Serum Soluble IL-2 Receptors Are Elevated in Febrile Illnesses and Useful for Differentiating Clinically Similar Malignant Lymphomas from Kikuchi Disease: A Cross-Sectional Study.

Background: The use of serum soluble interleukin 2 receptor (sIL-2R) for the diagnosis of febrile illnesses has not been examined. In this study, febrile patients were classified according to etiology and disease, and serum sIL-2R levels were evaluated. We determined whether serum sIL-2R is a useful marker for differentiating between malignant lymphoma (ML) and non-ML patients and between patients with ML and Kikuchi disease, which present similar clinical manifestations. Methods: This study was a cross-sectional study and included 344 patients with uncomplicated hemophagocytic syndrome, who had a fever of 38 °C or higher within 1 week of admission to our institution. Patient serum sIL-2R was measured, and the serum sIL-2R values are shown as median and IQR. Results: Serum sIL-2R increased above the upper reference limit in all disease groups with fever. The serum sIL-2R level in ML patients (n = 13) was 4760 (2120-6730) U/mL and significantly higher (p < 0.001) than the level of 998 (640-1625) U/mL in non-ML patients (n = 331). The serum sIL-2R level in ML patients (n = 13) was also significantly higher (p < 0.001) compared with that in patients with Kikuchi disease (n = 20; 705 (538-1091) U/mL). Conclusions: Serum sIL-2R tends to exceed the upper reference limit in patients with febrile illnesses. We conclude that the measurement of serum sIL-2R is useful for differentiating ML from non-ML and ML from Kikuchi disease.

Whole-Exome Sequencing Revealed a Pathogenic Germline Variant in the Fumarate Hydratase Gene, Leading to the Diagnosis of Hereditary Leiomyomatosis and Renal Cell Cancer.

The diagnosis of hereditary skin tumors is difficult for "old" diagnostic tools such as immunohistochemistry. Whole-exome sequencing analysis as a "new" diagnostic tool enables us to make a final diagnosis in spite of unknown hereditary diseases in the past. Hereditary leiomyomatosis and renal cell cancer are autosomal dominant hereditary cancer syndromes characterized by uterine myomas, cutaneous leiomyomas, and aggressive renal cell cancer. The syndrome is associated with pathogenic germline variants in the fumarate hydratase gene. Herein, we demonstrate a pathogenic germline variant of the fumarate hydratase gene in a 60-year-old woman with multiple cutaneous leiomyomas, leading to the diagnosis of hereditary leiomyomatosis and renal cell cancer. Whole-exome sequencing analysis using genomic DNA extracted from peripheral blood leukocytes revealed one germline variant in the FH gene on chromosome 1 (c.290G>A, p.Gly97Asp). She received total hysterectomy due to uterine myoma, which strongly supported the diagnosis. No tumor was detected in her kidney by computed tomography and ultrasound examination. Genetic examination for the mutation of the fumarate hydratase gene is important in order to reach the correct diagnosis and to detect renal cancer at its early stage.

Mitochondrial fractions located in the cytoplasmic and peridroplet areas of white adipocytes have distinct roles.

The role of mitochondria in white adipocytes (WAs) has not been fully explored. A recent study revealed that brown adipocytes contain functionally distinct mitochondrial fractions, cytoplasmic mitochondria, and peridroplet mitochondria. However, it is not known whether such a functional division of mitochondria exists in WA. Herein, we observed that mitochondria could be imaged and mitochondrial DNA and protein detected in pellets obtained from the cytoplasmic layer and oil layer of WAs after centrifugation. The mitochondria in each fraction were designated as cytoplasmic mitochondria (CMw) and peridroplet mitochondria (PDMw) in WAs, respectively. CMw had higher ß-oxidation activity than PDMw, and PDMw was associated with diacylglycerol acyltransferase 2. Therefore, CMw may be involved in ß-oxidation and PDMw in droplet expansion in WAs.

Sphingosine 1-Phosphate Regulates Obesity and Glucose Homeostasis.

