Effects of fatty acid hydroperoxides produced by lipoxygenase in wheat cultivars during dough preparation on volatile compound formation.

The formation of volatile compounds affects the flavor of processed wheat flour products. Herein, the effects of the composition of fatty acid hydroperoxides and the differences in the antioxidant contents among wheat cultivars on the flavor of wheat flour products were clarified. For this purpose, the volatile compounds in wheat flour doughs, LOX activity, fatty acid hydroperoxide composition from fractionated LOX, and antioxidant content were analyzed. Norin61 exhibited a high LOX activity and 9-fatty acid hydroperoxide production. Unsaturated aldehydes derived from 9-fatty acid hydroperoxides contributed significantly to the volatile compound profile of Norin61. Moreover, the lowest lutein content was observed in Norin61 among the analyzed cultivars. The LOX activity and composition of the fatty acid hydroperoxides produced by LOX affected the production of volatile compounds, whereas carotenoids had a suppressive effect. This study provides useful information for product design with the desired flavor for developing various processed wheat flour products.

Cell death and wing reduction during the metamorphosis of sex-specific flightless morphs in winter geometrid moths.

Winter geometrid moths show striking sexual dimorphism by having female-specific flightless morphs. The evolutionary grades of wing reduction in winter geometrid moths vary and range from having short wings, vestigial wings, to being wingless. Although the ontogenetic processes underlying the development of the wingless or short-wing morphs in Lepidoptera has been well studied, the mechanisms underlying the development of vestigial wing morphs in winter geometrid moths during metamorphosis are poorly understood. In the winter geometrid moth Sebastosema bubonaria Warren, 1896, the males have functional wings, but the females have vestigial wings. Here, we studied the ontogenetic processes affecting wing reduction in the winter geometrid moth S. bubonaria using light microscopy and transmission electron microscopy, and compared the ontogenetic process of wing reduction in this species with that in another species of the wingless-female winter moth that we investigated previously. Our results showed that, in the vestigial-wing morphs, the loss of pupal wing epithelium was terminated in the middle of the wing degeneration process, whereas in the wingless morph, the pupal wing epithelium disappeared almost completely and the final appearance of the wings differed slightly among flightless morphs. We propose that the extent and location of cell death in the pupal wing play an important role in the various patterns of reduced wings that are observed in flightless moths.

Deactivation of glycogen synthase kinase-3ß by heat shock­inducible tumor small protein attenuates hyperthermia­induced pro­migratory activity in colorectal cancer cells.

Hyperthermia is a promising approach for improving cancer treatment in combination with chemotherapy, radiotherapy and/or immunotherapy; however, its molecular mechanisms remain unclear. Although heat shock proteins (HSPs) are involved in hyperthermia via antigen presentation and immune activation, major HSPs including HSP90 are associated with cancer progression via tumor cell migration and metastasis. The present study showed that heat shock­inducible tumor small protein (HITS) could counteract the pro­migratory effects of HSPs in colorectal cancer (CRC) cells, which represents a novel function. Western blotting analysis revealed that overexpression of HITS increased the protein level of glycogen synthase kinase­3ß (GSK3ß) phosphorylated (p) at the serine 9 (pGSK3ßS9; inactive form) in HCT 116, RKO and SW480 CRC cells. GSK3ßS9 phosphorylation was reported to suppress migration in some cancer types; therefore, by using the wound healing assay, the present study revealed that HITS overexpression decreased the migration activity of CRC cells. Induction of HITS transcription was observed at 12 and 18 h after heat shock (HS) by using semi­quantitative reverse transcription­PCR analysis, followed by increased levels of pGSK3ßS9 protein at 24 and 30 h in CRC cells in western blotting. Thus, HS induced not only HSPs to promote cell migration, but also HITS to counteract the migratory activity of these HSPs in CRC cells. HITS knockdown in CRC cells subject to HS showed increased cell migration in wound healing assay, which was decreased by the GSK3ß inhibitor AR­A014418, confirming the anti­migratory effect of HITS via the deactivation of GSK3ß. The present findings indicated that the deactivation of GSK3ß sufficiently offset the pro­migratory effect of hyperthermia via major HSPs in CRC.

