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Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cell- cycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phase-dependent fluorescent marker Fucci to distinguish cells in G1-phase and those in S + G2/M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G1-phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G2–M phases, suggesting accelerated glycolysis in G1-phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G2–M, and G1 phases suggested that efflux of lactate was elevated significantly in G1-phase. By contrast, ATP production in G2–M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G1 and G2–M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G2–M to G1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased.Implications: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. Mol Cancer Res; 11(9); 973–85. ©2013 AACR.

PDF - 1735K, Table S1: Percentages of Fucci-HTC116 in S + G2 and G1 phases in mouse liver metastatic foci. Table S2: Numbers of MALDO-IMS measurement points in mouse liver metastatic foci. Figure S1: Frequency distribution of relative intensities of MALDI-IMS signal in mouse number 3. Figure S2: Synchronization Figure S3: Intracellular concentrations of metabolites Figure S4: Analysis of metabolites in HCT116 WT cells cultured under 1g/L glucose. Figure S5: Analysis of metabolites in HCT116 p53-null cells cultured under 3g/L glucose. Figure S6: Lactate efflux. Figure S7: Real-time RT-PCR analysis for monocarboxylate transporters (MCTs).

Objective Compared with the implementation speed of image-guided adaptive brachytherapy for uterine cervical cancer, that of intracavitary and interstitial brachytherapy is slow, possible because it requires more invasive procedure of inserting needles directly into tumours. To accelerate the implementation speed of intracavitary and interstitial brachytherapy, a first hands-on seminar for image-guided adaptive brachytherapy and intracavitary and interstitial brachytherapy for uterine cervical cancer was held on 26 November 2022, supported by Japanese Society for Radiology and Oncology. This article deals with this hands-on seminar and difference of degree of confidence of participants in starting intracavitary and interstitial brachytherapy before and after the seminar. Methods The seminar consisted of lectures regarding intracavitary and interstitial brachytherapy in the morning and hands-on practice of needle insertion and contouring, as well as dose calculation practice using the radiation treatment system in the evening. Prior to and following the seminar, participants completed a questionnaire asking about their level of confidence in performing intracavitary and interstitial brachytherapy, expressed between 0 and 10 (the higher the number, the stronger the confidence). Results A total of 15 physicians, six medical physicists and eight radiation technologists from 11 institutions attended the meeting. The median level of confidence before and after the seminar was 3 (range, 0–6) and 5.5 (range, 3–7), respectively, and a statistically significant improvement was observed (P Conclusion It was suggested that the hands-on seminar on intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer improved the level of confidence of the attendees and propelled their motivation, through which it is expected that the implementation of intracavitary and interstitial brachytherapy will be accelerated.

【要旨】嚥下調整食を導入した給食施設の事例から取り組みを整理し，管理栄養士および調理従事者の役 割について考察した。嚥下調整食の実施では，喫食者に適した食形態の設定や多職種による喫食状況の把 握，物性の安定と調理負担の調整が行われていた。特に，調理従事者の業務内容が従来の調理中心の業務 から拡大傾向にあり，施設職員，委託給食会社職員ともに嚥下調整食の調理方法・技術に関する研修のほ か，嚥下に関する知識研修や病棟訪問等に参加していた。今後，管理栄養士には，喫食者の栄養状態，摂 食・嚥下機能の維持・向上を目指した嚥下調整食の開発および質の向上に加えて，調理従事者の職務設計， 人材育成に関する職務遂行，委託給食会社との協力関係構築などの能力が求められると考える。 Abstract: This study summarized the initiatives of a meal-catering facility that had introduced a dysphagia diet and considered the roles of registered dietitians and cooks. Implementing a dysphagia diet involves identifying the forms of food suitable for the patient and appointing a multi-disciplinary team for understanding their eating condition, stabilizing the physical properties of food, and adjusting the burden of cooking. Notably, the work done by cooking staff in the mealcatering facility tended to expand beyond conventional cooking-centered duties; together with the facility staff and subcontracted meal-catering staff, the cooking staff undertook training on cooking methods and techniques for dysphagia diet, and training to increase their knowledge about swallowing, as well as visits to wards. In the future, registered dietitians would be required to acquire skills involving designing the duty of cooking staff, executing the duties related to human resource development, and establishing cooperative relations with sub-contracted meal-catering companies. They would also need to develop and improve the quality of dysphagia diet aimed at maintaining and improving the nutritional status, feeding, and swallowing function of the patient.

