Sudden stratospheric warming (SSW) events can form a window of forecast opportunity for polar vortex predictions on subseasonal‐to‐seasonal time scales. Analyzing numerical ensemble simulations, we ...quantify the associated enhanced predictability due to reduced upward planetary wave fluxes during the mostly radiatively driven recovery phase following SSWs. Ensembles that predict an SSW show reduced ensemble spread in terms of polar vortex strength for several weeks to follow, as well as a corresponding reduction in forecast errors. This increased predictability is particularly pronounced for strong SSWs and even occurs if not all ensemble members predict a major SSW. Furthermore, we found a direct impact of the occurrence of SSWs on the date of the final warming (FW): the decrease in upward wave fluxes delays the FW significantly. The reduced spread after SSWs and the delay in FW date have potentially further implications for (subseasonal) predictions of the tropospheric and mesospheric circulations.
Plain Language Summary
The polar vortex is a large scale circulation active during winter in the higher levels of the polar atmosphere. Changes in the strength of the polar vortex can have an impact on the weather over mid‐latitude regions like Europe. This is the case especially for the period after so‐called sudden stratospheric warming (SSW) events, where the polar vortex breaks down very abruptly and then slowly recovers over several weeks. Such a break‐down of the polar vortex tends to suppress wave activity and hence reduces the dynamical variability in the polar stratosphere, leading to a more predictable evolution of the circulation. We quantify the strength and timescale of this increase in predictability of the polar vortex after an SSW using a large set of winter time model forecasts.
Key Points
Sudden stratospheric warmings (SSWs) lead to reduced forecast spread in the polar stratosphere for several weeks after the event
Reduced forecast spread after SSWs is driven by suppressed vertical planetary wave propagation due to persistent negative wind anomalies
Final warmings are delayed for winters with SSW, consistent with reduced upward wave fluxes following the SSW
The effect of the Madden‐Julian Oscillation (MJO) on the Northern Hemisphere wintertime stratospheric polar vortex in the period preceding stratospheric sudden warmings is evaluated in operational ...subseasonal forecasting models. Reforecasts which simulate stronger MJO‐related convection in the Tropical West Pacific also simulate enhanced heat flux in the lowermost stratosphere and a more realistic vortex evolution. The time scale on which vortex predictability is enhanced lies between 2 and 4 weeks for nearly all cases. Those stratospheric sudden warmings that were preceded by a strong MJO event are more predictable at ∼20 day leads than stratospheric sudden warmings not preceded by a MJO event. Hence, knowledge of the MJO can contribute to enhanced predictability, at least in a probabilistic sense, of the Northern Hemisphere polar stratosphere.
Plain Language Summary
Atmospheric variability in the polar stratosphere, the atmospheric layer between approximately 10 km and 50 km above the surface, strongly impacts surface climate over the eastern United States and Eurasia. It is thought that variability in this region can be predicted up to 15 days in advance. Here we show that knowledge of the state of convection in the tropical Pacific and Indian Ocean can lead to enhanced predictability up to 4 weeks in advance.
Key Points
The MJO phase with convection in the West Pacific precedes a weaker vortex in two subseasonal forecast models
Time scale of predictability for SSW events may approach 4 weeks if a strong MJO event is realistically simulated
Ensemble spread in stratospheric circulation is related to ensemble spread in tropical convection
Trop-2 is a transmembrane signal transducer that can induce cancer growth. Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first ...thyroglobulin domain loop of its extracellular region, between residues R87 and T88. Molecular modeling indicated that this cleavage induces a profound rearrangement of the Trop-2 structure, which suggested a deep impact on its biological function. No Trop-2 cleavage was detected in normal human tissues, whereas most tumors showed Trop-2 cleavage, including skin, ovary, colon, and breast cancers. Coimmunoprecipitation and mass spectrometry analysis revealed that ADAM10 physically interacts with Trop-2. Immunofluorescence/confocal time-lapse microscopy revealed that the two molecules broadly colocalize at the cell membrane. We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease. Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo. A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination. Activatory proteolysis of Trop-2 was recapitulated in primary human breast cancers. Together with the prognostic impact of Trop-2 and ADAM10 on cancers of the skin, ovary, colon, lung, and pancreas, these data indicate a driving role of this activatory cleavage of Trop-2 on malignant progression of tumors.
