Subtype and targeted therapy for TNBC

Triple-negative breast cancer (TNBC) is a heterogenous disease. For personalized medicine, it is essential to identify and classify tumor subtypes to develop effective therapeutic strategies. Although gene expression profiling has identified several TNBC subtypes, classification of these tumors remains complex. Most TNBCs exhibit an aggressive phenotype, but some rare types have a favorable clinical course. In this review, we summarize the classification and characteristics related to the various TNBC subtypes, including the rare types. Therapeutic methods that are suitable for each subtype are also discussed. Of the intrinsic breast cancer subtypes identified by gene expression analysis, the basal-like subtype specifically displayed decreased expression of an estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) cluster. We also present results that characterize the TNBC and basal-like phenotypes. TNBC may be categorized into four major classes : basal-like, immune-enriched, mesenchymal, and luminal androgen receptor. Therapeutic strategies for each subtype have been proposed along with newly approved targeted therapies for TNBC, such as immune checkpoint inhibitors. Understanding the classification of TNBC based on gene expression profiling in association with clinicopathological factors will facilitate accurate pathological diagnosis and effective treatment selection

非アルコール性脂肪性肝炎における肝細胞へのα-synucleinの蓄積と病理組織学的診断における有用性

Backgrounds: Nonalcoholic steatohepatitis (NASH) is characterized by fat deposition, inflammation, and hepatocellular damage. The diagnosis of NASH is confirmed pathologically, and hepatocyte ballooning is an important finding for definite diagnosis. Recently, α-synuclein deposition in multiple organs was reported in Parkinson’s disease. Since it was reported that α synuclein is taken up by hepatocytes via connexin 32, the expression of α-synuclein in the liver in NASH is of interest. The accumulation of α-synuclein in the liver in NASH was investigated. Immunostaining for p62, ubiquitin, and α-synuclein was performed, and the usefulness of immunostaining in pathological diagnosis was examined. Methods: Liver biopsy tissue specimens from 20 patients were evaluated. Several antibodies against α-synuclein, as well as antibodies against connexin 32, p62, and ubiquitin were used for immunohistochemical analyses. Staining results were evaluated by several pathologists with varying experience, and the diagnostic accuracy of ballooning was compared. Results: Polyclonal α-synuclein antibody, not the monoclonal antibody, reacted with eosinophilic aggregates in ballooning cells. Expression of connexin 32 in degenerating cells was also demonstrated. Antibodies against p62 and ubiquitin also reacted with some of the ballooning cells. In the pathologists’ evaluations, the highest interobserver agreement was obtained with hematoxylin and eosin (H&E)-stained slides, followed by slides immunostained for p62 and α-synuclein, and there were cases with different results between H&E staining and immunostaining Conclusion: These results indicate the incorporation of degenerated α-synuclein into ballooning cells, suggesting the involvement of α-synuclein in the pathogenesis of NASH. The combination of immunostaining including polyclonal α-synuclein may contribute to improving the diagnosis of NASH

A proto-cluster of massive quiescent galaxies at z=4

We report on discovery of a concentration of massive quiescent galaxies located at z=4. The concentration is first identified using high-quality photometric redshifts based on deep, mutli-band data in Subaru/XMM-Newton Deep Field. Follow-up near-infrared spectroscopic observations with MOSFIRE on Keck confirm a massive (~10^{11} Msun) quiescent galaxy at z=3.99. Our spectral energy distribution (SED) analyses reveal that the galaxy experienced an episode of starburst about 500 Myr prior to the observed epoch, followed by rapid quenching. As its spectrum is sufficiently good to measure the stellar velocity dispersion, we infer its dynamical mass and find that it is consistent with its stellar mass. The galaxy is surrounded by 4 massive (>10^{10} Msun) quiescent galaxies on a ~1 physical Mpc scale, all of which are consistent with being located at the same redshift based on high-accuracy spectro-photometric redshifts. This is likely a (proto-)cluster dominated by quiescent galaxies, the first of the kind reported at such a high redshift as z=4. Interestingly, it is in a large-scale structure revealed by spectroscopic redshifts from VANDELS. Furthermore, it exhibits the red sequence, adding further support to the physical concentration of the galaxies. We find no such concentration in the Illustris-TNG300 simulation; it may be that the cluster is such a rare system that the simulation box is not sufficiently large to reproduce it. The total halo mass of the quiescent galaxies is ~10^{13} Msun, suggesting that they form a group-sized halo once they collapse together. We discuss implications of our findings for the quenching physics and conclude with future prospects.Comment: 16 pages, 12 figures, submitted to Ap

