[A Recurrent Colon Cancer Successfully Treated by Nivolumab plus Ipilimumab with On and Off for Preventing Exacerbation of Skin Disorders].

Here, we report a case in which nivolumab plus ipilimumab combination therapy was significantly effective for MSI-high recurrent colon cancer with acute exacerbation after 5-FU/L-OHP/CPT-11 treatment. At the end of 4 cycles of combination therapy, clinical CR was obtained on diagnostic imaging. At the end of the 2 cycles of transition from combination therapy to monotherapy, eosinophilia was observed in a quadratic function, and exacerbation of skin disorders was observed. Eosinophil counts normalized promptly after discontinuation of treatment, and skin disorders gradually improved. Two months after the discontinuation of treatment, monotherapy was restarted. After the resumption of treatment, an increase in eosinophils and worsening of skin symptoms were observed again, and stopped treatment. We report an interesting case in which immune checkpoint inhibiter were turned on and off according to eosinophil counts for preventing exacerbation of skin disorders, and for maintaining cancer remission by continuing immune checkpoint inhibitor treatment.

Copper isotope composition of hemocyanin.

BACKGROUND: Copper is a metal that plays a central role in biology, for example, as co-factor in various redox enzymes. Its stable isotopic composition is being used as tracer of its transport in living organisms and as a biomarker for diseases affecting its homeostasis. While the application of copper stable isotopes to biological studies is a growing field, there are presently no biological standards that are systematically analyzed in the different laboratories, as it is the case for geological samples (e.g., by using widely available basalt samples). It is therefore paramount for the community to establish such standard. Copper also binds oxygen in the respiratory protein, hemocyanin, in the hemolymph of mollusks and arthropods and is thus critical to respiration for these species. METHODS: Here, the Cu isotope composition of hemocyanin of different modern species of mollusks and arthropods (Megathura crenulate Keyhole limpet, Limulus polyphemus Horseshoe crab and Concholepas concholepas Chilean abalone), as well as theoretical constraints on the origin of these isotopic fractionations through ab initio calculations are reported. RESULTS: The isotopic fractionation factors for Cu(I) and Cu(II), both in hemocyanin and in seawater, predict an enrichment in the lighter isotope of Cu in the hemocyanin by over 1 permil compared to seawater. The hemocyanin of Chilean abalone and Horseshoe crab have Cu isotope compositions (δ65Cu = +0.63 ± 0.04‰ and +0.61 ± 0.04‰, respectively, with δ65Cu the permil deviation of the 65Cu/63Cu ratio from the NIST SRM 976 standard), similar to that of the octopus reported in literature (+0.62‰), that are undistinguishable from seawater, suggesting quantitative Cu absorption for these organisms. Conversely, the Keyhole limpet is enriched in the lighter isotope of Cu, which is in line with the ab initio calculation and therefore Cu isotopic fractionation during incorporation of Cu into the hemocyanin. CONCLUSIONS: Because these hemocyanin standard samples are widely available, they could serve in the future as inter-laboratory standards to verify the accuracy of the Cu isotopic measurements on biological matrices.

Laparoscopic Sutureless Rectopexy Using a Fixation Device for Complete Rectal Prolapse.

BACKGROUND: Complete rectal prolapse (CRP) commonly affects the daily life of older people and has no established operative treatment approach. We describe our simple method of laparoscopic, sutureless rectopexy, involving rectal mobilization (along with its peritoneum bilaterally) and fixation to the sacral promontory using a fixation device. We also present an analysis of short-term outcomes in patients treated using this procedure. MATERIALS AND METHODS: We retrospectively evaluated 62 patients with CRP, who underwent a laparoscopic rectopexy via tack fixation, between 2004 and 2017. The peritoneum was widely attached near the site of peritoneal reflection, as in rectal cancer surgery. The hypogastric nerve was carefully detached from the front of the sacrum. Keeping the nerve intact, we lifted and mobilized the dissected rectum cranially towards the promontory, and the rectal peritoneum was affixed to the sacrum by applying 2 to 3 fixed tacks bilaterally, using a fixation device. RESULTS: The median age of the study group was 80 (10 to 91) years. All procedures were successful without serious intraoperative complications; only 1 patient required conversion to open surgery. Median values for operative duration, intraoperative blood loss, and postoperative period of hospitalization were 177 (125 to 441) minutes, 5 (0 to 275) mL, and 7 (3 to 17) days, respectively. Only 6 (9.7%) patients experienced recurrence during the follow-up period. CONCLUSION: Laparoscopic tacking rectopexy performed using a fixation device for repairing CRP is a simple, safe, and sutureless procedure with no severe complications or mortality.

