, which led to the final diagnosis of plasma cell leukemia (PCL). Bortezomib and dexamethasone therapy was initiated, but the patient succumbed to the disease on the 8th day of hospitalization. A cytogenetic examination revealed a t (9;14)(p13;q32) translocation and the Western blotting confirmed high PAX5 expression. Similar to our present case, PCL cases with "lymphocytosis" have been widely reported, which some speculating the involvement of PAX5 overexpression in the pathogenesis. Such cases, including ours, may be classified as a unique group of disorders (PCL presenting as "lymphocytosis"), which requires accurate differential diagnosis and subsequent urgent multidisciplinary intensive treatment.

[Incidence of Secondary Malignancy of Chronic Myeloid Leukemia during Treatment of Breast Cancer with Hormone Therapy].

It is expected that the number of long-term breast cancer survivors will increase owing to the improvements in chemotherapy and irradiation, while the risk of double cancers, including secondary malignancy, may become an issue. There are many unclear points in the treatment policy with regard to when a secondary malignancy occurs or the primary cancer relapses during the management of a secondary malignancy. A 54-year-old woman who was diagnosed with ER/PgR-positive HER2 negative breast cancer Stage ⅢB received neoadjuvant chemotherapy FEC and docetaxel followed by breast surgery, adjuvant hormone therapy, and radiation therapy. Chronic myeloid leukemia diagnosed by the abnormal findings of leukocytosis and bone marrow aspiration emerged after 3 years of the diagnosis of the first breast cancer. After 3 years of imatinib therapy that achieved a major molecular response(MMR)of CML, a recurrence of sacral metastasis of breast cancer was revealed by MRI. The combination of imatinib and hormone or S-1 chemotherapy could be maintained without serious adverse events after the relapse of the primary cancer.

A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress.

New drugs have significantly improved the survival of patients with multiple myeloma (MM), but the prognosis of MM patients with high-risk cytogenetic changes such as t(4; 14), t(14; 16) or del17p remains very poor. A natural product, komaroviquinone (KQN), was originally isolated from the perennial semi-shrub Dracocephalum komarovi and has anti-protozoal activity against Trypanosoma cruzi, the organism causing Chagas' disease. Here we demonstrate that a novel KQN-derivative, GTN024, has an anti-MM effect both in vitro and in vivo. GTN024 induced the apoptosis of MM cell lines including those with high-risk cytogenetic changes. GTN024 produced reactive oxygen species (ROS) and increased phosphorylated eIF2α. The ROS production and subsequent endoplasmic reticulum (ER) stress are thought to play a key role in GTN024-induced apoptosis, as the apoptosis was completely abrogated by anti-oxidant treatment. In a mouse xenograft model, an intraperitoneal injection of 20 mg/kg of GTN024 significantly delayed tumor growth. Hematological toxicity and systemic toxicity as indicated by weight loss were not observed. These results suggest that the novel KQN-derivative GTN024 could become a candidate drug for treating high-risk MM.

[A case of primary intestinal tuberculosis in which small intestine perforation developed].

We report herein on a case of the primary intestinal tuberculosis in which small intestine perforation developed. A 60-year-old man with congestive heart failure developed fever and sudden onset of abdominal pain while he was in the hospital. Computed tomography of the abdomen showed a large amount of free-air and the thickening of a part of the ileum. Perforation of the gastrointestinal tract was diagnosed, The patient underwent emergency exploratory laparotomy and a partial resection of the ileum was performed. The presence of nodules in the ileum suggested possible tuberculosis of the intestine. Pathologically caseating epithelioid granulomas were noted and the diagnosis of tuberculosis of the ileum was made although microbiologically tuberculous bacilli were not documented. The patient was successfully treated with antituberculosis chemotherapy. Although intestinal tuberculosis is a rare cause of intestinal perforation, it is important to include intestinal tuberculosis as one of the cases.

A case of chylous ascites caused by reflux from the cisterna chyli to the disrupted common iliac lymphatic vessel: fluoroscopic records during intranodal lymphangiography.

