Drug-sensitive Group Research Articles

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.

Differences in pulmonary nodular consolidation and pulmonary cavity among drug-sensitive, rifampicin-resistant and multi-drug resistant tuberculosis patients: the Guangzhou computerized tomography study.

Pulmonary nodular consolidation (PN) and pulmonary cavity (PC) may represent the two most promising imaging signs in differentiating multidrug-resistant (MDR)-pulmonary tuberculosis (PTB) from drug-sensitive (DS)-PTB. However, there have been concerns that literature described radiological feature differences between DS-PTB and MDR-PTB were confounded by that MDR-PTB cases tend to have a longer history. This study seeks to further clarify this point. All cases were from the Guangzhou Chest Hospital, Guangzhou, China. We retrieved data of consecutive new MDR cases [n=46, inclusive of rifampicin-resistant (RR) cases] treated during the period of July 2020 and December 2021, and according to the electronic case archiving system records, the main PTB-related symptoms/signs history was ≤3 months till the first computed tomography (CT) scan in Guangzhou Chest Hospital was taken. To pair the MDR-PTB cases with assumed equal disease history length, we additionally retrieved data of 46 cases of DS-PTB patients. Twenty-two of the DS patients and 30 of the MDR patients were from rural communities. The first CT in Guangzhou Chest Hospital was analysed in this study. When the CT was taken, most cases had anti-TB drug treatment for less than 2 weeks, and none had been treated for more than 3 weeks. Apparent CT signs associated with chronicity were noted in 10 cases in the DS group (10/46) and 9 cases in the MDR group (10/46). Thus, the overall disease history would have been longer than the assumed <3 months. Still, the history length difference between DS patients and MDR patients in the current study might not be substantial. The lung volume involvement was 11.3%±8.3% for DS cases and 8.4%±6.6% for MDR cases (P=0.022). There was no statistical difference between DS cases and MDR cases both in PN prevalence and in PC prevalence. For positive cases, MDR cases had more PN number (mean of positive cases: 2.63 vs. 2.28, P=0.38) and PC number (mean of positive cases: 2.14 vs. 1.38, P=0.001) than DS cases. Receiver operating characteristic curve analysis shows, PN ≥4 and PC ≥3 had a specificity of 86% (sensitivity 25%) and 93% (sensitivity 36%), respectively, in suggesting the patient being a MDR cases. A combination of PN and PC features allows statistical separation of DS and MDR cases.

Risk factors of treatment interruptions among drug-sensitive and drug-resistant pulmonary tuberculosis patients - A study from South Delhi, New Delhi, India

BackgroundA variety of factors influence adherence to the lengthy duration of anti-tuberculosis treatment, making it a complicated and dynamic problem. The objective of this study was to investigate the treatment interruption patterns using pre-defined criteria among a cohort of pulmonary tuberculosis patients and to elicit the associated factors. MethodsThis prospective, observational study was conducted between October 2016 to May 2018. All smear and culture positive pulmonary tuberculosis patients (age ≥ 14 years) enrolled between October 1, 2016 to March 31, 2017 across 3 Designated Microscopy Centers (DMCs) were included and followed up till end of treatment for outcome in drug-sensitive, and till interim outcome at 6 months for drug-resistant TB patients. Patterns and reasons for interruptions were recorded as per the study protocol. Results171 patients were enrolled in this study, of which 135 (78.94 %) were on Category-I and Category-II treatment (drug-sensitive tuberculosis), 23 (13 %) were multidrug-resistant (MDR) and 13 (8 %) were extensively drug resistant (XDR) tuberculosis patients. Among the drug-sensitive group, 65 (48 %) patients completed their treatment without any interruption while 70 (52 %) patients interrupted with at least one missed dose. Among the 36 MDR/XDR patients, 19 (53 %) patients did not interrupt treatment, but 17 (47 %) patients interrupted with at least one missing dose. The 87 patients in both sub-groups interrupted for 232 times/episodes of which 140 were short and 84 were long interruptions. The main reasons for interruption were found to be busy schedule in 63 (29 %) patients, adverse drug reactions in 40 (18.4 %) and comorbidities in 43 (19.8 %) patients. Feeling of early improvement/no improvement in 23 (10.5 %) patients, addictions in 27 (12.4 %) patients, lack of family support in 14 (6.4 %), unawareness of dosage and duration of treatment in 7 (3.20 %) patients were other common reasons. ConclusionThe plurality of patients studied were found to be in the younger age group i.e., 14–25 years (n = 75), constituting nearly 44 % of all the patients included and male treatment interrupters (62 %) outnumbered the females (38 %), possibly owing to work schedule or addictions. The majority of interruptions were related to patient related factors (93.5 %), followed by DOTS provided factors (6.40 %) and system related factors (3.01 %). Further studies should be conducted to classify the factors of treatment interruptions in detail and also to study the impact of these interruptions’ patterns on final outcomes.

