[Sorafenib combined with chemotherapy and donor lymphocyte infusion as salvage therapy in patients with FLT3-positive acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation].

To explore the efficacy of sorafenib combined with chemotherapy and donor lymphocyte infusion (DLI) in patients with FLT3-positive acute myeloid leukemia (AML) relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Of the 14 patients relapsed after allo-HSCT, 9 achieved complete remission after salvage therapy of sorafenib combined with chemotherapy and DLI, 6 with complete molecular remission, 2 with partial remission, and 3 with no response. With a median follow up of 220 (range, 30-1 782) days after post-transplantation relapse, 7 patients were still alive and 7 died. Salvage therapy of sorafenib combined with chemotherapy and DLI shows a decent therapeutic effect for FLT3-positive AML relapsed after allo-HSCT.

[Metagenomic next-generation sequencing for the diagnosis of Pneumocystis jirovecii pneumonia after allogeneic hematopoietic stem cell transplantation].

Objectives: To investigate the value of metagenomic next-generation sequencing (mNGS) in the diagnosis of Pneumocystis jirovecii pneumonia (PJP) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: The data of 98 patients with suspected pulmonary infection after allo-HSCT who underwent pathogen detection from bronchoalveolar lavage fluid between June 2016 and August 2023 at Nanfang Hospital were analyzed. The diagnostic performance of mNGS, conventional methods, and real-time quantitative polymerase chain reaction (qPCR) for PJP were compared. Results: A total of 12 patients were diagnosed with PJP, including 11 with a proven diagnosis and 1 with a probable diagnosis. Among the patients with a proven diagnosis, 1 was positive by both conventional methods and qPCR, and 10 were positive by qPCR only. Pneumocystis jirovecii was detected by mNGS in all 12 patients. The diagnostic sensitivity of mNGS for PJP was 100%, which was greater than that of conventional methods (8.3%, P=0.001) and similar to that of qPCR (91.6%, P=1.000) . A total of 75% of the patients developed mixed pulmonary infections, and cytomegalovirus and Epstein-Barr virus were the most common pathogens. Mixed infection was detected in eight patients by mNGS and in five patients by qPCR, but not by conventional methods (P=0.008) . Conclusions: mNGS had good sensitivity for diagnosing PJP after allo-HSCT and was advantageous for detecting mixed infectious pathogens; therefore, mNGS might be an effective supplement to regular detection methods and qPCR.

Epstein-Barr virus (EBV) load in cerebrospinal fluid and peripheral blood of patients with EBV-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: To evaluate the diagnostic and prognostic utility of monitoring the Epstein-Barr virus (EBV) load in the cerebrospinal fluid (CSF) and peripheral blood for the patients with EBV-associated central nervous system (CNS) diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 172 patients undergoing allo-HSCT were enrolled in the study. METHODS: The EBV DNA levels of blood were monitored regularly in recipients of transplants for 3 years post transplantation. The EBV DNA levels of CSF were monitored in patients with EBV-associated CNS diseases before the treatment and at different points following the treatment. RESULTS: Post-transplant EBV-associated diseases developed in 27 patients, including 12 patients with EBV-associated CNS diseases. The 3-year cumulative incidences of EBV-associated diseases and EBV-associated CNS diseases were 19.5 ± 3.5% and 8.6 ± 2.4%, respectively. Patients with EBV-associated diseases showed higher loads of EBV DNA in their blood compared with patients with EBV DNA-emia. No difference was seen between the EBV DNA levels of blood in patients with CNS involvement and patients without CNS involvement. The EBV DNA loads of blood increased 3-14 days before the clinical manifestations of EBV-associated diseases emerged. The EBV DNA loads of CSF were higher than that of blood in patients with EBV-associated CNS diseases. In 12 patients with EBV-associated CNS diseases, EBV DNA levels were declining in both blood and CSF with the control of diseases, and the EBV DNA loads of CSF decreased faster than that of blood in 5 patients who responded to treatment, and the EBV DNA levels of CSF increased in 5 patients who were unresponsive to treatment. On multivariate analysis, the use of anti-thymocyte globulin and intensified conditioning regimens were independent risk factors for EBV-associated diseases and EBV-associated CNS diseases. CONCLUSIONS: EBV-associated CNS diseases are not rare after allo-HSCT. The EBV DNA loads of CSF could act as an important indicator, but the EBV DNA loads of blood could not, for the diagnosis, prognosis, and therapeutic evaluation of EBV-associated CNS diseases.

