A population-based study identifies an association of THBS2 with intervertebral disc degeneration.

OBJECTIVE: To clarify the genetic mechanisms underlying intervertebral disc degeneration (IDD), we examined the associations between single-nucleotide polymorphisms (SNPs) and indicated as coefficient of interaction term (IDD) in a general population in Japan. METHODS: This was a cross-sectional study. In 1,605 participants, C2-3 to L5/S1 in the total spine magnetic resonance imaging (MRI) were evaluated using the Pfirrmann's scoring system. Disc scores of 4 and 5 were defined as IDD. Eight SNPs in eight genes associated with IDD were examined at each disc level, considering the non-genetic risk factors of age, sex, and body mass index (BMI). RESULTS: The highest odds ratio was found for rs9406328 in the THBS2 gene at disc level T12-L1 (OR 1.27, 95%CI 1.05 to 1.53), and this association was strengthened after adjustment for age using logistic regression (OR 1.37, 95%CI 1.12 to 1.67). Among participants aged <50 years and 50-59, the average IDD score in those with 2 risk alleles of rs9406328 was markedly higher than in those with 0 or 1 risk allele, and the difference is much wider than the elderly participants. It indicates the genetic effect of rs9406328 is stronger in the younger age groups. Finally, multiple linear regression analyses of the association between rs9406328 and IDD, adjusted for age, sex, and BMI at each disc level, showed a statistical interaction between age and the number of risk alleles at C7-T1, T3-4 and T4-T5 as well as T12-L1. CONCLUSION: CONCLUSION: The association between rs9406328 in THBS2 and IDD was replicated. The contributions of genetic and environmental factors to IDD differed by disc level.

CO2 low-level laser therapy has an early but not delayed pain effect during experimental tooth movement.

OBJECTIVES: To test the hypothesis that the use of low-level laser therapy (LLLT) reduces elevated pain by controlling the release of neurochemicals during orthodontic tooth movement. SETTING AND SAMPLE POPULATION: Department of Orthodontics and Dentofacial Orthopedics, Okayama University. Sixty-five Sprague Dawley rats were subjected to tooth movement and LLLT. MATERIALS AND METHODS: Adult Sprague Dawley rats were used in this study. Groups included day 0 controls, irradiation only controls and with or without irradiation sacrificed at 1, 3, 5, 7 and 14 days after tooth movement (n=5 each, total n=65). Tooth movement was achieved by insertion of an elastic module between molar teeth. Immunohistochemistry for CD-11b, GFAP and c-fos in the brain stem was performed. Stains were quantified by constructing a three-dimensional image using IMARIS, and counted using NEURON TRACER and WinROOF software. Two-way ANOVA followed by a Tukey's post hoc test (P<.05) was used for statistical comparison between groups. RESULTS: C-fos expression was significantly increased at one and three days after tooth movement. LLLT significantly diminished this increase in c-fos expression only at one day after tooth movement CD-b11 and GFAP expression also significantly increased after tooth movement. No significant change was observed for CD-11b and GFAP expression in the central nervous system upon LLLT. CONCLUSION: Low-level laser therapy may reduce early neurochemical markers but have no effect on delayed pain neurochemical markers after tooth movement.

Impact of surgical margins on survival of 37 dogs with massive hepatocellular carcinoma.

AIMS: To compare the survival of dogs with completely resected massive hepatocellular carcinoma (HCC) with that of dogs in which HCC were incompletely excised. METHODS: A retrospective cohort study was conducted. Dogs that underwent surgical excision of massive HCC between November 2006 and April 2015 were included. Dogs that died in the perioperative period or were lost to follow-up within 2 months after surgery were excluded. Data were collected from the medical records and a single pathologist examined all available histology slides to confirm the diagnosis of HCC. Surgical margins were defined as complete if no neoplastic cells were seen at the edge of excised tissues, based on original histopathology reports. Progression-free survival (PFS) and overall survival (OS) were compared between dogs with complete surgical margins (CM) and those with incomplete margins (IM) using a log-rank test. RESULTS: Of the 37 dogs included in the study, 25 were allocated to the CM group and 12 to the IM group. Progressive local disease developed after surgery in three dogs in the CM group and seven dogs in the IM group. Three dogs in the CM group and five dogs in the IM group died due to tumour progression. Median PFS was longer for dogs in the CM group (1,000 (95% CI=562-1,438) days) compared to dogs in the IM group (521 (95% CI=243-799) days; p=0.007). OS was also longer for dogs in the CM group (>1,836 days) compared to those in the IM group (median 765 (95% CI=474-1,056) days; p=0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Compared with complete resection, incomplete resection decreased PFS and OS in dogs with massive HCC. Dogs with incompletely excised HCC should be closely monitored for local recurrence, although median OS was >2 years following incomplete excision. Further prospective studies are warranted to confirm these findings.

