Skull defect increases the tumor treating fields strength without detrimental thermogenic effect: A computational simulating research.

BACKGROUND: Tumor treating fields (TTFields) is an FDA-approved adjuvant therapy for glioblastoma. The distribution of an applied electric field has been shown to be governed by distinct tissue structures and electrical conductivity. Of all the tissues the skull plays a significant role in modifying the distribution of the electric field due to its large impedance. In this study, we studied how remodeling of the skull would affect the therapeutic outcome of TTFields, using a computational approach. METHODS: Head models were created from the head template ICBM152 and five realistic head models. The electric field distribution was simulated using the default TTFields array layout. To study the impact of the skull on the electric field, we compared three cases, namely, intact skull, defective skull, and insulating process, wherein a thin electrical insulating layer was added between the transducer and the hydrogel. The electric field strength and heating power were calculated using the FEM (finite element method). RESULTS: Removing the skull flap increased the average field strength at the tumor site, without increasing the field strength of "brain". The ATVs of the supratentorial tumors were enhanced significantly. Meanwhile, the heating power of the gels increased, especially those overlapping the skull defect site. Insulation lightly decreased the electric field strength and significantly decreased the heating power in deep tumor models. CONCLUSION: Our simulation results showed that a skull defect was beneficial for superficial tumors but had an adverse effect on deep tumors. Skull removal should be considered as an optional approach in future TTFields therapy to enhance its efficacy. An insulation process could be used as a joint option to reduce the thermogenic effect of skull defect. If excessive increase in heating power is observed in certain patients, insulating material could be used to mitigate overheating without sacrificing the therapeutic effect of TTFields.

A case of hepatocellular carcinoma with long-term survival by multidisciplinary treatment for cranial and skeletal muscle metastases.

We report a case in which multidisciplinary treatment was effective for hepatocellular carcinoma (HCC) with cranial and skeletal muscle metastases. A 55-year-old male with HCC received sorafenib for lung metastases. He was admitted to our hospital due to the skull metastasis detected by fluorodeoxyglucose positron emission tomography (FDG-PET). The patient underwent resection for skull metastasis. After the surgical treatment, he was treated with sorafenib again. Eight months after craniectomy, FDG-PET showed FDG uptake in the semimembranosus and semitendinosus muscles. Histopathological examination of the muscle biopsy revealed HCC muscle metastasis. Sorafenib treatment was discontinued. The investigational new drug (tegafur-gimeracil-oteracil) and tegafur-uracil were used for the treatment. These treatments proved to be ineffective as the lung metastases enlarged and new metastases appeared on the mediastinal lymph nodes and dura cava. The patient was unable to walk due to the enlarged thigh muscle metastases. Sorafenib was re-administered, which reduced the enlargement of the lung and mediastinal lymph nodes. Dural metastases were treated with resection and radiotherapy. Additional radiation therapy to the thigh muscles relieved the patient from pain experienced during walking. Sorafenib treatment was continued for the next 3 years. The patient survived for 4 years after the skull resection.

Metastatic cancer along ancient Silk Road: A possible case from Xinjiang (China).

OBJECTIVE: Palaeopathological evidence of cancer, especially metastatic cancer, is rare in China. This paper describes and diagnoses a cranium with multiple lytic lesions recovered from the Sampula cemetery in Xinjiang, attempting to diagnose the type of disease that could have caused the pathological lesions observed. MATERIAL: A cranium from an adult male (#00106) was recovered from the Sampula cemetery (dated to 55 BCE to 335 CE) located in the Luopu County, the Hotan River oasis on the southern edge of the Tarim Basin in southern Xinjiang. METHODS: The cranium was assessed macroscopically and radiographically (CT). RESULTS: Multiple osteolytic lesions with irregular and "moth-eaten" margins were detected in cranium #00106. CT scans revealed the development of the lesions began at the diploe and identified a "button sequestrum". CONCLUSIONS: Based on lesion characteristics, metastatic carcinoma was likely the cause of lesions found in cranium #00106. SIGNIFICANCE: This case has expanded our knowledge of the malignant neoplasms of ancient populations in northwest China and discusses the possible risk factors in the occurrence of cancer in the Sampula site, as well as the possible impacts of skeletal metastases on the individual. LIMITATIONS: The distribution of osteolytic lesions over the complete skeleton cannot be observed because of the unavailability of postcranial bone. SUGGESTIONS FOR FUTURE RESEARCH: With the increasing number of reports describing diseases in ancient China, the patterns of diseases occurrence and development can be further explored from spatial and temporal perspectives.

