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There is ample epidemiologic evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin lymphoma (B-NHL). B-NHL subtypes most frequently associated with HCV are marginal zone lymphoma and diffuse large B-cell lymphoma. The most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). In fact, for indolent HCV-associated B-NHL, first-line AVT instead of standard immune-chemotherapy might be considered. Molecular mechanisms of HCV-NHL development are still poorly understood. Three general theories have emerged to understand the HCV-induced lymphomagenesis: (1) continuous external stimulation of lymphocyte receptors by viral antigens and consecutive proliferation; (2) HCV replication in B cells with oncogenic effect mediated by intracellular viral proteins; (3) permanent B-cell damage, e.g., mutation of tumor suppressor genes, caused by a transiently intracellular virus (“hit and run” theory). This review systematically summarizes the data on epidemiology, interventional studies, and molecular mechanisms of HCV-associated B-NHL.
The PI3K/mammalian Target of Rapamycin (mTOR) pathway is often aberrantly activated in rhabdomyosarcoma (RMS) and represents a promising therapeutic target. Recent evaluation of AZD8055, an ATP-competitive mTOR inhibitor, by the Preclinical Pediatric Testing Program showed in vivo antitumor activity against childhood solid tumors, including RMS. Therefore, in the present study, we searched for AZD8055-based combination therapies. Here, we identify a new synergistic lethality of AZD8055 together with ABT-737, a BH3 mimetic that antagonizes Bcl-2, Bcl-xL, and Bcl-w but not Mcl-1. AZD8055 and ABT-737 cooperate to induce apoptosis in alveolar and embryonal RMS cells in a highly synergistic fashion (combination index < 0.2). Synergistic induction of apoptosis by AZD8055 and ABT-737 is confirmed on the molecular level, as AZD8055 and ABT-737 cooperate to trigger loss of mitochondrial membrane potential, activation of caspases, and caspase-dependent apoptosis that is blocked by the pan-caspase inhibitor Z-VAD-fmk. Similar to AZD8055, the PI3K/mTOR inhibitor NVP-BEZ235, the PI3K inhibitor NVP-BKM120 and Akt inhibitor synergize with ABT-737 to trigger apoptosis, whereas no cooperativity is found for the mTOR complex 1 inhibitor RAD001. Interestingly, molecular studies reveal a correlation between the ability of different PI3K/mTOR inhibitors to potentiate ABT-737-induced apoptosis and to suppress Mcl-1 protein levels. Importantly, knockdown of Mcl-1 increases ABT-737-induced apoptosis similar to AZD8055/ABT-737 cotreatment. This indicates that AZD8055-mediated suppression of Mcl-1 protein plays an important role in the synergistic drug interaction. By identifying a novel synergistic interaction of AZD8055 and ABT-737, our findings have important implications for the development of molecular targeted therapies for RMS.
Many snake venoms are known for their antithrombotic activity. They contain components that specifically target different platelet-activating receptors such as the collagen-binding integrin α2β1 and the von Willebrand factor receptor GPIb. In a search for an α2β1 integrin-blocking component from the venom of the habu snake (Trimeresurus flavoviridis), we employed two independent purification protocols. First, we used the integrin α2A domain, a major collagen-binding domain, as bait for affinity purification of an α2β1 integrin-binding toxin from the crude venom. Second, in parallel, we used classical protein separation protocols and tested for α2β1 integrin-inhibiting capabilities by ELISA. Using both approaches, we identified flavocetin-A as an inhibitor of α2β1 integrin. Hitherto, flavocetin-A has been reported as a GPIb inhibitor. However, flavocetin-A inhibited collagen-induced platelet aggregation even after GPIb was blocked with other inhibitors. Moreover, flavocetin-A antagonized α2β1 integrin-mediated adhesion and migration of HT1080 human fibrosarcoma cells, which lack any GPIb, on collagen. Protein chemical analyses proved that flavocetin-A binds to α2β1 integrin and its α2A domain with high affinity and in a cooperative manner, which most likely is due to its quaternary structure. Kinetic measurements confirmed the formation of a strong complex between integrin and flavocetin-A, which dissociates very slowly. This study proves that flavocetin-A, which has long been known as a GPIb inhibitor, efficiently targets α2β1 integrin and thus blocks collagen-induced platelet activation. Moreover, our findings suggest that the separation of GPIb- and α2β1 integrin-blocking members within the C-type lectin-related protein family is less strict than previously assumed.
Cellular cytotoxicity is the hallmark of NK cells mediating both elimination of virus-infected or malignant cells, and modulation of immune responses. NK cytotoxicity is triggered upon ligation of various activating NK cell receptors. Among these is the C-type lectin-like receptor NKp80 which is encoded in the human Natural Killer Gene Complex (NKC) adjacent to its ligand, activation-induced C-type lectin (AICL). NKp80-AICL interaction promotes cytolysis of malignant myeloid cells, but also stimulates the mutual crosstalk between NK cells and monocytes.
While many activating NK cell receptors pair with ITAM-bearing adaptors, we recently reported that NKp80 signals via a hemITAM-like sequence in its cytoplasmic domain. Here we molecularly dissect the NKp80 hemITAM and demonstrate that two non-consensus amino acids, in particular arginine 6, critically impair both hemITAM phosphorylation and Syk recruitment. Impaired Syk recruitment results in a substantial attenuation of cytotoxic responses upon NKp80 ligation. Reconstituting the hemITAM consensus or Syk overexpression resulted in robust NKp80-mediated responsiveness. Collectively, our data provide a molecular rationale for the restrained activation potential of NKp80 and illustrate how subtle alterations in signaling motifs determine subsequent cellular responses. They also suggest that non-consensus alterations in the NKp80 hemITAM, as commonly present among mammalian NKp80 sequences, may have evolved to dampen NKp80-mediated cytotoxic responses toward AICL-expressing cells.
