Peptides as innovative strategies to combat drug resistance in cancer therapy.

Drug resistance is the leading cause of treatment failure in patients with cancer. Thus, innovative therapeutic strategies are required to overcome this critical challenge and improve patient outcomes. In this review, we examine the potential of peptide-based therapies to combat drug resistance in cancer. We highlight the unique strategies and mechanisms that can be explored by using peptides, including their ability to selectively target tumours, facilitate drug delivery into cancer cells, and inhibit key intracellular proteins that drive cancer progression and resistance. Peptides offer a promising approach to overcoming both intrinsic and adaptative cancer resistance against chemotherapy, targeted therapies, and biologics.

A positive reminder to reflect on achievements.

With nominations open for the BVA Young Vet of the Year 2024, last year's winner Henry Lamb describes his experience of securing the prestigious award.

Cyclic tachyplesin I kills proliferative, non-proliferative and drug-resistant melanoma cells without inducing resistance.

Acquired drug resistance is the major cause for disease recurrence in cancer patients, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. To address this problem, we investigated cyclic membrane-active peptides as an alternative therapeutic modality to kill drug-tolerant and resistant melanoma cells to avoid acquired drug resistance. We selected two stable cyclic peptides (cTI and cGm), previously shown to have anti-melanoma properties, and compared them with dabrafenib, a drug used to treat cancer patients with the BRAF V600E mutation. The peptides act via a fast membrane-permeabilizing mechanism and kill metastatic melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Melanoma cells do not become resistant to long-term treatment with cTI, nor do they evolve their lipid membrane composition, as measured by lipidomic and proteomic studies. In vivo studies in mice demonstrated that the combination treatment of cTI and dabrafenib resulted in fewer metastases and improved overall survival. Such cyclic membrane-active peptides are thus well suited as templates to design new anticancer therapeutic strategies.

Early warning signals of the termination of the African Humid Period(s).

The transition from a humid green Sahara to today's hyperarid conditions in northern Africa ~5.5 thousand years ago shows the dramatic environmental change to which human societies were exposed and had to adapt to. In this work, we show that in the 620,000-year environmental record from the Chew Bahir basin in the southern Ethiopian Rift, with its decadal resolution, this one thousand year long transition is particularly well documented, along with 20-80 year long droughts, recurring every ~160 years, as possible early warnings. Together with events of extreme wetness at the end of the transition, these droughts form a pronounced climate "flickering", which can be simulated in climate models and is also present in earlier climate transitions in the Chew Bahir environmental record, indicating that transitions with flickering are characteristic of this region.

Pleistocene climate variability in eastern Africa influenced hominin evolution.

Despite more than half a century of hominin fossil discoveries in eastern Africa, the regional environmental context of hominin evolution and dispersal is not well established due to the lack of continuous palaeoenvironmental records from one of the proven habitats of early human populations, particularly for the Pleistocene epoch. Here we present a 620,000-year environmental record from Chew Bahir, southern Ethiopia, which is proximal to key fossil sites. Our record documents the potential influence of different episodes of climatic variability on hominin biological and cultural transformation. The appearance of high anatomical diversity in hominin groups coincides with long-lasting and relatively stable humid conditions from ~620,000 to 275,000 years bp (episodes 1-6), interrupted by several abrupt and extreme hydroclimate perturbations. A pattern of pronounced climatic cyclicity transformed habitats during episodes 7-9 (~275,000-60,000 years bp), a crucial phase encompassing the gradual transition from Acheulean to Middle Stone Age technologies, the emergence of Homo sapiens in eastern Africa and key human social and cultural innovations. Those accumulative innovations plus the alignment of humid pulses between northeastern Africa and the eastern Mediterranean during high-frequency climate oscillations of episodes 10-12 (~60,000-10,000 years bp) could have facilitated the global dispersal of H. sapiens.

Orbital controls on eastern African hydroclimate in the Pleistocene.

Understanding eastern African paleoclimate is critical for contextualizing early human evolution, adaptation, and dispersal, yet Pleistocene climate of this region and its governing mechanisms remain poorly understood due to the lack of long, orbitally-resolved, terrestrial paleoclimate records. Here we present leaf wax hydrogen isotope records of rainfall from paleolake sediment cores from key time windows that resolve long-term trends, variations, and high-latitude effects on tropical African precipitation. Eastern African rainfall was dominantly controlled by variations in low-latitude summer insolation during most of the early and middle Pleistocene, with little evidence that glacial-interglacial cycles impacted rainfall until the late Pleistocene. We observe the influence of high-latitude-driven climate processes emerging from the last interglacial (Marine Isotope Stage 5) to the present, an interval when glacial-interglacial cycles were strong and insolation forcing was weak. Our results demonstrate a variable response of eastern African rainfall to low-latitude insolation forcing and high-latitude-driven climate change, likely related to the relative strengths of these forcings through time and a threshold in monsoon sensitivity. We observe little difference in mean rainfall between the early, middle, and late Pleistocene, which suggests that orbitally-driven climate variations likely played a more significant role than gradual change in the relationship between early humans and their environment.

Paleo-ENSO influence on African environments and early modern humans.

In this study, we synthesize terrestrial and marine proxy records, spanning the past 620 ky, to decipher pan-African climate variability and its drivers and potential linkages to hominin evolution. We find a tight correlation between moisture availability across Africa to El Niño Southern Ocean oscillation (ENSO) variability, a manifestation of the Walker Circulation, that was most likely driven by changes in Earth's eccentricity. Our results demonstrate that low-latitude insolation was a prominent driver of pan-African climate change during the Middle to Late Pleistocene. We argue that these low-latitude climate processes governed the dispersion and evolution of vegetation as well as mammals in eastern and western Africa by increasing resource-rich and stable ecotonal settings thought to have been important to early modern humans.