Dual Delivery of BMP2 and IGF1 Through Injectable Hydrogel Promotes Cranial Bone Defect Healing.

Critical-sized cranial bone defect remains a great clinical challenge. With advantages in regenerative medicine, injectable hydrogels incorporated with bioactive molecules show great potential in promoting cranial bone repair. Recently, we developed a dual delivery system by sequential release of bone morphogenetic protein 2 (BMP2) followed by insulin-like growth factor 1 (IGF1) in microparticles (MPs), and an injectable alginate/collagen (alg/col)-based hydrogel. In this study, we aim to evaluate the effect of dual delivery of BMP2 and IGF1 in MPs through the injectable hydrogel in critical-sized cranial bone defect healing. The gelatin MPs loaded with BMP2 and poly(lactic-co-glycolic acid)-poly(ethylene glycol)-carboxyl (PLGA-PEG-COOH) MPs loaded with IGF1 were prepared, respectively. The encapsulation efficiency and release profile of growth factors in MPs were measured. A cranial defect model was applied to evaluate the efficacy of the dual delivery system in bone regeneration. Adult Sprague Dawley rats were subjected to osteotomy to make an ⌀8-mm cranial defect. The injectable hydrogel containing MPs loaded with BMP2 (2 µg), IGF1 (2 µg), or a combination of BMP2 (1 µg) and IGF1 (1 µg) were injected to the defect site. New bone formation was evaluated by microcomputed tomography, histological analysis, and immunohistochemistry after 4 or 8 weeks. Data showed that dual delivery of the low-dose BMP2 and IGF1 in MPs through alg/col-based hydrogel successfully restored cranial bone as early as 4 weeks after implantation, whose effect was comparable to the single delivery of high-dose BMP2 in MPs. In conclusion, this study suggests that dual delivery of BMP2 and IGF1 in MPs in alg/col-based hydrogel achieves early bone regeneration in critical-sized bone defect, with advantage in reducing the dose of BMP2. Impact Statement Sequential release of bone morphogenetic protein 2 (BMP2) followed by insulin-like growth factor 1 (IGF1) in two different microparticles promotes critical-sized bone defect healing. This dual delivery system reduces the dose of BMP2 by supplementing IGF1, which may diminish the potential side effects of BMP2.

Carnosol suppresses RANKL-induced osteoclastogenesis and attenuates titanium particles-induced osteolysis.

Osteolysis is a common medical condition characterized by excessive activity of osteoclasts and bone resorption, leading to severe poor quality of life. It is essential to identify the medications that can effectively suppress the excessive differentiation and function of osteoclasts to prevent and reduce the osteolytic conditions. It has been reported that Carnosol (Car), isolated from rosemary and salvia, has anti-inflammatory, antioxidative, and anticancer effects, but its activity on osteolysis has not been determined. In this study, we found that Car has a strong inhibitory effect on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation dose-dependently without any observable cytotoxicity. Moreover, Car can inhibit the RANKL-induced osteoclastogenesis and resorptive function via suppressing NFATc1, which is a result of affecting MAPK, NF-κB and Ca2+ signaling pathways. Moreover, the particle-induced osteolysis mouse model confirmed that Car could be effective for the treatment of bone loss in vivo. Taken together, by suppressing the formation and function of RANKL-induced osteoclast, Car, may be a therapeutic supplementary in the prevention or the treatment of osteolysis.

