Drug-resistant Group Research Articles

Clinical and biochemical assessments of circulating High Mobility Group Box Protein1 in children with epilepsy: relation to cognitive function and drug responsiveness.

Childhood epilepsy is a major health concern posing a significant burden and having disastrous consequences for cognitive function. High Mobility Group Box1 (HMGB1) is an activator of neuroinflammation, and it is possibly involved in the initiation and progression of epilepsy. We aimed to investigate circulating HMGB1 in children with epilepsy and its connection to cognitive function and drug responsiveness. Case-control research included 100 epileptic youngsters and 100 healthy matched controls. Serum HMGB1 was measured using a commercially available ELISA assay. Cognitive functions were evaluated by the Stanford-Binet test 5th edition. Drug-resistant epilepsy (DRE) was found in 37% of the investigated patients. Epileptic children have lower cognitive function parameter levels versus the control group and lower cognitive function in the DRE group compared to the drug-responsive group (P-value < 0.0001). HMGB1 levels were significantly higher in the patients' group (6.279µg/L) compared to the control group (2.093µg/L) and in the drug-resistant group (14.26µg/L) versus the drug-responsive group (4.88µg/L). A significant negative correlation was detected between HMGB1 with Full-scale IQ (r = - 0.547, P = 0.000), Visual-spatial reasoning (r = - 0.501, P = 0.000), fluid reasoning (r = - 0.510, P = 0.000), and working memory (r = - 0.555, P = 0.000). Serum HMGB1 cut-off levels > 6.85µg/L differentiate drug-responsive from resistant patients. Elevated HMGB1 levels, especially in patients with drug-resistant epilepsy, correlate negatively with cognitive performance, emphasizing its importance as a potential marker for early prediction of drug resistance and impairment of cognitive function.

TransCDR: a deep learning model for enhancing the generalizability of drug activity prediction through transfer learning and multimodal data fusion

BackgroundAccurate and robust drug response prediction is of utmost importance in precision medicine. Although many models have been developed to utilize the representations of drugs and cancer cell lines for predicting cancer drug responses (CDR), their performances can be improved by addressing issues such as insufficient data modality, suboptimal fusion algorithms, and poor generalizability for novel drugs or cell lines.ResultsWe introduce TransCDR, which uses transfer learning to learn drug representations and fuses multi-modality features of drugs and cell lines by a self-attention mechanism, to predict the IC50 values or sensitive states of drugs on cell lines. We are the first to systematically evaluate the generalization of the CDR prediction model to novel (i.e., never-before-seen) compound scaffolds and cell line clusters. TransCDR shows better generalizability than 8 state-of-the-art models. TransCDR outperforms its 5 variants that train drug encoders (i.e., RNN and AttentiveFP) from scratch under various scenarios. The most critical contributors among multiple drug notations and omics profiles are Extended Connectivity Fingerprint and genetic mutation. Additionally, the attention-based fusion module further enhances the predictive performance of TransCDR. TransCDR, trained on the GDSC dataset, demonstrates strong predictive performance on the external testing set CCLE. It is also utilized to predict missing CDRs on GDSC. Moreover, we investigate the biological mechanisms underlying drug response by classifying 7675 patients from TCGA into drug-sensitive or drug-resistant groups, followed by a Gene Set Enrichment Analysis.ConclusionsTransCDR emerges as a potent tool with significant potential in drug response prediction.

18F]FDG PET for mapping the cerebral glucose metabolic characteristics of drug-sensitive and drug-resistant epilepsy in pediatric patients.

This study aimed to investigate [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) mapping for cerebral glucose metabolism in drug-sensitive and drug-resistant pediatric epilepsy patients. This retrospective study enrolled 40 patients and 25 controls. Patients were categorized into drug-sensitive epilepsy (n = 22) and drug-resistant epilepsy (n = 18) according to the seizure frequency at follow-up. All patients underwent two [18F]FDG PET scans separated by a minimum of one year. Absolute asymmetry index (|AI|) was calculated for assessing metabolic differences and changes in epileptic foci. Statistical Parametric Mapping (SPM) was utilized to reveal voxel-wise metabolic characteristics and alterations throughout the brain. Network analysis based on graph theory was used to investigate network-level differences between the two patient groups. The drug-sensitive group showed a lower |AI| at both baseline (P = 0.038) and follow-up (P = 0.003) PET scans than the drug-resistant group. |AI| decreased in the drug-sensitive group and increased in the drug-resistant group across scans, but these trends were not statistically significant (P = 0.240 and P = 0.450, respectively). Both groups exhibited hypometabolism at baseline. The drug-sensitive group showed less hypometabolic brain regions than the drug-resistant group. The drug-sensitive maintained stable level of hypometabolism between the two scans, whereas the drug-resistant group showed an increasing hypometabolism. Network analysis demonstrated that the drug-sensitive group had a higher global efficiency, average degree, and clustering, along with a shorter characteristic path length compared to the drug-resistant group. For the first time, this study revealed in vivo cerebral glucose metabolic pattern of nonsurgical pediatric epilepsy patients treated by antiepileptic drugs. Especially, drug-resistant epilepsy patients represented significantly extensive and progressive hypometabolism with inefficient brain network connectivity compared with drug-sensitive epilepsy. [18F]FDG PET imaging may be a potential visual approach for theranostics of epilepsy patients.