A software tool for tomographic axial superresolution in STED microscopy.

A method for generating three-dimensional tomograms from multiple three-dimensional axial projections in STimulated Emission Depletion (STED) superresolution microscopy is introduced. Our STED< method, based on the use of a micromirror placed on top of a standard microscopic sample, is used to record a three-dimensional projection at an oblique angle in relation to the main optical axis. Combining the STED< projection with the regular STED image into a single view by tomographic reconstruction, is shown to result in a tomogram with three-to-four-fold improved apparent axial resolution. Registration of the different projections is based on the use of a mutual-information histogram similarity metric. Fusion of the projections into a single view is based on Richardson-Lucy iterative deconvolution algorithm, modified to work with multiple projections. Our tomographic reconstruction method is demonstrated to work with real biological STED superresolution images, including a data set with a limited signal-to-noise ratio (SNR); the reconstruction software (SuperTomo) and its source code will be released under BSD open-source license.

Orthodontic miniscrew failure rate and root proximity, insertion angle, bone contact length, and bone density.

OBJECTIVES: To test the hypothesis that there is no significant correlation between miniscrew failure rate and root proximity, insertion angle, bone contact length, and bone density. SETTING AND SAMPLE POPULATION: This study included 107 patients in whom 190 miniscrews had been placed from April 2008 to October 2009 in Tohoku University Hospital (Sendai, Japan). MATERIALS AND METHODS: Cone beam computed tomography scans (CBCT) and periapical radiographs were taken before and after miniscrew placement. Differences in root proximity, screw insertion angle, bone contact length, and bone density were statistically compared; comparisons were also made between the CBCT images and periapical radiographs. RESULTS: A significantly higher success rate was observed in the maxilla than in the mandible. The distance between the miniscrew and the root surface was significantly smaller in the failure group. There were no significant differences in the insertion angle, bone contact length, or bone density between the success group and the failure group. The concordance rate between the periapical dental radiographs and CBCT images was 46.5%. CONCLUSION: While bone contact length, miniscrew angle, and bone density did not exert major effects on miniscrew failure, root proximity was the factor that most affected miniscrew failure, especially for miniscrews placed in the mandible. CBCT was superior to periapical dental X-rays for evaluating the proximity of miniscrews to the root. Correction of the X-ray attenuation coefficient value was necessary for measuring bone density using CBCT.

A null mutation in the human CNTF gene is not causally related to neurological diseases.

We report a null mutation in the human ciliary neurotrophic factor gene (CNTF). The mutated allele shows a G to A transition producing a new splice acceptor site and the resulting mRNA species codes for an aberrant protein. Analysis of tissue samples and transfection of CNTF minigenes into cultured cells demonstrates that the mutated allele expresses only the mutated mRNA species. In 391 Japanese people tested, 61.9% were normal homozygotes, 35.8% heterozygotes and 2.3% mutant homozygotes. The distribution of the three genotypes is similar in healthy and neurological disease subjects, indicating that human CNTF deficiency is not causally related to neurological diseases.

Rapamycin causes upregulation of autophagy and impairs islets function both in vitro and in vivo.

Autophagy is a lysosomal degradation process of redundant or faulty cell components in normal cells. However, certain diseases are associated with dysfunctional autophagy. Rapamycin, a major immunosuppressant used in islet transplantation, is an inhibitor of mammalian target of rapamycin and is known to cause induction of autophagy. The objective of this study was to evaluate the in vitro and in vivo effects of rapamycin on pancreatic ß cells. Rapamycin induced upregulation of autophagy in both cultured isolated islets and pancreatic ß cells of green fluorescent protein-microtubule-associated protein 1 light chain 3 transgenic mice. Rapamycin reduced the viability of isolated ß cells and down-regulated their insulin function, both in vitro and in vivo. In addition, rapamycin increased the percentages of apoptotic ß cells and dead cells in both isolated and in vivo intact islets. Treatment with 3-methyladenine, an inhibitor of autophagy, abrogated the effects of rapamycin and restored ß-cell function in both in vitro experiments and animal experiments. We conclude that rapamycin-induced islet dysfunction is mediated through upregulation of autophagy, with associated downregulation of insulin production and apoptosis of ß cells. The results also showed that the use of an autophagy inhibitor abrogated these effects and promoted islet function and survival. The study findings suggest that targeting the autophagy pathway could be beneficial in promoting islet graft survival after transplantation.