Revelations of ancient head shape: Cranial modification in the Cuzco region of Peru, Early Horizon to Inca Imperial Period.

OBJECTIVES: Cranial vault modification (CVM), the intentional reshaping of the head, indicated group affiliation in prehistoric Andean South America. This study aims to analyze CVM data from the Cuzco region of Peru to illuminate patterns of early migration and settlement along with the later impact of the Inca Empire (AD 1438-1532) on the ethnic landscape. MATERIALS AND METHODS: 419 individuals from 10 archaeological sites spanning over 2300 years were assessed for CVM using morphological analysis. RESULTS: CVM patterns show distinct temporal attributes: the tabular type of modification appeared first and dominated the early sample (900 BC-AD 600), followed by an influx of unmodified crania during the Middle Horizon (AD 600-1000). The annular type appeared later during the Late Intermediate Period (AD 1000-1438). In the subsequent period of Inca imperialism, modification rates were higher at sites in the Cuzco countryside than in Cuzco city sites. DISCUSSION: The study results, combined with archaeological and ethnohistoric data, reveal the sociopolitical transformations that occurred prior to and during the rise of the Inca Empire. The influx of unmodified crania during the Middle Horizon resulted at least partly from Wari occupation, while the appearance of the annular type during the LIP points to migration into the area, possibly from the Lake Titicaca region. In the Inca Imperial Period, Inca individuals at Cuzco city sites refrained from modification as a sign of their ethnic identity, while modification patterns in the Cuzco countryside likely reflect state-coerced resettlement of different ethnic groups.

Violence in the first millennium BCE Eurasian steppe: Cranial trauma in three Turpan Basin populations from Xinjiang, China.

OBJECTIVES: Violence affected daily life in prehistoric societies, especially at conflict zones where different peoples fought over resources and for other reasons. In this study, cranial trauma was analyzed to discuss the pattern of violence experienced by three Bronze to early Iron Age populations (1,000-100 BCE) that belonged to the Subeixi culture. These populations lived in the Turpan Basin, a conflict zone in the middle of the Eurasian Steppe. METHODS: The injuries on 129 complete crania unearthed from the Subeixi cemeteries were examined for crude prevalence rate (CPR), trauma type, time of occurrence, possible weapon, and direction of the blow. Thirty-three injuries identified from poorly preserved crania were also included in the analyses except for the CPR. Data was also compared between the samples and with four other populations that had violence-related backgrounds. RESULTS: Overall, 16.3% (21/129) of the individuals showed violence-induced traumatic lesions. Results also indicated that most of the injuries were perimortem (81.6%), and that women and children were more involved in conflict than the other comparative populations. Wounds from weapons accounted for 42.1% of the identified cranial injuries. Distribution analysis suggested no dominant handedness of the attackers, and that blows came from all directions including the top (17.1%). Wounds caused by arrowheads and a special type of battle-ax popular in middle and eastern Eurasian Steppe were also recognized. DISCUSSION: A comprehensive analysis of the skeletal evidence, historical records, and archeological background would suggest that the raiding to be the most possible conflict pattern reflected by the samples. The attackers were likely to have been nomadic invaders from the steppe (such as the Xiongnu from historical records), who attacked the residents in the basin more likely for their resources rather than territory or labor force.

A wolf from Gravettian site Pavlov I, Czech Republic: Approach to skull pathology.

