Genomic hallmarks of localized, non-indolent prostate cancer.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Odontohypophosphatasia caused by a novel combination of two heterozygous variants: a case report.

Hypophosphatasia (HPP) is a rare genetic disorder mainly characterized by skeletal dysplasia that results from a deficiency in tissue-nonspecific alkaline phosphatase (TNSALP), which is encoded by the alkaline phosphatase (ALPL) gene. Odontohypophosphatasia (odonto-HPP) is a mild form of HPP characterized by oral symptoms, such as premature loss of primary teeth. This study was to describe a 4-year-old boy with premature loss of primary teeth who was diagnosed with odonto-HPP. X-ray radiography and laboratory examinations were performed for the diagnosis. Genetic etiology was revealed by whole-exome sequencing. A novel combination of two variants in the ALPL gene was identified in this case; this combination resulted in the odonto-HPP phenotype. c.346G>A (p.Ala116Thr) was inherited from the proband's father, whereas c.1563C>G (p.Ser521Arg) was inherited from the proband's mother. The proband's 8-year-old sister was a heterozygous carrier of c.346G>A (p.Ala116Thr) in the ALPL gene. Thus far, the proband's sister has been asymptomatic. Our findings indicate that c.346G>A is a pathogenic genetic alteration; c.1563C>G might cause a predisposition to the dental phenotype in combination with c.346G>A. It is important for pediatric dentists to consider a diagnosis of odonto-HPP in children with premature loss of primary teeth.

Stemness maintenance of stem cells derived from human exfoliated deciduous teeth (SHED) in 3D spheroid formation through the TGF-ß/Smad signaling pathway.

Mesenchymal stem cells (MSCs) have shown great potential as important therapeutic tools for dental pulp tissue engineering, with the maintenance and enhancement of their stemness being crucial for successful therapeutic application in vivo and three-dimensional (3D) spheroid formation considered a reliable technique for enhancing their pluripotency. Human exfoliated deciduous tooth stem cells (SHED) were cultured in a low attachment plate to form aggregates for five days. Then, the resulting spheroids were analyzed for pluripotent marker expression, paracrine secretory function, proliferation, signaling pathways involved, and distribution of key proteins within the spheroids. The results indicated that 3D spheroid formation significantly increased the activation of the transforming growth factor beta (TGF-ß)/Smad signaling pathway and upregulated the secretion and mRNA expression levels of TGF-ß, which in turn enhanced the expression of pluripotency markers in SHED spheroids. The activation of the TGF-ß/Smad signaling pathway through 3D spheroid formation was found to preserve the stemness properties of SHED. Thus, understanding the mechanisms behind pluripotency maintenance of SHED culture through 3D spheroid formation could have implications for the therapeutic application of MSCs in regenerative medicine and tissue engineering.

High efficacy of PD-1 inhibitor after initial failure of PD-L1 inhibitor in Relapsed/Refractory classical Hodgkin Lymphoma.

PURPOSE: We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. METHODS: Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I-II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. RESULTS: All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. CONCLUSIONS: PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.

Cerebral infarction After Laparoscopic Right Lung Wedge or Segment Resection: A Report of Four Cases.

Several cases have been reported of patients who experienced cerebral infarction following thoracoscope left lobectomy. Compared with right lung surgery, the pulmonary veins stump after left lobe surgery were longer and thrombosis was more likely. Besides, cases of cerebral infarction after right lung surgery are rarely reported. Left lobectomy is therefore considered as the main risk factor for postoperative cerebral infarction. However, here we report four cases of cerebral infarction after thoracoscopic wedge or segment resection of right lobe, which cause less damage to the pulmonary vein compared with lobectomy. Magnetic resonance imaging and computed tomography scan reveal intracranial vascular obstruction and cerebral infarction. The case 1 had a poor prognosis because doctors lacked experience treating such complications. In the case 2, the sequela of cerebral infarction was obvious due to the large cerebral infarction area. Benefiting from timely treatment, the rest recovered better.

Intraoperative management and early post-operative outcomes of patients with coronary artery disease who underwent orthotopic liver transplantation.

