A Phase II Study of Neoadjuvant PLD/Cyclophosphamide and Sequential nab-Paclitaxel Plus Dual HER2 Blockade in HER2-Positive Breast Cancer.

BACKGROUND: Neoadjuvant trastuzumab/pertuzumab (HP) plus chemotherapy for HER2-positive breast cancer (BC) achieved promising efficacy. The additional cardiotoxicity still existed. Brecan study evaluated the efficacy and safety of neoadjuvant pegylated liposomal doxorubicin (PLD)/cyclophosphamide and sequential nab-paclitaxel based on HP (PLD/C/HP-nabP/HP). PATIENTS AND METHODS: Brecan was a single-arm phase II study. Eligible patients with stages IIA-IIIC HER2-positive BC received 4 cycles of PLD, cyclophosphamide, and HP, followed by 4 cycles of nab-paclitaxel and HP. Definitive surgery was scheduled after 21 days for patients completing treatment or experiencing intolerable toxicity. The primary endpoint was the pathological complete response (pCR). RESULTS: Between January 2020 and December 2021, 96 patients were enrolled. Ninety-five (99.0%) patients received 8 cycles of neoadjuvant therapy and all underwent surgery with 45 (46.9%) breast-conserving surgery and 51 (53.1%) mastectomy. The pCR was 80.2% (95%CI, 71.2%-87.0%). Four (4.2%) experienced left ventricular insufficiency with an absolute decline in LVEF (43%-49%). No congestive heart failure and ≥grade 3 cardiac toxicity occurred. The objective response rate was 85.4% (95%CI, 77.0%-91.1%), including 57 (59.4%) complete responses and 25 (26.0%) partial responses. The disease control rate was 99.0% (95%CI, 94.3%-99.8%). For overall safety, ≥grade 3 AEs occurred in 30 (31.3%) and mainly included neutropenia (30.2%) and asthenia (8.3%). No treatment-related deaths occurred. Notably, age of >30 (P = .01; OR = 5.086; 95%CI, 1.44-17.965) and HER2 IHC 3+ (P = .02; OR = 4.398; 95%CI, 1.286-15.002) were independent predictors for superior pCR (ClinicalTrials.gov Identifier NCT05346107). CONCLUSION: Brecan study demonstrated the encouraging safety and efficacy of neoadjuvant PLD/C/HP-nabP/HP, suggesting a potential therapeutic option in HER2-positive BC.

New bioactive peptides from the venom gland of a social hornet Vespa velutina.

Bacterial resistance to drugs is a global problem requiring the urgent development of new antibiotics. Antimicrobial peptides (AMPs) are excellent candidates for the design of novel antibiotics to combat microbial resistance. In this research, we identified four new peptides (U-VVTX-Vp1a, U-VVTX-Vp1b, U-VVTX-Vp2a, and U-VVTX-Vp2b, respectively) from the venom of Vespa velutina, and tested their antimicrobial, antioxidant, and hemolytic effects. All four peptides showed scavenging ability against DPPH, ABTS+, and •OH free radicals. Of note, Vp1b strongly inhibited the growth of Staphylococcus aureus and Escherichia coli bacteria at concentrations of 60 and 120 µM. Due to their low hemolytic activity, all four peptides could be utilized in the development of new antioxidants and as candidates for the design of novel antimicrobial agents.

Ophiopogonin D improves osteointegration of titanium alloy implants under diabetic conditions by inhibition of ROS overproduction via Wnt/ß-catenin signaling pathway.

