FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters.

The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.

Successful use of casirivimab/imdevimab anti-spike monoclonal antibodies to enhance neutralizing antibodies in a woman on anti-CD20 treatment with refractory COVID-19.

Management of COVID-19 patients with humoral immunodeficiency is challenging. We describe a woman with COVID-19 with multiple relapses due to anti-CD20 monoclonal antibody treatment. She was successfully treated with casirivimab/imdevimab and confirmed to have neutralizing antibodies. This case suggests that monoclonal antibodies have therapeutic and prophylactic value in patients with humoral immunodeficiency.

Surgical risk assessment for super-elderly patients.

AIM: Super-elderly patients are often frail and the decision on surgical indications remains a difficult issue. The purpose of this study was to provide a certain preoperative surgical risk assessment tool for super-elderly people. METHODS: We selected 112 individuals who were super-elderly patients aged >90 years who had surgeries under general anesthesia in our department. Based on the quality of the postoperative outcome of each case, we categorized these patients into two groups: good and poor groups. We evaluated the fundamental examination items, such as American Society of Anesthesiologists physical status, skeletal muscle mass index and so on, and a couple of the well-known risk score systems represented by Estimation of Physiology Ability and Surgical Stress. RESULTS: A total of 85 of the 112 patients belonged to the good group and the rest belonged to the poor group. The quality of postoperative outcome is well characterized by Estimation of Physiology Ability and Surgical Stress (P = 0.001). Receiver operating characteristic analysis of Estimation of Physiology Ability and Surgical Stress for the quality of postoperative outcome shows sensitivity of 0.83 and specificity of 0.61. Multivariate logistic regression analysis showed that skeletal muscle mass index and American Society of Anesthesiologists physical status are prominent as the risk determinants affecting the quality of postoperative outcome. A scoring system based on the skeletal muscle mass index, which is a good index of sarcopenia, and American Society of Anesthesiologists physical status, named the "SAP score" has the following characteristics. P-value <0.001, sensitivity 0.76 and specificity 0.91. CONCLUSIONS: Informed consent based on the risk score might be able to reduce the regrettable situation where it would have been better to have had surgery or not to have had surgery. Geriatr Gerontol Int 2022; 22: 271-277.

MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells.

Cancer stem-like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c-Myc. c-Myc-dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient-derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S-phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c-Myc-MCM10 axis for preventing drug resistance and recurrence of tumors.

Materials informatics approach to understand aluminum alloys.

The relations between the mechanical properties, heat treatment, and compositions of elements in aluminum alloys are extracted by a materials informatics technique. In our strategy, a machine learning model is first trained by a prepared database to predict the properties of materials. The dependence of the predicted properties on explanatory variables, that is, the type of heat treatment and element composition, is searched using a Markov chain Monte Carlo method. From the dependencies, a factor to obtain the desired properties is investigated. Using targets of 5000, 6000, and 7000 series aluminum alloys, we extracted relations that are difficult to find via simple correlation analysis. Our method is also used to design an experimental plan to optimize the materials properties while promoting the understanding of target materials.

Accelerating small-angle scattering experiments on anisotropic samples using kernel density estimation.

We propose a method to accelerate small-angle scattering experiments by exploiting spatial correlation in two-dimensional data. We applied kernel density estimation to the average of a hundred short scans and evaluated noise reduction effects of kernel density estimation (smoothing). Although there is no advantage of using smoothing for isotropic data due to the powerful noise reduction effect of radial averaging, smoothing with a statistically and physically appropriate kernel can shorten measurement time by less than half to obtain sector averages with comparable statistical quality to that of sector averages without smoothing. This benefit will encourage researchers not to use full radial average on anisotropic data sacrificing anisotropy for statistical quality. We also confirmed that statistically reasonable estimation of measurement time is feasible on site by evaluating how intensity variances improve with accumulating counts. The noise reduction effect of smoothing will bring benefits to a wide range of applications from efficient use of beamtime at laboratories and large experimental facilities to stroboscopic measurements suffering low statistical quality.

Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.

Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

Towards understanding of magnetization reversal in Nd-Fe-B nanocomposites: analysis by high-throughput micromagnetic simulations.

We demonstrate how micromagnetic simulations can be employed in order to characterize and analyze the magnetic microstructure of nanocomposites. For the example of nanocrystalline Nd-Fe-B, which is a potential material for future permanent-magnet applications, we have compared three different models for the micromagnetic analysis of this material class: (i) a description of the nanocomposite microstructure in terms of Stoner-Wohlfarth particles with and without the magnetodipolar interaction; (ii) a model based on the core-shell representation of the nanograins; (iii) the latter model including a contribution of superparamagnetic clusters. The relevant parameter spaces have been systematically scanned with the aim to establish which micromagnetic approach can most adequately describe experimental data for this material. According to our results, only the last, most sophisticated model is able to provide an excellent agreement with the measured hysteresis loop. The presented methodology is generally applicable to multiphase magnetic nanocomposites and it highligths the complex interrelationship between the microstructure, magnetic interactions, and the macroscopic magnetic properties.

An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenance of breast cancer stem-like cells.

Cancer stem cells are thought to be responsible for tumor growth, recurrence, and resistance to conventional cancer therapy. However, it is still unclear how they are maintained in tumor tissues. Here, we show that the growth differentiation factor 15 (GDF15), a member of the TGFß family, may maintain cancer stem-like cells in breast cancer tissues by inducing its own expression in an autocrine/paracrine manner. We found that GDF15, but not TGFß, increased tumor sphere formation in several breast cancer cell lines and patient-derived primary breast cancer cells. As expected, TGFß strongly stimulated the phosphorylation of Smad2. GDF15 also stimulated the phosphorylation of Smad2, but the GDF15-induced tumor sphere forming efficiency was not significantly affected by treatment with SB431542, an inhibitor of the TGFß signaling. Although TGFß transiently activated ERK1/2, GDF15 induced prolonged activation of ERK1/2. Treatment with U0126, an inhibitor of the MEK-ERK1/2 signaling, greatly inhibited the GDF15-induced tumor sphere formation. Moreover, cytokine array experiments revealed that GDF15, but not TGFß, is able to induce its own expression; furthermore, it appears to form an autocrine/paracrine circuit to continuously produce GDF15. In addition, we found heterogeneous expression levels of GDF15 among cancer cells and in human breast cancer tissues using immunohistochemistry. This may reflect a heterogeneous cancer cell population, including cancer stem-like cells and other cancer cells. Our findings suggest that GDF15 induces tumor sphere formation through GDF15-ERK1/2-GDF15 circuits, leading to maintenance of GDF15high cancer stem-like cells. Targeting GDF15 to break these circuits should contribute to the eradication of tumors.

Multiple magnetic scattering in small-angle neutron scattering of Nd-Fe-B nanocrystalline magnet.

We have investigated the influence of multiple scattering on the magnetic small-angle neutron scattering (SANS) from a Nd-Fe-B nanocrystalline magnet. We performed sample-thickness- and neutron-wavelength-dependent SANS measurements, and observed the scattering vector dependence of the multiple magnetic scattering. It is revealed that significant multiple scattering exists in the magnetic scattering rather than the nuclear scattering of Nd-Fe-B nanocrystalline magnet. It is considered that the mean free path of the neutrons for magnetic scattering is rather short in Nd-Fe-B magnets. We analysed the SANS data by the phenomenological magnetic correlation model considering the magnetic microstructures and obtained the microstructural parameters.

[Induction chemotherapy with S-1/oxaliplatin prevented colostomy in a patient with advanced rectal cancer].

