Diagnosing malignant distal bile duct obstruction using artificial intelligence based on clinical biomarkers.

Diagnosing distal bile duct obstruction remains challenging. This study aimed to examine the diagnostic ability of artificial intelligence (AI) based on clinical biomarkers in diagnosing malignant distal bile duct obstruction. A total of 206 patients with distal bile duct obstruction were included in this study. Clinical laboratory parameters were collected from the patients and evaluated using AI. All clinical parameters were input into the AI algorithm, and the AI value for malignant distal bile duct obstruction was calculated. The benign and malignant diagnostic capabilities of AI and other factors (alkaline phosphatase [ALP], intrahepatic bile duct [IHBD] diameters, and total bile duct [CBD] diameters) were compared. Benign and malignant bile duct obstruction were diagnosed in 142 and 64 patients, respectively. The median AI value of malignant distal bile duct obstruction was significantly greater than that of benign distal bile duct obstruction (0.991 vs. 0.002, p < 0.001). The area under the receiver operating characteristic curve of AI, ALP, IHBD diameter, and CBD diameter were 0.908, 0.795, 0.794, and 0.775, respectively. AI showed a sensitivity, specificity, and accuracy of 83.1%, 87.2%, and 85.9%. AI-based on clinical biomarkers could serve as an auxiliary for diagnosing malignant bile duct obstruction.

Computed diffusion-weighted magnetic resonance imaging with high b-values in the diagnosis of gallbladder lesions.

PURPOSE: The diagnosis of gallbladder lesions remains challenging. The efficacy of computed diffusion-weighted imaging (DWI) with high b-values and apparent diffusion coefficient (ADC) for the diagnosis of gallbladder cancer remains unknown. We aimed to investigate the usefulness of computed DWI with high b-values and the combination of computed DWI and ADC in differentiating malignant and benign gallbladder lesions. METHODS: Sixty patients (comprising 30 malignant and 30 benign lesions) who underwent magnetic resonance imaging for gallbladder lesions were included in this retrospective study. Qualitative evaluations were performed using conventional DWI with b1000, computed DWI with b1500, b1000 DWI/ADC, and computed b1500 DWI/ADC, and their diagnostic performances were compared. RESULTS: The sensitivity, specificity, and accuracy of computed b1500 DWI/ADC were 90% (27/30), 80% (24/30), and 85% (51/60), respectively. The accuracy of computed b1500 DWI/ADC was higher than that of conventional b1000 DWI (52%, 31/60, p < 0.001), computed b1500 DWI (72%, 43/60, p = 0.008), and b1000 DWI/ADC (78%, 47/60, p = 0.125). The specificity of computed b1500 DWI/ADC was also higher than that of conventional b1000 DWI (7%, 2/30, p < 0.001), computed b1500 DWI (47%, 14/30, p = 0.002), and b1000 DWI/ADC (67%, 20/30, p = 0.125). No significant difference was observed in the sensitivity between the groups. CONCLUSION: This study shows that computed DWI with high b-values combined with ADC can improve diagnostic performance when differentiating malignant and benign gallbladder lesions. Computed diffusion-weighted magnetic resonance imaging with high b-values in the diagnosis of gallbladder lesions. *Computed DWI with b1500 combined with ADC can improve diagnostic performance when differentiating gallbladder lesions compared with conventional methods (b1000 DWI).

Prognostic Impact of Sarcopenia in Patients With Biliary Tract Cancer Undergoing Chemotherapy.

AIM: Sarcopenia affects the treatment of various cancer types but its impact on chemotherapy efficacy and prognosis in biliary tract cancer remains unclear. Thus, we evaluated whether sarcopenia independently affects the outcome of chemotherapy for biliary tract cancer. PATIENTS AND METHODS: Data of 50 patients who underwent chemotherapy for biliary tract cancer at two affiliated centres were retrospectively analysed. The association of clinical factors, including sarcopenia, with overall survival and time to treatment failure was analysed. RESULTS: Sarcopenia was an independent factor negatively influencing overall survival and time to treatment failure in univariate and multivariate analyses (median overall survival, sarcopenic vs. non-sarcopenic patients: 10.6 vs. 16.6 months; hazard ratio=2.19, p=0.018; time to treatment failure: 5.3 vs. 13.1 months, hazard ratio=2.50, p=0.019). CONCLUSION: Sarcopenia may affect the efficacy of chemotherapy and prognosis in biliary tract cancer. Thus, improving sarcopenia may improve the prognosis of patients with biliary tract cancer undergoing chemotherapy.

Design, synthesis, and biological evaluations of novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-8-methoxyquinolines with potent antibacterial activity against respiratory pathogens.

Novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2a and 2b were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound 2a possessing (S)-configuration for the asymmetrical carbon on the pyrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens including gram-positive (Streptococcus pneumoniae and Staphylococcus aureus), gram-negative (Haemophilus influenzae and Moraxcella catarrhalis), and atypical strains (Chalmydia pneumoniae and Mycoplasma pneumoniae), as well as multidrug-resistant Streptococcus pneumoniae and quinolone-resistant and methicillin-resistant Staphylococcus aureus). Furthermore, compound 2a showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant Streptococcus pneumoniae (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies.