Establishment of an Epicutaneously Sensitized Murine Model of Shellfish Allergy and Evaluation of Skin Condition by Raman Microscopy

Background: Shellfish allergy is one of the most common food allergies. Recent studies have shown that sensitization to allergens via the skin is involved in the development of food allergies. In this study, a mouse model of shrimp allergy was generated by epicutaneous sensitization and used to identify skin conditions associated with susceptibility to sensitization. Methods: Four-week-old female BALB/c mice were sensitized by repeated application of 0.1 mg of tropomyosin to tape-stripped skin on days 0, 7, and 15, followed by a challenge on days 28 and 35. Results: Epicutaneously sensitized mice exhibited higher serum levels of tropomyosin-specific IgE on day 15 than control mice. After the oral challenge, model mice had higher anaphylaxis scores and lower rectal temperature. After three tape-strip treatments for sensitization, the skin was analyzed by Raman microscopy. The sensitized mice exhibited lower relative intensities of Raman bands at 399, 915, and 1073 cm−1 than control mice, which could be helpful noninvasive markers in screening for potential sensitization via the skin. Conclusions: An epicutaneous sensitization shellfish allergy model was generated. This model will be useful in studies to elucidate the pathogenesis of skin sensitization. Raman microscopy may also be valuable for capturing subtle skin changes leading to sensitization

PESI-MS for Diagnostic Cytology

Objectives: Cytology and histology are 2 indispensable diagnostic tools for cancer diagnosis, which are rapidly increasing in importance with aging populations. We applied mass spectrometry (MS) as a rapid approach for swiftly acquiring nonmorphological information of interested cells. Conventional MS, which primarily rely on promoting ionization by pre-applying a matrix to cells, has the drawback of time-consuming both on data acquisition and analysis. As an emerging method, probe electrospray ionization-MS (PESI-MS) with a dedicated probe is capable to pierce sample and measure specimen in small amounts, either liquid or solid, without the requirement for sample pretreatment. Furthermore, PESI-MS is timesaving compared to the conventional MS. Herein, we investigated the capability of PESI-MS to characterize the cell types derived from the respiratory tract of human tissues. Study Design: PESI-MS analyses with DPiMS-2020 were performed on various type of cultured cells including 5 lung squamous cell carcinomas, 5 lung adenocarcinomas, 5 small-cell carcinomas, 4 malignant mesotheliomas, and 2 normal controls. Results: Several characteristic peaks were detected at around m/z 200 and 800 that were common in all samples. As expected, partial least squares-discriminant analysis of PESI-MS data distinguished the cancer cell types from normal control cells. Moreover, distinct clusters divided squamous cell carcinoma from adenocarcinoma. Conclusion: PESI-MS presented a promising potential as a novel diagnostic modality for swiftly acquiring specific cytological information

High-Grade Renal MTSCC

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare subtype of renal cell carcinoma. Although usually indolent, high-grade MTSCC has been reported to exhibit an aggressive clinical course. Herein, we report a case of high-grade renal MTSCC. An 86-year-old man visited our hospital with fever and fatigue. Based on contrast-enhanced computed tomography findings, the patient was diagnosed with clinical stage T2aN0M0 right renal cell carcinoma and underwent laparoscopic radical nephrectomy. Histological examination showed tubular to tubulopapillary structures accompanied by mucinous stroma, suggesting high-grade renal MTSCC. He remained recurrence- and metastasis-free 6 months after nephrectomy. Since high-grade renal MTSCC may have an aggressive clinical course, such patients should be observed carefully after radical nephrectomy

Verification of the Impact of Blood Glucose Level on Liver Carcinogenesis and the Efficacy of a Dietary Intervention in a Spontaneous Metabolic Syndrome Model

