The current molecular classification of small-cell lung cancer (SCLC) on the basis of the expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous ...group, necessitating more precise characterization of lineage subclasses.
To refine the current SCLC classification with epigenomic profiles and to identify features of the redefined SCLC subtypes.
We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9)-mediated deletion. NKX2-1-specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry.
and
mouse models were engineered to explore the function of
in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized.
We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the
locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. In addition, we found that maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1).
We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aα subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.
Osteoporosis is a multifactorial disease in which genetic determinants are modulated by hormonal, environmental and nutritional factors. An important clinical risk factor in the pathogenesis of ...osteoporosis is the presence of genetics polymorphism in/around susceptibility genes/regions. This study explored whether the region of 4q22.1, which confers risk of developing osteoporosis in some populations, associated with bone mineral density and osteoporosis susceptibility in postmenopausal women of Han Chinese. We investigated 32 SNPs with minor allele frequencies ≥0.05 between 20 kb upstream and 20 kb downstream (40 kb window) of rs6532023, mapping in the 4q22.1 region, which was reported to be significantly associated with osteoporosis in previous studies. We found that rs6532023 was significantly associated with bone mineral density and osteoporosis (corrected p = 0.015) in our sample, including 440 cases and 640 controls, and allele G was supposed as a risk factor while T worked as a protective factor. Further genotype association analyses suggested a similar pattern (corrected p = 0.040). Additionally, analyses by haplotypes indicated that a haplotype block rs7683315-rs6532023-rs1471400-rs1471403 in the region associated with bone mineral density and osteoporosis (global p = 0.032), and risk haplotype A-G-G-C had almost 1.5-fold increased in the cases. To our knowledge, this is the first report to examine 4q22.1 region polymorphisms and osteoporosis in Han Chinese. Our results provide further evidence for an effect of the region of 4q22.1 on the etiology of osteoporosis and suggest that 4q22.1 may be a genetic risk factor for bone mineral density and osteoporosis.
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•We employ a synthetic hybrid that mimics natural bone development but which employs PEKK in place of collagen.•The synthetic hybrid was made by using nanostructured Al2O3 and HA as ...seedbeds to grow PEKK molecules onto them.•HA hybrids increase the number of S-phase cells by elevating both mRNA and protein levels of cell cycle.•HA hybrids and S-PEKK/Al2O3 promote cellular osteogenic differentiation by upregulating mRNA and protein expression of osteogenic-related genes.
PEKK has good biocompatibility as an implantable material, but its mechanical properties and osseointegration are not satisfied enough. Aluminum oxide (Al2O3) is highly wear-resistant, while hydroxyapatite (HA) is a biologically active. However all previous biocomposites made via mechanical mixing of these two bioceramic materials have not been able to meet clinical standards. The aim of this work is to resolve these problems by using newly synthesized bioceramic hybrids. In vitro and in vivo experiments have demonstrated that these new biomaterials have significantly improved biocompatibility and biomechanical properties when compared to neat PEKK. Surface sulfonation of the hybrids also leads to further improvements of these two properties. S-PEKK/Al2O3 and S-PEKK/HA promote MC3T3-E1 adhesion. PEKK/HA and S-PEKK/HA significantly promote cell proliferation by upregulating both mRNA and protein levels of cell cycle genes to facilitate cells shift from G0/G1 phase to S phase. PEKK/HA hybrids and S-PEKK/Al2O3 promote cell differentiation by upregulating the expression of osteogenic differentiation genes and proteins. PEKK/HA, S-PEKK/Al2O3 and S-PEKK/HA are able to strongly bind to the new bone and exhibit good in vivo osseointegration properties. We conclude that PEKK/HA, S-PEKK/Al2O3 and S-PEKK/HA show good osteogenic ability, especially S-PEKK/HA, and could be promising materials for bone implants.