IgG4-related diseases (IgG4-RDs) are known to disrupt the functioning of multiple organs and are usually associated with mass lesions. Periaortitis, an inflammation of the adventitia and tissues surrounding the aorta, is an example of an IgG4-RD. In ophthalmology, an enlargement of the lacrimal gland is a well-known IgG4-RD, and scleritis has also been reported to be an IgG4-RD although it is rare. We report our findings in a case with periaortitis and posterior scleritis that were present at the same time, and they responded well to systemic steroid therapy.A 79-year-old man with dementia and Lewy bodies was referred to our hospital because of uveitis in both eyes that did not respond to topical steroid therapy.We found anterior scleritis in the right eye and uveitis with shallow anterior chambers in both eyes. B-mode echography showed choroidal detachments (CDs) and a T sign in the right eye. The CDs were assumed to have progressed to the posterior scleritis which then caused the severe vision reduction. The patient was referred to the Internal Medicine Department because the systemic inflammatory disease was suspected due to the high levels of C-reactive protein (CRP) and the fast erythrocyte sedimentation rate. Systemic CT scans showed periaortitis only at the lumbar region. Because of the high levels of IgG4, the patient was diagnosed with IgG4-RD.The patient received intravenous and oral steroid therapy. The first 125 mg of methylprednisolone (mPSL) for 3 days was intravenous, after which it was switched to oral prednisolone (PSL) therapy and the dosage was gradually reduced.The posterior scleritis and periaortitis responded well to the systemic steroid therapy. One year and a half after the onset of the disease, the patient is still taking 5 mg of PSL.Scleritis with multiple CDs and periaortitis were strongly suspected to be due to IgG4-RD although no definitive diagnosis was made by biopsy of the lesions. Clinicians should be aware that IgG4-RD should be considered as one of the causes of posterior scleritis.

Capsanthin, a characteristic red carotenoid found in the fruits of red pepper (Capsicum annuum), is widely consumed as a food and a functional coloring additive. An enzyme catalyzing capsanthin synthesis was identified as capsanthin/capsorubin synthase (CCS) in the 1990s, but no microbial production of capsanthin has been reported. We report here the first successful attempt to biosynthesize capsanthin in Escherichia coli by carotenoid-pathway engineering. Our initial attempt to coexpress eight enzyme genes required for capsanthin biosynthesis did not detect the desired product. The dual activity of CCS as a lycopene β-cyclase as well as a capsanthin/capsorubin synthase likely complicated the task. We demonstrated that a particularly high expression level of the CCS gene and the minimization of byproducts by regulating the seven upstream carotenogenic genes were crucial for capsanthin formation in E. coli. Our results provide a platform for further study of CCS activity and capsanthin production in microorganisms.

Mucolipidosis type IV (MLIV) is an autosomal recessively inherited lysosomal storage disorder characterized by progressive psychomotor delay and retinal degeneration that is associated with biallelic variants in the MCOLN1 gene. The gene, which is expressed in late endosomes and lysosomes of various tissue cells, encodes the transient receptor potential channel mucolipin 1 consisting of six transmembrane domains. Here, we described 14-year follow-up observation of a 4-year-old Japanese male MLIV patient with a novel homozygous in-frame deletion variant p.(F313del), which was identified by whole-exome sequencing analysis. Neurological examination revealed progressive psychomotor delay, and atrophy of the corpus callosum and cerebellum was observed on brain magnetic resonance images. Ophthalmologically, corneal clouding has remained unchanged during the follow-up period, whereas optic nerve pallor and retinal degenerative changes exhibited progressive disease courses. Light-adapted electroretinography was non-recordable. Transmission electron microscopy of granulocytes revealed characteristic concentric multiple lamellar structures and an electron-dense inclusion in lysosomes. The in-frame deletion variant was located within the second transmembrane domain, which is of putative functional importance for channel properties.

