The approval of immunotherapies such as checkpoint inhibitors (CPIs), adoptive cell therapies and cancer vaccines has revolutionized the way cancer treatment is approached.While immunotherapies have improved clinical outcome in a variety of tumor types, some cancers have proven harder to combat using single agents, underscoring the need for multi-targeted immunotherapy approaches. Efficacy of CPIs and cancer vaccines requires patients to have a competent immune system with adequate cell numbers while the efficacy of adoptive cellular therapy is limited by the expansion and persistence of cells after infusion. A promising strategy to overcome these challenges is combination treatment with common gamma-chain cytokines. Gamma-chain cytokines play a critical role in the survival, proliferation, differentiation and function of multiple immune cell types, including CD8 T-cells and NK cells, which are at the center of the anti-tumor response. While the short halflife of recombinant cytokines initially limited their application in the clinic, advancements in protein engineering have led to the development of several next-generation drug candidates with dramatically increased half-life and bioactivity. When combining these cytokines with other immunotherapies, strong evidence of synergy has been observed in preclinical and clinical cancer settings. This promising data has led to the initiation of 70 ongoing clinical trials including IL-2, IL-7, IL-15 and IL-21. This review summarizes the recent advancements of common gamma-chain cytokines and their potential as a cancer immunotherapy.

Mesenchymal stem cells (MSCs) are attractive alternatives to conventional anti-asthmatic drugs for severe asthma. Mechanisms underlying the anti-asthmatic effects of MSCs have not yet been elucidated. This study evaluated the anti-asthmatic effects of intravenously administered MSCs, focusing on macrophages and monocytes. Seven-week-old transgenic (Tg) mice with lung-specific overexpression of IL-13 were used to simulate chronic asthma.MSCs were intravenously administered four days before sampling. We examined changes in immune cell subpopulations, gene expression, and histological phenotypes. IL-13 Tg mice exhibited diverse features of chronic asthma, including severe type 2 inflammation, airway fibrosis, and mucus metaplasia. Intravenous administration of MSCs attenuated these asthmatic features just four days after a single treatment. MSC treatment significantly reduced SiglecF - CD11c - CD11b + monocyte-derived macrophages (MoMs) and inhibited the polarization of MoMs into M2 macrophages, especially M2a and M2c. Furthermore, MSCs downregulated the excessive accumulation of Ly6c - monocytes in the lungs. While an intravenous adoptive transfer of Ly6c - monocytes promoted the infiltration of MoM and Th2 inflammation, that of MSC-exposed Ly6c - monocytes did not. Ex vivo Ly6c - MoMs upregulated M2-related genes, which were reduced by MSC treatment. Molecules secreted by Ly6c - MoMs from IL-13 Tg mice lungs upregulated the expression of fibrosis-related genes in fibroblasts, which were also suppressed by MSC treatment. In conclusion, intravenously administered MSCs attenuate asthma phenotypes of chronic asthma by modulating macrophages. Identifying M2 macrophage subtypes revealed that exposure to MSCs transforms the phenotype and function of macrophages. We suggest that Ly6c - monocytes could be a therapeutic target for asthma management.

Anterior cervical discectomy and fusion (ACDF) immobilizes surgical segments and can lead to the development of adjacent segment degeneration and adjacent segment disease. Thus, cervical total disc replacement (CTDR) has been developed with the aim to preserve the biomechanics of spine. However, heterotopic ossification (HO), a complication following CTDR, can reduce the segmental range of motion (ROM) and defects the motion-preservation benefit of CTDR. The pathological process of HO in CTDR remains unknown. HO has been suggested to be a self-defense mechanism in response to the non-physiological biomechanics of the cervical spine following CTDR. The current literature review is concerned with the association between the biomechanical factors and HO formation and the clinical significance of HO in CTDR. Endplate coverage, disc height, segmental angle, and center of rotation may be associated with the development of HO. The longer the follow-up, the higher the rate of ROM-limiting HO. Regardless of the loss of motion-preservation benefit of CTDR in patients with HO, CTDR confers patients with a motion-preservation period before the development of ROM-limiting HO. This may delay the development of adjacent segment degeneration compared with ACDF. Future clinical studies should explore the association between HO and changes in biomechanical factors of the cervical spine.

Objective To investigate the correlation of cerebral small vessel disease with retinal vascular network parameters using fully automatic retinal image analysis of fundus photographs. Methods A total of 121 patients undertak?ing fundus photography in a sitting position were included. They were divided into either a cerebral small vessel disease group (n=80) or an artery atherosclerotic cerebral infarction group (n=41) according to their cerebral MRI findings. The clinical data and retinal vascular network parameters were compared between the two groups. We used logistic regression to analyse risk factors of the small vessel disease. Results The percentage of males, the incidence of smoking and serum uric acid level in the small vessel disease group were lower than those in the artery atherosclerotic cerebral infarction group(P<0.05). The bifurcation coefficient and asymmetry index of venule in the small vessel disease group were lower than those in the artery atherosclerotic cerebral infarction group(P<0.05). Logistic regression analysis showed that after adjusting vascular risk factors, decreased asymmetry index of venule was associated with cerebral small vessel disease (OR=1.16,95% CI:1.05-1.38,P<0.05). Conclusions The decreased asymmetry index of venule is associated with small vessel disease which can be used as an early diagnotic indicator.

Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-beta1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-beta1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-beta1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-beta1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-beta1 could be an alternative approach that selectively inhibits TGF-beta1-stimulated fibrotic tissue response while preserving major physiological function of TGF-beta1. Recent studies from our laboratory revealed that TGF-beta1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-beta1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-beta1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-beta1 plays a significant role.
Animals ; Drug Design ; Hexosaminidases/antagonists & inhibitors/metabolism ; Humans ; Lung/*drug effects/metabolism/pathology ; Molecular Targeted Therapy ; Pulmonary Fibrosis/*drug therapy/metabolism/pathology ; Receptor Cross-Talk ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Receptors, Transforming Growth Factor beta/antagonists & inhibitors/metabolism ; Signal Transduction ; Transforming Growth Factor beta1/*antagonists & inhibitors/metabolism

PURPOSE: To demonstrate our technical approach for robot-assisted ureteroneocystostomy (R-UNC) for benign and malignant distal ureteral pathologies. MATERIALS AND METHODS: Between January 2009 and January 2013, a total of 10 patients underwent R-UNC in the distal ureter by a single surgeon. Indications for R-UNC were as follows: idiopathic (3), fistula (2), iatrogenic (2), malignancy (2), and chronic vesicoureteral reflux (1). RESULTS: Tension-free anastomosis was attained in all 10 R-UNC procedures. A psoas hitch was performed in 6/10 cases (60%). Intravesical and extravesical reimplantations were completed in 5/10 (50%) and 5/10 cases (50%), respectively. A nonrefluxing ureter was constructed in 2/10 cases (20%). The patients' mean age was 52.9+/-16.6 years, their mean body mass index was 30.8+/-6.3 kg/m2, the mean operative time was 211.7+/-69.3 minutes, mean estimated blood loss was 102.5+/-110.8 mL, and mean length of stay was 2.8+/-2.3 days. There were no intraoperative complications. There was one Clavien-Dindo grade I and one Clavien-Dindo grade II postoperative complication. The mean postoperative follow-up duration was 28.5+/-15.5 months. Two patients had recurrence of ureteral strictures at 3 months postoperatively and were managed successfully with balloon dilation. CONCLUSIONS: Our technique for R-UNC demonstrates good perioperative outcomes. However, underlying periureteral inflammation and pelvic adhesions may predispose patients for stricture recurrence after R-UNC.
Adult ; Body Mass Index ; Constriction, Pathologic ; Fistula ; Follow-Up Studies ; Humans ; Inflammation ; Intraoperative Complications ; Length of Stay ; Operative Time ; Postoperative Complications ; Reconstructive Surgical Procedures ; Recurrence ; Replantation ; Surgical Procedures, Minimally Invasive ; Ureter ; Vesico-Ureteral Reflux

Rapid Rural Appraisal (RRA) is a systematic, semi-structured activity carried out in the field by a multidisciplinary team that is designed to obtain new information and hypotheses about rural life. This article reports the results of an RRA conducted in Kampung Paris 1 (KGP1), Kinabatangan, Sabah under the Annual Health Promotion Program of the School of Medicine, Universiti Malaysia Sabah. A systematic random sampling was used to recruit the villagers and data was obtained through compilation of pre-existing data, field observation, structured interviews with key informants and villagers. Cardiorespiratory diseases were prevalent in KGP1. Common water sources such as rain water collected in dug wells in KGP1 were unhygienic. Dangerous toxic fumes were produced by the burning of municipal wastes nearby village houses. The villagers of KGP1 were exposed to various farm animals, which may harbor zoonoses. Health care services are limited in KGP1. Villagers who were not poor (>RM897) represented 48% of the population, followed by the poor (RM503-897), 20% and the hardcore poor (1.00 person per bedroom. Poor water hygiene, polluted air from open burning, exposure to farm animals, poverty, poor education, overcrowding and inadequate health care services were among the few possible factors affecting the health of villagers in KGP1. Formal rigorous research should be conducted in the future to facilitate specific health interventions in areas of need such as KGP1.
Rural Population ; Rural Health ; Rural Health Services ; Health Status ; Malaysia