One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. Obesity, caused by the excessive accumulation of triglycerides in adipose tissues, induces adipocyte dysfunction, followed by inflammation, in adipose tissues and lipotoxicity in nonadipose tissues. Several studies have shown that obesity and glucose homeostasis are influenced by sphingolipid mediators, including ceramide and sphingosine 1-phosphate (S1P). Cellular accumulation of ceramide impairs pancreatic ß-cell survival, confers insulin resistance in the liver and the skeletal muscle, and deteriorates adipose tissue inflammation via unknown molecular mechanisms. The roles of S1P are more complicated, because there are five cell-surface S1P receptors (S1PRs: S1P1-5) which have altered functions, different cellular expression patterns, and inapparent intracellular targets. Recent findings, including those by our group, support the notable concept that the pharmacological activation of S1P1 or S1P3 improves obesity and associated metabolic disorders, whereas that of S1P2 has the opposite effect. In addition, the regulation of S1P production by sphingosine kinase (SphK) is an essential factor affecting glucose homeostasis. This review summarizes the current knowledge on SphK/S1P/S1PR signaling in and against obesity, insulin resistance, and associated disorders.

Detection of TRAF1-ALK fusion in skin lesions of systemic ALK+ anaplastic large cell lymphoma initially involving the skin and the draining lymph node.

A case of cytoplasmic anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) initially involving the skin in a 44-year-old Japanese female is reported. The patient had a hemorrhagic erythematous tumor on the right thigh without any systemic symptoms. Pathology showed diffuse infiltration of CD30-positive anaplastic large cells positive for epithelial membrane antigen and cytoplasmic ALK. The right inguinal lymph node showed infiltration of tumor cells in the marginal sinus. Only 2 weeks after radiation therapy, the patient developed multiple subcutaneous nodules and lung involvement. Even after subsequent multichemotherapy sessions, cutaneous recurrence occurred. Literature review of cytoplasmic ALK-positive ALCL initially involving in the skin revealed that skin lesions were mostly seen in the extremities and that half of the cases developed extracutaneous lesions. Radiation and chemotherapy were effective for most cases. Inverse RT-PCR identified a tumor necrosis factor receptor-associated factor (TRAF)1-ALK fusion in our case. Most reported cases with this translocation experienced repeated changes in chemotherapy, suggesting poorer prognosis. Although ALK-positive ALCL generally responds well to chemotherapy, the presence of a TRAF1-ALK fusion may suggest resistance to treatment. Detection of fusion partners of ALK is important for predicting clinical courses and deciding treatment options.

Differentiation between pleomorphic adenoma and schwannoma in the parapharyngeal space: histogram analysis of apparent diffusion coefficient.

OBJECTIVES: To elucidate the differences between pleomorphic adenomas and schwannomas occurring in the parapharyngeal space by histogram analyses of apparent diffusion coefficient (ADC) values measured with diffusion-weighted MRI. METHODS: This retrospective study included 29 patients with pleomorphic adenoma and 22 patients with schwannoma arising in the parapharyngeal space or extending into the parapharyngeal space from the parotid region. Using pre-operative MR images, ADC values of tumor lesions showing the maximum diameter were measured. The regions of interest for ADC measurement were placed by contouring the tumor margin, and the histogram metrics of ADC values were compared between pleomorphic adenomas and schwannomas regarding the mean, skewness, and kurtosis by Wilcoxon's rank sum test. Subsequent to the primary analysis which included all lesions, we performed two subgroup analyses regarding b-values and magnetic field strength used for MRI. RESULTS: The mean ADC values did not show significant differences between pleomorphic adenomas and schwannomas for the primary and subgroup analyses. Schwannomas showed higher skewness (p = 0.0001) and lower kurtosis (p = 0.003) of ADC histograms compared with pleomorphic adenomas in the primary analysis. Skewness was significantly higher in schwannomas in all the subgroup analyses. Kurtosis was consistently lower in schwannomas but did not reach statistical significance in one subgroup analysis. CONCLUSIONS: Skewness and kurtosis showed significant differences between pleomorphic adenomas and schwannomas occupying the parapharyngeal space, but the mean ADC values did not. Our results suggest that the skewness and kurtosis of ADC histograms may be useful in differentiating these two parapharyngeal tumors.

Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome.

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ­negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

Opposing Roles of Sphingosine 1-Phosphate Receptors 1 and 2 in Fat Deposition and Glucose Tolerance in Obese Male Mice.

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through 5 cognate G protein-coupled receptors (S1P1-S1P5). We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and an S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates, adipogenic differentiation of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist, SEW-2871, VPC23019, or their combination acts on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased messenger RNA levels of tumor necrosis factor-α and CD11c, whereas they increased those of CD206 and adiponectin in the epididymal fats isolated from ob/ob mice with no changes in the levels of peroxisome proliferator activated receptor γ and its regulated genes. By contrast, VPC23019 did not cause any such alterations but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.

Thermal conductivity and conductance of protein in aqueous solution: Effects of geometrical shape.