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.

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.

Studying the estimation levels of inflammatory markers and NF-κB in MDR and DS-TB patients

Tuberculosis (TB) is one of the most infectious and deadly diseases, especially after the emergence of drug-resistant bacteria. Therefore, in this study, we developed a method to evaluate the ability of using CXCL10, CXCL9, MMP9, suPAR and the expression gene (NF-κB) and their rolesin the diagnosis and treatment of the disease in patients. Also, we used ELISA and qPCR techniques to compare the serum levels of CXCL10, CXCL9, MMP9, suPAR and NF-κB gene in drug resistant and drug sensitive TB. The serum levels of CXCL10, CXCL9, MMP9, suPAR and the expression of NF-κB gene was compared among drug resistant and drug sensitive TB using ELISA and qPCR Techniques, respectively. Our results showed an increasing in the serum levels of CXCL10, CXCL9 and suPAR, in the drug resistant of TB patients but not in the drug sensitive group, however, all of them did not reach the significant level, it was found that expression of NF-κB in drug sensitive group was higher (3.22-fold) than that in the drug resistant-TB patients (2.70-fold).

Patient-Derived Tumor Organoids Can Predict the Progression-Free Survival of Patients With Stage IV Colorectal Cancer After Surgery.

Recent studies have shown patient-derived tumor organoids can predict the drug response of patients with cancer. However, the prognostic value of patient-derived tumor organoid-based drug tests in predicting the progression-free survival of patients with stage IV colorectal cancer after surgery remains unknown. This study aimed to explore the prognostic value of patient-derived tumor organoid-based drug tests in patients with stage IV colorectal cancer after surgery. Retrospective cohort study. Surgical samples were obtained from patients with stage IV colorectal cancer at the Nanfang Hospital. A total of 108 patients who underwent surgery with successful patient-derived tumor organoid culture and drug testing were recruited between June 2018 and June 2019. Patient-derived tumor organoid culture and chemotherapeutic drug testing. Progression-free survival. According to the patient-derived tumor organoid-based drug test, 38 patients were drug sensitive and 76 patients were drug resistant. The median progression-free survival was 16.0 months in the drug-sensitive group and 9.0 months in the drug resistant group ( p < 0.001). Multivariate analyses showed that drug resistance (HR, 3.38; 95% CI, 1.84-6.21; p < 0.001), right-sided colon (HR, 3.50; 95% CI, 1.71-7.15; p < 0.001), mucinous adenocarcinoma (HR, 2.47; 95% CI, 1.34-4.55; p = 0.004), and non-R0 resection (HR, 2.70; 95% CI, 1.61-4.54; p < 0.001) were independent predictors of progression-free survival. The new patient-derived tumor organoid-based drug test model, which includes the patient-derived tumor organoid-based drug test, primary tumor location, histological type, and R0 resection, was more accurate than the traditional clinicopathological model in predicting progression-free survival ( p = 0.001). A single-center cohort study. Patient-derived tumor organoids can predict progression-free survival in patients with stage IV colorectal cancer after surgery. Patient-derived tumor organoid drug resistance is associated with shorter progression-free survival, and the addition of patient-derived tumor organoid drug tests to existing clinicopathological models improves the ability to predict progression-free survival.

