RBM15B Promotes Prostate Cancer Cell Proliferation via PCNA m6A Modification.

Prostate cancer (PC) is the most frequently occurring cancer in men, characterized by the abnormal proliferation of cells within the prostate gland. This study explores the role of RNA binding motif protein 15B (RBM15B) in PC. RBM15B expression levels in PC patients were predicted using the Starbase database. The expression of RBM15B and proliferating cell nuclear antigen (PCNA) expression in PC cells was detected. Following RBM15B knockdown, cell proliferation assays were conducted. N6-methyladenosine (m6A) levels in PC cells were quantified, and RNA immunoprecipitation was performed to analyze the binding of m6A and YTH N-methyladenosine RNA binding protein 1 (YTHDF1) on PCNA mRNA. The stability of PCNA mRNA was assessed after treatment with actinomycin D. An in vivo nude mouse xenograft model was created to validate the role of RBM15B. The findings revealed the upregulation of RBM15B in PC. RBM15B knockdown resulted in decreased proliferation, colony formation, and EdU-positive cells. Mechanical analysis showed that RBM15B facilitated m6A modification of PCNA mRNA, leading to increasing m6A methylation. YTHDF1 bound to these m6A sites on PCNA mRNA, thus stabilizing it. Furthermore, PCNA overexpression mitigated the effects of RBM15B knockdown on PC cell proliferation. In conclusion, RBM15B promotes PC cell proliferation by enhancing the stability of PCNA mRNA through YTHDF1-mediated m6A modification.

Identification of salty peptides from enzymolysis extract of oyster by peptidomics and virtual screening.

Salty peptide as an important sodium substitute, which could reduce the risk of cardiovascular disease caused by excessive sodium intake. In this study, novel salty peptides were prepared and identified from enzymolysis extract of oysters by peptitomic identification, virtual screening and solid phase synthesis. Additionally, molecular simulation was used to study the taste mechanism of salty peptides. 316 peptides were identified in the enzymatic hydrolysates of oysters. 6 peptides, selected through virtual screening, were synthesized using solid-phase synthesis, and EK, LFE, LEY and DR were confirmed to possess a pleasing salty taste through electronic tongue evaluation. Molecular docking results indicated that these 4 peptides could enter the binding pocket within the transmembrane channel-like 4 (TMC4) cavity, wherein salt bridges, hydrogen bonds and attractive charges were the main binding forces. This study provides a rapid screening method for salty peptides in sea food products but possibly applied for other sources.

Chitosan/dextran-based organohydrogel delivers EZH2 inhibitor to epigenetically reprogram chemo/immuno-resistance in unresectable metastatic melanoma.

Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

Risk factors for reoperation after discectomy of lumbar herniated intervertebral disc disease.

Objectives: Discectomy is the most common surgery for lumbar herniated intervertebral disc (HIVD) disease. However, 5%-24% of patients undergo a second surgery due to recurrent disc herniation. Materials and Methods: This study was aimed to identify the risk factors for reoperation after discectomy of lumbar HIVD and recommend treatment for patients with a high risk of reoperation. We recruited patients diagnosed as having single-level lumbar HIVD who underwent open discectomy from January 1, 2000, to December 31, 2012 in our hospital. We used a survival curve to inspect the survival time and reoperation rate after surgery. We discussed the correlation of reoperation rate with discectomy level, body mass index, heavy lifting after surgery, sex, and age. Furthermore, we investigated the correlation between the experience of a surgeon and the reoperation rate. Results: A total of 619 patients were enrolled in our study. Most patients were 40-60 years old (48.8%), and most of them had herniation at L4/5 level (48.9%). The 8-year survival rate was 92%. Weight lifting after surgery may increase the reoperation rate by 115 and 18 times for those >60 years and <40 years, respectively. In addition, less experience of the surgeon and female sex had a high reoperation rate. Conclusion: Postoperative working modification may be very important for preventing patients from recurrent HIVD. For elderly people with HIVD, a more conservative therapy could be selected. If patients with lumbar spine hypermobility or severe degeneration require wide laminectomy, primary fusion should be considered.

Macrophage polarization: an important role in inflammatory diseases.