Identification of cancer stem cells derived from a canine lung adenocarcinoma cell line.

Accumulating evidence supporting the cancer stem cell (CSC) hypothesis is based on the finding that tumors contain a small population of self-renewing cells that generate differentiated progeny and thereby contribute to tumor heterogeneity. CSCs are reported to exist in several human cancers, yet only a few reports demonstrate the existence of CSCs in primary lung cancer in dogs. In this study, the authors established a cancer cell line derived from a canine primary lung adenocarcinoma and identified a side population (SP) of cells that displayed drug-resistant features. To confirm the characteristics of these SP cells, the authors investigated the tumorigenicity of the cells in vivo by using a nude mouse xenograft model. Only 100 SP cells were able to give rise to new tumors, giving a 10-fold enrichment over the main population (MP) of cells, suggesting that these cells have the cancer-initiating ability of CSCs. Further studies characterizing CSCs in canine lung adenocarcinoma might contribute to the elucidation of the mechanisms of tumorigenesis and to the establishment of novel therapeutic strategies.

Relationship between bone fragility of the mandibular inferior cortex and tooth loss related to periodontal disease in older people.

OBJECTIVE: The purpose of this study was to evaluate the relationship between bone fragility of the mandibular inferior cortex and tooth loss in older adults by accounting for periodontal disease and bone metabolism markers. RESEARCH DESIGN: A total of 177 subjects aged 77 years participated in this study. We counted the number of remaining teeth. The mandibular cortex condition was examined using the mandibular inferior cortex classification (MICC) on dental panoramic radiographs. The mandibular inferior cortex was detected on both sides of the mandible, distally from the mental foramen (C1, normal; C2, mild/moderate erosion; C3, severe erosion). Multiple linear regression analysis was performed to assess the relationship between the mandibular cortex condition with the MICC and the number of remaining teeth after controlling for confounding factors such as gender, the percentage of sites with > or = 4 mm clinical attachment levels, and serum osteocalcin levels. RESULTS: The mean +/- SD number of remaining teeth of MICC C1, C2 and C3 were 20.7 +/- 7.5, 14.6 +/- 8.1 and 4.0 +/- 0.0 for males, and MICC C1, C2, and C3 were 21.7 +/- 7.6, 17.2 +/- 8.0, and 16.2 +/- 10.4 for females. The MICC was significantly associated with the number of remaining teeth using multiple linear regression analysis (beta = -0.21, p = 0.031). CONCLUSION: This study suggests that there is a relationship between bone fragility of the mandibular inferior cortex and tooth loss related to periodontal disease.

Relationship between the mandibular inferior cortex and bone stiffness in elderly Japanese people.

UNLABELLED: SUMARRY: This study assessed the relationship between the mandibular inferior cortex (MIC) and bone stiffness in elderly Japanese subjects. Results suggest that MIC classification may be useful for screening patients for the possibility of osteoporosis by measuring bone stiffness with ultrasound bone densitometry. INTRODUCTION: The prevention of fractures is a priority for patients with osteoporosis. Dental panoramic radiographs are frequently taken for the examination of teeth and jaws in general dental practice worldwide. This study assessed the relationship between the mandibular inferior cortex (MIC) and bone stiffness in elderly Japanese subjects. METHODS: This study included 519 healthy subjects (263 men and 256 women) aged 70 years old. We evaluated the relationship between MIC classification and bone stiffness using Scheffe's multiple comparison test. Multiple linear regression analysis was used to assess the relationship between MIC classification and bone stiffness after controlling for confounding factors. RESULTS: A significant correlation was found between MIC classification and bone stiffness in men (C1 vs C2: p < 0.05) and women (C1 vs C2: p = NS, C1 vs C3: p < 0.01, C2 vs C3: p < 0.05). MIC classification was significantly associated with bone stiffness on multiple linear regression analysis after controlling for sex, body mass index, regular exercise, and smoking (beta = -0.11, p < 0.01, R(2) = 0.387, p < 0.001). CONCLUSIONS: Our study suggests that MIC classification may be useful for screening patients for the possibility of osteoporosis by measuring bone stiffness with ultrasound bone densitometry.