Should spring water cysts of the mediastinum require excisional resection? A case report.

INTRODUCTION AND IMPORTANCE: Mediastinal cysts account for 20-32% of all mediastinal lesions. Complete surgical excision is the standard therapy for mediastinal cysts. Translucent cysts containing crystal-clear fluid are called "spring water cysts." We experienced a case of mediastinal spring water cyst fenestrated under video-assisted thoracoscopy with a miniaturized endoscope (mini-VATS) as an alternative to excisional resection. CASE PRESENTATION: A 49-year-old woman presented with back pain. Chest CT revealed a posterior mediastinal mass measuring 4.2 × 1.8 × 3.2 cm closed to the tenth thoracic vertebra. Chest MRI demonstrated hypo-intensity on T1-weighted images and hyper-intensity on T2-weighted images. It was estimated that the posterior mediastinal mass did not contain a tumor component. The tumor was growing and symptomatic; therefore, we performed surgical cyst fenestration without excision of the cyst under mini-VATS. The patient experienced complete relief of symptoms. Fluid accumulation in the cyst was not observed on CT images 12 months postoperatively. CLINICAL DISCUSSION: Kozu et al. reported that all 108 primary mediastinal cysts were resected completely and were recurrence-free after a mean follow-up of 41 ± 26 months. In the case of a functional hydrocele such as spring water cyst, we believe that even if fluid is produced, the thoracic pleura is capable of absorbing the fluid, and the cyst wall might not recur even if the wall is left in place. Fluid drainage through fenestration may prevent recurrent fluid collection. CONCLUSION: Fenestration of non-neoplastic mediastinal cysts under mini-VATS might be a less invasive radical procedure compared to complete resection.

Floquet-engineered quantum walks.

The quantum walk is the quantum-mechanical analogue of the classical random walk, which offers an advanced tool for both simulating highly complex quantum systems and building quantum algorithms in a wide range of research areas. One prominent application is in computational models capable of performing any quantum computation, in which precisely controlled state transfer is required. It is, however, generally difficult to control the behavior of quantum walks due to stochastic processes. Here we unveil the walking mechanism based on its particle-wave duality and then present tailoring quantum walks using the walking mechanism (Floquet oscillations) under designed time-dependent coins, to manipulate the desired state on demand, as in universal quantum computation primitives. Our results open the path towards control of quantum walks.

High-gain and wide-band optical amplifications induced by a coupled excited state of organic dye molecules co-doped in polymer waveguide.

We investigated optical gain and lasing characteristics of a polymer thin film co-doped with Rhodamine 6G and 4-(Dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran dye molecules. By the co-doping of these dyes, the optical gain coefficient and its spectral range were enhanced and widened, respectively. These results cannot be accounted for by the linear combination of the optical gain properties of single-doped films. Owing to this high-gain and wide-band optical amplification property, a distributed feedback lasing with a low threshold of 70 µJ/cm2 as well as a widely tunable wavelength range of 587-613 nm was achieved. We attribute this amplification property of the co-doped film, which cannot be achieved with the single-doped films, to the appearance of a coupled excited state between the two molecules.

Theoretical isotopic fractionation of magnesium between chlorophylls.

Magnesium is the metal at the center of all types of chlorophyll and is thus crucial to photosynthesis. When an element is involved in a biosynthetic pathway its isotopes are fractionated based on the difference of vibrational frequency between the different molecules. With the technical advance of multi-collectors plasma-mass-spectrometry and improvement in analytical precision, it has recently been found that two types of chlorophylls (a and b) are isotopically distinct. These results have very significant implications with regards to the use of Mg isotopes to understand the biosynthesis of chlorophyll. Here we present theoretical constraints on the origin of these isotopic fractionations through ab initio calculations. We present the fractionation factor for chlorphyll a, b, d, and f. We show that the natural isotopic variations among chlorophyll a and b are well explained by isotopic fractionation under equilibrium, which implies exchanges of Mg during the chlorophyll cycle. We predict that chlorophyll d and f should be isotopically fractionated compared to chlorophyll a and that this could be used in the future to understand the biosynthesis of these molecules.

Calcium isotope fractionation between aqueous compounds relevant to low-temperature geochemistry, biology and medicine.

