Brief communication: The hidden labyrinth: deep groundwater in Wright Valley, Antarctica

Since the 1960s, a deep groundwater system in Wright Valley, Antarctica, has been the hypothesized source of brines to hypersaline Don Juan Pond and Lake Vanda, both of which are rich in calcium and chloride. Modeling studies do not support other possible mechanisms, such as evaporative processes, that could have led to the current suite of ions present in both waterbodies. In 2011 and 2018, an airborne electromagnetic survey was flown over Wright Valley to map subsurface resistivity (down to 600 m) in exploration of liquid water. The surveys revealed widespread unfrozen brine in the subsurface near Lake Vanda, Don Juan Pond, and the North Fork of Wright Valley. While our geophysical survey can neither confirm nor deny deep groundwater connectivity between Lake Vanda and Don Juan Pond, it does point to the potential for deep valley-wide brine, likely within the Ferrar Dolerite formation.</p

Homogeneous MGMT Immunoreactivity Correlates with an Unmethylated MGMT Promoter Status in Brain Metastases of Various Solid Tumors

The O6-methylguanine-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical reports on treating brain metastases with temozolomide describe varying effects. This may be due to the fact that MGMT promoter methylation of brain metastases has not yet been explored in depth. Therefore, we assessed MGMT promoter methylation of various brain metastases including those derived from lung (n = 91), breast (n = 72) kidney (n = 49) and from malignant melanomas (n = 113) by methylation-specific polymerase chain reaction (MS-PCR) and MGMT immunoreactivity. Fifty-nine of 199 brain metastases (29.6%) revealed a methylated MGMT promoter. The methylation rate was the highest in brain metastases derived from lung carcinomas (46.5%) followed by those from breast carcinoma (28.8%), malignant melanoma (24.7%) and from renal carcinoma (20%). A significant correlation of homogeneous MGMT-immunoreactivity (>95% MGMT positive tumor cells) and an unmethylated MGMT promoter was found. Promoter methylation was detected in 26 of 61 (43%) tumors lacking MGMT immunoreactivity, in 17 of 63 (27%) metastases with heterogeneous MGMT expression, but only in 5 of 54 brain metastases (9%) showing a homogeneous MGMT immunoreactivity. Our results demonstrate that a significant number of brain metastases reveal a methylated MGMT-promoter. Based on an obvious correlation between homogeneous MGMT immunoreactivity and unmethylated MGMT promoter, we hypothesize that immunohistochemistry for MGMT may be a helpful diagnostic tool to identify those tumors that probably will not benefit from the use of alkylating agents. The discrepancy between promoter methylation and a lack of MGMT immunoreactivity argues for assessing MGMT promoter methylation both by immunohistochemical as well as by molecular approaches for diagnostic purposes

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models.

Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials

Mapping geothermal heat flux using permafrost thickness constrained by airborne electromagnetic surveys on the western coast of Ross Island, Antarctica

© 2019, © 2019 Australian Society of Exploration Geophysicists. Permafrost is ubiquitous at high latitudes, and its thickness is controlled by important local factors like geothermal flux, ground surface temperature and thermal properties of the subsurface. We use airborne transient electromagnetic resistivity measurements to determine permafrost thickness on the coast of Ross Island, Antarctica, which contains the active volcano Mt Erebus. Here, resistivity data clearly distinguish resistive permafrost from the electrically conductive fluid-saturated materials underlying it. For our study, we define permafrost as frozen material with a resistivity \u3e 100 Ω·m; more conductive material contains a significant fraction of water or (more likely) brine. We observe that permafrost is very thin near the coast and thickens within several hundred metres inland to reach depths that are typically within the range of 300–400 m. We attribute the sharp near-shore increase in permafrost thickness to lateral heat conduction from the relatively warm ocean, possibly combined with seawater infiltration into the near-shore permafrost. We validate this result with a two-dimensional heat flow model and conclude that away from the thermal influence of the ocean, the local geothermal gradient and heat flux are about 45 ± 5 °C/km and 90 ± 13 mW/m2, respectively. These values are in line with published estimates in the vicinity of Mt Erebus and within the actively extending Terror Rift, but do not reflect a strong heat flow anomaly from volcanic activity of Mt Erebus. Measurements made previously in the McMurdo Dry Valleys, on the other side of McMurdo Sound, tend to be a few dozens of mW/m2 lower, likely reflecting its different tectonic setting on the uplifted rift shoulder of Transantarctic Mountains. Our study demonstrates a new approach towards constraining geothermal flux in polar regions using airborne electromagnetic (AEM) data that can be relatively efficiently collected on regional scales where ice coverage does not exceed the penetration limits of the AEM device, which for the device used is ∼ 500 m under the favourable conditions in the study area