A 40-year-old woman underwent laparoscopic common iliac lymphadenectomy for metastasis from rectal cancer. Two weeks after the surgery, she was found to have massive chylous ascites. After failure of conservative treatment, bilateral inguinal intranodal lymphangiography was performed. No definite extravasation was observed while lipiodol injected through the left inguinal node was ascending. When we punctured the right inguinal lymph nodes and started the injection of lipiodol, extravasation of diluted lipiodol was noted at the level of the first sacrum. Careful observation revealed that the ascending lipiodol became diluted in the cisterna chyli, refluxed through the median paraaortic route, leaked from the excised left common iliac lymph vessel, and flowed into the abdominal cavity. Lipiodol used in lymphangiography did not reduce chylous ascites at all. Twenty-seven days after lymphangiography, laparoscopic lymphatic ligation was performed, and the chylous ascites disappeared completely. CT obtained 40 days after surgical repair revealed disappearance of ascites and enlargement of the thoracic duct, which had not been observed on preoperative lymphangiography. Notably, lymphatic reflux from the cisterna chili can occur without obstruction of the thoracic duct and may result in chylous ascites.

Factors Associated with Refraining from Health Checkups during the COVID-19 Pandemic in Japan.

This study aimed to determine the characteristics of people who refrained from having regular checkups due to the spread of the novel coronavirus 2019 (COVID-19) infection and the factors associated with this behavior. We conducted a nationwide internet survey of 4593 males and females aged 20-69 in Japan regarding their health checkups from April 2020 to March 2021, when COVID-19 was widespread. Individuals who received checkups during this time were "the receiving group"; those who did not were "the refraining group". Personal attributes, responses to a health questionnaire and other items were used to compare the groups. The analysis showed that males over 53 refrained from having health checkups compared to those younger. On the other hand, males with higher personal incomes who never skipped breakfast received health checkups. Females with children under 18 years were less likely than those without to receive health checkups. For males, the characteristic factors were economic and health awareness and literacy. Females were less aware of medical checkups. Moreover, they demonstrated an inability to maintain an everyday rhythm. No factors were common to males and females, indicating the need to consider separate strategies for encouraging males and females to obtain annual health checkups.

Immunomodulatory Effect of Proteasome Inhibitors via the Induction of Immunogenic Cell Death in Myeloma Cells.

Several anti-cancer drugs are known to have immunomodulatory effects, including immunogenic cell death (ICD) of cancer cells. ICD is a form of apoptosis which is caused by the release of damage-associated molecular patterns (DAMPs), the uptake of cancer antigens by dendritic cells, and the activation of acquired immunity against cancer cells. ICD was originally reported in solid tumors, and there have been few reports on ICD in multiple myeloma (MM). Here, we showed that proteasome inhibitors, including carfilzomib, induce ICD in myeloma cells via an unfolded protein response pathway distinct from that in solid tumors. Additionally, we demonstrated the potential impact of ICD on the survival of patients with myeloma. ICD induced by proteasome inhibitors is expected to improve the prognosis of MM patients not only by its cytotoxic effects, but also by building strong immune memory response against MM cells in combination with other therapies, such as chimeric antigen receptor-T cell therapy.

GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c-MET tyrosine kinase.

