A Three-in-one ZIFs-Derived CuCo(O)/GOx@PCNs Hybrid Cascade Nanozyme for Immunotherapy/Enhanced Starvation/Photothermal Therapy.

Glucose oxidase (GOx) is regarded as an ideal endogenous natural enzyme for tumor starvation therapy and photothermal therapy (PTT) is a promising strategy for the ablation of primary tumor. In this work, Cu-doped cobalt oxide and porous carbon nanocomposites (CuCo(O)@PCNs) were synthesized from double-layered ZIF-8@ZIF-67 and GOx was loaded in the porous carbon to form a CuCo(O)/GOx@PCNs hybrid nanozyme. CuCo(O) was characterized as the Cu0.3Co2.7O4 phase through X-ray diffraction analysis and it can react with H2O2 to generate O2 and alleviate tumor hypoxia, resulting in the recovered enzymatic activity of GOx and the enhanced starvation therapy. The porous nanocarbon can ablate the primary tumor because of its high photothermal conversion efficiency of 40.04%. The three-in-one functions of oxygen supply, glucose consumption, and photothermal conversion were realized in the ZIFs-derived CuCo(O)/GOx@PCNs nanozyme and the starvation therapy effect was improved by PTT and oxygen supplement. Furthermore, the inhibition effect of CuCo(O)/GOx@PCNs on metastatic tumor is similar to combined therapy of the nanozyme and the immune checkpoint-blocking antibody, α-PD-1. The related antitumor immune mechanism was studied through the analysis of immune-related proinflammatory cytokines and the activated T cells. This work may provide new ideas for the development and application of the ZIFs-derived hybrid nanozyme in tumor therapy and the CuCo(O)/GOx@PCNs nanozyme may be a promising alternative to immune checkpoint inhibitors.

Exploiting Unique Alignment of Cobalt Ferrite Nanoparticles, Mild Hyperthermia, and Controlled Intrinsic Cobalt Toxicity for Cancer Therapy.

Nanoparticle-based magnetic hyperthermia is a well-known thermal therapy platform studied to treat solid tumors, but its use for monotherapy is limited due to incomplete tumor eradication at hyperthermia temperature (45 °C). It is often combined with chemotherapy for obtaining a more effective therapeutic outcome. Cubic-shaped cobalt ferrite nanoparticles (Co-Fe NCs) serve as magnetic hyperthermia agents and as a cytotoxic agent due to the known cobalt ion toxicity, allowing the achievement of both heat and cytotoxic effects from a single platform. In addition to this advantage, Co-Fe NCs have the unique ability to form growing chains under an alternating magnetic field (AMF). This unique chain formation, along with the mild hyperthermia and intrinsic cobalt toxicity, leads to complete tumor regression and improved overall survival in an in vivo murine xenograft model, all under clinically approved AMF conditions. Numerical calculations identify magnetic anisotropy as the main Co-Fe NCs' feature to generate such chain formations. This novel combination therapy can improve the effects of magnetic hyperthermia, inaugurating investigation of mechanical behaviors of nanoparticles under AMF, as a new avenue for cancer therapy.

Immobilization of novel inorganic nano-complexes onto MWCNT nanomaterials as a novel adsorbent and anti-inflammatory therapy in an induced model of rheumatoid arthritis.

Novel supported inorganic metal nano-complexes of Ag(I) and Co(II) derived from 4-amino-N-(4-methylpyrimidin-2-yl) benzene sulfonamide (SulMer) were synthesized using olive leaf extract as a reducing agent with grinding and microwave methods. The prepared samples were denoted as Comp1-6. The surface morphologies of the synthesized nanomaterials were analyzed using C, H, N, S analysis, Fourier-transform infrared spectroscopy, UV- visible spectroscopy, proton and carbon nuclear magnetic resonance, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis, and x-ray powder diffraction (XRD) analysis. The data revealed that all the synthesized complexes exhibited a 1:1 metal-to-ligand ratio with a coordination number of 4 or 6. The mean particle size of the nanomaterial samples was 25-35 nm. The XRD patterns indicated a crystalline nature for the complexes. The supported inorganic metal nano-complexes displayed good activity in the adsorptive removal of Direct Red 81 (DR-81) from aqueous solutions. In addition, the effect of the supported metal nano-complexes on the immune system was studied as well as how these anti-inflammatory compounds could be used to treat many autoimmune diseases, most notably rheumatoid arthritis. An experimental model for arthritis can be induced using complete Freund's adjuvant. It was shown that the supported complex offers several advantages such stability, eco-friendliness, simple experimental conditions, short reaction times, and easy work- up.

