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The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.
Extensive black shale deposits formed in the Early Cretaceous South Atlantic, supporting the notion that this emerging ocean basin was a globally important site of organic carbon burial. The magnitude of organic carbon burial in marine basins is known to be controlled by various tectonic, oceanographic, hydrological, and climatic processes acting on different temporal and spatial scales, the nature and relative importance of which are poorly understood for the young South Atlantic. Here we present new bulk and molecular geochemical data from an Aptian–Albian sediment record recovered from the deep Cape Basin at Deep Sea Drilling Project (DSDP) Site 361, which we combine with general circulation model results to identify driving mechanisms of organic carbon burial. A multimillion-year decrease (i.e., Early Aptian–Albian) in organic carbon burial, reflected in a lithological succession of black shale, gray shale, and red beds, was caused by increasing bottom water oxygenation due to abating hydrographic restriction via South Atlantic–Southern Ocean gateways. These results emphasize basin evolution and ocean gateway development as a decisive primary control on enhanced organic carbon preservation in the Cape Basin at geological timescales (> 1 Myr). The Early Aptian black shale sequence comprises alternations of shales with high (> 6 %) and relatively low (∼ 3.5 %) organic carbon content of marine sources, the former being deposited during the global Oceanic Anoxic Event (OAE) 1a, as well as during repetitive intervals before and after OAE 1a. In all cases, these short-term intervals of enhanced organic carbon burial coincided with strong influxes of sediments derived from the proximal African continent, indicating closely coupled climate–land–ocean interactions. Supported by our model results, we show that fluctuations in weathering-derived nutrient input from the southern African continent, linked to changes in orbitally driven humidity and aridity, were the underlying drivers of repetitive episodes of enhanced organic carbon burial in the deep Cape Basin. These results suggest that deep marine environments of emerging ocean basins responded sensitively and directly to short-term fluctuations in riverine nutrient fluxes. We explain this relationship using the lack of wide and mature continental shelf seas that could have acted as a barrier or filter for nutrient transfer from the continent into the deep ocean.
Extensive black shale deposits formed in the Early Cretaceous South Atlantic, supporting the notion that this emerging ocean basin was a globally important site of organic carbon burial. The magnitude of organic carbon burial in marine basins is known to be controlled by various tectonic, oceanographic, hydrological, and climatic processes acting on different temporal and spatial scales, the nature and relative importance of which are poorly understood for the young South Atlantic. Here we present new bulk and molecular geochemical data from an Aptian–Albian sediment record recovered from the deep Cape Basin at Deep Sea Drilling Project (DSDP) Site 361, which we combine with general circulation model results to identify driving mechanisms of organic carbon burial. A multi-million year decrease (i.e. Early Aptian–Albian) in organic carbon burial, reflected in a lithological succession of black shale, gray shale, and red beds, was caused by increasing bottom water oxygenation due to abating tectonic restriction via South Atlantic-Southern Ocean gateways. These results emphasize basin evolution and ocean gateway development as a decisive primary control on enhanced organic carbon preservation in the Cape Basin at geological time scales (>1 Myr). The Early Aptian black shale sequence comprises alternations of shales with high (>5%) and relatively low (~3%) organic carbon content of marine sources, the former being deposited during the global Oceanic Anoxic Event (OAE) 1a, as well as during repetitive events before and after OAE 1a. In all cases, these short-term events of enhanced organic carbon burial coincided with strong influxes of sediments derived from the proximal African continent, indicating closely coupled climate–land–ocean interactions. Supported by our model results, we propose that fluctuations in weathering-derived nutrient input from the southern African continent, linked to fluctuations in pCO2 and/or orbitally driven humidity/aridity, were the underlying drivers of short-term organic carbon burial in the deep Cape Basin. These results suggest that deep marine environments of emerging ocean basins responded sensitively and directly to short term fluctuations in riverine nutrient fluxes. We explain this relationship by the lack of wide and mature continental shelf seas that could have acted as a barrier or filter for nutrient transfer from the continent into the deep ocean.
Comparative proteomics reveals a diagnostic signature for pulmonary head‐and‐neck cancer metastasis
(2018)
Patients with head‐and‐neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head‐and‐neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types. Using supervised machine learning, we inferred a proteomic signature for the classification of squamous cell carcinomas as either SQCLC or HNSCC, with diagnostic accuracies of 90.5% and 86.8% in cross‐ and independent validations, respectively. Furthermore, application of this signature to a cohort of pulmonary squamous cell carcinomas of unknown origin leads to a significant prognostic separation. This study not only provides a diagnostic proteomic signature for classification of secondary lung tumours in HNSCC patients, but also represents a proteomic resource for HNSCC and SQCLC.
In 2013 Disney released its 53rd animated movie "Frozen". (Very) loosely based on Hans Christian Andersen's fairy tale "The Snow Queen", it tells the story of two sisters, one of which, Elsa, has the power to manipulate ice. Instead of making her the real villain of the film, Disney opted for a misunderstood and suppressed young woman, who flees her castle, which she deems a prison, when her subjects find out about her powers. Her younger sister Anna vows to bring her back and to show everyone that her "sister's not a monster. [i]t was an accident. [...] So [Anna] needs to go after her." "Frozen" is the story of the re-bonding of two sisters and Elsa even saves her kid sister eventually by showing Anna that she truly loves her and not some prince. According to Stephen Holden, it is supposed to be a story that "shakes up the hyper-romantic "princess" formula that has stood Disney in good stead for decades and that has grown stale." Holden's review reverberates a general agreement that "Frozen" is finally a movie that can be truly enjoyed by both sexes and that does not promote the idea that love triumphs over anything else.