BACKGROUND: Small cell lung cancer (SCLC) is characterized by poor differentiation, high malignancy and rapid growth fast, short double time, early and extensive metastatic malignancy. In clinical, chemotherapy is the main treatment method, while resistance to multiple chemotherapy drugs in six to nine months has been a major clinical challenge in SCLC treatment. Therefore, It has important clinical value to building SCLC aninimal model which is similar to patients with SCLC. Animal model of xenotransplantation (PDX) from the patients with small cell lung cancer can well retain the characteristics of primary tumor and is an ideal preclinical animal model. The study is aimed to establish SCLC PDX animal model and induce the chemoresistance model to help to study the mechanism of chemoresistance and individual treatment. METHODS: Fresh surgical excision or puncture specimens from SCLC patients were transplanted into B-NSGTM mice subcutaneous tissues with severe immunodeficiency in one hour after operation the B-NSGTM mice subcutaneous in 1 hour, and inject chemotherapy drugs intraperitoneally after its tumor growed to 400 mm³ with EP which is cisplatin 8 mg/kg eight days and etoposide 5 mg/kg every two days until 8 cycles. Measure the tumor volum and mice weights regularly, then re-engrafted the largest tumor and continue chemotherapy. RESULTS: Nine cases were conducted for B-NSG mice modeling. Three of nine cases could be engrafted to new B-NSG mice at least two generation. The SCLC PDX animal models have been established successfully. After adopting chemotherapy drugs, the chemoresistance PDX models have been established. High homogeneity was found between xenograft tumor and patient's tumor in histopathology, immunohistochemical phenotype (Syn, CD56, Ki67). CONCLUSIONS The SCLC PDX animal model and the chemoresistance PDX animal model have been successfully constructed, the success rate is 33%, which provides a platform for the clinical research, seeking for biological markers and choosing individual treatment methods of SCLC.
Animals ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Cisplatin ; administration & dosage ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Etoposide ; administration & dosage ; Female ; Humans ; Interleukin Receptor Common gamma Subunit ; deficiency ; genetics ; Lung Neoplasms ; drug therapy ; metabolism ; pathology ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Small Cell Lung Carcinoma ; drug therapy ; metabolism ; pathology ; Transplantation, Heterologous ; methods ; Xenograft Model Antitumor Assays

BACKGROUND: The shortage of human hearts for allotransplantation makes xenotransplantation a possible option for controllable organ providers. To detect acute xenograft rejection, invasive biopsy seems inevitable; however, this occasionally results in poor incision wound healing or infection. To date, no method of noninvasive imaging for early detection of xenograft rejection has been established. We hypothesized that ultrasound speckle tracking would better detect xenograft failure than routine left ventricular ejection fractions (EF). METHODS: From August 2013 to July 2015, a total of six cardiac heterotopic xenotransplants (α 1, 3-galactosyltransferase gene-knockout porcine heart) into cynomolgus monkeys were monitored with echocardiography every 3 to 7 days. M-mode and two-dimensional (2D)-EF measurements and myocardial strain analyses were performed. Cardiac xenograft pathology was reviewed from the immediate postoperative biopsy, as well as the necropsy. RESULTS: Myocardial speckle tracking analysis was feasible in all six cases. The longest survival was 43 days. Only one pathology-proven immunologic rejection occurred. Cardiac xenograft failure appeared as two types: a dilated pattern with decreased EF or a myocardial-thickening pattern with preserved EF. Both antibody-mediated rejection (n=1) and sepsis-induced myocardial dysfunction (n=2) revealed decreased radial or circumferential strains, but normal-range EF. Xenograft functional decline was significant with respect to radial or circumferential strain (P=0.028), but not to conventional M-mode or 2D-EFs (P=0.600, P=0.340, respectively). CONCLUSIONS: Radial and circumferential strains were significantly decreased in both types of xenograft failure, regardless of EF. Further studies are warranted to correlate the strain analysis and immunopathological details.
Biopsy ; Echocardiography ; Heart ; Heart Transplantation ; Heterografts ; Humans ; Macaca fascicularis ; Methods ; Pathology ; Stroke Volume ; Transplantation, Heterologous* ; Transplants* ; Ultrasonography ; Wound Healing

