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Background The reason for the poor prognosis of estrogen receptor (ER) + /human epidermal growth factor receptor 2 (HER2)− breast cancer patients with high levels of tumor-infiltrating lymphocytes (TILs) is poorly understood. The association between TILs and response to neoadjuvant endocrine therapy (NET) was examined. Methods We recruited 170 patients with ER + /HER2− breast cancer who were treated with preoperative endocrine monotherapy. TILs were evaluated before and after NET, and their changes were noted. Furthermore, T cell subtypes were examined using CD8 and FOXP3 immunohistochemical analyses. Neutrophil and lymphocyte counts in the peripheral blood were analyzed with reference to TIL levels or changes. Responders were defined as Ki67 expression levels ≤ 2.7% after treatment. Results Post-treatment (p = 0.016), but not pre-treatment (p = 0.464), TIL levels were significantly associated with the response to NET. TIL levels increased significantly after treatment among non-responders (p = 0.001). FOXP3 + T cell counts increased significantly after treatment in patients with increased TILs (p = 0.035), but not in those without increased TILs (p = 0.281). Neutrophil counts decreased significantly after treatment in patients without increased TILs (p = 0.026), but not in patients with increased TILs (p = 0.312). Conclusion An increase in TILs after NET was significantly associated with a poor response to NET. Given that FOXP3 + T-cell counts increased, and neutrophil counts did not decrease in patients with increased TILs after NET, the induction of an immunosuppressive microenvironment was speculated to play a role in the inferior efficacy. These data might partially indicate the involvement of the immune response in the efficacy of endocrine therapy.

Purpose: Breast cancer stem cells have been shown to be associated with resistance to chemotherapy in vitro, but their clinical significance remains to be clarified. The aim of this study was to investigate whether cancer stem cells were clinically significant for resistance to chemotherapy in human breast cancers.Experimental Design: Primary breast cancer patients (n = 108) treated with neoadjuvant chemotherapy consisting of sequential paclitaxel and epirubicin-based chemotherapy were included in the study. Breast cancer stem cells were identified by immunohistochemical staining of CD44/CD24 and aldehyde dehydrogenase 1 (ALDH1) in tumor tissues obtained before and after neoadjuvant chemotherapy. CD44+/CD24− tumor cells or ALDH1-positive tumor cells were considered stem cells.Results: Thirty (27.8%) patients achieved pathologic complete response (pCR). ALDH1-positive tumors were significantly associated with a low pCR rate (9.5% versus 32.2%; P = 0.037), but there was no significant association between CD44+/CD24− tumor cell proportions and pCR rates. Changes in the proportion of CD44+/CD24− or ALDH1-positive tumor cells before and after neoadjuvant chemotherapy were studied in 78 patients who did not achieve pCR. The proportion of ALDH1-positive tumor cells increased significantly (P < 0.001) after neoadjuvant chemotherapy, but that of CD44+/CD24− tumor cells did not.Conclusions: Our findings suggest that breast cancer stem cells identified as ALDH1-positive, but not CD44+/CD24−, play a significant role in resistance to chemotherapy. ALDH1-positive thus seems to be a more significantly predictive marker than CD44+/CD24− for the identification of breast cancer stem cells in terms of resistance to chemotherapy.

Supplementary Data from Association of Breast Cancer Stem Cells Identified by Aldehyde Dehydrogenase 1 Expression with Resistance to Sequential Paclitaxel and Epirubicin-Based Chemotherapy for Breast Cancers

Oligosaccharides are involved in numerous biological processes. Achieving optimal anomeric selectivity and regioselectivity remains challenging. Herein, we present a method for the oxidative glycosylation of thioglycosides with hypervalent iodine reagents derived from carboxylic acid to form C-O bonds. The reaction of thioglycosides with various hypervalent iodine carboxylates afforded acyl

C-H/N-H bond functionalization for direct intermolecular aryl C-N couplings is a useful synthetic process. In this study, we achieved metal-free cross-dehydrogenative coupling of phenols and anilines with phenothiazines using hypervalent iodine reagents. This method affords selective amination products under mild conditions. Electron-rich phenols and anilines could be employed, affording moderate-to-high yields of

