Predictive analysis of breast cancer response to neoadjuvant chemotherapy through plasma metabolomics.

PURPOSE: Preoperative chemotherapy is a critical component of breast cancer management, yet its effectiveness is not uniform. Moreover, the adverse effects associated with chemotherapy necessitate the identification of a patient subgroup that would derive the maximum benefit from this treatment. This study aimed to establish a method for predicting the response to neoadjuvant chemotherapy in breast cancer patients utilizing a metabolomic approach. METHODS: Plasma samples were obtained from 87 breast cancer patients undergoing neoadjuvant chemotherapy at our facility, collected both before the commencement of the treatment and before the second treatment cycle. Metabolite analysis was conducted using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry (LC-MS). We performed comparative profiling of metabolite concentrations by assessing the metabolite profiles of patients who achieved a pathological complete response (pCR) against those who did not, both in initial and subsequent treatment cycles. RESULTS: Significant variances were observed in the metabolite profiles between pCR and non-pCR cases, both at the onset of preoperative chemotherapy and before the second cycle. Noteworthy distinctions were also evident between the metabolite profiles from the initial and the second neoadjuvant chemotherapy courses. Furthermore, metabolite profiles exhibited variations associated with intrinsic subtypes at all assessed time points. CONCLUSION: The application of plasma metabolomics, utilizing CE-MS and LC-MS, may serve as a tool for predicting the efficacy of neoadjuvant chemotherapy in breast cancer in the future after all necessary validations have been completed.

Efficacy and safety of dose-dense neoadjuvant chemotherapy with nab-paclitaxel followed by epirubicin and cyclophosphamide for operable breast cancer.

OBJECTIVE: Dose-dense chemotherapy has shown a better prognosis than standard interval chemotherapy in adjuvant settings for high-risk breast cancer. This study aimed to evaluate the efficacy and safety of dose-dense nanoparticle albumin-bound paclitaxel followed by dose-dense epirubicin and cyclophosphamide as neoadjuvant chemotherapy for human epidermal growth factor 2 (HER2)-negative operable breast cancer. METHODS: Patients with histologically confirmed stage I-III HER2-negative breast cancer were enrolled in this study. Patients received nanoparticle albumin-bound paclitaxel (260 mg/m2) followed by epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks with pegfilgrastim. The primary endpoint was the pathological complete response rate. Patients also underwent prophylactic management for peripheral neuropathy, which involved a combination of cryotherapy, compression therapy using elastic stockings and medications including goshajinkigan. RESULTS: Among the 55 patients enrolled in this study, 13 (23.6%) achieved pathological complete response, of whom 10/26 (38.5%) patients had triple-negative disease and 3/29 (10.3%) had luminal disease. The objective response was observed in 46 (83.6%) patients. Of the 36 patients who were initially planned for mastectomy, 11 (30.6%) underwent breast-conserving surgery after neoadjuvant chemotherapy. The most common grade 3-4 adverse events were myalgia (14.5%), fatigue (12.7%) and elevated transaminase levels (9.1%). No patients experienced febrile neutropenia. Eight (14.5%) patients discontinued treatments due to adverse events. CONCLUSIONS: Neoadjuvant dose-dense biweekly nanoparticle albumin-bound paclitaxel followed by dose-dense epirubicin and cyclophosphamide was effective, especially in patients with triple-negative disease, and feasible with pegfilgrastim support.

Acute arterial occlusive disease due to tumor thrombus from lung metastasis of breast cancer with cartilaginous and osseous metaplasia: a case report.