Background: The activating NK receptor NKp80 triggers cytotoxicity by human NK cells via a cytoplasmic hemITAM sequence.
Results: A non-consensus hemITAM residue impairs the capacity of NKp80 to recruit Syk kinase and to trigger cytotoxicity.
Conclusion: Unlike typical hemITAM receptors, NKp80 does not efficiently recruit Syk kinase resulting in attenuated effector responses.
Significance: An attenuated cytotoxic responsiveness critically impacts on the immunomodulatory function of NKp80.
Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.
Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug-resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3rCDDP1000 in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases.
The antineoplastic alkaloid ellipticine is a prodrug, the pharmacological efficiency of which is dependent on its cytochrome P450 (CYP)- and/or peroxidase-mediated activation to species forming DNA adducts in target tissues. Here, we found that this compound is cytotoxic to human BHT-101, B-CPAP and 8505-C thyroid cancer cells and blocks one or more phases of cell cycle in these cancer cells. Ellipticine toxicity to the thyroid cancer cells corresponded to levels of DNA adducts generated by the CYP- and/or peroxidase-mediated ellipticine metabolites, 12-hydroxy- and 13-hydroxyellipticine, in these cells. Cultivation of all tested cells under hypoxic conditions (1 % oxygen) led to a decrease in ellipticine toxicity. Such a lower sensitivity of cells to ellipticine correlates with a decrease in the formation of ellipticine-derived DNA adducts in these cells. Using Western blotting, the expression of CYP1A1, 1B1, 3A4, thyroid peroxidase (TPO), cyclooxygenase-1 (COX-1) and cytochrome b5, the enzymes that catalyze, and/or influence ellipticine metabolism, was investigated in the cancer cells. Furthermore, the effects of ellipticine treatment on the expression levels of these proteins in thyroid cancer cells were also examined. The results indicate that the highest expression levels of cytochrome b5 together with CYP1A1 and 3A4 determine the highest DNA adduct formation and cytotoxicity of ellipticine in B-CPAP cells. They also demonstrate that formation of covalent DNA adducts by ellipticine is the predominant mechanism responsible for its cytotoxicity in studied cells.
The proportion of elderly women in the population is rising, and in tandem, the incidence of breast cancer rises with age. Because of health and tolerability concerns, as well as life expectancy, physicians may be reluctant to advise a standard treatment regimen for elderly patients with metastatic breast cancer. To elucidate this issue, we performed a literature review of clinical studies that included women with metastatic breast cancer who were over the age of 65. Our results show that although little clinical evidence exists, what is available suggests that standard treatment is tolerated and beneficial for patients meeting certain criteria. A geriatric assessment may identify specific patient groups (independent, dependent, or frail) and thereby guide treatment. Treatment recommendations for elderly patients with metastatic breast cancer are sparse, although first-line endocrine treatment, usually aromatase inhibitors or tamoxifen, is recommended for hormone-sensitive disease. In general, the evidence from clinical studies suggests that aromatase inhibitors are more effective than either tamoxifen or megestrol acetate as first- or second-line treatment in postmenopausal women with metastatic breast cancer. Ultimately, quality of life, treatment effects, and comorbidities are important aspects in this population and may guide treatment choice. To provide evidence-based treatment guidance, future clinical trials should include more patients over the age of 65 years.
In the stomach, neoplastic lesions often arise in the setting of precursor conditions such as gastritis, intestinal metaplasia, or adenomatous lesions. Biopsies may, therefore, underestimate disease severity or even miss the diagnosis (sampling error). Endomicroscopy is able to visualize typical features of such pathologies. It enables in vivo microscopy of gastritis with definition of enhanced vascularity and vascular leakage, but the typical cobblestone appearance of the gastric mucosa is preserved. The presence of intestinal metaplasia is confirmed by columnar absorptive cells with brush border and goblet cells within villiform foveolar epithelium. Gastric neoplasia is characterized by crowded glands with intraluminal folding and glandular budding and branching accompanied by increased density of dilated and distorted capillaries. Finally, in gastric cancer, gland and overall mucosal architecture is progressively lost. These features are shown side by side with white-light endoscopic findings. Endomicroscopy is used in such a setting to rapidly screen larger areas (optical biopsies) and subsequently target tissue sampling to areas with highly suspicious microscopic patterns. In experienced hands, it therefore constitutes an important part especially in the presence of neoplastic lesions within noncircumscript gastric premalignant conditions. This article is part of an expert video encyclopedia.
Stent insertion is an established technique of endoscopic retrograde cholangiopancreatography (ERCP) to treat symptomatic malignant or benign biliary strictures, and stent placement is accomplished by using the over-the-wire (OTW) method. In some cases, however, it might be challenging and sometimes time consuming to pass a complex biliary stricture with the guidewire. Stent-exchange technique with a guidewire left in place during stent removal might therefore be helpful to guarantee successful and time-sparing interventions.
A simple method is presented to remove the stent with the guidewire left in place, using the OTW stent-exchange method in ERCP. This technique simplifies stent OTW exchange by using a simple endoscopy snare. This article is part of an expert video encyclopedia.
