Effects of Patient-Controlled Transcutaneous Electrical Acupoint Stimulation on Cancer Induced Bone Pain Relief in Patients with Non-Small Cell Lung Cancer: Study Protocol for a Randomized Controlled Trial.

Background: Transcutaneous Electrical Acupoint Stimulation (TEAS) therapy opens up the possibility for individuals with Cancer-induced bone pain (CIBP) to receive a home-based, patient-controlled approach to pain management. The aim of this study is designed to evaluate the efficacy of patient-controlled TEAS (PC-TEAS) for relieving CIBP in patients with non-small cell lung cancer (NSCLC). Methods/Design: This is a study protocol for a prospective, triple-blind, randomized controlled trial. We anticipate enrolling 188 participants with NSCLC bone metastases who are also using potent opioid analgesics from 4 Chinese medical centers. These participants will be randomly assigned in a 1:1 ratio to either the true PC-TEAS or the sham PC-TEAS group. All participants will receive standard adjuvant oncology therapy. The true group will undergo patient-controlled TEAS intervention as needed, while the sham group will follow the same treatment schedule but with non-conductive gel patches. Each treatment course will span 7 days, with a total of 4 courses administered. There will be 4 assessment time points: baseline, the conclusion of weeks 4, 8, and 12. The primary outcome of this investigation is the response rate of the average pain on the Brief Pain Inventory (BPI) scale at week 4 after treatment. Secondary outcomes include pain related indicators, quality of life scale, mood scales, and routine blood counts on the assessment days. Any adverse events will be promptly addressed and reported if they occur. We will manage trial data using the EDC platform, with a data monitoring committee providing regular quality oversight. Discussion: PC-TEAS interventions offer an attempt to achieve home-based acupuncture treatment and the feasibility of achieving triple blinding in acupuncture research. This study is designed to provide more rigorous trial evidence for the adjuvant treatment of cancer-related pain by acupuncture and to explore a safe and effective integrative medicine scheme for CIBP. Trial Registration: ClinicalTrials.gov NCT05730972, registered February 16, 2023.

AFF4 regulates osteogenic potential of human periodontal ligament stem cells via mTOR-ULK1-autophagy axis.

Scaffold protein AF4/FMR2 family member 4 (AFF4) has been found to play a role in osteogenic commitment of stem cells. However, function of AFF4 in human periodontal ligament stem cells (hPDLSCs) has not been studied yet. This present study aims to investigate the biological effect of AFF4 on osteogenic differentiation of hPDLSCs and potential mechanistic pathway. First, AFF4 expression profile was evaluated in conditions of periodontitis and osteogenic differentiation of hPDLSCs by immunohistochemical staining, western blot and qRT-PCR. Next, si-RNA mediated knockdown and lentiviral transduction mediated overexpression of AFF4 were adopted to explore impact of AFF4 on osteogenic capacity of hPDLSCs. Then, possible mechanistic pathway was identified. At last, pharmacological agonist of autophagy, rapamycin, was utilized to affirm the role of autophagy in AFF4-regulated osteogenesis of hPDLSCs. First, AFF4 expressions were significantly lower in inflamed periodontal tissues and lipopolysaccharides-treated hPDLSCs than controls, and were up-regulated during osteogenic differentiation of hPDLSCs. Next, osteogenic potential of hPDLSCs was impaired by AFF4 knockdown and potentiated by AFF4 overexpression. Moreover, AFF4 was found to positively regulate autophagic activity in hPDLSCs. At last, rapamycin treatment was shown to be able to partly restore AFF4 knockdown-suppressed osteogenic differentiation. Our study demonstrates that AFF4 regulates osteogenic potential of hPDLSCs via targeting autophagic activity. The involvement of AFF4 in periodontal homeostasis was identified for the first time.

Intestinal microbiota: a new perspective on delaying aging?

The global aging situation is severe, and the medical pressures associated with aging issues should not be underestimated. The need and feasibility of studying aging and intervening in aging have been confirmed. Aging is a complex natural physiological progression, which involves the irreversible deterioration of body cells, tissues, and organs with age, leading to enhanced risk of disease and ultimately death. The intestinal microbiota has a significant role in sustaining host dynamic balance, and the study of bidirectional communication networks such as the brain-gut axis provides important directions for human disease research. Moreover, the intestinal microbiota is intimately linked to aging. This review describes the intestinal microbiota changes in human aging and analyzes the causal controversy between gut microbiota changes and aging, which are believed to be mutually causal, mutually reinforcing, and inextricably linked. Finally, from an anti-aging perspective, this study summarizes how to achieve delayed aging by targeting the intestinal microbiota. Accordingly, the study aims to provide guidance for further research on the intestinal microbiota and aging.

Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies.

The past decade has seen significant advances in our understanding of Hedgehog (HH) signaling pathway in various biological events. HH signaling pathway exerts its biological effects through a complex signaling cascade involved with primary cilium. HH signaling pathway has important functions in embryonic development and tissue homeostasis. It plays a central role in the regulation of the proliferation and differentiation of adult stem cells. Importantly, it has become increasingly clear that HH signaling pathway is associated with increased cancer prevalence, malignant progression, poor prognosis and even increased mortality. Understanding the integrative nature of HH signaling pathway has opened up the potential for new therapeutic targets for cancer. A variety of drugs have been developed, including small molecule inhibitors, natural compounds, and long non-coding RNA (LncRNA), some of which are approved for clinical use. This review outlines recent discoveries of HH signaling in tissue homeostasis and cancer and discusses how these advances are paving the way for the development of new biologically based therapies for cancer. Furthermore, we address status quo and limitations of targeted therapies of HH signaling pathway. Insights from this review will help readers understand the function of HH signaling in homeostasis and cancer, as well as opportunities and challenges of therapeutic targets for cancer.

Epigenetic regulation of dental-derived stem cells and their application in pulp and periodontal regeneration.

Dental-derived stem cells have excellent proliferation ability and multi-directional differentiation potential, making them an important research target in tissue engineering. An increasing number of dental-derived stem cells have been discovered recently, including dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHEDs), stem cells from apical papilla (SCAPs), dental follicle precursor cells (DFPCs), and periodontal ligament stem cells (PDLSCs). These stem cells have significant application prospects in tissue regeneration because they are found in an abundance of sources, and they have good biocompatibility and are highly effective. The biological functions of dental-derived stem cells are regulated in many ways. Epigenetic regulation means changing the expression level and function of a gene without changing its sequence. Epigenetic regulation is involved in many biological processes, such as embryonic development, bone homeostasis, and the fate of stem cells. Existing studies have shown that dental-derived stem cells are also regulated by epigenetic modifications. Pulp and periodontal regeneration refers to the practice of replacing damaged pulp and periodontal tissue and restoring the tissue structure and function under normal physiological conditions. This treatment has better therapeutic effects than traditional treatments. This article reviews the recent research on the mechanism of epigenetic regulation of dental-derived stem cells, and the core issues surrounding the practical application and future use of pulp and periodontal regeneration.

Gut microbiota and its roles in the pathogenesis and therapy of endocrine system diseases.

A new field of microbial research is the relationship between microorganisms and multicellular hosts. It is known that gut microbes can cause various endocrine system diseases, such as diabetes and thyroid disease. Changes in the composition or structure and the metabolites of gut microbes may cause gastrointestinal disorders, including ulcers or intestinal perforation and other inflammatory and autoimmune diseases. In recent years, reports on the interactions between intestinal microorganisms and endocrine system diseases have been increasingly documented. In the meantime, the treatment based on gut microbiome has also been paid much attention. For example, fecal microbiota transplantation is found to have a therapeutic effect on many diseases. As such, understanding the gut microbiota-endocrine system interactions is of great significance for the theranostic of endocrine system diseases. Herein, we summarize the relations of gut microbiome with endocrine system diseases, and discuss the potentials of regulating gut microbiome in treating those diseases. In addition, the concerns and possible solutions regarding the gut microbiome-based therapy are discussed.

Case report: Rapid recurrence of a chronic subdural haematoma associated with prostate cancer metastasis to a haematoma capsule.

Background: Chronic subdural haematoma (CSDH) has various causes, including trauma, coagulopathies, and intracranial hypotension. However, CSDH associated with extracranial malignancy is rare. Here, we report an extremely rare case of CSDH due to prostate cancer metastasis to a haematoma capsule. Case Description: A 79-year-old man with a history of prostate cancer had a progressive decline in consciousness during hospitalization for cancer treatment. CSDH was diagnosed from computed tomography (CT) imaging. We urgently performed burr hole drainage, and the patient's symptoms improved rapidly after surgery. After removing the drainage tube, the patient's symptoms worsened again, and the repeat head CT suggested recurrence of CSDH. In a second operation, most of the haematoma capsule was excised under craniotomy, and the thickened haematoma capsule was sent for routine pathologic examination. Pathological findings confirmed the metastasis of prostate cancer to the haematoma capsule, which we believed to be related to a rapid recurrence of CSDH. After the second operation, the disease course progressed without CSDH recurrence. Conclusions: For patients with malignant tumours diagnosed with CSDH, the possibility of metastasis to a haematoma capsule needs to be considered. Burr holes and drainage can easily lead to a rapid relapse. Excision of the haematoma capsule is the key to successful treatment.