OBJECTIVE: Describe pathological features on internal and external aspects of the skull of an ancient grey wolf. MATERIALS: Wolf remains that were found at the southwestern settlement Area A of Gravettian site Pavlov I. METHODS: Visual observation and description; microcomputed tomography; porosity and fragmentation indices for internal and external skull features; histological section of the fourth upper premolar tooth. RESULTS: Dorsally, the sagittal crest revealed bone healing and remodeling. The sagittal lesion differential diagnosis was blunt trauma with or without fracture. Ventrally, otic region pathology included severe proliferation and lysis (osteomyelitis). The pathology was not resolvable among differential (microbial) causes of osteomyelitis, although other potential etiologies were ruled out. CONCLUSIONS: Probable first report of otic region osteomyelitis in an ancient grey wolf. SIGNIFICANCE: The proximity of the wolf remains to human-related findings, and presence of red ochre and shells, suggest human involvement in the burial. LIMITATIONS: This is a single specimen with differential diagnoses that were not resolvable to a single definitive diagnosis. SUGGESTIONS FOR FURTHER RESEARCH: Further investigation of the possible anthropological significance of the burial circumstances.

Effect of Low- Level Laser Therapy on Bone Regeneration of Critical-Size Bone Defects: A Systematic Review of In Vivo Studies and Meta-Analysis.

OBJECTIVE: Low-level laser therapy is a method for osteogenesis since it stimulates cell proliferation, vascularization and osteoblastic activity. Various protocols applying low-level laser with different outcomes exist. The aim of the present study was to review the result of different methods on bone formation in critical-size defects of in vivo studies. DESIGN: According to PRISMA statement, electronic search of PubMed, google scholar, Scopus and Web of Science and a hand search limited to in vivo English language studies until December 2019. Studies used low-level laser therapy in bone regeneration of critical-size defects met the inclusion criteria and which used high power lasers or a defect size smaller than 5 mm, were excluded. RESULTS: Finally, 18 studies were included. Fourteen studies utilized low-level laser with a wavelength ranging from 606 to 980 nm and 53 % of studies applied low-level laser in a single session. Ten studies utilized continuous wave mode of laser. Highest and lowest values of power density were 1.5 W/cm2 and 0.1 W/cm2 in order. Eleven studies evaluated low-lever laser therapy on defects of 5 mm in calvaria. Meta-analysis showed the positive effect of low-level laser therapy on osteogenesis after 30 days compared to control group and no significant difference after 60 days. CONCLUSIONS: New bone formation can be increased in early stage by applying low-level laser therapy through stimulating osteoblasts and fibroblasts' proliferation. This effect would be more remarkable by combining with bone substitutes. Hence, for each case, protocol selection should be performed according defect's properties, attentively.

Marine spongin incorporation into Biosilicate® for tissue engineering applications: An in vivo study.

Biomaterials and bone grafts, with the ability of stimulating tissue growth and bone consolidation, have been emerging as very promising strategies to treat bone fractures. Despite its well-known positive effects of biosilicate (BS) on osteogenesis, its use as bone grafts in critical situations such as bone defects of high dimensions or in non-consolidated fractures may not be sufficient to stimulate tissue repair. Consequently, several approaches have been explored to improve the bioactivity of BS. A promising strategy to reach this aim is the inclusion of an organic part, such as collagen, in order to mimic bone structure. Thus, the present study investigated the biological effects of marine spongin (SPG)-enriched BS composites on the process of healing, using a critical experimental model of cranial bone defect in rats. Histopathological and immunohistochemistry analyzes were performed after two and six weeks of implantation to investigate the effects of the material on bone repair (supplemental material-graphical abstract). Histological analysis demonstrated that for both BS and BS/SPG, similar findings were observed, with signs of material degradation, the presence of granulation tissue along the defect area and newly formed bone into the area of the defect. Additionally, histomorphometry showed that the control group presented higher values for Ob.S/BS (%) and for N.Ob/T.Ar (mm2) (six weeks post-surgery) compared to BS/SPG and higher values of N.Ob/T.Ar (mm2) compared to BS (two weeks post-surgery). Moreover, BS showed higher values for OV/TV (%) compared to BS/SPG (six weeks post-surgery). Also, VEGF immunohistochemistry was increased for BS (two weeks post-surgery) and for BS/SPG (six weeks) compared to CG. TGFb immunostaining was higher for BS compared to CG. The results of this study demonstrated that the BS and BS/SPG scaffolds were biocompatible and able to support bone formation in a critical bone defect in rats. Moreover, an increased VEGF immunostaining was observed in BS/SPG.

