Synthesis and study of C-substituted methylthio derivatives of cobalt bis(dicarbollide)

The C-methylthio derivatives of cobalt bis(dicarbollide) were synthesized by reaction of anhydrous CoCl₂ with nido-carborane [7-MeS-7,8-C₂B₉H₁₁]⁻ and isolated as a mixture of rac-[1,1′-(MeS)₂-3,3′-Co(1,2-C₂B₉H₁₀)₂]⁻ and meso-[1,2′-(MeS)₂-3,3′-Co(1,2-C₂B₉H₁₀)₂]⁻ isomers. The structures of both isomers were studied using DFT quantum chemical calculations. The most preferable geometry of rotamers and the stabilization energy of C-methylthio derivatives of cobalt bis(dicarbolide) were calculated. The (BEDT-TTF)[1,1′-(MeS)₂-3,3′-Co(1,2-C₂B₉H₁₀)₂] salt was prepared and its structure was determined by single crystal X-ray diffraction. The cisoid conformation of the rac-[1,1′-(MeS)₂-3,3′-Co(1,2-C₂B₉H₁₀)₂]⁻ anion is stabilized by short intramolecular CH⋯S hydrogen and BH⋯S chalcogen bonds between the dicarbollide ligands, that is in good agreement with the data of quantum chemical calculations.

The C-methylthio derivatives of cobalt bis(dicarbollide) rac-[1,1′-(MeS)₂-3,3′-Co(1,2-C₂B₉H₁₀)₂]⁻ and meso-[1,2′-(MeS)₂-3,3′-Co(1,2-C₂B₉H₁₀)₂]⁻ were synthesized and studied by DFT calculations and X-ray diffraction.     

Phase 2 Trial of Gemcitabine,Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes

Background

Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored.

Current immunotherapeutic strategies in colon cancer

Because chemotherapy is standard in the treatment of colorectal cancer, it is important to demonstrate whether immunizations may be given to patients receiving systemic chemotherapy. Although some studies have demonstrated immune responses in patients with metastatic colorectal carcinoma who failed standard chemotherapy, the setting of minimal residual disease may be the preferred setting for cancer vaccines. It may be important to choose antigens that have functions important to the cancer cell. The best adjuvant is not well established and may depend on the type of immune response desired. The immune system is "programmed" to down-regulate immune responses once they have become activated to avoid the development of autoimmune disease.     

Cyclooxygenase 1 is required for pH control at the mouse gastric surface

BACKGROUND: Endogenous cyclooxygenase (COX) activity is required to maintain a relatively alkaline surface pH at the gastric luminal surface. AIMS: The purpose of this study was to determine which COX isoform, COX-1 or COX-2, is responsible for regulating the protective surface pH gradient and to test if COX inhibitors also had non-COX mediated effects in vivo. METHODS: Immunofluorescence and western blot analysis showed constitutive expression of both COX isoforms in the normal mouse stomach. We used in vivo confocal microscopy to measure pH near the mucosal surface of anaesthetised COX-1 (-/-), COX-2 (-/-), or wild-type mice of the same genetic background. RESULTS: When the gastric mucosal surface was exposed and superfused (0.2 ml/min) with a weakly buffered saline solution (pH 3) containing the pH indicator Cl-NERF, the pH directly at the gastric surface and thickness of the pH gradient were similar in wild-type and COX-2 (-/-) mice, but COX-1 (-/-) mice had a significantly thinner pH gradient. Addition of indomethacin had minimal effects on the residual surface pH gradient in COX-1 (-/-) mice, suggesting no role for COX-2 in surface pH regulation. Whole stomach perfusion studies demonstrated diminished net alkali secretion in COX-1 (-/-) mice, and application of SC-560 or rofecoxib to wild-type mice and mutant mice confirmed that only COX-1 inhibition reduced alkali secretion. CONCLUSION: COX-1 is the dominant isoform regulating the normal thickness of the protective surface pH gradient in mouse stomach.     

A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors

Purpose

Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination.

Methods

Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8?mg/kg and bevacizumab at 10?mg/kg every 2?weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity.

Results

Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5?mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5?mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91?%), mucositis/stomatitis (75?%), hypomagnesemia (72?%), hypocalcemia (56?%) and hypokalemia (50?%). There were 3 partial responses; an additional 10 subjects had stable disease ??6?months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40?months.

Conclusions

The recommended phase II dose is everolimus at 5?mg three times weekly plus panitumumab at 4.8?mg/kg and bevacizumab at 10?mg/kg every 2?weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.     

Heterogeneous hemoglobin system of anemic rats

The fractional composition of hemoglobin from the peripheral blood, spleen, and bone marrow of intact and anemic rats was studied by electrophoresis in polyacrylamide gel. Anemia was produced by injecting phenylhydrazine hydrochloride into the animals. The basic principles of formation of the heterogenous hemoglobin system, depending on the source from which it was obtained and on the state of the animals, were established. The possible causes of the observed reorganization of the fractional composition of hemoglobin and its biological significance are discussed.Institute of Molecular Biology and Genetics, Academy of Sciences of the Ukrainian SSR, Kiev. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Zhukov-Verezhnikov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 11, pp. 1328–1330, November, 1976.