A 72-year-old woman was admitted to our hospital with bloody stools and constipation. She was diagnosed with advanced lower rectal cancer with multiple liver and pulmonary metastases. Because the rectal cancer was located 2 cm from the anal verge, we suggested she undergo an abdominoperineal resection(Miles operation), but she refused to undergo a colostomy. Then, 6 courses of chemotherapy with S-1/oxaliplatin(SOX)were administered, and the local tumor, liver metastases, and pulmonary metastases were all significantly decreased in size(reduction rate 60%). After chemotherapy, she chose to undergo low anterior resection(LAR), D2. Postoperative recovery was uneventful, and she currently has stable disease with adjuvant SOX chemotherapy. Induction SOX chemotherapy was considered to be useful for maintaining the quality of life(QOL) in a patient with advanced rectal cancer.

Serum superoxide dismutase activity correlates with the components of metabolic syndrome or carotid artery intima-media thickness.

The activities of the enzymes to eliminate reactive oxygen species prevent the progression of atherosclerosis. We conducted a cross-sectional study among 3234 people that underwent total health check-up service, and studied the relationship between the serum superoxide dismutase (SOD) activity and risk factors of atherosclerosis or carotid artery intima-media thickness (IMT). Serum SOD activity negatively correlated with body mass index (BMI), systolic and diastolic blood pressure, serum triglyceride (TG) concentration and serum glucose concentration. Low serum SOD activity positively correlated with the carotid IMT thickening. But on the other hand, existence of carotid artery plaque positively correlated with serum SOD activity especially among men. Serum SOD activity negatively correlated with the components of metabolic syndrome and low serum SOD activity seems to be an independent risk of the thickening of carotid IMT. On the other hand, serum SOD activity level seems to elevate limitedly but reactively to the status of increased oxidative stress, such as carotid plaque formation.

Relationship between the adiponectin-leptin ratio and parameters of insulin resistance in subjects without hyperglycemia.

We previously reported that the adiponectin-leptin (A/L) ratio was more efficacious as a parameter of insulin resistance than adiponectin or leptin alone, and a more sensitive and reliable marker of insulin resistance than homeostasis model assessment (HOMA-R) as the fasting plasma glucose (FPG) level elevated in type 2 diabetes mellitus. In this study, we examined the usefulness of the A/L ratio as compared to HOMA-R for assessing insulin resistance in Japanese subjects without hyperglycemia. A total of 411 Japanese adults without hyperglycemia (205 men, aged 49 +/- 10 years; 206 women, aged 48 +/- 10 years) were enrolled. We investigated the correlation between fasting serum insulin level, FPG, leptin or adiponectin, and body mass index (BMI), fat mass (FM), triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, or preheparin serum lipoprotein lipase (LPL) as parameters of insulin resistance. Next, we examined the relationships between parameters of insulin resistance and the A/L ratio or HOMA-R. By simple regression of the correlation between serum insulin level, FPG, leptin or adiponectin, and each parameter of insulin resistance, the best correlation coefficients were seen in leptin (men, r = 0.501; women, r = 0.667) as compared with BMI, in leptin (men, r = 0.658; women, r = 0.747) as compared with FM, in adiponectin (r = -0.285) in men and leptin (r = 0.299) in women as compared with TGs, in adiponectin (men, r = 0.405; women; r = 0.442) as compared with HDL cholesterol, and in adiponectin (men, r = 0.228; women, r = 0.452) as compared with LPL. By simple regression of the correlation between A/L ratio or HOMA-R and each parameter of insulin resistance, the highest correlation coefficients were seen with the A/L ratio except HDL cholesterol in men. Next, we carried out multiple linear regression to analyze the association between A/L ratio or HOMA-R and FM, TGs, HDL cholesterol, and LPL, excluding BMI, simultaneously. In men, the A/L ratio was significantly correlated with FM and TGs, and HOMA-R was significantly correlated with FM. This model explained 34% of the variance in the A/L ratio and 17% of the variance in HOMA-R. In women, the A/L ratio was significantly correlated with FM and LPL, and HOMA-R was significantly correlated with FM and LPL. This model explained 39% of the variance in A/L ratio and 14% of the variance in HOMA-R. In conclusion, the present study suggested that the A/L ratio might be more useful than HOMA-R to accurately assess insulin resistance in subjects without hyperglycemia.