Correlation between Bone Marrow Microvascular Density, Angiogenesis Factors and Bortezomib Resistance in Multiple Myeloma

To investigate the correlation between bone marrow microvascular density, angiogenesis factors and bortezomib resistance in multiple myeloma (MM). The data of 200 patients with MM treated in our hospital from January 2020 to August 2023 were retrospectively analyzed, and the patients with MM were divided into drug-resistant group(n=68) and non-drug-resistant group(n=132) according to their drug resistance during bortezomib treatment. The univariate and multivariate logistic analysis were used to screen the independent influencing factors of bortezomib resistance in MM patients during treatment. The receiver operating characteristic (ROC) curve and clinical decision curve (DCA) were used to evaluate the predictive performance and clinical application value of the risk prediction model, the consistency between the actual incidence rate and the predicted incidence rate was judged by validating the calibration chart, and the goodness-of-fit of the model was judged by H-L test. 68 of the 200 MM patients developed resistance and poor clinical efficacy during bortezomib treatment, and the clinical resistance rate of bortezomib was 34.0%. The results of multivariate analysis showed that high bone marrow microvessel density (MVD) and high bone marrow supernatant VEGF, HGF, and bFGF expression levels were independent risk factors for bortezomib resistance in MM patients (P < 0.05). The area under the ROC curve (AUC) of the model jointly constructed by bone marrow MVD, serum VEGF, HGF, bFGF and TNF-α levels was 0.924, and its sensitivity and specificity were 92.6% and 78.8%, which were higher than those of the bone marrow MVD model (AUC=0.743) and the vasogenesis factor model (AUC=0.878). The calibration curve of the joint prediction model was close to the standard curve, indicating that the model is more consistent. The results of H-L goodness -of - fit test showed χ2=14.748， P =0.164, the joint prediction model had a good fit. The DCA curve showed that the clinical net benefit of intervention in the range of 0.0~1.0 was greater than that of full intervention and no intervention. The prediction model based on bone marrow MVD and vasogenesis factors (VEGF, HGF, bFGF) in MM patients has higher clinical evaluation performance and predictive value.

424. EFFECT OF GUT MICROBIOTA ON THE RESPONSE TO NEOADJUVANT IMMUNOTHERAPY COMBINED WITH CHEMOTHERAPY IN PATIENTS WITH ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background To explore the impact of gut microbiota diversity on the efficacy of immunotherapy combined with chemotherapy in esophageal squamous cell carcinoma (ESCC) patients, aiming to identify microbial markers for predicting treatment outcomes. Methods In this study, we prospectively enrolled patients diagnosed with locally advanced esophageal squamous cell carcinoma who were scheduled to undergo neoadjuvant immunotherapy combined with chemotherapy; stool specimens were collected before the first cycle, the second cycle of immunotherapy, and at the time of preoperative disease evaluation. To examine the gut microbiota's composition and abundance, we employed the 16S rDNA sequencing technique. The sequencing data were preprocessed with FLASH and Uparse software, and species annotation was performed using the SSUrRNA database. Microbiota analysis was conducted using the R language, and group differences were assessed using appropriate statistical methods. Results In this study, 43 patients (totally 122 stool samples) with neoadjuvant immunotherapy combined with chemotherapy for esophageal squamous cell carcinoma were enrolled from December 2020 to January 2022. 16S rDNA sequencing results suggested that patients in the sensitive group had higher total fecal microbiota diversity than those in the drug-resistant group, and a notable variation in the structure of the microbiota was detected between the two groups. During treatment, the results did not show any significant statistical difference in the number of species (alpha diversity) in the sensitive group compared to the resistant group, although there was a trend towards a higher number of species in the pre-treatment sensitive group. As the treatment progressed, starting from the second cycle of treatment, the sensitive group had a higher alpha diversity than the resistant group. And we found that Bray-Curtis distance assessment of beta diversity showed that the difference between the sensitive and resistant groups also became more pronounced as treatment progressed. At the phylum level, the gut flora composition of the sensitive group remained relatively stable as treatment progressed, while the microbial diversity of the resistant group appeared to decrease. At the genus level, Bifidobacterium, Faecalibacterium, Akkermansia and Ruminococcus were more abundant in the immunotherapy-sensitive group; whereas Ligilactobacillus and Escherichia-Shigella was more rich in the immunotherapy-resistant group. The prediction model based on the baseline differences of gut microbiota in the two groups using a random forest method can be applied to predict the efficacy of immunotherapy for esophageal squamous cell carcinoma. Conclusion There are differences in species diversity and microbiota structure between the sensitive and resistant groups of esophageal squamous cell carcinoma patients receiving immunotherapy combined with chemotherapy, and the predictive model, which is based on the microbiota differences between the two groups before treatment, could be clinically relevant in predicting the efficacy of immunotherapy combined with chemotherapy for esophageal squamous cell carcinoma.

