Mitochondria-targeted nanoplatforms for enhanced photodynamic therapy against hypoxia tumor.

BACKGROUND: Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers. RESULTS: The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment. CONCLUSIONS: This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment.

Sural biopsy to detect the axonal cytoskeleton defects in KIF5A-related Charcot-Marie-Tooth disease type 2.

Kinesins are microtubule-associated motor proteins involved in in regulating microtubule dynamics in neuronal and non-neuronal cells. However, the axonal cytoskeleton-related pathological changes in peripheral nerve have never been described in patients with KIF5A mutation. This study aims to report sural biopsy to detect axonal cytoskeleton abnormalities in a patient with KIF5A-related Charcot-Marie-Tooth disease type 2 (CMT2). We screened for the variants of CMT or related pathogenic genes using next-generation sequencing in a Chinese family with CMT2. The proband was a 13-year-old girl who presented with severe weakness and wasting of distal muscles of limbs starting at early childhood. The disease rapidly progressed, and the girl lost ambulation. Her mother showed absence of deep tendon reflexes in the lower limbs. Nerve conduction studies disclosed a more pronounced axonal sensory-motor neuropathy in the proband. The girl and her mother had a heterozygous p.E755K mutation of the KIF5A gene, which was previously reported only in hereditary spastic paraplegia and amyotrophic lateral sclerosis. Sural biopsy revealed loss of both myelinated and unmyelinated nerve fibers. Closely packed, irregularly oriented neurofilaments were observed in axons of unmyelinated nerve fibers. Another important finding was ubiquitous presence of elongated mitochondria with vacuole in the myelinated and unmyelinated axons. This study suggested the p.E755K mutation of KIF5A was a cause of early-onset CMT2 with defective axonal transport, and emphasized sural biopsy could be an important tool to detect axonal cytoskeleton defects in KIF5A related CMT2.

PLEKHG5-related autosomal recessive lower motor neuron disease with dysmyelination in peripheral nerves.

OBJECTIVE: Pleckstrin homology domain-containing family G member 5 (PLEKHG5) is a nuclear factor-κ-B-activator gene that predominantly expresses in the neurons and Schwann cells of the peripheral nervous system. Variations in the PLEKHG5 have shown an intermediate form of autosomal recessive Charcot-Marie-Tooth disease and lower motor neuron disease in childhood. MATERIALS AND METHODS: This study investigated clinically, electrophysiologically, genetically, and pathologically a young girl with lower motor neuron disease who had weakness and wasting of all limbs starting in early childhood. RESULTS: Next-generation sequencing found a novel compound heterozygous missense variation c.2038-1G>A and c.1219G>T of PLEKHG5 gene. Electromyography revealed a neurogenic pattern, and nerve conduction study indicated subclinical sensory neuropathy. Sural biopsy showed hypomyelination, hypermyelination, and infolding myelin membranes coiled into the myelinated axon. CONCLUSION: This study identifies, pathologically, novel compound heterozygous mutations and phenotype in PLEKHG5-related lower motor neuron disease and dysmyelination in a patient with PLEKHG5 mutation.

A novel mutation in PRPS1 causes X-linked Charcot-Marie-Tooth disease-5.

X-linked Charcot-Marie-Tooth disease-5 (CMTX5) is a rare hereditary disorder caused by mutations in the gene for phosphoribosyl pyrophosphate synthetase-1 (PRPS1). We investigated a boy with a novel PRPS1 mutation (c.334G>C, p.V112L) via genetic, neuropathological and enzymatic tests. The proband was a 13-year-old boy with congenital non-syndromic sensorineural deafness. At 3 year old, he developed progressive distal weakness of all limbs with muscle atrophy of both hands and shanks. Nerve conduction study revealed the loss of sensory nerve action potentials, and slowing down of motor nerve conduction velocities with a decrease of amplitudes of compound motor action potentials. Visual evoked potentials and brainstem auditory evoked potentials were not bilaterally evocable. Sural biopsy proved the loss of myelinated nerve fibers, with axonal degeneration, regenerating clusters and onion bulbs. Enzymatically, PRPS1 activity was close to zero in the proband and mildly reduced in his mother, compared with controls. To our knowledge, this is the first report of CMTX5 in a Chinese population. The genetic finding has expanded the genotypic spectrum of PRPS1 mutations.

