Clinical implications of exosome-derived noncoding RNAs in liver.

Exosomes, one of three main types of extracellular vesicles, are ~30-100 nm in diameter and have a lipid bilayer membrane. They are widely distributed in almost all body fluids. Exosomes have the potential to regulate unknown cellular and molecular mechanisms in intercellular communication, organ homeostasis, and diseases. They are critical signal carriers that transfer nucleic acids, proteins, lipids, and other substances into recipient cells, participating in cellular signal transduction and material exchange. ncRNAs are non-protein-coding genes that account for over 90% of the genome and include microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). ncRNAs are crucial for physiological and pathological activities in the liver by participating in gene transcription, posttranscriptional epigenetic regulation, and cellular processes through interacting with DNA, RNA, or proteins. Recent evidence from both clinical and preclinical studies indicates that exosome-derived noncoding RNAs (ncRNAs) are highly involved in the progression of acute and chronic liver diseases by regulating hepatic lipid metabolism, innate immunity, viral infection, fibrosis, and cancer. Therefore, exosome-derived ncRNAs have promising potential and clinical implications for the early diagnosis, targeted therapy, and prognosis of liver diseases.

In vivo quantitative whole-brain diffusion tensor imaging analysis of APP/PS1 transgenic mice using voxel-based and atlas-based methods.

INTRODUCTION: Diffusion tensor imaging (DTI) has been applied to characterize the pathological features of Alzheimer's disease (AD) in a mouse model, although little is known about whether these features are structure specific. Voxel-based analysis (VBA) and atlas-based analysis (ABA) are good complementary tools for whole-brain DTI analysis. The purpose of this study was to identify the spatial localization of disease-related pathology in an AD mouse model. METHODS: VBA and ABA quantification were used for the whole-brain DTI analysis of nine APP/PS1 mice and wild-type (WT) controls. Multiple scalar measurements, including fractional anisotropy (FA), trace, axial diffusivity (DA), and radial diffusivity (DR), were investigated to capture the various types of pathology. The accuracy of the image transformation applied for VBA and ABA was evaluated by comparing manual and atlas-based structure delineation using kappa statistics. Following the MR examination, the brains of the animals were analyzed for microscopy. RESULTS: Extensive anatomical alterations were identified in APP/PS1 mice, in both the gray matter areas (neocortex, hippocampus, caudate putamen, thalamus, hypothalamus, claustrum, amygdala, and piriform cortex) and the white matter areas (corpus callosum/external capsule, cingulum, septum, internal capsule, fimbria, and optic tract), evidenced by an increase in FA or DA, or both, compared to WT mice (p < 0.05, corrected). The average kappa value between manual and atlas-based structure delineation was approximately 0.8, and there was no significant difference between APP/PS1 and WT mice (p > 0.05). The histopathological changes in the gray matter areas were confirmed by microscopy studies. DTI did, however, demonstrate significant changes in white matter areas, where the difference was not apparent by qualitative observation of a single-slice histological specimen. CONCLUSION: This study demonstrated the structure-specific nature of pathological changes in APP/PS1 mouse, and also showed the feasibility of applying whole-brain analysis methods to the investigation of an AD mouse model.

[Changes of gamma-amino butyric acid and electrophysiology inferior colliculus after noise exposure in guinea pig].

OBJECTIVE: To explore the changes of inferior collicular (IC) neurons after noise exposure cochlea injury in guinea pig to elucidate the encoding mechanism of pure tones, observe the changes of IC gamma-amino butyric acid (GABA) after cochlear damage by acoustic trauma and understand the possible mechanism of symptoms such as noise-induced tinnitus, hyperacusis and loudness recruitment. METHODS: The responses of IC neurons to pure tone stimuli were observed in guinea pig at Day 1 and Days 11-21 after cochlear damage induced by noise exposure. And the IC neurons of normal guinea pig were assigned as the controls. Reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the concentrations of GABA(A) and GABA(B) receptors. RESULTS: (1) The types of frequency reaction area (FRA) in the experiment group were the same as those in the control group (V-shape 84.8%, W-shape 8.9%, N-shape 6.3%). But the percentages of types were markedly different at Day 1 (V-shape 63.9%, W-shape 18.1%, N-shape, 18.1%) and Days 11-21 (V-shape 84.2%, W-shape 12.3%, N-shape 3.5%) after noise exposure. (2) After noise exposure, there was a marked fault in characteristic frequency (CF) and depth function map corresponding to 4 kHz (noise frequency). The rake ratio of CF and depth linear function map in the experiment group was lower than that of the control group. The control group, Day 1 and Days 11-21 after noise exposure, the rake ratios were 6.6, 5.8, 5.2 respectively. (3) GABA(A)/GABA(B) receptors decreased markedly at Days 1, 11 and 21 post-exposure compared to normal controls. And the values increased gradually with the prolonged time after exposure. The above findings conformed to the changes of electrophysiology of IC. CONCLUSIONS: After acoustic trauma, the responses of IC neurons to pure tone stimuli change with the elongation of time. It may be explained by the changes of IC GABA receptors after noise exposure.

