Fat mass as an important predictor of persistent hypertension in patients with primary aldosteronism after adrenalectomy.

Aldosterone excess is present in obesity and is associated with involvement in the pathogenesis of obesity. We evaluate the impact of body obesity as measured by body composition monitor (BCM) on clinical outcomes in patients with unilateral primary aldosteronism (uPA) after adrenalectomy. The BCM device was used to assess body composition before and after adrenalectomy. We used fat mass (FM) and body mass index (BMI) to classify obesity and divided obesity into three groups: clinical overweight (BMI (kg/m2) ≥25); normal weight obesity (NWO, FM (%) ≥ 35 for women, >25 for men & BMI < 25); and no obesity (FM < 35 for women, <25 for men & BMI < 25). A total of 130 unilateral PA (uPA) patients received adrenalectomy, and 27 EH patients were identified; uPA patients with hypertension remission were found to have lower FM (p = 0.046), BMI (p < 0.001), and lower prevalence of overweight (p = 0.001). In the logistic regression model, patients with clinical overweight (OR = 2.9, p = 0.007), NWO (OR = 3.04, p = 0.041) and longer HTN duration (years, OR = 1.065, p = 0.013) were at the risk of persistent hypertension after adrenalectomy. Obesity status was strongly associated with persistent hypertension in uPA patients after adrenalectomy. However, patients in the NWO group also carried higher risk of persistent hypertension. Therefore, assessment of pre-obesity and overweight in uPA patients are extremely important, especially in those who have normal BMI.

Predicting lncRNA-disease associations based on combining selective similarity matrix fusion and bidirectional linear neighborhood label propagation.

Recent studies have revealed that long noncoding RNAs (lncRNAs) are closely linked to several human diseases, providing new opportunities for their use in detection and therapy. Many graph propagation and similarity fusion approaches can be used for predicting potential lncRNA-disease associations. However, existing similarity fusion approaches suffer from noise and self-similarity loss in the fusion process. To address these problems, a new prediction approach, termed SSMF-BLNP, based on organically combining selective similarity matrix fusion (SSMF) and bidirectional linear neighborhood label propagation (BLNP), is proposed in this paper to predict lncRNA-disease associations. In SSMF, self-similarity networks of lncRNAs and diseases are obtained by selective preprocessing and nonlinear iterative fusion. The fusion process assigns weights to each initial similarity network and introduces a unit matrix that can reduce noise and compensate for the loss of self-similarity. In BLNP, the initial lncRNA-disease associations are employed in both lncRNA and disease directions as label information for linear neighborhood label propagation. The propagation was then performed on the self-similarity network obtained from SSMF to derive the scoring matrix for predicting the relationships between lncRNAs and diseases. Experimental results showed that SSMF-BLNP performed better than seven other state of-the-art approaches. Furthermore, a case study demonstrated up to 100% and 80% accuracy in 10 lncRNAs associated with hepatocellular carcinoma and 10 lncRNAs associated with renal cell carcinoma, respectively. The source code and datasets used in this paper are available at: https://github.com/RuiBingo/SSMF-BLNP.

Analysis of clinical index changes of right heart hypofunction in patients with primary myelofibrosis / 白血病·淋巴瘤