Production responses and cost-benefit of long-acting pre-lambing anthelmintic treatment of yearling ewes in two commercial flocks in New Zealand.

AIMS: To investigate the production responses and cost-benefit of administering a controlled-release anthelmintic capsule (CRC) to pregnant yearling ewes prior to lambing. METHODS: Yearling ewes from two commercial sheep flocks (A, n=489; B, n=248) in the North Island of New Zealand were enrolled in the study. Prior to lambing, CRC containing albendazole and abamectin were administered to half the ewes while the other half remained untreated. Ewe liveweights and body condition scores were measured prior to lambing, at weaning and, for Flock B, prior to subsequent mating. Lambs were matched to dams shortly after birth and the weight and number of lamb weaned per ewe were determined. A cost-benefit analysis was undertaken for Flock B considering the increased weight of lamb weaned per ewe, and the weight of ewes at the next mating and the benefit in terms of lambs born. RESULTS: The mean weight at weaning of treated ewes was greater for treated than untreated ewes by 2.76 (95% CI 0.64-4.88) kg in Flock A (p<0.001) and 2.35 (95% CI -0.41-5.12) kg in Flock B (p=0.003); the weight of lamb weaned per ewe was greater for treated than untreated ewes by 1.43 (95% CI -0.71 to -3.49) kg in Flock A (p=0.041) and 3.97 (95% CI 1.59-6.37) kg in Flock B (p<0.001), and ewe liveweight prior to subsequent mating was greater for treated than untreated ewes in Flock B by 4.60 (95% CI 3.6-5.6) kg (p<0.001). There was no difference in the percentage of lambs reared to weaning between treated and untreated ewes in either flock (p>0.8). The overall cost-benefit of treatment for Flock B was NZ$9.44 per treated ewe. CONCLUSIONS AND CLINICAL RELEVANCE: Pre-lambing CRC administration to yearling ewes resulted in increased ewe weaning weights and weight of lamb weaned in both the flocks studied. There was an economic benefit in the one flock where this was assessed.

Suitability of microDiamond detectors for the determination of absorbed dose to water around high-dose-rate 192 Ir brachytherapy sources.

PURPOSE: Experimental dosimetry of high-dose-rate (HDR) 192 Ir brachytherapy (BT) sources is complicated due to high dose and dose-rate gradients, and softening of photon energy spectrum with depth. A single crystal synthetic diamond detector microDiamond (PTW 60019, Freiburg, Germany) has a small active volume, high sensitivity, direct readout, and nearly water-equivalent active volume. The purpose of this study was to evaluate the suitability of microDiamond detectors for the determination of absorbed dose to water around HDR 192 Ir BT sources. Three microDiamond detectors were used, allowing for the comparison of their properties. METHODS: In-phantom measurements were performed using microSelectron and VariSource iX HDR 192 Ir BT treatment units. Their treatment planning systems (TPSs), Oncentra (v. 4.3) and BrachyVision (v. 13.6), respectively, were used to create irradiation plans for a cubic PMMA phantom with the microDiamond positioned at one of three source-to-detector distances (SDDs) (1.5, 2.5, and 5.5 cm) at a time. The source was stepped in increments of 0.5 cm over a total length of 6 cm to yield absorbed dose of 2 Gy at the nominal reference-point of the detector. Detectors were calibrated in 60 Co beam in terms of absorbed dose to water, and Monte Carlo (MC) calculated beam quality correction factors were applied to account for absorbed-dose energy dependence. Phantom correction factors were applied to account for differences in dimensions between the measurement phantom and a water phantom used for absorbed dose calculations made with a TPS. The same measurements were made with all three of the detectors. Additionally, dose-rate dependence and stability of the detectors were evaluated in 60 Co beam. RESULTS: The percentage differences between experimentally determined and TPS-calculated absorbed doses to water were from -1.3% to +2.9%. The values agreed to within experimental uncertainties, which were from 1.9% to 4.3% (k = 2) depending on the detector, SDD and treatment delivery unit. No dose-rate or intrinsic energy dependence corrections were applied. All microDiamonds were comparable in terms of preirradiation dose, stability of the readings and energy response, and showed a good agreement. CONCLUSIONS: The results indicate that the microDiamond is potentially suitable for the determination of absorbed dose to water around HDR 192 Ir BT sources and may be used for independent verification of TPS's calculations, as well as for QA measurements of HDR 192 Ir BT treatment delivery units at clinical sites.