Spermatogonial stem cells (SSCs) are essential for spermatogenesis throughout the lifespan of the male. However, the rarity of SSCs has raised the need for an efficient selection method, but little is known about culture conditions that stimulate monkey SSC proliferation in vitro. In this study, we report the development of effective enrichment techniques and in vitro culturing of germ cells from pre-pubertal monkey testes. Testis cells were analyzed by fluorescence-activated cell sorting techniques and were transplanted into the testes of nude mice to characterize SSCs. Thy-1-positive cells showed a higher number of colonies than the unselected control after xenotransplantation. Extensive colonization of monkey cells in the mouse testes indicated the presence of highly enriched populations of SSCs in the Thy-1-positive sorted cells. Furthermore, monkey testis cells were enriched by differential plating using extracellular matrix, laminin, and gelatin, and then cultured under various conditions. Isolation of monkey testicular germ cells by differential plating increased germ cell purity by 2.7-fold, following the combinational isolation method using gelatin and laminin. These enriched germ cells actively proliferated under culture conditions involving StemPro medium supplemented with bFGF, GDNF, LIF, and EGF at 37 ℃. These results suggest that the enrichment and in vitro culture method proposed in the present study for harvesting a large number of functionally active monkey SSCs can be applied as the basis for efficient in vitro expansion of human SSCs.
Animals ; Colon ; Epidermal Growth Factor ; Extracellular Matrix ; Flow Cytometry ; Gelatin ; Germ Cells ; Glial Cell Line-Derived Neurotrophic Factor ; Haplorhini* ; Humans ; In Vitro Techniques* ; Laminin ; Male ; Methods ; Mice ; Mice, Nude ; Spermatogenesis ; Stem Cells* ; Testis* ; Transplantation, Heterologous

Solid organ xenotransplantation using transgenic pig organs is proposed as an alternative method for allo-transplantation. To accomplish this, immunologic and non-immunologic barriers for xenotransplantation should be overcome, and experiments on pigs to non-human primates (NHP) are now ongoing for clinical application. Before the clinical experiment, public consensus about ethical decisions must be considered. The results of NHP experiments on solid organ xenotransplantation are improving, and it is expected that xeno-solid organs can be used as new organs for human patients in the future.
Consensus ; Humans ; Methods ; Primates ; Swine ; Transplantation, Heterologous*

Bone xenograft bone for the treatment of bone defect is one of the current research focus, which has advantages of extensive sources, low cost, simple preparation method. While the process of single bone xenograft bone in repairing bone defect is very long, and the clinical outcome is not satisfactory. The main problems focus on formation of bone and vascularization. Reconstituted bone xenograft combined with cells and xenogenic bone material could promote vascularization and bone fusion in vivo, thus achieve a clinical effect of autogenous bone in repairing bone defect.
Bone Transplantation ; methods ; Bone and Bones ; blood supply ; Humans ; Transplantation, Heterologous

Patient-derived tumor xenograft is the transfer of primary human tumors directly into an immunodeficient mouse. Patient-derived tumor xenograft plays an important role in the development and evaluation of new chemotherapeutic agents. We succeeded in generating a patient-derived tumor xenograft of a biliary tumor obtained by endoscopic ultrasound-guided fine-needle aspiration from a patient who had an inoperable extrahepatic cholangiocarcinoma. This patient-derived tumor xenograft will be a promising tool for individualized cancer therapy and can be used in developing new chemotherapeutic agents for the treatment of biliary cancer in the future.
Aged ; Animals ; Bile Duct Neoplasms/*pathology/surgery ; Cholangiocarcinoma/*pathology/surgery ; Endoscopic Ultrasound-Guided Fine Needle Aspiration ; Heterografts/*pathology/surgery ; Humans ; Male ; Mice ; Mice, Nude ; Transplantation, Heterologous/*methods

OBJECTIVEThe aim of this study was to establish patient-derived lung cancer xenograft models in nude mice by subcutaneous and subrenal capsule transplantation, and to analyze the differences in biological characteristics of the xenografts.