BACKGROUND: Tumor embolization due to venous infiltration of breast cancer pulmonary metastases is very rare. CASE PRESENTATION: A 72-year-old female was diagnosed with triple-negative breast cancer. Neoadjuvant chemotherapy was discontinued because of progressive disease, and a right mastectomy with sentinel lymph node biopsy was performed. The pathological analysis of surgical specimens revealed carcinoma with cartilaginous and/or osseous metaplasia. At 22 months after surgery, lung metastasis was observed, and 6 months after initiating treatment for lung metastases, she complained of sudden numbness in the left-lower limb with trouble walking. Ultrasonography showed an embolism in the left popliteal artery, and contrast computed tomography showed enlarged lung metastases and infiltration of the left-upper lobe disease into the left superior pulmonary vein and left atrium. Acute arterial occlusive disease in the left-lower limb caused by the tumor embolism was suspected, so an endovascular thrombectomy was performed. Tumor emboli were removed by embolectomy catheter. CONCLUSION: This report of lung metastasis from breast cancer with cartilaginous and/or osseous metaplasia and acute lower-limb artery occlusion due to a tumor thrombus adds useful information to the literature on these extremely rare cases.

Stimulated Rayleigh Scattering Enhanced by a Longitudinal Plasma Mode in a Periodically Driven Dirac Semimetal Cd_{3}As_{2}.

Using broadband (12-45 THz) multi-terahertz spectroscopy, we show that stimulated Rayleigh scattering dominates the transient optical conductivity of cadmium arsenide, a Dirac semimetal, under an optical driving field at 30 THz. The characteristic dispersive line shape with net optical gain is accounted for by optical transitions between light-induced Floquet subbands, strikingly enhanced by the longitudinal plasma mode. Stimulated Rayleigh scattering with an unprecedentedly large refractive index change may pave the way for slow light generation in conductive solids at room temperature.

Diabatic and adiabatic transitions between Floquet states imprinted in coherent exciton emission in monolayer WSe2.

Floquet engineering is a promising way of controlling quantum system with photon-dressed states on an ultrafast time scale. So far, the energy structure of Floquet states in solids has been intensively investigated. However, the dynamical aspects of the photon-dressed states under ultrashort pulse have not been explored yet. Their dynamics become highly sensitive to the driving field transients, and thus, understanding them is crucial for ultrafast manipulation of a quantum state. Here, we observed the coherent exciton emission in monolayer WSe2 at room temperature at the appropriate photon energy and the field strength of the driving light pulse using high-harmonic spectroscopy. Together with numerical calculations, our measurements revealed that the coherent exciton emission spectrum reflects the diabatic and adiabatic dynamics of Floquet states of excitons. Our results provide a previosuly unexplored approach to Floquet engineering and lead to control of quantum materials through pulse shaping of the driving field.

Management of Crohn's disease relapse during neoadjuvant chemotherapy for bilateral breast cancer: a case report.

Diagnosis of breast cancer in a patient with Crohn's disease (CD) is uncommon. However, cytotoxic chemotherapy might help control CD during the treatment period. Here, we report a case of CD relapse during treatment with neoadjuvant chemotherapy (NAC) for bilateral breast cancer. A 39-year-old woman with CD controlled by infliximab and mesalazine was diagnosed with bilateral breast cancer. Infliximab treatment was discontinued temporarily so that the patient could receive NAC. However, her CD symptoms intensified during chemotherapy, and after her symptoms improved after a one-time administration of infliximab, the remainder of NAC was completed with a corticosteroid. Bilateral breast conservation surgery was performed. Histopathological examination revealed partial response of the left breast cancer and no residual cancer in the right breast. Breast irradiation and hormone therapy were added and no signs of recurrence have been observed for 5 years. CD has been well controlled with adalimumab and mesalazine.

Intra-body dynamics of D-serine reflects the origin of kidney diseases.