February‐March 2020 was marked by highly anomalous large‐scale circulations in the Northern extratropical troposphere and stratosphere. The Atlantic jet reached extreme strength, linked to some of ...the strongest and most persistent positive values of the Arctic Oscillation index on record, which provided conditions for extreme windstorms hitting Europe. Likewise, the stratospheric polar vortex reached extreme strength that persisted for an unusually long period. Past research indicated that such circulation extremes occurring throughout the troposphere‐stratosphere system are dynamically coupled, although the nature of this coupling is still not fully understood and generally difficult to quantify. We employ sets of numerical ensemble simulations to statistically characterize the mutual coupling of the early 2020 extremes. We find the extreme vortex strength to be linked to the reflection of upward propagating planetary waves and the occurrence of this reflection to be sensitive to the details of the vortex structure. Our results show an overall robust coupling between tropospheric and stratospheric anomalies: ensemble members with polar vortex exceeding a certain strength tend to exhibit a stronger tropospheric jet and vice versa. Moreover, members exhibiting a breakdown of the stratospheric circulation (e.g., sudden stratospheric warming) tend to lack periods of persistently enhanced tropospheric circulation. Despite indications for vertical coupling, our simulations underline the role of internal variability within each atmospheric layer. The circulation extremes during early 2020 may be viewed as resulting from a fortuitous alignment of dynamical evolutions within the troposphere and stratosphere, aided by each layer's modification of the other layer's boundary condition.
Key Points
Large‐ensemble simulations are needed to fully characterize coupled extremes in the polar vortex and tropospheric jet in early 2020
Details of the vortex structure play an important role in promoting either reflection or dissipation of upward propagating waves 1 and/or 2
Modulation of lowermost stratospheric circulation from above and below facilitates co‐evolution of tropospheric and stratospheric extremes
Refractory or relapsing metastatic triple‐negative breast cancer (mTNBC) has a poor prognosis. Sacituzumab govitecan (SG) is a novel antibody‐drug conjugate, targeting human trophoblast cell‐surface ...antigen 2 (Trop‐2). This is the first report of SG's efficacy and safety in Chinese patients with mTNBC. EVER‐132‐001 (NCT04454437) was a multicenter, single‐arm, Phase IIb study in Chinese patients with mTNBC who failed ≥2 prior chemotherapy regimens. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21‐day treatment cycle, until disease progression/unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the Independent Review Committee. Secondary endpoints included: duration of response (DOR), clinical benefit rate (CBR), progression‐free survival (PFS), overall survival (OS) and safety. Eighty female Chinese patients (median age 47.6 years; range 24‐69.9 years) received ≥1 SG dose with a median of 8 treatment cycles by the cutoff date (August 6, 2021). Median number of prior systemic cancer treatments was 4.0 (range 2.0‐8.0). ORR and CBR were reported 38.8% (95% confidence interval CI: 28.06‐50.30) and 43.8% (95% CI, 32.68‐55.30) of patients, respectively. The median PFS was 5.55 months (95% CI, 4.14‐N/A). SG‐related Grade ≥3 treatment‐emergent adverse events (TEAEs) were reported in 71.3%, the most common were neutrophil count decreased (62.5%), white blood cell count decreased (48.8%) and anemia (21.3%); 6.3% discontinued SG because of TEAEs. SG demonstrated substantial clinical activity in heavily pretreated Chinese patients with mTNBC. The observed safety profile was generally manageable.
What's new?
The novel antibody‐drug conjugate sacituzumab govitecan (SG) targets human trophoblast cell‐surface antigen, overexpression of which has been reported in various solid tumors, including breast cancer. This investigation examined the efficacy and safety of SG in Chinese patients with locally advanced or metastatic triple‐negative breast cancer (mTNBC). SG demonstrated substantial clinical activity and manageable toxicity in heavily pretreated mTNBC patients. More than three‐quarters of SG‐treated patients exhibited tumor shrinkage and half had at least a 30% reduction in target lesion size. The results support the use of SG as a new standard of care for pretreated Chinese patients with mTNBC.