Disturbance of bone homeostasis caused by
(
) is a key clinical manifestation in spinal tuberculosis (TB). However, the complete mechanism of this process has not been established, and an effective ...treatment target does not exist. Increasing evidence shows that abnormal osteoclastogenesis triggered by an imbalance of the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) axis may play a key role in the disturbance of bone homeostasis. Previous studies reported that RANKL is strongly activated in patients with spinal TB; however, the OPG levels in these patients were not investigated in previous studies. In this study, we investigated the OPG levels in patients with spinal TB and the dysregulation of osteoblasts caused by
infection. Inhibition of the
gene of
by an antisense locked nucleic acid (LNA) gapmer (Mce4a-ASO) was also investigated. Analysis of the serum OPG levels in clinical samples showed that the OPG levels were significantly decreased in patients with spinal TB compared to those in the group of non-TB patients. The internalization of
in osteoblasts, the known major source of OPG, was investigated using the green fluorescent protein (GFP)-labeled
strain H37Ra (H37RaGFP). The cell-associated fluorescence measurements showed that
can efficiently enter osteoblast cells. In addition,
infection caused a dose-dependent increase of the CD40 mRNA expression and cytokine (interleukin 6, IL-6) secretion in osteoblast cells. Ligation of CD40 by soluble CD154 reversed the increased secretion of IL-6. This means that the induced CD40 is functional. Considering that the interaction between CD154-expressing T lymphocytes and bone-forming osteoblast cells plays a pivotal role in bone homeostasis, the CD40 molecule might be a strong candidate for mediating the target for treatment of bone destruction in spinal TB. Additionally, we also found that Mce4a-ASO could dose-dependently inhibit the
gene of
and reverse the decreased secretion of IL-6 and the impaired secretion of OPG caused by
infection of osteoblast cells. Taken together, the current finding provides breakthrough ideas for the development of therapeutic agents for spinal TB.
Traumatic neuromas are rare benign tumors, which are common in trauma or post-operation and accompanied with obvious symptoms of pain. This study will show the superficial peroneal nerve neuroma ...occurring after resection of hemangioma.
A 44-year-old male had an operation of the right leg cavernous hemangioma resection in 1995. Half a year after the operation, pain around the wound appeared and gradually aggravated. The patient had the lesion exploration resection in 2013, and the pathological result showed traumatic neuroma. Within half a year of the second operation, severe pain showed up again, so neuroma resection proceeded in May 2015. The postoperative pathological and immunohistochemical results showed traumatic neuroma. According to the postoperative follow-up, there were no symptoms of pain appearing again.
The pain is obvious, and B ultrasonography is the most efficient way to find neuromas. Both conservative and operative therapy have their advantages and disadvantages.
There remain many unanswered questions in relation to the treatment of traumatic neuromas, and further research is required, although we have already had adequate understanding of traumatic neuromas.
Osteoporosis (OP) is a complex bone metabolism disorder characterized by the loss of bone minerals and an increased risk of bone fracture. A recent study reported the relationship of the macrophage ...erythroblast attacher gene (MAEA) with low bone mineral density in postmenopausal Japanese women. Our study aimed to investigate the association of MAEA with postmenopausal osteoporosis (PMOP) in Han Chinese individuals.
A total of 968 unrelated postmenopausal Chinese women comprising 484 patients with PMOP and 484 controls were recruited. Four tag single nucleotide polymorphisms (SNPs) that covered the gene region of MAEA were chosen for genotyping. Single SNP and haplotypic association analyses were performed, and analysis of variance was conducted to test the correlation between blood MAEA protein level and genotypes of associated SNPs.
SNP rs6815464 was significantly associated with the risk of PMOP. The C allele of rs6815464 was strongly correlated with the decreased risk of PMOP in our study subjects (OR95% CI=0.750.63-0.89, P=0.0015). Significant differences in MAEA protein blood levels among genotypes of SNP rs6815464 were identified in both the PMOP (F=6.82, P=0.0012) and control groups (F=11.5, P=0.00001). The C allele was positively associated with decreased MAEA protein levels in blood.
This case-control study on Chinese postmenopausal women suggested an association between SNP rs6815464 of MAEA and PMOP. Further analyses showed that genotypes of SNP rs6815464 were also associated with the blood level of MAEA protein.
In the past two decades, many tools have been reported to measure the cervical range of motion (CROM), but most of the results are controversial in healthy individuals and/or individuals with neck ...pain. The Coda Motion 3-D Analysis system is a new instrument that measures three-dimensional joint movement. However, measurements of CROM using this system have yet to be conducted. Here, we investigate the reliability and validity of the Coda Motion 3-D Analysis System for measuring CROM in healthy adults.
Sixty healthy volunteers were involved in this reliability study. Two trained investigators (M1 and M2) used the Coda Motion 3-D Analysis System to measure CROM. M1 and M2 measured all the volunteers once independently; after a short rest, M1 then measured all of them again. The intraclass correlation coefficient (ICC), standard error of the measurements (SEM), smallest detectable difference (SDD), a scatter diagram, and the limits of agreement (LoAs) were applied to evaluate the inter-tester and intra-tester reliability. Thirty healthy volunteers were involved in this validity study. The cervical flexion and extension ranges of motion were measured simultaneously with both the Coda Motion 3-D Analysis System and X-ray. A scatter diagram, the Pearson correlation coefficient and LoAs were used to evaluate the validity.