MiR-216b-5p promotes late apoptosis/necroptosis in trastuzumab-resistant SK-BR-3 cells.

Breast cancer is the most common cancer in women. The human epidermal growth factor receptor 2 (HER2) overexpressing subtype is related to poor prognosis with an aggressive phenotype and is reported as one of the most commonly seen subtypes. Trastuzumab is prevalently used as a treatment method for HER2+ breast cancer however, resistance to the drug frequently occurs following the treatment. MicroRNAs (miRNAs) are 19-23 nucleotide long small RNAs, which regulate gene expression at post-transcriptional level and studies show that there are differentially expressed miRNAs between drug sensitive and resistant groups, indicating that they might have some key roles in drug effectiveness. In this study, the aim is to find out the role of miR-216b-5p in trastuzumab resistance. SK-BR-3 cells developed resistance to trastuzumab after continuous treatment with increasing concentrations of the drug for 6 months. To investigate the effect of miR-216b-5p on cancer cell behavior in resistance state, proliferation, motility, and invasion capacities of these resistant cells were analyzed by xCELLigence real-time cell analyzer. To further understand the molecular mechanisms underlying the regulation of resistant SK-BR-3 cells by miR-216b-5p, microarray analysis was performed. Apoptosis analysis was also performed since the pathway enrichment analysis pointed out cell death related pathways. The proliferation, motility, and invasion capacities of the miR-216b-5p transfected resistant cells were diminished compared to sensitive cells. We identified the necroptosis signaling pathway as the result of microarray and pathway enrichment analyses. STAT1, IRF9, and PKR were validated as the significant elements of the pathway, which are also the putative targets of miR-216b-5p. Our apoptosis analysis showed that a significant amount of trastuzumab resistant SK-BR-3 cells entered to late apoptosis/necrosis stage upon miR-216b-5p overexpression, it could be concluded that reexpression of miR-216b-5p sensitizes trastuzumab resistance through necroptosis in breast cancer.

Airway microecology in rifampicin-resistant and rifampicin-sensitive pulmonary tuberculosis patients

BackgroundPulmonary tuberculosis is a chronic infectious disease of the respiratory system. It is still one of the leading causes of death from a single infectious disease, but it has been stuck in the study of a single pathogen. Recent studies have shown that many diseases are associated with disruption of the native microbiota. In this study we investigated the occurrence of tuberculosis and the correlation between drug resistance and respiratory flora. High-throughput 16 S rRNA gene sequencing was used to characterize the respiratory microbiota composition of 30 tuberculosis (TB) affected patients and compared with 30 healthy (H) controls. According to their Gene Xpert results, 30 pulmonary tuberculosis patients were divided into 12 persons in the drug-sensitive group (DS0) and 18 persons in the drug-resistant group (DR0). The microbial flora of the two were compared with the H group.ResultsThe data generated by sequencing showed that Firmicutes, Proteus, Bacteroides, Actinomyces and Fusobacterium were the five main bacterial phyla detected, and they constituted more than 96% of the microbial community. The relative abundances of Fusobacterium, Haemophilus, Porphyromonas, Neisseria, TM7, Spirochetes, SR1, and Tenericutes in the TB group was lower than that of the H group, and Granulicatella was higher than the H group. The PcoA diagrams of the two groups had obvious clustering differences. The Alpha diversity of the TB group was lower than that of the H group, and the Beta diversity was higher than that of the H group (P < 0.05). The relative abundance of Streptococcus in the DS0 group was significantly higher than that in the DR0 group (P < 0.05).ConclusionPulmonary tuberculosis can cause disorders of the respiratory tract microbial flora, in which the relative abundance of Streptococcus was significantly different between rifampicin-sensitive and rifampicin-resistant patients.