A high failure rate of titanium implants in diabetic patients has been indicated in clinical evidences. Excessive oxidative stress at the bone-implant interface plays an important role in the impaired osteointegration under diabetic conditions. While the underlying mechanisms remain unknown and the targeted treatments are urgently needed. Ophiopogonin D (OP-D), isolated from Chinese herbal Radix Ophiopogon japonicus, is generally reported to be a potent antioxidant agent. In the present study, we hypothesized that OP-D exerted promotive effects on osteointegration against oxidative stress, and investigated the underlying mechanisms associated with alteration of Wnt/ß-catenin signaling pathway. Rabbit osteoblasts incubated on titanium alloy implant were co-cultured with normal serum (NS), diabetic serum (DS), DS + OP-D, DS + NAC (a potent ROS inhibitor) and DS + OP-D + Dkk1 (a Wnt inhibitor) for examinations of osteoblast behaviors. For in vivo study, titanium alloy implants were implanted into the femoral condyle defects on diabetic rabbits. Results demonstrated that diabetes-induced oxidative stress resulted in osteoblast dysfunctions and apoptotic injury at the bone-implant interface, concomitant with the inactivation of Wnt/ß-catenin signaling. Importantly, OP-D administration attenuated oxidative stress, directly reactivating Wnt/ß-catenin signaling. Osteoblast dysfunctions were thus reversed as evidenced by improved osteoblast adhesion, proliferation and differentiation, and ameliorated apoptotic injury, exerting similar effects to NAC treatment. In addition, the positive effects afforded by OP-D were confirmed by improved osteointegration and oetogenesis within the titanium alloy implants in vivo by Micro-CT and histological analyses. Furthermore, the pro-osteogenic effects of OP-D were almost completely abolished by the Wnt inhibitor Dkk1. These results demonstrated, for the first time, OP-D administration alleviated the damaged osteointegration of titanium alloy implants under diabetic conditions by means of inhibiting oxidative stress via a Wnt/ß-catenin-dependent mechanism. The OP-D administration would become a reliable treatment strategy for implant failure therapy in diabetics due to the optimal anti-oxidative and pro-osteogenic properties.

Involvement of FAK-mediated BMP-2/Smad pathway in mediating osteoblast adhesion and differentiation on nano-HA/chitosan composite coated titanium implant under diabetic conditions.

Chitosan (CS)-based hydroxyapatite (HA) composites have emerged as a novel strategy for promoting bone regeneration. Here nanophase HA/CS composite coated porous titanium implants (nCT) were fabricated and their biological behavior under diabetic conditions was investigated. We proposed that the focal adhesion kinase (FAK)-mediated BMP-2/Smad pathway played a role in mediating the promotive effect of nCTs on osteoblast adhesion and differentiation under diabetes-induced high reactive oxygen species (ROS) condition. To confirm the hypothesis, rat osteoblasts on bare titanium implants (Ti) and nCT were subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and DS + cytochalasin D (an actin polymerization inhibitor). In vivo on diabetic sheep implanted with Ti or nCT showed that diabetes-induced ROS overproduction impaired osteoblast adhesion, evidenced by immunostaining of F-actin and vinculin and morphological observation through inhibition of FAK phosphorylation, which contributed to suppressed BMP-2-dependent Smad1/5/8 phosphorylation. nCT substrate reactivated the FAK-BMP-2/Smad pathway, thus reversing osteoblast dysfunction, which exerted a similar effect to NAC treatment on Ti. These effects were further confirmed by improved osteointegration within nCT in diabetic sheep, evidenced by micro-CT and histological examinations. Our study demonstrated that reactivation of the FAK-BMP-2/Smad pathway was involved in improving osteoblast adhesion and differentiation by nano-HA/CS composite coating, potentially directing biomaterial modification and biofunctionalization under diabetic conditions.

Reliability of the Footscan® Platform System in Healthy Subjects: A Comparison of without Top-Layer and with Top-Layer Protocols.