The aetiology of anal fistula has not been fully clarified. One of the causes of anal fistulas may be the markedly deep crypts that characterize the primary openings. We developed subcutaneous incision of the fistula tract and internal sphincterotomy (SIFT-IS) to eradicate these deep crypts. The aim of this study was to evaluate outcomes in patients with anal fistula treated with SIFT-IS.A retrospective study was performed over a 2-year period. Patients with transsphincteric anal fistula who underwent SIFT-IS were enrolled. The primary endpoint was the anal fistula healing rate at 16 weeks postoperatively. The secondary endpoints were healing time, postoperative complications and clinical continence status.One hundred and fifty one patients were enrolled. Primary healing was accomplished in 129 patients (85%). There were 17 patients (11%) with a remnant fistula and five (3%) with a recurrence. The remnant fistulas healed spontaneously at more than 16 weeks postoperatively in seven patients. The median healing time was 6 (3-96) weeks. Surgical intervention was required in seven patients with a remnant fistula and four with recurrence. At the final follow-up, the wounds had healed in 148 patients (98%). No significant postoperative complications or incontinence were observed.Subcutaneous incision of the fistula tract and internal sphincterotomy is a promising surgical option for transsphincteric anal fistulas, with a satisfactory healing rate.

Cannabidiol (CBD), a major non-psychoactive cannabinoid, has a lot of attention due to its potential relaxing properties and led the trend in commercial CBD aroma/oral hemp seed oil from the Japanese market. In this study, a routine assay for evaluating CBD oil samples was performed using LC coupled with tandem mass spectrometry (LC-MS/MS) and was used to apply the convertible tetrahydrocannabinol (THC) in acetic acid conditions. Based on the electrospray positive ion mode, the detection of cannabidiolic acid (CBDA; m/z 359 219), cannabigerolic acid (CBGA; m/z 361 343), cannabigerol (CBG; m/z 317 193), CBD (m/z 315 193), THC (m/z 315 193) and cannabinol (CBN; m/z 311 223) was performed by satisfying separation with high density of C

We report on the recommendation of the simple and versatility of methylated reference (MR) to improve applications in the single reference (SR)-LC based on relative molar sensitivity (RMS). Three curcuminoids (Curs) such as curcumin, demethoxycurcumin and bisdemethoxycurcumin in turmeric products were determined using authentic standards and methylated curcumin. In addition, high-speed countercurrent chromatography (HSCCC) purification is necessary to separate Curs for indicating the RMS. For HSCCC separation, a biphasic solvent system was used to obtain these fractions, which were then subjected to

Intussusception in adults is, especially with ulcerative colitis (UC), rare and only described in a few cases. Most adult patients with intussusception develop abdominal pain or other symptoms of bowel obstruction. This case describes an 18-year-old male with UC who treated with 5-aminosalycilicacid and underwent annual screening colonoscopies. Two attempts revealed that it was impossible to achieve total surveillance through the colonoscopy because multiple polyps were preventing the colonoscope from traversing the entire colon. Therefore, CT scan was performed and colonic intussusception was discovered incidentally, and the patient underwent elective laparoscopic total colectomy. To the best of our knowledge, this is the first reported case of asymptomatic intussusception in the adult patient with UC. When total surveillance colonoscopy fails to yield results, a CT may be advisable to pick up such an asymptomatic intussusception.

Background/aim Patients with non-luminal breast cancer subtypes with high levels of tumor infiltrating lymphocytes (TILs) have better prognosis than those with luminal subtype. We evaluated the role of TILs according to the subtype. Materials and methods An immunohistochemical analysis of 139 breast cancer cases was conducted to calculate the FOXP3+/CD8+ T cell ratios and their relationships with TILs and disease-free survival (DFS) were evaluated. Results FOXP3+/CD8+ T cell ratios were significantly associated with TIL levels only in luminal breast cancers (p=0.0001). Low FOXP3+/CD8+ T cell ratio was significantly associated with longer DFS (p=0.017). All luminal subtype patients with high TIL levels had high FOXP3+/CD8+ T cell ratios compared to only half of non-luminal subtype patients with high TIL levels. Conclusion High FOXP3+/CD8+ T cell ratios in breast cancers may partly explain the worse prognosis of luminal breast cancers, but not that of non-luminal breast cancers with high TIL levels.