Identification of Immune-Related Breast Cancer Chemotherapy Resistance Genes via Bioinformatics Approaches

Chemotherapy resistance in breast cancer is an important factor affecting the prognosis of breast cancer patients. We computationally analyzed the differences in gene expression before and after chemotherapy in breast cancer patients, drug-sensitive groups, and drug-resistant groups. Through functional enrichment analysis, immune microenvironment analysis, and other computational analysis methods, we identified PRC1, GGTLC1, and IRS1 as genes that may mediate breast cancer chemoresistance through the immune pathway. After validation of certain other clinical datasets and in vitro cellular assays, we found that the above three genes influenced drug resistance in breast cancer patients and were closely related to the tumor immune microenvironment. Our finding that chemoresistance in breast cancer could be influenced by the mediation of tumor immunity expanded our knowledge of how to address this problem and could guide future research involving chemoresistance.

Analysis of the Reactivity of Aspirin and Clopidogrel and Its Influencing Factors in Patients with Coronary Heart Disease at High Altitude.

Objective To evaluate the efficacy of dual-antiplatelet treatment (DAPT) in patients with coronary heart disease (CHD) at high altitude by using thrombelastogram (TEG) and to analyze the related biochemical factors affecting drug reactivity. Methods Totally 118 CHD patients who admitted to the Qinghai People's Hospital from September 2019 to September 2020 were enrolled in the group. Those people have lived in Qinghai for a long time. Seven days after DAPT, venous blood was collected on an empty stomach in the early morning of the next day; blood routine, coagulation function, and biochemical items were tested. Thrombelastogram (TEG) was used to draw curves to calculate platelet, coagulation and fibrinolysis functions, and drug inhibition rate. Patients were divided into the aspirin resistance (AR) group, clopidogrel resistance (CR) group, dual-antiplatelet drug resistance (DAR) group, and drug-sensitive group according to different inhibition rates. The drug efficacy was analyzed, and the clinical data, biochemical indexes, and TEG parameters of each group were compared to identify the risk factors of drug resistance. Results Those 118 CHD patients at high altitude were incorporated into the study, ranging from 38 to 84 years of age, including 81 males (68.64%) and 37 females (31.36%). The platelet function and coagulation-fibrinolysis function were detected by TEG, and MATHROMBI, MAADP, and MAAA were higher than the reference range. There were 82 cases (69.49%) of drug resistance, 36 cases (32.53%) of drug sensitivity, 17 cases (14.41%) of AR alone, and 16 cases (12.71%) of CR alone. There was no significant difference in age, gender, BMI, oxygen saturation, TG, GFR, and history of diabetes and hypertension between ACS and CCS groups (P > 0.05). PLT and FIB in the ACS group were higher than those in the CCS group, and the difference was statistically significant (P < 0.05). In addition, MATHROMBIN, MAFIBRIN, E, A, A30, and coagulation composite index were also higher than those in the CCS group, with a statistically significant difference (P < 0.05). Univariate analysis and logistic regression analysis suggested that age, HbA1c, FBG, and diabetes were the main factors of drug resistance. Conclusion Antiplatelet drugs aspirin and clopidogrel resistance are associated with increased age, elevated HbA1c and FBG, and diabetes. Therefore, it is necessary to take reasonable treatment measures based on the actual situation of patients.

Upregulation of TRIB2 by Wnt/β-catenin activation in BRAFV600E papillary thyroid carcinoma cells confers resistance to BRAF inhibitor vemurafenib.