Objective:To investigate the changes of related indicators of right heart hypofunction in patients with primary myelofibrosis (PMF).Methods:The clinical data of 55 PMF patients in the Second People's Hospital of Lianyungang in Jiangsu Province and Jiangsu Province Hospital from January 2015 to August 2019 were retrospectively analyzed. The differences in right heart function-related echocardiographic indexes and biochemical indexes between pre-fibrosis/early stage fibrosis patients and obvious stage fibrosis patients were compared. Single factor linear regression method was used to analyze the correlations of pulmonary artery pressure with biochemical indexes.Results:The hemoglobin level [119 g/L (47-224 g/L) vs. 78 g/L (33-182 g/L)] and platelet count [233×10 12/L (5×10 12/L-984×10 12/L) vs. 117×10 12/L (7×10 12/L-731×10 12/L)] of patients in the pre-fibrosis/early stage fibrosis group were higher than those in the obvious stage fibrosis group, and the differences were statistically significant (both P<0.05). Among 22 patients with complete results of cardiac ultrasound, 90.9% (20/22) patients had increased pulmonary artery pressure, 72.7% (16/22) patients had increased left atrial diameter, and 90.9% (20/22) patients had increased right ventricular diastolic diameter. There were no patients with abnormal ejection fraction. The pulmonary artery pressure [48 mmHg (46-90 mmHg) vs. 33 mmHg (20-50 mmHg) (1 mmHg = 0.133 kPa)], left ventricular diastolic diameter [46 mm (36-50 mm) vs. 47 mm (43-53 mm)] and fractional shortening rate [38.1% (36.0%-38.9%) vs. 35.4% (32.7%-37.8%)] of patients in the pre-fibrosis/early stage fibrosis group were higher than those in the obvious stage fibrosis group, and the differences were statistically significant (all P < 0.05). The pulmonary artery pressure of patients had positive correlations with age ( r = 0.590), serum ferritin (SF) ( r = 0.608), lactate dehydrogenase (LDH) ( r = 0.711) and soluble growth-stimulating expression gene 2 (ST-2) ( r = 0.580)(all P<0.05), and had negative correlation with platelet count ( r = -0.596, P = 0.003). Conclusion:PMF patients are prone to right heart hypofunction, the pulmonary artery pressure is higher in older patients and patients with high SF, LDH and ST-2 levels and low platelet count.

Erdafitinib Resensitizes ABCB1-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs.

The development of multidrug resistance (MDR) in cancer patients, which is often associated with the overexpression of ABCB1 (MDR1, P-glycoprotein) in cancer cells, remains a significant problem in cancer chemotherapy. ABCB1 is one of the major adenosine triphosphate (ATP)-binding cassette (ABC) transporters that can actively efflux a range of anticancer drugs out of cancer cells, causing MDR. Given the lack of Food and Drug Administration (FDA)-approved treatment for multidrug-resistant cancers, we explored the prospect of repurposing erdafitinib, the first fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA, to reverse MDR mediated by ABCB1. We discovered that by reducing the function of ABCB1, erdafitinib significantly resensitized ABCB1-overexpressing multidrug-resistant cancer cells to therapeutic drugs at sub-toxic concentrations. Results of erdafitinib-stimulated ABCB1 ATPase activity and in silico docking analysis of erdafitinib binding to the substrate-binding pocket of ABCB1 further support the interaction between erdafitinib and ABCB1. Moreover, our data suggest that ABCB1 is not a major mechanism of resistance to erdafitinib in cancer cells. In conclusion, we revealed an additional action of erdafitinib as a potential treatment option for multidrug-resistant cancers, which should be evaluated in future drug combination trials.

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs.

The development of multidrug resistance (MDR) in cancer patients driven by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells presents one of the most daunting therapeutic complications for clinical scientists to resolve. Despite many novel therapeutic strategies that have been tested over the years, there is still no approved treatment for multidrug-resistant cancers to date. We have recently adopted a drug repurposing approach to identify therapeutic agents that are clinically active and at the same time, capable of reversing multidrug resistance mediated by ABCB1 and ABCG2. In the present study, we investigated the effect of sitravatinib, a novel multitargeted receptor tyrosine kinase inhibitor, on human ABCB1 and ABCG2 in multidrug-resistant cancer cell lines. We discovered that at submicromolar concentrations, sitravatinib re-sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. We found that sitravatinib blocks the drug efflux function of ABCB1 and ABCG2 in a concentration-dependent manner but does not significantly alter the protein expression of ABCB1 or ABCG2 in multidrug-resistant cancer cells. In conclusion, we reveal a potential drug repositioning treatment option for multidrug-resistant cancers by targeting ABCB1 and ABCG2 with sitravatinib and should be further investigated in future clinical trials.

