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1.
Blood Cancer Discov ; 5(3): 139-141, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38651690

ABSTRACT

SUMMARY: The spatial distribution of cells carrying clonal hematopoiesis mutations in the bone marrow and the potential role of interactions with the microenvironment are largely unknown. This study takes clonal evolution to the spatial level by describing a novel technique examining the spatial location of mutated clones in the bone marrow and the first evidence that mutated hematopoietic clones are spatially constrained and have heterogenous locations within millimeters of distance. See related article by Young et al., p. 153 (10).


Subject(s)
Clonal Evolution , Clonal Hematopoiesis , Mutation , Clonal Evolution/genetics , Humans , Clonal Hematopoiesis/genetics , Bone Marrow , Hematopoiesis/genetics , Hematopoietic Stem Cells/cytology
2.
Nat Commun ; 14(1): 2155, 2023 04 14.
Article in English | MEDLINE | ID: mdl-37059710

ABSTRACT

Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.


Subject(s)
Hematologic Neoplasms , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/pathology , Oncogenes , Hematologic Neoplasms/genetics
3.
Nature ; 588(7836): 157-163, 2020 12.
Article in English | MEDLINE | ID: mdl-33239784

ABSTRACT

Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells1,2. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system3,4 and in haematopoietic cancers5. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones6,7, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2-ERK signalling and the maintenance of JAK2V617F malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2.


Subject(s)
Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Neoplasms/genetics , Neoplasms/pathology , Y-Box-Binding Protein 1/metabolism , Animals , Apoptosis/drug effects , Cell Line , Cells, Cultured , Clone Cells/metabolism , Clone Cells/pathology , Female , Heterografts , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Introns/genetics , Janus Kinase 2/antagonists & inhibitors , MAP Kinase Signaling System/drug effects , Male , Mice , Mutation , Neoplasm Transplantation , Neoplasms/drug therapy , Phosphoproteins/analysis , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proteome/analysis , Proteomics , RNA Splicing/genetics , Remission Induction , Y-Box-Binding Protein 1/antagonists & inhibitors , Y-Box-Binding Protein 1/chemistry
4.
Cell Stem Cell ; 27(1): 19-34, 2020 07 02.
Article in English | MEDLINE | ID: mdl-32619515

ABSTRACT

Single-cell sequencing approaches offer exploration of tissue architecture at unprecedented resolution. These tools are especially powerful when deconvoluting highly specialized microenvironments, such as stem cell (SC) niches. Here, we review single-cell studies that map the cellular and transcriptional makeup of stem and progenitor niches and discuss how these high-resolution analyses fundamentally advance our understanding of how niche factors shape SC biology and activity. In-depth characterization of the blueprint of SC-niche crosstalk, as well as understanding how it becomes dysregulated, will undoubtedly inform the development of more efficient therapies for malignancies and other pathologies.


Subject(s)
Stem Cell Niche
5.
Cell Rep ; 30(8): 2512-2525.e9, 2020 02 25.
Article in English | MEDLINE | ID: mdl-32101732

ABSTRACT

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4+ T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.


Subject(s)
Immunity/drug effects , Interferon Type I/pharmacology , Leishmaniasis, Visceral/immunology , Leishmaniasis, Visceral/parasitology , Parasites/immunology , Amphotericin B/pharmacology , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/immunology , Epitopes , Humans , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/pharmacology , Mice, Inbred C57BL , Nitriles , Parasites/drug effects , Pyrazoles/pharmacology , Pyrimidines , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/metabolism , Signal Transduction/drug effects
6.
Leukemia ; 34(4): 1075-1089, 2020 04.
Article in English | MEDLINE | ID: mdl-31732720

ABSTRACT

JAK2V617F is the most common mutation in patients with BCR-ABL negative myeloproliferative neoplasms (MPNs). The eradication of JAK2V617F hematopoietic stem cells (HSCs) is critical for achieving molecular remissions and cure. We investigate the distinct effects of two therapies, ruxolitinib (JAK1/2 inhibitor) and interferon-alpha (IFN-α), on the disease-initiating HSC population. Whereas ruxolitinib inhibits Stat5 activation in erythroid progenitor populations, it fails to inhibit this same pathway in HSCs. In contrast, IFN-α has direct effects on HSCs. Furthermore, STAT1 phosphorylation and pathway activation is greater after IFN-α stimulation in Jak2V617F murine HSCs with increased induction of reactive oxygen species, DNA damage and reduction in quiescence after chronic IFN-α treatment. Interestingly, ruxolitinib does not block IFN-α induced reactive oxygen species and DNA damage in Jak2V617F murine HSCs in vivo. This work provides a mechanistic rationale informing how pegylated IFN-α reduces JAK2V617F allelic burden in the clinical setting and may inform future clinical efforts to combine ruxolitinib with pegylated IFN-α in patients with MPN.