The BRAFV600E mutation is an oncogenic driver associated with aggressive tumor behaviors and increased mortality among patients with papillary thyroid cancer (PTC). Although the BRAF inhibitor vemurafenib gave promising results in BRAFV600E-mutant PTC, resistance development remains a major clinical challenge. This study aimed to explore the mechanisms underlying drug resistance in PTC. Two vemurafenib-resistant PTC cell lines (KTC1 and BCPAP) were established by continuous treatment with vemurafenib for 5months. The knockdown and upregulation of Tribbles homolog 2 (TRIB2) in PTC cells were achieved by the transfection with short hairpin RNA against TRIB2 or recombinant lentiviral vector carrying TRIB2, respectively. The β-catenin inhibitor, ICG-001, was used for the inhibition of the Wnt/β-catenin signaling in PTC cells. Vemurafenib-resistant PTC cells showed higher TRIB2 expression, upregulated ERK and AKT activation, enhanced invasive capacity, and increased epithelial-mesenchymal transition compared to the drug-sensitive groups. TRIB2 knockdown repressed the activation of ERK and AKT, inhibited invasion and EMT, and induced apoptosis of PTC cells. TRIB2 deficiency also enhanced the sensitivity of both PTC cells to vemurafenib. Vemurafenib-resistant PTC cells showed elevated expression of β-catenin in both cytoplasm and nucleus. The pre-incubation of cells with β-catenin inhibitor significantly inhibited TRIB2 expression, suppressed EMT, and repressed the activation of ERK and AKT in vemurafenib-resistant cells. Our study showed that the upregulation of TRIB2 by the Wnt/β-catenin activation confers resistance to vemurafenib in PTC with BRAFV600 mutation. These findings support the potential use of TRIB2 as a therapeutic target for resistant PTC.

A Comparative Study of Chest Computed Tomography Findings: 1030 Cases of Drug-Sensitive Tuberculosis versus 516 Cases of Drug-Resistant Tuberculosis

PurposeTo investigate the CT features of drug-resistant pulmonary tuberculosis (DR-PTB) and the diagnostic value of CT in DR-PTB diagnosis to provide imaging evidence for the timely detection of drug-resistant Mycobacterium tuberculosis.Materials and MethodsA total of 1546 cases of pulmonary tuberculosis (PTB) with complete clinical data, chest CT images and defined drug sensitivity testing results were consecutively enrolled; 516 cases of DR-PTB were included in the drug-resistant group, and 1030 cases of drug-sensitive pulmonary tuberculosis (DS-PTB) were included in the drug-sensitivity group. Comparative analyses of clinical symptoms and imaging findings were conducted. Univariate and logistic regression analyses were performed, a regression equation model was developed, and the receiver operating characteristic (ROC) curve was constructed.ResultsIn the univariate analysis, some features, including whole-lung involvement, multiple cavities, thick-walled cavities, collapsed lung, disseminated lesions along the bronchi, bronchiectasis, emphysema, atelectasis, calcification, proliferative lesions, encapsulated effusion, etc., were observed more frequently in the DR-PTB group than in the DS-PTB group, and the differences were statistically significant (p<0.05). Exudative lesions and pneumoconiosis were observed more frequently in the drug-sensitivity group than in the drug-resistant group (p<0.05). Logistic regression analysis indicated that whole-lung involvement, multiple cavities, thick-walled cavities, disseminated lesions along the bronchi, bronchiectasis, and emphysema were independent risk factors for DR-PTB, and exudative diseases were protective factors. The total prediction accuracy of the regression model was 80.6%, and the area under the ROC curve (AUC) was 82.6%.ConclusionChest CT manifestations of DR-PTB had certain characteristics that significantly indicated the possibility of drug resistance in tuberculosis patients, specifically when multifarious imaging findings, including multiple cavities, thick-walled cavities, disseminated lesions along the bronchi, whole-lung involvement, etc., coexisted simultaneously. These results may provide imaging evidence for timely drug resistance detection in suspected drug-resistant cases and contribute to the early diagnosis of DR-PTB.