METHODSSurgically resected lung cancer specimens from 11 patients were implanted subcutaneously and under the renal capsule in nude mice. The tumor growth and histopathological features were observed and human origin of the blood vessels in the first-generation xenograft tumors was evaluated by SP immunohistochemistry using anti-human CD31 antibody.

RESULTSThe patient-derived lung cancer tissues were successfully implanted subcutaneously and under the renal capsule in 11 nude mice. The operation time of subcutaneous implantation was 13 min, and the tumor formation rate was 36.4% (4/11). The operation time of implantation under the renal capsule was 45 min, and the tumor formation rate was 45.5% (5/11). Histopathological examination of the xenografts using HE staining showed the same morphology of the human lung cancers, and immunohistochemical observation with CD31staining showed that 83.3% (5/6) blood vessels in the xenograft tumors was of human origin.

CONCLUSIONSBoth methods of subcutaneous and subrenal capsule transplantation can be used to successfully establish patient-derived lung cancer xenograft models in nude mice. The subcutaneous implantation is simple to operate, less time-comsuming, and easy to observe the tumor growth, but with a lower success rate of tumor formation. Transplantation under the renal capsule has a higher tumor formation rate, but is more difficult to operate, taking more time, and difficult to observe the growth of the tumor. The xenograft tumors formed by both methods in the first generation display biological characteristics of human lung cancer, the xenograft tumor models are close to human lung cancer, and therefore may provide a stable, reliable, and useful animal model in human lung cancer research.

Animals ; Disease Models, Animal ; Heterografts ; Humans ; Immunohistochemistry ; Lung Neoplasms ; Mice ; Mice, Nude ; Neoplasm Transplantation ; methods ; Transplantation, Heterologous

OBJECTIVETo review the current status and progress on pig islet xenotransplantation.

DATA SOURCESData used in this review were mainly from English literature of Pubmed database. The search terms were "pig islet" and "xenotransplantation".

STUDY SELECTIONThe original articles and critical reviews selected were relevant to this review's theme.

RESULTSPigs are suggested to be an ideal candidate for obtaining available islet cells for transplantation. However, the potential clinical application of pig islet is still facing challenges including inadequate yield of high-quality functional islets and xenorejection of the transplants. The former can be overcome mainly by selection of a suitable pathogen-free source herd and the development of isolation and purification technology. While the feasibility of successful preclinical pig islet xenotranplantation provides insights in the possible mechanisms of xenogeneic immune recognition and rejection to overwhelm the latter. In addition, the achievement of long-term insulin independence in diabetic models by means of distinct islet products and novel immunotherapeutic strategies is promising.

CONCLUSIONSPig islet xenotransplantation is one of the prospective treatments to bridge the gap between the needs of transplantation in patients with diabetes and available islet cells. Nonetheless, further studies and efforts are needed to translate obtained findings into tangible applications.

Animals ; Graft Rejection ; immunology ; prevention & control ; Islets of Langerhans Transplantation ; immunology ; methods ; Swine ; Transplantation, Heterologous ; methods