Bacteria use flagella as propellers to move to favorable environments. Escherichia albertii, a growing cause of foodborne illness and diarrhea, is reportedly non-motile and lacks flagella on its surface. Here, we report that 27 out of 59 E. albertii strains, collected mainly from humans and birds, showed swimming motility when cultured at low osmotic pressure. The biosynthesis of flagella in E. albertii cells was induced under ambient temperature and hypoosmotic pressure: conditions which resemble aquatic environments. Flagellar induction increased E. albertii survival in the intestinal epithelial cell culture containing gentamicin. Although genes involved in chemotaxis are not present in the E. albertii genome, the addition of glutamic acid, an amino acid known to regulate the internal cell osmolarity, augmented the proportion of swimming cells by 35-fold. These results suggest that flagellar biosynthesis and motility in E. albertii cells are controlled by their internal and external osmolarity., Ikeda et al. report that enteropathogen E. albertii, thought to be a non-motile microorganism, may form flagella and acquire swimming motility in a hypoosmotic environment and ambient temperatures. Further addition of glutamic acid, an amino acid known to regulate the internal cell osmolarity, augments the proportion of swimming cells.

Pregabalin binds to the α2–δ1/α2–δ2 subunits of the voltage-gated L-type calcium channel (LTCC), which is expressed in rod/cone photoreceptor terminals. The purpose of this report was to describe electroretinographic abnormalities associated with pregabalin treatment. This is an observational case report. A 49-year-old female reported photophobia and night blindness in her left eye after 10 months of pregabalin administration. One month after the symptoms, ophthalmic examinations were performed, which revealed good visual acuity and no remarkable fundus findings. However, full-field electroretinography (ERG) of the left eye revealed a decreased b-wave in rod ERG, a slightly decreased a-wave and severely decreased b-wave (negative ERG) in bright flash ERG, decreased a- and b-waves in cone ERG, and decreased b-waves in 30-Hz flicker ERG. These findings are similar to those seen in incomplete congenital stationary night blindness, whereas the right eye ERG showed normal responses, except for a square a-wave in cone ERG. The ERG gradually improved from 1 to 12 months after discontinuing pregabalin. Finally, b-waves in bright flash ERG and cone ERG responses largely recovered, but b-waves in rod ERG and a-waves in bright flash ERG only partially recovered in the left eye. The square a-wave recovered to normal in the right eye. This is the first report to indicate that ERG abnormalities might be associated with pregabalin treatment. Our results suggest that pregabalin may affect LTCC function via the α2–δ1/α2–δ2 subunits, which leads to defective synaptic transmission from rod/cone photoreceptors to bipolar cells.

Carotenoids are naturally synthesized in some species of bacteria, archaea, and fungi (including yeasts) as well as all photosynthetic organisms. Escherichia coli has been the most popular bacterial host for the heterologous production of a variety of carotenoids, including even xanthophylls unique to photosynthetic eukaryotes such as lutein, antheraxanthin, and violaxanthin. However, conversion efficiency of these epoxy-xanthophylls (antheraxanthin and violaxanthin) from zeaxanthin remained substantially low. We here examined several factors affecting their productivity in E. coli. Two sorts of plasmids were introduced into the bacterial host, i.e., a plasmid to produce zeaxanthin due to the presence of the Pantoea ananatis crtE, crtB, crtI, crtY, and crtZ genes in addition to the Haematococcus pluvialis IDI gene, and one containing each of zeaxanthin epoxidase (ZEP) genes originated from nine photosynthetic eukaryotes. It was consequently found that paprika (Capsicum annuum) ZEP (CaZEP) showed the highest conversion activity. Next, using the CaZEP gene, we performed optimization experiments in relation to E. coli strains as the production hosts, expression vectors, and ribosome-binding site (RBS) sequences. As a result, the highest productivity of violaxanthin (231 μg/g dry weight) was observed, when the pUC18 vector was used with CaZEP preceded by a RBS sequence of score 5000 in strain JM101(DE3).