In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts.

Metastatic melanoma is a deadly form of cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel melanoma drug, the human recombinant Co-arginase (CoArgIPEG), against an aggressive A375 melanoma mouse model. CoArgIPEG is a modification of the naturally occurring human enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current amino acid-depleting drugs. Marked tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with CoArgIPEG treatment, both in the presence and in the absence of supplemental citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant arginase enzyme at lower doses of CoArgIPEG. Unfortunately, after 1 month, half of the relapsing tumors showed argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation - U0126 - in combination with CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13±0.10 and 0.14±0.10 with or without citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support CoArgIPEG as a potent, novel cancer therapeutic.

Understanding the differences between the wear of metal-on-metal and ceramic-on-metal total hip replacements.

Hip simulator studies have been carried out extensively to understand and test artificial hip implants in vitro as an efficient alternative to obtaining long-term results in vivo. Recent studies have shown that a ceramic-on-metal material combination lowers the wear by up to 100 times in comparison with a typical metal-on-metal design. The reason for this reduction remains unclear and for this reason this study has undertaken simple tribometer tests to understand the fundamental material loss mechanisms in two material combinations: metal-on-metal and ceramic-on-ceramic. A simple-configuration reciprocating pin-on-plate wear study was performed under open-circuit potential (OCP) and with applied cathodic protection (CP) in a serum solution using two tribological couples: firstly, cobalt-chromium (Co-Cr) pins against Co-Cr plates; secondly, Co-Cr pins against alumina (Al2O3) plates. The pin and plate surfaces prior to and after testing were examined by profilometry and scanning electron microscopy. The results showed a marked reduction in wear when CP was applied, indicating that total material degradation under the OCP condition was attributed to corrosion processes. The substitution of the Co-Cr pin with an Al2O3 plate also resulted in a dramatic reduction in wear, probably due to the reduction in the corrosion-wear interactions between the tribological pair.

Use of interstitial temperature self-regulating thermal rods in the treatment of prostate cancer.

Several groups are investigating a new technique for thermal treatment of the prostate involving permanent implantation of small biocompatable rods in a procedure similar to brachytherapy. The rods are then heated by an extracorporeal alternating magnetic field. The rods are composed of an alloy of palladium and cobalt such that they are temperature self-regulating; the regulated temperature is set during manufacture. Clinically, rods with a regulating temperature in the hyperthermia range are being employed as an adjuvant to external-beam radiation. Rods with a regulation temperature in the thermal ablation range are being used in two patient groups: those with newly diagnosed stage T(1) or T(2) prostate cancer and those who have localized recurrent disease after external-beam radiation. Early data appear promising.

The effect of cobalt compounds on uninfected and Ascaridia galli-infected chickens: a kinetic model for Ascaridia galli populations and chicken growth.

The effect of dietary cobalt from three different sources on uninfected and Ascaridia galli-infected Hisex chickens, has been studied. The chicken diet was supplemented with 0.06 Co2+ kg-1 food either in the form of two glycine-cobalt compounds or mixed zinc-cobalt basic salt. An excess of dietary cobalt in small doses increases the gain of body weight and decreases host mortality. A greater bioefficiency of cobalt was established in infected chickens. A mathematical model has been used to provide a quantitative interpretation of the observed results. The model solutions of the kinetics of worm numbers and body weight are in a good agreement with experimental data. The model is valid for different degrees of A. galli infections and for treatment with different trace elements. The value of the kinetic parameter, regarded as a phenomenological constant of the host immune response, depends on the degree of infection.

