Isolation and Characterization of Squamous Cell Carcinoma-Derived Stem-like Cells: Role in Tumor Formation

In human epidermis, keratinocyte stem cells (KSC) are characterized by high levels of β₁-integrin, resulting in the rapid adhesion to type IV collagen. Since epithelial tumors originate from KSC, we evaluated the features of rapidly adhering (RAD) keratinocytes derived from primary human squamous cell carcinoma of the skin (cSCC). RAD cells expressed higher levels of survivin, a KSC marker, as compared to non-rapidly adhering (NRAD) cells. Moreover, RAD cells proliferated to a greater extent and were more efficient in forming colonies than NRAD cells. RAD cells also migrated significantly better than NRAD cells. When seeded in a silicone chamber and grafted onto the back skin of NOD SCID mice, RAD cells formed tumors 2–4 fold bigger than those derived from NRAD cells. In tumors derived from RAD cells, the mitotic index was significantly higher than in those derived from NRAD cells, while Ki-67 and survivin expression were more pronounced in RAD tumors. This study suggests that SCC RAD stem cells play a critical role in the formation and development of epithelial tumors.     

Scientific workflows with the jABC framework

The jABC is a framework for process modelling and execution according to the XMDD (eXtreme model-driven design) paradigm, which advocates the rigorous use of user-level models in the software development process and software life cycle. We have used the jABC in the domain of scientific workflows for more than a decade now—an occasion to look back and take stock of our experiences in the field. On the one hand, we discuss results from the analysis of a sample of nearly 100 scientific workflow applications that have been implemented with the jABC. On the other hand, we reflect on our experiences and observations regarding the workflow development process with the framework. We then derive and discuss ongoing further developments and future perspectives for the framework, all with an emphasis on simplicity for end users through increased domain specificity. Concretely, we describe how the use of the PROPHETS synthesis plugin can enable a semantics-based simplification of the workflow design process, how with the jABC4 and DyWA frameworks more attention is paid to the ease of data management, and how the Cinco SCCE Meta-Tooling Suite can be used to generate tailored workflow management tools.     

Intrasphincteric injection of botulinum toxin is effective in long-term treatment of esophageal achalasia

We investigated the long-term efficacy and safety of intrasphincteric injections of botulinum toxin (100 U) in 57 patients with esophageal achalasia. One month after treatment, 50 patients had improved (88%); both symptom score and LES pressure were significantly reduced (P < 0.001). After a mean follow-up of 24+/-15 months (range 6-48), 43 patients (75%) are still in remission, although repeat injections of toxin were needed to achieve a stable effect on symptoms.     

Transgenic Mice for the Translational Study of Neuropathic Pain and Dystonia

Murine models are fundamental in the study of clinical conditions and the development of new drugs and treatments. Transgenic technology has started to offer advantages in oncology, encompassing all research fields related to the study of painful syndromes. Knockout mice or mice overexpressing genes encoding for proteins linked to pain development and maintenance can be produced and pain models can be applied to transgenic mice to model the most disabling neurological conditions. Due to the association of movement disorders with sensitivity and pain processing, our group focused for the first time on the role of the torsinA gene GAG deletion—responsible for DYT1 dystonia—in baseline sensitivity and neuropathic responses. The aim of the present report are to review the complex network that exists between the chaperonine-like protein torsinA and the baseline sensitivity pattern—which are fundamental in neuropathic pain—and to point at its possible role in neurodegenerative diseases.     

What Are the Biomarkers for Immunotherapy in SCLC?

Small-cell lung cancer (SCLC) is an aggressive malignancy that exhibits a rapid doubling time, a high growth fraction, and the early development of widespread metastases. The addition of immune checkpoint inhibitors to first-line chemotherapy represents the first significant improvement of systemic therapy in several decades. However, in contrast to its effects on non-SCLC, the advantageous effects of immunotherapy addition are modest in SCLC. In particular, only a small number of SCLC patients benefit from immune checkpoint inhibitors. Additionally, biomarkers selection is lacking for SCLC, with clinical trials largely focusing on unselected populations. Here, we review the data concerning the major biomarkers for immunotherapy, namely, programmed death ligand 1 expression and tumour mutational burden. Furthermore, we explore other potential biomarkers, including the role of the immune microenvironment in SCLC, the role of genetic alterations, and the potential links between neurological paraneoplastic syndromes, serum anti-neuronal nuclear antibodies, and outcomes in SCLC patients treated with immunotherapy.     