HADHB mutations cause infantile-onset axonal Charcot-Marie-Tooth disease: A report of two cases.

Mitochondrial trifunctional protein deficiency (MTPD) is a rare disorder caused by mutations in the HADHA and HADHB genes. Here, we report on two Han Chinese patients with HADHB mutation-associated infantile axonal Charcot-Marie-Tooth disease (IACMT). Both patients were unrelated. Case 1 was a 19-year-old man, and case 2 was a 5-year-old boy. Both had delayed motor development and slowly-progressing distal muscle weakness with areflexia and foot deformities. The electrophysiology findings were compatible with axonal polyneuropathy in both patients. Blood tandem mass spectrometry showed increased concentrations of multiple acylcarnitines. Nerve biopsies showed axonal neuropathy with a moderate loss of myelinated fibers. Gene analysis identified two compound heterozygous mutations (c.184A>G/c.340A>G and c.488G>A/c.1175C>T, respectively) in the HADHB gene. The c.488G>A mutation was novel. This study broadens the phenotype of MTPD and suggests that the genetic testing of patients suffering from IACMT should include the HADHB gene.
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Late-onset hereditary sensory and autonomic neuropathy expands the phenotypic spectrum of MFN2-related diseases.

Mutations in the Mitofusin 2 (MFN2) gene have been identified in patients with autosomal dominant axonal motor and sensory neuropathy or Charcot-Marie-Tooth 2A (CMT2A). Here we describe clinical and pathological changes in an adult patient with sporadic hereditary sensory and autonomic neuropathy (HSAN) due to an MFN2 mutation. The patient was a 53-year-old man who had sensory involvement and anhidrosis in all limbs without motor features. The electrophysiological assessment documented severe axonal sensory neuropathy. The sural nerve biopsy confirmed the electrophysiological findings, revealing severe loss of myelinated and unmyelinated fibers with regeneration clusters. Genetic analysis revealed the previously identified mutation c.776 G > A in MFN2. Our report expands the phenotypic spectrum of MFN2-related diseases. Sequencing of MFN2 should be considered in all patients presenting with late-onset HSAN.

Adult-onset demyelinating neuropathy associated with FBLN5 gene mutation.

Rare forms of autosomal-dominant Charcot-Marie-Tooth disease (AD-CMT) may be associated with mutations in Fibulin-5 (FBLN5) as AD-CMT is genetically heterogeneous. Here, we report the first pathological study of an Asian family. The proband was a 46-year-old man with slowly progressive distal numbness and weakness for 12 years. He had a history of diabetes mellitus for 12 years. His mother was 81 years old and had mild polyneuropathy. His 16-year-old daughter was asymptomatic. The nerve conduction velocities (NCVs) and compound muscular action potential (CMAP) amplitudes were moderately to severely reduced in the proband, and moderately reduced in his daughter and mother. A sensory response could not be elicited in the proband and was moderately to severely decreased in the daughter and mother. Nerve ultrasound indicated a general enlargement of the peripheral nerves in the proband, daughter, and mother. A sural nerve biopsy from the proband demonstrated a pronounced depletion of myelinated fibers, thin myelinated fibers, and onion-bulb formations. A reported heterozygous mutation of c.1117C>T in FBLN5 was identified in the proband, mother, and daughter. These findings confirm a novel subtype of AD-CMT 1 due to a mutation in the FBLN5 gene.
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INF2 mutations associated with dominant inherited intermediate Charcot-Marie-Tooth neuropathy with focal segmental glomerulosclerosis in two Chinese patients.