[Expert consensus on the biobank development of oral genetic diseases and rare diseases and storage codes of related biological samples from craniofacial and oral region].

The biological samples of oral genetic diseases and rare diseases are extremely precious. Collecting and preserving these biological samples are helpful to elucidate the mechanisms and improve the level of diagnose and treatment of oral genetic diseases and rare diseases. The standardized construction of biobanks for oral genetic diseases and rare diseases is important for achieving these goals. At present, there is very little information on the construction of these biobanks, and the standards or suggestions for the classification and coding of biological samples from oral and maxillofacial sources, and this is not conducive to the standardization and information construction of biobanks for special oral diseases. This consensus summarizes the background, necessity, principles, and key points of constructing the biobank for oral genetic diseases and rare diseases. On the base of the group standard "Classification and Coding for Human Biomaterial" (GB/T 39768-2021) issued by the National Technical Committee for Standardization of Biological Samples, we suggest 76 new coding numbers for different of biological samples from oral and maxillofacial sources. We hope the consensus may promote the standardization, and smartization on the biobank construction as well as the overall research level of oral genetic diseases and rare diseases in China.

[A single-center study on the distribution and antibiotic resistance of pathogens causing bloodstream infection in patients with hematological malignancies].

Objective: To study the incidence of bloodstream infections, pathogen distribution, and antibiotic resistance profile in patients with hematological malignancies. Methods: From January 2018 to December 2021, we retrospectively analyzed the clinical characteristics, pathogen distribution, and antibiotic resistance profiles of patients with malignant hematological diseases and bloodstream infections in the Department of Hematology, Nanfang Hospital, Southern Medical University. Results: A total of 582 incidences of bloodstream infections occurred in 22,717 inpatients. From 2018 to 2021, the incidence rates of bloodstream infections were 2.79%, 2.99%, 2.79%, and 2.02%, respectively. Five hundred ninety-nine types of bacteria were recovered from blood cultures, with 487 (81.3%) gram-negative bacteria, such as Klebsiella pneumonia, Escherichia coli, and Pseudomonas aeruginosa. Eighty-one (13.5%) were gram-positive bacteria, primarily Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecium, whereas the remaining 31 (5.2%) were fungi. Enterobacteriaceae resistance to carbapenems, piperacillin/tazobactam, cefoperazone sodium/sulbactam, and tigecycline were 11.0%, 15.3%, 15.4%, and 3.3%, with a descending trend year on year. Non-fermenters tolerated piperacillin/tazobactam, cefoperazone sodium/sulbactam, and quinolones at 29.6%, 13.3%, and 21.7%, respectively. However, only two gram-positive bacteria isolates were shown to be resistant to glycopeptide antibiotics. Conclusions: Bloodstream pathogens in hematological malignancies were broadly dispersed, most of which were gram-negative bacteria. Antibiotic resistance rates vary greatly between species. Our research serves as a valuable resource for the selection of empirical antibiotics.

[Clinical study of mesenchymal stem cells from third-party donors in the treatment of refractory late onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplanation].

Objective: To examine the efficacy and safety of third-party bone marrow-derived mesenchymal stem cells (MSCs) in the treatment of refractory delayed hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Twenty patients with refractory LOHC received conventional therapy combined with MSCs obtained from third-party donors' bone marrow (BM) . MSCs were given intravenously at a dose of 1 × 10(6) cells/kg once weekly until either the symptoms improved or no changes in LOHC were seen after continuous infusion four times. BK viruria (BKV) -DNA, JC viruria (JCV) -DNA, and CMV-DNA were detected by real-time quantitative PCR before and 8 weeks after the MSCs infusion. Results: ① Of the 20 patients with refractory LOHC, 15 were males, and 5 were females, and the median age was 35 (15-56) years. There were 5 cases of acute lymphoblastic leukemia (ALL) , 9 cases of acute myeloid leukemia (AML) , 5 cases of myelodysplastic syndrome (MDS) , and 1 case of maternal plasma cell like dendritic cell tumor (BPDCN) . There were 4 cases of HLA identical transplantation and 16 cases of HLA incomplete transplantation. ②The median number of MSC infusions for each patient was 3 (range: 2-8) . Seventeen patients achieved complete response, and one had a partial response after treatment. The overall response rate was 90%. Over a median follow-up period of 397.5 days (range 39-937 days) post-transplantations, 13 patients survived, and 7 died. The causes of death included aGVHD (1 case) , infections (5 cases) , and TMA (1 case) . ③The copy numbers of BKV-DNA and CMV-DNA in urine in the 8th week after MSCs infusion were significantly lower than those observed before treatment (11342.1×10(8) copies/L vs 5.2×10(8) copies/L, P=0.016; 3170.0×10(4) copies/L vs 0.2×10(4) copies/L, P=0.006, respectively) , while JCV-DNA did not significantly differ when compared to before treatment (P=0.106) . ④ No adverse reactions related to MSC infusion occurred in any of the 20 patients. Conclusion: Third-party bone marrow-derived MSC has significant efficacy and good safety in the treatment of refractory LOHC after allogeneic HSCT.