Molecular Evaluation of Aminoglycoside Resistance and Biofilm Formation Potential in Escherichia coli Isolates Collected from Hospitalized Patients

Background: Resistance to antibiotics and the ability to develop biofilms, two main virulence determinants of Escherichia coli, play a crucial role in the persistence of infections. Objectives: The aim of this study was to evaluate aminoglycoside resistance and biofilm formation potential in E. coli isolates collected from hospitalized patients in the Southwest of Iran. Methods: A total of 70 E. coli clinical isolates from different specimens were collected from Ahvaz teaching hospitals affiliated with Ahvaz Jundishapur University of Medical Sciences. All the isolates were identified as E. coli using conventional microbiological tests. Susceptibility to antibiotics was determined using the Kirby–Bauer disk diffusion method. Biofilm formation was assessed using the microtiter plate method. Finally, PCR was conducted to detect virulence gene determinants, including fimbrial genes, aminoglycoside modifying enzymes (AMEs), and 16S rRNA methylase (RMTase) genes. Results: Among aminoglycoside antibiotics, E. coli isolates showed the highest and lowest resistance rates to tobramycin (TOB; 51.4%) and gentamicin (GEN; 24.2%), respectively. Simultaneous resistance to GEN, amikacin, and TOB was observed in 28.5% of the isolates, representing the most common antibiotic resistance pattern. The prevalence of strong biofilm producers was higher in the extensively drug-resistant (XDR) phenotype group compared to the multiple drug-resistant (MDR) group (76.1% vs. 23.8%). Among the 36 isolates resistant to at least one of the aminoglycoside antibiotics, 36.1% had AME-related genes, either alone or in various combinations. Most isolates harboring AME genes were also positive for the presence of biofilm-related genes, including ecpA and fimA. Conclusions: The most frequent AME-related genes were ant(2”)-Ia and aph(3’)-Ia, followed by aac(3’)-IIa. The findings of the present study provide probable evidence that GEN is an effective aminoglycoside against biofilm-producing and antibiotic-resistant E. coli isolates.

The thickness of the retinal nerve fiber layer, macula, and ganglion cell-inner plexiform layer in people with drug-resistant epilepsy.

Using Optical coherence tomography (OCT), we evaluated the association between peripapillary retinal nerve fiber, macular thickness, macular ganglion cell-inner plexiform layer, and drug resistance. In this cross-sectional study, we recruited people diagnosed with epilepsy and healthy controls. People with epilepsy were further stratified as drug-resistant or non-drug-resistant based on their response to anti-seizure medications. OCT measurements were conducted, and findings in right eye were analyzed. Fifty-one drug-resistant participants, 37 non-drug-resistant, and 45 controls were enrolled. The average peripapillary retinal nerve fiber layer, ganglion cell-inner plexiform layer, and macular thickness were thinner in the epilepsy groups than in controls. The drug-resistant group had significantly lower average ganglion cell-inner plexiform layer thickness (p = 0.004) and a higher proportion of abnormal/borderline GC/IPL thickness (p = 5.40E-04) than the non-drug-resistant group. Nevertheless, no significant differences were seen between the average thickness of peripapillary retinal nerve fiber and macular thickness. The temporal sectors of these three parameters were also significantly thinner in the drug-resistant group than in the non-drug-resistant. In a multivariate regression model, drug resistance was an independent predictor of reduced ganglion cell-inner plexiform thickness (Odds ratios OR = 10.25, 95% CI 2.82 to 37.28). Increased seizure frequency (r = -0.23, p = 0.039) and a higher number of anti-seizure medications ever used (r = -0.27, p = 0.013) were negatively associated with ganglion cell-inner plexiform layer thickness. Individuals with drug-resistant epilepsy had a consistent reduction in average ganglion cell-inner plexiform layer thickness and the temporal sector of peripapillary retinal nerve fiber layer and macular thickness. This suggests that ganglion cell-inner plexiform layer thickness could potentially serve as an indicator of the burden of drug resistance, as it correlated with reduced thickness in individuals having more frequent seizures and greater exposure to ASMs. In our study, we used a special tool called OCT to measure how thick the retina is in people with epilepsy and in healthy control. We found that the retina was consistently thinner in all areas for those with epilepsy compared to healthy control. Particularly, a specific layer called the ganglion cell-inner plexiform layer was a lot thinner in the group that didn't respond to medications, and this thinning was related to how often seizures occurred and how much medications were taken. Also, certain parts of the retina were thinner in the drug-resistant group.

Clinical characteristics and prognostic analysis of metachronous bilateral breast carcinoma: a retrospective study based on propensity score matching.

