Enhanced Urinary Bladder, Liver and Colon Carcinogenesis in Zucker Diabetic Fatty Rats in a Multiorgan Carcinogenesis Bioassay: Evidence for Mechanisms Involving Activation of PI3K Signaling and Impairment of p53 on Urinary Bladder Carcinogenesis

In the present study, modifying effects of diabetes on carcinogenesis induced in type 2 diabetes mellitus model Zucker diabetic fatty (ZDF) rats were investigated using a multiorgan carcinogenesis bioassay. Our re sults demonstrated enhancement of urinary bladder, colon and liver carcinogenesis in ZDF rats treated with five types of carcinogens (DMBDD). Elevated insulin and leptin and decreased adiponectin levels in the serum may be responsible for the high susceptibility of type 2 diabetes mellitus model rats to carcinogenesis in these organs. Possible mechanisms of increased susceptibility of diabetic rats to bladder carcinogenesis could be activation of the PI3K pathway and suppression of p53 in the urothelium in consequence of the above serum protein alterations

Clinical Outcomes for Total Hip Arthroplasty with and without Previous Curved Periacetabular Osteotomy

There are currently no reports on the clinical outcomes after total hip arthroplasty (THA) with previous curved periacetabular osteotomy (CPO), although the outcomes after THA with non-CPO types of periacetabular osteotomy have been reported. This study aimed to clarify the differences in clinical outcomes and radiographic features after THA with or without previous CPO. We performed a retrospective case–control with individual matching study. The participants were 10 patients with 11 hips that underwent cementless THA between October 1998 and October 2018 with previous CPO (osteotomy group). For the control group, we matched age, sex, and follow-up period, and included 32 patients with 33 hips that underwent cementless THA without previous CPO at a 1:3 ratio. The Harris Hip Score (HHS), cup size, position, and alignment, global offset (GO), operative time, perioperative blood loss, frequency of osteophyte removal, and major complications were compared between the two groups. The osteotomy group had no cases with revision surgery and dislocation. No significant differences were found between the two groups as follows: mean HHS, 94.9 points in the osteotomy group versus 92.7 points in the control group at the final follow-up; mean GO, 70.1 mm in the osteotomy group versus 71.4 mm in the control group; cup size, position, and alignment after THA; operative time; and perioperative blood loss. The frequency of osteophyte removal was higher in the osteotomy group. The take-home messages were that the clinical outcomes, including HHS, and radiographic features, including GO, after THA were equivalent in the two groups

A case of total hip arthroplasty for nonunion after femoral trochanteric fracture surgery with complete breakage of only the compression screw of the InterTAN nail

Intramedullary nails are an effective treatment for common femoral trochanteric fractures. However, one of their complications is implant breakage due to poor reduction and nonunion after surgery. We herein report a case of a 54-year-old man who underwent total hip arthroplasty for nonunion after internal fixation of a femoral trochanteric fracture. The femoral trochanteric fracture was treated by internal fixation using the Trigen InterTAN nail. The patient developed symptoms of hip pain 6 months after internal fixation. Nine months after internal fixation, hip radiographs and computed tomography scans showed breakage of only the compression screw. During total hip arthroplasty, we were unable to remove the lag screw and compression screw before the femoral head dislocation because no gap was present between the two screws. Thus, we removed these screws with the femoral head after dislocation of the femoral head. The removed nail was partially damaged at the lag screw hole. This change was retrospectively observed on the preoperative computed tomography scan. Three months after total hip arthroplasty, the patient was able to walk unaided and the hip pain had resolved. If only the compression screw is completely broken after internal fixation with the Trigen InterTAN nail, both the lag screw and compression screw will be difficult to remove with preservation of the femoral head. We effectively managed such a case by not only revision internal fixation but also total hip arthroplasty

Screening of Protein–Protein Interaction Modulators via Sulfo-Click Kinetic Target-Guided Synthesis

Kinetic target-guided synthesis (TGS) and in situ click chemistry are among unconventional discovery strategies having the potential to streamline the development of protein–protein interaction modulators (PPIMs). In kinetic TGS and in situ click chemistry, the target is directly involved in the assembly of its own potent, bidentate ligand from a pool of reactive fragments. Herein, we report the use and validation of kinetic TGS based on the sulfo-click reaction between thio acids and sulfonyl azides as a screening and synthesis platform for the identification of high-quality PPIMs. Starting from a randomly designed library consisting of 9 thio acids and 9 sulfonyl azides leading to 81 potential acylsulfonamides, the target protein, Bcl-XL, selectively assembled four PPIMs, acylsulfonamides SZ4TA2, SZ7TA2, SZ9TA1, and SZ9TA5, which have been shown to modulate Bcl-XL/BH3 interactions. To further investigate the Bcl-XL templation effect, control experiments were carried out using two mutants of Bcl-XL. In one mutant, phenylalanine Phe131 and aspartic acid Asp133, which are critical for the BH3 domain binding, were substituted by alanines, while arginine Arg139, a residue identified to play a crucial role in the binding of ABT-737, a BH3 mimetic, was replaced by an alanine in the other mutant. Incubation of these mutants with the reactive fragments and subsequent LC/MS-SIM analysis confirmed that these building block combinations yield the corresponding acylsulfonamides at the BH3 binding site, the actual “hot spot” of Bcl-XL. These results validate kinetic TGS using the sulfo-click reaction as a valuable tool for the straightforward identification of high-quality PPIMs

Rational design of proteolytically stable, cell-permeable peptide-based selective Mcl-1 inhibitors

Direct chemical modifications provide a simple and effective means to "translate" bioactive helical peptides into potential therapeutics targeting intracellular protein-protein interactions. We previously showed that distance-matching bisaryl cross-linkers can reinforce peptide helices containing two cysteines at the i and i+7 positions and confer cell permeability to the cross-linked peptides. Here we report the first crystal structure of a biphenyl-cross-linked Noxa peptide in complex with its target Mcl-1 at 2.0 a resolution. Guided by this structure, we remodeled the surface of this cross-linked peptide through side-chain substitution and N-methylation and obtained a pair of cross-linked peptides with substantially increased helicity, cell permeability, proteolytic stability, and cell-killing activity in Mcl-1-overexpressing U937 cells