Stable Ca isotopes are fractionated between bones, urine and blood of animals and between soils, roots and leaves of plants by >1000 ppm for the 44Ca/40Ca ratio. These isotopic variations have important implications to understand Ca transport and fluxes in living organisms; however, the mechanisms of isotopic fractionation are unclear. Here we present ab initio calculations for the isotopic fractionation between various aqueous species of Ca and show that this fractionation can be up to 3000 ppm. We show that the Ca isotopic fractionation between soil solutions and plant roots can be explained by the difference of isotopic fractionation between the different first shell hydration degree of Ca2+ and that the isotopic fractionation between roots and leaves is controlled by the precipitation of Ca-oxalates. The isotopic fractionation between blood and urine is due to the complexation of heavy Ca with citrate and oxalates in urine. Calculations are presented for additional Ca species that may be useful to interpret future Ca isotopic measurements.

Copper transporters are responsible for copper isotopic fractionation in eukaryotic cells.

Copper isotopic composition is altered in cancerous compared to healthy tissues. However, the rationale for this difference is yet unknown. As a model of Cu isotopic fractionation, we monitored Cu uptake in Saccharomyces cerevisiae, whose Cu import is similar to human. Wild type cells are enriched in 63Cu relative to 65Cu. Likewise, 63Cu isotope enrichment in cells without high-affinity Cu transporters is of slightly lower magnitude. In cells with compromised Cu reductase activity, however, no isotope fractionation is observed and when Cu is provided solely in reduced form for this strain, copper is enriched in 63Cu like in the case of the wild type. Our results demonstrate that Cu isotope fractionation is generated by membrane importers and that its amplitude is modulated by Cu reduction. Based on ab initio calculations, we propose that the fractionation may be due to Cu binding with sulfur-rich amino acids: methionine and cysteine. In hepatocellular carcinoma (HCC), lower expression of the STEAP3 copper reductase and heavy Cu isotope enrichment have been reported for the tumor mass, relative to the surrounding tissue. Our study suggests that copper isotope fractionation observed in HCC could be due to lower reductase activity in the tumor.

Medical applications of Cu, Zn, and S isotope effects.

This review examines recent applications of stable copper, zinc and sulfur isotopes to medical cases and notably cancer. The distribution of the natural stable isotopes of a particular element among coexisting molecular species varies as a function of the bond strength, the ionic charge, and the coordination, and it also changes with kinetics. Ab initio calculations show that compounds in which a metal binds to oxygen- (sulfate, phosphate, lactate) and nitrogen-bearing moieties (histidine) favor heavy isotopes, whereas bonds with sulfur (cysteine, methionine) favor light isotopes. Oxidized cations (e.g., Cu(ii)) and low coordination numbers are expected to favor heavy isotopes relative to their reduced counterparts (Cu(i)) and high coordination numbers. Here we discuss the first observations of Cu, Zn, and S isotopic variations, three elements closely related along multiple biological pathways, with emphasis on serum samples of healthy volunteers and of cancer patients. It was found that heavy isotopes of Zn and to an even greater extent Cu are enriched in erythrocytes relative to serum, while the difference is small for sulfur. Isotopic variations related to age and sex are relatively small. The 65Cu/63Cu ratio in the serum of patients with colon, breast, and liver cancer is conspicuously low relative to healthy subjects. The characteristic time over which Cu isotopes may change with disease progression (a few weeks) is consistent with both the turnover time of the element and albumin half-life. A parallel effect on sulfur isotopes is detected in a few un-medicated patients. Copper in liver tumor tissue is isotopically heavy. In contrast, Zn in breast cancer tumors is isotopically lighter than in healthy breast tissue. 66Zn/64Zn is very similar in the serum of cancer patients and in controls. Possible reasons for Cu isotope variations may be related to the cytosolic storage of Cu lactate (Warburg effect), release of intracellular copper from cysteine clusters (metallothionein), or the hepatocellular and biosynthetic dysfunction of the liver. We suggest that Cu isotope metallomics will help evaluate the homeostasis of this element during patient treatment, notably by chelates and blockers of Cu trafficking, and understand the many biochemical pathways in which this element is essential.

Electrolyzed Saline Irrigation for Elimination of Bacterial Colonization in the Empyema Space.

BACKGROUND: The empyema space is refractory to elimination of bacterial colonization. Electrolyzed saline (ES) was used as intra-pleural irrigation for rapid disinfection of the empyema space. PATIENTS AND METHODS: Twenty consecutive patients with para-pneumonic empyema were reviewed in this study from 2007 to 2015. The empyema space was irrigated by miniaturized thoracoscopic surgery (mini VATS), and the efficacy and safety of the use of ES were evaluated. RESULTS: Sixteen patients were male and four were female, with a mean age of 66.5 ± 9.5 y (27-90 y). Bacterial cultures of the purulent effusions from all 20 patients had positive results. Seventeen patients subsequently underwent continuous catheter irrigation and drainage. No patient had chest pain during ES irrigation. Fever duration after mini VATS was 2.8 ± 1.8 d (0-5 d). Catheter indwelling time was 10.3 ± 7.2 d (3-33 d). Inflammatory markers significantly improved (p < 0.05) within a week after mini VATS. Eighteen patients achieved pleural disinfection, and two patients had residual pathogens, one of whom later died of lung abscess. Space closure was successful in 14 patients. No patient underwent subsequent open drainage. Nineteen (95%) patients were discharged from the hospital. This treatment was successful in 18 (90%) patients, and one (5.6%) patient experienced recurrence. CONCLUSIONS: The ES irrigation facilitates the rapid disinfection and closure of the empyema space.