Marine collagen scaffolds and photobiomodulation on bone healing process in a model of calvaria defects.

INTRODUCTION: Collagen from marine esponges has been used as a promising material for tissue engineering proposals. Similarly, photobiomodulation (PBM) is able of modulating inflammatory processes after an injury, accelerating soft and hard tissue healing and stimulating neoangiogenesis. However, the effects of the associated treatments on bone tissue healing have not been studied yet. In this context, the present study aimed to evaluate the biological temporal modifications (using two experimental periods) of marine sponge collagen or sponging (SPG) based scaffold and PBM on newly formed bone using a calvaria bone defect model. MATERIAL AND METHODS: Wistar rats were distributed into two groups: SPG or SPG/PBM and euthanized into two different experimental periods (15 and 45 days post-surgery). A cranial critical bone defect was used to evaluate the effects of the treatments. Histology, histomorfometry and immunohistological analysis were performed. RESULTS: Histological findings demonstrated that SPG/PBM-treated animals, 45 days post-surgery, demonstrated a higher amount of connective and newly formed bone tissue at the region of the defect compared to CG. Notwithstanding, no difference among groups were observed in the histomorphometry. Interestingly, for both anti-transforming growth factor-beta (TGF-ß) and anti-vascular endothelial growth factor (VEGF) immunostaining, higher values for SPG/PBM, at 45 days post-surgery could be observed. CONCLUSION: It can be concluded that the associated treatment can be considered as a promising therapeutical intervention.

Treponematosis in a pre-Columbian hunter-gatherer male from Antofagasta (1830 ± 20 BP, Northern Coast of Chile).

OBJECTIVE: This paper reports a new case of treponemal disease in a pre-Columbian hunter-gatherer inhabiting the desert coast of South America. MATERIALS: A well-preserved adult male skeleton from the "Vertedero Municipal" archaeological cemetery, located near the city of Antofagasta (Northern Chile). METHODS: The skeleton was radiocarbon dated, and isotopic analyses were performed to assess diet and mobility. Lytic and proliferative lesions identified were evaluated macroscopically and radiologically. RESULTS: A radiocarbon date of 1830 ± 20 BP and isotopic values indicating a marine diet and coastal residence were obtained. The cranium shows reactive changes as focal superficial cavitation, radial scarring and nodular cavitation, while the ribs, sternum, clavicles, and scapulae exhibit multiple lytic and proliferative lesions. The right femur has a node while both tibiae show mild anterior cortical thickening with a narrowed medullary cavity. CONCLUSIONS: Cranial lesions are pathognomonic for treponemal disease while postcranial changes are typical, and highly consistent with this pathology. SIGNIFICANCE: The type, morphology, and pattern of lesions make this case a good candidate for venereal syphilis. The case is relevant to the origin of venereal syphilis due to the lifestyle, temporal and ecological context of the individual. LIMITATIONS: Diagnosis of venereal syphilis is based on skeletal lesions; thus, it must be confirmed by molecular analysis. SUGGESTIONS FOR FURTHER RESEARCH: A comprehensive review of cases of pre-Columbian treponemal disease in South America as well as molecular studies are needed to confirm the presence of venereal syphilis in the New World before European contact.

Early needle aspiration of large infant cephalohematoma: a safe procedure to avoid esthetic complications.

