The development of drugs to restore protein function has been a major advance facilitated by molecular medicine. Allosteric regulation, a phenomenon widely observed in nature, in which a molecule binds to control a distance active site, holds great promise for regulating proteins, yet how to rationally design such a molecule remains a mystery. Over the past few years, we and others have developed several techniques based on molecular dynamics (MD) simulations: MD-Markov state models to capture global conformational substates, and network theory approach utilizing the interaction energy within the protein to confer local allosteric control. We focus on the key case study of the p53 Y220C mutation restoration by PK11000, a compound experimentally shown to reactivate p53 native function in Y220C mutant present tumors. We gain insights into the mutation and allosteric reactivation of the protein, which we anticipate will be applicable to de novo design to engineer new compounds not only for this mutation, but in other macromolecular systems as well.

OBJECTIVES: Circulating tumor cells (CTCs) in the blood have been used as diagnostic markers in patients with colorectal cancer (CRC). In this study, we evaluated a CTC detection system based on cell size to assess CTCs and their potential as early diagnostic and prognostic biomarkers for CRC. METHODS: From 2014 to 2015, 88 patients with newly diagnosed CRC, who were scheduled for surgery, and 31 healthy volunteers were enrolled and followed up in Pusan National University Hospital. CTCs were enriched using a centrifugal microfluidic system with a new fluid-assisted separation technique (FAST) and detected by cytomorphological evaluation using fluorescence microscopy. RESULTS: Two or more CTCs were detected using FAST in 74 patients and 3 healthy volunteers. The number of CTCs in the CRC group was significantly higher than that in the healthy volunteers ( P < 0.001). When a receiver operating characteristic curve was created to differentiate patients with CRC from healthy volunteers, the sensitivity and specificity were almost optimized when the critical CTC value was 5/7.5 mL of blood. When this value was used, the sensitivity and specificity in differentiating patients with CRC from the healthy controls were 75% and 100%, respectively. In patients with CRC with ≥5 CTCs, vascular invasion was frequently identified ( P = 0.035). All patients with stage IV were positive for CTCs. Patients with ≥5 CTCs showed a trend toward poor overall and progression-free survival. DISCUSSION: Our study demonstrated promising results with the use of FAST-based CTC detection for the early diagnosis and prognosis of CRC.

Background Gastrointestinal (GI) diseases are common in patients with human immunodeficiency virus (HIV) infection. There are few reports on the epidemiology and endoscopic findings of gastric cancer in patients with HIV infection in the era of combination antiretroviral therapy (cART). We retrospectively analyzed upper GI endoscopic findings in patients with HIV infection and investigated their role as gastric cancer screening. Materials and Methods We retrospectively investigated endoscopies conducted in Korean patients with HIV infection referred for endoscopy at a tertiary hospital between January 2004 and December 2018. Endoscopic and pathologic findings were analyzed according to the reason for endoscopy, patient age, and cART duration. All endoscopic findings were reevaluated by gastroenterologists. Results Three hundred ten endoscopies in 201 patients with HIV infection were investigated. Of these, 118 (38.1%) endoscopies in 81 (40.1%) patients were performed for cancer screening purposes. Gastric cancer was found in 4 patients (2.0%); one of them presented with gastric cancer at the time of HIV diagnosis, and the other 3 patients were diagnosed with early gastric cancer on screening endoscopy, which was cured with endoscopic submucosal dissection or surgery. The prevalence of gastric cancer in screening endoscopies was 3.7%. Atrophic gastritis was a more common finding in screening endoscopies than in diagnostic endoscopies ( P <0.001), and was significantly associated with longer durations of cART ( P <0.001). The overall prevalence of gastric cancer, atrophic gastritis, and intestinal metaplasia was 2.0, 57.8, and 25.4%, respectively. The prevalence of atrophic gastritis and intestinal metaplasia increased with age. Conclusion Regular gastric cancer screening might be useful for early diagnosis and treatment of gastric cancer in patients with HIV infection.

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