Tumor microenvironment immune subtypes for classification of novel clear cell renal cell carcinoma profiles with prognostic and therapeutic implications

Currently, no effective prognostic model of clear cell renal cell carcinoma (ccRCC) based on immune cell infiltration has been developed. Recent studies have identified 6 immune groups (IS) in 33 solid tumors. We aimed to characterize the expression pattern of IS in ccRCC and evaluate the potential in predicting patient prognosis. The clinical information, immune subgroup, somatic mutation, copy number variation, and methylation score of patients with TCGA ccRCC cohort were downloaded from UCSC Xena for further analysis. The most dominant IS in ccRCC was the inflammatory subgroup (immune C3) (86.5%), regardless of different pathological stages, pathological grades, and genders. In the C3 subgroup, stage IV (69.1%) and grade 4 (69.9%) were the least presented. Survival analysis showed that the IS could effectively predict the overall survival (OS) (P < .0001) and disease-specific survival (DSS) (P < .0001) of ccRCC alone, of which group C3 (OS, HR = 2.3, P < .001; DSS, HR = 2.84, P < .001) exhibited the best prognosis. Among the most frequently mutated ccRCC genes, only VHL and PBRM1 were found to be common in the C3 group. The homologous recombination deficiency score was also lower. High heterogeneity was observed in immune cells and immunoregulatory genes of IS. Notably, CD4+ memory resting T cells were highly infiltrating, regulatory T cells (Treg) showed low infiltration, and most immunoregulatory genes (such as CX3CL1, IFNA2, TLR4, SELP, HMGB1, and TNFRSF14) were highly expressed in the C3 subgroup than in other subgroups. Enrichment analysis showed that adipogenesis, apical junction, hypoxia, IL2 STAT5 signaling, TGF-beta signaling, and UV response DN were activated, whereas E2F targets, G2M checkpoint, and MYC targets V2 were downregulated in the C3 group. Immune classification can more accurately classify ccRCC patients and predict OS and DSS. Thus, IS-based classification may be a valuable tool that enables individualized treatment of patients with ccRCC.     

Clinical study of herbal mixture “Diding Oral Medicine” as an alternative to preventative antibiotics in perioperative hemorrhoids: A CARE-compliant article

To study the clinical effects of Diding Oral Medicine as an alternative to preventative antibiotics in perioperative hemorrhoids.From August 2017 to February 2018, a total of 214 patients who were treated with external exfoliation and internal ligation of mixed hemorrhoids in our hospital were divided into the control group and experimental group by way of stratified random (107 cases in each group). Patients in the control group were given antibiotics preventatively before operation, while patients in the experimental group took Diding Oral Medicine before operation, and the white blood cell count, neutrophil count, wound recovery, pain score, anal bulge score, and pathogen culture of wound secretions were compared between the 2 groups.There was no significant difference in white blood cell count and neutrophil count between both groups before and after operation (P > .05). The wound seepage score, wound edema score, and wound area score in the experimental group were lower than those in the control group, and the wound healing in the experimental group was shorter than that in the control group (all P < .05). The pain score and anal bulge score of the experimental group were decreased significantly compared to the control group (P < .05). In addition, the detection rate of pathogenic bacteria in the experimental group was downregulated significantly compared to the control group (P < .05).The Diding Oral Medicine has prominent bacteriostatic and antibacterial effects on patients with hemorrhoids during perioperative period, and promotes wound healing, reduces pain stress, and anal bulge.     