Correction: All-purpose nanostrategy based on dose deposition enhancement, cell cycle arrest, DNA damage, and ROS production as prostate cancer radiosensitizer for potential clinical translation.

Correction for 'All-purpose nanostrategy based on dose deposition enhancement, cell cycle arrest, DNA damage, and ROS production as prostate cancer radiosensitizer for potential clinical translation' by Xiao-xiao Guo et al., Nanoscale, 2021, 13, 14525-14537, https://doi.org/10.1039/D1NR03869A.

[Temporal and Spatial Evolution of Storm Runoff and Water Quality Assessment in Jinpen Reservoir].

To explore the temporal and spatial intrusion process of runoffs and the response of water quality during the flood season in the Jinpen Reservoir (JPR) in Xi'an. Continuous in-situ monitoring was carried out on the water quality indexes (WQI) from the upstream river channel to the reservoir of two runoffs in early August and mid-September 2019. The single factor WQI and comprehensive WQI were used to assess the water quality vertically. Different inflow conditions of rain storm runoffs evolved into different intrusions. The initial inflow of the two runoffs was small, the runoff experienced a full-section intrusion, bottom intrusion, and mid-intrusion process along the way; the position of mid-intrusion in reservoir changed from 545-565 m at the beginning of the runoff to 535-580 m at the end in early August, and developed from 540-575 m of mid-intrusion to 575 m below the bottom of the intrusion in mid-September. The continuous inflow weakened the thermal stratification structure and replenished the DO in the reservoir. Meanwhile, mass particulate pollutants sank into the reservoir, and vertically, the nutrients of middle and bottom parts were higher than at the surface. The single factor WQI showed that the TP and permanganate index values of underflow location increased to some extent, and both exceeded the class Ⅲ water quality standard of surface water at the end. The comprehensive WQI showed that the middle layer of runoff was moderately polluted in early August, while the bottom layer was heavily polluted due to the dual effects of anaerobic and particle deposition, and reached the peak after one week of runoff, while the bottom intrusion of below 575 m directly caused heavy pollution in the middle layer, and bottom layer was medium polluted due to the supplement of dissolved oxygen in mid-September. The discharge of the spillway tunnel and the intake of stratified water could effectively guarantee the safety of the water supply during the flood season.

All-purpose nanostrategy based on dose deposition enhancement, cell cycle arrest, DNA damage, and ROS production as prostate cancer radiosensitizer for potential clinical translation.

Radiotherapy (RT) is one of the main treatments for men with prostate cancer (PCa). To date, numerous sophisticated nano-formulations as radiosensitizers have been synthesized with inspiring therapeutic effects both in vitro and in vivo; however, almost all the attention has been paid on the enhanced dose deposition effect by secondary electrons of nanomaterials with high atomic numbers (Z); despite this, cell-cycle arrest, DNA damage, and also reactive oxygen species (ROS) production are critical working mechanisms that account for radiosensitization. Herein, an 'all-purpose' nanostrategy based on dose deposition enhancement, cell cycle arrest, and ROS production as prostate cancer radiosensitizer for potential clinical translation was proposed. The rather simple structure of docetaxel-loaded Au nanoparticles (NPs) with prostate specific membrane antigen (PSMA) ligand conjugation have been successfully synthesized. Enhanced cellular uptake achieved via the selective internalization of the NPs by PCa cells with positive PSMA expression could guarantee enhanced dose deposition. Moreover, the as-synthesized nanosystem could effectively arrest the cell cycle at G2/M phases, which would reduce the ability of DNA damage repair for more irradiation sensitive of the PCa cells. Moreover, the G2/M phase arrest would further promote cascade retention and the enrichment of NPs within the cells. Furthermore, ROS generation and double strand breaks greatly promoted by NPs under irradiation (IR) could also provide an underlying basis for effective radiosensitizers. In vitro and in vivo investigations confirmed the as-synthesized NPs as an effective nano-radiosensitizer with ideal safety. More importantly, all moieties within the present nanosystem have been approved by FDA for the purpose of PCa treatment, thus making it highly attractive for clinical translation.