The Footscan platform is a useful tool for plantar pressure measurement. However, there is still controversy over whether or not the platform should be covered by top-layer during the test. This study was designed to compare the reliability of the Footscan platform and identify the differences of the foot loading parameters between without top-layer (WOT) and with top-layer (WT) protocols. Measurements were taken from thirty-two healthy subjects. Participants were tested with a Footscan platform using the WOT and WT protocols. Three trials were performed during two separate testing sessions with a 7-day interval. Peak pressure, contact time, contact area, and pressure-time integral at ten foot zones were recorded and calculated for intra- and intersession reliability using intraclass correlation coefficients (ICCs) and coefficients of variation (CVs). The reliability and values of the analyzed parameters for the two protocols were compared. Both protocols produced a moderate to good level of intra- and intersession reliability. Compared with the WT protocol, the WOT protocol showed higher ICCs, lower CVs, and higher values in most of the parameters analyzed. The results suggest that the WOT protocol showed better reliability than the WT protocol. We recommend not using the top-layer when performing the plantar pressure test.

Influence of the shape of the micro-finite element model on the mechanical properties calculated from micro-finite element analysis.

Assessing the biomechanical properties of trabecular bone is of major biological and clinical significance for the research of bone diseases, fractures and their treatments. Micro-finite element (µFE) models are becoming increasingly popular for investigating the biomechanical properties of trabecular bone. The shapes of µFE models typically include cube and cylinder. Whether there are differences between cubic and cylindrical µFE models has not yet been studied. In the present study, cubic and cylindrical µFE models of human vertebral trabecular bone were constructed. A 1% strain was prescribed to the model along the superior-inferior direction. E values were calculated from these models, and paired t-tests were performed to determine whether these were any differences between E values obtained from cubic and cylindrical models. The results demonstrated that there were no statistically significant differences in the E values between cubic and cylindrical models, and there were no significant differences in Von Mises stress distributions between the two models. These findings indicated that, to construct µFE models of vertebral trabecular bone, cubic or cylindrical models were both feasible. Choosing between the cubic or cylindrical µFE model is dependent upon the specific study design.

Normal foot loading parameters and repeatability of the Footscan® platform system.

BACKGROUND: The Footscan® platform system is one of the most commonly used clinical tools for the measurement of the foot pressure. The present study was designed to assess the repeatability of the system and identify the range of loading parameters observed in the normal foot. METHODS: Measurements were collected from 32 healthy participants, 15 females and 17 males, twice at an interval of 1 week. Peak pressure (PP), contact time (CT), contact area (CA), pressure-time integral (PTI), and maximum force (MaF) were recorded; these parameters were investigated in 10 areas of the foot: medial heel, lateral heel, midfoot, first to fifth metatarsals, hallux, and toes 2-5. The intra-session repeatability was evaluated by calculating the intraclass correlation coefficients (ICCs) and coefficients of variation (CVs) across the three repeated trials within the same session. The inter-session repeatability was assessed using the average of the three trials in each session to determine the ICCs and CVs. RESULTS: The ICCs showed moderate to good repeatability for every variable of interest, and the CVs were all <28%. The highest zones of PP were found under the second and third metatarsals, followed by the medial heel. The CT was 68.5-82.8% of the total stance time under the metatarsal heads. CA was highest under the midfoot, PTI was highest under the second metatarsal, and MaF was highest under the medial heel. CONCLUSIONS: Footscan® platform system was found to be repeatable. Thus, it can be used as a valuable tool in the assessment of plantar pressure distribution, and the normal values of the foot loading parameters identified in this study can be employed to provide a reference range for the gait analysis performed by the Footscan® system.

Relationship between sample volumes and modulus of human vertebral trabecular bone in micro-finite element analysis.

