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The mortality rate for acute kidney injury (AKI) due to sepsis remains high, and effective therapies based on its pathogenesis remain elusive. Macrophages are crucial for clearing bacteria from vital organs, including the kidney, under septic conditions. Excessive macrophage activation results in organ injury. C-reactive protein (CRP) peptide (174-185), a functional product of proteolyzed CRP in vivo, effectively activates macrophages. We investigated the therapeutic efficacy of synthetic CRP peptide on septic AKI, focusing on effects on kidney macrophages. Mice underwent cecal ligation and puncture (CLP) to induce septic AKI and were intraperitoneally administered 20 mg/kg of synthetic CRP peptide 1 h post-CLP. Early CRP peptide treatment improved AKI while still clearing infection. Ly6C-negative kidney tissue-resident macrophages did not significantly increase at 3 h after CLP, while Ly6C-positive monocyte-derived macrophages significantly accumulated in the kidney 3 h post-CLP. CRP peptide augmented the phagocytic ROS production in both subtypes of kidney macrophage at 3 h. Interestingly, both subtypes of macrophage increased ROS production 24 h post-CLP compared to the control group, while CRP peptide treatment maintained ROS production at the same level seen 3 h post-CLP. Although bacterium-phagocytic kidney macrophages produced TNF-α, CRP peptide reduced bacterial propagation and tissue TNF-α levels in the septic kidney at 24 h. Although both subsets of kidney macrophages showed populations of M1 at 24 h post-CLP, CRP peptide therapy skewed the macrophages population toward M2 at 24 h. CRP peptide alleviated murine septic AKI via the controlled activation of kidney macrophages and is an excellent candidate for future human therapeutic studies.

A 41-year-old Japanese man was admitted to our hospital with acute perimyocarditis 4 weeks after coronavirus disease 2019 (COVID-19) infection. Ten days after admission, the patient showed bilateral facial nerve palsy in the course of improvement of perimyocarditis under treatment with aspirin and colchicine. After prednisolone therapy, perimyocarditis completely improved, and the facial nerve palsy gradually improved. Acute perimyocarditis and facial nerve palsy can occur even 4 weeks after contracting COVID-19., Internal Medicine, 61 (15), pp. 2327-2332; 2022

Recent studies have revealed that mammalian B cells ingest particulate Ags, such as bacteria, although little is known about the effect of this function on acquired immunity. We investigated the role of bacterium-phagocytosing B cells in acquired host immune responses. Cultured mouse liver B cells substantially phagocytosed serum-opsonized Streptococcus pneumoniae and produced IgM. On adoptive transfer of liver B cells that phagocytose S. pneumoniae labeled with pHrodo Red succinimidyl ester, recipient mice showed elevated plasma levels of IgG specific for bacterial Ags. In particular, the levels of IgG2a and IgG2b specific for pneumococcal surface protein A, as well as IgG3 for pneumococcal polysaccharide, were markedly increased compared with total IgG specific for each Ag. When phagocytic liver B cells were cultured with spleen CD4+ T cells obtained from mice primed with heat-killed S. pneumoniae 7 d before, they induced IL-2 production and proliferation of the CD4+ T cells, along with Th1 cytokine production. However, they induced neither the CD4+ T cell production of IL-21, a suggested marker promoting B cell proliferation and differentiation, nor the expression of genes important for somatic hypermutation or isotype switching; such responses were particularly evident when splenic B cells merely capturing S. pneumoniae without processing them were cultured with spleen CD4+ T cells. These findings suggest that phagocytic liver B cells may be involved in acquired immune responses by presenting derivative peptides to CD4+ T cells without their own somatic hypermutation or isotype switching.

The frequency accuracy of optical atomic clocks has dramatically increased over the past 15 years, improving by more than two orders of magnitude from 16 digits of precision to 18 or even 19 digits of precision. Since around 2015 researchers from around the world began to consider a redefinition of the second that uses optical atomic clocks. Since then, the development of optical atomic clocks has progressed and the recent results demonstrated to detect the frequency change with 18 digits of precision.The National Institute of Information and Communications Technology (NICT) has developed the Sr optical lattice clock and optical ion clocks employing In+ and Ca+, as well as a Sr optical lattice clock that provides calibration data to BIPM. On the other hand, the centimeter-level uncertainty of site elevation has caused 10-18-level frequency uncertainties of optical frequency standards. Therefore, it is significantly important to understand frequency changes caused by solid-earth tides that often range from 10 to 20 cm in amplitude, by oceanic tidal loading, crustal deformations due to earthquakes, and ground movements with groundwater changes for the stable operation of optical atomic clocks.NICT, in collaboration with partners including the Geospatial Information Authority of Japan (GSI), has begun observations and data analysis to evaluate how these effects interact with optical atomic clocks. Since early 2021, NICT and GSI have been jointly conducting leveling surveys and relative gravimeter observations at NICT’s headquarters in Koganei. These observations reduce the contribution of gravitational redshift to the total uncertainty of the NICT-Sr1 optical lattice clock has been reduced to the 10-19 level.With the support of National Institute of Polar Research (NIPR), absolute gravity measurements were performed in the August 2019 and May 2022 to evaluate the effects of the 2011 March 11 Tohoku megaquake on coseismic vertical crustal movement. The obtained absolute gravity change between the two periods was -43.8 μGal. This matches the trend of GNSS result obtained by GSI, which show a vertical movement of up to 31.5 mm from August 2019 to May 2022, equivalent to about -10 μGal gravity change, even though the values do not agree precisely.We have introduced a Micro-g LaCoste's gPhoneX gravimeter for continuous gravity measurements near by the optical clocks in the end of 2021. The preliminary results over seven months detects stable gravity change due to solid-earth tide with about 22 μGal precision. In addition, we have started to investigate the temporal variation of the ground water level at Koganei. We are also monitoring vertical crustal movements by geodetic GNSS measurements. We will investigate uncertainties of optical clocks due to vertical movements caused by geodetic phenomena using continuous gravity and GNSS measurements.