Antibody–drug conjugates (ADCs)—a groundbreaking class of agents for targeted oncological therapies—consist of monoclonal antibodies with strong antigenic specificity coupled with highly active ...cytotoxic agents (also referred to as “payloads”). Over the past 2 decades, breast cancer research has evolved into a focal point for the research and development of ADCs, leading to several recent landmark publications. These advancements are ushering in a transformative era in breast cancer treatment and redefining conventional classifications by introducing a prospective subtype termed “HER2‐low.” The latest iterations of ADCs have demonstrated enhanced efficacy in disease management through the optimization of various factors, notably the incorporation of the bystander effect. These conjugates are no longer limited to the oncogenic driver human epidermal growth factor receptor 2 (HER2). Other antigens, including human epidermal growth factor receptor 3 (HER3), trophoblast cell surface antigen 2 (Trop‐2), zinc transporter ZIP6 (LIV‐1), and folate receptor α (FRα), have recently emerged as intriguing tumor cell surface nondriver gene targets for ADCs, each with one or more specific ADCs that showed encouraging results in the breast cancer field. This article reviews recent advances in the application of ADCs in the treatment of HER2‐low breast cancer. Additionally, this review explores the underlying factors contributing to the impact of target selection on ADC efficacy to provide new insights for optimizing the clinical application of ADCs in individuals with low HER2 expression in advanced breast cancer.
This review explores the underlying factors contributing to the impact of target selection on antibody–drug conjugate efficacy to provide new insights for optimizing the clinical application of antibody–drug conjugates in individuals with low HER2 expression in advanced breast cancer.
Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER‐localized eukaryotic glycoprotein secretion checkpoint, UDP‐glucose glycoprotein glucosyl‐transferase (UGGT). The ...enzyme recognizes a misfolded glycoprotein and flags it for ER retention by re‐glucosylating one of its N‐linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT‐mediated ER retention can cause rare disease, even if the mutant glycoprotein retains activity (“responsive mutant”). Using confocal laser scanning microscopy, we investigated here the subcellular localization of the human Trop‐2‐Q118E, E227K and L186P mutants, which cause gelatinous drop‐like corneal dystrophy (GDLD). Compared with the wild‐type Trop‐2, which is correctly localized at the plasma membrane, these Trop‐2 mutants are retained in the ER. We studied fluorescent chimeras of the Trop‐2 Q118E, E227K and L186P mutants in mammalian cells harboring CRISPR/Cas9‐mediated inhibition of the UGGT1 and/or UGGT2 genes. The membrane localization of the Trop‐2 Q118E, E227K and L186P mutants was successfully rescued in UGGT1−/−cells. UGGT1 also efficiently reglucosylated Trop‐2‐Q118E‐EYFP in cellula. The study supports the hypothesis that UGGT1 modulation would constitute a novel therapeutic strategy for the treatment of pathological conditions associated to misfolded membrane glycoproteins (whenever the mutation impairs but does not abrogate function), and it encourages the testing of modulators of ER glycoprotein folding quality control as broad‐spectrum rescue‐of‐secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants.
“The figure depicts the transformative impact of UGGT1 gene deletion in mammalian cells on the intracellular fate of fluorescent chimeras representing human Trop‐2 Q118E, E227K and L186P glycoprotein mutants, implicated in gelatinous drop‐like corneal dystrophy. In wild‐type cells (UGGT1+/+), the mutants are ensnared within the endoplasmic reticulum (ER), symbolized by the trapped green protein. Conversely, in UGGT1 knockout cells (UGGT1/−), the green protein successfully navigates to the cell membrane, illustrating the rescue of secretion. Notably, the Trop‐2‐Q118E glycoprotein, a disease mutant, undergoes efficient glucosylation by UGGT1 in human cells, establishing its classification as a genuine cellular UGGT1 substrate.
GEORHETORIC Eremchenko, E. N.
InterCarto. InterGIS,
01/2016, Letnik:
2, Številka:
22
Journal Article
Recenzirano
Odprti dostop
There is an opinion that the ultimate goal of a geographical map is accurate reproduction of the World. This is true but it is not a whole truth. Really, one of the function of maps is information ...function. However, any language, including the language of maps, have a number of other non-informational functions. The set of methods for solving such problems in ordinary language is called «rhetoric». Accordingly, a set of similar methods and techniques in cartography we propose to call «georhetoric». The existence of rhetorical techniques in cartography is discussed, some of them are shown, the possible applications of georhetoric, especially in decision support systems, are discussed.
PDF