Recently, mutations in the inverted formin 2 (INF2) gene have been indentified in patients with dominant inherited intermediate Charcot-Marie-Tooth neuropathy (DI-CMT) with focal segmental glomerulosclerosis (FSGS). We report clinical and nerve pathological changes in two Chinese patients. Case 1 is 27 years old and presented with distal muscle weakness and atrophy of legs at the age of 13 and renal failure at the age of 26. Three of his family members died due to pure renal failure. Case 2 is 22 years old and presented with distal muscle weakness and atrophy of the legs with transient attacks of difficulty in speaking at age 17. Proteinuria was found by routine urine test at the same time. Sural nerve biopsy revealed moderate-to-severe loss of myelinated fibers with union bulbs and regeneration clusters in both patients. Ultrastructurally, numerous elongated extensions of Schwann cells of unmyelinated fibers could be seen in both patients. INF2 gene mutation screening revealed c.451 T>C in case 1 and c.341 G>A in case 2. This is the first report of Chinese patients with INF2-related DI-CMT. The c.451 T>C mutant was responsible for both isolated FSGS and a dual phenotype of FSGS and neuropathy within one family. Intrafamilial variability can be found with the same INF2 mutation. The CNS manifestations further broadened the clinical spectrum of INF2- associated disorders.

Mitofusin 2 gene mutation causing early-onset CMT2A with different progressive courses.

Charcot-Marie-Tooth disease Type 2A2 (CMT2A2), caused by mitofusin 2 (MFN2) genes, has been clinically classified into two types: severe early-onset and mild benign. Here we reported 3 early onset patients with different progressive courses. The 3 patients had mutations R94W, R364W and a novel W740R in the MFN2 gene. Two patients presented with progressive distal limb muscle weakness and wasting from the ages of 5 and 6 years, respectively. The disease developed slowly, with loss of ambulation after 35 years of age. The third patient presented with similar symptoms after birth, and has never been able to walk independently. Sural nerve biopsies revealed severe axonal neuropathy with mitochondrial aggregation in axons. Our data confirmed that early-onset CMT2A2 can present with different courses in Chinese patients. The novel mutation in MFN2 found in this study broadens the genotypic spectrum associated with MFN2 related CMT.

Evaluation of the median nerve by shear wave elastography in patients with Charcot-Marie-Tooth disease type 1A.

AIMS: Charcot-Marie-Tooth disease type 1A (CMT1A) is characterized by enlargement and stiffness of peripheral nerves due to edema with large numbers of "onion bulbs" in the endoneurium. Ultrasound elastography seems to be an ideal method to detect this condition. The aim of this study was to analyze the shear wave elastography (SWE) features of peripheral nerves in patients with CMT1A. MATERIAL AND METHODS: We included 24 CMT1A patients with a mean age of 28 years, along with 24 age- and gender-matched controls. All patients presented with mutations of the PMP22 gene and showed length-dependent polyneuropathy. The motor nerve conduction velocity (MNCV) of the median nerve ranged from 5.2 to 37.4 m/s. SWE and cross-sectional area (CSA) were used to evaluate the bilateral median nerves at predefined sites in both patients and con-trols. RESULTS: The average elastography value (EV) of the median nerve was 73.5±11.7 kPa in patients with CMT1A and 37.5±6.1 kPa in control subjects. The difference between the two groups was statistically significant (P<0.05). In CMT1A pa-tients, the average EV at the proximal and distal parts of the median nerve were 81.4±9.4 kPa and 65.2±8.1 kPa, respectively. The average CSAs at the proximal and distal parts of the median nerve were 0.29±0.06 cm2 and 0.20±0.05 cm2, respectively. The EV on SWE was positively correlated with CSA (p< 0.01) and negatively correlated with MNCV in the median nerve (p< 0.01). CONCLUSIONS: Peripheral nerve stiffness dramatically increases in CMT1A and is correlated with the severity of nerve involvement.

Pathogenic PSAT1 Variants and Autosomal Recessive Axonal Charcot-Marie-Tooth Disease With Ichthyosis.