Supplementary Table 1 from RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAFV600E point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAFV600E mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (Ptrend = 0.002). In contrast, BRAFV600E mutation was less frequent in cases exposed to higher radiation dose (Ptrend < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAFV600E mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis. [Cancer Res 2008;68(17):7176–82]

Supplementary Figure Legend from RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

Supplementary Table 2 from RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

Supplementary Figure 1 from RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are common differentiated thyroid cancers, but the detection of a collision tumor is an extremely rare event. Case Presentation: The patient was a 69-year-old Japanese female with multiple cervical lymph node swellings and a thyroid tumor. Preoperative fine needle aspiration cytology of the enlarged lymph node revealed a cytological diagnosis of papillary thyroid carcinoma (PTC). A total thyroidectomy, right cervical dissection and paratracheal dissection were performed. Histopathological immunohistochemistry (IHC) analyses of resected specimens revealed a collision tumor of PTC and FTC. Multiple metastases of papillary carcinoma were found in the dissected lymph nodes. In the PTC lesion, IHC for BRAF (V600E) was positive but negative for the FTC lesion. Genetic analyses further revealed a TERT prompter C228T mutation in PTC and a NRAS codon 61 mutation in FTC. The patient died of recurrent cancer 8 months after surgery. Conclusions: A case of a collision tumor of PTC and FTC is very rare, and even fewer cases have been subjected to genetic scrutiny. The present case was successfully diagnosed by pathological examination using IHC and genetic analyses. The TERT promoter mutation in the PTC lesion was consistent with the aggressive behavior of the cancer.

We classified kidney macrophages (Mφs) into bone marrow-derived (BM-) macrophages expressing high CD11b and tissue-specific resident (Res-) macrophages expressing low CD11b. In diabetic nephropathy (DN) model mice, TLR9 expression and TNF-α production via TLR9 activation in BM-Mφs and ROS production in Res-Mφs were enhanced. Furthermore, CCR2 antagonist suppressed the kidney infiltration of BM-Mφs and their function and the ROS production by Res-Mφs, with concomitant TLR9 suppression. Our study presents a new therapeutic strategy for DN.

Spinocerebellar ataxia (SCA) type 17-digenic TBP/STUB1 disease (SCA17-DI) has been recently segregated from SCA17, caused by digenic inheritance of two gene mutations – intermediate polyglutamine-encoding CAG/CAA repeat expansions (polyQ) in TBP (TBP41 − 49) and STUB1 heterozygosity – the former being associated with SCA17, and the latter with SCA48 and SCAR16 (autosomal recessive). In SCA17, most patients carry intermediate TBP41 − 49 alleles but show incomplete penetrance, and the missing heritability can be explained by a new entity whereby TBP41 − 49 requires the STUB1 variant to be symptomatic. The STUB1 gene encodes the chaperone-associated E3 ubiquitin ligase (CHIP) involved in ubiquitin-mediated proteasomal control of protein homeostasis. However, reports of the neuropathology are limited and role of STUB1 mutations in SCA17-DI remain unknown. Here we report the clinicopathologic features of identical twin siblings, one of whom was autopsied and was found to carry an intermediate allele (41 and 38 CAG/CAA repeats) in TBP and a heterozygous missense mutation in STUB1 (p.P243L). These patients developed autosomal recessive Huntington’s disease-like symptoms. Brain MRI showed diffuse atrophy of the cerebellum and T2WI revealed hyperintense lesions in the basal ganglia and periventricular deep white matter. The brain histopathology of the patient shared features characteristic of SCA17, such as degeneration of the cerebellar cortex and caudate nucleus, and presence of 1C2-positive neurons. Here we show that mutant CHIP fails to generate the polyubiquitin chain due to disrupted folding of the entire U box domain, thereby affecting the E3 activity of CHIP. When encountering patients with cerebellar ataxia, especially those with Huntington’s disease-like symptoms, genetic testing for STUB1 as well as TBP should be conducted for diagnosis of SCA17-DI, even in cases of sporadic or autosomal recessive inheritance.

We conducted an internet survey to assess sociodemographic variables, lifestyle factors, sleep problems, and comorbidities for sleep apnea syndrome (SAS) in COVID-19 and influenza (FLU) infections. Data from 10,323 workers (50.0% male) were analyzed. COVID-19 was diagnosed in 144 subjects (COVID-19+), and 8,693 were classified as not suspected to be infected (COVID-19−). SAS had been diagnosed in 35.4% of the COVID-19+ subjects, but only 231 (2.7%) of the 8,693 COVID-19− subjects. COVID-19+ subjects were more susceptible to FLU (35.4%) compared to COVID-19− subjects (3.0%). A multivariate analysis revealed that higher risks of COVID-19+ were linked to the following factors: going out without a face mask (OR 7.05, 95% CI 4.53–11.00), FLU+ (OR 6.33, 95% CI 3.80–10.54), excessive exercise before going to sleep (OR 2.10, 95% CI 1.63–2.70), SAS+ (OR 5.08, 95% CI 2.88–8.94), younger age (OR 1.05, 95% CI 1.03–1.07), falling sleep while sitting or talking with someone (OR 3.70, 95% CI 2.30–5.95), and use of hypnotics (OR 2.28, 95% CI 1.20–4.30). Since sleep impairment played a relatively small role in COVID-19+/SAS− subjects, we assume that SAS itself was a more significant risk factor for COVID-19 infection rather than sleep impairment. A better understanding of the mechanisms that result in increased susceptibility to COVID-19 in SAS is vital for helping prevent COVID-19.

OBJECTIVE We examined the hypothesis that antibiotic treatment with or without gonadotropin releasing hormone agonist (GnRHa) may decrease intrauterine infection with consequent decrease in tissue inflammation, cell proliferation and angiogenesis in human endometriosis. STUDY DESIGN This is a prospective non-randomized observational study. Endometrial/endometriotic samples were collected during surgery from 53 women with endometriosis and 47 control women who were treated with levofloxacin (LVFX, 500 mg, once per os) or GnRHa (1.88 mg/IM for 3 months) before surgery. Endometrial samples were analyzed by broad-range polymerase-chain reaction (PCR) amplification of bacteria targeting V5-V6 region of 16S rRNA gene. Immunohistochemical analysis was performed using antibodies against CD138 (Syndecan-1, a marker of plasma cells), CD68 (marker of macrophages), Ki-67 (cell proliferation marker), and CD31 (vascular cells marker). RESULTS 16S rDNA metagenome assay indicated that treatment with either of LVFX or GnRHa + LVFX significantly decreased some components of major bacterial genera comparing to untreated group. In women with endometriosis, treatment with either of LVFX or GnRHa + LVFX significantly decreased Gardnerella, Prevotella, Acidibactor, Atopobium, Megasphaera, and Bradyrhizobium (p