Considering the importance of elucidating the heat transfer in living cells, we evaluated the thermal conductivity κ and conductance G of hydrated protein through all-atom non-equilibrium molecular dynamics simulation. Extending the computational scheme developed in earlier studies for spherical protein to cylindrical one under the periodic boundary condition, we enabled the theoretical analysis of anisotropic thermal conduction and also discussed the effects of protein size correction on the calculated results. While the present results for myoglobin and green fluorescent protein (GFP) by the spherical model were in fair agreement with previous computational and experimental results, we found that the evaluations for κ and G by the cylindrical model, in particular, those for the longitudinal direction of GFP, were enhanced substantially, but still keeping a consistency with experimental data. We also studied the influence by salt addition of physiological concentration, finding insignificant alteration of thermal conduction of protein in the present case.

Age-dependent sex difference of non-alcoholic fatty liver disease in TSOD and db/db mice.

According to previous clinical studies, the prevalence of non-alcoholic fatty liver disease (NAFLD) is higher in men than women only during the reproductive age. Animal models of NAFLD that reflect sex differences in humans have not been established. In this study, we examined sex differences in the hepatic lesions of Tsumura Suzuki obese diabetes (TSOD) and db/db mice, which are representative genetic models of NAFLD. Male and female TSOD and db/db mice were fed with a normal diet and tap water ad libitum. Six male and female mice of each strain were sacrificed at the ages of 3 and 9 months, respectively, and serum biochemical, pathological, and molecular analyses were performed. Serum aspartate aminotransferase (AST) levels were significantly higher in male than female mice of both strains at the age of 3 months; however, at 9 months, significant sex differences were not observed. Similarly, alanine aminotransferase (ALT) levels were significantly higher in male mice than in female TSOD mice at the age of 3 months; however, at 9 months, significant sex differences were not observed. Image analysis of histological slides revealed that the frequency of the steatotic area was significantly higher in male than female db/db mice at the age of 3 months; however, significant sex differences were not observed at 9 months. The frequency of Sirius red-positive fibrotic area was significantly higher in male than female mice in both strains at the age of 3 months; however, significant sex differences were not observed at 9 months. Serum AST and ALT levels and hepatic steatosis and fibrosis in TSOD and db/db mice showed age-dependent sex differences consistent with those observed in human NAFLD. These mice may be suitable for studying sex differences of the disease.

Current Status of Whole Slide Image (WSI) Standardization in Japan.

A whole slide image (WSI) is a digitized microscopic image that is particularly useful in histochemistry and cytochemistry. Several WSI scanners have been introduced in Japan and all use their own native format. Thus, there is basically no interchangeability. However, the Digital Imaging and Communications in Medicine (DICOM) standard format for WSI has been available since 2010. In this review, the configuration and differences among the native WSI and DICOM formats are examined, and the advantages and issues of DICOM standardization are discussed.

Substantial improvement of histopathological diagnosis by whole-slide image-based remote consultation.

Consultation by subspecialty experts is the most common mode of rendering diagnosis in challenging cases in pathological practice. Our study aimed to highlight the diagnostic benefits of whole-slide image (WSI)-based remote consultation. We obtained diagnostically challenging cases from two institutions from the years 2010 and 2013, with histological diagnoses that contained keywords "probable," "suggestive," "suspicious," "inconclusive," and "uncertain." A total of 270 cases were selected for remote consultation using WSIs scanned at 40 × . The consultation process consisted of three rounds: the first and second rounds each with 12 subspecialty experts and the third round with six multi-expertise senior pathologists. The first consultation yielded 44% concordance, and a change in diagnosis occurred in 56% of cases. The most frequent change was from inconclusive to definite diagnosis (30%), followed by minor discordance (14%), and major discordance (12%). Out of the 70 cases which reached the second round, 31 cases showed discrepancy between the two consultants. For these 31 cases, a consensus diagnosis was provided by six multi-expertise senior pathologists. Combining all WSI-based consultation rounds, the original inconclusive diagnosis was changed in 140 (52%) out of 266 cases. Among these cases, 80 cases (30%) upgraded the inconclusive diagnosis to a definite diagnosis, and 60 cases (22%) changed the diagnosis with major or minor discordance, accounting for 28 cases (10%) and 32 cases (12%), respectively. We observed significant improvement in the pathological diagnosis of difficult cases by remote consultation using WSIs, which can further assist in patient healthcare. A post-study survey highlighted various benefits of WSI-based consults.