The biary unit having heteroatom as important scaffolds widely exist in a large number of biologically active compounds and functional organic molecules. Since the cross-coupling is a useful synthetic method for constructing biaryl and heterobiaryl structures, the development of novel cross-coupling methods has been studied intensively. The oxidative biaryl coupling reaction of aromatic compounds having heteroatoms is an attractive method since they do not require the prefunctionalization of arenes. This report describes recent advances in hypervalent iodine(III) induced metal-free synthesis of biaryls having heteroatoms.

An oxidation system comprising phenyliodine(III) diacetate (PIDA) and iodosobenzene with inorganic bromide, i.e., sodium bromide, in an organic solvent led to the direct introduction of carboxylic acids into benzylic C–H bonds under mild conditions. The unique radical species, generated by the homolytic cleavage of the labile I(III)–Br bond of the in situ-formed bromo-λ3-iodane, initiated benzylic carboxylation with a high degree of selectivity for the secondary benzylic position.

Recent studies suggest a functional involvement of Epithelial-Mesenchymal Transition (EMT) in tumor chemoresistance. Specifically, EMT is associated with chemoresistance and poor prognosis in triple-negative breast cancer. However, no effective therapy targeting EMT has been developed. Here, we report that periostin, an extracellular matrix protein, was induced upon chemotherapy and tightly correlated with the EMT gene signature and poor prognosis in breast cancer. In triple-negative breast cancer xenografts, chemotherapy upregulated periostin expression in tumor cells, triggered expansion of mesenchymal tumor cells and promoted invasion in residual tumors. Knockdown of periostin inhibited outgrowth and invasion of mesenchymal tumor cells upon chemotherapy. Furthermore, chemotherapy upregulated cancer-specific variants of periostin and application of a blocking antibody specifically targeting those variants overcame chemoresistance and halted disease progression without toxicity. Together, these data indicate that periostin plays a key role in EMT-dependent chemoresistance and is a promising target to overcome chemoresistance in triple-negative breast cancer.

Biaryl diamines are important building blocks in organic ­synthesis. Consequently, it is desirable to develop a general and mild synthetic approach to diverse biaryl diamines. Oxidative coupling is an efficient and promising strategy for the synthesis of these targets. We have now developed a direct formation of biaryl diamines by oxidative coupling using a hypervalent iodine(III) reagent.

The metal-free arylative coupling of carboxylic acids using iodosoarenes without the use of a catalyst and base, which is applicable to even a highly-polar molecule bearing multiple alcohol groups, is reported. The in situ preparation of the reactive diaryliodonium(III) carboxylates is the important key to this approach, and the introduction of the trimethoxybenzene auxiliary enables both the smooth salt formations and the selective aryl transfer events during the couplings.

A simple and efficient synthesis of phenol biaryls by the cross-couplings of quinone monoacetals (QMAs) and phenols is reported. The Brønsted acid catalytic system in 1,1,1,3,3,3-hexafluoro-2-propanol was found to be particularly efficient for this transformation. This reaction can be extended to the synthesis of various phenol biaryls, including sterically hindered biaryls, with yields ranging from 58 to 90 % under mild reaction conditions and in a highly regiospecific manner.

Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C‐C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead‐based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease‐free survival (DFS) of patients with high CCL5 levels (cut‐off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10‐0.39; P, We found that high levels of serum C‐C motif chemokine ligand 5 (CCL5), a chemokine produced by immune cells, were significantly associated with improved prognosis of patients with operated breast cancer. As the relative expression of mRNA CCL5 was elevated in stromal cells, serum CCL5 seems to be derived not from cancer cells, but from stromal cells. CCL5 might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms.

We evaluated the recent incidence of surgery and the changing surgery trends for ulcerative colitis (UC) in Japan due to the increasing use of anti-tumor necrosis factor (TNF) agents. A questionnaire survey was performed to assess the number of surgeries, surgical indications, surgical timing, and immunosuppressive treatments before surgery between 2007 and 2017. A total of 3801 surgical cases were reported over 11 years. The prevalence of UC surgery decreased over the period studied. The rate of prednisolone (PSL) use did not change. The prevalence of both calcineurin inhibitors (CNIs) and anti-TNF agents increased during the period studied (p