Heatstroke can cause acute kidney injury (AKI), which reportedly progresses to chronic kidney disease. Kidney macrophages may be involved in such injury. Although heat acclimation (HA) provides thermal resilience, its renoprotective effect and mechanism remain unclear. To investigate heat stress-induced kidney injuries in mice and the mitigating effect of HA on them, male C57/BL6J mice were exposed to heat stress (40°C, 1 h) with or without 5-day HA (38°C, 3 h/day) prior to heat stress. Heat stress damaged kidney proximal tubules with an elevation of urinary kidney injury molecule-1. Kidney fibrosis was observed on

Background Heat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the conformational maintenance of several client proteins that play important roles in DNA damage repair, apoptosis following radiation, and resistance to radiation therapy. DS-2248 (tricyclic pyrazolopyrimidine derivative) is a newly-developed, orally available inhibitor of HSP90 with low adverse effects. We investigated the combined effects of radiation and DS-2248 in vitro and in vivo. Methods SCCVII squamous cell carcinoma cells and tumors transplanted in C3H/HeN mice were used. In vitro combined effects of X-ray radiation and DS-2248 were investigated using a colony assay. Phosphorylated histone H2AX (γH2AX) was quantified after 2-Gy irradiation with or without 24-hour pretreatment with DS-2248. The mice bearing SCCVII tumors received oral DS-2248 10 times over 2 weeks and received local irradiation with doses of 1, 2, 3, and 4 Gy delivered 6 times over 2 weeks. Then, tumor volumes were measured. Results Radiation plus pretreatment with 50 nM DS-2248 for 24 hours produced synergistic effects on SCCVII cells. γH2AX foci persisted after radiation for longer periods (6 and 24 hours) in DS-2248-treated cells than in control cells. In vivo, the combined effects appeared to be additive when 5 or 10 mg/kg DS-2248 was combined with total radiation doses of 6–18 Gy, but the effect was considered supra-additive when 15 mg/kg of DS-2248 was combined with a total dose of 24 Gy. Conclusions The combined effects of DS-2248 and radiation were additive at low drug and radiation doses, but may have been supra-additive at higher doses. Inhibition of slow repair of DNA double strand breaks (i.e., homologous recombination) was considered to contribute to this combined effect.

Although the association between radiation exposure and thyroid carcinogenesis is epidemiologically evident, ’true’ radiation-induced cancers cannot be identified from biological evidence of radiation-associated cases. To assess the individual risk for thyroid cancer due to radiation exposure, we aimed to identify biomarkers that are specifically altered during thyroid carcinogenesis after irradiation in a time-dependent manner in an animal model. Thyroid glands were obtained from rats (n = 175) at 6–16 months after local X-ray (0.1–4 Gy) irradiation of the neck at 7 weeks of age. The gene expression profile in thyroid glands was comprehensively analyzed using RNA microarray. Subsequently, the expression levels of the genes of interest were verified using droplet digital PCR (ddPCR). The expression level of candidate genes as biomarkers for irradiated thyroid was examined in a randomized, controlled, double-blind validation study (n = 19) using ddPCR. The incidence of thyroid cancer increased in a dose- and time-dependent manner and was 33% at 16 months after irradiation with 4 Gy. The Ki-67 labeling index in non-tumorous thyroid was significantly higher in the exposed group than in the control. Comprehensive analysis identified radiation-dependent alteration in 3329 genes. Among them, ddPCR revealed a stepwise increase in CDKN1A expression from early pre-cancerous phase in irradiated thyroid compared to that in the control. The irradiated thyroids were accurately distinguished (positive predictive value 100%, negative predictive value 69%) using 11.69 as the cut-off value for CDKN1A/β-actin. Thus, CDKN1A expression can be used as a biomarker for irradiated thyroid glands at the pre-cancerous phase.

Current histopathological diagnosis methods cannot distinguish the two types of thyroid carcinoma: clinically significant carcinomas with a potential risk of recurrence, metastasis, and cancer death, and clinically insignificant carcinomas with a slow growth rate. Both thyroid tumors are diagnosed as "carcinoma" in current pathology practice. The clinician usually recommends surgery to the patient and the patient often accepts it because of cancer terminology. The treatment for these clinically insignificant carcinomas does not benefit the patient and negatively impacts society. The author proposed risk stratification of thyroid tumors using the growth rate (Ki-67 labeling index), which accurately differentiates four prognostically relevant risk groups based on the Ki-67 labeling index, ≥30%, ≥10 and30%,5 and10%, and ≤5%. Indolent thyroid tumors with an excellent prognosis have the following four features: young age, early-stage (T1-2 M0), curatively treated, and low proliferation index (Ki-67 labeling index of ≤5%), and are unlikely to recur, metastasize, or cause cancer death. Accurate identification of these indolent tumors helps clinicians select more conservative treatments to avoid unnecessary aggressive (total thyroidectomy followed by radio-active iodine) treatments. Clinicians can alleviate the fears of patients by confirming these four features, including the low proliferation rate, in a pathology report immediately after surgery when patients are most concerned.

We conducted an internet survey to assess sociodemographic variables, lifestyle factors, sleep hygiene, and comorbidities for sleep apnea syndrome (SAS) in COVID-19 and influenza (FLU) infections. Data from 10,323 workers (50.0% male) were analyzed. COVID-19 was diagnosed in 144 subjects (COVID-19+), and 8,693 were classified as not suspected to be infected (COVID-19-). SAS had been diagnosed in 35.4% of the COVID-19+ subjects, but only 231 (2.7%) of the 8,693 COVID-19- subjects. COVID-19+ subjects were more susceptible to FLU (35.4%) compared to COVID-19- subjects (3.0%). A multivariate analysis revealed that higher risks of COVID-19+ were linked to the following factors: going out without a face mask (OR 7.05, 95% CI: 4.53-11.00), FLU+ (OR 6.33, 95% CI: 3.80-10.54), excessive exercise before going to sleep (OR 2.10, 95% CI: 1.63-2.70), SAS+ (OR 5.08, 95% CI: 2.88-8.94), younger age OR 1.05, 95% CI: 1.03-1.07), tendency for dozing off (OR 3.70, 95% CI: 2.30-5.95), and use of hypnotics (OR 2.28, 95% CI: 1.20-4.30). Since sleep impairment played a relatively small role in COVID-19+/SAS- subjects, we assume that SAS itself was a more significant risk factor for COVID-19 infection rather than sleep impairment. A better understanding of the mechanisms that result in increased susceptibility to COVID-19 in SAS is vital for helping prevent COVID-19.