Tonsillectomy and steroid pulse therapy for recurrent IgA nephropathy in renal allograft.

We experienced two cases of steroid pulse therapy combined with tonsillectomy for recurrent IgA nephropathy (IgAN) in a renal allograft. We defined recurrent IgAN in renal allograft as IgA deposits in glomeruli with persistent proteinuria (> 0.5 g/ day) and microscopic hematuria in renal transplant recipients with biopsy-proven IgAN of their native kidneys. We performed steroid pulse therapy following tonsillectomy as therapeutic protocol for recurrent IgAN. The first patient was diagnosed with recurrent IgAN by allograft biopsy 3 years after renal transplantation, and a second patient was diagnosed after one year. The former patient's proteinuria disappeared 4 months after treatment and the latter patient's proteinuria disappeared after one month. Tonsillectomy combined with steroid pulse therapy can induce clinical remission in patients with recurrent IgAN after renal transplantation.

The common mechanisms of anterior cruciate ligament injuries in judo: a retrospective analysis.

BACKGROUND: Although high prevalence of anterior cruciate ligament injuries (ACL) in judokas has been reported, there has been very little research concerning events preceding the injury. OBJECTIVE: To determine the common situations and mechanisms of ACL injury in judo. METHODS: A total of 43 cases of ACL injuries that had occurred during judo competition or practice were investigated, using questionnaires with interviews conducted by a single certified athletic trainer who has 20 years of judo experience to obtain information regarding the situation and mechanism in which the ACL injury occurred. RESULTS: The number of ACL injuries when the participant's grip style was different from the style of the opponent (ie, kenka-yotsu style) (28 cases) was significantly greater than when the participant's grip style was the same as that of the opponent (ie, ai-yotsu style) (15 cases; p<0.001). The number of ACL injuries was significantly higher when the participant was attacked by the opponent than when counterattacked or when attempting the attack (p<0.001). In addition, being attacked with osoto-gari was revealed as the leading cause of ACL injury incidence among the participants (16.8%). CONCLUSIONS: Grip style may be associated with ACL injury occurrence in judo. In addition, direct contact due to the opponent's attack may be a common mechanism for ACL injuries in judo.

Serum VEGF increases in diabetic polyneuropathy, particularly in the neurologically active symptomatic stage.

AIM: To identify the relationship between vascular endothelial growth factor (VEGF) and diabetic polyneuropathy (DPN). METHODS: Two hundred and twenty diabetic patients participated, 113 with DPN and 107 without DPN. All patients were also classified according to the four stages of DPN (no neuropathy: stage 0; asymptomatic neuropathy: stage 1; symptomatic neuropathy: stage 2; disabling neuropathy: stage 3). Serum VEGF concentration was measured using an enzyme-linked immunosorbent assay (ELISA) and levels between the patients with and without DPN and also between the different stages of DPN, were compared. RESULTS: The mean serum VEGF level in all patients was 264.6 +/- 218.8 pg/ml. The mean serum VEGF level was higher in patients with DPN (310.1 +/- 224.3 pg/ml) than in the patients without DPN (216.5 +/- 204.0 pg/ml, P = 0.0014). Serum VEGF was higher in the 'symptomatic' stage (stage 2, 364.8 +/- 225.9 pg/ml) in comparison with the 'asymptomatic' (stage 1, 256.7 +/- 224.4 pg/ml, P = 0.015) and 'disabling' (stage 3, 180.3 +/- 109.4 pg/ml, P = 0.042) stages. The mean serum VEGF level in patients with diabetic retinopathy (261.1 +/- 210.6 pg/ml) and in patients with diabetic nephropathy (241.5 +/- 185.7 pg/ml) was not increased. CONCLUSIONS: The serum VEGF level is increased in patients with DPN, particularly in patients in the neurologically active 'symptomatic' stage.