To investigate clinical characteristics, treatment, outcomes, and prognostic risk factors of metachronous bilateral breast carcinoma (MBBC) and provide a theoretical basis for clinical management of MBBC. This was a retrospective study. From January 1, 2010 to March 31, 2022, a total of 23,010 patients with breast cancer underwent surgical treatment at the Breast Center of the Fourth Hospital of Hebei Medical University, including 386 patients with MBBC. Propensity score matching (PSM) was performed on MBBC patients and unilateral breast cancer (UBC) patients in a 1:1 ratio, and 210 UBC patients and 210 MBBC patients were finally matched. Clinical medical records of all patients were collected, including age of onset, family history of breast cancer, tumor size, lymph node status, TNM stage, mode of surgery, menstruation, pathological type, immunohistochemical (IHC) typing, treatment, disease-free survival (DFS), and overall survival (OS). The result showed that age of onset of the second primary cancer (SPC) was significantly older than that of the first primary cancer (FPC) (P = 0.024). Baseline data from MPPC patients showed that the tumor size of FPC was significantly larger than that of SPC (P = 0.043), and the proportion of PR ( +) in FPC is significantly higher than that in SPC (P = 0.045). Among MBBC patients with FPC for estrogen receptor (ER) or progesterone receptor (PR) ( +) and Her-2 (-), clinical characteristics and treatment results showed that the proportion of PR ( +) in the drug-resistant group was significantly lower than that in the non-drug-resistant group. The 2-year OS rate of SPC in the drug-resistant group was significantly shorter than those of the non-drug-resistant group (78.9% vs 100%, P < 0.05). The result of PSM-based comparison between MBBC patients and UBC patients showed significantly lower proportion of MBBC patients with SPC received chemotherapy compared to UBC patients (P = 0.026), and there was no significant difference in OS and DFS between SPC course of MBBC patients and UBC patients (P > 0.05). The univariate analysis showed that high TNM stage was a risk factor for death and disease progression in MBBC patients, with the risk of death in stage III MBBC patients being about 5 times higher than that in stage I MBBC patients (HR = 4.97, 95%CI = 1.42-17.31, P = 0.012), and the risk of disease recurrence being about 3.5 times higher than that in stage I MBBC patients (HR = 3.55, 95%CI = 1.07-11.81, P = 0.039). In summary, this study presented clinical characteristics, treatment options, and outcomes of MBBC patients and patients with MBBC who were resistant to endocrine therapy have a worse SPC survival prognosis. The course of SPC in MBBC patients was similar to that of UBC in terms of prognosis and survival, which suggested that SPC can be treated according to UBC treatment regimen. High TNM stage was a prognostic risk factor for SPC patients.

Dynamic Single-Cell RNA-Seq reveals mechanism of Selinexor-Resistance in Chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a type of hematologic malignancies caused by BCR-ABL chimeric oncogene. Resistance to tyrosine kinase inhibitors (TKIs) leads to the progression of CML into advanced stages. Selinexor is a small molecule inhibitor that targets a nuclear transporter called Exportin 1. Combined with imatinib, selinexor has been shown to disrupt nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in cell death. The objective of this study was to investigate the mechanism of drug resistance to selinexor in CML. We established K562 cell line resistant to selinexor and conducted single cell dynamic transcriptome sequencing to analyze the heterogeneity within the parental and selinexor resistant cell populations. We identified specific gene expression changes associated with resistance to selinexor. Our results revealed differential expression patterns in genes such as MT2A, TFPI, MTND3, and HMGCS1 in the total RNA, as well as MT-TW, DNAJB1, and HSPB1 in the newly synthesized RNA, between the parental and drug-resistant groups. By applying pseudo-time analysis, we discovered that a specific cluster of cells exhibited characteristics of tumor stem cells. Furthermore, we observed a gradual decrease in the expression of ferroptosis-related molecules as drug resistance developed. In vitro experiments confirmed that the combination of a ferroptosis inducer called RSL3 effectively overcame drug resistance. In conclusion, this study revealed the resistance mechanism of selinexor in CML. In conclusion, we identified a subgroup of CML cells with tumor stem cell properties and demonstrated that ferroptosis inducer improved the efficacy of selinexor in overcoming drug resistance.

Chlorogenic acid attenuates tet (X)-mediated doxycycline resistance of Riemerella anatipestifer.

The increasing resistance of R. anatipestifer has posed a significant threat to the poultry industry in recent years. The tet gene is the primary determinant of tetracycline resistance in numerous bacteria, and the enzyme modification gene tet(X) is predominantly detected in tetracycline-resistant R. anatipestifer strains. In this study, we evaluated the susceptibility of both the standard strain and clinical isolates of R. anatipestifer to doxycycline. And the expression levels of tet(X), tet(A), and tet(O) genes were detected. To assess drug susceptibility, shuttle plasmids were constructed to transfer the tet(X) gene into the standard strain of R. anatipestifer followed by treatment with chlorogenic acid. The results revealed that the minimum inhibitory concentration of doxycycline for the standard strain was 0.25μg/mL, whereas it exceeded 8μg/mL for the clinical isolates. Furthermore, there was a significant upregulation observed in expression levels of tet(X), tet(A), and tet(O) genes among induced strains. Interestingly, when transferring the tet(X) gene into the standard strain, its sensitivity to doxycycline decreased; however, MIC values for chlorogenic acid remained consistent between both standard and drug-resistant strains of R. anatipestifer. Moreover, we made a surprising discovery that screening passage with chlorogenic acid resulted in increased sensitivity of R. anatipestifer to doxycycline. Further analysis demonstrated a reversal in expression trends among three differentially expressed genes within induced drug resistance group after intervention with chlorogenic acid. The main objective behind this study is to investigate both killing effect exerted by chlorogenic acid on drug-resistant R. anatipestifer as well as its regulatory impact on drug resistance genes. This will provide novel insights and theoretical basis towards development of chlorogenic acid as a promising drug for treatment and control of drug resistance in R. anatipestifer.