Summary The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5., Graphical abstract, Highlights • KAT5-mediated DNA damage repair acts against ischemia-reperfusion (IR) injuries • K-Cl cotransporter3 (KCC3) expression is decreased in damaged proximal tubular cells • Decreased KCC3 may lead to AKI via acceleration of tubuloglomerular feedback • KAT5 induces KCC3 expression through an epigenetic mechanism, Pathophysiology; Cell biology

BEIIb plays a specific role in determining the structure of amylopectin in rice endosperm, whereas BEIIa plays the similar role in the culm where BEIIb is absent. Cereals have three types of starch branching enzymes (BEs), BEI, BEIIa, and BEIIb. It is widely known that BEIIb is specifically expressed in the endosperm and plays a distinct role in the structure of amylopectin because in its absence the amylopectin type changes to the amylose-extender-type (ae-type) or B-type from the wild-type or A-type and this causes the starch crystalline allomorph to the B-type from the wild-type A-type. This study aimed to clarify the role of BEIIa in the culm where BEIIb is not expressed, by using a be2a mutant in comparison with results with be2b and be1 mutants. The results showed that the amylopectin structure exhibited the B-type in the be2a culm compared with the A-type in the wild-type culm. The starch granules from the be2a culm also showed the B-type like allomorph when examined by X-ray diffraction analysis and optical sum frequency generation spectroscopy. Both amylopectin chain-length profile and starch crystalline properties were found to be the A-type at the very early stage of endosperm development at 4-6 days after pollination (DAP) even in the be2b mutant. All these results support a view that in the culm as well as in the endosperm at 4-6 DAP, BEIIa can play the role of BEIIb which has been well documented in maturing endosperm. The possible mechanism as to how BEIIa can play its role is discussed.

Human papillomavirus vaccination is not widespread in Japan, and the low screening rates result in many cases of locally advanced cervical cancer. We investigated the prognostic significance of sarcopenia in patients with cervical cancer to guide healthcare policies to improve treatment outcomes.This retrospective study included 83 patients with cervical cancer without distant metastasis who underwent primary concurrent chemoradiotherapy between 2013 and 2018. We analyzed the indicators of physical condition and muscle quantity using the SYNAPSE VINCENT software. Muscle mass and the relationship between treatment toxicity and prognosis were evaluated.The patients' median age was 60 (range 33‒80) years. Cancer stage distribution was as follows: cT2b or higher, 84.3%; N1, 65.1%; and MA, 27.7%. The overall sarcopenia (skeletal muscle index [SMI] 38.5) rate was 30.1%, and the rate was 33.9 and 22.2% in patients aged 64 and ≥ 65 years, respectively. No correlation was observed between clinical stage and musculoskeletal indices. Treatment resulted in decreased body weight and SMI; after treatment, the sarcopenia rate increased to 37.3%. A higher intramuscular adipose tissue content (IMAC) reduced the number of chemotherapy cycles needed. Treatment-associated SMI decreases of ≥ 7% indicated poor prognosis, with significant differences in progression-free survival and overall survival (p = 0.013 and p = 0.012, respectively). Patients who were very lean (body mass index 18.5 kg/mOur findings emphasize the importance of assessing original nutritional status and maintaining muscle mass and quality during the treatment of patients with cervical cancer.

BackgroundUnderstanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response.MethodsWe investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody.ResultsSystemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/β-catenin signaling and by CD8+ effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8+ T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8+ T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment.ConclusionsSCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.