INTRODUCTION: D-Serine, present only in trace amounts in humans, is now recognized as a biomarker of chronic kidney disease (CKD). CKD is heterogeneous in its original kidney diseases, whose diagnoses require kidney biopsy. In this study, we examined whether the intra-body dynamics of D-serine, indexed by its blood and urinary levels, reflects the origin of kidney diseases. METHODS: Patients with six kinds of kidney disease undergoing kidney biopsy were enrolled in a single center. Levels of D- and L-serine were measured using two-dimensional high-performance liquid chromatography. The associations between the origin of kidney diseases and the intra-body dynamics of D-serine were examined using multivariate cluster analyses. RESULTS: Unlike the non-CKD profile, patients with CKD showed broadly-distributed profiles of intra-body dynamics of D-serine. The plasma level of D-serine plays a key role in the detection of kidney diseases, whereas a combination of plasma and urinary levels of D-serine distinguished the origin of CKD, especially lupus nephritis. CONCLUSION: Intra-body dynamics of D-serine have the potential to predict the origin of kidney diseases. Monitoring of D-serine may guide specific treatments for the origin of kidney diseases.

Identification of Diabetic Nephropathy in Patients Undergoing Kidney Biopsy through Blood and Urinary Profiles of d-Serine.

Background: The diagnosis of diabetic nephropathy (DN), the major cause of ESKD, requires kidney biopsy. d-Serine, present only in trace amounts in humans, is a biomarker for kidney diseases and shows potential to distinguish the origin of kidney diseases, whose diagnoses usually require kidney biopsy. We extended this concept and examined the potential of d-serine in the diagnosis of DN. Methods: We enrolled patients with biopsy sample-proven DN and primary GN (minimal change disease and IgA nephropathy) and participants without kidney disease. A total of 388 participants were included in this study, and d-serine levels in blood and urine were measured using two-dimensional high-performance liquid chromatography, and urinary fractional excretion (FE) of d-serine was calculated. Using data from 259 participants, we developed prediction models for detecting DN by logistic regression analyses, and the models were validated in 129 participants. Results: A d-serine blood level of >2.34 µM demonstrated a high specificity of 83% (95% CI, 70% to 93%) for excluding participants without kidney diseases. In participants with a d-serine blood level >2.34 µM, the threshold of 47% in FE of d-serine provided an optimal threshold for the detection of DN (AUC, 0.85 [95% CI, 0.76 to 0.95]; sensitivity, 79% [95% CI, 61% to 91%]; specificity, 83% [95% CI, 67% to 94%]). This plasma-high and FE-high profile of d-serine in combination with clinical factors (age, sex, eGFR, and albuminuria) correctly predicted DN with a sensitivity of 91% (95% CI, 72% to 99%) and a specificity of 79% (95% CI, 63% to 80%), and outperformed the model based on clinical factors alone in the validation dataset (P<0.02). Conclusions: Analysis of d-serine in blood and urinary excretion is useful in identifying DN in patients undergoing kidney biopsy. Profiling of d-serine in patients with kidney diseases supports the suitable treatment through the auxial diagnosis of the origins of kidney diseases.

General description for nonequilibrium steady states in periodically driven dissipative quantum systems.

Laser technology has developed and accelerated photo-induced nonequilibrium physics, from both the scientific and engineering viewpoints. Floquet engineering, i.e., controlling material properties and functionalities by time-periodic drives, is at the forefront of quantum physics of light-matter interaction. However, it is limited to ideal dissipationless systems. Extending Floquet engineering to various materials requires understanding of the quantum states emerging in a balance of the periodic drive and energy dissipation. Here, we derive a general description for nonequilibrium steady states (NESSs) in periodically driven dissipative systems by focusing on systems under high-frequency drive and time-independent Lindblad-type dissipation. Our formula correctly describes the time average, fluctuation, and symmetry properties of the NESS, and can be computed efficiently in numerical calculations. This approach will play fundamental roles in Floquet engineering in a broad class of dissipative quantum systems from atoms and molecules to mesoscopic systems, and condensed matter.

Time Crystals Protected by Floquet Dynamical Symmetry in Hubbard Models.

We investigate an unconventional symmetry in time-periodically driven systems, the Floquet dynamical symmetry (FDS). Unlike the usual symmetries, the FDS gives symmetry sectors that are equidistant in the Floquet spectrum and protects quantum coherence between them from dissipation and dephasing, leading to two kinds of time crystals: the discrete time crystal and discrete time quasicrystal that have different periodicity in time. We show that these time crystals appear in the Bose- and Fermi-Hubbard models under ac fields and their periodicity can be tuned only by adjusting the strength of the field. These time crystals arise only from the FDS and thus appear in both dissipative and isolated systems and in the presence of disorder as long as the FDS is respected. We discuss their experimental realizations in cold atom experiments and generalization to the SU(N)-symmetric Hubbard models.