[A Patient with Stage IV Advanced Gastric Cancer with Multiple Liver Metastases Living for More Than 6 Years after Treatment with TS-1 Alone].

The patient was a 58-year-old man with advanced gastric cancer with multiple liver metastases. He received TXL/TS-1 therapy during February 2009, but treatment was stopped immediately when he developed anorexia, diarrhea, and numbness in his fingers. Therefore, only TS-1 was administered. Following treatment initiation, tumor marker levels promptly dropped. The gastric lesion disappeared and, to date, only a slight scar remains since April 2010. Similarly, liver metastases have not been detected since August 2011. There has been no lesion progression for 6 years since the start of the chemotherapy.

[Current status and issues of regional clinic network for hip fractures in the elderly].

I investigated presence of taking medicine and a taking medicine continuation rate to evaluate how to use the regional post-referral treatment plan about the osteoporosis treatment for the secondary hip fractures prevention. I evaluated the present conditions of the regional post-referral treatment plan that I considered from acute care hospital points of view. The osteoporosis treatment that continued and expanse of the osteoporosis liaison service are necessary to quit the chain of the osteoporotic fracture. It is necessary to improve a taking medicine continuation rate.

Copper isotope effect in serum of cancer patients. A pilot study.

The isotope effect describes mass-dependent variations of natural isotope abundances for a particular element. In this pilot study, we measured the (65)Cu/(63)Cu ratios in the serums of 20 breast and 8 colorectal cancer patients, which correspond to, respectively, 90 and 49 samples taken at different times with molecular biomarker documentation. Copper isotope compositions were determined by multiple-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). When compared with the literature data from a control group of 50 healthy blood donors, abundances of Cu isotopes predict mortality in the colorectal cancer group with a probability p = 0.018. For the breast cancer patients and the group of control women the probability goes down to p = 0.0006 and the AUC under the ROC curve is 0.75. Most patients considered in this preliminary study and with serum δ(65)Cu lower than the threshold value of -0.35‰ (per mil) did not survive. As a marker, a drop in δ(65)Cu precedes molecular biomarkers by several months. The observed decrease of δ(65)Cu in the serum of cancer patients is assigned to the extensive oxidative chelation of copper by cytosolic lactate. The potential of Cu isotope variability as a new diagnostic tool for breast and colorectal cancer seems strong. Shifts in Cu isotope compositions fingerprint cytosolic Cu chelation by lactate mono- and bidentates. This simple scheme provides a straightforward explanation for isotopically light Cu in the serum and isotopically heavy Cu in cancer cells: Cu(+) escaping chelation by lactate and excreted into the blood stream is isotopically light. Low δ(65)Cu values in serum therefore reveal the strength of lactate production by the Warburg effect.

Heterogeneous distribution of natural zinc isotopes in mice.

Zinc (Zn) is required for the function of more than 300 enzymes involved in many metabolic pathways, and is a vital micronutrient for living organisms. To investigate if Zn isotopes could be used to better understand metal homeostasis, as well as a biomarker for diseases, we assessed the distribution of natural Zn isotopes in various mouse tissues. We found that, with respect to Zn isotopes, most mouse organs are isotopically distinct and that the total range of variation within one mouse encompasses the variations observed in the Earth's crust. Therefore, biological activity may have a major impact on the distribution of Zn isotopes in inorganic materials. The most striking aspect of the data is that red blood cells and bones are enriched by ~0.5 per mil in (66)Zn relative to (64)Zn when compared to serum, and up to ~1 per mil when compared to the brain and liver. This fractionation is well explained by the equilibrium distribution of isotopes between different bonding environments of Zn in different organs. Differences in gender and genetic background did not appear to affect the isotopic distribution of Zn. Together, these results suggest the potential use of Zn isotopes as a tracer for dietary Zn, and for detecting disturbances in Zn metabolism due to pathological conditions.

Ab initio calculation of the Zn isotope effect in phosphates, citrates, and malates and applications to plants and soil.