Rapamycin for treatment of tyrosine kinase inhibitor-resistant chronic myelogenous leukemia: report of two cases and review of literature / 白血病·淋巴瘤

Objective:To investigate the effect of rapamycin in treatment of tyrosine kinase inhibitor (TKI)-resistant chronic myelogenous leukemia (CML) without ABL mutation.Methods:Flow cytometry was used to detect the positive expressions of p-mTOR and p-S6 in CD33 positive cells of 2 CML patients with TKI resistance in Jiangsu Province Hospital, and the influence of rapamycin on the positive expressions of p-mTOR and p-S6 in vitro.Results:Rapamycin in vitro inhibited the positive expressions of p-mTOR and p-S6 in CD33 positive cells. After 3 months of oral administration of rapamycin, the positive expressions of p-mTOR and p-S6 in CD33 positive cells were decreased, and the copy number of BCR-ABL fusion gene was also decreased simultaneously.Conclusion:Part of the resistance of CML patients to TKI may be related to the activation of intracellular signaling pathway of mTOR.

Clinical analysis of 100 adult patients with pure red cell aplasia / 中国实用内科杂志

OBJECTIVE: To evaluate clinical characteristics and treatment response of 100 patients with pure red cell aplasia(PRCA).METHODS: We retrospectively analyzed the clinical data of 100 adult patients with acquired PRCA from October2009 to July 2019, and compared the difference in efficacy between idiopathic and secondary patients.RESULTS: 100 patients were evaluated, including 60 idiopathic patients and 40 secondary patients.The most common reasons for secondary PRCA were large granular lymphocytic leukemia(LGLL)(28 cases,70.0%)and thymoma(6 cases, 15.0%). The remission induced regimens included corticosteroids(CS), cyclosporine A(CsA), or other agents, and the response rate were 66.7%,71.4% and 50%, respectively(P=0.336). Secondary PRCA was less effective than idiopathic PRCA(52.5%,78.3%,P=0.007). PRCA related to large granular lymphocytic leukemia was also less effective compared to idiopathic PRCA(46.4%,79.3%,P=0.003). When treated by CsA, idiopathic PRCA was more effective than secondary PRCA and LGLL related PRCA(P=0.001, P=0.000). Logistic regression analysis showed that lower response rate was related to secondary PRCA and LGLL related PRCA.CONCLUSION: The response rate were similar by different induced regimens. Idiopathic PRCA could acquired better response to CsA than secondary, LGLL related PRCA was less effective to treatment.

Synthesis of l-indospicine, [5,5,6-(2)H3]-l-indospicine and l-norindospicine.

Indospicine is a non-proteogenic amino acid that accumulates as the free amino acid in livestock grazing Indigofera plant species and causes both reproductive losses and hepatotoxic effects. An efficient synthetic route to l-indospicine from l-homoserine lactone is described. The methodology is applicable for the synthesis of both deuterium labelled isotopomers and structural analogues for utilisation in biological studies. The key steps are a zinc mediated Barbier reaction with acrylonitrile and a Pinner reaction that together introduce the target amidine moiety.

Vitamin D and the Immune System from the Nephrologist's Viewpoint.

Vitamin D and its analogues are widely used as treatments by clinical nephrologists, especially when treating chronic kidney disease (CKD) patients with secondary hyperparathyroidism. As CKD progresses, the ability to compensate for elevations in parathyroid hormone (PTH) and fibroblast growth factor-23 and for decreases in 1,25(OH)2D3 becomes inadequate, which results in hyperphosphatemia, abnormal bone disorders, and extra-skeletal calcification. In addition to its calciotropic effect on the regulation of calcium, phosphate, and parathyroid hormone, vitamin D has many other noncalciotropic effects, including controlling cell differentiation/proliferation and having immunomodulatory effects. There are several immune dysregulations that can be noted when renal function declines. Physicians need to know well both the classical and nonclassical functions of vitamin D. This review is an analysis from the nephrologist's viewpoint and focuses on the relationship between the vitamin D and the immune system, together with vitamin's clinical use to treat kidney diseases.

Correlation of interleukin-17-producing effector memory T cells and CD4+CD25+Foxp3 regulatory T cells with the phosphate levels in chronic hemodialysis patients.