Dieulafoy's lesion (DL) is a rare source of gastrointestinal tract bleeding that may occur at any site in the gastrointestinal tract and may be difficult to detect by endoscopy. DL is characterized by a large, tortuous arteriole in the submucosa. This is a case of duodenal DL that is detected and treated by endoscopy. This article is part of an expert video encyclopedia.
This is the case report of a 58-year-old male patient who presented with recurring abdominal pain of 4 months duration. He had undergone multiple investigations including upper and lower gastrointestinal tract endoscopies and diagnostic laparoscopy, but there were no significant findings detected.
Capsule endoscopy revealed a submucosal small bowel tumor that was suspected to originate from the distal third of the small bowel. Surgery was indicated and a highly differentiated neuroendocrine tumor was found at laparotomy at the distal ileum. An ileocecal resection was performed confirming a neuroendocrine tumor of the small bowel (G2T2N1M1). This article is part of an expert video encyclopedia.
A rare cause of recurrent melena was identified by capsule endoscopy: arteriovenous malformation
(2013)
Small bowel endoscopy is indicated for patients with an unidentified bleeding site in esophagogastroduodenoscopy and ileocolonoscopy and symptoms of intestinal blood loss or unexplained anemia. In approximately two-thirds of these cases, capsule endoscopy (CE) detects a lesion within the small bowel that explains the patient's symptoms.
The case of an 80-year-old female patient with recurrent melena and anemia is presented here by the authors. Endoscopy of the upper gastrointestinal tract as well as ileocolonoscopy did not show any pathological findings. CE revealed an area with abnormal mucosa in the middle third of the small bowel, which was strongly suspected of having malignant origin. Surgical exploration led to resection of a small jejunal segment with a palpable mass and increased blood flow. Surprisingly, the final diagnosis determined by the pathologist was arteriovenous malformation (AVM). This article is part of an expert video encyclopedia.
The author presents the case of a patient with severe bleeding from a duodenal ulcer that could not be controlled by endoscopic application of metal clips and injection of fibrin glue. Angiographic embolization with placement of coils into the feeding vessel stopped the bleeding. However, 3 days later, a fistula emerged from coil material penetrating into the dorsal duodenum and a peritoneal leakage developed. The fistula was completely closed by placing an over-the-scope clip on the enteral opening of the fistula. This article is part of an expert video encyclopedia.
Small bowel varices may be found in less than 5% of patients with suspected small bowel bleeding. These varices are associated with portal hypertension or thrombosis of mesenteric venous vessels and with altered abdominal vascular anatomy with or without prior small bowel surgery. In bleeding small bowel varices, therapeutic options include endoscopic injection of tissue adhesives, endovascular approaches such as balloon-occluded retrograde transvenous or percutaneous obliteration and transjugular intrahepatic portosystemic shunt, and surgical resection. This is a case report of a 53-year-old patient with ethylic liver cirrhosis who presented with severe, life-threatening hematochezia due to small bowel varices. This article is part of an expert video encyclopedia.
Peutz–Jeghers syndrome (PJS) is a rare autosomal-dominant inherited disorder characterized by gastrointestinal hamartomas, mucocutaneous pigmentation, and an elevated cancer risk. Moreover, intussusception risk may be as high as 50% at the age of 20 years and is caused by large polyps. There is some evidence that endoscopic surveillance of PJS patients with removal of small intestinal polyps with a diameter of more than 15 mm efficiently prevents intussusceptions. In recent years, capsule endoscopy (CE) has largely replaced small-bowel radiography techniques to screen for small-bowel polyps. Magnetic resonance imaging may be equally efficient as CE for screening of large polyps. Balloon enteroscopy may be used for endoscopic snare resection of polyps. This article is part of an expert video encyclopedia.
The small intestine is a part of the gastrointestinal tract in which digestion and absorption of nutrients takes place. The small bowel follows the stomach and is followed by the large intestine, reaching from the pylorus to the valve of Bauhin and is separated into the duodenum, the jejunum, and the ileum.
Capsule endoscopy (CE) has the potential to offer a perfect overview of the small-bowel mucosa and complete visualization of the entire small bowel is achieved in most cases. In this video, there is an overview offered on normal findings in small-bowel CE and typical anatomical landmarks are indicated. This article is part of an expert video encyclopedia.
This is an example of capsule endoscopy (CE) revealing terminal ileitis in an young male patient with recurrent abdominal pain who had previously been investigated with colonoscopy and esophagogastroduodenoscopy without any significant findings. CE revealed severe inflammation of the terminal ileum. This article is part of an expert video encyclopedia.
Small bowel tumors are detected in approximately 10% of patients with small bowel endoscopies for obscure or overt mid-intestinal bleeding. Small bowel tumors may be of malignant or benign etiology. Malignant etiologies include adenocarcinoma, neuroendocrine tumors, or lymphoma, whereas benign lesions are typically lipomas, inflammatory polyps, or adenomas. Within the group of nonneoplastic lesions inflammatory polyps are most frequent. Significant bleeding and bowel obstruction due to intussusception might occur, and surgical or endoscopic treatment has been reported for symptomatic patients. A case is demonstrated with an inflammatory fibroid polyp detected by capsule endoscopy and confirmed by balloon enteroscopy. This article is part of an expert video encyclopedia.
Operatively altered anatomy such as Billroth II gastroenterostomy represents a challenge in endoscopic retrograde cholangiopancreatography and might require dedicated instruments. In this article, the authors demonstrate the technique of endoscopic retrograde cholangiography and sphincterotomy in a patient with Billroth's operation-II. Sphincterotomy is performed with a specially designed Billroth papillotome to enable papillotomy in the direction of the papillary roof. This article is part of an expert video encyclopedia.