Macrophages are crucial cells in the human body's innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when stimulated by distinct internal environments: pro-inflammatory M1-like macrophages and anti-inflammatory M2-type macrophages. During inflammation, the two kinds of macrophages are activated alternatively, and maintaining a reasonably steady ratio is critical for maintaining homeostasis in vivo. M1 macrophages can induce inflammation, but M2 macrophages suppress it. The imbalance between the two kinds of macrophages will have a significant impact on the illness process. As a result, there are an increasing number of research being conducted on relieving or curing illnesses by altering the amount of macrophages. This review summarizes the role of macrophage polarization in various inflammatory diseases, including autoimmune diseases (RA, EAE, MS, AIH, IBD, CD), allergic diseases (allergic rhinitis, allergic dermatitis, allergic asthma), atherosclerosis, obesity and type 2 diabetes, metabolic homeostasis, and the compounds or drugs that have been discovered or applied to the treatment of these diseases by targeting macrophage polarization.

Therapeutic advantage of teriparatide in very elderly patients with proximal femoral fractures: a functional and BMD analysis.

BACKGROUND: Teriparatide, a recombinant parathyroid hormone, is pivotal in osteoporosis treatment, particularly in post-surgical recovery for hip fractures. This study investigates its efficacy in functional recovery post-hip fracture surgery in elderly patients, a demographic particularly susceptible to osteoporotic fractures. METHODS: In this retrospective cohort study, 150 elderly patients with proximal femoral fractures undergoing open reduction and internal fixation were enrolled. They were categorized into two groups: receiving 20 µg of daily teriparatide injections for 18 months and receiving standard antiresorptive medications during a 24-month follow-up. Detailed records of patient demographics, Fracture Risk Assessment Tool scores, and comorbidities were kept. Key outcomes, including bone mineral density (BMD) and functional scores (Barthel Index and Visual Analog Scale for hip pain), were evaluated at 3 and 24 months post-surgery. RESULTS: Out of the original cohort, 126 patients (20 men and 106 women with an average age of 85.5 ± 9.3 years) completed the study. The teriparatide group exhibited significant enhancements in both functional scores and BMD when compared to the control group. Notably, functional improvements were less pronounced in male patients compared to female patients. Additionally, the incidence of new fractures was markedly lower in the teriparatide group. CONCLUSION: Administering teriparatide daily for 18 months post-surgery for proximal femoral fractures significantly benefits very elderly patients by improving functionality and bone density, with observed differences in recovery between genders. These results reinforce the efficacy of teriparatide as a potent option for treating osteoporosis-related fractures in the elderly and highlight the importance of considering gender-specific treatment and rehabilitation strategies.

Epigallocatechin-3-gallate stabilizes aqueous curcumin by generating nanoparticles and its application in beverages.

In this study, we addressed the limited water solubility of curcumin by utilizing epigallocatechin-3-gallate to form nanoparticles through self-assembly. The resulting particles, ranging from 100 to 150 nm, exhibited a redshift in the UV-visible spectrum, from 425 nm to 435 nm, indicative of potential π-π stacking. Molecular docking experiments supported this finding. Curcumin loaded with epigallocatechin-3-gallate showed exceptional dispersibility in aqueous solutions, with 90.92 % remaining after 60 days. The electrostatic screening effect arises from the charge carried by epigallocatechin-3-gallate on the nanoparticles, leading to enhanced retention of curcumin under different pH, temperature, and ionic strength conditions. Furthermore, epigallocatechin-3-gallate can interact with other hydrophobic polyphenols, improving their dispersibility and stability in aqueous systems. Applying this principle, a palatable beverage was formulated by combining turmeric extract and green tea. The nanoparticles encapsulated with epigallocatechin-3-gallate show potential for improving the applicability of curcumin in aqueous food systems.

Effect of Osteoporosis Treatments on Osteoarthritis Progression in Postmenopausal Women: A Review of the Literature.

PURPOSE OF REVIEW: The purpose of this literature review was to determine if medications used to treat osteoporosis are also effective for treating osteoarthritis (OA). RECENT FINDINGS: A total of 40 relevant articles were identified. Studies were categorized into those (1) discussing estrogen and selective estrogen receptor modulators (SERMs), (2) bisphosphonates, (3) parathyroid hormone (PTH) analogs, and (4) denosumab, and (5) prior review articles. A large amount of evidence suggests that estrogen and SERMs are effective at reducing OA symptoms and disease progression. Evidence suggests that bisphosphonates, the most common medications used to treat osteoporosis, can reduce OA symptoms and disease progression. In vivo studies suggest that PTH analogs may improve the cartilage destruction associated with OA; however, few human trials have examined its use for OA. Denosumab is approved to treat osteoporosis, bone metastases, and certain types of breast cancer, but little study has been done with respect to its effect on OA. The current evidence indicates that medications used to treat osteoporosis are also effective for treating OA. Estrogen, SERMs, and bisphosphonates have the most potential as OA therapies. Less is known regarding the effectiveness of PTH analogs and denosumab in OA, and more research is needed.