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

[A Case of Non-Small Cell Lung Cancer Successfully Treated with Anti-PD-L1 Therapy after Exacerbation Caused by Anti-PD-1 Therapy].

A 52-year-old male was diagnosed with cT4N3M1b, cStage Ⅳ adenocarcinoma of the lung, and underwent 6 courses of pemetrexed(PEM), carboplatin(CBDCA), and bevacizumab(Bev)therapy, followed by 4 courses of PEM/Bev maintenance therapy. Due to the deterioration of his condition, 4 courses of pembrolizumab(Pembro)therapy were administered as second- line therapy, but the treatment was discontinued due to disease progression. Third-line therapy with docetaxel(DTX)/ ramucirumab(Rmab)was administered, resulting in a partial response, but discontinued due to adverse events. Finally, fourth-line therapy with atezolizumab(Atezo)was initiated. After 6 courses of Atezo therapy, partial response was achieved, and the tumor continued to shrink for 3 years. The aim of the treatment strategy for both PD-1 and PD-L1 antibody drugs is to suppress T-cell exhaustion, and if either drug fails, the other drug may theoretically fail. However, in this case, the PD-L1 antibody drug was effective against non-small cell lung cancer that had shown resistance to PD-1 antibody drugs, suggesting that even if a patient becomes resistant to PD-1 antibody drugs, PD-L1 antibody drugs may result in effective outcomes.

Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum.

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 µL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5-125.0 ng/mL for afatinib, 2.5-125.0 ng/mL for dacomitinib, 4.0-800.0 ng/mL for osimertinib, 1.0-125.0 ng/mL for AZ5104, and 2.5-125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

[Role of Palliative Care in the Introduction of Chemotherapy in Patients with Poor Performance Status].

Chemotherapy for patients with poor performance status(PS)is not recommended because it increases the risk of death and shortens their survival. We report on 3 cases in which palliative care improved PS and enabled chemotherapy, resulting in a prolonged prognosis. Case 1 involves a 57‒year‒old woman with multiple lung, liver, and bone metastases from breast cancer who was administered celecoxib and oxycodone. She received Mohs paste therapy. Her PS improved from 3 to 2, and paclitaxel and trastuzumab were started; however, the patient died on day 861. Case 2 involves a 53‒year‒old woman with multiple lymph node metastases from carcinoma of an unknown primary cause. She was administered oxycodone, loxoprofen, and dexamethasone. Her PS improved from 4 to 3. The biopsy of her bone marrow showed diffuse large B‒cell lymphoma. The patient is still alive, 6 years and 10 months after the introduction of R‒CHOP. In case 3, a 57‒year‒old man with multiple bone metastases from small cell lung cancer was administered loxoprofen and betamethasone. His PS improved from 4 to 3. Etoposide and carboplatin were administered to him, but the patient died on day 692. Palliative care may enable the introduction of chemotherapy and consequently improve prognosis.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

[Advanced Gastric Cancer with Tumor Shrinkage Persisting after the Discontinuation of Nivolumab-A Case Report].

The patient was a 65-year-old man with advanced gastric cancer, cT4bN3aM1, cStage Ⅳ. The SOX therapy was administered as the primary treatment but discontinued after 9 courses because of disease progression. The PTX plus RAM therapy was then administered for 1 courses as the secondary treatment but discontinued because of the development of peritoneal dissemination, increased number of ascites, and increased number of lymph node metastases. The nivolumab(NIV)therapy was initiated as the tertiary treatment, but the patient complained of fatigue and diplopia after 2 courses. Ptosis was observed, and transaminase and creatine kinase levels were elevated. Electrocardiography showed complete right bundle branch block. The patient showed immune-related adverse events and was diagnosed with myocarditis and myasthenia gravis due to NIV. Consequently, systemic steroids were administered. Although 2 course of CPT-11 was administered as the fourth-line treatment, the treatment was discontinued upon the patient's request. Ten months after the discontinuation of chemotherapy, the disease showed no progression. The patient is being followed-up as an outpatient. Here, we reported a case of gastric cancer with tumor shrinkage after the discontinuation of NIV.

