BACKGROUND: Recruitment and homing cells into graft materials from host tissue is crucial for bone regeneration. METHODS: Highly porous, multi-level structural, hydroxyapatite bone void filler (HA-BVF) have been investigated to restore critical size bone defects. The aim was to investigate a feasibility of bone regeneration of synthetic HA-BVF compared to commercial xenograft (Bio-Oss). HA-BVF of 0.7 mm in average diameter was prepared via template coating method. Groups of animals (n = 6) were divided into two with normal (Sham) or induced osteoporotic conditions (Ovx). Subsequently, subdivided into three treated with HA-BVF as an experiment or Bio-Oss as a positive control or no treatment as a negative control (defect). The new bone formation was analyzed by micro-CT and histology. RESULTS: At 4 weeks post-surgery, new bone formation was initiated from all groups. At 8 weeks post-surgery, new bone formation in the HA-BVF groups was greater than Bio-Oss groups. Extraordinarily greater bone regeneration within the Ovx-HA group than Sham-Bio-Oss or Ovx-Bio-Oss group (p<0.05). CONCLUSION: This study suggests that the immediate wicking property of HA-BVF from host tissue activates a natural healing cascade without the addition of exogeneous factors or progenitor cells. HA-BVF may be an effective alternative for repairing bone defects under both normal and osteoporotic bone conditions.
Animals ; Bone Regeneration* ; Capillary Action* ; Durapatite ; Heterografts ; Methods ; Models, Animal* ; Osteogenesis ; Osteoporosis ; Rats* ; Stem Cells ; Transplants*

PURPOSE: The selective elimination of cancer stem cells (CSCs) in tumor patients is a crucial goal because CSCs cause drug refractory relapse. To improve the current conventional bispecific immune-engager platform, a 16133 bispecific natural killer (NK) cell engager (BiKE), consisting of scFvs binding FcγRIII (CD16) on NK cells and CD133 on carcinoma cells, was first synthesized and a modified interleukin (IL)-15 crosslinker capable of stimulating NK effector cells was introduced. MATERIALS AND METHODS: DNA shuffling and ligation techniques were used to assemble and synthesize the 1615133 trispecific NK cell engager (TriKE). The construct was tested for its specificity using flow cytometry, cytotoxic determinations using chromium release assays, and lytic degranulation. IL-15–mediated expansion was measured using flow-based proliferation assays. The level of interferon (IFN)-γ release was measured because of its importance in the anti-cancer response. RESULTS: 1615133 TriKE induced NK cell–mediated cytotoxicity and NK expansion far greater than that achieved with BiKE devoid of IL-15. The drug binding and induction of cytotoxic degranulation was CD133+ specific and the anti-cancer activity was improved by integrating the IL-15 cross linker. The NK cell–related cytokine release measured by IFN-γ detection was higher than that of BiKE. NK cytokine release studies showed that although the IFN-γ levels were elevated, they did not approach the levels achieved with IL-12/IL-18, indicating that release was not at the supraphysiologic level. CONCLUSION: 1615133 TriKE enhances the NK cell anti-cancer activity and provides a self-sustaining mechanism via IL-15 signaling. By improving the NK cell performance, the new TriKE represents a highly active drug against drug refractory relapse mediated by CSCs.
Antibody-Dependent Cell Cytotoxicity ; Chromium ; DNA Shuffling ; Flow Cytometry ; Humans ; Interferons ; Interleukin-15 ; Interleukins ; Killer Cells, Natural ; Ligation ; Neoplastic Stem Cells ; Recurrence ; Sensitivity and Specificity

Purpose: Postoperative pancreatic fistula (POPF) remains a devastating complication of pancreatoduodenectomy (PD). Minimally invasive PD (MIPD), including laparoscopic (LPD) and robotic (RPD) approaches, have comparable POPF rates to open PD (OPD). However, we hypothesize that the likelihood of having a more severe POPF, as defined as clinically relevant POPF (CR-POPF), would be higher in an MIPD relative to OPD. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) targeted pancreatectomy dataset (2014–2020) was reviewed for any POPF after OPD. Propensity score matching (PSM) compared MIPD to OPD, and then RPD to LPD. Results: Among 3,083 patients who developed a POPF, 2,843 (92.2%) underwent OPD and 240 (7.8%) MIPD; of these, 25.0% were LPD (n = 60) and 75.0% RPD (n = 180). Grade B POPF was observed in 45.4% (n = 1,400), and grade C in 6.0% (n = 185). After PSM, MIPD patients had higher rates of CR-POPF (47.3% OPD vs. 54.4% MIPD, p = 0.037), as well as higher reoperation (9.1% vs. 15.3%, p = 0.006), delayed gastric emptying (29.2% vs. 35.8%, p = 0.041), and readmission rates (28.2% vs. 35.1%, p = 0.032). However, CR-POPF rates were comparable between LPD and RPD (56.8% vs. 49.3%, p = 0.408). Conclusion The impact of POPF is more clinically pronounced after MIPD than OPD with a more complex postoperative course. The difference appears to be attributed to the minimally invasive environment itself as no difference was noted between LPD and RPD. A clear biological explanation of this clinical observation remains missing. Further studies are warranted.