Femoral neck system versus multiple cannulated screws for the fixation of Pauwels classification type II femoral neck fractures in older female patients with low bone mass.

BACKGROUND: Femoral neck fractures in older adult patients are a major concern and often necessitate surgical intervention. This study compared the clinical outcomes of 2 surgical techniques: the femoral neck system (FNS) and cannulated compression screws (CCSs). METHODS: A total of 40 female patients (mean age 73.50 ± 11.55 years) with femoral neck fractures of Pauwels classification type II and receiving surgical fixation between 2020 and 2022 were enrolled. The patients were categorized into an FNS group (n = 12) or a CCS group (n = 28), and surgical duration, intraoperative blood loss, length of hospital stay, and incidence of postoperative adverse events were analyzed. RESULTS: No significant intergroup differences in demographic characteristics were discovered. The mean surgical duration for all patients was 52.88 ± 22.19 min, with no significant difference between the groups. However, the FNS group experienced significantly higher intraoperative blood loss (P = 0.002) and longer hospital stay (P = 0.023) than did the CCS group. The incidence of osteonecrosis was higher in the CCS group, whereas the incidence of nonunion or malunion was higher in the FNS group. The surgical method did not appear to be a significant risk factor. The main risk factor for revision surgery was longer duration until the first adverse event (P = 0.015). CONCLUSION: The FNS does not appear to provide superior surgical outcomes compared with CCSs in older adult women with Pauwels classification type II femoral neck fractures. A longer duration between surgical fixation and the first adverse event before stabilization of the fracture site may be a risk factor for revision surgery.

The effect of a helmet type, home-use low-level light therapy device for chemotherapy-induced alopecia: study protocol for a randomized controlled trial.

BACKGROUND: Alopecia is one of the most common adverse effects of chemotherapy. It reduces the patient's self-esteem and quality of life and the effect of therapy. Scalp cooling is the only verified current method for prevention but success is not guaranteed, particularly after receiving anthracycline-based combinations. Low-level light therapy has been clinically proven to inhibit the progress of androgenic alopecia. A previous study using human subjects shows limited benefits for low-level light therapy for patients who suffer chemotherapy-induced alopecia but an increase in the number of probes and the optimization of light sources may improve the efficacy. This study determines the efficacy of low-level light therapy for the prevention of chemotherapy-induced hair loss for patients with breast cancer using a randomized controlled trial. METHODS: One hundred six eligible breast cancer patients were randomly distributed into a low-level light therapy group and a control group, after receiving chemotherapy. Subjects in the low-level light therapy group received 12 courses of intervention within 4 weeks. Subjects in the control group received no intervention but were closely monitored. The primary outcome is measured as the difference in the hair count in a target area between the baseline and at the end of week 4, as measured using a phototrichogram (Sentra scalp analyzer). The secondary outcomes include the change in hair count at the end of week 1, week 2, and week 3 and hair width at the end of week 1, week 2, week 3, and week 4, as measured using a phototrichogram, and the change in distress, the quality of life, and self-esteem due to chemotherapy-induced alopecia, at the end of week 4, as measured using a questionnaire. DISCUSSION: This study improves cancer patients' quality of life and provides clinical evidence. TRIAL REGISTRATION: Registered at ClinicalTrials.gov- NCT05397457 on 1 June 2022.

A functional nucleic acid-based fluorescence sensing platform based on DNA supersandwich nanowires and cation exchange reaction.