BACKGROUND: Coronary artery disease (CAD) is frequently observed in aging end-stage liver disease (ESLD) patients who require orthotopic liver transplantation (OLT). This situation is challenging for both the patients and the medical staff. METHODS: We retrospectively studied the case records of 26 ESLD patients with CAD who underwent OLT with total clamping of the inferior vena cava between 2014 and 2018. We analyzed the details of the pre-operative evaluation, intraoperative anesthetic management and post-operative prognosis of these patients. RESULTS: All patients tolerated the anhepatic stage well. Post-reperfusion syndrome (PRS) was observed in 13 patients (50%) and 2 of them were severe but corrected well. ST-segment depression was frequently observed during the anhepatic stage and reperfusion stage. No mortality due to cardiac-related events occurred among the patients during hospitalization. OLT with the modified piggyback technique could successfully be performed in ESLD patients with mild and moderate CAD. CONCLUSIONS: A thorough evaluation and optimization of recipients, strict monitoring and optimized management of circulation, knowledge of the complicated changes during OLT procedures, and strategies to ameliorate post-reperfusion syndrome favorite the outcomes.

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk.

Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10-10 ) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10-5 ) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.

Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer.

The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy.

Intrarenal resistance index for the assessment of acute renal injury in a rat liver transplantation model.

BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation (LT) and associated with a high mortality. The renal resistive index (RI) is used to assess early renal function impairment in critical care patients. However, limited data are available concerning changes of renal RI and the development of AKI early after reperfusion. We approached to investigate the changes of renal RI and AKI after reperfusion in a rat liver transplantation model. METHODS: Rats were randomly divided into sham group or LT group. Ten rats in each group were used for the hemodynamic study and twenty for Doppler measurements during the procedure. Ten rats were sacrificed 30 min or 2 h after the reperfusion. We harvested kidneys, serum and urine for further analysis of the renal function. RESULTS: The intrarenal RI increased significantly in the anhepatic stage and decreased significantly after the reperfusion in the LT group compared with sham group (P < 0.05). AKI was seen after the reperfusion in the LT group. No correlation was noted between the RI and renal function parameters 30 min after reperfusion. CONCLUSIONS: The intrarenal RI increased significantly during the anhepatic stage, and decreased significantly early after the reperfusion. Intrarenal RI was unable to assess renal function in a rat liver transplantation model.

Endogenous and microbial biomarkers for periodontitis and type 2 diabetes mellitus.

It has been well documented that there is a two-way relationship between diabetes mellitus and periodontitis. Diabetes mellitus represents an established risk factor for chronic periodontitis. Conversely, chronic periodontitis adversely modulates serum glucose levels in diabetic patients. Activated immune and inflammatory responses are noted during diabetes and periodontitis, under the modulation of similar biological mediators. These activated responses result in increased activity of certain immune-inflammatory mediators including adipokines and microRNAs in diabetic patients with periodontal disease. Notably, certain microbes in the oral cavity were identified to be involved in the occurrence of diabetes and periodontitis. In other words, these immune-inflammatory mediators and microbes may potentially serve as biomarkers for risk assessment and therapy selection in diabetes and periodontitis. In this review, we briefly provide an updated overview on different potential biomarkers, providing novel diagnostic and therapeutic insights on periodontal complications and diabetes mellitus.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: The Novel Therapeutic Option for Regenerative Dentistry.

Dental mesenchymal stem cells (MSCs) are characterized by unlimited self-renewal ability and high multidirectional differentiation potential. Since dental MSCs can be easily isolated and exhibit a high capability to differentiate into odontogenic cells, they are considered as attractive therapeutic agents in regenerative dentistry. Recently, MSC-derived extracellular vesicles (MSC-EVs) have attracted widespread attention as carriers for cell-free therapy due to their potential functions. Many studies have shown that MSC-EVs can mediate microenvironment at tissue damage site, and coordinate the regeneration process. Additionally, MSC-EVs can mediate intercellular communication, thus affecting the phenotypes and functions of recipient cells. In this review, we mainly summarized the types of MSCs that could be potentially applied in regenerative dentistry, the possible molecular cargos of MSC-EVs, and the major effects of MSC-EVs on the therapeutic induction of osteogenic differentiation.

