Isolated limb perfusion with actinomycin D and TNF-alpha results in improved tumour response in soft-tissue sarcoma-bearing rats but is accompanied by severe local toxicity

Previously we demonstrated that addition of Tumour Necrosis Factor-α to melphalan or doxorubicin in a so-called isolated limb perfusion results in synergistic antitumour responses of sarcomas in both animal models and patients. Yet, 20 to 30% of the treated tumours do not respond. Therefore agents that synergise with tumour necrosis factor alpha must be investigated. Actinomycin D is used in combination with melphalan in isolated limb perfusion in the treatment of patients with melanoma in-transit metastases and is well known to augment tumour cell sensitivity towards tumour necrosis factor alpha in vitro. Both agents are very toxic, which limits their systemic use. Their applicability may therefore be tested in the isolated limb perfusion setting, by which the tumours can be exposed to high concentrations in the absence of systemic exposure. To study the beneficial effect of the combination in vivo, BN-175 soft tissue sarcoma-bearing rats were perfused with various concentrations of actinomycin D and tumour necrosis factor alpha. When used alone the drugs had only little effect on the tumour. Only when actinomycin D and tumour necrosis factor alpha were combined a tumour response was achieved. However, these responses were accompanied by severe, dose limiting, local toxicity such as destruction of the muscle tissue and massive oedema. Our results show that isolated limb perfusion with actinomycin D in combination with tumour necrosis factor alpha leads to a synergistic anti-tumour response but also to idiosyncratic locoregional toxicity to the normal tissues. Actinomycin D, in combination with tumour necrosis factor alpha, should not be explored in the clinical setting because of this. The standard approach in the clinic remains isolated limb perfusion with tumour necrosis factor alpha in combination with melphalan

Hydrological and climatological change associated with glacial recession in the Rwenzori Mountains of Uganda

The areal extent of tropical icefields in the Rwenzori Mountains of East Africa has reduced steadily over the last century from 7.5 km^{2} 2 in 1906 to <1 km^{2} in 2003. Considerable debate persists regarding the impact of deglaciation on alpine riverflow and changes in climate driving glacial recession in the East African Highlands. Recent field surveys combined with historical observations reveal continued, rapid retreat in the terminal positions of valley glaciers (Speke, Elena). Observed acceleration in the rate of termini retreat since the 1960s is shown to arise, in part, from the morphologies of the glaciers and the beds within which those glaciers reside. Historical data combined with the first measurements of alpine riverflow in the Rwenzori Mountains show that the contribution of meltwater flows from dwindling icefields to alpine riverflow is negligible, contributing <0.5% of the mean annual river discharge recorded at the base of the mountains. Preliminary high-frequency monitoring of air temperature and humidity in the vicinity of icefields on the Rwenzori Mountains indicates that elevated daily maximum air temperatures coincide with episodic reductions in relative humidity and increased meltwater fluxes observed during the dry season. A sustained reduction in humidity to account for observed deglaciation is not evident from records of lowland precipitation, humidity or river discharge. Lakelevel records in East Africa are also inconsistent with a sudden decrease in regional humidity around 1880AD that is proposed to have triggered deglaciation in the East African Highlands. Water levels in the lakes proximate to the icefields of Mount Kenya and Kilimanjaro are rising in the late 19th century when glaciers on these mountains are observed to be in retreat. Lake levels do not, furthermore, indicate that enhanced humidity over the 19th century prior to 1880AD relative to the 20th century. Evidence of warming over the latter half of the 20th century and an earlier onset of deglaciation (~1870AD) from meteorological and palaeolimnological data suggest that the timing and drivers of deglaciation in the Rwenzori Mountains are consistent with the recession of alpine icefields elsewhere in the tropics

Biomarkers in melanoma

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques--DNA and RNA microarrays--have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers--lactate dehydrogenase, S100B and melanoma-inhibiting activity--as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the futur

Biomarkers in melanoma

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques—DNA and RNA microarrays—have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers—lactate dehydrogenase, S100B and melanoma-inhibiting activity—as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the future

Independent Set Reconfiguration in Cographs

We study the following independent set reconfiguration problem, called TAR-Reachability: given two independent sets $I$ and $J$ of a graph $G$, both of size at least $k$, is it possible to transform $I$ into $J$ by adding and removing vertices one-by-one, while maintaining an independent set of size at least $k$ throughout? This problem is known to be PSPACE-hard in general. For the case that $G$ is a cograph (i.e. $P_4$-free graph) on $n$ vertices, we show that it can be solved in time $O(n^2)$, and that the length of a shortest reconfiguration sequence from $I$ to $J$ is bounded by $4n-2k$, if such a sequence exists. More generally, we show that if $X$ is a graph class for which (i) TAR-Reachability can be solved efficiently, (ii) maximum independent sets can be computed efficiently, and which satisfies a certain additional property, then the problem can be solved efficiently for any graph that can be obtained from a collection of graphs in $X$ using disjoint union and complete join operations. Chordal graphs are given as an example of such a class $X$

Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents

Enhancement of electroporation facilitated immunogene therapy via T-reg depletion

Regulatory T cells (T-regs) can negatively impact tumor antigen-specific immune responses after infiltration into tumor tissue. However, depletion of T-regs can facilitate enhanced anti-tumor responses, thus augmenting the potential for immunotherapies. Here we focus on treating a highly aggressive form of cancer using a murine melanoma model with a poor prognosis. We utilize a combination of T-reg depletion and immunotherapy plasmid DNA delivered into the B16F10 melanoma tumor model via electroporation. Plasmids encoding murine granulocyte macrophage colony-stimulating factor and human B71 were transfected with electroporation into the tumor and transient elimination of T-regs was achieved with CD25-depleting antibodies (PC61). The combinational treatment effectively depleted T-regs compared to the untreated tumor and significantly reduced lung metastases. The combination treatment was not effective in increasing the survival, but only effective in suppression of metastases. These results indicate the potential for combining T-reg depletion with immunotherapy-based gene electrotransfer to decrease systemic metastasis and potentially enhance survival