Subject(s)
Hematopoietic Stem Cells/drug effects , Interferon-alpha/pharmacology , Janus Kinase 2/genetics , Mutation , Myeloproliferative Disorders/drug therapy , Pyrazoles/pharmacology , STAT1 Transcription Factor/metabolism , Animals , Antiviral Agents/pharmacology , Cell Proliferation , Cells, Cultured , Drug Therapy, Combination , Female , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/pathology , Nitriles , Pyrimidines , STAT1 Transcription Factor/genetics
7.
Fam Med ; 51(5): 434-437, 2019 May.
Article in English | MEDLINE | ID: mdl-31081916

ABSTRACT

BACKGROUND AND OBJECTIVES: Given the current opioid epidemic, national practice guidelines and many state laws are shifting the treatment paradigm for chronic, noncancer pain to a judicious use of opioids. This has prompted a need to teach family medicine residents how to appropriately taper opioids. We created a multifaceted approach to integrate teaching of opioid tapering into a family medicine curriculum with an emphasis on guided instruction. We assessed the degree to which this curriculum affected guideline-concordant opioid prescribing within the family medicine practice. METHODS: A retrospective chart review of 707 patients on chronic opioid therapy (COT) for noncancer pain was conducted before and after the incorporation of a guided instruction experience to the residency curriculum. The primary outcomes included the number of patients on chronic opioids, the average morphine equivalent daily (MED) per patient, the percentage of patients on >50 MED or >90 MED, and the number of patients on concomitant benzodiazepines. RESULTS: Of the original 707 patients, 188 tapered off COT. Of those remaining on COT, the average MED did not change (53.4±76.9 vs 58.5+89.1, P=0.053). The percentage of patients on >50 MED and >90 MED decreased significantly (30.6% vs 25.0%, P=0.001; 19.4% vs 14.0%, P=0.027). The total number of patients on concomitant benzodiazepine decreased from 212 to 131. CONCLUSIONS: Providing opportunities for guided instruction with opioid tapering allowed for an increased concordance with national practice guidelines.


Subject(s)
Analgesics, Opioid/administration & dosage , Chronic Pain/drug therapy , Family Practice/education , Internship and Residency , Practice Patterns, Physicians' , Aged , Female , Humans , Male , Pain Management , Retrospective Studies
8.
Blood ; 132(26): 2707-2721, 2018 12 27.
Article in English | MEDLINE | ID: mdl-30366920

ABSTRACT

Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a-/- Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.


Subject(s)
Amino Acid Substitution , DNA (Cytosine-5-)-Methyltransferases , Hematologic Neoplasms , Hematopoietic Stem Cells , Mutation, Missense , Primary Myelofibrosis , Signal Transduction/genetics , Animals , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , Hematologic Neoplasms/enzymology , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Hematopoietic Stem Cells/enzymology , Hematopoietic Stem Cells/pathology , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Mice , Mice, Mutant Strains , Primary Myelofibrosis/enzymology , Primary Myelofibrosis/genetics , Primary Myelofibrosis/pathology
9.
J Immunol ; 200(4): 1443-1456, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29321276

ABSTRACT

Differentiation of CD4+ Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage Plasmodium parasites, yet their influence over Th cell immunity remains unclear. In this study, we used Plasmodium-reactive TCR transgenic CD4+ T cells, termed PbTII cells, during nonlethal P. chabaudi chabaudi AS and P. yoelii 17XNL infection in mice, to examine Th cell development in vivo. We found no role for caspase1/11, stimulator of IFN genes, or mitochondrial antiviral-signaling protein, and only modest roles for MyD88 and TRIF-dependent signaling in controlling PbTII cell expansion. In contrast, IFN regulatory factor 3 (IRF3) was important for supporting PbTII expansion, promoting Th1 over T follicular helper (Tfh) differentiation, and controlling parasites during the first week of infection. IRF3 was not required for early priming by conventional dendritic cells, but was essential for promoting CXCL9 and MHC class II expression by inflammatory monocytes that supported PbTII responses in the spleen. Thereafter, IRF3-deficiency boosted Tfh responses, germinal center B cell and memory B cell development, parasite-specific Ab production, and resolution of infection. We also noted a B cell-intrinsic role for IRF3 in regulating humoral immune responses. Thus, we revealed roles for IRF3 in balancing Th1- and Tfh-dependent immunity during nonlethal infection with blood-stage Plasmodium parasites.