Manganese-Doped Layered Double Hydroxide: A Biodegradable Theranostic Nanoplatform with Tumor Microenvironment Response for Magnetic Resonance Imaging-Guided Photothermal Therapy.

Theranostic nanoplatforms with easy fabrication, high efficiency, and biodegradability are imperative to achieve efficacious and safe cancer treatment outcome. Toward this end, we prepared manganese-doped layered double hydroxide nanoparticles (Mn-LDH NPs) via a facile two-step synthetic method and revealed their excellent photothermal property coupled with simultaneous T1-weighted magnetic resonance imaging enhancement ability. By virtue of these unique properties, imaging-guided photothermal treatment has been achieved to eliminate tumors by using the Mn-LDH NPs without additional photosensitizer, drug, or imaging agent. Specifically, Mn(ox)-LDH NPs (oxidized Mn-LDH NPs) exhibited highly efficient tumor killing ability by activating apoptosis of tumor cells under external NIR 808 nm laser irradiation with the imaging guidance. More importantly, both the MR imaging and in vitro/vivo testing revealed that the Mn-LDH NPs are able to degrade in physiological conditions and demonstrate a high degree of biosafety. Considering the excellent T1-weighted MRI contrast property, effective photothermal performance, biodegradation, and biosafety, the Mn-LDH NPs have presented a potential generation inorganic biodegradable theranostic nanoplatform for efficacious cancer treatment.

Ferrimagnetic Vortex Nanoring-Mediated Mild Magnetic Hyperthermia Imparts Potent Immunological Effect for Treating Cancer Metastasis.

Cancer metastasis is a serious concern and a major reason for treatment failure. Herein, we have reported the development of an effective and safe nanotherapeutic strategy that can eradicate primary tumors, inhibit metastasizing to lung, and control the metastasis and growth of distant tumors. Briefly, ferrimagnetic vortex-domain iron oxide nanoring (FVIO)-mediated mild magnetic hyperthermia caused calreticulin (CRT) expression on the 4T1 breast cancer cells. The CRT expression transmitted an "eat-me" signal and promoted phagocytic uptake of cancer cells by the immune system to induce an efficient immunogenic cell death, further leading to the macrophage polarization. This mild thermotherapy promoted 88% increase of CD8+ cytotoxic T lymphocyte infiltration in distant tumors and triggered immunotherapy by effectively sensitizing tumors to the PD-L1 checkpoint blockade. The percentage of CD8+ cytotoxic T lymphocytes can be further increased from 55.4% to 64.5% after combining with PD-L1 blockade. Moreover, the combination treatment also inhibited the immunosuppressive response of the tumor, evidenced by significant down-regulation of myeloid-derived suppressor cells (MDSCs). Our results revealed that the FVIO-mediated mild magnetic hyperthermia can activate the host immune systems and efficiently cooperate with PD-L1 blockade to inhibit the potential metastatic spreading as well as the growth of distant tumors.

Hepatic resection for elderly patients with hepatocellular carcinoma: a systematic review of more than 17,000 patients.