[Prognostic significance of IKZF1 gene deletions in patients with B-cell acute lymphoblastic leukemia].

Objective: This study aimed to investigate the prognostic significance of IKZF1 gene deletion in patients with acute B lymphoblastic leukemia (B-ALL) . Methods: The clinical data of 142 patients with B-ALL diagnosed in Nanfang Hospital between March 2016 and September 2019 were analyzed. Results: IKZF1 deletion was found in 36.0% of the 142 patients with B-ALL, whereas exon 4-7 deletion was found in 44.0% . White blood cell counts were higher in patients with the IKZF1 deletion (52.0% and 28.3% , P=0.005) ; these patients also experienced worse effects of mid-term induction therapy (40.0% and 70.7% , P<0.001) and had a higher proportion of Philadelphia chromosome-positive (52.0% and 21.7% , respectively, P<0.001) . Univariate analysis revealed that the 3-year overall survival rate (OS) and event-free survival rate (EFS) in the IKZF1 deletion group were significantly lower than the IKZF1 wild-type group [ (37.1±7.3) % vs (54.7±5.4) % , (51.8±7.9) % vs (73.9±4.7) % ; P=0.025, 0.013, respectively]. Multivariable analysis showed that harboring IKZF1 deletion was an adverse factor of EFS and OS (HR=1.744, 2.036; P=0.022, 0.020, respectively) . Furthermore, the IKZF1 deletion/chemotherapy group had significantly lower 3-year OS, EFS, and disease-free survival rates than other subgroups. In the IKZF1 deletion cohort, allo-hematopoietic stem cell transplantation (HSCT) significantly improved OS and EFS compared to non-allo-HSCT[ (67.9±10.4) % vs (31.9±11.0) % , (46.6±10.5) % vs (26.7±9.7) % ; P=0.005, 0.026, respectively]. Conclusion: Pediatric-inspired chemotherapy was unable to completely reverse the negative effect of IKZF1 deletion on prognosis. Pediatric-inspired regimen therapy combined with allo-HSCT, in contrast, significantly improved the overall prognosis of IKZF1 deletion B-ALL.

Peripheral blood stem cell transplantation compared with bone marrow transplantation from unrelated donors in patients with leukemia: a single institutional experience.

We analyzed data for 89 patients with leukemia undergoing bone marrow transplantation (BMT) (n=44) or peripheral blood stem cell transplantation (PBSCT) (n=45) from unrelated donors between May 2000 and February 2009 in our institution. PBSCT resulted in faster hematopoietic engraftment, compared with BMT (P<0.001). There was no difference between BMT and PBSCT in infectious episodes and CMV antigenemia within the first 100 days post-transplantation. The frequency of acute graft-versus-host disease (GVHD) grades II-IV was 49.7% and 47.0% (P=0.838) and of chronic GVHD 42.4% and 43.9% (P=0.827) in BMT and PBSCT. The 5-year cumulative percent of relapse was 18.5 in BMT and 48.6 in PBSCT (P=0.041), and the transplant-related mortality (TRM) was 40% and 29.5% (P=0.800), respectively. The 5-year cumulative percent of disease-free survival (DFS) was 50.8 and 38.9 (P=0.439); overall survival (OS) was 55.3% and 48.5% (P=0.447) in BMT and PBSCT, respectively. The reconstitution of T and B cells at 1, 3, 6, 9, and 12 months post-transplantation was not different between BMT and PBSCT, except that the level of regulatory T cells (T-regs) was higher after PBSCT than after BMT at 1 month (P=0.001).