Abstract 3384: Rapid and automated tumor cell phenotyping based on annexin-mediated enforce blebbing response

Abstract Introduction: Accumulating evidence supports the tight correlation between the physical characteristics of cells (including morphology, mechanical, and electrical properties) with the progression of cancer. Cellular blebbing, a distinctive feature observed during apoptosis and cell migration, has gained significant recognition. However, existing tools such as atomic force microscopy and optical tweezers have limitations in terms of throughput and complexity. Microfluidics has emerged as a promising technology to overcome these limitations. Methods: In this study, we developed a novel microfluidic device with a double-layer compression mechanism to induce controlled blebbing of cells. We implemented a convolution-based tracing program to enhance the accuracy and efficiency of cell area measurement. The device was used to examine the enforced blebbing response of two human breast cancer cell lines (MDA-MB-231 and MCF-7) and investigate the potential of blebbing as a marker for drug resistance using a human lung cancer cell line (HCC4006). Additionally, we elucidated the role of annexin-6 (A6) in enforced blebbing and its underlying mechanism. Results: Our microfluidic device successfully implemented a double-layered design that induced cell deformation through compression from the second pressurized polydimethylsiloxane layer. The findings revealed that highly invasive cell lines, such as MDA-MB-231 and osimertinib-resistant HCC4006, required significantly higher critical compression levels compared to their non-invasive counterparts (MCF-7 cell line) or osimertinib-sensitive cells. Moreover, the drug-resistant groups exhibited a greater compression strain requirement for blebbing compared to the control group, indicating their enhanced resilience against disruptive forces and superior survivability. Prior studies have demonstrated that A6 protein is recruited to the site of membrane injury and facilitates the formation of blebs, thereby contributing to cellular repair processes. Our further investigation into the role of A6 protein demonstrated its involvement in cell blebbing. Knockdown of A6 resulted in a notable 27% reduction in cellular volume, reflecting reduced intracellular pressure, and a corresponding 1.7-fold increase in the critical compressive strain necessary for inducing blebbing. Conclusion: Our microfluidic device allows for rapid and simultaneous testing and automated analysis of hundreds of cells, making it suitable for applications such as cell sorting, highly invasive and drug-resistant cancer cell detection, without the need for labeling. Furthermore, it serves as a powerful tool for fundamental studies of membrane and cytoskeleton dynamics. The label-free nature of the device, coupled with its high throughput capabilities, highlights its potential in future applications, including cancer monitoring and drug-resistance screening. Citation Format: Wei Huang, Zheng Wang, Dennis Wai-Yin Au, Bingxian Tang, Baiqian Qi, William C. Cho, Yuan Lin. Rapid and automated tumor cell phenotyping based on annexin-mediated enforce blebbing response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3384.

Single Sequence Whole-Spine Screening Magnetic Resonance Imaging: Diagnostic and Therapeutic Role in Multiple-Level Spinal Tuberculosis.

Spinal tuberculosis (TB) is the most common form of skeletal tuberculosis. Paradiscal continuous vertebral involvement at a single level is the most prevalent pattern among all forms of spinal TB. There is a wide range of reported incidences of multiple-level non-contiguous spinal TB in the literature. We would like to discuss on the utility of single whole spine screening T2-weighted (T2W) mid-sagittal magnetic resonance imaging (MRI) film in diagnosing multiple-level spinal TB and therapeutic benefits it can provide. We have done a retrospective review of the collected data of patients in Vardhman Mahavir Medical College and Safdarjung Hospital from August 2017 to October 2021 to find the incidence of multiple-level spinal TB and possible factors attributed to this specific disease pattern. All the patients who had been diagnosed of spinal TB either microbiologically or histopathologically or by a good clinical response to anti-tubercular treatment (ATT) and had a whole spine screening MRI film, were included. Patients of spinal TB who did not have a whole spine screening MRI were excluded from the study. Multiple-level spinal TB was diagnosed when lesions were identified in vertebral levels other than a typical paradiscal lesion, and additional lesions were separated from the primary disease by at least one normal spinal segment. Among the patients, 242 met the inclusion criteria, and 76 showed multiple-level non-contiguous spinal TB on MRI, incidence being 31.4%. The rest of the 166 patients showed typical single-segment contiguous lesions. By doing multivariate analysis to determine the independent risk factors for multiple-level spinal TB, extremes of age (<20 years and >50 years) have been found to be a significant factor with p value of 0.0001. Though drug resistance was not found to be a significant risk factor (p value 0.051), the proportion of patients having multiple-level TB was far more in the drug-resistant group (13/76). Single sequence whole spine screening MRI film is an effective, economical, and time-saving tool to detect multiple-level spinal TB. Along with its diagnostic accuracy, it also provides therapeutic benefits like access to a more approachable site for biopsy.

Plasma cytokine levels as markers of pathogenesis and treatment response in patients with non-tuberculous mycobacterial pulmonary disease.

We investigated the value of plasma cytokine levels as markers of pathogenesis and treatment response in patients with non-tuberculous mycobacteria (NTM) pulmonary disease. Plasma cytokine levels were measured and compared among patients with NTM pulmonary disease (n=111), tuberculosis (TB) patients (n=50), and healthy individuals (n=40). Changes during treatment were monitored at 3 and 6 months after treatment. According to the treatment response, NTM patients were classified as 'resistance' or 'sensitivity' responders. The results revealed that five out of twelve cytokines exhibited significantly higher levels in NTM patients compared to controls. Among these, interleukin (IL)-6 demonstrated the strongest discriminating capacity for NTM. Furthermore, when combined with IL-1β, they efficiently distinguished between NTM drug-resistant and drug-sensitive patients, as well as between NTM and TB groups. Additionally, IL-6 levels initially rose and then decreased in the NTM drug-resistant group during the six months of treatment, similar to the behavior of IL-1β in the NTM drug-sensitive group. Subgroup analyses of the sensitive group with differential treatment responses revealed an increase in IL-10 levels in the six-month treatment responders. A high IL-6/IL-10 ratio was associated with increased disease severity of NTM and TB. Collectively, combinations of various plasma cytokines, specifically IL-1β, IL-6, and IL-10, effectively distinguished NTM patients with varying mycobacterial burdens, with IL-6 and IL-10 emerging as potential biomarkers for early treatment response. The combination of IL-6 and IL-1β demonstrated the highest discriminatory value for distinguishing between NTM-resistant and NTM-sensitive groups as well as between NTM and TB groups.