BACKGROUND AND OBJECTIVES: Hyperparathyroidism and hyperphosphatemia contribute to the inflammatory effects in chronic hemodialysis (HD) patients. Interleukin-17-producing CD4+ effector memory T (Th17) cells and CD4+CD25+Foxp3 regulatory T (Treg) cells both play critical roles in immune activation and inflammation. We investigated the relationship between the Treg and Th17 cells and the phosphate level in chronic HD patients. METHODS: 105 patients aged ≥35 years on chronic HD over 3 months were enrolled. The peripheral blood mononuclear cells were collected, cultured, and stimulated by phytohemagglutinin-L, phorbol myristate acetate, and ionomycin at different time points for T cell differentiation. RESULTS: The T cell differentiation was as follows: Th17 cells (mean±standard deviation (SD): 25.61%±10.2%) and Treg cells (8.45%±4.3%). The Th17 cell differentiation was positively correlated with the phosphate and albumin levels and negatively correlated with age. The Treg cell differentiation was negatively correlated with albumin level and age. In the nondiabetes group (n=53), the Th17 cell differentiation was predominantly correlated with the phosphate and iPTH (intact parathyroid hormone) levels as well as the dialysis vintage. CONCLUSION: Higher phosphate and iPTH levels and longer dialysis duration may increase Th17 cell differentiation, especially in the nondiabetic chronic HD patients.

Altered molecular repertoire of immune system by renal dysfunction in the elderly: is prediction and targeted prevention in the horizon?

BACKGROUND: Patients on chronic hemodialysis (HD) have impaired cellular and humoral immunity. The percentage of elderly people among the total population in Taiwan is increasing dramatically, and HD is the primary alternative for renal replacement therapy when renal function declines. Activated vitamin D is widely used in HD patients with secondary hyperparathyroidism (SHPT) and is a well-known immunomodulatory agent. Personalized medicine and integrative medical approach has been a trend in current clinical practice. Can we improve their immune function using vitamin D in spite of the mineral aspect? Here, we investigated the relationship between serum 25-hydroxyvitamin D (25(OH)D) level and T cell differentiation in chronic HD patients. METHODS: Forty patients with chronic HD were enrolled. HD patients with SHPT had been treated with activated vitamin D for 3 months. Peripheral blood mononuclear cells obtained from the patients were cultured and stimulated by mitogens, and T cells were analyzed by flow cytometry. Serum 25(OH)D levels were detected by enzyme-linked immunosorbent assay. RESULTS: The incidence of T cell differentiation to the T helper cell (Th)2 subtype was more prevalent in the elderly group than in the controls (p = 0.001). Th2 differentiation was also correlated with age (p = 0.004) and serum 25(OH)D levels (p < 0.05). After treated with activated vitamin D, the level of Th1 cytokines decreased while the Th2 cytokine level increased in the sera (p < 0.05). The T cell differentiation tended toward the Th2 subtype (p = 0.027) after treatment of activated vitamin D in SHPT patients. CONCLUSIONS: These results demonstrated that Th2 differentiation is correlated with age and the serum 25(OH)D level of patients. Treatment with activated vitamin D influenced T cell differentiation and cytokine expression in SHPT patients. Taking vitamin D is the possible prediction and targeted treatment in the immune dysfunction in chronic HD patients.

Bisphophonates in CKD patients with low bone mineral density.

Patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) have a high risk of bone fracture because of low bone mineral density and poor bone quality. Osteoporosis also features low bone mass, disarranged microarchitecture, and skeletal fragility, and differentiating between osteoporosis and CKD-MBD in low bone mineral density is a challenge and usually achieved by bone biopsy. Bisphosphonates can be safe and beneficial for patients with a glomerular filtration rate of 30 mL/min or higher, but prescribing bisphosphonates in advanced CKD requires caution because of the increased possibility of low bone turnover disorders such as osteomalacia, mixed uremic osteodystrophy, and adynamic bone, even aggravating hyperparathyroidism. Therefore, bone biopsy in advanced CKD is an important consideration before prescribing bisphosphonates. Treatment also may induce hypocalcemia in CKD patients with secondary hyperparathyroidism, but vitamin D supplementation may ameliorate this effect. Bisphosphonate treatment can improve both bone mineral density and vascular calcification, but the latter becomes more unlikely in patients with stage 3-4 CKD with vascular calcification but no decreased bone mineral density. Using bisphosphonates requires considerable caution in advanced CKD, and the lack of adequate clinical investigation necessitates more studies regarding its effects on these patients.