Efficient Terahertz Harmonic Generation with Coherent Acceleration of Electrons in the Dirac Semimetal Cd_{3}As_{2}.

We report strong terahertz (∼10^{12} Hz) high harmonic generation at room temperature in thin films of Cd_{3}As_{2}, a three-dimensional Dirac semimetal. Third harmonics are detectable with a tabletop light source and can be as strong as 100 V/cm by applying a fundamental field of 6.5 kV/cm inside the film, demonstrating an unprecedented efficiency for terahertz frequency conversion. Our time-resolved terahertz spectroscopy and calculations also clarify the microscopic mechanism of the nonlinearity originating in the coherent acceleration of Dirac electrons in momentum space. Our results provide clear insights for nonlinear currents of Dirac electrons driven by the terahertz field under the influence of scattering, paving the way toward novel devices for high-speed electronics and photonics based on topological semimetals.

Overexpression of Nuclear Receptor 5A1 Induces and Maintains an Intermediate State of Conversion between Primed and Naive Pluripotency.

Naive and primed human pluripotent stem cells (hPSCs) have provided useful insights into the regulation of pluripotency. However, the molecular mechanisms regulating naive conversion remain elusive. Here, we report intermediate naive conversion induced by overexpressing nuclear receptor 5A1 (NR5A1) in hPSCs. The cells displayed some naive features, such as clonogenicity, glycogen synthase kinase 3ß, and mitogen-activated protein kinase (MAPK) independence, expression of naive-associated genes, and two activated X chromosomes, but lacked others, such as KLF17 expression, transforming growth factor ß independence, and imprinted gene demethylation. Notably, NR5A1 negated MAPK activation by fibroblast growth factor 2, leading to cell-autonomous self-renewal independent of MAPK inhibition. These phenotypes may be associated with naive conversion, and were regulated by a DPPA2/4-dependent pathway that activates the selective expression of naive-associated genes. This study increases our understanding of the mechanisms regulating the conversion from primed to naive pluripotency.

Multivalley Free Energy Landscape and the Origin of Stripe and Quasi-Stripe CDW Structures in Monolayer MX2 Compounds.

Ultrathin sheets of transition metal dichalcogenides (MX2) with charge density waves (CDWs) is increasingly gaining interest as a promising candidate for graphene-like devices. Although experimental data including stripe/quasi-stripe structure and hidden states have been reported, the ground state of ultrathin MX2 compounds and, in particular, the origin of anisotropic (stripe and quasi-stripe) CDW phases is a long-standing problem. Anisotropic CDW phases have been explained by Coulomb interaction between domain walls and inter-layer interaction. However, these models assume that anisotropic domain walls can exist in the first place. Here, we report that anisotropic CDW domain walls can appear naturally without assuming anisotropic interactions: We explain the origin of these phases by topological defect theory (line defects in a two-dimensional plane) and interference between harmonics of macroscopic CDW wave functions. We revisit the McMillan-Nakanishi-Shiba model for monolayer 1T-TaS2 and 2H-TaSe2 and show that CDWs with wave vectors that are separated by 120° (i.e. the three-fold rotation symmetry of the underlying lattice) contain a free-energy landscape with many local minima. Then, we remove this 120° constraint and show that free energy local minima corresponding to the stripe and quasi-stripe phases appear. Our results imply that Coulomb interaction between domain walls and inter-layer interaction may be secondary factors for the appearance of stripe and quasi-stripe CDW phases. Furthermore, this model explains our recent experimental result (appearance of the quasi-stripe structure in monolayer 1T-TaS2) and can predict new CDW phases, hence it may become the basis to study CDW further. We anticipate our results to be a starting point for further study in two-dimensional physics, such as explanation of "Hidden CDW states", study the interplay between supersolid symmetry and lattice symmetry, and application to other van der Waals structures.