Subject(s)
Cell Differentiation/immunology , Interferon Regulatory Factor-3/immunology , Malaria/immunology , T-Lymphocytes, Helper-Inducer/immunology , Th1 Cells/immunology , Animals , Female , Germinal Center/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Spleen/immunology
10.
Liver Int ; 38(6): 1074-1083, 2018 06.
Article in English | MEDLINE | ID: mdl-29171144

ABSTRACT

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality. Risk factors for developing HCC include viral hepatitis, alcohol and obesity. Fatty acid-binding proteins (FABPs) bind long-chain free fatty acids (FFAs) and are expressed in a tissue-specific pattern; FABP1 being the predominant hepatic form, and FABP4 the predominant adipocyte form. The aims of this study were to investigate the expression and function of FABPs1-9 in human and animal models of obesity-related HCC. METHODS: FABP1-9 expression was determined in a mouse model of obesity-promoted HCC. Based on these data, expression and function of FABP4 was determined in human HCC cells (HepG2 and HuH7) in vitro. Serum from patients with different underlying hepatic pathologies was analysed for circulating FABP4 levels. RESULTS: Livers from obese mice, independent of tumour status, exhibited increased FABP4 mRNA and protein expression concomitant with elevated serum FABP4. In vitro, FABP4 expression was induced in human HCC cells by FFA treatment, and led to FABP4 release into culture medium. Treatment of HCC cells with exogenous FABP4 significantly increased proliferation and migration of human HCC cells. Patient serum analysis demonstrated significantly increased FABP4 in those with underlying liver disease, particularly non-alcoholic fatty liver disease (NAFLD) and HCC. CONCLUSIONS: These data suggest FABP4, an FABP not normally expressed in the liver, can be synthesized and secreted by hepatocytes and HCC cells, and that FABP4 may play a role in regulating tumour progression in the underlying setting of obesity.


Subject(s)
Carcinoma, Hepatocellular/pathology , Fatty Acid-Binding Proteins/metabolism , Liver Neoplasms/pathology , Obesity/metabolism , Animals , Carcinoma, Hepatocellular/metabolism , Disease Models, Animal , Hep G2 Cells , Hepatocytes/metabolism , Humans , Liver/pathology , Liver Neoplasms/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/complications , RNA, Messenger/analysis , Risk Factors
11.
Crit Rev Oncol Hematol ; 103: 62-77, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27247119

ABSTRACT

Acute myeloid leukaemia (AML) is an aggressive blood cancer caused by the proliferation of immature myeloid cells. The genetic abnormalities underlying AML affect signal transduction pathways, transcription factors and epigenetic modifiers. In solid tumours, it is emerging that the genetic landscape of the tumour has a direct effect on the anti-tumour immune responses and response to immunotherapeutic treatment. However, there remains little information as to whether genetic abnormalities affect anti-leukemic immune responses. This review discusses current knowledge of AML antigens and immune responses to AML with a particular focus on the role of T cells and natural killer cells. Understanding immune responses to AML has implications for the development and use of immunotherapies to treat AML patients with distinct genetic abnormalities.


Subject(s)
Leukemia, Myeloid, Acute/immunology , Animals , Antigen Presentation , Cancer Vaccines/therapeutic use , Cytokines/immunology , Humans , Immunotherapy , Leukemia, Myeloid, Acute/genetics , T-Lymphocytes/pathology
13.
Cell Stem Cell ; 15(6): 775-90, 2014 Dec 04.
Article in English | MEDLINE | ID: mdl-25479751

ABSTRACT

Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs.