Background and aim Lipopolysaccharide (LPS) preconditioning drastically augments bactericidal activity but reduces the host inflammatory response. Therefore, it may be beneficial to prevent postoperative infectious complications and mitigate host damage by surgical stress. Considering its clinical application, how LPS preconditioning influences the antitumor effect in the liver is an important issue. We then investigated the effect of LPS preconditioning on antitumor activity against Colon26 tumor cells in mice. Methods Lipopolysaccharide preconditioning was induced in mice by the intraperitoneal injection of 5 μg/kg LPS for three consecutive days. Intraportal inoculation of Colon26 cells, which express luminescent protein called Nano-lantern, was performed to evaluate the effect of LPS preconditioning on tumor liver metastasis. The antitumor activities of cytotoxic liver lymphocytes, especially natural killer (NK) cells and natural killer T (NKT) cells, against Colon26 cells were also examined in LPS preconditioned mice. Results Lipopolysaccharide preconditioning remarkably prevented liver metastasis of Colon26 cells, as observed by IVIS imaging system, and prolonged survival after tumor inoculation. LPS preconditioning increased the proportions and number of liver NK cells and NKT cells and augmented their intracellular perforin and granzyme B expression, while reducing their intracellular expression of IFN-γ. An in vitro antitumor cytotoxicity assay revealed that LPS preconditioning significantly augmented antitumor cytotoxicities of the liver NK cells and NKT cells, especially NKT cells, against Colon26 cells. Conclusions Lipopolysaccharide preconditioning potently augmented antitumor cytotoxicity of liver NK cells and NKT cells, thereby improving mouse survival after intraportal inoculation of Colon26 tumor cells. It may be useful for perioperative care in oncological patients.

Purpose The aim of this study was to evaluate the usefulness of transcatheter arterial embolization (TAE) using the triaxial system with N-butyl-2-cyanoacrylate (NBCA) for acute arterial bleeding in comparison to TAE using the triaxial system with gelatin sponges (GS) and/or coils. Material and methods Between October 2013 and November 2018, 95 patients with acute arterial bleeding underwent emergency TAE using the triaxial system. Six patients underwent multiple TAEs and thus, 104 TAEs using the triaxial system were performed. In 26 of the 104 cases, TAE were performed with NBCA (NBCA group), and in the remaining 78 cases, TAE were performed with GS and/or coils (control group). Results Hemorrhagic shock and coagulopathy more often occurred in the NBCA group. Procedure time was shorter in the NBCA group. The technical success rate was 100% in both groups (p > 0.99). The clinical success rate in the NBCA and control groups was 92% and 96%, respectively (p = 0.6). There was one minor complication (4%, 1/26) of liver dysfunction in a patient of the NBCA group, but no complication in the control group (p = 0.26). Conclusion TAE using the triaxial system with NBCA may be useful for acute arterial bleeding, especially in patients with hemorrhagic shock and coagulopathy.

The experiment was performed in support of a Japanese initiative to investigate the biological effects of irradiation from residual neutron-activated radioactivity that resulted from the A-bombing. Radionuclide 56Mn (T1/2 = 2.58 h) is one of the main neutron-activated emitters during the first hours after neutron activation of soil dust particles. In our previous studies (2016–2017) related to irradiation of male Wistar rats after dispersion of 56MnO2 powder, the internal doses in rats were found to be very inhomogeneous: distribution of doses among different organs ranged from 1.3 Gy in small intestine to less than 0.0015 Gy in some of the other organs. Internal doses in the lungs ranged from 0.03 to 0.1 Gy. The essential pathological changes were found in lung tissue of rats despite a low level of irradiation. In the present study, the dosimetry investigations were extended: internal doses in experimental mice and rats were estimated for various activity levels of dispersed neutron-activated 56MnO2 powder. The following findings were noted: (a) internal radiation doses in mice were several times higher in comparison with rats under similar conditions of exposure to 56MnO2 powder. (b) When 2.74 × 108 Bq of 56MnO2 powder was dispersed over mice, doses of internal irradiation ranged from 0.81 to 4.5 Gy in the gastrointestinal tract (small intestine, stomach, large intestine), from 0.096 to 0.14 Gy in lungs, and doses in skin and eyes ranged from 0.29 to 0.42 Gy and from 0.12 to 0.16 Gy, respectively. Internal radiation doses in other organs of mice were much lower. (c) Internal radiation doses were significantly lower in organs of rats with the same activity of exposure to 56MnO2 powder (2.74 × 108 Bq): 0.09, 0.17, 0.29, and 0.025 Gy in stomach, small intestine, large intestine, and lungs, respectively. (d) Doses of internal irradiation in organs of rats and mice were two to four times higher when they were exposed to 8.0 × 108 Bq of 56MnO2 (in comparison with exposure to 2.74 × 108 Bq of 56MnO2). (e) Internal radiation doses in organs of mice were 7–14 times lower with the lowest 56MnO2 amount (8.0 × 107 Bq) in comparison with the highest amount, 8.0 × 108 Bq, of dispersed 56MnO2 powder. The data obtained will be used for interpretation of biological effects in experimental mice and rats that result from dispersion of various levels of neutron-activated 56MnO2 powder, which is the subject of separate studies.

Typically, local spread and lymph-vascular space invasion (LVSI) occur before lymph node (LN) and distant metastases during the progression of uterine cervical cancer. The prognostic value of LVSI in cervical superficially invasive squamous cell carcinoma (SISCC) is still debated. We encountered a rare case of cervical SISCC without LVSI presenting with multiple LN metastases, including pelvic, para-aortic, and left supraclavicular LNs. Immunohistochemical analysis of p16 and in situ hybridization of human papillomavirus confirmed the relationship of the cervical SISCC and pelvic LN metastases. Aspiration cytology of the left supraclavicular LN showed squamous cell carcinoma and our final diagnosis was uterine cervical squamous cell carcinoma, stage IVB. The patient underwent adjuvant chemotherapy. Although relapse was observed at the vaginal stump and in pelvic and para-aortic LNs, chemotherapy and radiotherapy were effective. The patient is alive without disease 40 mo after initial treatment. This is the first case report of cervical SISCC without LVSI presenting with supraclavicular LN metastasis, which contributes to our understanding of the value of LVSI. Immunohistochemical analysis of p16 and in situ hybridization of human papillomavirus were useful in confirming the relationship of cervical SISCC and its metastases. As cervical SISCC with LN metastasis is rare, multi-institutional joint research is needed to clarify its prognosis and appropriate treatment.