Bruton's tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is an aggressive lymphoma confined to central nervous system. Current treatments including surgery, chemotherapy and whole-brain radiotherapy often fail to achieve satisfactory effect, especially in elderly. As a regimen in targeted therapy, Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been tested in several clinical trials against PCNSL, offering hope for patients unfit for chemotherapy. We aim to evaluate and compare the anti-PCNSL ability of three different BTK inhibitors, ibrutinib, zanubrutinib and tirabrutinib, providing direct evidence for the targeted therapy of PCNSL. METHODS: Retrospective study was done on patients who received ibrutinib-based therapy in our hospital. Cerebrospinal fluid (CSF) from one patient was collected to measure the concentration of ibrutinib. Inhibition assay and apoptosis assay were done on lymphoma cells to determine the anti-tumoral effects of three inhibitors. Pharmacokinetic study was conducted to evaluate their ability in penetrating blood brain barrier and distributing in brain. RESULTS: In retrospective study, we found three patients with PCNSL who had good clinical response to ibrutinib-based therapy (2 complete remission, 1 partial remission), which further support the use of BTK inhibitors in PCNSL. In vitro studies show that ibrutinib has the best anti-tumoral ability among three inhibitors. In vivo study on pharmacokinetic profiles indicate that both ibrutinib and tirabrutinib are good in distributing in brain parenchyma. CONCLUSIONS: In conclusion, our study results suggest that BTK inhibitors can be promising candidates for PCNSL treatment, preferring the use of ibrutinib and tirabrutinib as anti-PCNSL agents among the three inhibitors.

Dimensions of trust: the tensions and challenges in provider--interpreter trust.

In this study we examined the challenges to providers' and interpreters' collaboration in bilingual health care. We conducted in-depth interviews and focus groups with 26 medical interpreters (speaking 17 languages) and 32 providers (from four specialties) in the United States to provide an empirically based framework of provider-interpreter trust. Constant comparative analysis was used for data analysis. We identified four dimensions of trust, theoretical constructs that can strengthen or compromise provider-interpreter trust: interpreter competence, shared goals, professional boundaries, and established patterns of collaboration. In this article we describe how these dimensions highlight tensions and challenges that are unique in provider-interpreter relationships. We conclude with practical guidelines that can enhance provider-interpreter trust, and propose future research directions in bilingual health care.

Anaesthetic management in endovascular total aortic arch repair via needle-based in situ fenestration: a case series of 14 patients.

OBJECTIVE: Endovascular total aortic arch repair (ETAAR) via needle-based in situ fenestration (ISF) is a major challenge for anaesthesiologists because of haemodynamic instability and the risk of cerebral hypoxia. We herein summarise our experience with anaesthetic management of patients who underwent this procedure. METHODS: Fourteen patients who underwent ETAAR via ISF for arch pathologies involving the major supra-arch branches were included. Regional cerebral oxygen saturation was measured to monitor cerebral perfusion. Partial extracorporeal circulation (EC) support from the right common femoral vein to the right axillary artery was introduced to provide cerebral perfusion. RESULTS: During ISF, vessel rupture occurred in three patients and ventricular fibrillation occurred in one patient. The regional cerebral oxygen saturation significantly decreased during the potential risk period for cerebral ischaemia. Establishment of EC effectively prevented cerebral ischaemia. CONCLUSIONS: During ETAAR, the risks of haemodynamic instability caused by the procedure and vessel rupture during ISF need to be overcome. Partial EC ensured good cerebral protection in our study, and regional cerebral oxygen saturation monitoring may help to reduce the rate of desaturation.

[Assessment of BIOMED-2 assays for detection of clonal Ig gene rearrangements in mature B-cell lymphomas].

OBJECTIVE: To evaluate the efficiency of the BIOMED-2 PCR assay and its implication in the diagnosis of mature B-cell non-Hodgkin's lymphomas. METHODS: Clinical, morphological and immunohistochemical features of 72 cases of non-Hodgkin's lymphomas were studied, including 25 reactive lymphoid hyperplasia, 37 diffuse large B cell lymphomas (DLBCL) and 35 extranodal marginal zone lymphomas of mucosa associated lymphoid tissues (MALT lymphoma and in addition, 25 cases of reactive lymphoid hyperplasia were used as the controls). DNA was exacted from the paraffin embedded formalin fixed tissue blocks and the quality of DNA was assessed using the BIOMED-2 specimen control reaction. Adequate samples were then analyzed by BIOMED-2 for immunoglobulin heavy and kappa light chain rearrangements. RESULTS: Adequate DNA was obtained in 83 of 97 samples, including 60 mature B cell lymphomas and 23 reactive lymphoid hyperplasia. Clonal B-cell gene rearrangements were detected in 57 of 60 (95%) lymphomas. In contrast, clonal Ig gene rearrangements were not detected in any of the 23 cases of reactive lymphoid hyperplasia. CONCLUSION: BIOMED-2 assay is highly sensitive and specific for the detection of clonal B cell gene rearrangement using routine paraffin embedded formalin fixed specimens.

Anesthetic management of off-pump simultaneous coronary artery bypass grafting and lobectomy: Case report and literature review.