In this article, the video demonstrated is an example of a 76-year-old male patient who presented with recurrent intestinal bleeding of unknown origin at the university hospital. Previously performed upper and lower gastrointestinal tract endoscopy did not reveal a bleeding lesion. Capsule endoscopy revealed small-bowel angiectasia that were treated by argon plasma coagulation at subsequent balloon enteroscopy. This article is part of an expert video encyclopedia.
Small bowel endoscopy is indicated for patients with an unidentified bleeding site in esophagogastroduodenoscopy and ileocolonoscopy and symptoms of intestinal blood loss or unexplained anemia. In approximately two-thirds of these cases, capsule endoscopy (CE) detects a lesion within the small bowel that explains the patient's symptoms. In few cases, though, lesions outside of the small bowel might be revealed by CE. Therefore, attention to all intestines that are visualized by CE might be necessary not to overlook bleeding sites that had not been discovered by prior flexible endoscopy.
Here the case of a 71-year-old male patient with unexplained anemia is presented by the authors. Small-bowel CE revealed minor bleeding from a neoplastic mass in the cecum. The final diagnosis of an adenocarcinoma of the ascending colon was established after the patient underwent a right hemicolectomy. This article is part of an expert video encyclopedia.
Small bowel endoscopy is indicated for patients with an unidentified bleeding site in esophago-gastro-duodenoscopy and ileo-colonoscopy and symptoms of intestinal blood loss or unexplained anemia. In approximately two-thirds of these cases, capsule endoscopy (CE) detects a lesion within the small bowel that explains the patient's symptoms. In few cases, though, lesions outside of the small bowel might be revealed by CE. Therefore, attention to all intestines that are visualized by CE might be necessary not to overlook bleeding sites that had not been discovered by prior flexible endoscopy.
The authors present the case of a 71-year-old male patient who presented to their outpatient clinic for unexplained anemia. Small bowel CE revealed minor bleeding from an adenocarcinoma in the cecum. This article is part of an expert video encyclopedia.
Operatively altered anatomy might provide a challenge for endoscopic retrograde cholangiopancreatography. However, with the support of the balloon-assisted enteroscopy technique the access route to the biliary system even in long-limb Roux-Y anastomosis is feasible in most cases.
In this video case report, an 81-year-old woman was symptomatic for stone obstruction of the common bile duct (CBD). Complete gastrectomy had been performed in this patient for stomach cancer many years earlier. Balloon-assisted enteroscopy was used for retrograde access of the duodenum via a Roux-Y anastomosis. There was major difficulty in intubating the CBD via the native papilla in this case because access was prevented by the tangential approach of the enteroscope. After performing an incomplete papillectomy, the insertion of a guidewire into the CBD was feasible and the bile duct stone was removed. This article is part of an expert video encyclopedia.
Here the authors report the case of an elderly woman who had upper abdominal pain, upper gastrointestinal hemorrhage, and jaundice (a symptomatic triad termed the ‘Quincke’ triad) a few days after endoscopic sphincterotomy. Abdominal ultrasonography demonstrated an echo-rich filling of the choledochus consistent with hemobilia. Endoscopic retrograde cholangiography was immediately performed and blood clots were removed from the common bile duct. A nasobiliary catheter was placed to irrigate the bile duct for prevention of recurring obstruction of the bile ducts from blood clots. Further follow-up of the patient was uneventful. This article is part of an expert video encyclopedia.
Small-bowel tumors are rare and account for approximately 5% of all gastrointestinal tumors. Approximately 65% of small-bowel tumors are malignant, and approximately 40% of these tumors are adenocarcinomas. Similar to colorectal adenocarcinoma, premalignant adenomas of the small bowel may progress to carcinoma. This occurs both sporadically and in the context of hereditary tumor syndromes such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer (Lynch syndrome). Herein cases with small-bowel adenocarcinomas visualized with both capsule endoscopy and double-balloon enteroscopy are presented. This article is part of an expert video encyclopedia.
Herbal hepatotoxicity is a rare but highly disputed disease because numerous confounding variables may complicate accurate causality assessment. Case evaluation is even more difficult when the WHO global introspection method (WHO method) is applied as diagnostic algorithm. This method lacks liver specificity, hepatotoxicity validation, and quantitative items, basic qualifications required for a sound evaluation of hepatotoxicity cases. Consequently, there are no data available for reliability, sensitivity, specificity, positive and negative predictive value. Its scope is also limited by the fact that it cannot discriminate between a positive and a negative causality attribution, thereby stimulating case overdiagnosing and overreporting. The WHO method ignores uncertainties regarding daily dose, temporal association, start, duration, and end of herbal use, time to onset of the adverse reaction, and course of liver values after herb discontinuation. Insufficiently considered or ignored are comedications, preexisting liver diseases, alternative explanations upon clinical assessment, and exclusion of infections by hepatitis A-C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). We clearly prefer as alternative the scale of CIOMS (Council for International Organizations of Medical Sciences) which is structured, quantitative, liver specific, and validated for hepatotoxicity. In conclusion, causality of herbal hepatotoxicity is best assessed by the liver specific CIOMS scale validated for hepatotoxicity rather than the obsolete WHO method that is liver unspecific and not validated for hepatotoxicity. CIOMS based assessments will ensure the correct diagnosis and exclude alternative diagnosis that may require other specific therapies.
For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.