Epstein-Barr virus-associated pneumonia in patients with post-transplant lymphoproliferative disease after hematopoietic stem cell transplantation.

Epstein-Barr virus (EBV) reactivation or infection after hematopoietic stem cell transplantation (HSCT) most often induces post-transplant lymphoproliferative disease (PTLD), but it also may be associated with clinical symptoms such as pneumonia. Our aim was to investigate and describe the clinical manifestations of PTLD and PTLD accompanied by EBV-associated pneumonia in 323 patients after HSCT. PTLD within extravisceral lymphoid tissue was identified in 7 cases (5 with CD20(+) diffuse large B-cell lymphoma, 1 with CD20(+) polymorphic B-cell hyperplasia, and 1 with CD3(+)CD45RO(+) peripheral T-cell lymphoma unspecified). Six of the patients with PTLD were EBV positive. Three patients had EBV-associated pneumonia, and chest computed tomography revealed multifocal patchy and diffuse ground-glass attenuation in both lungs. EBV-DNA was positive in bronchoalveolar lavage (BAL) fluid, which contained mainly CD3(+) T cells but no CD19(+) or CD20(+) B cells. Lung biopsy showed interstitial intra-alveolar infiltrates of mainly CD3(+) T cells and some CD68(+) macrophages without CD19(+) and CD20(+) B cells. The patients with PTLD accompanied by EBV-associated pneumonia developed hyperpyrexia and dyspnea, which progressed rapidly, and eventually all died within 2 weeks of the onset of PTLD. EBV-associated PTLD accompanied by EBV-associated pneumonia after HSCT is rare. Cytology of BAL fluid and lung biopsy may help establish the diagnosis.

A mutant HBs antigen (HBsAg)183-191 epitope elicits specific cytotoxic T lymphocytes in acute hepatitis B patients.

HBs antigen (HBsAg)183-191 (FLLTRILTI, R187 peptide) is a dominant human leucocyte antigen-A2 (HLA-A2)-restricted epitope associated with hepatitis B virus (HBV) infection in Caucasian populations. However, its prevalence is poorly understood in China, where there is a high incidence of HBV infection. In this report, we sequenced the region of HBsAg derived from 103 Chinese patients. Approximately 16.5% of the patients bore a mutant HBsAg183-191 epitope in which the original arginine (R187) was substituted with a lysine (K187 mutant peptide). Importantly, K187 still bound to HLA-A2 with high affinity, and elicited specific cytotoxic T lymphocyte (CTL) responses in HLA-A2/K(b) transgenic mice. K187-specific CTLs were also generated successfully in acute hepatitis B (AHB) patients, indicating that this mutant epitope is processed and presented effectively. Our findings show that R187-specific CTLs can cross-react with the K187 peptide. These findings reveal that K187 still has the property of an HLA-A2 restricted epitope, and elicits a protective anti-HBV CTL response in humans.

[The key factors which affect the bio-root regeneration].

The morbidity of tooth missing is the highest one among all the human organ diseases. The present restorations used in clinic, including fixed bridges, removable dentures and implant prosthetics, all exhibit their own defects, and hardly to restore the whole tooth structure and function. With the development of stem cells and tissue engineering, as an alternative, tooth regeneration, aiming at the generation of a structure like nature tooth, will be the therapeutic orientation to restore the lost tooth. The dental root, which supports the crown and occlusal force, is the fundamental part for tooth function. Based on the theory of tissue engineering, bio-roots were successfully generated by using mesenchymal stem cells (MSC) in miniature pigs. But the success rate of bio-root is not too high, is urgent to be improved for future clinic application. MSC mediated bio-root regeneration is depended on the dentinogenic differentiation regulation of MSC. Up to now, many factors affect the directed differentiation of MSC and further for the success rate of bio-root, including seeding cells, scaffold, growth factors and microenvironmental niche, etc. Microenvironmental niche is the key factor for affecting the MSC characteristics and special tissue regeneration. Basically, the bio-root is regenerated in jaw, while the jaw microenvironmental niche is prone to induce MSC for osteogenic differentiation, instead of dentinogenic differentiation. How to improve the dentinogenic differentiation of MSC in jaw microenvironmental niche is the key issue for increasing the success rate of bio-root.