Cephalohematoma is a common pathology in newborns. Observation is the primary treatment for most patients with small uncomplicated cephalohematoma. Conversely, a large cephalohematoma can lead to calcification with unesthetic local deformation or deformational plagiocephaly. The objective of the study was to evaluate the iatrogenic risk associated with early puncture under local anesthesia and oral sucrose. This is a retrospective study of 67 consecutive newborns followed at Montpellier University Hospital, France, between 2010 and 2017. Large cephalohematoma was defined on the basis of the bump projection. Due to the uncertainty of the spontaneous resorption and the risk of calcification after 4 weeks which render the needle aspiration ineffective, puncture was performed between 2 and 4 weeks of life after coagulation evaluation and ultrasound of the skull and scalp. Puncture was performed in 43 boys (64%) and 24 (36%) girls between day 15 and day 30 after birth. The cephalohematoma maximal projection measured by ultrasound ranged from 9 to 13 mm (Q1,Q4) with a median value of 12 mm. No puncture-related complication was recorded during the intervention and at the 1-month follow-up visit.Conclusion: In newborns with large and persistent unesthetic cephalohematoma, puncture under local anesthesia with oral sucrose can be safely proposed between day 15 and day 30 after birth.What is Known:• Infant cephalohematoma is a frequent pathology of newborns, consisting of a traumatic subperiosteal hematoma of the skull. Most cephalohematomas are small and require no treatment because they spontaneously disappear within the first month.• Large and non-resorptive cephalohematomas may have significant esthetic and functional consequences.What is New:• Early puncture under local anesthesia is a safe, effective, and rapid procedure, decreasing the risk of persistent skull deformities.• Puncture can be proposed for newborns with a large (high projection and/or high angle connection) persistent anesthetic cephalohematoma, between day 15 and day 30, before spontaneous calcification.

Skeletal evidence for violent trauma from the bronze age Qijia culture (2,300-1,500 BCE), Gansu Province, China.

This research explores how social and environmental factors may have contributed to conflict during the early Bronze Age in Northwest China by analyzing violent trauma on human skeletal remains from a cemetery of the Qijia culture (2300-1500 BCE). The Qijia culture existed during a period of dramatic social, technological, and environmental change, though minimal research has been conducted on how these factors may have contributed to violence within the area of the Qijia and other contemporaneous material cultures. An osteological assessment was conducted on 361 individuals (n = 241 adults, n = 120 non-adults) that were excavated from the Mogou site, Lintan County, Gansu, China. Injuries indicative of violence, including sharp- and blunt-force trauma that was sustained ante- or peri-mortem, were identified, and the patterns of trauma were analysed. Violent injuries were found on 8.58% (n = 31/361) of individuals, primarily adult males. No evidence of trauma was found on infants or children. Cranial trauma was found on 11.8% (n = 23/195) of the adult individuals examined. Of these, 43.5% (n = 10/23) presented with severe peri-mortem craniofacial trauma. The high rate of perimortem injuries and their locations indicate lethal intent. This lethality, in addition to the fact that individuals with trauma were predominantly male, suggest intergroup violence such as raiding, warfare, or feuding. Both social and environmental factors may have contributed to this conflict in the TaoRiver Valley, though future systematic archaeological and paleoenvironmental data will be needed to disentangle the many potential causal factors.

Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway.

Interleukin (IL)-37, a pivotal anti-inflammatory cytokine and a fundamental inhibitor of innate immunity, has recently been shown to be abnormally expressed in several autoimmune-related orthopedic diseases, including rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. However, the role of IL-37 during osteogenic differentiation of mesenchymal stem cells (MSCs) remains largely unknown. In this study, extracellular IL-37 significantly increased osteoblast-specific gene expression, the number of mineral deposits, and alkaline phosphatase activity of MSCs. Moreover, a signaling pathway was activated in the presence of IL-37. The enhanced osteogenic differentiation of MSCs due to supplementation of IL-37 was partially rescued by the presence of a PI3K/AKT signaling inhibitor. Using a rat calvarial bone defect model, IL-37 significantly improved bone healing. Collectively, these findings indicate that extracellular IL-37 enhanced osteogenesis of MSCs, at least in part by activation of the PI3K/AKT signaling pathway.

Identification of a Kavain Analog with Efficient Anti-inflammatory Effects.