BACKGROUND: With the aging population and increasing incidence of hepatic malignancies in elderly patients, establishing the safety and efficacy of hepatic resection for elderly patients with hepatocellular carcinoma (HCC) is crucial. The present systematic review investigates postoperative morbidity, hospital mortality, median survival time, overall and disease-free survival in elderly patients with undergoing hepatic resection. METHODS: Some databases were systematically searched for prospective or retrospective studies to reveal the safety and efficacy of hepatic resection for elderly patients with primary HCC. RESULTS: Fifty studies involving 4,169 elderly patients and 13,158 young patients with HCC were included into analyses. Elderly group patients had similar rate of median postoperative morbidity (28.2% vs. 29.6%) but higher mortality (3.0% vs. 1.2%) with young group patients. Moreover, elderly group patients had slightly lower median survival time (55 vs. 58 months), 5-years overall survival (51% vs. 56%) and 5-years disease-free survival (27% vs. 28%) than young group patients. There was an upward trend in 5-years overall and disease-free survival in either elderly or young group. CONCLUSION: Though old age may increase the risk of hospital mortality for patients with HCC after hepatic resection, elderly patients can obtain acceptable long-term prognoses from hepatic resection.

Ultrasmall Ferrite Nanoparticles Synthesized via Dynamic Simultaneous Thermal Decomposition for High-Performance and Multifunctional T1 Magnetic Resonance Imaging Contrast Agent.

Large-scale synthesis of monodisperse ultrasmall metal ferrite nanoparticles as well as understanding the correlations between chemical composition and MR signal enhancement is critical for developing next-generation, ultrasensitive T1 magnetic resonance imaging (MRI) nanoprobes. Herein, taking ultrasmall MnFe2O4 nanoparticles (UMFNPs) as a model system, we report a general dynamic simultaneous thermal decomposition (DSTD) strategy for controllable synthesis of monodisperse ultrasmall metal ferrite nanoparticles with sizes smaller than 4 nm. The comparison study revealed that the DSTD using the iron-eruciate paired with a metal-oleate precursor enabled a nucleation-doping process, which is crucial for particle size and distribution control of ultrasmall metal ferrite nanoparticles. The principle of DSTD synthesis has been further confirmed by synthesizing NiFe2O4 and CoFe2O4 nanoparticles with well-controlled sizes of ∼3 nm. More significantly, the success in DSTD synthesis allows us to tune both MR and biochemical properties of magnetic iron oxide nanoprobes by adjusting their chemical composition. Beneficial from the Mn2+ dopant, the synthesized UMFNPs exhibited the highest r1 relaxivity (up to 8.43 mM-1 s-1) among the ferrite nanoparticles with similar sizes reported so far and demonstrated a multifunctional T1 MR nanoprobe for in vivo high-resolution blood pool and liver-specific MRI simultaneously. Our study provides a general strategy to synthesize ultrasmall multicomponent magnetic nanoparticles, which offers possibilities for the chemical design of a highly sensitive ultrasmall magnetic nanoparticle based T1 MRI probe for various clinical diagnosis applications.

Capsaicin and dihydrocapsaicin induce apoptosis in human glioma cells via ROS and Ca2+­mediated mitochondrial pathway.

Human glioma is the most common type of primary brain tumor and one of the most invasive and aggressive tumors, which, even with treatments including surgery, radiotherapy and chemotherapy, often relapses and exhibits resistance to conventional treatment methods. Developing novel strategies to control human glioma is, therefore, an important research focus. The present study investigated the mechanism of apoptosis induction in U251 human glioma cells by capsaicin (Cap) and dihydrocapsaicin (DHC), the major pungent ingredients of red chili pepper, using the Cell Counting Kit­8 assay, transmission electron microscopy analysis, flow cytometry analysis, laser scanning confocal microscope analysis and immunohistochemical staining. Treatment of U251 glioma cells with Cap and DHC resulted in a dose­ and time­dependent inhibition of cell viability and induction of apoptosis, whereas few effects were observed on the viability of L929 normal murine fibroblast cells. The apoptosis­inducing effects of Cap and DHC in U251 cells were associated with the generation of reactive oxygen species, increased Ca2+ concentrations, mitochondrial depolarization, release of cytochrome c into the cytosol and activation of caspase­9 and ­3. These effects were further confirmed by observations of the anti­tumor effects of Cap and DHC in vivo in a U251 cell murine tumor xenograft model. These results demonstrate that Cap and DHC are effective inhibitors of in vitro and in vivo survival of human glioma cells, and provide the rationale for further clinical investigation of Cap and DHC as treatments for human glioma.

Synthesis of Ferromagnetic Fe0.6 Mn0.4 O Nanoflowers as a New Class of Magnetic Theranostic Platform for In Vivo T1 -T2 Dual-Mode Magnetic Resonance Imaging and Magnetic Hyperthermia Therapy.