BACKGROUND: Biallelic pathogenic phosphoserine aminotransferase 1 (PSAT1) variants generally cause a severe phenotype predominantly involving the central nervous system. Here, for the first time, we report two patients harboring pathogenic PSAT1 variants only manifested as polyneuropathy and ichthyosis. METHODS: Two patients from unrelated families presenting with polyneuropathy and ichthyosis were enrolled. Whole exome sequencing was performed to identify possible disease-causing variants. Their clinical, electrophysiological, imaging, biochemical, and pathologic changes were in detail assessed and investigated. RESULTS: Homozygous variant c.43G>C and compound heterozygous variants c.112A>C and c.43G>C in PSAT1 were identified in patients 1 and 2, respectively. Nerve conduction studies revealed preserved or mild slowing motor nerve conduction velocities of the median nerves in the two patients, whereas the compound motor action potential in patient 1 was severely decreased. Brain magnetic resonance imaging of the two patients found no abnormalities. Median nerve enlargement was observed on ultrasound in patient 1. Both patients had normal level of serine and glycine in plasma and cerebrospinal fluid. Sural nerve biopsy found severe loss of myelinated fibers. Electron microscopy revealed neurofilament accumulation and mitochondrial aggregation in axons. Both variants in PSAT1 were classified as likely pathogenic or pathogenic variants according to the standard guidelines. CONCLUSIONS: Our study confirms that pathogenic PSAT1 variants can cause a mild phenotype, predominantly as autosomal recessive axonal Charcot-Marie-Tooth disease.

The Pathological Features of Common Hereditary Mitochondrial Dynamics Neuropathy.

OBJECTIVES: Mitofusin 2 and ganglioside-induced differentiation-associated protein 1 are two main mitochondrial dynamics-related proteins. Dysfunction of these two proteins leads to different subtypes of Charcot-Marie-Tooth disease type 2A (CMT2A) and CMT2K. This study aims to report the pathological difference between CMT2A and CMT2K in a large cohort. METHODS: Thirty patients with molecularly confirmed CMT2A and nine with CMT2K were identified by next-generation sequencing. Sural nerve biopsies were performed in 29 patients. RESULTS: The patients with both diseases showed length-dependent neuropathy with distal weakness, sensory loss, and no deep tendon reflex. Optic neuropathy appeared in 3/30 (10%) patients with CMT2A. Tendon contracture appeared in 4/9 (50.0%) patients with CMT2K. Sural biopsy revealed the loss of both myelinated and unmyelinated nerve fibers. Closely packed, irregularly oriented neurofilaments were observed in axons of unmyelinated nerve fibers in both diseases. Another important finding was the ubiquitous presence of smaller, rounded, and fragmented mitochondria in CMT2A and elongated mitochondria in CMT2K in the myelinated and unmyelinated axons. CONCLUSION: This study confirmed large diversity in phenotypes between CMT2A and CMT2K. Mitochondrial dynamics-related variations can induce different mitochondrial morphological changes and neurofilament accumulation in axons.

Study on the safety and effectiveness of drug-coated balloons in patients with acute myocardial infarction.

BACKGROUND: Drug-coated balloon (DCB) is a new technology that has emerged in recent years and has been proven to be effective and safe in the treatment of in-stent restenosis. The purpose of this article is to observe the safety and effectiveness of drug-coated balloons in patients with acute myocardial infarction. METHOD: We selected 80 patients admitted to the hospital for STEMI from January 2018 to December 2019. The subjects were randomly divided into a Yinyi (Liaoning) Biotech Bingo Drug Coated Balloon treatment group (balloon group, n = 38) and a drug-eluting stent (DES) treatment group (stent group, n = 42). Patients were followed up to understand the incidence of major adverse cardiovascular events (MACE) at 1 month, 6 months and 1 year after surgery. Coronary angiography was rechecked 1 year after surgery to understand the late lumen loss (LLL) in the two groups. RESULT: During the one-year follow-up, the LLL of the target lesion in the balloon group was -0.12±0.46 mm, while the target lesion in the stent group was 0.14±0.37 mm ( P <0.05). Within 1 year, the incidence of MACE in the balloon group was 11%, while the incidence of MACE in the stent group was 12%. There was no significant difference between the two groups. IN CONCLUSION: When PCI is used for STEMI, only DCB therapy is safe and effective, and has shown good clinical effects during a one-year follow-up period.

