De Novo Direct Inverse QSPR/QSAR: Chemical Variational Autoencoder and Gaussian Mixture Regression Models.

Herein, we propose a de novo direct inverse quantitative structure-property relationship/quantitative structure-activity relationship (QSPR/QSAR) analysis method, based on the chemical variational autoencoder (VAE) and Gaussian mixture regression (GMR) models, to generate molecules with the desired target variables of interest for properties and activities (y). A data set of molecules was analyzed, and an encoder was used to transform the simplified molecular input line entry system (SMILES) strings to latent variables (x), while a decoder was used to transform x to SMILES strings. A chemical VAE model was used for analysis and a GMR model (between x and y) was constructed for direct inverse analysis. The target y values were input into the GMR model to directly predict the x values. Following this, the predicted x values were input into the decoder associated with the chemical VAE model and the SMILES string representations (or chemical structures of molecules) were obtained as the output, indicating that the proposed method could be used to selectively obtain the molecules that were characterized by the target y values. We confirmed that the proposed method can be used to generate molecules within the target y ranges even when the conventional chemical VAE model failed to generate the target molecules.

Successful salvage treatment with paclitaxel, ifosfamide, and cisplatin in a patient with methotrexate-resistant gestational trophoblastic neoplasia who developed hypersensitivity reaction to etoposide.

We report a 34-year-old woman with recurrent gestational trophoblastic neoplasia (GTN) who showed hypersensitivity to etoposide. Computed tomography (CT) revealed a 32-mm solid mass in the right lung and a 101-mm cystic mass with solid components in the left side of the liver. The patient's serum human chorionic gonadotropin (HCG) level was 689 439 mIU/mL. After eight cycles of combined paclitaxel 175 mg/m2 on day 1, ifosfamide 1 g/m2 on days 2-5, and cisplatin 20 mg/m2 on days 2-5 (TIP) every 3 weeks, the serum HCG level decreased to 2.4 mIU/mL. CT scan revealed disappearance of the lung tumor and significant reduction in the solid components of the liver tumor. Then, left hemihepatectomy was performed. After 3 months, there was no evidence of the disease, and the serum HCG level normalized. Thus, TIP chemotherapy, followed by residual mass resection, might be effective for methotrexate-resistant GTN.

Presynaptic inhibitory actions of pregabalin on excitatory transmission in superficial dorsal horn of mouse spinal cord: further characterization of presynaptic mechanisms.

Pregabalin is widely used as an analgesic for the treatment of neuropathic pain. In the present experiments using mouse spinal slices, we recorded electrically evoked glutamatergic excitatory postsynaptic currents (eEPSCs) from superficial dorsal horn neurons. Pregabalin reduced the amplitude of eEPSCs, and increased the paired pulse ratio. Pregabalin also inhibited the frequency of spontaneously occurring miniature EPSCs without affecting their amplitude. Partial ligation of the sciatic nerve increased the expression of the calcium channel α2δ-1 subunit, and increased the presynaptic inhibitory action of pregabalin. Intrathecal injection of antisense oligodeoxynucleotide against the α2δ-1 subunit, decreased the expression of α2δ-1 mRNA in the spinal dorsal horn, and decreased pregabalin's action. These results provide further evidence that pregabalin exerts its presynaptic inhibitory action via binding with the α2δ subunit in a state-dependent manner. Furthermore, presynaptic actions of pregabalin were attenuated in knockout mice lacking the protein syntaxin 1A, a component of the synaptic vesicle release machinery, indicating that syntaxin 1A is required for pregabalin to exert its full presynaptic inhibitory action. These observations might suggest that direct and/or indirect interactions with the presynaptic proteins composing the release machinery underlie at least some part of pregabalin's presynaptic actions.