OBJECTIVE: Despite the development of newly developed drugs, most multiple myeloma (MM) patients with high-risk cytogenetic abnormalities such as t(4;14) or del17p relapse at anin early stage of their clinical course. We previously reported that a natural product,komaroviquinone (KQN), isolated from the perennial semi-shrub Dracocephalum komarovi, i.e., komaroviquinone (KQN) and its derivative GTN024 induced the apoptosis of MM cells by producing reactive oxygen species (ROS), but both exhibited significant hematological toxicity. Aim of this study is to clarify anti-tumor activity, safety and pharmacokinetics of GTN057, an optimization compound of KQN in vivo. METHODS: ICR/SCID xenograft model of KMS11, a t(4;14) translocation-positive MM cell line, was used for in vivo study. Mice pharmacokinetics of GTN057 and the degradation products were analyzed by LC-MS/MS. RESULTS: Herein, our in vitro experiments revealed that GTN057 is much less toxic to normal hematopoietic cells, induced the apoptosis of both MM cell lines andpatient samples, including those with high-risk cytogenetic changes. A xenograft model of a high-risk MM cell line demonstrated that GTN057 significantly delayed the tumor growth with no apparent hematological or systemic toxicities in vivo. The pathological examination of GTN057-treated tumors in vivoshowed revealed apoptosis of MM cells and anti-angiogenesis. In addition to the production of ROS, GTN057 inhibited the downstream signaling of c-MET, a receptor tyrosine kinase a receptor forand hepatocyte growth factor (HGF) receptor. Thus, GTN057 is less toxic and is able tomay be a candidate drug for treating MM patients, via multifunctional mechanisms. We have also extensively studied the pharmacologyical analysis of GTN057. The metabolites of GTN057, (e.g.,such as GTN054), may also have anti-tumorantitumor activity. CONCLUSION: Natural products or and their derivatives can could be good sources of antineoplastic drugs even for high-risk cancer.

Total Hip Arthroplasty with a Cementless Acetabular Component and Impaction Bone Grafting for Dysplastic Osteoarthritis Complicated by Multiple Myeloma.

Total hip arthroplasty (THA) for pathologic and impending fracture due to periacetabular multiple myeloma (MM) lesions has been reported. We report a case of radiographic progression of dysplastic osteoarthritis, complicated by periacetabular MM lesions, treated by THA. A 69-year-old female with a 13-year history of MM presented with right hip pain. Plain radiographs and CT showed that dysplastic osteoarthritis had progressed, while the periacetabular MM lesions remained unchanged. Pathologic fracture was not observed on MRI. THA with a cementless acetabular component and impaction bone grafting was done. Bone graft incorporation was confirmed on CT at 1 year after surgery. There were no signs of bone absorption or implant loosening at last follow-up 3 years after surgery. Due to the advances in the treatment of MM and antiresorptive drugs, cementless acetabular component and impaction bone grafting may be an option for dysplastic osteoarthritis complicated by acetabular bone loss due to MM.

Rare evolution of CSF3R-mutated chronic neutrophilic leukemia to t(4;12)(q12;p13) acute myeloid leukemia with SETBP1 mutation.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disease accompanied by mutations in CSF3R. Here, we present a patient with CNL who developed to acute myeloid leukemia (AML) at the same time that a t(4;12)(q12;p13) translocation appeared. The uniqueness of this cytogenetic abnormality led us to delineate the molecular aberrations relevant for clonal evolution. While the CSF3R mutation was present throughout the course of the disease, the SETBP1 mutation was newly acquired at the AML transformation. The present case suggests that careful monitoring of t(4;12)(q12;p13) and SETBP1 is crucial to predict AML evolution in CNL patients.

Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Incidentally Detected by Fluorodeoxyglucose-positron Emission Tomography/Computed Tomography at a Health Checkup.

We herein report a case of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) that was incidentally detected by fluorodeoxyglucose-positron emission tomography (18F-FDG PET)/computed tomography (CT) at a health checkup. At that time, the findings of a physical examination and blood tests were all normal, except for the diffuse bone marrow uptake (maximum standardized uptake value: 6.3). One month later, when the blood counts remained in the normal ranges, a bone marrow examination confirmed the diagnosis of Ph-ALL. Although a diffuse bone marrow uptake of 18F-FDG is observed in some benign conditions, physicians should also consider the possibility of hematological malignancies, including acute leukemia, even when that is the only abnormal finding.

Health state utilities of patients with hepatitis B and C and hepatitis-related conditions in Japan.