A pH-responsive bioassay for paper-based diagnosis of exosomes via mussel-inspired surface chemistry.

The analysis of exosomes, which shows an increasing potential as prognostic biomarkers for non-invasive cancer diagnosis, can reveal their biological functions and disease associations. Nevertheless, the development of a convenient and quantitative method for determination of exosomes is still challenging. Herein, a novel approach for exosome quantification using pH test paper is developed via HRP-mediated promotion of mussel-inspired surface engineering and reagent-free functionalization of urease molecules. Uerase can hydrolyse urea into ammonia and carbon dioxide, and simultaneously raise the pH value of the solution. By establishing the relationship between exosome recognition and the change of pH value of the sensing solution, we can directly employ the low-cost, widely used and commercially available pH test paper to quantitatively analyse exosomes. The pH-responsive bioassay enables sensitive detection of exosomes with a detection of limit down to 4.46 × 103 particles/µL and can be successfully applied for determination of exosomes in clinical specimens. The versatility and reliability of our sensing platform may open up opportunities towards paper-based diagnosis of cancer.

Magnetic-responsive and targeted cancer nanotheranostics by PA/MR bimodal imaging-guided photothermally triggered immunotherapy.

While theranostic nanoparticle (TNP)-based photothermal therapy (PTT) exhibits prominent promise for cancer therapy, metastatic cancers remain one of the main obstacles of effective PTT. Immunotherapy has been developed vigorously to inhibit metastatic cancers, but the heterogeneity of patients and the complexities of manufacturing cancer vaccines significantly hinder its further clinical applications. Herein, a photothermally triggered immunotherapeutic paradigm under imaging guidance was designed based on magnetic-responsive immunostimulatory nanoagents (MINPs) loaded with superparamagnetic iron oxide (SPIO) nanoparticles and cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). The fabricated MINPs with the clinically approved components acted not only as a contrast agent for photoacoustic (PA)/magnetic resonance (MR) bimodal imaging but also as a magnetic-targeting therapeutic agent for photothermally triggered immunotherapy. Under external magnetic fields, the MINPs showed a great magnetic-targeting ability, leading to high accumulation of the photoabsorber (SPIO) and the immunoadjuvant (CpG ODNs) in the tumors for precise bimodal imaging guidance. More importantly, the excellent photothermal conversion effect of the MINPs upon near-infrared (NIR) exposure enabled the effective photothermal destruction of the primary tumors, releasing tumor-associated antigens and showing 'autologous cancer vaccine'-like functions, thus activating robust antitumor immune responses, especially in the presence of CpG ODN-containing immunostimulatory nanoagents. Such generated immune responses can further attack the remaining tumors and distant metastatic tumors in mice. This work provides an imaging-guided photothermally triggered immunotherapeutic strategy based on multifunctional MINPs to effectively eliminate primary tumors and inhibit metastatic tumors simultaneously with high specificity, easy maneuverability and favorable biocompatibility. This strategy may potentially be applicable for precise individualized diagnosis and therapy of various tumors.

Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients.