Oncocytic cell tumor of the thyroid is composed of large polygonal cells with eosinophilic cytoplasm that is rich in mitochondria. These tumors frequently have the mutations in mitochondrial DNA encoding the mitochondrial electron transport system complex I. However, the mechanism for accumulation of abnormal mitochondria is unknown. A noncanonical mitophagy system has recently been identified, and mitochondria‐eating protein (MIEAP) plays a key role in this system. We therefore hypothesized that accumulation of abnormal mitochondria could be attributed to defective MIEAP expression in these tumors. We first show that MIEAP was expressed in all the conventional thyroid follicular adenomas (FAs)/adenomatous goiters (AGs) but not in oncocytic FAs/AGs; its expression was defective not only in oncocytic thyroid cancers but also in the majority of conventional thyroid cancers. Expression of MIEAP was not correlated with methylation status of the 5′‐UTR of the gene. Our functional analysis showed that exogenously induced MIEAP, but not PARK2, reduced the amounts of abnormal mitochondria, as indicated by decreased reactive oxygen species levels, mitochondrial DNA / nuclear DNA ratios, and cytoplasmic acidification. Therefore, together with previous studies showing that impaired mitochondrial function triggers compensatory mitochondrial biogenesis that causes an increase in the amounts of mitochondria, we conclude that, in oncocytic cell tumors of the thyroid, increased abnormal mitochondria cannot be efficiently eliminated because of a loss of MIEAP expression, ie impaired MIEAP‐mediated noncanonical mitophagy., In this study, we sought to clarify the mechanisms for accumulation of abnormal mitochondria in oncocytic tumor of the thyroid and found a lack of expression of mitochondria‐eating protein (MIEAP), a molecule critical for non‐canonical mitophagy, in these tumors, and that exogenous expression of MIEAP accelerated mitochondrial turnover in oncocytic tumor cell line XTC.UC1. These data indicate that defective MIEAP expression causes accumulation of abnormal mitochondria in these tumors.

Transforming growth factor-β (TGFβ) has pleiotropic actions, including both anti- and pro-tumorigenic abilities. We have previously shown no tumor development in the thyroid-specific TGFβ receptor type II knockout (Tgfβr2 KO) mice, indicating the insufficiency of defective TGFβ signal itself for thyroid cancer initiation. In the current study, we evaluated whether defective TGFβ signal accelerates BRAFV600E-mediated thyroid carcinogenesis in our mouse model, in which intrathyroidal injection of adenovirus expressing Cre under thyroglobulin (TG) promoter (Ad-TgP-Cre) into thyroid lobes of conditional BrafV600E knock-in mice (BrafCA) induces thyroid cancers 12 months later. BrafCA/wt;Tgfbr2floxE2/floxE2 mice were generated by crossing Tgfbr2floxE2/floxE2 and BrafCA mice, and Ad-TgP-Cre was injected into the left lobes of 4–6-week-old mice. Mice were sacrificed at 6 and 12 months, and the thyroid tissues were subjected to HETgfbr2floxE2/floxE2 mice were all E-cadherin+/vimentin−, that is, epithelial type. In a mouse model, defective TGFβ signaling pathway accelerates BRAFV600E-induced thyroid cancer development, which is occasionally accompanied by reduced TG expression implying dedifferentiation. The former finding is consistent with anti-tumorigenic ability of TGFβ in early tumorigenic process, but the latter is contradictory to generally accepted concept for TGFβ-induction of dedifferentiation.

Would a properly designed educational programme offered to young women improve their awareness and fundamental knowledge of menstrual pain and endometriosis?A multinational cross-sectional study using a pen-and-paper questionnaire among women aged 19-24 years was conducted between 2017 and 2019 to assess fundamental knowledge of menstrual pain and endometriosis. Improvement in knowledge was also analysed using a separate questionnaire completed before, and 1-3 months after, a group discussion, lecture on menstrual pain and endometriosis, or both.Among three groups of students (college [n = 271], medical [n = 877] and nursing [n = 763]), knowledge of menstrual pain and endometriosis was lowest among college students, modest among nursing students and fair among medical students (P0.001 for each). The experience of cyclical pain, even when painkillers were taken, was reported by 15.5%, 4.6% and 3.8% of students, respectively. Most students managed their cyclical pain by enduring it or by taking over-the-counter medication. An informative education programme with group discussions, lectures, or both, was successful in improving knowledge and consequences of menstrual pain and endometriosis. Proper education and dissemination of knowledge to college students failed to motivate them to visit gynaecologists; however, medical and nursing students became highly interested in visiting gynaecologists.An educational programme can improve awareness and knowledge of endometriosis and dysmenorrhoea among young women. The programme motivated nursing and medical students, but not college students, to seek medical attention for early detection and management of endometriosis.

Objective We compared the 52-week effectiveness and safety of tofacitinib (TOF) and abatacept (ABT) in patients with RA in a real-world setting and investigated a role of human leucocyte antigens (HLA)-DRB1 shared epitope (SE) in the effectiveness. Methods RA patients starting TOF (n = 187) and ABT (n = 183) were enrolled. Effectiveness was compared after reducing the selection bias to a minimum using the inverse probability of treatment weighting (IPTW) based on propensity scores. The influence of SE alleles on effectiveness was compared within each treatment group. A treatment group comparison was also performed within SE-positive and SE-negative groups. Results Herpes zoster and some laboratory abnormalities were more frequent in the TOF group than in the ABT group. Patient characteristics did not differ significantly between treatment groups after adjustments with IPTW. The TOF group had a significantly higher proportion of DAS in 28 joints using ESR (DAS28-ESR) remission at week 52 than the ABT group. The DAS28-ESR at week 12 and thereafter was not affected by the copy number of SE alleles in the TOF group, but decreased significantly as the copy number increased in the ABT group. In SE-positive patients, remission and drug retention rates did not differ significantly between the two treatment groups. In SE-negative patients, the TOF group showed significantly higher remission and drug retention rates than the ABT group. Conclusion The present results suggest that TOF is more effective with regard to remission at week 52 based on treatment responses in SE-negative RA patients.