Uniform wüstite Fe0.6 Mn0.4 O nanoflowers have been successfully developed as an innovative theranostic agent with T1 -T2 dual-mode magnetic resonance imaging (MRI), for diagnostic applications and therapeutic interventions via magnetic hyperthermia. Unlike their antiferromagnetic bulk counterpart, the obtained Fe0.6 Mn0.4 O nanoflowers show unique room-temperature ferromagnetic behavior, probably due to the presence of an exchange coupling effect. Combined with the flower-like morphology, ferromagnetic Fe0.6 Mn0.4 O nanoflowers are demonstrated to possess dual-modal MRI sensitivity, with longitudinal relaxivity r1 and transverse relaxivity r2 as high as 4.9 and 61.2 mm(-1) s(-1) [Fe]+[Mn], respectively. Further in vivo MRI carried out on the mouse orthotopic glioma model revealed gliomas are clearly delineated in both T1 - and T2 -weighted MR images, after administration of the Fe0.6 Mn0.4 O nanoflowers. In addition, the Fe0.6 Mn0.4 O nanoflowers also exhibit excellent magnetic induction heating effects. Both in vitro and in vivo magnetic hyperthermia experimentation has demonstrated that magnetic hyperthermia by using the innovative Fe0.6 Mn0.4 O nanoflowers can induce MCF-7 breast cancer cell apoptosis and a complete tumor regression without appreciable side effects. The results have demonstrated that the innovative Fe0.6 Mn0.4 O nanoflowers can be a new magnetic theranostic platform for in vivo T1 -T2 dual-mode MRI and magnetic thermotherapy, thereby achieving a one-stop diagnosis cum effective therapeutic modality in cancer management.

Comparative study of DSC-PWI and 3D-ASL in ischemic stroke patients.

The purpose of this study was to quantitatively analyze the relationship between three dimensional arterial spin labeling (3D-ASL) and dynamic susceptibility contrast-enhanced perfusion weighted imaging (DSC-PWI) in ischemic stroke patients. Thirty patients with ischemic stroke were included in this study. All subjects underwent routine magnetic resonance imaging scanning, diffusion weighted imaging (DWI), magnetic resonance angiography (MRA), 3D-ASL and DSC-PWI on a 3.0T MR scanner. Regions of interest (ROIs) were drawn on the cerebral blood flow (CBF) maps (derived from ASL) and multi-parametric DSC perfusion maps, and then, the absolute and relative values of ASL-CBF, DSC-derived CBF, and DSC-derived mean transit time (MTT) were calculated. The relationships between ASL and DSC parameters were analyzed using Pearson's correlation analysis. Receiver operative characteristic (ROC) curves were performed to define the thresholds of relative value of ASL-CBF (rASL) that could best predict DSC-CBF reduction and MTT prolongation. Relative ASL better correlated with CBF and MTT in the anterior circulation with the Pearson correlation coefficients (R) values being 0.611 (P<0.001) and-0.610 (P<0.001) respectively. ROC curves demonstrated that when rASL ≤0.585, the sensitivity, specificity and accuracy for predicting ROIs with rCBF<0.9 were 92.3%, 63.6% and 76.6% respectively. When rASL ≤0.952, the sensitivity, specificity and accuracy for predicting ROIs rMTT>1.0 were 75.7%, 89.2% and 87.8% respectively. ASL-CBF map has better linear correlations with DSC-derived parameters (DSC-CBF and MTT) in anterior circulation in ischemic stroke patients. Additionally, when rASL is lower than 0.585, it could predict DSC-CBF decrease with moderate accuracy. If rASL values range from 0.585 to 0.952, we just speculate the prolonged MTT.

Magnetic nanoparticle-loaded polymer nanospheres as magnetic hyperthermia agents.