BACKGROUND: Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophy (LGMD2C, LGMD2D, LGMD2E, and LGMD2F) that are caused, respectively, by mutations in the SGCG, SGCA, SGCB, and SGCD genes. Knowledge about the clinical and genetic features of sarcoglycanopathies in Chinese patients is limited. The aims of this study were to investigate in detail the clinical manifestations, sarcoglycan expression, and gene mutations in Chinese patients with sarcoglycanopathies and to identify possible correlations between them. RESULTS: Of 3638 patients for suspected neuromuscular diseases (1733 with inherited myopathies, 1557 with acquired myopathies, and 348 unknown), 756 patients had next-generation sequencing (NGS) diagnostic panel. Twenty-five patients with sarcoglycanopathies (11.5%) were identified from 218 confirmed LGMDs, comprising 18 with LGMD2D, 6 with LGMD2E, and one with LGMD2C. One patient with LGMD2D also had Charcot-Marie-Tooth 1A. The clinical phenotypes of the patients with LGMD2D or LGMD2E were markedly heterogeneous. Muscle biopsy showed a dystrophic pattern in 19 patients and mild myopathic changes in 6. The percentage of correct prediction of genotype based on expression of sarcoglycan was 36.0% (4 LGMD2D, 4 LGMD2E, and one LGMD2C). There was a statistically significant positive correlation between reduction of α-sarcoglycan level and disease severity in LGMD2D. Thirty-five mutations were identified in SGCA, SGCB, SGCG, and PMP22, 16 of which were novel. Exon 3 of SGCA was a hotspot region for mutations in LGMD2D. The missense mutation c.662G > A (p.R221H) was the most common mutation in SGCA. Missense mutations in both alleles of SGCA were associated with a relative benign disease course. No obvious clinical, sarcoglycan expression, and genetic correlation was found in LGMD2E. CONCLUSIONS: This study expands the clinical and genetic spectrum of sarcoglycanopathies in Chinese patients and provides evidence that disease severity of LGMD2D may be predicted by α-sarcoglycan expression and SGCA mutation.

A light-controllable specific drug delivery nanoplatform for targeted bimodal imaging-guided photothermal/chemo synergistic cancer therapy.

Breast cancer is a severe threat to the health and lives of women due to its difficult early diagnosis and the unsatisfactory therapeutic efficacy of breast cancer treatments. The development of theranostic strategies to combat breast cancer with high accuracy and effectiveness is therefore urgently needed. In this study, we describe a near-infrared (NIR) light-controllable, targeted and biocompatible drug delivery nanoplatform (PFH-PTX@PLGA/SPIO-Her) for photoacoustic (PA)/ultrasound (US) bimodal imaging-guided photothermal (PTT)/chemo synergistic cancer therapy of breast cancer. Carboxyl-modified PEGylated poly (lactic-co-glycolic acid) (PLGA-PEG-COOH) constituted the skeleton of the nanoplatform. Especially, the antibody Herceptin was modified onto the surface of nanoplatform for active HER2-targing to facilitate the tumor accumulation of the nanoplatform. The encapsulated superparamagnetic iron oxide (SPIO) nanoparticles could be employed as an excellent PA imaging agent to guide tumor therapy. When exposed to NIR light, the SPIO also could transform NIR light into thermal energy for photothermal ablation of tumor. The NIR-induced thermal effect subsequently triggered the optical droplet vaporization (ODV) of perfluorohexane (PFH) to generate PFH gas bubbles, which not only achieved the US imaging enhancement, but also contributed to the release of loaded paclitaxel (PTX) from the nanoplatform for significantly improving PTT therapeutic efficacy. Our results demonstrated that the targeted tumor accumulation, accurate real-time bimodal imaging, and the abundant drug release at the tumor site were all closely associated with the PTT therapeutic efficacy. Therefore, the theranostic nanoplatform is a very promising strategy for targeted imaging-guided photothermal/chemo synergistic tumor therapy with high therapeutic efficacy and minimized side effects. STATEMENT OF SIGNIFICANCE: Breast cancer is the most frequent cancer in women. Herein, we successfully developed a light-controllable and HER2 targeted theranostic nanoparticels (PFH-PTX@PLGA/SPIO-Her) as a specific drug delivery nanoplatform to overcome the low accuracy of tumor detection and the low specificity of traditional chemo-therapeutic protocols. The study demonstrated that PFH-PTX@PLGA/SPIO-Her could actively target to breast cancer cells with positive HER2 expression. The biocompatible PFH-PTX@PLGA/SPIO-Her nanoparticles as both photoacoustic/ultrasound bimodal imaging agents, photothermal-conversion nanomaterials (photothermal hyperthermia) and controllable drug delivery nanoagents (optical droplet vaporization) have completely eradicated the tumor without severe side effects. The theranostic strategy not only integrates strengthens of traditional imaging or therapeutic modalities, but also paves a new way for the efficient cancer treatment by taking the advantage of quickly-developing nanomedicine.