Circadian rhythm of serotonin N-acetyltransferase activity in organ culture of chicken pineal gland.

When chicken pineal glands were organ-cultured in darkness, serotonin N-acetyltransferase activity was low during daytime, increased at midnight, and decreased on the next morning. The autonomous increase of N-acetyltransferase activity was suppressed by illumination of the glands. When pineal glands were cultured under a light-dark cycle (LD 12:12), the change of N-acetyltransferase activity continued to oscillate in phase with the light-dark cycle for 3 days.

Relation of bone turnover markers to periodontal disease and jaw bone morphology in elderly Japanese subjects.

OBJECTIVE: The purpose of this study was to evaluate the relation of bone turnover markers such as bone formation and resorption to periodontal disease and jaw bone morphology in elderly Japanese subjects. SUBJECTS AND METHODS: We selected 148 subjects for participation in this study. All subjects were aged 77 years. The periodontal examination included the assessment of clinical attachment level (CAL). Biochemical parameters of bone turnover measured included urinary deoxypyridinoline, serum osteocalcin (S-OC), and serum bone-specific alkaline phosphatase. In addition, to evaluate the jawbone, we used the mandibular inferior cortex classification (MIC). RESULTS: Serum osteocalcin had significantly higher (males: P = 0.038, females: P = 0.041) tendency for MIC Class (ANOVA). Multiple linear regression results showed that the number of remaining teeth and S-OC were negatively associated with the percentage of sites with > or =6 mm CAL (R(2) = 0.322, P < 0.001). Coefficients and betas were -0.71, -0.46 (P < 0.001) and -1.11, -0.28 (P = 0.002), respectively. CONCLUSION: In conclusion, this study suggests that there is a significant relation of bone turnover markers to periodontal disease and jaw bone morphology in elderly Japanese subjects.

Adenovirus-mediated gene expression of the human c-FLIP(L) gene protects pig islets against human CD8(+) cytotoxic T lymphocyte-mediated cytotoxicity.

Cell-mediated immunity, especially of human CD8+ cytotoxic T lymphocytes (CTLs) is believed to have an important role in the long-term survival of pig islet xenografts. Protection against human CD8+ CTL cytotoxicity may reduce the direct damage to pig islets and enable long-term xenograft survival in pig-to-human islet xenotransplantation. We have previously reported that c-FLIP(S/L) genes, which are potent inhibitors of death receptor-mediated proapoptotic signals through binding competition with caspase-8 for recruitment to the Fas-associated via death domain (FADD), markedly suppress human CD8+ CTL-mediated xenocytotoxicity. In addition, the cytoprotective effects of c-FLIP(L) seem to be significantly stronger than those of c-FLIP(S). Accordingly, in the present study, expression of c-FLIP(L) was induced in intact pig islets by adenoviral transduction. Consequently, the cytoprotective capacity of the transgene in pig islets was examined in in vitro and in vivo exposure to human CD8+ CTLs. Cells from untransduced islets or mock islets were sensitive to CD8+ CTL-mediated lysis (59.3% +/- 15.9% and 64.0% +/- 8.9% cytotoxicity, respectively). In contrast, cells from pig islets transduced with the c-FLIP(L) gene were markedly protected from lysis (30.5% +/- 3.5%). Furthermore, prolonged xenograft survival was elicited from pig islets transduced with this molecule as assessed using an islet transplant model using the rat kidney capsule. Thus, these data indicate that intact pig islets can be transduced to express c-FLIP(L) with adenovirus. Pig islets expressing c-FLIP(L) are significantly resistant to human CTL killing and further exhibit beneficial effects to prolong xenograft survival.

In vivo controlling of cellular response to pig islet xenografts by adenovirus-mediated expression of either membrane-bound human FasL or human decoy Fas.