Illudin S from mushroom, such as Omphalotus japonicus and illudens, is a natural sesquiterpene analog with strong anti-tumor and antiviral activities. These illudins compounds are highly effective against various drug-resistant cancers that show extreme cytotoxicity an in vitro assay. However, it is difficult to obtain a sufficient amount of highly pure illudin S from a natural product by simple, efficient and low-cost purification techniques. Here, we offer to apply the high-speed countercurrent chromatography for the preparative purification of illudin S from mushroom extract. For a two-solvent system, the optimal condition of hexane/ethyl acetate/methanol/water (1/5/1/5, v/v/v/v) was optimized to obtain pure illudin S from a crude extract. This purified component was evaluated by liquid chromatography (high-purity >99%) and tandem mass spectrometry. The yield amounts of illudin S (1.3 mg/about 10 g Omphalotus japonicus) at one running are determined by liquid chromatographic calibration. It is concluded that by requiring a natural material and cost-effectiveness, our method represents a significant improvement over complicated techniques for the purification of illudin S from natural materials.

Tetramethylrhodamine (TAMRA)-phenyl azide is a chemical probe used to detect intracellular acrolein directly in live cells. Herein, we demonstrated that TAMRA is the optimum fluorophore for the probe. TAMRA-phenyl azide was used to reveal that high levels of acrolein are generated in a variety of breast cancer cells, regardless of the tumor subtype. These findings corroborate the analysis presented in our previous report, in which TAMRA-phenyl azide was used to label breast cancer tissues resected from breast cancer patients. Because high levels of acrolein were generated in all cancer cell types, we believe that acrolein detection may be useful as a general method for labeling cancerous tissues.

Pyrrole-aryl derivatives are important due to their unique biological activities in medicinal chemistry. We now report a new oxidative biaryl coupling for pyrroles and indoles toward various arenes using a hypervalent iodine reagent and an appropriate stabilizer for pyrrolyl iodonium intermediates. The reactions readily provide a variety of desired coupling products in good yields.

Thioglycosides are available donors in glycosylation due to the stability of the anomeric C-S bond under general reaction conditions of protection and deprotection, and offer orthogonality in their activation. We report now that the hypervalent iodine effectively induced glycosylation reaction of thioglycosides with various alcohols. This method features a high efficiency, completion in a short time, and proceeding under very mild conditions.

A combination of phenyliodine bis(trifluoroacetate) (PIFA) and trifluoromethanesulfonic acid was found to be an effective activator for the glycosylation reaction, of which the glycosyl donor was p-(octyloxy)phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-D-glucopyranoside or p-(octyloxy)phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-D-galactopyranoside. The reaction proceeded with good yields when naturally occurring and derived alkanols, such as cholestanol, (–)-menthol, 1- and 2-adamantanols and nor-kauranol, were employed as acceptor substrates. Interestingly, the glycosylation reaction of sterically hindered terpenoid alcohols, such as (–)- and (+)-borneols and (+)-fenchyl alcohol, with p-(octyloxy)phenyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-1-thio-D-glucopyranoside afforded the desired β-glycoside in quantitative yield. Moreover, the present reaction was useful to synthesize disaccharides of which the non-reducing end was composed of a D-glucosamine or D-galactosamine unit.

The facile and clean oxidative coupling reaction of pyrroles with azoles has been achieved using the recyclable hypervalent iodine(III) reagents having adamantane structures. These iodine(III) reagents could be recovered from the reaction mixtures by a simple solid-liquid separation, i.e., filtration, for reuse.

In a previous study, we established a one-step methylation-specific polymerase chain reaction (OS-MSP) assay for the detection of methylated DNA (met-DNA) and total DNA levels in serum. For the present study, this OS-MSP assay was used for patients with breast cancer treated with neoadjuvant chemotherapy (NAC) in order to investigate the prognostic significance of met-DNA and total DNA levels. Following treatment with NAC and prior to surgery, serum samples obtained from 120 patients with stage II/III breast cancer were subjected to the OS-MSP assay for analysis of the glutathione S-transferase pi 1, Ras association (RalGDS/AF-6) domain family member 1 and retinoic acid receptor β2 genes. The detection of methylation in a minimum of one of these genes indicated a positive outcome of the assay. The total DNA content of the serum was also determined. Of the 120 stage II/III patients, seven (6%) were positive for met-DNA in serum and showed a significantly worse overall survival (OS) time compared with patients negative for met-DNA (n=113) (5-year OS, 43 vs. 85%; P=0.002). The patients with high total DNA levels in serum (n=40) also showed a significantly worse OS compared with those with low total DNA levels (n=80) (65 vs. 91%; P

The hypervalent-iodine-mediated oxidative metal-free cross-coupling reaction of thiophenes with various pyrroles was developed. The corresponding thiophene–pyrrole derivatives were obtained in moderate to high yields (up to 85 %). This method features high efficiency and regioselectivity and broad functional group tolerance. We further determined the highly planar characteristics of the 3,4-ethylenedioxythiophene–pyrrole biaryls caused by intramolecular hydrogen bonding.