Emission of sulfur dioxide from polyurethane foam and respiratory health effects.

Recently, health damage to children exposed to synthetic polyurethane (PU) running tracks has aroused social panic in China. Some possible toxic volatiles may be responsible for these damages. However, the exact cause remains unclear. We have detected a low concentration of sulfur dioxide (SO2; 1.80-3.30 mg/m3) on the surface of the PU running track. Surprisingly, we found that SO2 was generated from the PU running track, and even such a low concentration of SO2 could induce severe lung inflammation with hemorrhage, inflammatory cell infiltration, and inflammatory factor secretion in mice after 2-week exposure. Prolonged exposure (5 weeks) to the SO2 caused chronic pulmonary inflammation and pulmonary fibrosis in the mice. Peripheral hemogram results showed that platelet concentration increased significantly in the SO2 group compared to that in the control group, and the proportion of blood neutrophils and monocytes among total leukocytes was more imbalanced in the SO2 group (16.6%) than in the control group (8.0%). Further histopathology results of sternal marrow demonstrated that hematopoietic hyperplasia was severely suppressed with increased reticular stroma and adipocytes under SO2 exposure. These data indicate that a low concentration of SO2 generated spontaneously from PU running track outdoors as a secondary product is still harmful to health, as it impairs the respiratory system, hematopoiesis, and immunologic function. This indicates that the low-concentration SO2 could be a major cause of diseases induced by air pollution, such as chronic obstructive pulmonary disease.

Clinical and Pathological Variation of Charcot-Marie-Tooth 1A in a Large Chinese Cohort.

Charcot-Marie-Tooth 1A (CMT1A) caused by peripheral myelin protein 22 (PMP22) gene duplication is the most common form of hereditary polyneuropathy. Twenty-four genetically confirmed CMT1A patients with sural nerve biopsies were enrolled in this study. The clinical picture included a great variability of phenotype with mean onset age of 22.2 ± 14.5 years (1-55 years). Pathologically, we observed a severe reduction in myelinated fiber density showing three types of changes: pure onion bulb formation in 3 cases (12.5%), onion bulb formation with axonal sprouts in 10 cases (41.7%), and focally thickened myelin with onion bulb formation or/and axonal sprouts in 11 cases (45.8%). We observed no significant correlation between nerve fiber density and disease duration. There was no significant difference between the 3 pathological types in terms of clinical manifestations, nerve fiber density, and g-ratio. Our study indicates that there is marked variability in the age of onset of CMT1A, as well as significant pathological changes without deterioration with the development of the disease. Focally thickened myelin is another common morphological feature of demyelination.

Similar clinical, pathological, and genetic features in Chinese patients with autosomal recessive and dominant Charcot-Marie-Tooth disease type 2K.

Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause rare subtypes of Charcot-Marie-Tooth disease (CMT2K and CMT4A). CMT2K is an axonal neuropathy while CMT4A is a demyelinating type. In a series of 169 Chinese CMT patients (79 CMT1, 52 CMT2 and 38 unclassified), four unrelated patients (2.37%) were identified with GDAP1 mutations, including two with autosomal recessive CMT2K (AR-CMT2K) and two dominant CMT2K (AD-CMT2K). All patients had disease onset before 5 years of age, and presented with muscle weakness, atrophy, and mild sensory disturbance in distal limbs. Motor nerve conduction velocities of the median nerve were within normal ranges, and compound muscle action potential ranged from 1.5 to 3.8 mV. Sural nerve biopsy revealed loss of large myelinated fibers with regeneration clusters and a few onion bulbs. Electron microscopy showed mitochondrial aggregation in both axons and Schwann cells, and neurofilament accumulation in giant unmyelinated fibers. The p.H256R mutation was found in all patients with GDAP1 compound heterozygous mutations, suggesting that it might be a common mutation in Chinese patients. This study observed no difference in the disease onset, phenotype severity, electrophysiological findings, or pathological changes between AR-CMT2K and AD-CMT2K patients.