The critical problem with clinical islet transplantation for patients with type 1 diabetes is the severe shortage of human donors. Pig islet xenotransplantation has the potential to provide a virtually unlimited source of donor pancreata. However, our previous studies demonstrated that cell-mediated rejection, especially human CD8(+) cytotoxic T lymphocyte (CTL)-mediated cytotoxicity, remains a major obstacle for long-term islet xenograft survival. Moreover, we have demonstrated that the overexpression of either membrane-bound human FasL (mFasL) or human decoy Fas antigen (decoy Fas) in pig islets not only prevented CTL xenocytotoxicity in vitro, but also prolonged histological survival of pig islet xenografts in vivo. Therefore, the aim of the present study was to determine whether adenoviral transfer of these genes into pig islets ex vivo prior to transplantation had a beneficial effect on posttransplantation glycemic control of diabetic recipients. Isolated pig islets were transfected with adenovirus vector carrying complementary DNA (cDNA) of either mFasL or decoy Fas. The transfected islets were transplanted under the kidney capsule of diabetic recipient rats. Rats transplanted with either mFasL- or decoy Fas-transfected pig islet grafts showed significantly suppressed blood glucose levels from 12 hours to 18 hours posttransplantation compared with control groups transplanted with empty vector-transfected pig islets. Unfortunately, blood glucose levels of these groups were increased, with no significant difference observed at 24 hours posttransplantation. However, transgenic expression of these molecules with clinically tolerable amount of immunosuppressants may be more effective to achieve islet xenograft survival in the future.

Rapamycin induces autophagy in islets: relevance in islet transplantation.

Islet transplantation can provide insulin independence in patients with type 1 diabetes mellitus. However, islet allograft recipients exhibit a gradual decline in insulin independence, and only 10% do not require insulin at 5 years. This decline may reflect drug toxicity to islet beta cells. Rapamycin, a central immunosuppressant in islet transplantation, is a mammalian target of rampamycin inhibitor that induces autophagy. The relative contributions of autophagy in transplanted islets are poorly understood. Therefore, in the present study we sought to evaluate the effects of rapamycin on islet beta cells. Rapamycin treatment of islets resulted in accumulation of membrane-bound light chain 3 (LC3-II) protein, an early marker of autophagy. In addition, rapamycin treatment of isolated islets elicited not only reduction of viability but also downregulation of in vitro potency. To further examine the occurrence of autophagy in rapamycin-treated islets, we used GFP (green fluorescent protein)-LC3 transgenic mice that express a fluorescent autophagosome marker. The GFP-LC3 signals were markedly increased in rapamycin treated islets compared with control islets. In addition, to show improvement by blockade of autophagic signaling, islets were treated with rapamycin in the presence of 3-methyladenine, which inhibits autophagy. Thereafter, both islet viability and islet potency were dramatically improved. The number of GFP-LC3 dots clearly increased after 3-MA treatment. Thus, rapamycin treatment of islets induces autophagy in vitro. This phenomenon may contribute to the progressive graft dysfunction of transplanted islets. Therapeutically targeting this novel signaling may yield significant benefits for long-term islet survival.

Intracellular and extracellular remodeling effectively prevents human CD8(+)cytotoxic T lymphocyte-mediated xenocytotoxicity by coexpression of membrane-bound human FasL and pig c-FLIP(L) in pig endothelial cells.

Human CD8(+) cytotoxic T lymphocyte (CTL)-mediated cytotoxicity, which participates in xenograft rejection, is mediated mainly by the Fas/FasL apoptotic pathway. We previously developed methods to inhibit human CTL xenocytotoxicity by extracellular remodeling using overexpression of membrane-bound human FasL on pig xenograft cells, and by intracellular blockade of death receptor-mediated apoptotic signals, such as the Fas/FasL pathway using the pig c-FLIP(L) molecule. To investigate the cooperative effects of both membrane-bound FasL and pig c-FLIP(L), we cotransfected both genes into pig endothelial cells (PEC). The double remodeling with these molecules effectively prevented CD8(+) CTL killing. Although double transfectants and single high transfectants of either membrane-bound FasL or c-FLIP(L) gene displayed similar inhibition of CTL cytotoxicity, the expression levels of these 2 molecules in double transfectants were almost half the expression levels of single transfectants. Furthermore, to show in vivo prolongation of xenograft survival, we transplanted PEC transfectants under the rat kidney capsule. Prolonged survival was displayed by PEC double transfectant xenografts whereas those from either parental PEC or MOCK (vehicle control) were completely rejected by day 5 posttransplantation. These data suggested that intracellular and extracellular remodeling by coexpression of membrane-bound FasL and pig c-FLIP(L) in xenograft cells may prevent an innate cellular response to xenografts. The gene compatibility of these molecules to generate transgenic pigs may be sufficient to create a window of opportunity to facilitate long-term xenograft survival.