Correlation between the adiponectin-leptin ratio and parameters of insulin resistance in patients with type 2 diabetes.

We studied the correlation between the adiponectin-leptin (A/L) ratio and parameters of insulin resistance in 220 Japanese patients with type 2 diabetes (138 men and 82 women). Body mass index (BMI), triglycerides (TGs), HDL cholesterol (HDL), and preheparin serum lipoprotein lipase (LPL mass) were examined as laboratory parameters of the insulin resistance. The correlations between these laboratory parameters and adiponectin, leptin, or A/L ratio were studied. Adiponectin levels correlated significantly with BMI (r = -0.298, P = .0003), TGs (r = -0.221, P = .0092), HDL (r = 0.31, P = .0002), and LPL mass (r = 0.26, P = .0021) in men, and with TGs (r = -0.29, P = .0093), HDL (r = 0.239, P = .0338), and LPL mass (r = 0.499, P < .0001) in women. Leptin levels correlated significantly with only BMI (r = 0.31, P = .0002) in men, and with BMI (r = 0.71, P < .0001) and TGs (r = 0.26, P = .0201) in women. Adiponectin and leptin levels tended to correlate with these parameters in an opposite manner. On the other hand, A/L ratio significantly correlated with BMI (r = -0.4, P < .0001), TG (r = -0.199, P = .0192), HDL (r = 0.235, P = .0054), and LPL mass (r = 0.244, P = .0390) in men, and with BMI (r = -0.482, P < .0001), TG (r = -0.402, P = .0002), HDL (r = 0.358, P = .0011), and LPL mass (r = 0.487, P < .0001) in women. Next, the patients were divided into 3 groups classified by their fasting plasma glucose (FPG) level, and the correlations between the parameters and A/L ratio or homeostasis model assessment (HOMA-R), and the correlation between A/L ratio and HOMA-R were investigated in each group. Significant correlations between the parameters and A/L ratio were tended to be observed as the FPG level rose; however, the significant correlations between the parameters and HOMA-R were no longer seen as FPG level elevated. The results suggested that the A/L ratio was effective in relevance as a parameter of insulin resistance to adiponectin or leptin alone, and a more sensitive and reliable marker of insulin resistance than HOMA-R as the FPG level elevated, in patients with type 2 diabetes.

Increased electronegative charge of serum low-density lipoprotein in patients with diabetes mellitus.

BACKGROUND: Patients with diabetes mellitus have been reported to show increased serum levels of modified low-density lipoprotein (LDL), including glycosylated, oxidized and small, dense LDL. This change has been suggested to represent an important risk factor for diabetic macroangiopathy. A common characteristic shared by these modified LDL species is the increase in electronegative charge on particle surfaces, which can be detected by agarose gel electrophoresis as "LDL charge modified frequency" (LDL-CMF) determined from the relative mobility of LDL fraction. METHODS: LDL-CMF was measured in the sera from 129 outpatients with type 2 diabetes mellitus and compared with the data from 34 normal subjects. RESULTS: The LDL fraction from diabetics migrates more closely to the anode side as compared with that from normal subjects. The LDL-CMF measured in diabetics, 5.5+/-8.1%, was significantly (p<0.0001) higher than 0.6+/-3.4% in normal subjects. Serum LDL-CMF showed significant positive correlations with triglyceride at r=0.552 (p<0.0001) and malondialdehyde modified LDL at r=0.390 (p<0.0001), as well as systolic blood pressure, body mass index, fasting plasma glucose, hemoglobin A(1c), total cholesterol, free fatty acid (FFA) and homeostasis model assessment ratio. It showed negative correlations with high-density lipoprotein and total superoxide dismutase activity. CONCLUSION: The results indicate that LDL-CMF reflects the degree of serum LDL modification in diabetics and can be regarded as an important risk factor for diabetic macroangiopathy.