Endoscopically assisted transoral resection of a Bailey type IV second branchial cleft cyst: A case report

Rationale:The diagnosis of type IV branchial cleft cyst (BCC) according to the Bailey classification is very challenging due to lack of specific clinical manifestations in the early stage of the disease. Here, we present the transoral surgical route of endoscopic resection of second BCC in the parapharyngeal space (PPS) with good outcomes.Patient concerns:A 21-year-old man with a 1-year history of snoring complained about sore throat for 1 month and a fever that lasted for 3 days.Diagnoses:On admission, physical examination revealed a temperature of 39°C, pain when swallowing accompanied with a lump sensation in the throat, and inability to open mouth more than 3 cm. Blood testing revealed 19.29 × 10⁹ white blood cells (WBCs)/L and 14.94 × 10⁹ neutrophils/L. A cervical computed tomography (CT) examination revealed a mass with liquid density of 6.2 × 4.0 × 7.7 cm³ in the left parapharyngeal space (PPS) and pharyngeal cavity stenosis. Postoperative pathology showed the existence of lymphoepithelial cysts (left PPS), which was in accordance with the diagnosis of BCC.Interventions:The patient was administered 1.5 g ceftazidime every 12 hours, anti-inflammatory drugs, and incision drainage was performed subsequently. Then, endoscopy-assisted resection of the left PPS was performed via the transoral route. We used low-temperature plasma and an 8-Fr Foley catheter with a water capsule during the surgery.Outcomes:After resection of the mass, the patient''s blood results returned to within the normal range and his symptoms improved. Five days postoperatively, the incision made in the palatine arch of the pharynx opened up by 1 cm, and eventually the wound and laceration healed. Normal oral eating was restored, and no complications were observed.Lessons:Magnetic resonance imaging (MRI), and color Doppler ultrasound can be useful to diagnose BCC in PPS, which rarely occurs in the clinical setting. Extended endoscopy provides a satisfactory surgical field for trans-oral resection allowing complete resection of the BCC without serious postoperative complications.     

Evaluation on blood coagulation and C-reactive protein level among children with mycoplasma pneumoniae pneumonia by different chest imaging findings

Mycoplasma pneumoniae infection may induce a systemic hypercoagulable abnormality, like organ embolism and infarction. Indexes of blood coagulation and C-reactive protein (CRP) have been reported different between healthy people and mycoplasma pneumoniae pneumonia (MPP) patients, but this difference in MPP patients with different chest imaging findings has rarely been reported.We performed a retrospective study of 101 children with MPP and 119 controls, combined with radiological examination and blood tests, to compare the blood coagulation and CRP level among MPP children with different chest imaging findings.For the MPP children with different chest imaging findings, there were significant differences in CRP, fibrinogen (FIB) and D-dimer (D-D) levels among subgroups (P = .004, P = .008 and P < .001 respectively). The CRP level in group of interstitial pneumonia was significantly higher than that in groups of bronchopneumonia and hilar shadow thickening (P = .003 and P = .001 respectively). And the FIB and D-D values in group of lung consolidation were significantly higher than that in the other 3 groups (all P < .05). When compared with controls, the white blood cell, CRP, FIB, and D-D levels in MPP children were significantly higher, and the activated partial thromboplastin time and thrombin time levels were significantly lower (all P < .05).Our results showed that CRP level changed most significantly in group of interstitial pneumonia, whereas FIB, D-D levels changed most significantly in the lung consolidation group.     

Diagnostic value of copeptin combined with hypersensitive cardiac troponin T detection in early acute myocardial infarction: A protocol of randomized double-blind diagnostic trial

Background:The sensitivity and specificity of the routine detection of acute myocardial infarction (AMI) in early diagnosis are not high, which can not meet the clinical needs. Copeptin combined with hypersensitive cardiac troponin T (hs-cTnT) is a new detection scheme, and its value in the early diagnosis of acute myocardial infarction is still unclear. Accordingly, the aim of this study is to evaluate the diagnostic value of copeptin combined with hypersensitive troponin T detection in early acute myocardial infarction.Methods:This is a prospective, randomized; double-blind diagnostic trial to investigate the diagnostic value of copeptin combined with hypersensitive troponin T detection in early acute myocardial infarction. Approved by the clinical research ethics of our hospital. Patients were randomly divided into one of 2 test protocols: (A) copeptin combined with hs-cTnT group and (B) cardiac troponin I (cTnI) group. Patients, doctors, nurses, inspectors, and data-gathering assistants were blinded to group allocation. We will focus on the sensitivity comparison of the 2 detection methods at different time periods and the sensitivity and specificity comparison of the two detection methods. Data were analyzed using the statistical software package SPSS version 25.0 (Chicago, IL).Discussion:The purpose of this study is to evaluate the diagnostic value of copeptin combined with hypersensitive cardiac troponin T detection in early acute myocardial infarction. The results of this study will establish clinical evidence for the detection of high sensitivity cardiac troponin T in the early diagnosis of acute myocardial infarction.Ethics and dissemination:Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.OSF Registration number:DOI 10.17605/OSF.IO/6TE5Z.     