Uniform magnetic nanoparticle-loaded polymer nanospheres with different loading contents of manganese ferrite nanoparticles were successfully synthesized using a flexible emulsion process. The MnFe2O4-loaded polymer nanospheres displayed an excellent dispersibility in both water and phosphate buffer saline. The effect of loading ratio and size of MnFe2O4 nanoparticles within the nanospheres on the specific absorption rate (SAR) under an alternating magnetic field was investigated. Our results indicate that a large size (here 18 nm) and a low loading ratio are preferable for a high SAR. For a smaller particle size (6 nm), the low loading ratio did not result in an enhancement of the SAR value, while a very low SAR value is expected for 6 nm. In addition, the SAR of low-content MnFe2O4 (18 nm)-loaded polymer nanospheres in the agarose gel which is simulated for in vivo environment is the highest among the samples and does not change substantially in physiological environments. This differs largely from the behaviour of singly dispersed nanoparticles. Our results have paved the way for the design of MnFe2O4-loaded polymer nanospheres as magnetic hyperthermia agents for in vivo bio-applications.

Voxel-based diffusion tensor imaging of an APP/PS1 mouse model of Alzheimer's disease.

Increasing evidence has demonstrated that white matter (WM) disruptions, due to the injury of the axon and myelin, play an important role in the pathogenesis of Alzheimer's disease (AD). Diffusion tensor imaging (DTI) is a sensitive modality to evaluate the WM integrity in both AD patients and animal models. In this study, an advanced DTI modality, employing a 7.0-T magnetic resonance imaging system, was used to analyze WM changes across the whole brain of an amyloid precursor protein/presenilin 1 (APP/PS1) mouse model. A voxel-based analysis was used to compare the quantitative DTI parameters automatically in both APP/PS1 mice (n = 9) and wild-type (WT) controls (n = 9). After DTI examination, the ultrastructure analysis was compared with DTI findings. Compared with WT controls, gray matter (GM) areas in APP/PS1 mice such as the cingulate cortex and the striatum showed significant fractional anisotropy (FA) and axial diffusivity (DA) increase, while the thalamus only showed a significant FA increase (p < 0.01). Similarly, a significant mean diffusivity, DA, and radial diffusivity increase was observed in the bilateral neocortex (p < 0.01). The left hippocampus only showed significant FA increase in APP/PS1 mice (p < 0.01). The changes in WM regions were detected in the forceps minor of the corpus callosum, the anterior part of the anterior commissure, and the internal capsule, with a significant FA or DA increase (p < 0.01). Abnormalities derived from diffusion measurements were in-line with the ultrastructure findings, including extensive pathological damage of the neurons, neutrophils, and vessels. In conclusion, voxel-based diffusion tensor imaging can detect diffusion alterations not only in GM but also in WM areas in AD models, reflecting the extensive pathological changes of AD.

In vitro study on the feasibility of magnetic stent hyperthermia for the treatment of cardiovascular restenosis.

Thermal treatment or hyperthermia has received considerable attention in recent years due to its high efficiency, safety and relatively few side-effects. In this study, we investigated whether it was possible to utilize targeted thermal or instent thermal treatments for the treatment of restenosis following percutaneous transluminal coronary angioplasty (PTCA) through magnetic stent hyperthermia (MSH). A 316L stainless steel stent and rabbit vascular smooth muscle cells (VSMCs) were used in the present study, in which the inductive heating characteristics of the stent under alternative magnetic field (AMF) exposure, as well as the effect of MSH on the proliferation, apoptosis, cell cycle and proliferating cell nuclear antigen (PCNA) expression of the rabbit VSMCs, were evaluated. The results demonstrated that 316L stainless steel coronary stents possess ideal inductive heating characteristics under 300 kHz AMF exposure. The heating properties were shown to be affected by the field intensity of the AMF, as well as the orientation the stent axis. MSH had a significant effect on the proliferation and apoptosis of VSMCs, and the effect was temperature-dependent. While a mild temperature of 43°C demonstrated negligible effects on the growth of VSMCs, MSH treatment above 47°C effectively inhibited the VSMC proliferation and induced apoptosis. Furthermore, a 47°C treatment exhibited a significant and long-term inhibitory effect on VSMC migration. The results strongly suggested that MSH may be potentially applied in the clinic as an alternative approach for the prevention and treatment of restenosis.

Antitumor effect and immune response induced by local hyperthermia in B16 murine melanoma: Effect of thermal dose.