Accurate and sensitive analysis of p53 DNA is important for early diagnosis of cancer. In this work, a fluorescence sensing system based on DNA supersandwich nanowires and cation exchange (CX)-triggered multiplex signal amplification was constructed for the detection of p53 DNA. In the presence of p53 DNA, the DNA self-assembles to form a DNA supersandwich nanowire that generates long double-stranded DNA. Subsequently, the cation exchange (CX) reaction between ZnS and Ag+ was utilized to release free Zn2+. With the participation of Zn2+, DNAzyme catalyzes the hydrolysis of numerous catalytic molecular beacons, resulting in a greatly enhanced fluorescence signal due to the cycling of DNAzyme. The fluorescence values increased in proportion to the concentrations of p53 DNA in the range of 10 pM to 200 nM, and a detection limit (LOD) of 2.34 pM (S/N = 3) was obtained. This method provides an effective strategy for the quantitative detection of p53 DNA.

COVID-19 Infection Was Associated with the Functional Outcomes of Hip Fracture among Older Adults during the COVID-19 Pandemic Apex.

Background and Objectives: Hip fractures are associated with mortality and poor functional outcomes. The COVID-19 pandemic has affected patterns of care and health outcomes among fracture patients. This study aimed to determine the influence of COVID-19 infection on hip fracture recovery. Materials and Methods: We prospectively collected data on patients with hip fractures who presented at Hualien Tzu Chi Hospital between 9 March 2022 and 9 September 2022. The data included demographic information and functional scores taken before, during, and after surgery. The patients were divided into two groups: COVID-19 (+) and COVID-19 (-). Results: This study recruited 85 patients, 12 of whom (14.12%) were COVID-19 (+). No significant differences in preoperative or perioperative parameters between the two groups were observed. The postoperative Barthel index score was significantly impacted by COVID-19 infection (p = 0.001). The incidence of postoperative complications was significantly correlated with general anesthesia (p = 0.026) and the length of stay (p = 0.004) in hospital. Poor postoperative functional scores were associated with lower preoperative Barthel index scores (p < 0.001). Male sex (p = 0.049), old age (p = 0.012), a high American Society of Anesthesiologists grade (p = 0.029), and a high Charlson comorbidity index score (p = 0.028) were associated with mortality. Conclusions: Hip fracture surgeries were not unduly delayed in our hospital during the COVID-19 pandemic, but the patients' postoperative Barthel index scores were significantly influenced by COVID-19 (+). The preoperative Barthel index score may be a good predictive tool for the postoperative functional recovery of these patients.

Macrophage-organoid co-culture model for identifying treatment strategies against macrophage-related gemcitabine resistance.

BACKGROUND: Gemcitabine resistance (GR) is a significant clinical challenge in pancreatic adenocarcinoma (PAAD) treatment. Macrophages in the tumor immune-microenvironment are closely related to GR. Uncovering the macrophage-induced GR mechanism could help devise a novel strategy to improve gemcitabine treatment outcomes in PAAD. Therefore, preclinical models accurately replicating patient tumor properties are essential for cancer research and drug development. Patient-derived organoids (PDOs) represent a promising in vitro model for investigating tumor targets, accelerating drug development, and enabling personalized treatment strategies to improve patient outcomes. METHODS: To investigate the effects of macrophage stimulation on GR, co-cultures were set up using PDOs from three PAAD patients with macrophages. To identify signaling factors between macrophages and pancreatic cancer cells (PCCs), a 97-target cytokine array and the TCGA-GTEx database were utilized. The analysis revealed CCL5 and AREG as potential candidates. The role of CCL5 in inducing GR was further investigated using clinical data and tumor sections obtained from 48 PAAD patients over three years, inhibitors, and short hairpin RNA (shRNA). Furthermore, single-cell sequencing data from the GEO database were analyzed to explore the crosstalk between PCCs and macrophages. To overcome GR, inhibitors targeting the macrophage-CCL5-Sp1-AREG feedback loop were evaluated in cell lines, PDOs, and orthotopic mouse models of pancreatic carcinoma. RESULTS: The macrophage-CCL5-Sp1-AREG feedback loop between macrophages and PCCs is responsible for GR. Macrophage-derived CCL5 activates the CCR5/AKT/Sp1/CD44 axis to confer stemness and chemoresistance to PCCs. PCC-derived AREG promotes CCL5 secretion in macrophages through the Hippo-YAP pathway. By targeting the feedback loop, mithramycin improves the outcome of gemcitabine treatment in PAAD. The results from the PDO model were corroborated with cell lines, mouse models, and clinical data. CONCLUSIONS: Our study highlights that the PDO model is a superior choice for preclinical research and precision medicine. The macrophage-CCL5-Sp1-AREG feedback loop confers stemness to PCCs to facilitate gemcitabine resistance by activating the CCR5/AKT/SP1/CD44 pathway. The combination of gemcitabine and mithramycin shows potential as a therapeutic strategy for treating PAAD in cell lines, PDOs, and mouse models.