Composite hemangioendothelioma of the spleen with multiple metastases: CT findings and review of the literature

Composite hemangioendothelioma (CHE) is a rare vascular neoplasm of intermediate malignant potential. Only 52 cases have been reported in the English literature, and one case previously reported occurred in the spleen. The purpose of our study was to report a 65-year-old man diagnosed as CHE primary arising from the spleen with multiple metastases.Clinical and imaging features, laboratory tests, and pathological results about CHE were described in detail in this study.The patient presented with multiple lesions in bilateral lungs and spleen that had been incidentally detected by computed tomography (CT). Except for thrombocytopenia, other laboratory tests were not significant. The CT scan of the abdomen revealed multiple round-like and irregularly mixed density masses with unclear borders in enlarged spleen. And contrast enhancement showed mild heterogeneous enhancement. CT scan also showed widespread liver, ribs, lungs, and vertebral bodies metastases. This diagnosis was confirmed by histopathological examination. The patient underwent splenectomy and still survives with tumors after six months followed-up.Due to the lack of specificity of clinical features and laboratory tests, it is necessary to combine imaging features and pathological findings to make a correct diagnosis.     

Preclinical pharmacokinetics of TPN729MA,a novel PDE5 inhibitor,and prediction of its human pharmacokinetics using a PBPK model

Aim:

TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model.

Methods:

The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg.

Results:

After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min⁻¹·kg⁻¹ in rats and 26.3 mL·min⁻¹·kg⁻¹ in dogs, and the steady-state volumes of distribution (V_ss) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T_max, C_max and AUC values were within 2-fold of the observed values.

Conclusion:

TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.     

Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease

Aim:

Protopanaxtriol (Ppt) is extracted from Panax ginseng Mayer. In the present study, we investigated whether Ppt could protect against 3-nitropropionic acid (3-NP)-induced oxidative stress in a rat model of Huntington''s disease (HD) and explored the mechanisms of action.

Methods:

Male SD rats were treated with 3-NP (20 mg/kg on d 1, and 15 mg/kg on d 2–5, ip). The rats received Ppt (5, 10, and 20 mg/kg, po) daily prior to 3-NP administration. Nimodipine (12 mg/kg, po) or N-acetyl cysteine (NAC, 100 mg/kg, po) was used as positive control drugs. The body weight and behavior were monitored within 5 d. Then the animals were sacrificed, neuronal damage in striatum was estimated using Nissl staining. Hsp70 expression was detected with immunohistochemistry. Reactive oxygen species (ROS) generation was measured using dihydroethidium (DHE) staining. The levels of components in the Nrf2 pathway were measured with immunohistochemistry and Western blotting.

Results:

3-NP resulted in a marked reduction in the body weight and locomotion activity accompanied by progressive striatal dysfunction. In striatum, 3-NP caused ROS generation mainly in neurons rather than in astrocytes and induced Hsp70 expression. Administration of Ppt significantly alleviated 3-NP-induced changes of body weight and behavior, decreased ROS production and restored antioxidant enzymes activities in striatum. Moreover, Ppt directly scavenged free radicals, increased Nrf2 entering nucleus, and the expression of its downstream products heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidase 1 (NQO1) in striatum. Similar effects were obtained with the positive control drugs nimodipine or NAC.