Lutein is an industrially important carotenoid pigment, which is essential for photoprotection and photosynthesis in plants. Lutein is crucial for maintaining human health due to its protective ability from ocular diseases. However, its pathway engineering research has scarcely been performed for microbial production using heterologous hosts, such as Escherichia coli, since the engineering of multiple genes is required. These genes, which include tricky key carotenoid biosynthesis genes typically derived from plants, encode two sorts of cyclases (lycopene ε- and β-cyclase) and cytochrome P450 CYP97C. In this study, upstream genes effective for the increase in carotenoid amounts, such as isopentenyl diphosphate isomerase (IDI) gene, were integrated into the E. coli JM101 (DE3) genome. The most efficient set of the key genes (MpLCYe, MpLCYb and MpCYP97C) was selected from among the corresponding genes derived from various plant (or bacterial) species using E. coli that had accumulated carotenoid substrates. Furthermore, to optimize the production of lutein in E. coli, we introduced several sorts of plasmids that contained some of the multiple genes into the genome-inserted strain and compared lutein productivity. Finally, we achieved 11 mg/l as lutein yield using a mini jar. Here, the high-yield production of lutein was successfully performed using E. coli through approaches of pathway engineering. The findings obtained here should be a base reference for substantial lutein production with microorganisms in the future.

Capsanthin, a characteristic red carotenoid found in the fruits of red pepper (

Purpose To assess the treatment results of definitive radiotherapy for esophageal cancer at Tokushima University Hospital and clarify the prognostic factors. Methods Seventy consecutive patients with esophageal cancer who underwent definitive radiotherapy between May 2004 and March 2012 were included in the present study. Local control rate, overall survival rate, and radiation morbidity were examined and univariate and multivariate analyses were performed to investigate prognostic factors. Results The 5-yearoverall survival rates of stages I, II, III, and IVA were 81%, 71%, 0%, and 9%, respectively. Performance status, clinical stage, and neoadjuvant chemotherapy were significant prognostic factors. A past history of interstitial pneumonia was associated with severe radiation-induced lung injury. Conclusions Patients who underwent definitive chemoradiotherapy for esophageal cancer in stage I/II showed good prognosis. However, treatment results of the patients in stage III/IV were not satisfactory, and those who could not undergo surgery after neoadjuvant chemotherapy had the worst prognosis.J.Med.Invest.66:99-105, February, 2019.

We report the combined enzymatic synthesis of five glucan dendrimers with control of molecular weight and particle size. Amphiphilic properties were introduced through dodecyl group substitution. A Tokyo-green fluorescence assay showed that amphiphilic glucan dendrimers were able to successfully deliver active β-galactosidase to cells.

Volumetric-modulated arc therapy (VMAT) can be used to design hypofractionated radiotherapy treatment plans for multiple brain metastases. The purpose of this study was to evaluate treatment outcomes of hypofractionated image-guided multifocal irradiation using VMAT (HFIGMI–VMAT) for brain metastases. From July 2012 to December 2016, 67 consecutive patients with 601 brain metastases were treated with HFIGMI–VMAT at our institution. The prescribed dose was 50 Gy to a 95% volume of the planning target volume in 10 fractions. Fifty-five of the 67 patients had non-small-cell lung cancer, and the remaining 12 had other types of cancer. The median number of brain metastases was five, and the median maximum diameter was 1.2 cm. The median duration of follow-up was 12.0 months (range, 1.9–44.8 months), and the median survival time 18.7 months. Four patients with six lesions had local recurrences. The local control rate in the 64 assessed patients was 98.4% and 95.3% at 6 and 12 months, respectively (three died before assessment). The local control rate for the 572 assessed lesions was 99.8% and 99.3% at 6 and 12 months, respectively. Thirty-nine patients developed distant brain metastases, the distant brain control rate being 59.7% and 40.5% at 6 and 12 months, respectively. Acute toxicities were generally mild (Grade 1–2). Three patients (4.5%) developed radiation necrosis requiring corticosteroid therapy. The HFIGMI–VMAT technique with flat dose delivery was well tolerated and achieved excellent local control. This technique is a promising treatment option for patients with multiple and large brain metastases.