A total of 18 Newcastle disease virus (NDV) isolates that were recovered from 1949 through 1997 were characterized and pathotyped. All viruses were highly virulent as determined by intracerebral pathogenicity indices > or = 1.81 in day-old. These pathotypes are typical for viscerotropic velogenic NDV (VVNDV) pathotype viruses. Some differences were observed for the chicken red blood cell elution rate and thermostability of the hemagglutinin at 56degrees C. Three antigenic groups were identified by a hemagglutination-inhibition assay using NDV monoclonal antibodies. And the predominant gross lesions were as follows: discharge from the nasal cavity, tracheal mucus, petechial hemorrhage in the heart fat, kidney urates and hemorrhage with or without necrosis in the gastrointestinal tract. Severe hemorrhagic or necrotic lesions were also noted in the lymphoid organs and were localized primarily in the spleen and cecal tonsil. However, differences in the occurrence and frequency of the gross lesions were observed between the virus strains. Among them, NDV strains that induced neurological symptoms belonged only to genotype VI. This strain had spread throughout Korea during the late 1980s to the 1990s, which suggests that specific VVNDVs genotypes might result in neurological symptoms.
Animals ; Antibodies, Monoclonal ; Avulavirus ; Chickens ; Erythrocytes ; Gastrointestinal Tract ; Genotype ; Heart ; Hemagglutinins ; Hemorrhage ; Kidney ; Korea ; Mucus ; Nasal Cavity ; Necrosis ; Newcastle Disease ; Newcastle disease virus ; Palatine Tonsil ; Spleen ; Sprains and Strains ; Viruses

Recent clinical evidence indicates that the non-eosinophilic subtype of severe asthma is characterized by fixed airway obstruction, which may be related to emphysema. Transgenic studies have demonstrated that high levels of IFN-gamma in the airways induce emphysema. Fibroblast growth factor 2 (FGF2), which is the downstream mediator of TGF-beta, is important in wound healing. We investigated the role of FGF2 in IFN-gamma-induced emphysema and the therapeutic effects of recombinant FGF2 in the prevention of emphysema in a severe non-eosinophilic asthma model. To evaluate the role of FGF2 in IFN-gamma-induced emphysema, lung targeted IFN-gamma transgenic mice were cross-bred with FGF2-deficient mice. A severe non-eosinophilic asthma model was generated by airway application of LPS-containing allergens twice a week for 4 weeks. To evaluate protective effects of FGF2, recombinant FGF2 (10 microg) was injected subcutaneously during allergen challenge in the severe asthma model. We found that non-eosinophilic inflammation and emphysema induced by transgenic overexpression of IFN-gamma in the airways were aggravated by the absence of FGF2. Airway challenge with LPS-containing allergens induced more inflammation in mice sensitized with LPS-containing allergens compared to challenge with allergens alone. In addition, LPS-induced lung inflammation and emphysema depended on IFN-gamma but not on IL-13. Interestingly, emphysema in the severe asthma model was significantly inhibited by treatment with recombinant FGF2 during allergen challenge, whereas lung inflammation was unaffected. Therefore, our present data suggest that FGF2 may help protect against IFN-gamma-induced emphysema, and that recombinant FGF2 may help lessen the severity of emphysema.
Animals ; Asthma/drug therapy/*prevention & control ; Bronchoalveolar Lavage Fluid ; Disease Models, Animal ; Emphysema/drug therapy/*prevention & control ; Enzyme-Linked Immunosorbent Assay ; Fibroblast Growth Factor 2/deficiency/*metabolism/*therapeutic use ; Flow Cytometry ; Inflammation/immunology ; Interferon-gamma/*biosynthesis/genetics ; Interleukin-13 ; Lipopolysaccharides/administration & dosage/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pulmonary Eosinophilia ; Recombinant Proteins/administration & dosage/therapeutic use

BRP-39 and its human homolog YKL-40 have been regarded as a prototype of chitinase-like proteins (CLP) in mammals. Exaggerated levels of YKL-40 protein and/or mRNA have been noted in a number of diseases characterized by inflammation, tissue remodeling, and aberrant cell growth. Asthma is an inflammatory disease characterized by airway hyperresponsiveness and airway remodeling. Recently, the novel regulatory role of BRP-39/YKL-40 in the pathogenesis of asthma has been demonstrated both in human studies and allergic animal models. The levels of YKL-40 are increased in the circulation and lungs from asthmatics where they correlate with disease severity, and CHI3L1 polymorphisms correlate with serum YKL-40 levels, asthma and abnormal lung function. Animal studies using BRP-39 null mutant mice demonstrated that BRP-39 was required for optimal allergen sensitization and Th2 inflammation. These studies suggest the potential use of BRP-39 as a biomarker as well as a therapeutic target for asthma and other allergic diseases. Here, we present an overview of chitin/chitinase biology and summarize recent findings on the role of BRP-39 in the pathogenesis of asthma and allergic responses.
Airway Remodeling ; Animals ; Asthma ; Biology ; Breast ; Humans ; Hypersensitivity ; Inflammation ; Lung ; Mammals ; Mice ; Models, Animal ; Proteins ; RNA, Messenger