Evidence for Pathways of Concentrated Submarine Groundwater Discharge in East Antarctica from Helicopter-Borne Electrical Resistivity Measurements

The Southern Ocean receives limited liquid surface water input from the Antarctic continent. It has been speculated, however, that significant liquid water may flow from beneath the Antarctic Ice Sheet, and that this subglacial flow carries that water along with dissolved nutrients to the coast. The delivery of solutes, particularly limiting nutrients like bioavailable iron, to the Southern Ocean may contribute to ecosystem processes including primary productivity. Using a helicopter-borne time domain electromagnetic survey along the coastal margins of the McMurdo Dry Valleys region of Southern Victoria Land, Antarctica, we detected subsurface connections between inland lakes, aquifers, and subglacial waters. These waters, which appear as electrically conductive anomalies, are saline and may contain high concentrations of biologically important ions, including iron and silica. Local hydraulic gradients may drive these waters to the coast, where we postulate they emerge as submarine groundwater discharge. This high latitude groundwater system, imaged regionally in the McMurdo Dry Valleys, may be representative of a broader system of Antarctic submarine groundwater discharge that fertilizes the Southern Ocean. In total, it has the potential to deliver tens of gigagrams of bioavailable Fe and Si to the coastal zone

Evidence for pathways of concentrated submarine groundwater discharge in east Antarctica from helicopter-borne electrical resistivity measurements

© 2019 by the authors. The Southern Ocean receives limited liquid surface water input from the Antarctic continent. It has been speculated, however, that significant liquid water may flow from beneath the Antarctic Ice Sheet, and that this subglacial flow carries that water along with dissolved nutrients to the coast. The delivery of solutes, particularly limiting nutrients like bioavailable iron, to the Southern Ocean may contribute to ecosystem processes including primary productivity. Using a helicopter-borne time domain electromagnetic survey along the coastal margins of the McMurdo Dry Valleys region of Southern Victoria Land, Antarctica, we detected subsurface connections between inland lakes, aquifers, and subglacial waters. These waters, which appear as electrically conductive anomalies, are saline and may contain high concentrations of biologically important ions, including iron and silica. Local hydraulic gradients may drive these waters to the coast, where we postulate they emerge as submarine groundwater discharge. This high latitude groundwater system, imaged regionally in the McMurdo Dry Valleys, may be representative of a broader system of Antarctic submarine groundwater discharge that fertilizes the Southern Ocean. In total, it has the potential to deliver tens of gigagrams of bioavailable Fe and Si to the coastal zone

Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer.

Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC). However, resistance often develops, leading to treatment failure. This expansion cohort (part C2) of the previously reported phase 1b trial (NCT02157792) is based on the recommended phase 2 dose of the combination of the ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib and cisplatin observed in patients with advanced solid tumors, including TNBC. Forty-seven patients aged ≥18 years with advanced TNBC received cisplatin (75 mg/m2; day 1) and berzosertib (140 mg/m2; days 2 and 9), in 21-day cycles. Berzosertib was well tolerated, with a similar toxicity profile to that reported previously for this combination. The overall response rate (90% confidence interval) was 23.4% (13.7, 35.8). No relevant associations were observed between response and gene alterations. Further studies combining ATR inhibitors with platinum compounds may be warranted in highly selected patient populations

Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer

\ua9 2022, The Author(s). Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC). However, resistance often develops, leading to treatment failure. This expansion cohort (part C2) of the previously reported phase 1b trial (NCT02157792) is based on the recommended phase 2 dose of the combination of the ataxia-telangiectasia and Rad3-related (ATR) inhibitor berzosertib and cisplatin observed in patients with advanced solid tumors, including TNBC. Forty-seven patients aged ≥18 years with advanced TNBC received cisplatin (75 mg/m2; day 1) and berzosertib (140 mg/m2; days 2 and 9), in 21-day cycles. Berzosertib was well tolerated, with a similar toxicity profile to that reported previously for this combination. The overall response rate (90% confidence interval) was 23.4% (13.7, 35.8). No relevant associations were observed between response and gene alterations. Further studies combining ATR inhibitors with platinum compounds may be warranted in highly selected patient populations