Health state utilities are global measurements of quality of life and have been used to evaluate health outcomes for the cost-utility analysis. This study aimed to estimate the health state utilities of patients with hepatitis B (HB), hepatitis C (HC), and hepatitis-related diseases in Japan. We distributed a self-administered questionnaire, including the EuroQol 5-Dimension 5-Level (EQ-5D-5L), to 9,952 outpatients with several clinical conditions caused by HB or HC virus infection (such as asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, and decompensated cirrhosis) and estimated the condition-specific utilities of patients with HB or HC. In patients with more severe conditions (patients with acute hepatitis, fulminant hepatitis, and hepatocellular carcinoma and patients undergoing post-liver transplantation), the utilities of these severe conditions were estimated by three hepatitis experts using the EQ-5D-5L. The means of the utilities for acute hepatitis, fulminant hepatitis, asymptomatic chronic hepatitis, chronic hepatitis, compensated cirrhosis, compensated cirrhosis, hepatocellular carcinoma stage I/II, hepatocellular carcinoma stage III/IV, and post-liver transplantation were 0.529, - 0.111, 0.904, 0.868, 0.845, 0.722, 0,675, 0,428, and 0.651 and 0.876, 0.821, 0.737, 0.671, 0.675, 0.428, and 0.651 in HB and HC, respectively. To the best of our knowledge, this is the first study that comprehensively assessed the health state utilities of patients with HB, HC and hepatitis-related conditions from a nationwide survey in Japan using the EQ-5D-5L.

Negative E-cadherin expression on bone marrow myeloma cell membranes is associated with extramedullary disease.

Background: The loss of E-cadherin expression and the induction of N-cadherin are known as hallmarks of the epithelial-to-mesenchymal transition, an essential initial step in the process of metastasis in solid tumors. Although several studies have reported expressions of these cadherins in patients with multiple myeloma (MM), their clinical significance is unknown as MM cells are non-epithelial. Methods: In this study, we examined the expression of E- and N-cadherins by immunohistochemistry using bone marrow (BM) biopsy specimens from 31 newly diagnosed MM patients and in subsequent biopsy specimens from six of these. Results: Negative E-cadherin expression on BM myeloma cell membranes was significantly associated with the presence of soft-tissue masses arising from bone lesions and breaking through the cortical bone, referred to as extramedullary disease (EMD). Conclusions: Given the aggressive nature of EMD, our study suggests that screening for E-cadherin using BM immunohistochemistry is one measure that could predict the development of EMD in patients with MM.

Detection of Bartonella quintana Infection among the Homeless Population in Tokyo, Japan, from 2013-2015.

Several outbreaks of trench fever caused by Bartonella quintana occurred in soldiers during World Wars I and II. Although trench fever cases have been decreasing worldwide, the disease was reported among the homeless population in developing and developed countries. The current prevalence of B. quintana infection in Japan is unclear. Blood and body louse (Pediculus humanus humanus) samples were obtained from homeless inpatients with body lice during emergency hospitalization in Tokyo from January 2013 to March 2015. Patients were tested for B. quintana infections using the culture method, polymerase chain reaction, and indirect immunofluorescence assay (IFA). Among the 29 patients tested, the presence of Bartonella spp. was confirmed by genomic sequencing of DNA extracted from two samples from blood culture performed for 15 out of 29 patients and from body louse samples of 20 patients (69%). Immunoglobulin G against B. quintana was detected in 10 patients (34.5%) at a cut-off titer of 1:256 in IFA. B. quintana infection was detected in samples obtained between 2013 and 2015 in Tokyo and needs to be on the list of differential diagnoses performed for febrile homeless individuals.

A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder.