The relationship between achievement of a pathologic complete response (pCR) and favorable long-term outcome varies among breast cancer subtypes. We aimed to highlight which neoadjuvant treatment strategy could be most successful in each breast cancer subtype. A recent FDA meta-analysis on randomized neoadjuvant breast cancer trials suggests that the survival differences of patients with or without a pCR were less pronounced in luminal A-like tumors, despite the overall favorable prognosis of these patients. Moreover, even though the strong prognostic effect of pCR in HER2 positive and TNBC, the NOAH study was the only trial which showed a trend in surrogacy of pCR for long-term outcome in HER2-positive subtype. Results from GeparTrio study suggest that patients with hormone-positive tumors might need a response-guided approach, with either an intensification of treatment in case of an early response or a change to other chemotherapy in case of no early response. Furthermore, data from German neoadjuvant trials confirm that an increasing number of chemotherapy cycles is associated with a higher pCR rate, especially in patients with HER2-positive/hormone-positive tumors. In line with these suggestions, Tryphaena study showed a pCR rate that exceeding the 60% threshold, the highest pCR results presented in a large multicenter study. In TNBC, the highest pCR rate in the German neoadjuvant studies was obtained with the simultaneous application of docetaxel, doxorubicin and cyclophosphamide for 6 cycles. However, as shown in GaparQuinto and NSABP 40 trials, treatment effect in TNBC might be further maximized by adding bevacizumab, and two randomized neoadjuvant trials are expected this year to report data on the efficacy of carboplatin.
Hepatology highlights
(2013)
Inflammation has been recognized as a common trait in the pathogenesis of multifactorial diseases including obesity, where a low-grade inflammation has been established and may be responsible for the cardiovascular risk related to the disease. Obesity has also been associated with the increased incidence and a worse outcome of rheumatoid arthritis (RA) and osteoarthritis (OA). RA is characterized by systemic inflammation, which is thought to play a key role in accelerated atherosclerosis and in the increased incidence of cardiovascular disease, an important comorbidity in patients with RA. The inflammatory process underlying the cardiovascular risk both in obesity and RA may be mediated by adipocytokines, a heterogeneous group of soluble proteins mainly secreted by the adipocytes. Many adipocytokines are mainly produced by white adipose tissue. Adipocytokines may also be involved in the pathogenesis of OA since a positive association with obesity has been found for weight-bearing and nonweight-bearing joints, suggesting that, in addition to local overload, systemic factors may contribute to joint damage. In this review we summarize the current knowledge on experimental models and clinical studies in which adipocytokines were examined in obesity, RA, and OA and discuss the potential of adipocytokines as comorbidity biomarkers for cardiovascular risk.
Introduction. The use of ultrasound during resuscitation is emphasized in the latest European resuscitation council guidelines of 2013 to identify treatable conditions such as pericardial tamponade. The recommended standard treatment of tamponade in various guidelines is pericardiocentesis. As ultrasound guidance lowers the complication rates and increases the patient’s safety, pericardiocentesis should be performed under ultrasound guidance. Acute care physicians actually need to train emergency pericardiocentesis. Methods. We describe in detail a pericardiocentesis ultrasound model, using materials at a cost of about 60 euros. During training courses of focused echocardiography n=67, participants tested the phantom and completed a 16-item questionnaire, assessing the model using a visual analogue scale (VAS). Results. Eleven of fourteen questions were answered with a mean VAS score higher than 60% and thus regarded as showing the strengths of the model. Unrealistically outer appearance and heart shape were rated as weakness of the model. A total mean VAS score of all questions of 63% showed that participants gained confidence for further interventions. Conclusions. Our low-cost pericardiocentesis model, which can be easily constructed, may serve as an effective training tool of ultrasound-guided pericardiocentesis for acute and critical care physicians.
Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A ≤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations, “intensive treatment moments” and “year of birth” (proxy for different treatment periods). HRI occurred in 71/288 children (24.7%). In multivariate analysis adjusted for “year of birth”, underlying risk gene mutations (HR/CI: 2.37/1.40–3.99), FVIII dose, measured per one IU increase per kgbw (HR/CI: 1.05/1.04–1.07), and first FVIII administration before the age of three months showed a significant impact on HR development. The risk of HRI development was similar for recombinant or plasmatic FVIII products. Children at risk should be treated with carefully calculated lower dose regimens, adapted to individual bleeding situations.
Background. Incomplete revascularization negatively affects survival after coronary artery bypass surgery (CABG). Since gender and classification technique might impact outcome and reporting, we investigated their effect on revascularization patterns and mortality. Methods. A cohort of bypass patients (N = 1545, 23% women) was enrolled prospectively. The degree of revascularization was determined as mathematical difference between affected vessels upon diagnosis and number of grafts or the surgeon’s rating on the case file. Results. Although men displayed more triple-vessel disease, they obtained complete revascularization more frequently than women (85% versus 77%, P < 0.001). The two calculation methods identified analogous percentages of incompletely revascularized patients, yet there was only a 50% overlap between the two groups. Mathematically, more women, older patients, and patients with NYHA class III/IV appeared incompletely revascularized, while the surgeons identified more patients undergoing technically challenging procedures. Regardless of the definition, incompleteness was a significant risk factor for mortality in both genders (mathematical calculation: HR 2.62, 95% CI 1.76–3.89, P < 0.001; surgeon: HR 2.04, 95% CI 1.35–3.89, P = 0.001). Conclusions. Given the differences in identification patterns, we advise that the mathematical calculation be performed after-procedure in all patients regardless of the surgeons’ rating to uncover additional subjects at increased risk.
Objective. To test the influence of personalized ultrasound (PersUS) on patient management in critical care. Design of the Study. Prospective, observational, and critical care setting. Four substudies compared PersUS and mobile ultrasound, work distribution, and diagnostic and procedural quality. Patients and Interventions. 640 patient ultrasound exams including 548 focused diagnostic exams and 92 interventional procedures. Main Outcome Measures. Number of studies, physician’s judgement of feasibility, time of usage per patient, and referrals to echo lab. Results. Randomized availability of PersUS increased its application in ICU work shifts more than twofold from 33 to 68 exams mainly for detection and therapy of effusions. Diagnostic and procedural quality was rated as excellent/very good in PersUS-guided puncture in 95% of cases. Integrating PersUS within an initial physical examination of 48 randomized cases in an emergency department, PersUS extended the examination time by 100 seconds. Interestingly, PersUS integration into 53 randomized regular ward rounds of 1007 patients significantly reduced average contact time per patient by 103 seconds from 8.9 to 7.2 minutes. Moreover, it lowered the patient referral rate to an echo lab from 20% to 2% within the study population. Conclusions. We propose the development of novel ultrasound-based clinical pathways by integration of PersUS.
The mitogen-activated protein kinase (MAPK) pathway is the canonical signaling pathway for many receptor tyrosine kinases, such as the Epidermal Growth Factor Receptor. Downstream of the receptors, this pathway involves the activation of a kinase cascade that culminates in a transcriptional response and affects processes, such as cell migration and adhesion. In addition, the strength and duration of the upstream signal also influence the mode of the cellular response that is switched on. Thus, the same components can in principle coordinate opposite responses, such as proliferation and differentiation. In recent years, it has become evident that MAPK signaling is regulated and fine-tuned by proteins that can bind to several MAPK signaling proteins simultaneously and, thereby, affect their function. These so-called MAPK scaffolding proteins are, thus, important coordinators of the signaling response in cells. In this review, we summarize the recent advances in the research on MAPK/extracellular signal-regulated kinase (ERK) pathway scaffolders. We will not only review the well-known members of the family, such as kinase suppressor of Ras (KSR), but also put a special focus on the function of the recently identified or less studied scaffolders, such as fibroblast growth factor receptor substrate 2, flotillin-1 and mitogen-activated protein kinase organizer.
There is a wide range of important pharmaceuticals used in treatment of cancer. Besides their known effects on tumor cells, there is growing evidence for modulation of the immune system. Immunomodulatory drugs (IMiDs®) play an important role in the treatment of patients with multiple myeloma or myelodysplastic syndrome and have already demonstrated antitumor, anti-angiogenic, and immunostimulating effects, in particular on natural killer (NK) cells. Tyrosine kinase inhibitors are directly targeting different kinases and are known to regulate effector NK cells and expression of NKG2D ligands (NKG2DLs) on tumor cells. Demethylating agents, histone deacetylases, and proteasome inhibitors interfere with the epigenetic regulation and protein degradation of malignant cells. There are first hints that these drugs also sensitize tumor cells to chemotherapy, radiation, and NK cell-mediated cytotoxicity by enhanced expression of TRAIL and NKG2DLs. However, these pharmaceuticals may also impair NK cell function in a dose- and time-dependent manner. In summary, this review provides an update on the effects of different novel molecules on the immune system focusing NK cells.
Aberrant epigenetic regulators control expansion of human CD34+ hematopoietic stem/progenitor cells
(2013)
Transcription is a tightly regulated process ensuring the proper expression of numerous genes regulating all aspects of cellular behavior. Transcription factors regulate multiple genes including other transcription factors that together control a highly complex gene network. The transcriptional machinery can be “hijacked” by oncogenic transcription factors, thereby leading to malignant cell transformation. Oncogenic transcription factors manipulate a variety of epigenetic control mechanisms to fulfill gene regulatory and cell transforming functions. These factors assemble epigenetic regulators at target gene promoter sequences, thereby disturbing physiological gene expression patterns. Retroviral vector technology and the availability of “healthy” human hematopoietic CD34+ progenitor cells enable the generation of pre-leukemic cell models for the analysis of aberrant human hematopoietic progenitor cell expansion mediated by leukemogenic transcription factors. This review summarizes recent findings regarding the mechanism by which leukemogenic gene products control human hematopoietic CD34+ progenitor cell expansion by disrupting the normal epigenetic program.
The overall staining by GS clearly reveals astrocytes, including all cells of the astroglial family (1), i.e., Bergmann glia, Müller cells (2), tanycytes (3), and ependymal cells. The star shaped morphology from classical silver impregnations relates to cortical and hippocampal astrocytes, which display a comparable pattern in material stained for GFAP. However, the dense population of GS stained astrocytes found in all diencephalic and mesencephalic regions, known to display faint GFAP-labeling (unpublished observations) indicated that while apparently all astrocytes contain GS they have GFAP-ir filaments only in a region-dependent pattern. This is complicated by the emerging view that "astrocytes" constitute a heterogeneous population even within a given region. In the rat hippocampus, combined immunostainings have revealed that the "classical" GFAP-ir astrocyte constitutes a subpopulation of GS-ir astrocytes, which can also lack GFAP staining [direct double staining (4)]. In view of several astroglial subtypes and/or glial precursors present in the adult rodent brain, anti-GS appears to be the most general astrocyte marker, covering all subtypes. In addition, GS has been found early on to label exclusively astrocytic cells and no other glial or neuronal cell types in situ or in culture [reviewed by (5)]. GS has, thus, been applied as a reliable astrocyte marker in very many studies since.
"Complex cells" in rat hippocampus, initially assumed to be an astrocyte subtype (6) but now understood to belong to NG2 cells, a fourth glial type in the CNS (7), may display faint GS-ir in the soma but not its fine processes. Oligodendrocyte precursor cells, possibly also related to NG2 cells, were found to be devoid of GS-ir (8). The immunocytochemical profile and possible heterogeneity of NG2 cells is still under debate to date. Disputing the exclusion of non-astrocytic cells in GS staining, some authors have later reported GS+ oligodendrocytes, although this has not been investigated systematically. Reports on non-astrocytic GS will be discussed in detail here.
The effect of 10 Hz transcranial alternating current stimulation (tACS) on corticomuscular coherence
(2013)
Synchronous oscillatory activity at alpha (8–12 Hz), beta (13–30 Hz), and gamma (30–90 Hz) frequencies is assumed to play a key role for motor control. Corticomuscular coherence (CMC) represents an established measure of the pyramidal system's integrity. Transcranial alternating current stimulation (tACS) offers the possibility to modulate ongoing oscillatory activity. Behaviorally, 20 Hz tACS in healthy subjects has been shown to result in movement slowing. However, the neurophysiological changes underlying these effects are not entirely understood yet. The present study aimed at ascertaining the effects of tACS at 10 and 20 Hz in healthy subjects on CMC and local power of the primary sensorimotor cortex. Neuromagnetic activity was recorded during isometric contraction before and at two time points (2–10 min and 30–38 min) after tACS of the left primary motor cortex (M1), using a 306 channel whole head magnetoencephalography (MEG) system. Additionally, electromyography (EMG) of the right extensor digitorum communis (EDC) muscle was measured. TACS was applied at 10 and 20 Hz, respectively, for 10 min at 1 mA. Sham stimulation served as control condition. The data suggest that 10 Hz tACS significantly reduced low gamma band CMC during isometric contraction. This implies that tACS does not necessarily cause effects at stimulation frequency. Rather, the findings suggest cross-frequency interplay between alpha and low gamma band activity modulating functional interaction between motor cortex and muscle.
The present study investigates the hemispheric contributions of neuronal reorganization following early single-sided hearing (unilateral deafness). The experiments were performed on ten cats from our colony of deaf white cats. Two were identified in early hearing screening as unilaterally congenitally deaf. The remaining eight were bilaterally congenitally deaf, unilaterally implanted at different ages with a cochlear implant. Implanted animals were chronically stimulated using a single-channel portable signal processor for two to five months. Microelectrode recordings were performed at the primary auditory cortex under stimulation at the hearing and deaf ear with bilateral cochlear implants. Local field potentials (LFPs) were compared at the cortex ipsilateral and contralateral to the hearing ear. The focus of the study was on the morphology and the onset latency of the LFPs. With respect to morphology of LFPs, pronounced hemisphere-specific effects were observed. Morphology of amplitude-normalized LFPs for stimulation of the deaf and the hearing ear was similar for responses recorded at the same hemisphere. However, when comparisons were performed between the hemispheres, the morphology was more dissimilar even though the same ear was stimulated. This demonstrates hemispheric specificity of some cortical adaptations irrespective of the ear stimulated. The results suggest a specific adaptation process at the hemisphere ipsilateral to the hearing ear, involving specific (down-regulated inhibitory) mechanisms not found in the contralateral hemisphere. Finally, onset latencies revealed that the sensitive period for the cortex ipsilateral to the hearing ear is shorter than that for the contralateral cortex. Unilateral hearing experience leads to a functionally-asymmetric brain with different neuronal reorganizations and different sensitive periods involved.
Human deep sleep is characterized by reduced sensory activity, responsiveness to stimuli, and conscious awareness. Given its ubiquity and reversible nature, it represents an attractive paradigm to study the neural changes which accompany the loss of consciousness in humans. In particular, the deepest stages of sleep can serve as an empirical test for the predictions of theoretical models relating the phenomenology of consciousness with underlying neural activity. A relatively recent shift of attention from the analysis of evoked responses toward spontaneous (or “resting state”) activity has taken place in the neuroimaging community, together with the development of tools suitable to study distributed functional interactions. In this review we focus on recent functional Magnetic Resonance Imaging (fMRI) studies of spontaneous activity during sleep and their relationship with theoretical models for human consciousness generation, considering the global workspace theory, the information integration theory, and the dynamical core hypothesis. We discuss the venues of research opened by these results, emphasizing the need to extend the analytic methodology in order to obtain a dynamical picture of how functional interactions change over time and how their evolution is modulated during different conscious states. Finally, we discuss the need to experimentally establish absent or reduced conscious content, even when studying the deepest sleep stages.
Human adipose tissue derived stem cells promote liver regeneration in a rat model of toxic injury
(2013)
In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC) is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20). Injection of cell culture medium performed in group 2 (n = 20) served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017), total protein (P < 0.031), glutamic oxaloacetic transaminase (P < 0.001), and lactate dehydrogenase (P < 0.04) levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.
The objective of this systematic review was to assess tooth wear against ceramic crowns in posterior region in vitro and in vivo. An electronic PubMed search was conducted to identify studies on tooth wear against ceramic crowns in posterior region. The selected studies were analyzed in regard to type of crowns, natural antagonist, measuring protocol and outcome. From a yield of 1 000 titles, 43 articles were selected for full-text analysis; finally, no in vitro and only five in vivo studies met the inclusion criteria. As there is heterogeneity in design, used measuring method, ceramics and analysis-form, a meta-analysis was not possible. Results of these studies are very controversial which makes a scientifically valid comparison impossible. This review indicated that some all-ceramic crowns are as wear friendly as metal-ceramic crowns. Up to now, it has been impossible to associate tooth wear with any specific causal agent. The role of ceramic surface treatment that might be responsible for the changing in rate of tooth wear seems undetermined as yet through clinical trials. The literature reveals that studies on this topic are subject to a substantial amount of bias. Therefore, additional clinical studies, properly designed to diminish bias, are warranted.
Choriocarcinoma is the most malignant tumor of gestational trophoblastic disease arising from any gestation. It has a tendency toward relapse as well as metastasis. Here, a case of relapsed high-risk choriocarcinoma (FIGO stage IV, WHO score 12) in a 37-year-old female presenting with vaginal bleedings is described. Relapse developed at the site of the surgical scar from hysterectomy that had been performed 2 years earlier. Although the patient was treated with aggressive chemotherapy, she was in a bad general condition and died from infection and liver insufficiency.
Background: Self-management support is a key component of effective chronic care management, yet in practice appears to be the least implemented and most challenging. This study explores whether and how self-management support is integrated into chronic care approaches in 13 European countries. In addition, it investigates the level of and barriers to implementation of support strategies in health care practice.
Methods: We conducted a review among the 13 participating countries, based on a common data template informed by the Chronic Care Model. Key informants presented a sample of representative chronic care approaches and related self-management support strategies. The cross-country review was complemented by a Dutch case study of health professionals’ views on the implementation of self-management support in practice.
Results: Self-management support for chronically ill patients remains relatively underdeveloped in Europe. Similarities between countries exist mostly in involved providers (nurses) and settings (primary care). Differences prevail in mode and format of support, and materials used. Support activities focus primarily on patients’ medical and behavioral management, and less on emotional management. According to Dutch providers, self-management support is not (yet) an integral part of daily practice; implementation is hampered by barriers related to, among others, funding, IT and medical culture.
Conclusions: Although collaborative care for chronic conditions is becoming more important in European health systems, adequate self-management support for patients with chronic disease is far from accomplished in most countries. There is a need for better understanding of how we can encourage both patients and health care providers to engage in productive interactions in daily chronic care practice, which can improve health and social outcomes.
Objectives: This study explores whether and how self-management support (SMS), a key element of well-coordinated chronic care, is integrated into existing chronic care approaches in 13 European countries.
Methodology: An expert review was conducted using a data template informed by the Chronic Care Model. Key informants (researchers and policymakers) from the 13 countries presented a sample of exemplary chronic care approaches and related SMS strategies. This was complemented by interviews with 27 Dutch care professionals investigating SMS implementation in practice.
Results: SMS remains relatively underdeveloped in Europe. Country-specific strategies are similar in involved providers (nurses) and settings (primary care), yet differ considerably in mode, format and materials used. SMS focuses mainly on patients medical and behavioral management, and less on emotional management. According to Dutch providers, barriers in financing and medical culture (e.g. length of consultation, patient-doctor communication) hamper implementation of SMS as an integral part of chronic care.
Conclusion: While Europe might increasingly be talking the talk of patient participation in chronic care, it appears far from walking the walk. Care professionals experience difficulties in operationalizing SMS in their daily routines. Stronger integration with the health promotion field may help patients and professionals to engage in productive partnerships.
Objective: Loss of function mutations in PINK1 typically lead to early onset Parkinson disease (PD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink−/−) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular mechanisms leading to mitochondrial dysfunction and loss of dopaminergic neurons in PINK1 deficiency.
Methods: The effect of PINK1 deficiency on the number of dopaminergic neurons, mitochondrial function, and morphology was assessed in both zebrafish embryos and adults. Genome-wide gene expression studies were undertaken to identify novel pathogenic mechanisms. Functional experiments were carried out to further investigate the effect of PINK1 deficiency on early neurodevelopmental mechanisms and microglial activation.
Results: PINK1 deficiency results in loss of dopaminergic neurons as well as early impairment of mitochondrial function and morphology in Danio rerio. Expression of TigarB, the zebrafish orthologue of the human, TP53-induced glycolysis and apoptosis regulator TIGAR, was markedly increased in pink−/− larvae. Antisense-mediated inactivation of TigarB gave rise to complete normalization of mitochondrial function, with resulting rescue of dopaminergic neurons in pink−/− larvae. There was also marked microglial activation in pink−/− larvae, but depletion of microglia failed to rescue the dopaminergic neuron loss, arguing against microglial activation being a key factor in the pathogenesis.
Interpretation: Pink1−/− zebrafish are the first vertebrate model of PINK1 deficiency with loss of dopaminergic neurons. Our study also identifies TIGAR as a promising novel target for disease-modifying therapy in PINK1-related PD. Ann Neurol 2013;74:837–847
Celiac disease (CD) is an immune-mediated enteropathy that is characterized by intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy. Prevalence is high and has been estimated to range between 0.5% and 1.5%. Capsule endoscopy (CE) has a sensitivity and specificity of approximately 90%. CD is an important differential diagnosis for diagnostic workup for anemia, malabsorption, or diarrhea, and must be recognized reliably by the investigator. Moreover, CE is the preferred method to screen for complications in CD, such as enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and small bowel adenocarcinoma. This article is part of an expert video encyclopedia.