Background: The semi-dry dot-blot (SDB) method, a diagnostic procedure for detecting lymph node (LN) metastases using an anti-cytokeratin (CK) antibody, is based on the theory that epithelial components, such as CK, are not found in normal LNs. Thus, metastases are diagnosed according to the presence of CK in the lavage fluid of sectioned LNs. We prospectively evaluated novel SDB kits that use a newly developed anti-CK19 antibody and an automatic reader for diagnosing sentinel LN metastases in patients with breast cancer as a multi-center study. Methods: We obtained 924 sentinel LNs dissected from 405 patients with breast cancer between January 2021 and December 2021 at six institutes in Japan. We excluded patients who underwent neoadjuvant chemotherapy and neoadjuvant endocrine therapy. LNs were sectioned at 2-mm intervals and washed with phosphate-buffered saline. Cells suspended in the lavage fluid of sectioned LNs were centrifuged and lysed to extract protein. The extracted protein was applied to the SDB kit to diagnose LN metastasis using an automatic absorbance reader. Hematoxylin and eosin (H&E) stained and washed LNs were blindly examined by pathologists using intraoperative and permanent histological examination. Diagnoses based on SDB kit and automatic reader findings were compared with diagnoses made by permanent histological examination of paraffin-embedded H&E-stained sections of LNs. Primary endpoints were the sensitivity, specificity, and overall agreement of the SDB kit for distinguishing macrometastases from non-macrometastases. Results: Ninety-four of the 924 LNs were assessed as macrometastases, 40 as micrometastases, and 790 as isolated tumor cells by histological examination. Compared with patients with non-macrometastases, those with macrometastases had significantly younger age (p< 0.01), larger primary tumor (p< 0.01), higher nuclear grade (p=0.04), increased lymphatic invasion (p< 0.01), and increased venous invasion (p=0.01). Using a borderline CK19 absorbance of 11.9 milli-absorbance for detecting macrometastases with an area under the curve of 0.989, the sensitivity, specificity, and overall agreement of the SDB kit were 94.7%, 98.3%, and 97.9%, respectively. Moreover, the sensitivity, specificity, and overall agreement of the intraoperative histological examination compared with permanent histological examination for distinguishing macrometastases from non-macrometastases were 91.4%, 99.1%, and 98.3%, respectively. Furthermore, the kits and automatic reader yielded diagnoses within approximately 20 min at a cost of < 30 USD for the SDB kit and < 3,000 USD for the automatic reader. Conclusions: The kits with an automatic reader used in our study were accurate, quick, and cost-effective in diagnosing LN metastases without the loss of LN tissue and were particularly useful for distinguishing macrometastases. We plan to make the SDB kit and automatic reader commercially available worldwide soon. Citation Format: Megumi Matsumoto, Masaaki Baba, Aya Tanaka, Sayaka Kuba, Michi Morita, Fujiko Kaseida, Hiroko Hayashi, Shigeto Maeda, Hiroshi Yano, Eiko Inamasu, Akiko Ogiya, Kenta Sekiya, Masahiro Nakashima, Hideki Ikari, Shinji Ohno, Hiroyuki Takei, Katsunori Yanagihara, Susumu Eguchi, Takeshi Nagayasu, Ryota Otsubo. Evaluation of novel diagnostic kits using the semi-dry dot-blot method combined with an automatic reader for detecting metastases in sentinel lymph nodes of patients with breast cancer: a multi-center prospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-01-03.

Introduction: In diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs), and triggers their activation. Methods: We orally administered L-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of L-carnitine on kidney mitochondrial reactive oxygen species (mtROS) production, circulating mtDNA content, and kidney CD11bhigh/CD11blow Mφ functions. Results: In db/db mice, mtROS production increased in proximal tubular cells and kidney CD11blow Mφs; both Mφ types showed enhanced TLR9 expression. L-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11blow Mφs (p < 0.01), with improved SOD2 expression in the kidney (p < 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (p < 0.01), thereby lowering tumor necrosis factor-α production in CD11bhigh Mφs (p < 0.05) and ROS production by CD11blow Mφs (p < 0.01). Collectively, these changes alleviated DN symptoms. Conclusion: The positive effects of L-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.

Malaria remains a grave concern for humans, as effective medical countermeasures for Plasmodium infection have yet to be developed. Phagocytic clearance of parasitized red blood cells (pRBCs) by macrophages is an important front-line innate host defense against Plasmodium infection. We previously showed that repeated injections of low-dose lipopolysaccharide (LPS) prior to bacterial infection, called LPS preconditioning, strongly augmented phagocytic/bactericidal activity in murine macrophages. However, whether LPS preconditioning prevents murine Plasmodium infection is unclear. We investigated the protective effects of LPS preconditioning against lethal murine Plasmodium infection, focusing on CD11b(high) F4/80(low) liver macrophages, which are increased by LPS preconditioning. Mice were subjected to LPS preconditioning by intraperitoneal injections of low-dose LPS for 3 consecutive days, and 24 h later, they were intravenously infected with pRBCs of Plasmodium yoelii 17XL. LPS preconditioning markedly increased the murine survival and reduced parasitemia, while it did not reduce tumor necrosis factor (TNF) secretions, only delaying the peak of plasma gamma interferon (IFN-γ) after Plasmodium infection in mice. An in vitro phagocytic clearance assay of pRBCs showed that the CD11b(high) F4/80(low) liver macrophages, but not spleen macrophages, in the LPS-preconditioned mice had significantly augmented phagocytic activity against pRBCs. The adoptive transfer of CD11b(high) F4/80(low) liver macrophages from LPS-preconditioned mice to control mice significantly improved survival after Plasmodium infection. We conclude that LPS preconditioning stimulated CD11b(high) F4/80(low) liver macrophages to augment the phagocytic clearance of pRBCs, which may play a central role in resistance against Plasmodium infection.

