Cannabis sativa Extract Induces Apoptosis in Human Pancreatic 3D Cancer Models: Importance of Major Antioxidant Molecules Present Therein

In recent years, interest in Cannabis sativa L. has been rising, as legislation is moving in the right direction. This plant has been known and used for thousands of years for its many active ingredients that lead to various therapeutic effects (pain management, anti-inflammatory, antioxidant, etc.). In this report, our objective was to optimize a method for the extraction of cannabinoids from a clone of Cannabis sativa L. #138 resulting from an agronomic test (LaFleur, Angers, FR). Thus, we wished to identify compounds with anticancer activity on human pancreatic tumor cell lines. Three static maceration procedures, with different extraction parameters, were compared based on their median inhibitory concentration (IC₅₀) values and cannabinoid extraction yield. As CBD emerged as the molecule responsible for inducing apoptosis in the human pancreatic cancer cell line, a CBD-rich cannabis strain remains attractive for therapeutic applications. Additionally, while gemcitabine, a gold standard drug in the treatment of pancreatic cancer, only triggers cell cycle arrest in G0/G1, CBD also activates the cell signaling cascade to lead to programmed cell death. Our results emphasize the potential of natural products issued from medicinal hemp for pancreatic cancer therapy, as they lead to an accumulation of intracellular superoxide ions, affect the mitochondrial membrane potential, induce G1 cell cycle arrest, and ultimately drive the pancreatic cancer cell to lethal apoptosis.     

Dynamic contrast-enhanced MRI of Implanted VX2 tumors in rabbit muscle: comparison of Gd-DTPA and NMS60

We studied the dynamics of injected contrast enhancement in implanted VX2 tumors in rabbit thigh muscle. We compared two contrast agents Gd-DTPA and NMS60, a novel gadolinium containing trimer of molecular weight 2.1 kd. T1-weighted spin echo images were acquired preinjection and at 5-60 min after i.v. injection of 0.1 mmol/kg of agent. Dynamic T1-weighted SPGR images (1.9 s/image) were acquired during the bolus injection. Male NZW rabbits (n = 13) were implanted with approximately 2 x 10(6) VX2 tumor cells and grew tumors of 28+/-27 mL over 12 to 21 days. NMS60 showed significantly greater peak enhancement in muscle, tumor rim, and core compared to DTPA in both T1-weighted and SPGR images. NMS60 also showed delayed peak enhancement in the dynamic scans (compared to Gd-DTPA) and significantly reduced leakage rate constant into the extravascular space for tumor rim (K21 = 5.1 min(-1) vs. 11.5 min(-1) based on a 2 compartment kinetic model). The intermediate weight contrast agent NMS60 offers greater tumor enhancement than Gd-DTPA and may offer improved regional differentiation on the basis of vascular permeability in tumors.     

Synthesis of O-Alkylbenzohydroximoyl Iodides and a Comparison of their Structures to other Oxime Derivatives

Abstract  The first general synthesis of (Z)-O-alkylbenzohydroximidoyl iodides [ArC(I)=NOR] is reported. X-ray crystallographic structures of two of these compounds confirm that they are in the Z-configuration: p-NO₂ArC(I)=NOCH₃ crystallizes in space group Pnma with lattice constants a = 12.682(2) ?, b = 6.5217(15) ?, and c = 11.755(2) ?, and p-ClArC(I)=NOCH₃ crystallizes in space group P2₁/n with lattice constants a = 15.670(4) ?, b = 5.742(4) ?, and c = 27.156(7) ? and beta angle 102.71(2). Their structures are compared to other O-alkylbenzohydroximoyl halides including p-NO₂ArC(F)=NOCH₃ which crystallizes in space group P2₁/c with lattice constants a = 3.8475(10) ?, b = 22.501(5) ?, and c = 10.088(2) ? and beta angle 91.130(11). The synthesis of two additional compounds containing the N-alkoxyimine moiety {methyl (Z)-O-methyl-4-nitrobenzothiohydroximate [p-NO₂ArC(SCH₃)=NOCH₃] which crystallizes in space group P2₁/n with lattice constants a = 11.8046(15) ?, b = 7.0774(10) ?, and c = 12.2741(15) ? and beta angle 100.401(9) and (Z)-O-methyl-4-nitrobenzohydroximoyl azide [p-NO₂ArC(N₃)=NOCH₃] which crystallizes in space group P2₁/c with lattice constants a = 11.753(2) ?, b = 11.310(3) ?, and c = 7.351(2) ? and beta angle 103.805(15) are also reported. Their structures are compared to (Z)-ethyl benzohydroximate [PhC(OEt)=NOH] and (Z)-O-methyl-4-nitrobenzohydroximoyl cyanide [p-NO₂ArC(CN)=NOCH₃] respectively. Characterizations include spectrometric identifications employing IR, ¹H-NMR, ¹³C-NMR and mass spectrometry. Index Abstract  X-ray structures of several N-alkoxyimines, including the newly synthesized N-alkoxyimidoyl iodides and azide, have been performed, and these structures unambiguously show the geometric configuration (E vs. Z) of these compounds.

Synthesis of pyrimidinones by action of benzamidine on a benzocycloheptenic β‐keto ester

The synthesis of a polycyclic heterocyclic ring system compound, ethyl 7‐hydroxy‐4‐oxo‐2‐phenyl‐4,5‐dihydro‐3H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidine‐6‐carboxylate was carried out by condensation of benzamidine on diethyl 5,9‐dihydroxy‐7H‐benzo[a]cycloheptene‐6,8‐dicarboxylate, after opening and then closure of the seven membered ring.     

Röntgenstrukturanalyse großer Biomoleküle

Crystallography is a powerful tool for the determination of three-dimensional structures of large biomolecules. In recent years, the number of published crystal structures has dramatically increased. this is due in part to the knowledge on the three-dimensional structure to the general understanding of biochemical processes is demonstrated for three selected examples. Crystal structures of human growth hormone bound to receptor peptides strongly suggests a general principle of receptor-mediated signal transduction. A self-splicing RNA nitron, seen in three dimensions, reveals general folding patterns in nucleic acids. Finally, HIV protease is discussed as a paradigm for structure-based drug design.     

Uniform law of the logarithm for the local linear estimator of the conditional distribution function

In this Note, we first recall the results of the behaviour of the nonparametric estimator of the conditional distribution function which we can find in the literature. We establish exact rate of strong uniform consistency for the local linear estimator of the conditional distribution function. Our methods of proofs are based upon modern empirical process theory in the spirit of the results of Einmahl and Mason (2000) [5] and Deheuvels and Mason (2004) [3].