Whole-lesion histogram analysis of apparent diffusion coefficient for the assessment of non-mass enhancement lesions on breast MRI.

Objectives: To investigate the application of apparent diffusion coefficient (ADC) histogram analysis in differentiating between benign and malignant breast lesions detected as non-mass enhancement on MRI. Materials and Methods: A retrospective study was conducted for 25 malignant and 26 benign breast lesions showing non-mass enhancement on breast MRI. An experienced radiologist without prior knowledge of the pathological results drew a region of interest (ROI) outlining the periphery of each lesion on the ADC map. A histogram was then made for each lesion. Following a univariate analysis of 18 summary statistics values, we conducted statistical discrimination after hierarchical clustering using Ward's method. A comparison between the malignant and the benign groups was made using multiple logistic regression analysis and the Mann-Whitney U test. A P -value of less than 0.05 was considered statistically significant. Results: Univariate analysis for the 18 summary statistics values showed the malignant group had greater entropy (P < 0.001) and lower uniformity (P < 0.001). While there was no significant difference in mean and skewness values, the malignant group tended to show a lower mean (P = 0.090) and a higher skewness (P = 0.065). Hierarchical clustering of the 18 summary statistics values identified four values (10th percentile, entropy, skewness, and uniformity) of which the 10th percentile values were significantly lower for the malignant group (P = 0.035). Conclusions: Whole-lesion ADC histogram analysis may be useful for differentiating malignant from benign lesions which show non-mass enhancement on breast MRI.

Neurosarcoidosis pathologically diagnosed via biopsy of a normal-sized inguinal lymph node with fluorodeoxyglucose accumulation on positron emission tomography/computed tomography in a patient with a history of brain Ewing's sarcoma.

Neurosarcoidosis is a rare disease and is often difficult to diagnose. Herein, we report a case of neurosarcoidosis in a patient with a history of Ewing's sarcoma of the brain. He presented with fever of unknown origin, and a pathological diagnosis was obtained via biopsy of a normal-sized inguinal lymph node with fluorodeoxyglucose (FDG) accumulation on positron emission tomography/computed tomography (PET/CT). The condition could not have been diagnosed without FDG-PET/CT.

Lactic acid as a major contributor to hand surface infection barrier and its association with morbidity to infectious disease.

Although the surface of the human hands contains high antimicrobial activity, studies investigating the precise components involved and the relationship between natural antimicrobial activity and morbidity in infectious diseases are limited. In this study, we developed a method to quantitatively measure the antimicrobial activity of hand surface components. Using a clinical survey, we validated the feasibility of our method and identified antimicrobial factors on the surface of the human hand. In a retrospective observational study, we compared the medical histories of the participants to assess infectious diseases. We found that the antimicrobial activity on the surface of the hands was significantly lower in the high morbidity group (N = 55) than in the low morbidity group (N = 54), indicating a positive association with the history of infection in individuals. A comprehensive analysis of the hand surface components indicated that organic acids, especially lactic acid and antimicrobial peptides, are highly correlated with antimicrobial activity. Moreover, the application of lactic acid using the amount present on the surface of the hand significantly improved the antimicrobial activity. These findings suggest that hand hygiene must be improved to enhance natural antimicrobial activity on the surface of the hands.

Rapid Response to Pembrolizumab in a Chemo-Refractory Testicular Germ Cell Cancer with Microsatellite Instability-High.

Testicular germ cell tumor (TGCT) is highly chemo-sensitive cancer; however, there is no established treatment for TGCT relapsed after multiple chemotherapy. Although pembrolizumab showed durable stable disease in some patients, no reliable biomarker for predicting response is available. High microsatellite instability (MSI) is rare in chemo-naïve TGCT. We report a TGCT patient with a rapid response to pembrolizumab. A 34-year-old Japanese male diagnosed with advanced TGCT underwent PCR-based testing of the primary site; it did not reveal MSI. He relapsed after four chemotherapy regimens: bleomycin, etoposide and cisplatin; paclitaxel, ifosfamide and cisplatin; vinblastine, ifosfamide and cisplatin; and irinotecan+nedaplatin with a total of 20 treatment cycles. Chemotherapy was thus discontinued. Re-examination by a CT-guided needle biopsy for progressing retroperitoneal lymph node (RPLN) metastases showed MSI-high; pembrolizumab was initiated. After only two doses, the human chorionic gonadotropin level decreased from 6500 to <1.0 IU/L. PET-CT showed shrinkage of the RPLN metastases with diminished metabolism. The patient is currently free from disease progression for 6 months from the start of pembrolizumab. This is the first report of refractory TGCT with MSI-high responding to pembrolizumab. We emphasize the utility of a metastatic-site biopsy to check the MSI status for refractory TGCT even when primary site is MSI-negative.