Oxaliplatin-induced increase in splenic volume: experiences from multicenter study in Japan.

BACKGROUND: Chemotherapy with oxaliplatin is known to induce sinusoidal obstruction syndrome (SOS). In a previous single-center study, we reported that oxaliplatin-induced increase in splenic volume (SV) is strongly indicative of SOS, and that this increase in SV persisted for > 1 year after completing chemotherapy. The aim of this study was to confirm the oxaliplatin-induced SV change in a multicenter study in patients with stage III colon cancer in Japan. METHODS: We enrolled 59 patients who underwent curative resection for stage III colon cancer in the FACOS study in a phase II multi-center clinical study. Participants received mFOLFOX6 or CAPOX as adjuvant chemotherapy. SV change was assessed three times by computed tomographic volumetry: before surgery, on completion of adjuvant chemotherapy, and 1 year after completing adjuvant chemotherapy. RESULTS: SV on completing and 1 year after chemotherapy was significantly higher than that before surgery (P < 0.001). Oxaliplatin-induced SOS persisted for > 1 year after the completion of adjuvant chemotherapy in half of the patients. There was no difference in 3-year disease-free survival with respect to the presence or absence of increased SV. An increase in SV was observed in 72% of patients treated with mFOLFOX6 and 94% of patients treated with CAPOX (P = 0.13). CONCLUSION: This study can be verified the findings observed in our previous single-center study, oxaliplatin-based adjuvant chemotherapy was associated with an increase in SV. Furthermore, this increase can persist for > 1 year. The continuous presence of SOS may have a negative impact on prognosis in patients that develop recurrent disease.

A Japanese multicenter phase II study of adjuvant chemotherapy with mFOLFOX6/CAPOX for stage III colon cancer treatment after D2/D3 lymphadenectomy.

PURPOSE: A phase II trial was conducted to investigate the benefit of oxaliplatin-based adjuvant chemotherapy in Japanese stage III colon cancer patients. METHODS: Eligible patients were scheduled to receive 12 cycles of mFOLFOX6 or 8 cycles of CAPOX in adjuvant settings. The primary endpoint was the 3-year disease-free survival (DFS). Cox proportional hazards regression was performed to identify risk factors for a worse DFS. RESULTS: A total of 130 patients, including 73 patients receiving mFOLFOX6 and 57 patients receiving CAPOX, were enrolled from 16 institutions between April 2010 and April 2014. The 3-year DFS was 82.2%, exceeding the expected primary endpoint of 81.7%. The 3-year DFS tended to be higher in patients receiving mFOLOFOX6 than in those receiving CAPOX (mFOLFOX6, 86.3%; CAPOX, 76.9%; P = 0.06). The 3-year DFS rates did not differ markedly based on the risk stratification (T1/T2/T3 N1 vs. T4 or N2) indicated by the IDEA COLLABORATION study (P = 0.22). In the multivariate analysis, stage IIIC (P = 0.046) and early discontinuation (P < 0.01) were identified as independent significant risk factors for a worse DFS. CONCLUSION: Our findings represent the first positive results in a Japanese phase II trial of adjuvant chemotherapy with mFOLFOX6/CAPOX. Early discontinuation within 2 months was an independent risk factor for a shorter DFS.

A New Technique for Posterior Distraction in Craniosynostosis: The Double-Door Technique.