Expression of ProEXC and PRMT5 in cervical adenocarcinoma and their clinical significance

This study observed the expression of ProEXC protein and PRMT5 protein in cervical adenocarcinoma and adjacent tissues, exploring the relationship between the expression of ProEXC and PRMT5 and the auxiliary diagnosis of cervical adenocarcinoma, as well as the clinical pathological parameters. A total of 88 specimens diagnosed with cervical adenocarcinoma from the Second Affiliated Hospital of Soochow University between 2015 and 2020 were collected. Immunohistochemistry was employed to detect the expression of ProEXC and PRMT5 in cervical adenocarcinoma and adjacent tissues, and statistical analysis was conducted. The Cancer Genome Atlas (TCGA) database was utilized to analyze the correlation between the prognosis of cervical adenocarcinoma patients and the expression of ProEXC and PRMT5, as well as their related gene pathways. The GSE39293 dataset from the Gene Expression Omnibus (GEO) was selected to compare the expression levels of ProEXC and PRMT5 in cervical adenocarcinoma cell lines (HELA) before and after antiviral drug treatment.In cervical adenocarcinoma tissues, the expression of ProEXC protein (95.5% vs 4.6%, P<0.001) and PRMT5 protein (81.8% vs 26.1%, P<0.001) was significantly higher than in surrounding adjacent tissues. Their expression was correlated with the tumor's T stage, lymph node metastasis, and human papillomavirus (HPV) infection (P<0.05). TCGA database analysis showed that patients with high expression of MCM2 in PRMT5 and ProEXC had a lower overall survival rate (P<0.05), while the expression of TOP2A was not significantly correlated with survival. In the GSE39293 dataset, the expression of MCM2 (9.34 vs 9.68, P<0.001) and PRMT5 (8.16 vs 8.26, P=0.087) in cells decreased after treatment with cidofovir, while TOP2A (8.54 vs 8.42, P=0.056) expression did not change significantly. In the drug-resistant group, the expression of PRMT5 (8.42 vs 8.16, P=0.002) and MCM2 (9.51 vs 9.34, P=0.029) increased, while TOP2A (8.06 vs 8.54, P<0.001) expression decreased. Gene set enrichment analysis (GSEA) suggested that high expression of ProEXC mainly affected the cell cycle pathway, while high expression of PRMT5 mainly affected the RNA splicing pathway.This study found that ProEXC protein and PRMT5 protein were highly expressed in cervical adenocarcinoma tissues, and the high-expression group had a poorer prognosis, showing a certain correlation with the clinical and pathological characteristics of cervical adenocarcinoma. This may be related to their influence on the cell cycle and RNA synthesis pathways, suggesting their potential significant roles in the progression of cervical adenocarcinoma.

Clinical features associated with epilepsy occurrence, resolution, and drug resistance in children with cerebral palsy: A population-based study.

To investigate clinicoradiological features associated with epilepsy, its resolution, and drug resistance in children with cerebral palsy (CP). Data were gathered from the New South Wales/Australian Capital Territory CP Register, encompassing children with CP born between 2003 and 2015 (n = 1916). Clinical features and the severity of impairments were compared among three groups: children with current epilepsy (n = 604), those with resolved epilepsy by age 5 years (n = 109), and those without epilepsy (n = 1203). Additionally, a subset of the registry cohort attending Children's Hospital Westmead (n = 256) was analysed to compare epilepsy and treatment characteristics between drug-responsive (n = 83) and drug-resistant groups (n = 147) using logistic regression and hierarchical cluster analysis. Manual Ability Classification System levels IV and V, intellectual impairment, and vision impairment were found to be associated with epilepsy in children with CP on multivariable analysis (p < 0.01). Moderate to severe intellectual impairment and bilateral spastic CP were independent positive and negative predictors of epilepsy persistence at the age of 5 years respectively (p < 0.05). Microcephaly and multiple seizure types were predictors of drug-resistant epilepsy (area under the receiver operating characteristic curve of 0.83; 95% confidence interval 0.77-0.9). Children with a known genetic cause (14%) and CP epilepsy surgery group (4.3%) formed specific clinical subgroups in CP epilepsy. Our study highlights important clinical associations of epilepsy, its resolution, and treatment response in children with CP, providing valuable knowledge to aid in counselling families and identifying distinct prognostic groups for effective medical surveillance and optimal treatment. Severe motor and non-motor impairments in cerebral palsy (CP) increase epilepsy risk. Epilepsy more likely resolves in bilateral spastic and milder CP impairments. Epilepsy in CP often manifests at an early age with multiple seizure types and high drug resistance. Children with a known genetic cause and CP epilepsy surgery group represent distinct clinical subgroups.