Long-term fire resilience of the Ericaceous Belt, Bale Mountains, Ethiopia.

Fire is the most frequent disturbance in the Ericaceous Belt (ca 3000-4300 m.a.s.l.), one of the most important plant communities of tropical African mountains. Through resprouting after fire, Erica establishes a positive fire feedback under certain burning regimes. However, present-day human activity in the Bale Mountains of Ethiopia includes fire and grazing systems that may have a negative impact on the resilience of the ericaceous ecosystem. Current knowledge of Erica-fire relationships is based on studies of modern vegetation, lacking a longer time perspective that can shed light on baseline conditions for the fire feedback. We hypothesize that fire has influenced Erica communities in the Bale Mountains at millennial time-scales. To test this, we (1) identify the fire history of the Bale Mountains through a pollen and charcoal record from Garba Guracha, a lake at 3950 m.a.s.l., and (2) describe the long-term bidirectional feedback between wildfire and Erica, which may control the ecosystem's resilience. Our results support fire occurrence in the area since ca 14 000 years ago, with particularly intense burning during the early Holocene, 10.8-6.0 cal ka BP. We show that a positive feedback between Erica abundance and fire occurrence was in operation throughout the Lateglacial and Holocene, and interpret the Ericaceous Belt of the Ethiopian mountains as a long-term fire resilient ecosystem. We propose that controlled burning should be an integral part of landscape management in the Bale Mountains National Park.

Author Correction: 150,000-year palaeoclimate record from northern Ethiopia supports early, multiple dispersals of modern humans from Africa.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

150,000-year palaeoclimate record from northern Ethiopia supports early, multiple dispersals of modern humans from Africa.

Climatic change is widely acknowledged to have played a role in the dispersal of modern humans out of Africa, but the timing is contentious. Genetic evidence links dispersal to climatic change ~60,000 years ago, despite increasing evidence for earlier modern human presence in Asia. We report a deep seismic and near-continuous core record of the last 150,000 years from Lake Tana, Ethiopia, close to early modern human fossil sites and to postulated dispersal routes. The record shows varied climate towards the end of the penultimate glacial, followed by an abrupt change to relatively stable moist climate during the last interglacial. These conditions could have favoured selection for behavioural versatility, population growth and range expansion, supporting models of early, multiple dispersals of modern humans from Africa.

Evidence for a bi-partition of the Younger Dryas Stadial in East Asia associated with inversed climate characteristics compared to Europe.

The Younger Dryas Stadial (YDS) was an episode of northern hemispheric cooling which occurred within the Last Glacial Interglacial Transition (LGIT). A major driver for the YDS climate was a weakening of the Atlantic Meridional Overturning Circulation (AMOC). It has been inferred that the AMOC began to strengthen mid-YDS, producing a bipartite structure of the YDS in records from continental Europe. These records imply that the polar front and westerlies shifted northward, producing a warmer second phase of the YDS in Europe. Here we present multi-proxy data from the sediments of Lake Suigetsu (Japan), as evidence that a related bi-partition of the YDS also occurred in East Asia. Besides showing for the first time that the bi-partition was not limited to the North Atlantic/European region, the data also imply a climatic dipole between Europe and East Asia since the cold-warm characteristics are reversed at Lake Suigetsu. We suggest that changes in eastward moisture transport from the North Atlantic are the primary mechanism by which the teleconnection can be explained.

Climatic variability, plasticity, and dispersal: A case study from Lake Tana, Ethiopia.

The numerous dispersal events that have occurred during the prehistory of hominin lineages are the subject of longstanding and increasingly active debate in evolutionary anthropology. As well as research into the dating and geographic extent of such dispersals, there is an increasing focus on the factors that may have been responsible for dispersal. The growing body of detailed regional palaeoclimatic data is invaluable in demonstrating the often close relationship between changes in prehistoric environments and the movements of hominin populations. The scenarios constructed from such data are often overly simplistic, however, concentrating on the dynamics of cyclical contraction and expansion during severe and ameliorated conditions respectively. This contribution proposes a two-stage hypothesis of hominin dispersal in which populations (1) accumulate high levels of climatic tolerance during highly variable climatic phases, and (2) express such heightened tolerance via dispersal in subsequent low-variability phases. Likely dispersal phases are thus proposed to occur during stable climatic phases that immediately follow phases of high climatic variability. Employing high resolution palaeoclimatic data from Lake Tana, Ethiopia, the hypothesis is examined in relation to the early dispersal of Homo sapiens out of East Africa and into the Levant. A dispersal phase is identified in the Lake Tana record between c. 112,550 and c. 96,975 years ago, a date bracket that accords well with the dating evidence for H. sapiens occupation at the sites of Qafzeh and Skhul. Results are discussed in relation to the complex pattern of H. sapiens dispersal out of East Africa, with particular attention paid to the implications of recent genetic chronologies for the origin of non-African modern humans.

A complete terrestrial radiocarbon record for 11.2 to 52.8 kyr B.P.

Radiocarbon ((14)C) provides a way to date material that contains carbon with an age up to ~50,000 years and is also an important tracer of the global carbon cycle. However, the lack of a comprehensive record reflecting atmospheric (14)C prior to 12.5 thousand years before the present (kyr B.P.) has limited the application of radiocarbon dating of samples from the Last Glacial period. Here, we report (14)C results from Lake Suigetsu, Japan (35°35'N, 135°53'E), which provide a comprehensive record of terrestrial radiocarbon to the present limit of the (14)C method. The time scale we present in this work allows direct comparison of Lake Suigetsu paleoclimatic data with other terrestrial climatic records and gives information on the connection between global atmospheric and regional marine radiocarbon levels.