A novel mutation in ALK-1 causes hereditary hemorrhagic telangiectasia type 2.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant bleeding disorder and has two variants, HHT1 and HHT2, associated with mutations in the ENG and ALK-1 genes, respectively. We identified one Chinese HHT2 family to investigate the pathogenic gene and its possible mechanism of action by mutation screening and functional study. One substitution mutation (1717C>T) in exon 10 of the ALK-1 was found by sequencing of all exons of ENG and ALK-1 and caused a R479X mutation in the ALK-1 protein. ALK-1 mRNA and plasma thrombomodulin were measured by real-time quantitative PCR and ELISA, respectively. There was no significant difference in the expression levels of ALK-1 mRNA between patients and healthy individuals. A significantly higher level of thrombomodulin was found in HHT patients. These findings indicate that the mutation causes truncation of the ALK-1 protein at the post-transcriptional level; the plasma thrombomodulin may provide an easy diagnostic indicator in HHT patients.

Spatial and temporal expression of histone demethylase, Kdm2a, during murine molar development.

The histone demethylase, lysine (K)-specific demethylase 2A (Kdm2a), is highly conserved and expressed ubiquitously. Kdm2a can regulate cell proliferation and osteo/dentinogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells (MSCs) derived from dental tissue. We used quantitative real-time RT-PCR analysis and immunohistochemistry to detect Kdm2a expression during development of the murine molar at embryonic days E12, E14, E16 and E17 and postnatal days P3 and P14. Immunohistochemistry results showed no positive staining of Kdm2a at E12. At E14, Kdm2a was expressed weakly in the inner enamel epithelium, stellate reticulum cells and dental sac. At E16, Kdm2a was expressed mainly in the inner and outer enamel epithelium, stratum intermedium and dental sac, but weaker staining was found in cervical loop and dental papilla cells adjacent to the basement membrane. At E17, the strongest Kdm2a staining was detected in the ameloblasts and stronger Kdm2a staining also was detected in the stratum intermedium, outer enamel epithelium and dental papilla cells compared to the expression at E16. Postnatally, we found that Kdm2a was localized in secretory and mature ameloblasts and odontoblasts, and dentin was unstained. Real-time RT-PCR showed that Kdm2a mRNA levels in murine germ cells increased from E12 to E14 and from E14 to E16; no significant change occurred at E16, E17 or P3, then the levels decreased at P14 compared to P3. Kdm2a expression may be closely related to cell proliferation, to ameloblast and odontoblast differentiation and to the secretion of extracellular enamel and dentin during murine tooth development.

Bio-Root and Implant-Based Restoration as a Tooth Replacement Alternative.

We previously reported that dental stem cell-mediated bioengineered tooth root (bio-root) regeneration could restore tooth loss in a miniature pig model. As a potential new method for tooth restoration, it is essential to compare this method with the widely used commercial dental implant-based method of tooth restoration. Tooth loss models were created by extracting mandibular incisors from miniature pigs. Allogeneic periodontal ligament stem cells (PDLSCs) and dental pulp stem cells (DPSCs) were isolated and cultured. A PDLSC sheet was prepared by adding 20.0 µg/mL vitamin C to the culture medium; in addition, a hydroxyapatite tricalcium phosphate (HA/TCP)/DPSC graft was fabricated and cultured in a 3-dimensional culture system. A total of 46 bio-root implantations and 9 dental implants were inserted, and crown restorations were performed 6 mo after implantation. Histological, radiological, biomechanical, and elemental analyses were used to evaluate and compare tissue-engineered bio-roots and dental implants to the natural tooth roots. After 6 mo, both computed tomography scans and histological examinations showed that root-like structures and dentin-like tissues had formed. Three months after crown restoration, clinical assessments revealed that tooth function was equivalent in the regenerated bio-root and the dental implant. Biomechanical testing showed that the bio-roots were similar to natural tooth roots in compressive strength, modulus of elasticity, and torsional force; however, these properties were significantly higher in the dental implants. Elemental analysis revealed a higher similarity in elemental composition between bio-roots and natural tooth roots than between bio-roots and dental implants. However, the dental implant success rate was 100% (9 of 9) and the bio-root success rate was only 22% (10 of 46). Taken together, we showed that an allogeneic HA/TCP/DPSC/PDLSC sheet could successfully build a bio-root with structure and function similar to the natural tooth root; however, tissue engineering procedures must be optimized further to improve the success rate.