Micro-finite element (µFE) models have been widely used to assess the biomechanical properties of trabecular bone. How to choose a proper sample volume of trabecular bone, which could predict the real bone biomechanical properties and reduce the calculation time, was an interesting problem. Therefore, the purpose of this study was to investigate the relationship between different sample volumes and apparent elastic modulus (E) calculated from µFE model. 5 Human lumbar vertebral bodies (L1-L5) were scanned by micro-CT. Cubic concentric samples of different lengths were constructed as the experimental groups and the largest possible volumes of interest (VOI) were constructed as the control group. A direct voxel-to-element approach was used to generate µFE models and steel layers were added to the superior and inferior surface to mimic axial compression tests. A 1% axial strain was prescribed to the top surface of the model to obtain the E values. ANOVA tests were performed to compare the E values from the different VOIs against that of the control group. Nonlinear function curve fitting was performed to study the relationship between volumes and E values. The larger cubic VOI included more nodes and elements, and more CPU times were needed for calculations. E values showed a descending tendency as the length of cubic VOI decreased. When the volume of VOI was smaller than (7.34mm(3)), E values were significantly different from the control group. The fit function showed that E values approached an asymptotic values with increasing length of VOI. Our study demonstrated that apparent elastic modulus calculated from µFE models were affected by the sample volumes. There was a descending tendency of E values as the length of cubic VOI decreased. Sample volume which was not smaller than (7.34mm(3)) was efficient enough and timesaving for the calculation of E.

Pedobarographic Analysis Following Pemberton's Pericapsular Osteotomy for Unilateral Developmental Dysplasia of the Hip: An Observational Study.

Successful clinical and radiographic outcomes have been reported in patients with unilateral developmental dysplasia of the hip (DDH) following Pemberton pericapsular osteotomy (PPO). However, residual gait deviations are seen in both the affected and unaffected limbs. To date it is not known whether these deviations result in abnormal plantar pressure in such patients. This study investigated this possibility by performing pedobarographic, clinical, and radiographic examinations after PPO in 20 patients (age: 102.5 ±â€Š19.0 months) with unilateral DDH who underwent PPO at 34.2 ±â€Š9.8 months of age. Plantar pressure was evaluated using the Footscan pressure plate (RsScan International, Olen, Belgium). Each foot was subdivided into 10 zones and peak pressure, force-time integral as a percentage of total FTI, and contact time as a percentage of total stance time was estimated. The minimum duration of follow-up was 24 months (mean: 68.3 ±â€Š20.3 months). The data were compared with 20 age- and weight-matched healthy controls. Despite clinical and radiographic examinations showing satisfactory results according to modified McKay and Severin criteria, significant differences in plantar pressure parameters were identified between the affected limbs, the unaffected limbs, and normal controls. No significant differences were found between patients classified as "excellent or good" and those rated as "fair" according to the modified Severin criteria. Pedobarographic results showed the existence of the residual plantar pressure deviations during walking in patients treated with PPO for unilateral DDH. Longer follow-up will be needed to more fully evaluate the effect of these deviations on gait.

Time Related Changes of Mineral and Collagen and Their Roles in Cortical Bone Mechanics of Ovariectomized Rabbits.

As cortical bone has a hierarchical structure, the macroscopic bone strength may be affected by the alterations of mineral crystal and collagen, which are main components of cortical bone. Limited studies focused on the time related alterations of these two components in osteoporosis, and their contributions to bone mechanics at tissue level and whole-bone level. Therefore, the purpose of this study was to elucidate the time related changes of mineral and collagen in cortical bone of ovariectomized (OVX) rabbits, and to relate these changes to cortical bone nanomechanics and macromechanics. 40 Rabbits (7-month-old) were randomly allocated into two groups (OVX and sham). OVX group received bilateral ovariectomy operation. Sham group received sham-OVX operation. Cortical bone quality of five rabbits in each group were assessed by DXA, µCT, nanoindentation, Fourier transform infrared (FTIR) spectroscopy and biomechanical tests (3-point bending of femoral midshaft) at pre-OVX, 4, 6, and 8 weeks after OVX. As time increased from pre-OVX to 8 weeks, the mineral to matrix ratio decreased with time, while both collagen crosslink ratio and crystallinity increased with time in OVX group. Elastic modulus and hardness measured by nanoindentation, whole-bone strength measured by biomechanical tests all decreased in OVX group with time. Bone material properties measured by FTIR correlated well with nano or whole-bone level mechanics. However, bone mineral density (BMD), structure, tissue-level and whole-bone mechanical properties did not change with age in sham group. Our study demonstrated that OVX could affect the tissue-level mechanics and bone strength of cortical bone. And this influence was attributed to the time related alterations of mineral and collagen properties, which may help us to design earlier interventions and more effective treatment strategies on osteoporosis.

Temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit.

This study was aimed at elucidating the temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit model induced by ovariectomy (OVX) combined with glucocorticoid (GC) administration. Osteoporotic (OP) group received bilateral OVX combined with injections of GC, while sham group only received sham operation. Cancellous bone quality in vertebrae and femoral condyles in each group was assessed by DXA, µCT, nanoindentation, and biomechanical tests at pre-OVX and 4, 6, and 8 weeks after injection. With regard to femoral condyles, nanoindentation test could detect significant decline in tissue modulus and hardness at 4 weeks. However, BMD and microarchitecture of femoral condylar cancellous bone changed significantly at 6 weeks. In vertebrae, BMD, microarchitecture, nanoindentation, and biomechanical tests changed significantly at 4 weeks. Our data demonstrated that temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit were significant. The temporal changes of cancellous bone in different anatomical sites might be different. The nanoindentation method could detect the changes of bone quality at an earlier stage at both femoral condyle and vertebra in the osteoporotic rabbit model than other methods (µCT, BMD).

Optimal sample volumes of human trabecular bone in µCT analysis within vertebral body and femoral head.

Trabecular bones of different skeletal sites have different bone morphologies. How to select an appropriate volume of region of interest (ROI) to reflect the microarchitecture of trabecular bone in different skeletal sites was an interesting problem. Therefore, in this study, the optimal volumes of ROI within vertebral body and femoral head, and if the relationships between volumes of ROI and microarchitectural parameters were affected by trabecular bone morphology were studied. Within vertebral body and femoral head, different cubic volumes of ROI (from (1 mm)(3) to (20 mm)(3)) were set to compare with control groups(whole volume of trabecular bone). Five microarchitectural parameters (BV/TV, Tb.N, Tb.Th, Tb.Sp, and BS/BV) were obtained. Nonlinear curve fitting functions were used to explore the relationships between the microarchitectural parameters and the volumes of ROI. The volumes of ROI could affect the microarchitectural parameters when the volume was smaller than (8 mm)(3) within the vertebral body and smaller than (13 mm)(3) within the femoral head. As the volume increased, the variable tendencies of BV/TV, Tb.N, and Tb.Sp were different between these two skeletal sites. The curve fitting functions between these two sites were also different. The relationships between volumes of ROI and microarchitectural parameters were affected by the different trabecular bone morphologies within lumbar vertebral body and femoral head. When depicting the microarchitecture of human trabecular bone within lumbar vertebral body and femoral head, the volume of ROI would be larger than (8 mm)(3) and (13 mm)(3).

Involvement of bone marrow stem cells in periodontal wound healing.

OBJECTS: To test the hypothesis whether bone marrow stem cells (BMSCs) could migrate into the periodontium as the precursor available for the repair of tissue injury. METHODS: A chimeric mouse model was established by transplanting BMSCs derived from red fluorescent protein mouse into irradiated BALB/c mice. Subsequently, a periodontal defect was created beside the maxillary first molar and filled with ceramic bovine bone. Finally, the chimeric mice were divided into three groups and were observed 3, 14 and 28 days later respectively. The involvement of BMSCs in periodontal defects was analysed using an in vivo imaging system and immunohistochemical staining of CD45, CD105 and CD31. Cell surface marker expression in injured tissue was also compared with that in normal tissue. RESULTS: Increasing numbers of BMSCs migrated into the periodontal defect with time. The distribution was initially limited to ceramic bovine bone and then around blood vessels and near alveolar bone. Furthermore, expression of CD105 and CD31 was much higher in injured periodontal tissue than that in healthy periodontium, although CD45 was not expressed in either of these tissues. CONCLUSION: BMSCs, but not haemopoietic stem cells, were involved in periodontal defect; they entered the periodontium probably via blood vessels.