Metabolic syndrome (MS) is a risk factor for type 2 diabetes mellitus, vascular inflammation, atherosclerosis, and renal, liver, and heart diseases. Non-alcoholic steatohepatitis (NASH) is a progressive representative liver disease and may lead to the irreversible calamities of cirrhosis and hepatocellular carcinoma. Metabolic disorders such as hyperglycemia have been broadly reported to be related to hepatocarcinogenesis in NASH; however, direct evidence of a link between hyperglycemia and carcinogenesis is still lacking. Tsumura Suzuki Obese Diabetic (TSOD) mice spontaneously develop metabolic syndrome, including obesity, insulin resistance, and NASH-like liver phenotype, and eventually develop hepatocellular carcinomas. TSOD mice provide a spontaneous human MS-like model, even with significant individual variations. In this study, we monitored mice in terms of their changes in blood glucose levels, body weights, and pancreatic and liver lesions over time. As a result, liver carcinogenesis was delayed in non-hyperglycemic TSOD mice compared to hyperglycemic mice. Moreover, at the termination point of 40 weeks, liver tumors appeared in 18 of 24 (75%) hyperglycemic TSOD mice; in contrast, they only appeared in 5 of 24 (20.8%) non-hyperglycemic mice. Next, we investigated three kinds of oligosaccharide that could lower blood glucose levels in hyperglycemic TSOD mice. We monitored the levels of blood and urinary glucose and assessed pancreatic lesions among the experimental groups. As expected, significantly lower levels of blood and urinary glucose and smaller deletions of Langerhans cells were found in TSOD mice fed with milk-derived oligosaccharides (galactooligosaccharides and lactosucrose). At the age of 24 weeks, mild steatohepatitis was found in the liver but there was no evidence of liver carcinogenesis. Steatosis in the liver was alleviated in the milk-derived oligosaccharide-administered group. Taken together, suppressing the increase in blood glucose level from a young age prevented susceptible individuals from diabetes and the onset of NAFLD/NASH, as well as carcinogenesis. Milk-derived oligosaccharides showed a lowering effect on blood glucose levels, which may be expected to prevent liver carcinogenesis

A novel COL4A1 variant associated with recurrent epistaxis and glioblastoma

COL4A1-related disorders are characterized by a higher incidence of cerebral hemorrhage than other hereditary cerebral small vessel diseases. Accumulating data have shown broad phenotypic variations, and extracerebral hemorrhages have been linked to these disorders. Moreover, the coexistence of neural tumors has been described. Here, we report a Japanese family with a novel COL4A1 variant, including a patient with recurrent epistaxis and glioblastoma

A massive quiescent galaxy in a group environment at z=4.53z=4.53

We report on the spectroscopic confirmation of a massive quiescent galaxy at $z_\mathrm{spec}=4.53$ in the COSMOS field with Keck/MOSFIRE. The object was first identified as a galaxy with suppressed star formation at $z_\mathrm{phot}\sim4.65$ from the COSMOS2020 catalog. The follow-up spectroscopy with MOSFIRE in the $K$-band reveals a faint [OII] emission and the Balmer break, indicative of evolved stellar populations. We perform the spectral energy distribution fitting using both the photometry and spectrum to infer physical properties. The obtained stellar mass is high ($M_*\sim 10^{10.8}\,M_\odot$) and the current star formation rate is more than 1 dex below that of main-sequence galaxies at $z=4.5$. Its star formation history suggests that this galaxy experienced starburst at $z\sim5$ followed by a rapid quenching phase. This is one of the youngest quiescent galaxies at $z>3$ and is likely a galaxy in the process of being quenched. An unique aspect of the galaxy is that it is in an extremely dense region; there are four massive star-forming galaxies at $4.4<z_\mathrm{phot}<4.7$ located within 150 physical kpc from the galaxy. Interestingly, three of them have strongly overlapping virial radii with that of the central quiescent galaxy ($\sim 70\,\mathrm{kpc}$), suggesting that the over-density region is likely the highest redshift candidate of a dense group with a spectroscopically confirmed quiescent galaxy at the center. The group provides us with an unique opportunity to gain insights into the role of the group environment for quenching at $z\sim$ 4 - 5 corresponding to the formation epoch of massive elliptical galaxies in the local Universe.Comment: 13 pages, 7 figures, 2 tables; submitted to Ap

地域中核病院から病理解剖を依頼したALS

An 82-year-old man, who developed dysphagia several months ago, presented Tokushima University Hospital and was diagnosed of ALS in December 2019. The patient got gradually worse and became bedridden in May 2020. He was admitted into Tokushima University Hospital suffering an aspiration pneumonia in June 2020. The pneumonia rapidly improved with a treatment ; however, the patient failed to be treated at home against his wish and was transferred to Kaminaka Hospital. We accepted his wish for refusing mechanical ventilation or tube feeding. Later, we requested autopsy consent from the patient. He did not refuse our proposal ; therefore, we presearched transporters capable to deceased bodies and contacted the division of pathology in Tokushima University. 60 days later, the patient died due to a suddenly developed putamen hemorrhage. After getting the family's consent, as previously arranged, we transferred the deceased body to Tokushima University and accomplished an autopsy. Although the number of autopsies is declining, we suggest that hospital collaboration may help perform autopsies