We report a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage. Blood analysis revealed a decreased fibrinogen level with markedly elevated fibrinogen/fibrin degradation products and D-dimer levels. Despite hemostatic surgery and administration of several medications, such as nafamostat mesylate, tranexamic acid, and unfractionated heparin, the coagulation abnormalities were not corrected, and the patient experienced repeated hemorrhagic events. We found that administration of recombinant human thrombomodulin (rhTM) remarkably improved the patient's pathophysiology. Screening and sequencing of the TM gene (THBD) revealed a previously unreported homozygous variation: c.793T>A (p.Cys265Ser). Notably, the Cys265 residue forms 1 of 3 disulfide bonds in the epidermal growth factor (EGF)-like domain 1 of TM. Transient expression experiments using COS-1 cells demonstrated markedly reduced expression of TM-Cys265Ser on the plasma membrane relative to wild-type TM. The TM-Cys265Ser mutant was intracellularly degraded, probably because of EGF-like domain 1 misfolding. The reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular-coagulation-like symptoms observed in the patient. In summary, we identified a novel TM variant, c.793T>A (p.Cys265Ser). Patients homozygous for this variant may present with severe bleeding events; rhTM should be considered a possible treatment option for these patients.

NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+ levels in Saccharomyces cerevisiae.

Nicotine adenine dinucleotide (NAD(+)) performs key roles in electron transport reactions, as a substrate for poly(ADP-ribose) polymerase and NAD(+)-dependent protein deacetylases. In the latter two processes, NAD(+) is consumed and converted to ADP-ribose and nicotinamide. NAD(+) levels can be maintained by regeneration of NAD(+) from nicotinamide via a salvage pathway or by de novo synthesis of NAD(+) from tryptophan. Both pathways are conserved from yeast to humans. We describe a critical role of the NAD(+)-dependent deacetylase Hst1p as a sensor of NAD(+) levels and regulator of NAD(+) biosynthesis. Using transcript arrays, we show that low NAD(+) states specifically induce the de novo NAD(+) biosynthesis genes while the genes in the salvage pathway remain unaffected. The NAD(+)-dependent deacetylase activity of Hst1p represses de novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect. The known Hst1p binding partner, Sum1p, is present at promoters of highly inducible NAD(+) biosynthesis genes. The removal of HST1-mediated repression of the NAD(+) de novo biosynthesis pathway leads to increased cellular NAD(+) levels. Transcript array analysis shows that reduction in cellular NAD(+) levels preferentially affects Hst1p-regulated genes in comparison to genes regulated with other NAD(+)-dependent deacetylases (Sir2p, Hst2p, Hst3p, and Hst4p). In vitro experiments demonstrate that Hst1p has relatively low affinity toward NAD(+) in comparison to other NAD(+)-dependent enzymes. These findings suggest that Hst1p serves as a cellular NAD(+) sensor that monitors and regulates cellular NAD(+) levels.

Inhibitors of Sir2: evaluation of splitomicin analogues.

Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay. Lactone ring or naphthalene (positions 7-9) substituents decrease activity, but other naphthalene substitutions (positions 5 and 6) are well-tolerated. The hydrolytically unstable aromatic lactone is important for activity. Lactone hydrolysis rates were used as a measure of reactivity; hydrolysis rates correlate with inhibitory activity. The most potent Sir2 inhibitors were structurally similar to and had hydrolysis rates similar to 1.

Identification and characterization of Sir2 inhibitors through phenotypic assays in yeast.

Yeast Sir2 is a defining member of a large family of protein deacetylases found in organisms ranging from bacteria to humans. SIR2 was discovered as a gene required for mating in S. cerevisiae 25 years ago, but it was only recently that Sir2's activity as an NAD-dependent protein deacetylase was established. However, years of extensive research did generate a large body of knowledge about the cellular roles of Sir2 in yeast long before its biochemical function was discovered. In addition to Sir2, yeast have four additional NAD-dependent histone deacetylases Hst1-4 (for homologue of Sir2), with distinct cellular roles. Detailed knowledge of the phenotypes of SIR2 and HST loss of function mutants has allowed design of a series of cell based screens that yielded the first inhibitors of NAD-dependent protein deacetylases. These phenotypic assays, amenable to high throughput screening, and coupled with transcript array analysis for evaluation of compound specificity, allowed the identification and detailed characterization of a series of Sir2 inhibitors, entirely bypassing traditional biochemical approaches.