High expression of soluble CD155 in estrogen receptor-negative breast cancer.

BACKGROUND: The poliovirus receptor (CD155) is expressed ubiquitously at low levels on both hematopoietic and nonhematopoietic cells, but its expression is upregulated in various tumor cells. An activating receptor DNAM-1 expressed on cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells binds to CD155 and mediates the cytotoxic activity of CTLs and NK cells against tumors. Unlike mouse tissues, human tissues express a soluble form of CD155 (sCD155), which is a splicing isoform of CD155 lacking the transmembrane region. We previously reported that the serum levels of sCD155 were higher in lung, gastrointestinal, breast, and gynecologic cancer patients than in healthy donors. Here, we focus on breast cancer patients. METHODS: To analyze the association between serum level of sCD155 and clinicopathological parameters of breast cancer, we quantified sCD155 in the sera of 153 breast cancer patients by sandwich ELISA. RESULTS: sCD155 levels in the sera of breast cancer patients were positively correlated with patient age, disease stage, and invasive tumor size. Moreover, they were higher in patients with estrogen receptor (ER)-negative cancers than in those with ER-positive tumors, and higher in those with Ki-67-high cancers than in those with Ki-67-low cancers. CONCLUSIONS: The serum level of sCD155 is correlated with high risk factors in breast cancer.

Antibodies to a CA 19-9 Related Antigen Complex Identify SOX9 Expressing Progenitor Cells In Human Foetal Pancreas and Pancreatic Adenocarcinoma.

The Sialyl Lewis A antigen, or CA 19-9, is the prototype serum biomarker for adenocarcinoma of the pancreas. Despite extensive clinical study of CA 19-9 in gastrointestinal malignancies, surprisingly little is known concerning the specific cell types that express this marker during development, tissue regeneration and neoplasia. SOX9 is a transcription factor that plays a key role in these processes in foregut tissues. We report the biochemistry and tissue expression of the GCTM-5 antigen, a pancreatic cancer marker related to, but distinct from, CA19-9. This antigen, defined by two monoclonal antibodies recognising separate epitopes on a large glycoconjugate protein complex, is co-expressed with SOX9 by foregut ductal progenitors in the developing human liver and pancreas, and in pancreatic adenocarcinoma. These progenitors are distinct from cell populations identified by DCLK1, LGR5, or canonical markers of liver and pancreatic progenitor cells. Co-expression of this antigen complex and SOX9 also characterises the ductal metaplasia of submucosal glands that occurs during the development of Barrett's oesophagus. The GCTM-5 antigen complex can be detected in the sera of patients with pancreatic adenocarcinoma. The GCTM-5 epitope shows a much more restricted pattern of expression in the normal adult pancreas relative to CA19-9. Our findings will aid in the identification, characterisation, and monitoring of ductal progenitor cells during development and progression of pancreatic adenocarcinoma in man.

D-Serine reflects kidney function and diseases.

D-Amino acids, long-term undetected enantiomers of L-amino acids, are now emerging as potential biomarkers, especially for kidney diseases. Management of chronic kidney disease (CKD), a global problem with its high prevalence and poor prognosis, is currently unsatisfactory due to the difficulty in estimating kidney function and in early detection of diseases. We now show that intra-body dynamics of D-serine reflect kidney function and diseases. The blood level of D-serine correlated well with the actual glomerular filtration ratio, a key kidney function. This correlation was compatible with those of conventional kidney markers, and blood level of D-serine was relatively unaffected by such clinical factors as body size. The balance between excretion and reabsorption of amino acids by the kidney was controlled with chiral selectivity, and the reabsorption of D-serine was sensitive to the presence of CKD. The combination of blood level and urinary dynamics of D-serine effectively distinguished CKD from non-CKD. These lines of evidence provide new insights into the enantioselective amino acid dynamics in the human body that reflect disease pathophysiology. D-Serine may serve as a vital biomarker that suppress CKD onset through the precise assessment of kidney function and the diagnosis of CKD.