Black Phosphorus as a Targeting PPAR-γ Agonist to Reverse Chemoresistance in Patient-derived Organoids, Mice, and Pancreatic Tumor Cells.

Black phosphorus (BP) exhibits significant potential for clinical applications. However, further research is necessary to uncover the unknown biological functions of BP and broaden its applications across various fields. This study investigates the potential of BP as a targeting PPAR-γ agonist to overcome chemoresistance in the treatment of pancreatic adenocarcinoma (PAAD) using 2D and 3D cell lines, patient-derived organoids (PDOs), and mouse models. RNA-sequencing analysis shows that BP treatment enriches differentially expressed genes in the PPAR pathway, and molecular modeling predicts the potential docking site between BP and PPAR-γ. Transcriptional activity assays are further to verify the activation of PPAR-γ. BP-activated PPAR-γ inhibits cancer stem cell (CSC) properties and expression of biomarkers such as CD44 and c-Myc, which are involved in chemoresistance. Notably, CD44 overexpression in tumor cells renders them susceptible to BP while insensitive to gemcitabine. This indicates that BP preferentially targets stem-like cells, which exhibit heightened resistance to chemotherapeutic drugs. A combination treatment strategy involving BP and gemcitabine is developed, demonstrating enhanced treatment efficacy of PAAD in both in vitro and in vivo models. Thus, BP serves as a PPAR-γ agonist capable of reversing chemoresistance, establishing it as a potent anti-tumor approach for the treatment of PAAD.

Characteristic aroma improvement mechanisms of heat-sterilized bayberry juice regulated by exogenous polyphenols.

Bayberry juice is favored for its unique taste and flavor, while heat sterilization tends to reduce the aroma quality during processing, which limits its acceptability to consumers. To address this issue, we use exogenous polyphenols to regulate flavor compounds to improve the product quality. Total 13 differential key aroma-active compounds were identified between fresh bayberry juice (FBJ) and heat-sterilized bayberry juice (HBJ) using aroma extract dilution analysis (AEDA), orthogonal partial least squares-discriminant analysis (OPLS-DA) and odor activity values (OAVs). Further, eight polyphenols were added to investigate their influences on the aroma quality of HBJ respectively. The results showed that all tested polyphenols could maintain the aroma profile of HBJ closer to FBJ and improve the odor preference of HBJ, among which resveratrol and daidzein were most effective. Their aroma molecular regulatory mechanism involved enhancing the characteristic aroma of bayberry and reducing the certain off-flavored compounds produced by heat sterilization.

Early diagnosis of coronary microvascular dysfunction by myocardial contrast stress echocardiography.

Coronary microvascular dysfunction (CMD) is one of the basic mechanisms of myocardial ischemia. Myocardial contrast echocardiography (MCE) is a bedside technique that utilises microbubbles which remain entirely within the intravascular space and denotes the status of microvascular perfusion within that region. Some pilot studies suggested that MCE may be used to diagnose CMD, but without further validation. This study is aimed to investigate the diagnostic performance of MCE for the evaluation of CMD. MCE was performed at rest and during adenosine triphosphate stress. ECG triggered real-time frames were acquired in the apical 4-chamber, 3-chamber, 2-chamber, and long-axis imaging planes. These images were imported into Narnar for further processing. Eighty-two participants with suspicion of coronary disease and absence of significant epicardial lesions were prospectively investigated. Thermodilution was used as the gold standard to diagnose CMD. CMD was present in 23 (28%) patients. Myocardial blood flow reserve (MBF) was assessed using MCE. CMD was defined as MBF reserve < 2. The MCE method had a high sensitivity (88.1%) and specificity (95.7%) in the diagnosis of CMD. There was strong agreement with thermodilution (Kappa coefficient was 0.727; 95% CI: 0.57-0.88, p < 0.001). However, the correlation coefficient (r = 0.376; p < 0.001) was not high.

MiR-122-5p regulates the mevalonate pathway by targeting p53 in non-small cell lung cancer.