Kavain, a compound derived from Piper methysticum, has demonstrated anti-inflammatory properties. To optimize its drug properties, identification and development of new kavain-derived compounds was undertaken. A focused library of analogs was synthesized and their effects on Porphyromonas gingivalis (P. gingivalis) elicited inflammation were evaluated in vitro and in vivo. The library contained cyclohexenones (5,5-dimethyl substituted cyclohexenones) substituted with a benzoate derivative at the 3-position of the cyclohexanone. The most promising analog identifed was a methylated derivative of kavain, Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate.) In an in vitro assay of anti-inflammatory effects, murine macrophages (BMM) and THP-1 cells were infected with P. gingivalis (MOI = 20:1) and a panel of cytokines were measured. Both cell types treated with Kava-205Me (10 to 200 µg/ml) showed significantly and dose-dependently reduced TNF-α secretion induced by P. gingivalis. In BMM, Kava-205Me also reduced secretion of other cytokines involved in the early phase of inflammation, including IL-12, eotaxin, RANTES, IL-10 and interferon-γ (p < 0.05). In vivo, in an acute model of P. gingivalis-induced calvarial destruction, administration of Kava-205Me significantly improved the rate of healing associated with reduced soft tissue inflammation and osteoclast activation. In an infective arthritis murine model induced by injection of collagen-antibody (ArthriomAb) + P. gingivalis, administration of Kava-205Me was able to reduce efficiently paw swelling and joint destruction. These results highlight the strong anti-inflammatory properties of Kava-205Me and strengthen the interest of testing such compounds in the management of P. gingivalis elicited inflammation, especially in the management of periodontitis.

Licorice isoliquiritigenin-encapsulated mesoporous silica nanoparticles for osteoclast inhibition and bone loss prevention.

Mesoporous silica nanoparticles (MSNs) are extensively used in bone tissue regeneration and local drug delivery. However, the effects of MSNs alone on osteoclast formation and function, as well as the utilization of MSNs to deliver natural molecules against bone resorption, remain unexplored. Here, we report the development of licorice-derived bioactive flavonoid isoliquiritigenin (ISL)-encapsulated MSNs (MSNs-ISL) as a potent bone-bioresponsive nanoencapsulation system for prevention of osteoclast-mediated bone loss in vitro and in vivo. Methods: We synthesized MSNs-ISL and then investigated the drug loading and release characteristics of the resulting nanoparticles. In vitro experiments on osteoclast differentiation and bone resorption were performed using mouse primary bone marrow-derived macrophages (BMMs). In vivo animal experiments were conducted using a lipopolysaccharide (LPS)-mediated calvarial bone erosion model. Results: The resulting MSNs-ISL were spherical and highly monodispersed; they possessed a large specific surface area and superior biocompatibility, and allowed acid-sensitive sustained drug release. Compared with free ISL and MSNs alone, MSNs-ISL significantly and additively inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast generation, decreased the size and quantity of sealing zones, and reduced the osteolytic capacity of osteoclasts in vitro. MSNs-ISL treatment also downregulated RANKL-stimulated mRNA expression of osteoclast-associated genes and transcription factors. Mechanistically, MSNs-ISL remarkably attenuated the RANKL-initiated expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of mitogen-activated protein kinases (MAPKs), and phosphorylation and degradation of inhibitor of κBα (IκBα), together with the nuclear translocation of nuclear factor-κB (NF-κB) p65 and the activator protein (AP)-1 component c-Fos. Moreover, MSNs-ISL almost completely restrained the expression of nuclear factor of activated T cells (NFATc1). Consistent with the in vitro results, MSNs-ISL could block osteoclast activity; relieve inflammation-related calvarial bone destruction in vivo; and suppress c-Fos, NFATc1, and cathepsin K expression levels. Conclusion: Licorice ISL-encapsulated MSNs exhibit notable anti-osteoclastogenetic effects and protect against inflammatory bone destruction. Our findings reveal the feasibility of applying MSNs-ISL as an effective natural product-based bone-bioresponsive nanoencapsulation system to prevent osteoclast-mediated bone loss.