The Japanese Society of Thyroid Pathology and the Japan Association of Endocrine Surgeons developed the eighth edition of the General Rules for the Description of Thyroid Cancer (GRDTC) in December 2019. This article describes the pathological diagnosis of the GRDTC, which has been improved through repeated revisions based on the experience of Japanese pathologists and translated into English to introduce the Japanese diagnostic standard to foreign countries. In this edition of the GRDTC, the histopathological classification and descriptions differ in some respects from those of the fourth edition of the World Health Organization (WHO) classification as revised in 2017. For example, the GRDTC does not adopt the concept of borderline lesions (FT-UMP, WDT-UMP, and NIFTP) of the WHO, taking into consideration the popular histological criteria accepted by Japanese pathologists. The cytological reporting system of the GRDTC was partly modified from the Bethesda system in 2015. It has an additional cyst fluid category separated from the unsatisfactory category that has been demonstrated to be useful in Japan. This translated edition makes it easy to submit Japanese clinicopathological studies of thyroid tumors in an international journal. We also wish to contribute to the improvement, standardization, and globalization of the pathological diagnosis of thyroid tumors.

Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3′-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1, encoding a 218amino acid isoform. This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after completion of AES formation. Our analyses revealed that the 218-amino acid isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is also possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris.

Human adenomyosis has an adverse effect on female fertility. Exact mechanistic basis is still unclear. We investigated the occurrence of chronic endometritis (CE) in different types of human adenomyosis.This is a prospective non-randomized observational study enrolling patients with focal (In GnRHa-untreated groups, a higher trend in the occurrence of CE, as characterized by infiltration of ≥1 plasma cells in endometrial stroma, was found in women with focal (58.8%,A variable occurrence of CE in different types of adenomyosis may be involved in adverse reproductive outcome.

The development of multiple histologic types of lymphoma in a single patient has been sporadically reported as sequential or composite lymphoma. However, the incidence pattern of such patients has been rarely evaluated in a large population-based setting. We investigated the incidence of sequential or composite lymphoma based on 11,174 lymphoma records from a population-based cancer registry between 1985-2012 in Nagasaki Prefecture, Japan. We identified 99 lymphoma records were of 49 independent patients other than relapse. The prevalence of the sequential or composite lymphomas in a single patient was 0.44% (95% confidence interval [95% CI], 0.32-0.56%) without sex difference. Among the 49 patients, five (10.2%) were composite/discordant lymphoma. The most frequent "composite lymphoma" was a combination of diffuse large B-cell lymphomas (DLBCL) and adult T-cell leukemia (n = 3). A case of "discordant lymphoma" was a combination of follicular lymphoma on spleen and Waldenstrom macroglobulinemia on bone marrow. The rest of the patients (n = 44, 89.8% of all composite lymphoma) were "sequential lymphoma" with various combination of lymphoma subtypes on different dates. The major combination of the sequential lymphoma was DLBCL after marginal zone lymphomas (n = 4). In the era of improved survival of lymphoma patients, hematologists should be aware of the development of additional lymphomas.

Löfgren's syndrome is an acute form of sarcoidosis that is characterised by articular symptoms, erythema nodosum and bilateral hilar lymphadenopathy. This syndrome is rare in Japan. We report a 62-year-old Japanese woman with Löfgren's syndrome and describe the articular manifestations as evaluated by multiple imaging modalities. Musculoskeletal ultrasound, magnetic resonance imaging and positron emission tomography-computed tomography findings indicated periarticular and subcutaneous inflammation. These imaging modalities facilitated the diagnosis of Löfgren's syndrome and helped differentiate from other rheumatic diseases.

Autophagy is a catabolic process that involves the degradation of cellular components through the lysosomal machinery, relocating nutrients from unnecessary processes to more pivotal processes required for survival. It has been reported that systemic disruption of the Atg5 or Atg7 gene, a component of autophagy, is lethal and that its tissue-specific disruption causes tissue degeneration in several organs. However, the functional significance of autophagy in the thyroid glands remains unknown. Our preliminary data imply the possible involvement of dysfunctional autophagy in radiation-induced thyroid carcinogenesis. Therefore, we evaluated the effect of Atg5 gene knockout (KO) on thyroid morphology and function. To this end, Atg5flox/flox mice were crossed with TPO-Cre mice, yielding the thyroid follicular epithelial cell (thyrocyte)?specific ATG5-deficient mice (Atg5thyr-KO/KO). Atg5 gene KO was confirmed by a lack of ATG5 expression, and disruption of autophagy was demonstrated by a decrease in microtubule-associated protein 1 light chain 3-II puncta and an increase in p62. Atg5thyr-KO/KO mice were born normally, and thyroid morphology, thyroid weights, and serum T4 and TSH levels were almost normal at 4 months. However, at 8 and 12 months, a decrease in the number of thyrocytes and an increase in TUNEL+-thyrocytes were observed in Atg5thyr-KO/KO mice even though thyroid function was still normal. The number of irregularly shaped (gourd-shaped) follicles was also increased. Excess oxidative stress was indicated by increased 8-hydroxy-2'-deoxyguanosine and 53BP1 foci in Atg5thyr-KO/KO mice. These data demonstrate that thyrocytes gradually undergo degradation/cell death in the absence of basal levels of autophagy, indicating that autophagy is critical for the quality control of thyrocytes., Endocrinology, 160(9), pp.2085-2092; 2019

Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients. The mechanism underlying disease progression is largely unknown. p53-binding protein 1 (53BP1) is a DNA damage response protein that rapidly localizes at the site of DNA double-strand breaks. In this study, we investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease liver tissues by immunofluorescence microscopy. A total of 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls, were studied. Our results show that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 μM) was significantly increased in nonalcoholic fatty liver disease patients compared to that in controls, both in nonalcoholic fatty liver (p

A 70-year-old Japanese male with psoriasis vulgaris was admitted for neck, elbow, knee, ankle and buttock pain. He had chilblain-like rashes on the face and auricle and lower extremity purpura. He was diagnosed with psoriatic arthritis (PsA) according to enthesitis detected by musculoskeletal ultrasound. Blood examination showed IgG-κ type M protein and cryoglobulin. Skin biopsy of lower extremity showed thrombus in the artery. Bone marrow aspiration demonstrated no proliferation of plasma cells initially, and he was considered with monoclonal gammopathy of undetermined significance (MGUS). Two months later, plasma cell clonal expansion was detected in the bone marrow, and he was diagnosed with PsA and type I cryoglobulinemia associated with multiple myeloma. PsA may be a risk factor for MGUS. We described a case of PsA complicated with MGUS, which developed to multiple myeloma.