Preoperative diagnosis of a giant cell tumor of soft tissue arising from the breast by ultrasound-guided core needle biopsy.

Giant cell tumors of soft tissue (GCT-ST) arising in the breast are extremely rare. Herein, we report a case of a 45-year-old woman with a 5-cm mass in her left breast. Ultrasonography revealed a mainly well-circumscribed mass that contained a cystic lesion. Magnetic resonance imaging showed a fibrous capsule-covered mass that contained a high-intensity area, suggesting hemorrhaging. Ultrasound-guided core needle biopsy (CNB) revealed mononuclear histiocytic cells with a round shape or spindled appearance that was mixed with multinucleated giant cells. Immunohistochemical analysis revealed CD68-positive staining in the mononuclear and giant cells but negative staining for pancytokeratin. Preoperatively, the tumor was highly suspected of being GCT-ST. Histopathological results after a left mastectomy showed similar findings to CNB. The final diagnosis was GCT-ST in the breast. To the best of our knowledge, this is the first case report of a GCT-ST arising in the breast diagnosed by ultrasound-guided CNB.

Chemically defined and growth-factor-free culture system for the expansion and derivation of human pluripotent stem cells.

The large-scale and cost-effective production of quality-controlled human pluripotent stem cells (hPSCs) for use in cell therapy and drug discovery would ideally require a chemically defined xenobiotic-free culture system. Towards the development of such a system, costs associated with the use of recombinant proteins as supplements in basal culture media need to be reduced. Here, we describe a growth-factor-free culture medium that uses just three chemical compounds and a lower number of recombinant proteins than used in commercially available media. We show that the culture medium supports the long-term propagation of hPSCs, as confirmed by karyotype, the expression of pluripotency markers and the capacity to differentiate into cell types derived from the three embryonic germ layers. hPSCs growing in the medium were less dependent on glycolytic pathways than cells grown in medium containing growth factors. Moreover, the medium supported the generation of induced pluripotent stem cells derived from either human dermal fibroblasts or peripheral blood mononuclear cells. Our findings should facilitate the ongoing development of a completely xeno-free, chemically defined, synthetic culture system for hPSCs.

Acute 40% exchange-transfusion with hemoglobin-vesicles in a mouse pneumonectomy model.

OBJECTIVES: Hemoglobin vesicles (HbVs) function as a red blood cell (RBC) substitute and are composed of purified hemoglobin encapsulated in a phospholipid bilayer membrane. The performance of HbVs as a substitute for RBC transfusions was examined in a mouse model of pneumonectomy following acute 40% exchange-transfusion with HbVs. METHODS: Before performing left pneumonectomies, 40% of the blood volume of mice was replaced with a) lactated Ringer's solution (control), b) 5% recombinant human serum albumin (rHSA), c) mouse RBCs shed in rHSA (mRBCs/rHSA), or d) HbV suspended in rHSA (HbV/rHSA). We compared postoperative a) survival, b) functional recovery, and c) histopathological, immunohistochemical, and inflammatory responses among the study groups. RESULTS: In the HbV/rHSA and mRBC/rHSA groups, all mice survived ≥7 days after pneumonectomy, whereas 100% of the control mice died within a few h and 50% of mice in the rHSA group died within 24 h after pneumonectomy. Immunohistochemical staining for hypoxia-inducible factor-1α showed that hepatic and renal hypoxic injuries were prominently mitigated by HbV and mRBCs. CONCLUSIONS: The oxygen-carrying performance of HbV was similar to that of mRBCs, even with impaired lung functions following pneumonectomy. HbV infusion did not interfere with the recovery from surgical injury. In the near future, HbVs could be used clinically as a substitute for the perioperative transfusion of RBCs, when or where donated RBCs are not immediately available.