First automatic radiosynthesis of 11C labeled Telmisartan using a multipurpose synthesizer for clinical research use.

OBJECTIVE: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [(11)C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic OATP1B3. We developed a first automatic preparation system of [(11)C]Telmisartan to applicable clinical research using a new (11)C and (18)F multipurpose synthesizer. METHODS: Two milligrams of precursor (1) in 5 µl of 1 M KOH in 0.5 ml of dimethyl sulfoxide was reacted with [(11)C]CH(3)I for 5 min at 120°C. The resultant solution was hydrolyzed with 1 M NaOH at 100°C for 3 min. The neutralization was carried out with acetic acid, followed by purification with high-performance liquid chromatography. The desired radioactive fraction was collected and solvent was replaced by 10 ml saline containing 0.3 ml of EtOH and 0.5 ml of PEG400, and then passed through a sterile 0.22 µm filter (Millex-GV, Millipore) to a pyrogen-free vial as the final product. RESULTS: The yield of [(11)C]Telmisartan for clinical research use was 16.8 ± 2.9% EOB as decay corrected (n = 8, mean ± SD) in 32-36 min. The radiochemical purity of [(11)C]Telmisartan was >97%, and specific activity was higher than 86.3 MBq/nmol. CONCLUSIONS: We succeeded in the first synthesis of [(11)C]Telmisartan for clinical research use by appropriate quality tests.

Synthesis and biological evaluation of imidazole derivatives as novel NOP/ORL1 receptor antagonists: exploration and optimization of alternative pyrazole structure.

Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett.2009, 19, 3627; Kobayashi et al., Bioorg. Med. Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group demonstrated that examining the structure-activity relationship for novel templates allowed the identification of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole. These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or reduced hERG affinity.

A novel class of cycloalkano[b]pyridines as potent and orally active opioid receptor-like 1 antagonists with minimal binding affinity to the hERG K+ channel.

A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.

4-(Pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4 antagonist.

A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.

Design, synthesis, and biological evaluation of indole derivatives as novel nociceptin/orphanin FQ (N/OFQ) receptor antagonists.

A novel series of 2-(1,2,4-oxadiazol-5-yl)-1H-indole derivatives as nociceptin/orphanin FQ (N/OFQ) receptor antagonists was discovered. Systematic modification of our original lead by changing the pendant functional groups, linker, heterocyclic core, and basic side chain revealed the structure-activity requirements for this novel template and resulted in the identification of more potent analog with improved potency as compared to the parent compound.

IPC synthase as a useful target for antifungal drugs.

Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.

Synthesis of a key intermediate of novel galbonolide analogues via efficient construction of a conjugated diene system.

The development of an efficient synthetic method enabled multi-gram synthesis of a key intermediate, which is useful for the modification at the C6-functional group of galbonolide analogues. The structure of a key intermediate including a conjugated diene was afforded by Horner-Emmons reaction, alkylation of Weinreb amide with alkyl lithium and a subsequent Wittig reaction.

Synthesis and antifungal activity of novel 14-membered benzomacrolides, as galbonolide analogues.

Asymmetric total synthesis of benzene analogues of galbonolide, a 14-membered antifungal macrolide, possessing a benzene ring instead of a conjugated diene structure, was achieved starting from chiral 1-aryl-1-propanol obtained by enzyme-catalyzed kinetic resolution with high enantioselectivity. Representatively, a method for the introduction of a methylthio and chloride function at the vinyl position was also established. The resulting analogues unfortunately exhibited very little antifungal potency in comparison with galbonolide A.

Novel galbonolide derivatives as IPC synthase inhibitors: design, synthesis and in vitro antifungal activities.

A series of novel galbonolide derivatives having a modified methyl enol ether moiety were prepared in total synthetic procedures and evaluated for their in vitro antifungal activities. The antifungal activity was labile to modification of the enol ether functionality and almost all of the modified compounds lacked the activity except for the analogue with an introduction of a methylthio group at the C-6 position, which retained a modest antifungal potency against Cryptococcus neoformans.

Structure--activity relationships of 1beta-methyl-2-(5-phenylpyrrolidin-3-ylthio)carbapenems.

Structure--activity relationship studies of 1beta-methyl-2-[(3S,5R)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio]carbapenems, especially those pertaining to the relationship between antibacterial activity and side-chain structure were conducted. These studies suggested that the trans-(3S,5R)-5-phenylpyrrolidin-3-ylthio side-chain and the aminomethyl group at the 4-position of the phenyl ring play a key role in enhancing the antibacterial activity against the MRSA and Pseudomonas aeruginosa strains. In particular, the basicity of a substituent at the 4-position of the phenyl ring were shown to greatly contribute to the antibacterial activity against MRSA and methicillin-resistant Staphyloccocus epidermidis strains. In contrast, the amidine group was shown to lead to potent antibacterial activity against P. aeruginosa strains comparable to that of imipenem, however, a good correlation between the basicity of the 4-substituent and antipseudomonal activity was not observed. In conclusion, the 4-aminomethyl or methylaminomethyl group on the phenyl ring was the best substituent for antipseudomonal activity.