Alchemical absolute protein-ligand binding free energies for drug design.

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based absolute binding free energy estimates for 128 pharmaceutically relevant targets. We use a novel rigorous method to generate protein-ligand ensembles for the ligand in its decoupled state. Not only do the calculations deliver accurate protein-ligand binding affinity estimates, but they also provide detailed physical insight into the structural determinants of binding. We identify subtle rotamer rearrangements between apo and holo states of a protein that are crucial for binding. When compared to relative binding free energy calculations, obtaining absolute binding free energies is considerably more challenging in large part due to the need to explicitly account for the protein in its apo state. In this work we present several approaches to obtain apo state ensembles for accurate absolute ΔG calculations, thus outlining protocols for prospective application of the methods for drug discovery.

Primary adenocarcinoma, signet-ring, and transitional cell carcinoma of the bladder with penile metastasis.

This article reports a rare case of primary signet-ring cell carcinoma of the bladder with transitional cell and adenocarcinoma variants and metachronous metastases to the penis and lungs. This combination of lesions has not previously been reported. Together, they portend widespread dissemination and an early demise as is frequently the case with signet-ring cell carcinomas arising in other organs such as the breast and gastrointestinal tract. The optimal therapeutic intervention for this myriad of neoplasms with metastasis to the penis has yet to be ascertained because of the rarity of the lesions. Early diagnosis and an aggressive surgical approach appear to offer the best chance for quality survival and possible cure.

Fine-needle aspiration biopsy: application to pediatric head and neck masses.

Fine-needle aspiration biopsy cytology is widely used to screen masses in adults. The authors present a series of 89 fine-needle aspiration biopsies performed between January 1973 and December 1988 on 86 pediatric patients with clinically significant head and neck masses. All fine-needle aspiration diagnoses were confirmed by subsequent surgical biopsy, autopsy, or clinical follow-up for a minimum of 18 months. Of 21 tumors identified, 19 were malignant. Of the 89 aspirations performed, 67 required no subsequent surgical biopsy. In 11 of these cases, metastatic or recurrent tumor was diagnosed and appropriate therapy instituted. Fifteen of the 89 aspirates revealed previously undiagnosed tumors requiring surgical intervention. One false-negative and two false-positive results were obtained. No radical treatment resulted from the false-positive diagnoses, and no patient delay in treatment occurred because of the false-negative result. The sensitivity was 94.4%, and the specificity was 97.1%. The usefulness and cost-effectiveness of fine-needle aspiration is stressed.

Lymphangioma. An otolaryngologic perspective.

Lymphangiomas are relatively rare congenital hamartomas of the lymphatic system usually diagnosed in infancy and early childhood. Although the precise pathogenesis has not been clearly defined, abnormal development leads to formation of fluid-filled sinuses lined by vascular endothelium. In the head and neck, lymphangioma may encroach on vital structures and infiltrate surrounding tissues making complete surgical removal difficult. A number of children (n = 137) with lymphangioma have been treated at Texas Children's Hospital from 1972-1985. In 45 (33%), the tumors were diagnosed at birth and in an additional 51 (37%), by two years of age. Commonly affected areas included the head and neck (45%), trunk (26%), and axilla (17%). Mediastinal involvement occurred in 4%. Surgical removal was the preferred treatment method and with complete removal the recurrence rate was 6%; known incomplete removal increased this rate to 35%. Although lymphangiomas are slow growing, early removal was preferable: recurrences increased as the time interval between tumor identification and surgical intervention lengthened. Size fluctuation with a history of infection, another unfavorable prognostic factor, also increased recurrence rate.