The inhibitory effect of quercetin on chemotherapeutic drug resistance of gastric cancer through forkhead box D3 signaling pathway

Most gastric cancer patients have cancer cell metastasis at the time of being diagnosed. Cisplatin chemotherapy can slow down the development of gastric cancer, but the drug resistance will develop after a long time of chemotherapy. Previous studies have found that quercetin improves resistance of chemotherapy drugs. Therefore, this study intends to explore quercetin’s role in gastric cancer. SGC-7901 drug-resistant cell line was cultured and intervened. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay assessed cell proliferation, cell survival rate, IC50 value and sensitivity along with analysis of cell apoptosis, proliferation by colony formation assay and qRT-PCR (real-time reverse transcription-PCR) and Western blot detection of FOXD3 (Forkhead box D3) levels. Gastric cancer xenograft tumor mouse model was established to assess its in vivo role. The drug-resistant cell model of gastric cancer was successfully constructed and quercetin inhibited cell survival to a certain extent and improved its chemosensitivity. The pro-apoptotic effect of quercetin on cisplatin chemotherapy resistance in gastric cancer is related to the increased FOXD3 level. Quercetin can directly regulate the expression of FOXD3, which is an activation effect. The inhibition rate of gastric cancer mice in vivo was the most prominent in the quercetin+drug resistance group. The tumor-bearing site was significantly reduced and the number of surviving mice was the highest, whose tumor volume was consistently lower than that of other groups. Conclusively, quercetin has a strong anti-tumor effect. It can inhibit gastric cancer cell activity and accelerate apoptosis by activating FOXD3 signaling pathway.

Dynamic Single-Cell RNA-Seq Reveals Mechanism of Selinexor-Resistance in Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm caused by BCR-ABL chimeric oncogene. The administration of tyrosine kinase inhibitors (TKI) has been shown to significantly improve the prognosis of the CML cases. TKI-resistance may lead to progression of the disease into accelerated and blast phases. To tackle this problem, there are currently several strategies that can be employed to manage or overcome the difficulties associated with TKI-resistance. Selinexor is a small molecule inhibitor that targets the nuclear transporter Exportin 1 (XPO1). This inhibition leads to disruptions in various signaling pathways involved in tumor cell cycle regulation, DNA repair, and apoptosis. In CML, Selinexor can increase the nuclear-cytoplasmic distribution ratio of BCR/ABL, cause cell cycle arrest, inhibit the proliferation of CML cell line K562, and exhibit anti-tumor properties in mouse model. When combined with imatinib, Selinexor can effectively disrupt the nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in reduced formation of clones and increased apoptosis. In this work, we were aiming at investigating the mechanism of drug-resistance of Selinexor in CML cell lines K562. We performed single cell dynamic transcriptome sequence to analysis intratumor heterogeneity of subpopulation of CML and identified key gene expression changes that occur as Selinexor-resistance. We generated Selinexor-resistant (SR) lines by culturing K562 cell lines with increasing concentrations of Selinexor. At first, we conducted an analysis of differential gene expression between the parental group and various levels of SR groups. Our findings revealed differential expression patterns in MT2A, TFPI, MTND3, and HMGCS1 in total RNA, as well as MT-TW, DNAJB1, and HSPB1 in newly synthesized RNA, within both the parental and drug-resistant groups. These results suggest that mitochondrial metabolism and heat shock proteins play a significant role in the regulation of cellular drug resistance. Furthermore, we found hallmark signaling pathways of epithelial mesenchymal transition and protein secretion upregulated in SR groups. Through the application of pseudo-time analysis, it was observed that cluster 6 persisted in both the parental and drug-resistant groups, and displayed characteristics indicative of tumor stem cells. Notably, a set of distinct genes were identified that distinguish cluster 6 from the other clusters, these genes are associated with lysosomes and ferroptosis pathways by KEGG enrichment analysis. Next, it was determined that the gene set in the newly synthesized RNA exhibits a consistent upregulation by the expression pattern clustering analysis. Within this gene set, we revealed an enrichment of the endoplasmic reticulum protein processing and ferroptosis signaling pathway. Finally, to provide additional evidence for the ferroptosis-related pathway in the SR group, we observed that the expression of ferroptosis-inhibitory molecules FTH1 and SLC7A11 increased gradually with the development of drug resistance. Conversely, the expression of ferroptosis-driving molecules HMGB1 and MTDH decreased gradually. Subsequently, in vitro experiments were conducted to validate that the combination of the ferroptosis inducer RSL3 can effectively overcome Selinexor resistance. In summary, this study identified a subgroup exhibiting tumor stem cell properties. Additionally, it demonstrated that the combination of ferroptosis inducer can improve resistance to Selinexor. Through single-cell dynamic transcriptome RNA-seq technology, this investigation elucidated the mechanism of resistance to Selinexor in the K562 cell line, highlighting the potential involvement ferroptosis in drug resistance. These findings offer novel insights for the treatment of CML.

The safety and efficacy of decortication for stage III drug-resistant tuberculous empyema.