Stable Zn isotopes are fractionated in roots and leaves of plants. Analyses demonstrate that the heavy Zn isotopes are enriched in the root system of plants with respect to shoots and leaves as well as the host soil, but the fractionation mechanisms remain unclear. Here we show that the origin of this isotope fractionation is due to a chemical isotope effect upon complexation by Zn malates and citrates in the aerial parts and by phosphates in the roots. We calculated the Zn isotope effect in aqueous citrates, malates, and phosphates by ab initio methods. For pH<5, the Zn isotopic compositions of the various parts of the plants are expected to be similar to those of groundwater. In the neutral to alkaline region, the calculations correctly predict that (66)Zn is enriched over (64)Zn in roots, which concentrate phosphates, with respect to leaves, which concentrate malates and citrates, by about one permil. It is proposed that Zn isotope fractionation represents a useful tracer of Zn availability and mobility in soils.

Development of a mass-producible on-chip plasmonic nanohole array biosensor.

We have developed a polymer film based plasmonic device whose optical properties are tuned for measuring biological samples. The device has a circular nanohole array structure fabricated with a nanoimprint technique using a UV curable polymer, and then gold thin film is deposited by electron beam deposition. Therefore, the device is mass-producible, which is also very important for bioaffinity sensors. First the gold film thickness and hole depth were optimized to obtain the maximum dip shift for the reflection spectra. The dip shift is equivalent to the sensitivity to refractive index changes at the plasmonic device surface. We also calculated the variation in reflection spectra by changing the above conditions using the finite-difference time domain method, and we obtained agreement between the theoretical and experimental curves. The nanohole periodicity was adjusted from 400 to 900 nm to make it possible to perform measurements in the visible wavelength region to measure the aqueous samples with less optical absorption. The tuned bottom filled gold nanohole array was incorporated in a microfluidic device covered with a PDMS based microchannel that was 2 mm wide and 20 µm deep. As a proof of concept, the device was used to detect TNF-α by employing a direct immunochemical reaction on the plasmonic array, and a detection limit of 21 ng mL(-1) was obtained by amplification with colloidal gold labeling instead of enzymatic amplification.

Early Archean serpentine mud volcanoes at Isua, Greenland, as a niche for early life.

The Isua Supracrustal Belt, Greenland, of Early Archean age (3.81-3.70 Ga) represents the oldest crustal segment on Earth. Its complex lithology comprises an ophiolite-like unit and volcanic rocks reminiscent of boninites, which tie Isua supracrustals to an island arc environment. We here present zinc (Zn) isotope compositions measured on serpentinites and other rocks from the Isua supracrustal sequence and on serpentinites from modern ophiolites, midocean ridges, and the Mariana forearc. In stark contrast to modern midocean ridge and ophiolite serpentinites, Zn in Isua and Mariana serpentinites is markedly depleted in heavy isotopes with respect to the igneous average. Based on recent results of Zn isotope fractionation between coexisting species in solution, the Isua serpentinites were permeated by carbonate-rich, high-pH hydrothermal solutions at medium temperature (100-300 °C). Zinc isotopes therefore stand out as a pH meter for fossil hydrothermal solutions. The geochemical features of the Isua fluids resemble the interstitial fluids sampled in the mud volcano serpentinites of the Mariana forearc. The reduced character and the high pH inferred for these fluids make Archean serpentine mud volcanoes a particularly favorable setting for the early stabilization of amino acids.

Experimental and theoretical investigation of isotope fractionation of zinc between aqua, chloro, and macrocyclic complexes.

This work reports on the chemical isotope fractionation of Zn(II) by a solvent extraction method with the crown ether dicyclohexano-18-crown-6. The (m)Zn/(64)Zn ratios (m = 66, 67, and 68) were analyzed by multiple-collector inductively coupled plasma mass spectrometry. The relative deviations of the (66)Zn/(64)Zn ratios relative to the unprocessed material (delta(66)Zn) was determined to be -0.51 to -0.32 in the acidity region 1.0-6.0 mol dm(-3) (M) HCl. The acidity dependence of delta(m)Zn was explained by the isotope exchange reactions between Zn(II) species (Zn(2+), ZnCl(+), ZnCl(2), ZnCl(3)(-), and ZnCl(4)(2-)) and the mole fractions of them. The magnitude of delta(m)Zn due to the related Zn(II) species estimated by quantum chemical calculations was in agreement with delta(m)Zn experimentally obtained. Contribution of nuclear field shift to the isotope fractionation was estimated to be less than 10% of delta(m)Zn by quantum chemical calculations.