[Determination of the rate of micronucleus formation in lymphocytes in liver diseases and its clinical significance].

The rate of micronucleus formation in lymphocytes was determined in 42 patients (including 10 acute icteric hepatitis B, 15 chronic active hepatitis B (CAH), 8 liver cirrhosis and 9 liver cancer) and 13 normal subjects. The results showed that the rate of micronucleus formation in lymphocytes in the patients with CAH (12.267 +/- 5.298%), liver cirrhosis (12.375 +/- 8.551%) or liver cancer (19.444 +/- 13.324%) was markedly higher than that in those with acute icteric hepatitis B (5.400 +/- 1.430%) or normal subjects (3.308 +/- 1.284%) (P less than 0.01). The rate of micronucleus formation in lymphocytes is higher in the liver cancer group than that in the CAH group or cirrhosis group (P less than 0.05). The rate of presence of two or more micronuclei in the lymphocytes was obviously higher in the liver cancer group (3.667 +/- 4.743%) than that in the liver cirrhosis group (1.500 +/- 1.690%), CAH group (1.467 +/- 1.807%), acute icteric hepatitis B group (0.600 +/- 1.075%) or healthy group (0.462 +/- 0.660%) (P less than 0.01 or less than 0.05). This method is much simpler than the measurement of chromosomal damage, and its reliability is as good as the latter. Measurement of micronuclei in lymphocytes can reflect the degree of liver damage in patients with the infection of hepatitis B virus. It may be used as the subclinical marker of the patients with liver cancer too.

Epiregulin can promote proliferation of stem cells from the dental apical papilla via MEK/Erk and JNK signalling pathways.

OBJECTIVES: Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration, but their molecular mechanisms of differentiation and proliferation remain unclear; this situation has restricted use of MSCs to a limited number of applications. A previous study of ours found a member of the epidermal growth factor family, epiregulin (EREG), to be involved in regulation of MSC differentiation. In the present study, we have used human dental stem cells from the apical papilla (SCAPs) to investigate the role of EREG on proliferation of MSCs. MATERIALS AND METHODS: SCAPs were isolated from apical papillae of immature third molars. Retroviral short hairpin RNA (shRNA) was used to silence EREG gene expression, and human recombinant EREG protein was used to stimulate SCAPs. SCAP proliferation was examined using tetrazolium dye colorimetric assay/cell growth curve. Western blotting was performed to detect expressions of extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), mitogen-activated protein kinases 1 and 2 (MEK1/2), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). RESULTS: Depletion of EREG with shRNA inhibited SCAP proliferation and repressed phosphorylation of Erk1/2 and JNK. Human recombinant EREG protein promoted cell proliferation and enhanced Erk1/2, MEK and JNK phosphorylation in SCAPs. Furthermore, blocking MEK/Erk signalling with specific Erk1/2 inhibitor PD98059, or JNK signalling with specific inhibitor SP600125, abolished effects of EREG on cell proliferation. CONCLUSION: These findings indicate that EREG could enhance cell proliferation in dental tissue-derived MSCs by activating MEK/Erk and JNK signalling pathways.

Early-stage pathogenic sequence of jaw osteoradionecrosis in vivo.

The mechanism underlying jaw osteoradionecrosis (ORN) is not fully understood, particularly in the early stages. To investigate bone and vessel pathogenesis in the early stages of jaw ORN, we generated a mandibular ORN model in miniature pigs (minipigs) by applying a combination of single-dose 25-Gy irradiation (IR) and tooth extraction. We studied 6 ORN model minipigs and 6 control, non-irradiated minipigs. We measured dynamic morphological changes, bone-remodeling-associated gene expression, sphingomyelinase activity, and local blood flow. Bone remodeling, including bone resorption and new bone formation, was observed within 15 days post-IR. Later, an ORN-related imbalance in bone metabolism gradually occurred, with loss of bone regeneration capacity, collagen collapse, and microvascular obliteration. Within 24 hrs post-IR, sphingomyelinase significantly increased in irradiated tissues. At 1 wk post-IR, local blood flow increased, but at 15 days post-IR, it significantly decreased to 50% below normal levels. This study provided details of the sequential occurrences in early-stage ORN in a large animal model. Our results suggested that reduced local blood flow and consequent hypovascularity may have caused an imbalance in bone remodeling. This suggested that microvessel damage may play a key role in the initiation of ORN.