In article number 1801479, Shinzaburo Noguchi, Katsunori Tanaka, and co‐workers use a click‐to‐sense probe to detect acrolein, which is universally produced by cancer cells under oxidative stress, within five minutes at room temperature. All cancer types tested are imaged and discriminated through multiple cascade reactions in the living tissue of human patients. This probe can be used to quickly and accurately diagnose cancer morphology during breast‐conserving surgery, by reforming the conventional pathological methods.

Clean operating margins in breast cancer surgery are important for preventing recurrence. However, the current methods for determining margins such as intraoperative frozen section analysis or imprint cytology are not satisfactory since they are time‐consuming and cause a burden on the patient and on hospitals with a limited accuracy. A “click‐to‐sense” probe is developed based on the detection of acrolein, which is a substance released by oxidatively stressed cancer cells and can be visualized under fluorescence microscopy. Using live breast tissues resected from breast cancer patients, it is demonstrated that this method can quickly, selectively, and sensitively differentiate cancer lesion from normal breast gland or benign proliferative lesions. Since acrolein is accumulated in all types of cancers, this method could be used to quickly assess the surgical margins in other types of cancer.

Neurodegeneration causes dysfunction and degeneration of neurons and is triggered by various factors including genetic defects, free radicals, injury, and glutamate excitotoxicity. Among those, glutamate excitotoxicity is implicated in chronic disorders including AD and ALS, and in acute insults in the CNS including traumatic brain injury. Neurological disorders show hallmark morphological abnormalities such as axon degeneration and cell body death. The molecular mechanisms underlying excitotoxicity-induced neurodegeneration are complex and deciphering a molecular mechanism from one angle is beneficial to understand the process, however, still difficult to develop strategies to suppress excitotoxicity-induced degeneration due to existence of other mechanisms. Thus, directly identifying compounds that can modulate excitotoxicity-induced neurodegeneration and subsequently clarifiying the molecular mechanism is a valid approach to develop effective strategies to suppress neurodegeneration. We searched for compounds that can suppress excitotoxicity-induced neurodegeneration and found that CP-31398, a known compound that can rescue the structure and function of the tumor suppressor protein p53 mutant form and stabilize the active conformation of the p53 wild-type form, suppresses excitotoxicity-induced axon degeneration and cell body death. Moreover, CP-31398 suppresses mitochondrial dysfunction which has a strong correlation with excitotoxicity. Thus, our findings identify a compound that can serve as a novel modulator of neurodegeneration induced by glutamate excitotoxicity.

Direct oxidative coupling is an attractive tool for environmentally benign green chemistry. We report the novel oxidative synthesis of hexahydroxytriphenylene by using a hypervalent iodine reagent. The reaction proceeds under very mild conditions for reducing acid waste and in a very short time at room temperature.

[Purpose] This study examined differences in neck muscle activity in two different head positions during tackles with the aim of contributing to the prevention of sports injuries. [Subjects] The subjects were 28 male high-school rugby players. [Methods] Two tackle positions were considered: a head-up position and a head-down position. Muscle activities of the sternocleidomastoid muscles and the upper, middle, and lower parts of the trapezius muscles were measured. [Results] Muscle activities of the sternocleidomastoid muscles and the right upper trapezius muscle were significantly increased in the head-up position, and the activity of the lower trapezius was significantly increased in the head-down position. [Conclusion] Tackling with the head-up position increases neck muscle activity and stability of the head and the neck.

We have successfully established an efficient route to the core structure of donor-acceptor head-to-tail (H-T)-linked regioregular oligothiophenes, which includes the following key synthetic steps, that is, hypervalent iodine induced direct and regioselective coupling of thiophenes and the use of the obtained bithiophenes as excellent coupling substrates for the Suzuki and Stille couplings. The versatility of this new approach is highlighted in the dramatic improvement of the yield (ca. 59 % overall yield) of MK-2, a high-performance organic dye, for photovoltaic applications.