RATIONALE: Survey data show approximately 10% patients with lung cancer may present concomitant coronary heart disease. Simultaneous surgery is a challenge for anesthetist. We review our experience in the anesthesia with 5 patients who required simultaneous off-pump coronary artery bypass grafting (OPCABG) and pulmonary resection for lung cancer. PATIENT CONCERNS: Between 2014 and 2016, 5 patients with ASA (American Society of Anesthesiologists) grade II or III, underwent combined OPCABG and lung resection in the first Affiliated Hospital, Zhejiang University School of Medicine. DIAGNOSES: All five patients were diagnosed with coronary heart disease and peripheral pulmonary carcinoma INTERVENTIONS:: Five patients received general anesthesia with double-lumen endobronchial tube for lung separation. The anesthetics were used, which caused slight hemodynamic fluctuations during induction of anesthesia; while during the maintenance of anesthesia, supplemented by Dexmedetomidine, the drug doses were titrated according to the depth of anesthesia. Guided by cardiac index (CI), stroke volume variation (SVV) and oxygen delivery (DO2), different strategies were taken at the different stage of surgery, during lung resection, SVV was kept about 13% to 15%, and less than 10% during OPCABG. OUTCOMES: Five patients were transferred to intensive care unit (ICU) with intubation after surgery, duration of ventilation was 10 to 18 hours, and length of ICU stay and hospital stay were 1.8 to 2.5 ds and 11 to 16 ds, respectively. All of patients were discharged with not any perioperative complication. LESSONS: In summary, anesthetists should focus on the maintenance of the balance between oxygen supply and demanding, which was achieved by close monitoring, titration of anesthetics and goal-directed fluid therapy during surgical procedures.

Plasma levels of tumor necrotic factor-alpha and interleukin-6, -8 during orthotopic liver transplantation and their relations to postoperative pulmonary complications.

BACKGROUND: Pulmonary complications after orthotopic liver transplantation (OLT) include high morbidity and mortality. Experimental data have suggested hepatic ischemia and reperfusion are induced by pro-inflammatory cytokines. The high level of inflammatory cytokines might additionally influence pulmonary capillary fluid filtration. The objectives of this study were to measure the concentrations of tumor necrotic factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8) during OLT and to investigate the relationship between these cytokines and postoperative pulmonary complications. METHODS: Twenty-two patients undergoing OLT were divided into two groups according to whether they had postoperative pulmonary complications: group A consisting of 8 patients with postoperative pulmonary complications, and group B consisting of 14 patients without postoperative pulmonary complications. Enzyme-linked immunoassay (ELISA) was used to determine serum TNF-alpha, IL-6 and IL-8. Blood samples were taken at the beginning of operation (T0), clamping and cross-clamping of the inferior cava and portal vein (T1, T2), 90 minutes and 3 hours after reperfusion (T3, T4) and 24 hours after operation (T5). RESULTS: The level of PaO2/FiO2 in group A was lower than that in group B (P<0.05). The concentrations of TNF-alpha, IL-6 and IL-8 in the two groups increased rapidly at T2, peaked at T3, decreased rapidly after T3 until 24 hours after operation. The concentrations of TNF-alpha, IL-6 and IL-8 in group A were higher than those in group B at T2, T3, and T4 (P<0.05). CONCLUSION: After un-clamping of the inferior cava and portal vein, the serum concentrations of TNF-alpha, IL-6 and IL-8 increased may be related to pulmonary injury after hepatic ischemic reperfusion.

Suture of the right internal jugular vein catheter in a mitral valve replacement: a case report.

INTRODUCTION: Central venous catheterization can be necessary for patients undergoing a cardiac operation. Accidental suturing of the catheter to the heart is a rare complication that is difficult to correct; excessive traction force on the central venous catheter can lead to heart breakage or even death. CASE PRESENTATION: We describe the case of a 56-year-old Han Chinese woman who was scheduled to undergo mitral valve replacement. The central venous catheter placed into her right internal jugular vein was accidentally sutured to the left atrial suture line during the operation. The stuck catheter was successfully removed without having to perform a cardiopulmonary bypass. CONCLUSIONS: Attaching a catheter to the heart by cardiac sutures can occur when the tip of the catheter locates directly above the atrial-caval junction. Care should be taken when closing the cephalad end of a left atrial incision in a mitral valve replacement. Although rare, accidental suturing of the central venous catheter must be kept in mind, and an approach should be chosen to remove the catheter that best avoids additional insult to the heart function.