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm−1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm−1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance., Graphical abstract Image 1, Highlights • Cystathionine-γ-lyase predicts post-operative chemoresistance in ovarian cancer. • SERS visualizes on-tissue polysulfides in non-responders against chemotherapy. • Polysulfides ameliorate cisplatin-induced DNA damages to block cancer cell death. • Ambroxol degrades polysulfides to unlock chemoresistance in vitro and in vivo.

Purpose During treatment planning for head‐and‐neck volumetric‐modulated arc therapy (VMAT), manual contouring of the metal artifact area of artificial teeth is done, and the area is replaced with water computed tomography (CT) values for dose calculation. This contouring of the metal artifact areas, which is performed manually, is subject to human variability. The purpose of this study is to evaluate and analyze the effect of inter‐observer variation on dose distribution. Methods The subjects were 25 cases of cancer of the oropharynx for which VMAT was performed. Six radiation oncologists (ROs) performed metal artifact contouring for all of the cases. Gross tumor volume, clinical target volume, planning target volume (PTV), and oral cavity were evaluated. The contouring of the six ROs was divided into two groups, small and large groups. A reference RO was determined for each group and the dose distribution was compared with those of the other radiation oncologists by gamma analysis (GA). As an additional experiment, we changed the contouring of each dental metal artifact area, creating enlarged contours (L), reduced contours (S), and undrawn contours (N) based on the contouring by the six ROs and compared these structure sets. Results The evaluation of inter‐observer variation showed no significant difference between the large and small groups, and the GA pass rate was 100%. Similar results were obtained comparing structure sets L and S, but in the comparison of structure sets L and N, there were cases with pass rates below 70%. Conclusions The results show that the artificial variability of manual artificial tooth metal artifact contouring has little effect on the dose distribution of VMAT. However, it should be noted that the dose distribution may change depending on the contouring method in cases where the overlap between PTV and metal artifact areas is large.

Background Acquired color anomalies caused by cerebral trauma are classified as either achromatopsias or dyschromatopsias (Zeki, Brain 113:1721–1777, 1990). The three main brain regions stimulated by color are V1, the lingual gyrus, which was designated as human V4 (hV4), and the fusiform gyrus, designated as V4α. (Zeki, Brain 113:1721–1777, 1990). An acquired cerebral color anomaly is often accompanied by visual field loss (hemi- and quadrantanopia), facial agnosia, prosopagnosia, visual agnosia, and anosognosia depending on the underlying pathology (Bartels and Zeki, Eur J Neurosci 12:172–193, 2000), (Meadows, Brain 97:615–632, 1974), (Pearman et al., Ann Neurol 5:253–261, 1979). The purpose of this study was to determine the characteristics of a patient who developed dyschromatopsia following a traumatic injury to her brain. Case presentation The patient was a 24-year-old woman who had a contusion to her right anterior temporal lobe. After the injury, she noticed color distortion and that blue objects appeared green in the left half of the visual field. Although conventional color vision tests did not detect any color vision abnormalities, short wavelength automated perimetry (SWAP) showed a decrease in sensitivity consistent with a left hemi-dyschromatopsia. Magnetic resonance imaging (MRI) detected abnormalities in the right fusiform gyrus, a part of the anterior temporal lobe. At follow-up 14 months later, subjective symptoms had disappeared, but the SWAP abnormalities persisted and a thinning of the sectorial ganglion cell complex (GCC) was detected. Conclusion The results indicate that although the subjective symptoms resolved early, a reduced sensitivity of SWAP remained and the optical coherence tomography (OCT) showed GCC thinning. We conclude that local abnormalities in the anterior section of fusiform gyrus can cause mild cerebral dyschromatopsia without other symptoms. These findings indicate that it is important to listen to the symptoms of the patient and perform appropriate tests including the SWAP and OCT at the early stage to objectively prove the presence of acquired cerebral color anomaly.