Clinical application of drug sensitive gene detection in postoperative instillation for non-muscle invasive bladder cancer

BackgroundBladder cancer is the most common malignant tumor of the urinary system. One of the biological characteristics of NMIBC is the high recurrence rate after surgery. The implementation of this project aimed to investigate the role of pharmacogenomic testing-guided intravesical perfusion of chemotherapeutic agents in the postoperative perfusion therapy for non-muscle invasive bladder cancer.MethodFrom January 2015 to December 2016, 298 patients with non-muscle-invasive bladder cancer were enrolled in this prospective study. These patients received chemotherapy drugs after electrotherapy. According to the presence or absence of tumor susceptibility gene detection after surgery, they were divided into two groups, including the drug sensitive group(N = 44) and the control group(N = 254). The drug sensitive group received bladder infusion therapy with sensitive chemotherapy drugs based on drug sensitivity gene detection results. The control group received intravesical instillation of pirarubicin. The preoperative general data and tumor grade of patients were recorded. Cystoscopy was performed before and every 3 months after surgery. The chest CT, upper abdomen CT, renal function, and urinary routine tests were performed. Tumor recurrence, metastasis and tumor-related death were recorded and evaluated during follow-up.ResultsThe drug sensitive group, which selected high-sensitivity drugs for intravesical instillation therapy based on gene expression, has a significantly lower relapse rate (11.36% vs 37.40%, P < 0.05) and a significantly longer time to relapse (17.80 ± 7.20 month vs11.20 ± 6.10 month, P < 0.05) compared with the control group. There were no significant differences in the time of mortality and death time between two groups.ConclusionThe pharmacogenomic testing-directed bladder instillation of chemotherapeutic drugs may be more effective than empiric drug administration in reducing the recurrence rate of non-muscle-invasive bladder cancer.

Risk factors for pneumonia caused by antimicrobial drug-resistant or drug-sensitive Acinetobacter baumannii infections: A retrospective study.

Acinetobacter baumannii (AB) is one of the major types of infection in hospitalized patients. The development of AB resistance is becoming a global clinical challenge. To assist in the clinical management of AB-induced pneumonia, we designed the present retrospective observational study to investigate the risk factors for antimicrobial drug-resistant/-sensitive AB infections.A total of 214 individuals were reviewed, in which 100 and 55 pneumonia patients were infected with drug-resistant and drug-sensitive AB, respectively. Fifty-nine pneumonia patients without AB infection served as a control group. Age, sex, duration of hospital stay, prior surgery history, the presence of coinfection and companion diseases, routine blood test results, and immunogenicity were recorded. Logistic regression was performed to identify risk factors of AB infections.Multivariate analysis revealed that long duration of hospital stay (odds ratio = 1.091 [95% CI: 1.010–1.178], P = .027) and the absence of coinfection (odds ratio = 0.507 [95% CI: 0.265–0.970], P = .040) were independent risk factors for AB infections. Same pattern of risk factors was identified for the drug-sensitive group (long duration of hospital stay: odds ratio = 1.119 [95% CI: 1.016–1.232], P = .022; absence of coinfection: odds ratio = 0.328 [95% CI: 0.135–0.797], P = .014), while high blood urea nitrogen (odds ratio: 1.382 [95% CI: 1.042–1.833], P = .025) was the only significant risk factor for drug-resistant AB infection.Long duration of hospital stay and the absence of coinfection might predict AB infections in hospitalized patients. Antimicrobial drug-resistant and drug-sensitive AB infections possess different risk factor profiles. A poor kidney function may be predictive of drug-resistant AB infection. Further prospective studies are required to validate our findings.

Evidence for Mycobacterium leprae Drug Resistance in a Large Cohort of Leprous Neuropathy Patients from India.