A genome-wide association analysis: m6A-SNP related to the onset of oral ulcers.

Oral ulcers are one of the most common inflammatory diseases on oral mucosa that have obvious impacts on patients. Studies have shown that N6-methyladenosine (m6A) RNA transcription modification may be involved in the development of various inflammatory responses, and whether the pathogenesis of oral ulcers is related to m6A is unclear. This study aims to identify how m6A-related single nucleotide polymorphisms (m6A-SNPs) may affect oral ulcers. The UKBB dataset containing 10,599,054 SNPs was obtained from the GWAS database using the keyword "oral ulcer" and compared with the M6AVar database containing 13,703 m6A-SNPs.With 7,490 m6A-SNPs associated with oral ulcers identified, HaploReg and RegulomeDB were used for further functional validation and differential gene analysis was performed using the GEO database dataset GSE37265. A total of 7490 m6A-SNPs were detected in this study, 11 of which were related to oral ulcers (p<5E-08), and all of these SNPs showed eQTL signals. The SNP rs11266744 (p=2.00E-27) may regulate the expression of the local gene CCRL2, thereby participating in the pathogenesis of oral ulcers. In summary, by analyzing genome-wide association studies, this study showed that m6A modification may be involved in the pathogenesis of oral ulcers and CCRL2 may be the targeted gene.

Case Report: Clinical and Procedural Implications of Ommaya Reservoir Implantation in Cystic Brain Metastases Followed by Radiosurgery Treatment.

Background: Therapy for large or deep cystic brain metastases is a troublesome procedure in clinical departments. Stereotactic cyst aspiration, combined with Gamma Knife radiosurgery, can be an effective treatment for cystic brain metastases. However, there is still a possibility that a reaccumulation of cystic fluid may lead to poor efficacy or even reoperation. Case presentation: We present a case of a 67-year-old man who was diagnosed with lung cancer brain metastasis. The intracranial lesion seen on imaging appeared to be cystic and located deep inside the brain with associated limb dysfunction. The patient did not respond well to chemotherapy and underwent cyst aspiration with Ommaya reservoir implantation under neuronavigation. Repeated cystic fluid reaccumulation and exacerbation of symptoms occurred during treatment. We performed repeated aspiration via the Ommaya reservoir to control the symptoms and combined it with radiotherapy. During the follow-up period of 14 months, the intracranial tumor was effectively and satisfactorily controlled. Conclusions: We highlight that Ommaya reservoir implantation during stereotactic cyst aspiration is necessary to prevent fluid reaccumulation, thereby avoiding the need for a second surgical procedure.

Delayed PET imaging using image synthesis network and nonrigid registration without additional CT scan.

PURPOSE: Attenuation correction is critical for positron emission tomography (PET) image reconstruction. The standard protocol for obtaining attenuation information in a clinical PET scanner is via coregistered computed tomography (CT) images. Therefore, for delayed PET imaging, the CT scan is repeated twice, which increases the radiation dose for the patient. In this paper, we propose a zero-extradose delayed PET imaging method that requires no additional CT scans. METHODS: A deep learning-based synthesis network is designed to convert PET data into pseudo-CT images for delayed scans. Then, nonrigid registration is performed between this pseudo CT image and the CT image of the first scan, warping the CT image of the first scan to an estimated CT image for the delayed scan. Finally, the PET image attenuation correction in the delayed scan is obtained from this estimated CT image. Experiments with clinical datasets are implemented to assess the effectiveness of the proposed method with the well-recognized Generative Adversarial Networks (GAN) method. The average peak signal-to-noise ratio (PSNR) and the mean absolute percent error (MAPE) are used for comparison. We also use scoring from three experienced radiologists as subjective measurement means based on the diagnostic consistency of the PET images reconstructed from GAN and the proposed method with respect to the ground truth images. RESULTS: The experiments show that the average PSNR is 47.04 dB (the proposed method) vs. 44.41 dB (the traditional GAN method) for the reconstructed delayed PET images in our evaluation dataset. The average MAPEs are 1.59% for the proposed method and 3.32% for the traditional GAN method across five organ regions of interest (ROIs). The scores for the GAN and the proposed method rated by three experienced radiologists are 8.08±0.60 and 9.02±0.52, indicating that the proposed method yields more consistent PET images with the ground truth. CONCLUSIONS: This work proposes a novel method for CT-less delayed PET imaging based on image synthesis network and nonrigid image registration. The PET image reconstructed using the proposed method yields delayed PET images with high image quality without artifacts and is quantitatively more accurate than the traditional GAN method.