Although oxidative stress plays central roles in postischemic renal injury, region-specific alterations in energy and redox metabolism caused by short-duration ischemia remain unknown. Imaging mass spectrometry enabled us to reveal spatial heterogeneity of energy and redox metabolites in the postischemic murine kidney. After 10-minute ischemia and 24-hour reperfusion (10mIR), in the cortex and outer stripes of the outer medulla, ATP substantially decreased, but not in the inner stripes of the outer medulla and inner medulla. 10mIR caused renal injury with elevation of fractional excretion of sodium, although histological damage by oxidative stress was limited. Ischemia-induced NADH elevation in the cortex indicated prolonged production of reactive oxygen species by xanthine oxidase (XOD). However, consumption of reduced glutathione after reperfusion suggested the amelioration of oxidative stress. An XOD inhibitor, febuxostat, which blocks the degradation pathway of adenine nucleotides, promoted ATP recovery and exerted renoprotective effects in the postischemic kidney. Because effects of febuxostat were canceled by silencing of the hypoxanthine phosphoribosyl transferase 1 gene in cultured tubular cells, mechanisms for the renoprotective effects appear to involve the purine salvage pathway, which uses hypoxanthine to resynthesize adenine nucleotides, including ATP. These findings suggest a novel therapeutic approach for acute ischemia/reperfusion renal injury with febuxostat through salvaging high-energy adenine nucleotides.

Gold deposition with diagonal angle towards boehmite-based nanostructure creates random arrays of horse-bean-shaped nanostructures named gold-nanofève (GNF). GNF generates many electromagnetic hotspots as surface-enhanced Raman spectroscopy (SERS) excitation sources, and enables large-area visualization of molecular vibration fingerprints of metabolites in human cancer xenografts in livers of immunodeficient mice with sufficient sensitivity and uniformity. Differential screening of GNF-SERS signals in tumours and those in parenchyma demarcated tumour boundaries in liver tissues. Furthermore, GNF-SERS combined with quantum chemical calculation identified cysteine-derived glutathione and hypotaurine (HT) as tumour-dominant and parenchyma-dominant metabolites, respectively. CD44 knockdown in cancer diminished glutathione, but not HT in tumours. Mechanisms whereby tumours sustained HT under CD44-knockdown conditions include upregulation of PHGDH, PSAT1 and PSPH that drove glycolysis-dependent activation of serine/glycine-cleavage systems to provide one-methyl group for HT synthesis. HT was rapidly converted into taurine in cancer cells, suggesting that HT is a robust anti-oxidant for their survival under glutathione-suppressed conditions., Surface-enhanced Raman spectroscopy (SERS) visualizes fingerprints of intermolecular vibrations of many metabolites. Here the authors report a SERS imaging technique that enables the visualization of metabolites distribution and automated extraction of tumour boundaries in frozen tissues.

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au-S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm

Background: We assessed the change in LUTS after prostate brachytherapy to reveal factors for prolonged urination disorder. Materials and Methods: Four hundred and four patients received prostate brachytherapy at our institution and were followed-up for at least 2 years. We evaluated the correlation of mean IPSS changes and clinical factors. Using multivariate analysis, we also evaluated clinical factors with potential to delay IPSS resolution. Results: In cases with prostate volume more than 30 cm3, radiation dose to 90% of prostate volume (D90) more than 160 Gy, and radiation dose to 30% of the urethral volume (UD30) more than 240 Gy, mean IPSS levels were significantly higher, even 30 months after treatment. On multivariate analysis, baseline IPSS more than 8 points and D90 more than 160 Gy were significant predictors for delayed IPSS resolution. Conclusion: Our data suggest that higher baseline IPSS and higher D90 were predictors for prolonged urination disorder.