BACKGROUND: Posterior cranial vault distraction osteogenesis is a common treatment for syndromal patients of brachycephaly and oxycephaly. Although posterior distraction can increase intracranial volume, the flattened head phenotype is difficult to correct. The authors examined a new posterior distraction technique termed double-door distraction for improvement of the flattened head phenotype. METHODS: From 2010 to 2013, 6 patients with flattened posterior craniums were operated on using the double-door distraction technique. The calvarial segment was cut at the midline and divided into 2 pieces. Distractors were then fixed in parallel to join the calvarial pieces. The distraction was initiated at a rate of 1.0 mm/day and continued until proper cranial form was confirmed by radiography and appearance. RESULTS: The average surgery time was 2 hours 47 minutes and the amount of distraction ranged from 15 to 22 mm. An improved head shape and expanded cranial vault was achieved in all patients without any complications. CONCLUSIONS: The double-door distraction technique is a useful technique not only for calvarial expansion, but also for correction of the flattened posterior cranium phenotype.

Preparation and Thermal Properties of Fatty Alcohol/Surfactant/Oil/Water Nanoemulsions and Their Cosmetic Applications.

Physicochemical properties of oil-in-water (O/W) emulsions containing fatty alcohols and surfactants have been investigated with the aim of developing new formulations that are less viscous and more transparent than conventional milky lotions, as well as for providing greater skin-improving effects. O/W-based creams can be converted to low viscosity milky lotions following their emulsification with a homogenizer at temperatures greater than the transition temperatures of their molecular assemblies (α-gel). The stability of the O/W emulsions evaluated in the current study increased as the transition temperatures of the molecular assemblies formed from their fatty alcohol and surfactant constituents increased. A decrease in the emulsion droplet size led to the formation of a new formulation, which was transparent in appearance and showed a very low viscosity. The absence of a molecular assembly (α-gel) formed by the fatty alcohol and surfactant molecules in the aqueous phase allowed for the formation of a stable transparent and low viscosity nanoemulsion. Furthermore, this decrease in droplet size led to an increase in the interfacial area of the emulsion droplets, with almost all of the fatty alcohol and surfactant molecules being adsorbed on the surfaces of the emulsion droplets. This was found to be important for preparing a stable transparent formulation. Notably, this new formulation exhibited high occlusivity, which was equivalent to that of an ordinary cosmetic milky lotion, and consequently provided high skin hydration. The nanoemulsion was destroyed following its application to the skin, which led to the release of the fatty alcohol and surfactant molecules from the surface of the nanoemulsion into the aqueous phase. These results therefore suggest that the fatty alcohol and surfactant molecules organized the molecular assembly (α-gel) and allowed for the reconstruction of the network structure.

Measuring body composition using the bioelectrical impedance method can predict the outcomes of gemcitabine-based chemotherapy in patients with pancreatobiliary tract cancer.

In order to examine the effect on body composition of anticancer drug treatments, the body composition rate in patients being treated with gemcitabine (GEM)-based chemotherapy was measured over time on an outpatient basis with a simple body composition monitor using the bioelectrical impedance (BI) method. The results revealed a significant reduction in the body fat rate (P=0.01) over the course of treatment in patients with pancreatobiliary tract cancer who became unable to continue GEM-based chemotherapy due to progressive disease or a decreased performance status. Meanwhile, no changes were observed in the body composition of control patients with urothelial carcinoma receiving GEM-based chemotherapy. In association with the adverse reactions to GEM and the hematotoxicity profile, a decreased white blood cell count was more likely to occur in body fat-dominant patients (mean fat rate, 25.8%; mean muscle rate, 26.2%), whereas a decreased blood platelet count was more likely to occur in skeletal muscle-dominant patients (mean fat rate, 23.3%; mean muscle rates, 28.7%). The correlation between body composition parameters and the relative dose intensity (RDI) associated with GEM administration was also analyzed. The results revealed a positive correlation between the RDI and basal metabolism amount (P=0.03); however, the RDI did not correlate with the body fat rate, skeletal muscle rate or body mass index (P=0.61, P=0.14 and P=0.20, respectively). In conclusion, the body composition rate measurement using the BI method over time may be useful for predicting the outcome of GEM-based chemotherapy and adverse events in patients with pancreatobiliary tract cancer. In particular, the present findings indicate that the changes in body fat rate may be helpful as an adjunct index for assessing potential continuation of chemotherapy and changes in physical conditions.