Subject(s)
Indoles/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Neoplastic Stem Cells/drug effects , Niacinamide/analogs & derivatives , Telomerase/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/genetics , Cells, Cultured , Disease Models, Animal , Gene Expression Regulation, Neoplastic/genetics , Gene Knockout Techniques , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred C57BL , Neoplastic Stem Cells/physiology , Neoplastic Stem Cells/transplantation , Niacinamide/administration & dosage , Oligonucleotides , RNA, Small Interfering/genetics , Recurrence , Telomerase/genetics , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
14.
Blood ; 121(18): 3692-702, 2013 May 02.
Article in English | MEDLINE | ID: mdl-23487027

ABSTRACT

Interferon-α (IFNα) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFNα reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNα on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNα on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNα treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNα treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNα on Jak2V617F mutant and normal hematopoiesis and suggest that IFNα achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNα and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy.


Subject(s)
Hematologic Neoplasms/pathology , Interferon-alpha/pharmacology , Janus Kinase 2/genetics , Neoplastic Stem Cells/drug effects , Polycythemia Vera/pathology , Amino Acid Substitution/genetics , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Hematologic Neoplasms/genetics , Humans , Janus Kinase 2/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutant Proteins/genetics , Mutant Proteins/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/physiology , Phenylalanine/genetics , Polycythemia Vera/drug therapy , Polycythemia Vera/genetics , Valine/genetics
15.
Langmuir ; 23(10): 5735-9, 2007 May 08.
Article in English | MEDLINE | ID: mdl-17402759

ABSTRACT

Herein we report a new strategy for protein refolding by taking advantage of the unique surface and pore characteristics of ethylene-bridged periodic mesoporous organosilica (PMO), which can effectively entrap unfolded proteins and assist refolding by controlled release into the refolding buffer. Hen egg white lysozyme was used as a model protein to demonstrate the new method of protein refolding. Through loading of denatured proteins inside uniform mesoporous channels tailored to accommodate individual protein, protein aggregation was minimized, and the folding rate was increased. Poly(ethyleneglycol) (PEG)-triggered continuous release of entrapped denatured lysozyme allowed high-yield refolding with high cumulative protein concentrations. The new method enhances the oxidative refolding of lysozyme (e.g., over 80% refolding yield at about 0.6 mg/mL).


Subject(s)
Muramidase/chemistry , Polyethylene Glycols/chemistry , Protein Folding , Silanes/chemistry , Silicon Dioxide/chemistry , Oxidation-Reduction , Protein Denaturation
16.
J Endourol ; 18(9): 879-82, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15659925

ABSTRACT

PURPOSE: To demonstrate a novel application of laparoscopy to assist in the correction of ureteropelvic junction (UPJ) obstruction. PATIENTS AND METHODS: A retroperitoneal space is created, and the UPJ is identified and dissected from the surrounding tissue with a 1 x 10-mm 0 degrees telescope and 2 x 5-mm endoscopic instruments. Using a 5-0 Prolene stay suture, the UPJ is brought up through the 10-mm trocar site to the skin level, and the pyeloplasty is performed ex vivo over a double-J stent with loop magnification. Between July 2002 and March 2003, nine male and two female patients with UPJ obstruction underwent a pyeloplasty using this retroperitoneal-assisted laparoscopic pyeloplasty (RALP). The operative time, hospital stay, pain management, and follow-up radiologic studies were reviewed. RESULTS: In nine patients, RALP (bilateral in one patient) was performed (nine on the left side and one on the right). In the remaining two patients, mobilization of the UPJ was inadequate, and open conversion was performed. The average RALP operative time was 160 minutes (range 121-193 minutes). Postoperative pain management was optimal using oral codeine in eight patients, while one patient (RALP and pyelolithotomy) received parenteral analgesic postoperatively. The average length of stay in the hospital was 2 days (range 1-3 days). Follow-up (5-14 months) radiologic studies after stent removal showed improvement in the hydronephrosis in all except one patient. Furosemide renal scan at 3 to 6 months postoperatively was done in all patients and showed no obstruction. CONCLUSION: We consider RALP as the technique of choice for surgeons who want to increase their reconstructive laparoscopic skills. It provides an additional technique when skilled laparoscopists are faced with technically difficult pyeloplasties.


Subject(s)
Kidney Pelvis/surgery , Laparoscopy , Ureteral Obstruction/surgery , Child , Child, Preschool , Female , Humans , Length of Stay , Male , Pain, Postoperative , Urologic Surgical Procedures/methods
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