The goal of this study was to evaluate the safety and efficacy of decortication for stage III drug-resistant tuberculous empyema (TE). We analysed all patients with stage III TE who underwent decortication between March 2015 and October 2019 at Wuhan Pulmonary Hospital. The patients were divided into 2 groups according to drug-susceptibility testing of bronchoscopy lavage fluid, pleural effusion and tissue specimens, including a drug-resistant group and a drug-sensitive group. We collected and compared the preoperative, perioperative and postoperative data from the 2 groups to evaluate the safety and efficacy of decortication for stage III drug-resistant TE. In total, 135 cases met the inclusion criteria and were enrolled, including 30 cases in the drug-resistant group and 105 cases in the drug-sensitive group. No deaths were recorded for the entire study population. Compared to the drug-sensitive group, the drug-resistant group had longer operation times (259.8 ± 78.4 min vs 187.2 ± 56.0 min, P = 0.00), a larger volume of intraoperative blood loss [300 (200,400) ml vs 200 (130, 300) ml, P = 0.00] and a higher intraoperative transfusion rate (5/30, 16.7% vs 4/105, 3.8%, P = 0.04). The rate of complications was significantly higher in the drug-resistant group (23; 76.7%) than in the drug-sensitive group (53; 50.5%) (P = 0.01). Recurrence was not reported in any of the patients. Twenty-three (76.7%) patients in the drug-resistant group and 90 (85.7%) patients in the drug-sensitive group recovered to an "excellent" level, and 3 cases in each group recovered to a "poor" level; there was no significant difference between the 2 groups in surgical effects (P = 0.21). Decortication is a safe, effective and feasible option for patients with stage III drug-resistant TE, although the operation is difficult and risky.

Prevalence and risk factors of multidrug-resistant tuberculosis in Jazan, Saudi Arabia

Abstract Background Drug-resistant tuberculosis (DR-TB) is a global challenge. Owing to its high annual mortality and morbidity rates, as stated in the annual global TB reports provided by WHO, the prevalence of multidrug-resistant tuberculosis (MDR-TB) or rifampicin-resistant tuberculosis was shown to be increasing worldwide in 2021. Patients with tuberculosis from 2018 to 2022 represented ~40 million individuals, including 1.5 million with DR-TB. The study’s goal was to identify MDR-TB prevalence and risk factors in Jazan, Saudi Arabia. Patients and methods The research was done on 114 patients diagnosed with pulmonary TB in Jazan Chest Hospital from January to April, 2019. Demographic data were collected. Monteux test, chest radiograph, sputum smear, and Lowenstein–Jensen culture were performed for all patients with pulmonary TB. Patients were allocated in either group A, with 103 (90.4%) patients, if they had Mycobacterium tuberculosis-susceptible isolates, or in group B, with 11 (9.7%) patients, if they had M. tuberculosis-resistant isolates. Results The observed overall DR-TB prevalence was 9.7%. The proportion of MDR isolates was 7%, polyresistant isolate TB was 0.9%, rifampicin-resistant tuberculosis was 0.9%, and ethambutol-resistant TB was 0.9%. Females were more in group B (54.5%) than in group A (26.2%). Unmarried patients were higher in group A (60.2%) than in group B (29.3%). Comorbidities had significant values in the drug-resistant groups (90.9%). Conclusion The study showed that screening and treatment of DR-TB are crucial for the control of TB in Jazan and Saudi Arabia as a whole.

Comprehensive analysis of resistance mechanisms to EGFR-TKIs and establishment and validation of prognostic model.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the first-line therapy for patients with lung adenocarcinoma (LUAD) harboring activating EGFR mutations. However, the emergence of drug resistance to EGFR-TKIs remains a critical obstacle for successful treatment and is associated with poor patient outcomes. The overarching objective of this study is to apply bioinformatics tools to gain insights into the mechanisms underlying resistance to EGFR-TKIs and develop a robust predictive model. The genes associated with gefitinib resistance in the LUAD cell Gene Expression Omnibus (GEO) database were identified using gene chip expression data. Functional enrichment analysis, gene set enrichment analysis (GSEA), and immune infiltration analysis were performed to comprehensively explore the mechanism of gefitinib resistance. Furthermore, a GRRG_score was constructed by integrating genes related to LUAD prognosis from The Cancer Genome Atlas (TCGA) database with the screened Gefitinib Resistant Related differentially expressed genes (GRRDEGs) using the Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analyses. Furthermore, we conducted an in-depth analysis of the tumor microenvironment (TME) features and their association with immune infiltration between different GRRG_score groups. A prognostic model for LUAD was developed based on the GRRG_score and validated. The HPA database was used to validate protein expression. The CTR-DB database was utilized to validate the results of drug therapy prediction based on the relevant genes. A total of 110 differentially expression genes were identified. Pathway enrichment analysis of DEGs showed that the differentially expressed genes were mainly enriched in Mucin type O-glycan biosynthesis, Cytokine-cytokine receptor interaction, Sphingolipid metabolism. Gene set enrichment analysis showed that biological processes strongly correlated with gefitinib resistance were cell proliferation and immune-related pathways, EPITHELIAL_MESENCHYMAL_TRANSITION, APICAL_SURFACE, and APICAL_JUNCTION were highly expressed in the drug-resistant group; KRAS_SIGNALING_DN, HYPOXIA, and HEDGEHOG_SIGNALING were highly expressed in the drug-resistant group. The GRRG_score was constructed based on the expression levels of 13 genes, including HSPA2, ATP8B3, SPOCK1, EIF6, NUP62CL, BCAR3, PCSK9, NT5E, FLNC, KRT8, FSCN1, ANGPTL4, and ID1. We further screened and validated two key genes, namely, NUP62CL and KRT8, which exhibited predictive value for both prognosis and drug resistance. Our study identified several novel GRRDEGs and provided insight into the underlying mechanisms of gefitinib resistance in LUAD. Our results have implications for developing more effective treatment strategies and prognostic models for LUAD patients.