Homeopathic treatment of Chronic Fatigue Syndrome: three case studies using Jan Scholten's methodology.

This paper explores the treatment of Chronic Fatigue Syndrome following a viral infection in young people. The methodology is based on that of Dr Jan Scholten, Holland, who has systematically described the homeopathic themes of all elements in the periodic table. Three case studies are presented, Cobaltum Phosphoricum, Calcium Phosphoricum and Cadmium Phosphoricum were prescribed. The common themes and the differentiating features of these Phosphate salts are described in detail to show how the homeopathic similimum is found and cure achieved.

Micosis fungoides en fase tumoral: comunicación de un caso / Mycosis fungoides in tumoral stage: Case report

Se presenta un caso de micosis fungoides en fase tumoral que ha respondido favorablemente al manajo con cobalto luego de 15 sesiones con dosis fraccionadas de 200 rads diarios. Posteriormente, se ha manejado con puvaterapia, obteniendo excelentes resultados hasta el momento

Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas.

After neoadjuvant chemotherapy, a routine conservative approach followed by salvage surgery was evaluated in terms of local control and survival in cases of advanced potentially resectable hypopharyngeal carcinoma. Between 1985 and 1989, 92 patients with T3 or T4-NO,N3 operable squamous cell hypopharyngeal carcinomas received three courses of neoadjuvant chemotherapy every 2 weeks involving a combination of cisplatin, 100 mg/m2, on day 1 and fluorouracil, 1 g/m2, on days 2 to 5, followed by total laryngopharyngectomy plus postoperative radiotherapy in 47 patients (arm A) or radiotherapy alone in 45 patients (arm B). Randomization was always performed prior to chemotherapy. The response rates of tumor and node to chemotherapy were, respectively, 67% in arm A versus 79% in arm B (P > 0.05) and 54% in arm A versus 73% in arm B (P > 0.05). Grade III or IV toxicity was similar, affecting 15% of patients and 7% of cycles in arm A versus 16% of patients and 6% of cycles in arm B. After a mean follow-up of 92 months, survival was statistically better (P = 0.04) in arm A (5-year overall survival, 37%; median survival, 40 months) than in arm B (19% and 20 months) because of a better local control rate (63% versus 39%; P < 0.01). Better results were obtained for mutilant surgery in terms of local control and overall survival, regardless of response to neoadjuvant chemotherapy.

Effect of cobalt supplementation on serum vitamin B12 levels, weight gain and survival rate in lambs grazing cobalt-deficient pastures.

The effect of cobalt supplementation on serum vitamin B12, growth rate and survival rate was measured in controlled field experiments with Texel twin lambs of the same sex, grazing cobalt-deficient pastures. The non-supplemented lambs had lower serum vitamin B12 concentrations than their supplemented brothers or sisters. During the experiments more lambs died in the non-supplemented than in the supplemented group. At the end of the experiments supplemented lambs weighed (mean live weight) 7.2, 9.5, and 11.0 kg more than non-supplemented lambs in 1991, 1992, and 1993, respectively. Sex-related differences in weight gain and survival rate were observed.

Increased tolerance to annual ryegrass toxicity in sheep given a supplement of cobalt.

To determine whether oral cobalt supplements could modify the clinical onset of annual ryegrass toxicity, groups (n = 5) of sheep were dosed orally with 0, 4 or 16 mg cobalt/day. After 3 weeks on this treatment, toxic ryegrass seed was added to their feed to provide 0, 0.15 and 0.30 mg corynetoxins/kg body weight, daily. Sheep receiving cobalt ingested 30% more toxin than did unsupplemented sheep before clinical signs developed (P = 0.03). There was no significant difference between groups receiving 4 and 16 mg cobalt. The results showed that cobalt delayed, but did not prevent, the onset of clinical signs of annual ryegrass toxicity.

Beneficial vascular and metabolic effects of cobalt-ATP in spontaneously hypertensive rabbits with diffuse chronic cerebral ischaemia.

The in vivo effects of adenosine triphosphate (ATP) have not been investigated in cerebrovascular diseases. The use of the long-acting cobalt-ATP complex (Co-ATP) permits us to observe the effects of ATP without the influence of its metabolites. This study was designed to compare the effects of intravenous Co-ATP on the cerebral blood flow (CBF), polarographically detected oxygen currents (O2a), mean arterial blood pressure (MABP), heart rate, respiration rate, cerebral electrical activity, arterial blood gases, pH, and glucose in 13 normotensive (NT) rabbits to those in 14 stroke-prone spontaneously hypertensive (HT) animals. CBF was measured by the hydrogen and heat clearance methods. In response to Co-ATP, MABP decreased and CBF increased significantly in both groups. The decrease in MABP was more marked in HT rabbits, while CBF response was 25% smaller than in NT animals. The ratio of O2a to CBF diminished moderately and simultaneously with the CBF increase in NT rabbits. In HT rabbits, the decrease in O2a/CBF was larger and began when CBF response reached its maximum. We suggest that despite the restricted CBF response, long-acting ATP should still be taken into consideration as a supplementary treatment of hypertensive encephalopathy because of its beneficial effects on cerebral metabolism and hypertension.

[The use of a complex cobalt compound as a cyanide antidote]. / Primenenie kompleksnogo soedineniia kobal'ta v kachestve protivotsianidnogo antidota.

The medical effect of the cobalt (III) complex compound [Co(DH)2(H2O)2]Cl poisoning by potassium cyanide has been experimentally found. The poisoning has been caused by intravenous potassium cyanide, 1 mg/kg. The aqueous solution of the complex was added the same to cyanide in doses of 40 and 80 mg/kg. The poison and antidote effects were controlled by bioelectrical tests of the brain and heart. The advantage of the preparation is its direct interaction with cyanide and significantly lower doses as compared with the well-known anticyanide antidotes.

Heliotropium europaeum poisoning of sheep with low liver copper concentrations and the preventive efficacy of cobalt and antimethanogen.

In a field experiment in the Mallee district of Victoria, Merlno xBorder Leicester ewes and wethers grazed Heliotropium europaeum (heliotrope) over periods of 3 to 4 months in 4 successive years. By the end of the second year 12% (14 of 120) of the sheep had died; after 4 years the loss attributable to heliotrope was between 18% and 35%. Mortality was not affected by intraruminal treatment with cobalt or antimethanogen. At the end of the experiment the highest concentration of copper in the liver was 1.95 mmol/kg wet weight (approximately 413 micrograms/g dry weight). The relatively low mortality from primary heliotrope poisoning and the low concentration of copper in the liver of sheep grazing the plant are discussed in relation to the contrasting situation that prevails in the Riverina area of New South Wales. The importance of local environmental factors in the management of heliotrope grazing by sheep is emphasised, particularly in relation to the number of seasons in which the plant may be a major component of the diet.

Genotoxic effects of radiotherapy and chemotherapy on the circulating lymphocytes of breast cancer patients. I. Chromosome aberrations induced in vivo.

Unstable chromosome aberrations were scored in peripheral blood lymphocytes (PBL) serially collected from 21 breast cancer patients before and after radiotherapy (RT), chemotherapy (CT) and combined treatments. Local radiotherapy as treatment for mammary cancer induced unstable chromosome aberrations in peripheral blood lymphocytes. Only a fraction of these lymphocytes were exposed to irradiation during treatment and the chromosomal damage observed in PBL was equivalent to that induced by irradiation in vitro with 2 Gy at high dose rate, i.e., about 4% of the total dose delivered locally. Chemotherapy alone did not induce such anomalies. Apart from the observed interindividual variations in either the level or the fate of dicentrics with time, different features of chromosome damage were found when chemotherapy was given before or after local cobaltotherapy: secondary chemotherapy did not alter the frequency and the overdispersed distribution of dicentrics observed after first-line radiotherapy; in contrast, when CT was given before radiotherapy, a lower dicentric frequency was scored, the distribution of dicentrics was not always found to be overdispersed and there was a time-dependent decrease in dicentrics after in vivo exposure.