Resistance to anti-leprosy drugs is on the rise. Several studies have documented resistance to rifampicin, dapsone, and ofloxacin in patients with leprosy. We looked for point mutations within the folP1, rpoB, and gyrA gene regions of the Mycobacterium leprae genome predominantly in the neural form of leprosy. DNA samples from 77 nerve tissue samples were polymerase chain reaction (PCR)-amplified for M leprae DNA and sequenced for drug resistance-determining regions of genes rpoB, folP1, and gyrA. The mean age at presentation and onset was 38.2 ± 13.4 (range 14-71) years and 34.9 ± 12.6 years (range 10-63) years, respectively. The majority had borderline tuberculoid leprosy (53 [68.8%]). Mutations associated with resistance were identified in 6/77 (7.8%) specimens. Mutations seen were those associated with resistance to rifampicin, ofloxacin, and dapsone. All the six patients were drug-naive. The clinical and pathological manifestations in this group did not differ from the drug-sensitive group. This study highlights the occurrence of resistance to the standard multidrug therapy and ofloxacin in leprosy. Among the entire cohort, 1/77 (1.3%) showed resistance to rifampicin, 2/77 (2.6%) to dapsone, and 5/77 (6.4%) to ofloxacin. Six new patients showing infection by mutant strains indicated the emergence of primary resistance. Resistance to ofloxacin could be due to frequent use of quinolones for many bacterial infections. The results of the study indicate the need for development of a robust and strict surveillance system for detecting drug resistance in leprosy in India.

Sal-Like Protein 4 Transcription Factor: A Significant Diagnostic Biomarker Involved in Childhood ALL Resistance and Relapse.

PurposeSal‐like protein 4 transcription factor (SALL4) is a stem cell transcription factor that plays an essential role in the maintenance and self-renewal of embryonic and hematopoietic stem cells, functioning as an oncogene in several cancers. However, the role of SALL4 in the biological behavior of childhood acute lymphoblastic leukemia and its relationship with multidrug resistance and relapse has remained largely unknown.Patients and MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) was used to characterize the expression pattern of SALL4 in the bone marrow samples of 43 patients with Philadelphia negative ALL and 18 children in the non-cancer control group. The presence of minimal residual disease was measured a year after the initial therapy using SSCP (single-strand conformation polymorphism). In addition, the correlation between the expression of SALL4 and ABCA3 in relapsed patients was analyzed statistically.ResultsResults showed an overexpression of SALL4 in de novo patients compared with the control group (P=0.0001, AUC= 0.93), indicating the importance of this gene in the induction of leukemia. A significant increase in the ABCA3 expression levels was revealed in the relapsed patients, in comparison with the drug-sensitive group (P = 0.0005). The leukemogenetic effect of SALL4 can be related to the effect of this gene on the maintenance of pluripotency in cancer stem cells. Results also suggest that the expression of SALL4 can be considered as a diagnostic marker for pediatric ALL. Moreover, SALL4 expression levels in the minimal residual disease positive (mrd+) ALL group was significantly higher than those in the mrd− group (p=0.0001, AUC= 0.92).ConclusionThese data demonstrate the prognostic impact of SALL4 in childhood ALL. Our findings also indicated a direct correlation between the mRNA expression levels of SALL4 and ABCA3 transporter in the relapsed group of ALL patients (r=0.7). These results describe a possible mechanism by which SALL4 may lead to the development of multidrug resistance.

Mass spectrometry-based identification of new serum biomarkers in patients with multidrug resistant pulmonary tuberculosis