Colocalization and Interaction Study of Neuronal JNK3, JIP1, and β-Arrestin2 Together with PSD95

c-Jun N-terminal kinases (JNKs) are stress-activated serine/threonine protein kinases belonging to the mitogen-activated protein kinase (MAPK) family. Among them, JNK3 is selectively expressed in the central nervous system, cardiac smooth muscle, and testis. In addition, it is the most responsive JNK isoform to stress stimuli in the brain, and it is involved in synaptic dysfunction, an essential step in neurodegenerative processes. JNK3 pathway is organized in a cascade of amplification in which signal transduction occurs by stepwise, highly controlled phosphorylation. Since different MAPKs share common upstream activators, pathway specificity is guaranteed by scaffold proteins such as JIP1 and β-arrestin2. To better elucidate the physiological mechanisms regulating JNK3 in neurons, and how these interactions may be involved in synaptic (dys)function, we used (i) super-resolution microscopy to demonstrate the colocalization among JNK3–PSD95–JIP1 and JNK3–PSD95–β-arrestin2 in cultured hippocampal neurons, and (ii) co-immunoprecipitation techniques to show that the two scaffold proteins and JNK3 can be found interacting together with PSD95. The protein-protein interactions that govern the formation of these two complexes, JNK3–PSD95–JIP1 and JNK3–PSD95–β-arrestin2, may be used as targets to interfere with their downstream synaptic events.     

Role of Bevacizumab on Vascular Endothelial Growth Factor in Apolipoprotein E Deficient Mice after Traumatic Brain Injury

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB). Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI and to be overexpressed in the absence of apolipoprotein E (ApoE). Bevacizumab, a VEGF inhibitor, demonstrated neuroprotective activity in several models of TBI. However, the effects of bevacizumab on Apo-E deficient mice are not well studied. The present study aimed to evaluate VEGF expression and the effects of bevacizumab on BBB and neuroinflammation in ApoE^−/− mice undergoing TBI. Furthermore, for the first time, this study evaluates the effects of bevacizumab on the long-term consequences of TBI, such as atherosclerosis. The results showed that motor deficits induced by controlled cortical impact (CCI) were accompanied by increased brain edema and VEGF expression. Treatment with bevacizumab significantly improved motor deficits and significantly decreased VEGF levels, as well as brain edema compared to the control group. Furthermore, the results showed that bevacizumab preserves the integrity of the BBB and reduces the neuroinflammation induced by TBI. Regarding the effects of bevacizumab on atherosclerosis, it was observed for the first time that its ability to modulate VEGF in the acute phase of head injury prevents the acceleration of atherosclerosis. Therefore, the present study demonstrates not only the neuroprotective activity of bevacizumab but also its action on the vascular consequences related to TBI.     

A General Approach to L(h, k)-Label Interconnection Networks

Given two non-negative integers h and k,an L(h,k)-labeling of a graph G=(V,E) is a function from the set V to a set of colors,such that adjacent nodes take colors at distance at least h,and nodes at distance 2 take colors at distance at least k.The aim of the L(h,k)-labeling problem is to minimize the greatest used color.Since the decisional version of this problem is NP-complete,it is important to investigate particular classes of graphs for which the problem can be efficiently solved.It is well known that the most common interconnection topologies,such as Butterfly-like,Bene(?),CCC,Trivalent Cayley networks,are all characterized by a similar structure:they have nodes organized as a matrix and connections are divided into layers.So we naturally introduce a new class of graphs,called (1×n)-multistage graphs,containing the most common interconnection topologies,on which we study the L(h,k)-labeling.A general algorithm for L(h,k)-labeling these graphs is presented,and from this method an efficient L(2,1)-labeling for Butterfly and CCC networks is derived.Finally we describe a possible generalization of our approach.