This study was purposed to investigate the conditions for improving human-mouse xenograft and the erythroid differentiation of human hematopoietic stem cells (HSC) in the xenotransplant model. The engraftments of different mouse strains (NOD/SCID or NOD/SCID/IL2rγ(null)), schemes of irradiation (single-time or 2-times radiation; Co(60)γ-ray or X-ray) and strategies of CB CD34(+) cells ex vivo culture time and lentivirus infection were compared. The results showed that at 4 weeks after transplantation, the ratio of hCD45 positive cells in bone marrow of NOD/SCID/IL2rγ(null) mice increased to (51.4 ± 13.9)%, and erythroid precursor could be detected. All of the mice receiving X-ray irradiation for 2 times (a dose of 1 Gy, then the second of 1.5 Gy, with an interval of 15 min) survived. Fresh isolated CB CD34(+) cells were cultured and infected with lentivirus for 72 h and then transplanted into receptor mouse. After 4 weeks, higher engraftment [hCD45 (51.4 ± 13.9)%] and better erythroid development [hCD71(+) GPA(+) (5.98 ± 3.46)%] were observed. It is concluded that NOD/SCID/IL2rγ(null) mice receiving X-ray irradiation for 2 times and were injected with fresh isolated CB CD34(+) cells cultured and infected with lentivirus ex vivo within 72 h show a better xenograft and erythroid development.
Animals ; Antigens, CD34 ; Bone Marrow Cells ; cytology ; Cells, Cultured ; Erythrocytes ; cytology ; Erythropoiesis ; Female ; Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Transplantation, Heterologous

OBJECTIVETo explore the effect of human umbilical cord blood mononuclear cells (UCBMC) promoting nerve behavior function and brain tissue recovery of neonatal SD rat with hypoxic ischemic brain injury (HIBI).

METHODA modified newborn rat model that had a combined hypoxic and ischemic brain injury as described by Rice-Vannucci was used, early nervous reflex, the Morris water maze and walking track analysis were used to evaluate nervous behavioral function, and brain MRI, HE staining to evaluate brain damage recovery.

RESULTNewborn rat Rice-Vannucci model showed significant brain atrophy, obvious hemiplegia of contralateral limbs,e.g right step length [(7.67 ± 0.46) cm vs. (8.22 ± 0.50) cm, F = 1.494] and toe distance [(0.93 ± 0.06) cm vs. (1.12 ± 0.55) cm, F = 0.186] were significantly reduced compared with left side, learning and memory ability was significantly impaired compared with normal control group (P < 0.01); Cliff aversion [(8.44 ± 2.38) s vs.(14.22 ± 5.07) s, t = 4.618] and negative geotaxis reflex time [(7.26 ± 2.00) s vs. (11.76 ± 3.73) s, t = 4.755] on postnatal 14 days of HIBI+ transplantation group were significantly reduced compared with HIBI+NaCl group (P < 0.01) ; the Morris water maze experiment showed escape latency [ (23.11 ± 6.64) s vs. (34.04 ± 12.95) s, t = 3.356] and swimming distance [ (9.12 ± 1.21) cm vs.(12.70 ± 1.53) cm, t = 17.095] of HIBI+transplantation group were significantly reduced compared with those of HIBI+NaCl group (P < 0.01) ; the residual brain volume on postnatal 10 d [ (75.37 ± 4.53)% vs. (67.17 ± 4.08)%, t = -6.017] and 67 d [ (69.05 ± 3.58)% vs.(60.83 ± 3.69)%, t = -7.148]of HIBI+ transplantation group were significantly larger than those of HIBI+NaCl group (P < 0.01); After human UCBMC transplantation, left cortical edema significantly reduced and nerve cell necrosis of HIBI+ transplantation group is not obvious compared with HIBI+NaCl group.

CONCLUSIONHuman UCBMC intraperitoneal transplantation significantly promoted recovery of injured brain cells and neurobehavioral function development.

Animals ; Animals, Newborn ; Atrophy ; etiology ; pathology ; Brain ; diagnostic imaging ; pathology ; Cerebral Cortex ; pathology ; Cord Blood Stem Cell Transplantation ; methods ; Disease Models, Animal ; Female ; Fetal Blood ; cytology ; Humans ; Hypoxia-Ischemia, Brain ; complications ; pathology ; therapy ; Learning Disorders ; etiology ; prevention & control ; Leukocytes, Mononuclear ; cytology ; transplantation ; Magnetic Resonance Imaging ; Male ; Maze Learning ; Neurons ; pathology ; Psychomotor Performance ; Radiography ; Rats ; Rats, Sprague-Dawley ; Transplantation, Heterologous