What's that big thing on your head? Diagnosis of a large frontoparietal lesion on an Eastern Zhou skull from Henan, China.

We carried out a differential diagnosis of a large frontoparietal lesion on a human skull from a Late Bronze Age archaeological site located on the Central Plain of China, dating to between 771 and 476 BC. The head of this individual was covered in cinnabar, a mercury-based pigment that later was used for medicinal purposes in China. The lesion was well-circumscribed and involved the outer and inner tables of the skull, slight diploë thickening, and coarsening of bone trabeculae with expansion of intertrabecular spaces. We show that the observed changes are most consistent with cavernous hemangioma of the skull, a benign vascular malformation that preferentially affects older adults. Hemangiomas are often neglected in the paleopathological literature because of their benign nature - they tend to be asymptomatic and do not affect quality of life to a significant degree. Nevertheless, they produce characteristic lesions that can be confused with several other conditions with unrelated etiologies, including congenital hemoglabinopathies, traumas, malignant or benign neoplasms, and Paget's disease. We outline the diagnostic criteria that distinguish cavernous hemangioma from other conditions affecting the skull.

Near-Infrared Light-Triggered Porous AuPd Alloy Nanoparticles To Produce Mild Localized Heat To Accelerate Bone Regeneration.

The treatment of massive bone defects is still a significant challenge for orthopedists. Here we have engineered synthetic porous AuPd alloy nanoparticles (pAuPds) as a hyperthermia agent for in situ bone regeneration through photothermal therapy (PTT). After being swallowed by cells, pAuPds produced a mild localized heat (MLH) (40-43 °C) under the irradiation of a near-infrared laser, which can greatly accelerate cell proliferation and bone regeneration. Almost 97% of the cranial defect area (8 mm in diameter) was covered by the newly formed bone after 6 weeks of PTT. RNA sequencing analysis was used to obtain insight into the molecular mechanism of the MLH on cell proliferation and bone formation. These results demonstrated that the Wnt signaling pathway was involved in the MLH. This Letter provides a unique strategy with mild heat stimulation and high efficiency for in situ bone regeneration.

The influence of LLLT applied on applied on calvarial defect in rats under effect of cigarette smoke.

OBJECTIVE: Considering the global public health problem of smoking, which can negatively influence bone tissue repair, the aim of this study is to analyze the influence of photobiomodulation therapy (PBM) on calvaria defects created surgically in specimens under the effect of cigarette smoke and analyzed with use of histomorphometric and immunohistochemistry techniques. METHODOLOGY: Calvaria defects 4.1 mm in diameter were surgically created in the calvaria of 90-day-old rats (n=60) that were randomly divided into 4 experimental groups containing 15 animals each: control group (C), smoking group (S), laser group (L), and smoke associated with laser group (S+L). The animals were subjected to surgery for calvaria defects and underwent PBM, being evaluated at 21, 45, and 60 days post-surgery. The specimens were then processed for histomorphometric and immunohistochemistry analyses. The area of bone neoformation (ABN), percentage of bone neoformation (PBNF), and the remaining distance between the edges of the defects (D) were analyzed histometrically. Quantitative analysis of the TRAP immunolabeled cells was also performed. The data were subjected to analysis of variance (ANOVA) in conjunction with Tukey's test to verify the statistical differences between groups (p<0.05). RESULTS: The smoking group showed less ABN compared to the other experimental groups in all periods, and it also showed more D at 21 days compared to the remaining groups and at 45 days compared to the laser group. The smoking group showed a lower PNBF compared to the laser group in all experimental periods and compared to smoking combined with LLLT group at 21 days. CONCLUSIONS: PBM acted on bone biomodulation, thus stimulating new bone formation and compensating for the negative factor of smoking, which can be used as a supportive therapy during bone repair processes.