Analysis of hand environment factors contributing to the hand surface infection barrier imparted by lactic acid.

BACKGROUND: Organic acids on the surface of human hands contribute to the barrier against transient pathogens. This is the first study to explore the synergistic contribution of lactic acid and other hand environment-related features on the antibacterial properties of the hand surface. MATERIALS AND METHODS: We estimated the contribution of fingerprint depth, skin pH, stratum corneum water content, skin temperature, and sweat rate of the hands to the infection barrier using an observational survey of 105 subjects. The relationship between each factor and the antibacterial activity of the hands was analyzed using Pearson's correlation coefficient. We performed molecular dynamics simulations to study the interaction between lactic acid and bacterial membranes. RESULTS: The amount of lactic acid on the hands and skin temperature contributed positively to the antimicrobial activity (r = 0.437 and P = 3.18 × 10-6 , r = 0.500 and P = 5.66 × 10-8 , respectively), while the skin pH contributed negatively (r = -0.471, P = 3.99 × 10-7 ). The predicted value of the combined antimicrobial effect of these parameters was [antimicrobial activity] = 0.21 × [lactic acid] - 0.25 × [skin pH] + 0.26 × [skin temperature] + 0.98. The coefficient of determination (R2 ) was 0.50. CONCLUSION: The increase in the amount of non-ionic lactic acid due to lower pH and improvement in the fluidity of the cell membrane due to higher temperatures enable the efficient transport of lactic acid into cells and subsequent antimicrobial activity. The proposed mechanism could help to develop an effective hand infection barrier technology.

Feasibility and Clinical Usefulness of a Novel Nonwearable Sheet-Type Monitor (Nemuri SCAN): Prognostic Value of Increased Respiratory Rate in Actively Dying Patients.

Objective: The objective of this study was to explore the feasibility of monitoring actively dying patients hospitalized in a palliative care unit using a nonwearable sheet-type monitor that measured the state of sleep and vital signs per minute. In addition, we aimed to clarify the incidence of increased respiratory rate and its relationship with survival time. Design and Measurement: This study was conducted at a 51-bed palliative care unit in Japan from April 2018 through October 2019. Actively dying patients hospitalized in the palliative care unit were eligible to participate. Increased respiratory rate was measured by Nemuri SCAN, and patient's information was extracted from their medical records. Results: In this study, 23 patients were monitored until death; 19 patients with an observational period of 7 days or longer (163 patient days in total) were included in this analysis. There were no adverse events due to use of the nonwearable device. The cumulative incidence of increased respiratory rate (defined as more than 30 respiratory rate per minute) was 63.16% during the observational period, and the mean time between appearance of increased respiratory rate and death was 4.17 ± 4.04 days. Conclusion: This study clearly shows that hospitalized actively dying patients can be monitored using a nonwearable sheet-type monitor that measures sleeping state and vital signs per minute. Further studies are needed to utilize these noninvasive continuous monitoring devices in daily clinical practice.

The Efficacy of Vitamin K, A Member Of Naphthoquinones in the Treatment of Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Redox dysregulation originating from metabolic alterations in cancer cells contributes to their proliferation, invasion, and resistance to therapy. Conversely, these features represent a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. Amongst them, Vitamin K (VitK) carries the potential against cancer stem cells, in addition to the rest of tumor mass. OBJECTIVES: To assess the possible benefits and safety of VitK for cancer treatment using a systematic review and meta-analysis with a mixed-methods approach. METHODS: We performed a systematic search on several electronic databases for studies comparing VitK treatment with and without combination to the control groups. For quantitative studies, fully or partially reported clinical outcomes such as recurrence rates, survival, overall response and adverse reactions were assessed. For qualitative studies, a narrative synthesis was accomplished. RESULTS: Our analysis suggested that the clinical outcome of efficacy, the pooled hazard ratio for progression-free survival, and the pooled relative risk for overall survival, and overall response were significantly higher in the VitK therapy group compared to the placebo group (p<0.05). We did not observe any significant difference in the occurrence of adverse events between groups. Among qualitative studies, VitK treatment targeting myelodysplastic syndrome and advanced solid tumors resulted in 24.1% and 10% of clinical response, respectively. CONCLUSION: VitK not only exerts antitumor effects against a wide range of tumor types, but it also has excellent synergism with other therapeutic agents.