This study aimed at investigating the antitumor effect and immune response induced by local high-temperature hyperthermia at different thermal doses in B16 murine melanoma. The screened optimal thermal dose (50°C, 15 min) which was demonstrated to be the most effective in immune response activation was applied to the treatment of lung metastasis. The optimal thermal dose was determined by evaluating the tumor volume change, survival period of tumor-bearing mice, and immune indices including interleukin (IL)-2, interferon (IFN)-γ and TNF-α mRNA expression in the spleen of mice subjected to local hyperthermia at various thermal doses. The activation of the immune response was further investigated by rechallenging the cured mice 60 days after hyperthermia treatment. The screened optimal thermal dose combined with immunoadjuvant compound 48/80 was applied for melanoma lung metastasis. While local hyperthermia effectively inhibited B16 melanoma tumor growth and prolonged the survival period of tumor-bearing mice, the antitumor immunity was significantly enhanced and the effect was thermal dose-dependent. Higher temperatures (≥50°C) induced a significant effect even with a short treatment time (≤15 min). No tumor regrowth was observed for rechallenged B16 melanoma in mice following treatment with local hyperthermia at a higher temperature. Local hyperthermia by optimal thermal dose in combination with immunoadjuvant compound 48/80 is an effective approach for the treatment of B16 melanoma lung metastasis. This study indicated that the use of a local high-temperature hyperthermia protocol inhibits tumor growth and stimulates a favorable antitumor immune response against malignant melanoma. The results of these experiments may have clinical significance for the treatment of melanoma.

Magnetic stent hyperthermia for esophageal cancer: an in vitro investigation in the ECA-109 cell line.

Magnetic stent hyperthermia (MSH) is a novel approach for targeted thermotherapy for esophageal cancer, which is based on the mechanism that inductive heat can be generated by the esophageal stent upon exposure under an alternative magnetic field (AMF). A positive effect of MSH on esophageal cancer has been demonstrated, however, there is no study on the in vitro effects of heating treatment or of the effects of AMF exposure on human esophageal cancer cells. This study aimed to investigate the effect of MSH and of AMF exposure in esophageal cancer cells. Inductive heating characteristics of esophageal stents were assessed by exposing the stents under AMF. A rather rapid temperature rise of the Ni-Ti stent when subjected to AMF exposure was observed and the desired hyperthermic temperature could be controlled by adjusting the field parameter of the AMF. Human esophageal squamous carcinoma (ESCC) ECA-109 cells were divided into four groups: the control group, the water-bath heating group, the MSH group and the AMF exposure group. Hyperthermic temperatures were 43, 48 and 53˚C and the treatment time was in the range of 5-30 min. The MTT assay, apoptotic analysis and TUNEL staining were applied in the current investigation. Exposure of ECA-109 cells under AMF with a field intensity of 50 to 110 kA/m had negligible effect on cell viability, cell necrosis and apoptosis. Hyperthermia had a remarkable inhibitory effect on the cell viability and the effect was dependent on the thermal dose (temperature and time). The optimal thermal dose of MSH for ECA-109 cells was 48˚C for 20-30 min. The study also elucidated that there was a difference in the effects on cell necrosis and apoptosis between the heating mode of water bath and MSH. The data suggest that MSH may have clinical significance for esophageal cancer treatment.

Clinical assessment and genomic landscape of a consanguineous family with three Kallmann syndrome descendants.

Although some genes that cause Kallmann syndrome (KS) have been identified by traditional linkage analysis and candidate gene techniques, the syndrome's molecular etiology in the majority of patients remains poorly understood. In this paper, we present the clinical assessments of a consanguineous Han Chinese family with three KS descendants. To understand the molecular etiology of KS from a genome-wide perspective, we investigated the genome-wide profile of structural variation in this family using the Affymetrix Genome-Wide Human SNP Array 6.0 platform. The results revealed that the three affected individuals had common copy number variants (microdeletions) on chromosomes 1p21.1, 2q32.2, 8q21.13, 14q21.2 and Xp22.31. Moreover, the copy number variants on Xp22.31 were located in the intron of KAL1, which causes X-linked KS. Two PCR assays were performed on these regions to validate the results obtained using the chips. In addition, genomic microdeletions in this region were verified in one of 29 Han Chinese sporadic KS cases and one of four other family cases, but not in 26 Han Chinese sporadic normosmic idiopathic hypogonadotropic hypogonadism cases and 100 unrelated Han Chinese normal controls. Our results provide a novel insight into the relative contributions of certain copy number variants to KS's molecular etiology and generate a list of interesting candidate regions for further studies.