Excellent intra-tester and inter-tester reliabilities were observed for the Coda Motion 3-D Analysis System (intra-tester ICC: 0.84–0.95, inter-tester ICC: 0.84–0.90). Good validity was achieved in extension and flexion with Pearson correlation coefficients ranging from 0.78 to 0.91.
The Coda Motion 3-D Analysis System has excellent reliability for the measurement of CROM and good validity for measurements of flexion and extension in healthy subjects. This system has the potential to be used to measure the normal active CROM in the clinic and is accurate, safe, non-invasive, and radiation free.
Beta-tricalcium phosphate (β-TCP) bioceramics have an inorganic composition similar to the human bone. While conventional methods can only produce ceramic scaffolds with poor controllability, the ...advancement of 3D-printing, especially stereolithography, made it possible to manufacture controllable, highly precise, micropore ceramic scaffolds. In this study, the stereolithography was applied to produce β-TCP bioceramics, while ZrO
, Al
, Ti6Al4V, and polyetheretherketone (PEEK) were used as controls. Phase analysis, water contact angle tests, and Micro-CT were applied to evaluate the surface properties and scaffold. Hemolytic toxicity, cell proliferation, and morphological assessment were performed to evaluate the biocompatibility. Alkaline phosphatase (ALP) level, mineralization, and qRT-PCR were measured to evaluate the osteointegration. During the manufacturing of β-TCP, no evident impurity substance and hemolytic toxicity was found. Cells on β-TCP had good morphologies, and their proliferation capability was similar to Ti6Al4V, which was higher than the other materials. Cells on β-TCP had higher ALP levels than PEEK. The degree of mineralization was significantly higher on β-TCP. The expression of osteogenesis-related genes on β-TCP was similar to Ti6Al4V and higher than the other materials. In this study, the β-TCP produced by stereolithography had no toxicity, high accuracy, and excellent osteointegration capability, thus resulting as a good choice for bone implants.
Spinal cord injury (SCI) is catastrophic damage for patients, their family, and society. Researchers and clinicians have been trying to find neurorestorative methods to recover their injured ...functions and structures. Cell therapy is one of the effective therapeutic strategies for SCI. And it can partially restore their neurological functions, which are once thought as permanent neurological deficits. Currently, cells being used therapeutically in clinic include olfactory ensheathing cells (OECs), mononuclear cells (MNCs), mesenchymal stromal cells (MSCs), Schwann cells, and hematopoietic stem cells, cell products differentiated from embryonic stem cells, mesenchymal stem cells, induced pluripotent stem cells, and neural stem cells as well as other kinds of cells. Real world data from these cell therapies showed some benefits in some patients with SCI. Due to being affected by many factors, the therapeutic results of some kinds of cells are contradictory and it is hard to compare effects among different types of cells. According to the data of cell therapies, OEC, MNC and MSC transplantation are applied for patients in majority percentage of cases, and OEC transplantation had a higher percentage of benefits. In next step, under the unified standard of cell preparation and quality control as well as the guidelines of clinical cell application, each kind of cells including OECs should be studied using prospective, multicenter, double-blind or observing-blind, placebo-control, randomized studies for SCI patients with different level of injury and chronicity.
Purpose
To compare the use of intraoperative ultrasound with X-ray fluoroscopy during sacral neuromodulation lead electrode placement in patients with neurogenic bladder secondary to spinal cord ...disease.
Methods
We reviewed the medical records of 52 patients who underwent sacral neuromodulation (SNM) lead electrode implantation under fluoroscopy or ultrasound guidance from July 2016 to July 2019. The operating time, number of electrode contacts with stimulus responses, minimum voltage that causes a stimulus response, and rate of standard lead electrode placement were used to assess the differences between the two methods. All patients were evaluated by recording bladder diaries, postvoid residual volumes before and during the testing period. Permanent SNM implantation is acceptable if symptoms improve by at least 50%.
Results
The operating time decreased from 87.1 ± 25.19 min in the X-ray group to 68.2 ± 25.20 min (
p
< 0.05) in the ultrasound group. The number of electrode contacts with stimulus responses, rate of standard lead electrode placement, and implantable pulse generator (IPG) placement rate were not significantly different between the two groups (
p
> 0.05). There was no radiation exposure during the operation in the ultrasound group. No incisional infections, hematomas, or other critical complications were reported in either groups.
Conclusion
Ultrasound can be applied to safely place lead electrode for sacral neuromodulation and leads to no radiation exposure to the patient, surgeon, and operating room staff and a shortened operating time while maintaining the same efficacy as X-ray.
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