Conclusion:

Ppt exerts a protective action against 3-NP-induced oxidative stress in the rat model of HD, which is associated with its anti-oxidant activity.     

Polyethylene glycol modification decreases the cardiac toxicity of carbonaceous dots in mouse and zebrafish models

Aim:

Carbonaceous dots (CDs), which have been used for diagnosis, drug delivery and gene delivery, are accumulated in heart at high concentrations. To improve their biocompatibility, polyethylene glycol-modified CDs (PEG-CDs) were prepared. In this study we compared the cardiac toxicity of CDs and PEG-CDs in mouse and zebrafish models.

Methods:

Mice were intravenously treated with CDs (size: 4.9 nm, 5 mg·kg⁻¹·d⁻¹) or PEG-CDs (size: 8.3 nm, 5 mg·kg⁻¹·d⁻¹) for 21 d. Their blood biochemistry indices, ECG, and histological examination were examined for evaluation of cardiac toxicity. CDs or PEG-CDs was added in incubator of cmlc2 transgenic Zebrafish embryos at 6 hpf, and the shape and size of embryos'' hearts were observed at 48 hpf using a fluorescent microscope. Furthermore, whole-mount in situ hybridization was used to examine the expression of early cardiac marker gene (clml2) at 48 hpf.

Results:

Administration of CDs or PEG-CDs in mice caused mild, but statistically insignificant reduction in serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels detected at 7 d, which were returned to the respective control levels at 21 d. Neither CDs nor PEG-CDs caused significant changes in the morphology of heart cells. Administration of CDs, but not PEG-CDs, in mice caused marked increase of heart rate. Both CDs and PEG-CDs did not affect other ECG parameters. In the zebrafish embryos, addition of CDs (20 μg/mL) caused heart development delay, whereas addition of CDs (80 μg/mL) led to heart malformation. In contrast, PEG-CDs caused considerably small changes in heart development, which was consistent with the results from the in situ hybridization experiments.

Conclusion:

CDs causes greater cardiac toxicity, especially regarding heart development. Polyethylene glycol modification can attenuate the cardiac toxicity of CDs.     

Physical performance and life quality in postmenopausal women supplemented with vitamin D: a two-year prospective study

Aim:

To investigate the effects of calcium and vitamin D supplementation on bone turnover marker levels, muscle strength and quality of life in postmenopausal Chinese women.

Methods:

A total of 485 healthy postmenopausal Chinese women (63.44±5.04 years) were enrolled in this open-label, 2-year, prospective, community-based trial. The participants were divided into group A, B, C, which were treated with calcium (600 mg/d) alone, calcium (600 mg/d) and cholecalciferol (800 IU/d) or calcium (600 mg/d) and calcitriol (0.25 μg/d), respectively, for 2 years. Serum levels of 25-hydroxyvitamin D, parathyroid hormone, β-CTX and P1NP were measured, and the muscle strength and quality of life were assessed at baseline and at 12- and 24-month follow-ups.

Results:

Four hundred and sixty one participants completed this study. Serum levels of 25-hydroxyvitamin D were significantly increased in group C, but not changed in groups A and B at 24-month follow-up. Serum levels of parathyroid hormone, bone turnover marker β-CTX and bone formation marker P1NP were significantly decreased in group C, while serum levels of β-CTX were increased in group A at 24-month follow-up. The participants in group C maintained the grip strength, while those in groups A and B exhibited decreased grip strength at 24-month follow-up. The quality of life for the participants in groups B and C remained consistent, but that in group A was deteriorated at 24-month follow-up.

Conclusion:

Supplementation with calcitriol and calcium modifies the bone turnover marker levels, and maintains muscle strength and quality of life in postmenopausal Chinese women, whereas supplementation with cholecalciferol and calcium prevents aging-mediated deterioration in quality of life.