The rhombic bilobed flap, a simple, geometrically designed flap.

We describe a combination of the common rhomboid flap and bilobed flap and provide an example of its use. The rhombic bilobed flap is simple to use and is associated with fewer complications, such as pin-cushioning and standing cone deformities, while minimizing the risk of skin necrosis and tension on the flap.

Transoral vs. endoscopic endonasal approach for clival/upper cervical chordoma.

The surgical results of 18 cases of clival/upper cervical chordoma treated in the last decade via the endoscopic endonasal approach (EEA, 9 cases) and the transoral-transpalatal approach (TO-TPA, 9 cases) were compared. Each group showed the same incidence of subdural invasion, with 5 cases each. The superior (frontal base) and lateral surgical fields were wider by EEA, but the inferior view lower than the cranio-vertebral junction (CVJ) was wider by TO-TPA. Gross total removal was achieved in 3 cases in the EEA group, but in only 1 case in the TO-TPA group. Differences in radicality might be due to the extent of the lateral and subdural overview. However for large tumors extending below the CVJ, TO-TPA was the only viable approach for surgical removal. Surgical complications were higher in the EEA (4 cases) than the TO-TPA group (1 case), and were mainly caused by aggressive management of subdural invasion in the EEA group. Post-operative oral intake was earlier and the operative time was shorter in the EEA group. The surgical results were more radical and less invasive in the EEA group than the TO-TPA group. However in tumors extending below the CVJ, the surgical field in EEA was limited, indicating the need to use the transoral route or a combination of routes. A higher complication rate following subdural management was a negative factor that requires improvement in the EEA group and two-staged EEA followed by a transcranial approach may be considered for the cases with subdural invasion.

Family with sequence similarity 107: A family of stress responsive small proteins with diverse functions in cancer and the nervous system (Review).

Under conditions of acute stress, rapid adaptation is crucial for maximizing biological survival. The responses to environmental stress are often complex, involving numerous genes and integrating events at the cellular and organismal levels. The heat shock proteins (HSPs) are a family of highly conserved proteins that play critical roles in maintaining cell homeostasis and protecting cells under chronic and acute stress conditions. The genes for these stress-responding proteins are widely distributed in organisms, tissues and cells. HSPs participate in a variety of physiological processes and are associated with various types of disease. In this review, we focused on family with sequence similarity 107 (FAM107), a novel unique protein family that exhibits functional similarity with HSPs during the cellular stress response. This review aimed to summarize the biological properties of FAM107 in cancer and the nervous system.

Serotonin induces the migration of PC12 cells via the serotonin receptor 6/cAMP/ERK pathway.

Serotonin (5-HT) functions as a chemoattractant that modulates neural migration during prenatal and early postnatal development. However, its molecular mechanism remains to be elucidated. The effect of 5-HT on neural cell migration was examined using PC12 neuron-like cell line. Transwell migration assay was used to determine the effect of 5-HT on PC12 cell migration. The results demonstrated that 5-HT and nerve growth factor (NGF) induced PC12 cell migration in a dose-dependent manner. Additionally, 5-HT receptor antagonists suggest that 5-HT-induced migration was mediated by serotonin receptor 6 (5-HT6), a Gs-protein coupled receptor that elevates the intercellular cAMP level. By contrast, antagonists of serotonin receptor 3 (5-HT3) did not show any effects on PC12 cell migration. Clozapine, an inhibitor of cAMP accumulation mediated by 5-HT6, significantly reduced the effect of 5-HT on the PC12 cell migration. An inhibitor of extracellular signal-regulated kinase (ERK) also suppressed migration. These results suggest that 5-HT induces PC12 cell migration by activating cAMP/ERK signaling pathways, which is mediated by 5-HT6 receptor.