The 5-year survival rate of non-small cell lung cancer (NSCLC) patients is very low. MicroRNAs (miRNAs) are involved in the occurrence of NSCLC. miR-122-5p interacts with wild-type p53 (wtp53), and wtp53 affects tumor growth by inhibiting the mevalonate (MVA) pathway. Therefore, this study aimed to evaluate the role of these factors in NSCLC. The role of miR-122-5p and p53 was established in samples from NSCLC patients, and human NSCLC cells A549 using the miR-122-5p inhibitor, miR-122-5p mimic, and si-p53. Our results showed that inhibiting miR-122-5p expression led to the activation of p53. This inhibited the progression of the MVA pathway in the NSCLC cells A549, hindered cell proliferation and migration, and promoted apoptosis. miR-122-5p was negatively correlated with p53 expression in p53 wild-type NSCLC patients. The expression of key genes in the MVA pathway in tumors of p53 wild-type NSCLC patients was not always higher than the corresponding normal tissues. The malignancy of NSCLC was positively correlated with the high expression of the key genes in the MVA pathway. Therefore, miR-122-5p regulated NSCLC by targeting p53, providing potential molecular targets for developing targeted drugs.

Prevalence and clinical predictors of spasticity after intracerebral hemorrhage.

BACKGROUND: Spasticity is a common complication of intracerebral hemorrhage (ICH). However, no consensus exists on the relation between spasticity and initial clinical findings after ICH. METHODS: This retrospective study enrolled adult patients with a history of ICH between January 2012 and October 2020. The modified Ashworth scale was used to assess spasticity. A trained image analyst traced all ICH lesions. Multivariable logistic regression was used to examine the association between ICH lesion sites and spasticity. RESULTS: We finally analyzed 304 patients (mean age 54.86 ± 12.93 years; 72.04% men). The incidence of spasticity in patients with ICH was 30.92%. Higher National Institutes of Health stroke scale (NIHSS) scores were associated with an increased predicted probability for spasticity (odds ratio, OR = 1.153 [95% confidence interval, CI 1.093-1.216], p < .001). Logistic regression analysis revealed that lower age, higher NIHSS scores, and drinking were associated with an increased risk of moderate-to-severe spasticity (OR = 0.965 [95% CI 0.939-0.992], p = .013; OR = 1.068 [95% CI 1.008-1.130], p = .025; OR = 4.809 [95% CI 1.671-13.840], p = .004, respectively). However, smoking and ICH in the thalamus were associated with a reduced risk of moderate-to-severe spasticity (OR = 0.200 [95% CI 0.071-0.563], p = .002; OR = 0.405 [95% CI 0.140-1.174], p = .046, respectively) compared with ICH in the basal ganglia. CONCLUSIONS: Our results suggest that ICH lesion locations are at least partly associated with post-stroke spasticity rather than the latter simply being a physiological reaction to ICH itself. The predictors for spasticity after ICH were age, NIHSS scores, past medical history, and ICH lesion sites.

Sample size calculation for the combination test under nonproportional hazards.

For sample size calculation in clinical trials with survival endpoints, the logrank test, which is the optimal method under the proportional hazard (PH) assumption, is predominantly used. In reality, the PH assumption may not hold. For example, in immuno-oncology trials, delayed treatment effects are often expected. The sample size without considering the potential violation of the PH assumption may lead to an underpowered study. In recent years, combination tests such as the maximum weighted logrank test have received great attention because of their robust performance in various hazards scenarios. In this paper, we propose a flexible simulation-free procedure to calculate the sample size using combination tests. The procedure extends the Lakatos' Markov model and allows for complex situations encountered in a clinical trial, like staggered entry, dropouts, etc. We evaluate the procedure using two maximum weighted logrank tests, one projection-type test, and three other commonly used tests under various hazards scenarios. The simulation studies show that the proposed method can achieve the target power for all compared tests in most scenarios. The combination tests exhibit robust performance under correct specification and misspecification scenarios and are highly recommended when the hazard-changing patterns are unknown beforehand. Finally, we demonstrate our method using two clinical trial examples and provide suggestions about the sample size calculations under nonproportional hazards.

Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma.

BACKGROUND: Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m6A regulators in hepatocellular carcinoma (HCC). METHODS: Pan-cancer genomic analysis of the crosstalk between 5mC and m6A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m6A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications. RESULTS: 5mC and m6A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients' clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m6A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME. CONCLUSIONS: Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m6A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape.