From recipe to research: introducing undergraduate students to the nature of science using a hybrid practical course centred on drug discovery for neglected diseases

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Heart assist systems--current status

BACKGROUND: Heart failure is the leading cause of death in the developed countries. Organ-preserving operative procedures on the failing heart like coronary artery bypass procedures or resection of left ventricular aneurysms are part of the routine care in cardiac surgery today. Terminal heart failure refractory to optimized drug therapy, however, will require a heart transplantation or the implantation of artificial blood pumps. While heart transplantation has proven to provide excellent long-term results with 10-year survival rates at 50%, it will remain a casuistic therapy, limited by the comparatively small number of procedures which can be performed. ARTIFICIAL BLOOD PUMPS: The current status of development of artificial blood pumps is represented by the broad availability of partially-implantable electric motor-driven left ventricular assist devices (LVAD), which still require a percutaneous cable for energy supply and device control from external sources while the blood pump itself resides inside the body. The recently introduced axial-flow devices (DeBakey, Jarvik 2000 and HeartMate II LVADs) deliver a continuous blood flow and obviously provide distinct advantages with regard to a reduction in size, weight and energy demands, simplified implantation technique and device control when compared to the previously available partially-implantable electric motor-driven pulsatile blood pumps (Novacor N100, TCl Heart Mate LVADs). The first systems designed for long-term or permanent use (Lion Heart LVAD, AbioCor replacement heart) are completely implantable devices featuring percutaneous energy transmission and device control. However, the latter are more complex devices and their clinical application is still limited to a small number of cases, which precludes a judgment about their potential at this time. INDICATIONS: The use of paracorporeal pneumatically accentuated blood pump systems is still indicated in cases of most severe biventricular heart failure and multiorgan failure or if only short- to mid-term circulatory support is anticipated. Well established indications for utilization of artificial blood pumps are the bridge-to-transplant procedure, which yields results comparable to primary heart transplantation, and acute cardiac failure following myocardial infarction or cardiac surgical procedures. In newborns and children, encouraging results were obtained when miniaturized blood pumps of the Berlin Heart System were utilized for heart failure in myocarditis or dilative cardiomyopathy. With advanced reliability of artificial blood pumps and in face of the high incidence of heart failure, especially in the older age group, the long-term application of artificial bloods pump appears to be justified.     

Cellular‐FLIP,Raji isoform (c‐FLIPR) modulates cell death induction upon T‐cell activation and infection

Dysregulation of apoptosis caused by an imbalance of pro‐ and anti‐apoptotic protein expression can lead to cancer, neurodegenerative, and autoimmune diseases. Cellular‐FLIP (c‐FLIP) proteins inhibit apoptosis directly at the death‐inducing signaling complex of death receptors, such as CD95, and have been linked to apoptosis regulation during immune responses. While the isoforms c‐FLIP_L and c‐FLIP_S are well characterized, the function of c‐FLIP_R remains poorly understood. Here, we demonstrate the induction of endogenous murine c‐FLIP_R in activated lymphocytes for the first time. To analyze c‐FLIP_R function in vivo, we generated transgenic mice expressing murine c‐FLIP_R specifically in hematopoietic cells. As expected, lymphocytes from c‐FLIP_R transgenic mice were protected against CD95‐induced apoptosis in vitro. In the steady state, transgenic mice had normal cell numbers and unaltered frequencies of B cells and T‐cell subsets in lymphoid organs. However, when challenged with Listeria monocytogenes, c‐FLIP_R transgenic mice showed less liver necrosis and better bacterial clearance compared with infected wild‐type mice. We conclude that c‐FLIP_R expression in hematopoietic cells supports an efficient immune response against bacterial infections.     

Enhanced discrimination between threatening and safe contexts in high-anxious individuals

Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality. Two virtual office rooms served as the conditioned contexts. One virtual office room (CXT+) was paired with unpredictable electrical stimuli. In the other virtual office room, no electrical stimuli were delivered (CXT−). High-anxious participants tended to show faster acquisition of startle potentiation in the CXT+ versus the CXT− than low-anxious participants. This enhanced contextual fear learning might function as a risk factor for anxiety disorders that are characterized by sustained anxiety.     

Food avoidance is associated with reduced dentitions and edentulousness

Objectives

To investigate associations between food avoidance and dental status, age, gender, and socio-economic status (SES).

Materials and methods

The Chinese sample comprised 1463 dentulous (≥ 1 tooth in each jaw) and 124 edentulous (in one or both jaws) participants aged ≥ 40 yrs. The Vietnamese sample comprised 2820 dentulous and 253 edentulous participants aged ≥ 20 yrs. Food avoidance due to chewing difficulties was scored for regionally common 4 soft and 4 hard foods. Dental status was classified according to the multi-level hierarchical dental functional classification system (HDFC) based on the number and location of teeth and posterior occlusal pairs. Associations were analyzed using multivariate logistic regression analyses.

Results

For dentulous participants, the chance of avoiding foods was significantly larger with < 10 teeth in each jaw (OR = 2.26 (Chinese sample), respectively 1.74 (Vietnamese sample)), incomplete anterior region (OR = 1.78, respectively 1.84), “impaired” premolar region (OR = 2.22, respectively 1.71), or “impaired” molar region (OR = 2.46, respectively 1.84). Edentulous participants had twice the chance of avoiding foods (OR = 2.01 respectively 2.20). Avoiding foods was significantly associated with higher age. Participants of low SES (Chinese sample, OR = 1.93) and females (Vietnamese sample, OR = 1.27) had a larger chance of avoiding foods.

Conclusions

Avoiding foods was significantly associated with reduced dentitions, edentulousness, and higher age; low SES only in the Chinese and being female only in the Vietnamese sample.

Clinical relevance

Incomplete anterior regions, “impaired” premolar or molar regions, and especially edentulousness can be considered significant risk indicators for food avoidance.

     

Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14⁺ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14⁺ epithelial tumor cell clusters disseminate collectively to colonize distant organs.During metastasis, cancer cells escape the primary tumor, travel through the circulation, and colonize distant organs. Conventional models of cancer progression propose that each metastasis arises from the clonal outgrowth of a single tumor cell and this conceptual framework is a foundation for models, such as epithelial-mesenchymal transition (EMT) and migratory cancer stem cells (1).Challenging the generality of the single-cell/single-metastasis model are long-standing clinical observations that tumor cell clusters (also termed “tumor clumps”) are also observed across the stages of metastasis. Tumor cell clusters are detected in the bloodstream of cancer patients (2), clusters can efficiently seed metastases (3), and though rare, circulating tumor cell (CTC) clusters have prognostic significance (4, 5). Furthermore, metastases are composed of multiple genetically distinct tumor cell clones, in mouse models of breast, pancreas, and small cell carcinoma (5–7), and in human metastatic prostate cancer patients (8). Taken together, these observations provide accumulating evidence that tumor cell clusters contribute to metastasis. However, they leave unresolved two important questions: how do tumor cell clusters emerge from the primary tumor, and which molecular features identify cell clusters that metastasize?An important clinical observation is that cancer cells invade the surrounding stroma as cohesive clusters in the majority of epithelial tumors, a process termed “collective invasion” (9, 10). In breast cancer, collective invasion is facilitated by invasive leader cells, a subpopulation of tumor cells that highly express keratin 14 (K14) and other basal epithelial markers (11). K14⁺ cells are migratory, protrusive, and lead trailing K14⁻ cells, while maintaining cell–cell cohesion and E-cadherin–based cell contacts.In this study, we sought to understand how these K14⁺ cells exit collective invasion strands in the primary tumor and travel to distant organs (12). One hypothesis is that collective invasion is an intermediate step toward eventual single-cell dissemination and monoclonal metastasis. However, tumor cell clusters are detected in circulation (5) and primary human breast tumors can disseminate collectively into the surrounding extracellular matrix in ex vivo assays (13–15). These data prompted an alternative hypothesis, that collectively invading K14⁺ cancer cells could initiate and complete the metastatic process as a cohesive multicellular unit. Here we define the clonal nature of metastases in a spontaneous mouse model of metastasis to the lungs (16, 17), in which the predominant invasive form in the primary tumor is collective invasion strands led by K14⁺ cells (11). We establish that the majority of metastases arise from polyclonal seeds, and show that disseminated tumor cell clusters are predominantly composed of K14⁺ cells. We propose a mechanism for polyclonal metastasis via the collective invasion, dissemination, and colonization of clusters of K14⁺ cancer cells.     

A temporal requirement for Hippo signaling in mammary gland differentiation,growth, and tumorigenesis

Despite recent progress, the physiological role of Hippo signaling in mammary gland development and tumorigenesis remains poorly understood. Here we show that the Hippo pathway is functionally dispensable in virgin mammary glands but specifically required during pregnancy. In contrast to many other tissues, hyperactivation of YAP in mammary epithelia does not induce hyperplasia but leads to defects in terminal differentiation. Interestingly, loss of YAP causes no obvious defects in virgin mammary glands but potently suppresses oncogene-induced mammary tumors. The selective requirement for YAP in oncogenic growth highlights the potential of YAP inhibitors as molecular targeted therapies against breast cancers.     

Dental functional status with and without tooth replacement in a Chinese adult population

The objective of this study is to investigate the prevalence of missing teeth and prosthodontic replacements in a Chinese adult population using a hierarchical dental functional classification system. A total of 1,462 dentate subjects over 40 years from Shandong Province, China were included and categorized in the functional classification system with and without tooth replacements. Depending on replacements, subjects could be reclassified (promoted) to categories reflecting higher functionality. "Promotions" were considered indicators for prosthodontic effectiveness. Homogeneities after dichotomization into functional categories appeared to be moderate to good. In the "≥10 teeth in each jaw" branch, mean number of teeth and posterior occluding pairs were 27.93 ± 2.74 and 7.10 ± 1.94, respectively. In the branch "<10 teeth in each jaw," these figures were 16.17 ± 5.54 and 1.49 ± 1.45. Fixed dental prostheses (FDPs) added on average 3.5 artificial teeth; 46% of subjects with FDP promoted to a higher functional level. For removable dental prostheses (RDPs), these numbers were 8.5% and 79%, respectively. Promotion value per tooth added was significantly higher for FDPs. The classification system was able to quantify the effectiveness of teeth replacements. It was shown that RDPs were more effective when higher numbers of teeth were replaced, while FDPs were more effective per artificial tooth added.