Research question Is there any relationship between numbers of FOXP3+ regulatory T-cells (Treg) and occurrence of peritoneal lesions in women with ovarian endometrioma and dermoid cysts? Design Retrospective and prospective case-controlled cohort study. Peritoneal lesions were collected from 27 women with ovarian endometrioma and 25 women with dermoid cysts. Peritoneal fluid was collected from 36 women with ovarian endometrioma and 42 women with dermoid cysts. Tissue expression of Forkhead box P3 (FOXP3), one of the transcription factors of Treg cells, and transforming growth factor-beta (TGF-β) were examined by immunohistochemistry. Interleukin-6 (IL-6) and TGF-β levels in the peritoneal fluid were measured by enzyme-linked immunosorbent assay. Results Ovarian endometrioma cases with coexisting peritoneal lesions were significantly more frequent than dermoid cyst cases with coexistent peritoneal lesions (269/350 [76.9%] versus 74/414 [17.9%]; P Conclusions This study confirms current speculation that endometriosis is related to alteration in Treg cells, causing survival and implantation of ectopic endometrial lesions in women with endometrioma and dermoid cysts. The findings may clarify why only 10% of women in the general population develop endometriosis despite cyclic menstruation with retrograde flow occurring in >90% of women.

To evaluate the clinical outcomes of bronchial artery embolization (BAE) using a gelatin sponge for hemoptysis from pulmonary aspergilloma and compare them with treatment outcomes for hemoptysis from other diseases. Fifty-two patients underwent BAE using a gelatin sponge. The etiology of hemoptysis was pulmonary aspergilloma in 8 (PA group) and other diseases in 44 (control group). The technical success rate, clinical success rate, hemoptysis-free rate, and complication rate were compared between the PA group and control group. Technical success was defined as the complete cessation of the targeted feeding artery as confirmed by digital subtraction angiography, and clinical success as the cessation of hemoptysis within 24 h of BAE. Recurrent hemoptysis was defined as a single or multiple episodes of hemoptysis causing > 30 ml of bleeding per day. Technical and clinical success rates were 100% in both groups. Hemoptysis-free rates were 85% at 6 months and 72% at 12–60 months in the control group, and 38% at 6–12 months and 25% thereafter in the PA group (P = 0.0009). No complications were observed following BAE in any case in the two groups. BAE using a gelatin sponge may not be effective for hemoptysis from pulmonary aspergilloma.

OBJECTIVE: To identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH. METHODS:We performed whole-exome sequencing (WES) on a Japanese family with multiple individuals with NPH and identified a candidate gene.Then we generated knockout mouse using CRISPR/Cas9 to confirm the effect of the candidate gene on the pathogenesis of hydrocephalus.RESULTS: In WES, we identified a loss-of-function variant in CFAP43 that segregated with the disease. CFAP43 encoding cilia- and flagella-associated protein is preferentially expressed in the testis.Recent studies have revealed that mutations in this gene cause male infertility owing to morphologic abnormalities of sperm flagella. We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia. CONCLUSION: Our results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH., Neurology, 92(20), pp.e2364-e2374; 2019

Background: Malignant lymphoma (ML) is a heterogeneous neoplasm with a wide range of etiological factors, pathological patterns, incidence rates, and outcomes. Most epidemiological studies have reported the incidence pattern of ML by simply dividing into 2 groups, Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). However, differences in the incidence pattern by cell-lineage or by cell-maturity have been rarely evaluated. The aim of this study was to characterize the incidence pattern of ML by cell-lineage and cell-maturity in Japanese population. Methods: This is a descriptive study based on regional cancer registry data. We obtained a dataset of anonymized 12,645 cases with ICD-O histology codes of ML diagnosed 1960–2012 from the Nagasaki Prefectural Cancer Registry. From those, we excluded 1,477 records because of codes other than ML, diagnosed before 1985, and possible relapse records of identical cases. Records based on ICD-O-1 or ICD-O-2 were substituted by the corresponding ICD-O-3 code. We also treated patients having multiple types of MLs at same diagnosis date as a single case of “composite/discordant lymphoma,” and patients having multiple types of MLs at different diagnosis date as a single case based on the first lymphoma. We finally confirmed 11,118 patients of ML that occurred in 1985–2012. The overall age-adjusted incidence rate (per 100,000 population) during 1985–2012 was already reported to be 20.5 for men and 12.9 for women. Then we divided them into the following cell-lineage/maturity groups: precursor B (B1), mature B (B2), other B (B3), precursor T (T1), mature T/NK (T2), undetermined cell-lineage NHL (U), HL (H), and other lymphomas (O). Results: The median age at diagnosis of all patients was 69.7 years (interquartile range, 59.4–78.0 years) and male sex were 5,980 (53.8%). The frequency of B-cell lineage, T/NK-cell lineage, and Hodgkin lymphoma were 5,196 (46.7%), 3,257 (29.3%), and 209 (1.9%), respectively, with a significant sex difference (PPConclusion: This preliminary analysis suggests a significant sex difference in the cell-lineage and cell-maturity of ML. Additional analysis to elucidate whether there are any differences in the incidence pattern by cell-lineage and by cell-maturity of ML between general population and Nagasaki atomic bomb survivors are underway.

BACKGROUND/AIM P53-binding protein 1 (53BP1) is one of the DNA damage response (DDR) molecules. This study aimed to assess 53BP1 expression by immunofluorescence (IF) as a biomarker to differentiate between oral squamous epithelial lesions (OSELs). MATERIALS AND METHODS We analyzed 129 archival oral biopsy samples, including 18 benign squamous lesions (BSLs), 37 low-grade dysplasias (LGDs), 22 high-grade dysplasias (HGDs), and 52 oral squamous cell carcinomas (OSCCs). 53BP1 and Ki-67 expressions were examined by double IF to assess the type of 53BP1 expression. RESULTS We found that OSCC exhibited several 53BP1 nuclear foci, particularly high-DNA damage response (HDDR) and large focus (LF)-type, suggesting the presence of endogenous DNA double-strand breaks in the cancer genome, which could disrupt DDR and induce genomic injury. We also found a difference in 53BP1 expression between LGD and HGD, but not between BSL and LGD. Among the Ki-67-positive cells, HDDR- and LF-type expressions were higher in OSELs of higher grades. CONCLUSION 53BP1 expression can be a valuable biomarker for OSELs to help estimate the grade of oral epithelial dysplasia.