To screen new serum metabolic biomarkers for different drug resistance profiles of pulmonary tuberculosis (TB) and explore their mechanisms and functions. We collected serum samples from TB patients with drug sensitivity (DS), monoresistance to isoniazid (MR-INH), monoresistance to rifampin (MR-RFP), multidrug resistance (MDR), and polyresistance (PR). The metabolites in the serum samples were extracted by oscillatory and deproteinization for LC-MS/MS analysis, and the results were normalized by Pareto-scaling method and analyzed using Metaboanalyst 4.0 software to identify the differential metabolites. The differential metabolites were characterized by function enrichment and co-expression analysis to explore their function and possible pathological mechanisms. Compared with the DS group, 286 abnormally expressed metabolites were identified in MR-INH group, 362 in MR-RPF group, 277 in MDR group and 1208 in PR group by LC-MS/MS analysis. Acetylagmatine (P < 0.05), aminopentol (P < 0.05), and tetracosanyl oleate (P < 0.05) in MR-INH group; Ala His Pro Thr (P < 0.001) and glycinoprenol-9 (P < 0.05) in MR-RFP group; trimethylamine (P < 0.05), penaresidin A (P < 0.05), and verazine (P < 0.05) in MDR group; and PIP (18:1(11Z)/ 18:3(6Z, 9Z, 12Z)) (P < 0.001), Pro Arg Trp Tyr (P < 0.001), N-methyldioctylamine (P < 0.001), and phytolaccoside E (P < 0.05) in PR group all showed significant differential expressions. Significant differential expressions of phthalic acid mono-2-ethylhexyl ester (P < 0.05) and eicosanoyl-EA (P < 0.05) were found in all the drug resistant groups as compared with DS group. Acetylagmatine, aminopentol, tetracosanyl oleate, Ala His Pro Thr, glycinoprenol-9, trimethylamine, penaresidin A, verazine, PIP(18:1(11Z)/18:3(6Z, 9Z, 12Z)), Pro Arg Trp Tyr, N-methyldioctylamine, phytolaccoside E, phthalic acid mono-2-ethylhexyl ester, and eicosanoyl-EA are potentially new biomarkers that indicate monoresistance, multi-drug resistance and polyresistance of Mycobacterium tuberculosis. The combined use of these biomarkers potentially allows for assessment of drug resistance in TB and enhances the diagnostic sensitivity and specificity.

Association of MDR1 gene polymorphisms with refractory epilepsy in children

To assess the association of single nucleotide polymorphisms of multidrug resistance gene 1 (MDR1) with refractory epilepsy in children. Peripheral blood samples were collected from 200 children with epilepsy and 100 healthy controls. Genomic DNA was extracted and subjected to PCR amplification, agarose gel electrophoresis and target site sequencing. Genotypes of rs1922242, rs2235048, rs10808072, rs868755 and rs1202184 loci of the MDR1 gene were analyzed. No significant difference was found in genotypic distribution and allelic frequencies of the rs1922242, rs2235048, rs10808072 and rs868755 loci between the drug-resistant and drug-sensitive groups. For the rs1202184 locus, a significant difference in genotypic distribution was found (P=0.008). No significant difference was found in the frequencies of various haplotypes between the two groups. Genotypes of the rs1202184 locus of the MDR1 gene are associated with refractory epilepsy in children, for which the AA genotype plays a dominant role.

Impaired hippocampal functional connectivity in patients with drug resistant, generalized tonic-clonic seizures.

The aim of this study was to better understand the imaging features of drug-resistant epilepsy (DRE), especially in idiopathic generalized tonic-clonic seizure (GTCS), as well as to discover the associated mechanisms and functional connectivity (FC). A total of 31 idiopathic generalized epilepsy-GTCS patients and 17 healthy controls were enrolled. For each patient, resting-state functional MRI was performed. After a 12-month follow-up observation, patients were further divided into either drug-resistant (DR) or drug-sensitive (DS) groups. Compared to the DS group, DR patients had previously received more types of antiepileptic drugs and had taken more types of failed antiepileptic drugs. There were distinct FC changes toward the left thalamus, left putamen, left precuneus, and right precentral gyrus in the left hippocampus between DR and DS patients. FCs in the DR group largely decreased or remained unchanged, while DS patients exhibited compensatory enhancement. Disease duration was negatively correlated with FC between the left hippocampus and the left thalamus-putamen in patients with DRE. Further, DRE patients had an extremely high area under the curve (0.978) and a cut-off FC between the left hippocampus and thalamus-putamen of 0.282. Together, hippocampal FCs in patients with DR GTCS were impaired and time-dependently correlated with disease duration. Hippocampal FCs in DS patients showed overall compensatory enhancement, which could be used as a sensitive and specific marker to identify and predict DR GTCS.