[Bacteriophage Therapy: Retrospective Review and Future Prospects].

At present, bacterial infections are mainly treated with antibiotics, but new treatment methods are urgently needed because of growing problems with antibiotic resistance. Therefore, phage therapy will be a potential solution to the problem of bacterial drug resistance, and the combined use of bacteriophage and antibiotics is also considered a potential treatment option. However, there has not been any well-designed clinical controlled trials on phage therapy. More future research needs to be done to solve the problems of phage therapy, for example, its narrow antibacterial spectrum, the uncertainty regarding treatment safety, and the bacterial resistance. Some refractory diseases such as breast cancer and alcoholic hepatitis are difficult to treat clinically. The successful experimental research on bacteriophages reported in these fields provides new ideas of treatment for more refractory diseases in the future. In addition, bacteriophages also showed promising performance in vaccine applications and osteanagenesis. We herein summarize the existing weaknesses of phage therapy and its application prospects in treating systemic diseases, hoping to promote further clinical application research of phage therapy.

Analysis of potential genes and pathways associated with the colorectal normal mucosa-adenoma-carcinoma sequence.

This study aimed to identify differentially expressed genes (DEGs) related to the colorectal normal mucosa-adenoma-carcinoma sequence using bioinformatics analysis. Raw data files were downloaded from Gene Expression Omnibus (GEO) and underwent quality assessment and preprocessing. DEGs were analyzed by the limma package in R software (R version 3.3.2). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with the DAVID online tool. In a comparison of colorectal adenoma (n = 20) and colorectal cancer (CRC) stage I (n = 31), II (n = 38), III (n = 45), and IV (n = 62) with normal colorectal mucosa (n = 19), we identified 336 common DEGs. Among them, seven DEGs were associated with patient prognosis. Five (HEPACAM2, ITLN1, LGALS2, MUC12, and NXPE1) of the seven genes presented a sequentially descending trend in expression with tumor progression. In contrast, TIMP1 showed a sequentially ascending trend. GCG was constantly downregulated compared with the gene expression level in normal mucosa. The significantly enriched GO terms included extracellular region, extracellular space, protein binding, and carbohydrate binding. The KEGG categories included HIF-1 signaling pathway, insulin secretion, and glucagon signaling pathway. We discovered seven DEGs in the normal colorectal mucosa-adenoma-carcinoma sequence that was associated with CRC patient prognosis. Monitoring changes in these gene expression levels may be a strategy to assess disease progression, evaluate treatment efficacy, and predict prognosis.

Circulating tumor cells predict survival benefit from chemotherapy in patients with lung cancer.

BACKGROUND: This meta-analysis was to explore the clinical significance of circulating tumor cells (CTCs) in predicting the tumor response to chemotherapy and prognosis of patients with lung cancer. METHODS: We searched PubMed, Embase, Cochrane Database, Web of Science and reference lists of relevant articles. Our meta-analysis was performed by Stata software, version 12.0, with a random effects model. Risk ratio (RR), hazard ratio (HR) and 95% confidence intervals (CI) were used as effect measures. RESULTS: 8 studies, including 453 patients, were eligible for analyses. We showed that the disease control rate (DCR) in CTCs-negative patients was significantly higher than CTCs-positive patients at baseline (RR = 2.56, 95%CI [1.36, 4.82], p < 0.05) and during chemotherapy (RR = 9.08, CI [3.44, 23.98], p < 0.001). Patients who converted form CTC-negative to positive or persistently positive during chemotherapy had a worse disease progression than those with CTC-positive to negative or persistently negative (RR = 8.52, CI [1.66, 43.83], p < 0.05). Detection of CTCs at baseline and during chemotherapy also indicated poor overall survival (OS) (baseline: HR = 3.43, CI [2.21, 5.33], p<0.001; during chemotherapy: HR = 3.16, CI [2.23, 4.48], p < 0.001) and progression-free survival (PFS) (baseline: HR = 3.16, 95%CI [2.23, 4.48], p < 0.001; during chemotherapy: HR = 3.78, CI [2.33, 6.13], p < 0.001). CONCLUSIONS: Detection of CTCs in peripheral blood indicates poor tumor response to chemotherapy and poor prognosis in patients with lung cancer.