12 research outputs found
StructureâActivity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents
Historically known for its role in blood coagulation
and bone formation,
vitamin K (VK) has begun to emerge as an important nutrient for brain
function. While VK involvement in the brain has not been fully explored,
it is well-known that oxidative stress plays a critical role in neurodegenerative
diseases. It was recently reported that VK protects neurons and oligodendrocytes
from oxidative injury and rescues Drosophila from mitochondrial defects associated with Parkinsonâs disease.
In this study, we take a chemical approach to define the optimal and
minimum pharmacophore responsible for the neuroprotective effects
of VK. In doing so, we have developed a series of potent VK analogues
with favorable drug characteristics that provide full protection at
nanomolar concentrations in a well-defined model of neuronal oxidative
stress. Additionally, we have characterized key cellular responses
and biomarkers consistent with the compoundsâ ability to rescue
cells from oxidative stress induced cell death
A Novel Class of Small Molecule Inhibitors of HDAC6
Histone deacetylases (HDACs) are a family of enzymes
that play
significant roles in numerous biological processes and diseases. HDACs
are best known for their repressive influence on gene transcription
through histone deacetylation. Mapping of nonhistone acetylated proteins
and acetylation-modifying enzymes involved in various cellular pathways
has shown protein acetylation/deacetylation also plays key roles in
a variety of cellular processes including RNA splicing, nuclear transport,
and cytoskeletal remodeling. Studies of HDACs have accelerated due
to the availability of small molecule HDAC inhibitors, most of which
contain a canonical hydroxamic acid or benzamide that chelates the
metal catalytic site. To increase the pool of unique and novel HDAC
inhibitor pharmacophores, a pharmacological active compound screen
was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central
naphthoquinone structure, displayed a selective inhibition profile
against HDAC6. Here we present the results of a unique class of HDAC6
inhibitors identified using this compound library screen. In addition,
we demonstrated that treatment of human acute myeloid leukemia cell
line MV4-11 with the selective HDAC6 inhibitors decreases levels of
mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation,
all of which are associated with the inhibitorâs selective
toxicity against leukemia
A Novel Class of Small Molecule Inhibitors of HDAC6
Histone deacetylases (HDACs) are a family of enzymes
that play
significant roles in numerous biological processes and diseases. HDACs
are best known for their repressive influence on gene transcription
through histone deacetylation. Mapping of nonhistone acetylated proteins
and acetylation-modifying enzymes involved in various cellular pathways
has shown protein acetylation/deacetylation also plays key roles in
a variety of cellular processes including RNA splicing, nuclear transport,
and cytoskeletal remodeling. Studies of HDACs have accelerated due
to the availability of small molecule HDAC inhibitors, most of which
contain a canonical hydroxamic acid or benzamide that chelates the
metal catalytic site. To increase the pool of unique and novel HDAC
inhibitor pharmacophores, a pharmacological active compound screen
was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central
naphthoquinone structure, displayed a selective inhibition profile
against HDAC6. Here we present the results of a unique class of HDAC6
inhibitors identified using this compound library screen. In addition,
we demonstrated that treatment of human acute myeloid leukemia cell
line MV4-11 with the selective HDAC6 inhibitors decreases levels of
mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation,
all of which are associated with the inhibitorâs selective
toxicity against leukemia
Engineering antigenâspecific NK cell lines against the melanomaâassociated antigen tyrosinase via TCR gene transfer
Introduction of Chimeric Antigen Receptors to NK cells has so far been the main practical method for targeting NK cells to specific surface antigens. In contrast, T cell receptor (TCR) gene delivery can supply large populations of cytotoxic Tâlymphocytes (CTL) targeted against intracellular antigens. However, a major barrier in the development of safe CTLâTCR therapies exists, wherein the mispairing of endogenous and genetically transferred TCR subunits leads to formation of TCRs with offâtarget specificity. To overcome this and enable specific intracellular antigen targeting, we have tested the use of NK cells for TCR gene transfer to human cells. Our results show that ectopic expression of TCR α/ÎČ chains, along with CD3 subunits, enables the functional expression of an antigenâspecific TCR complex on NK cell lines NKâ92 and YTS, demonstrated by using a TCR against the HLAâA2ârestricted tyrosinaseâderived melanoma epitope, Tyr368â377. Most importantly, the introduction of a TCR complex to NK cell lines enables MHCârestricted, antigenâspecific killing of tumor cells both in vitro and in vivo. Targeting of NK cells via TCR gene delivery stands out as a novel tool in the field of adoptive immunotherapy which can also overcome the major hurdle of âmispairingâ in TCR gene therapy
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Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1+ or NKG2D+ GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1+ or NKG2D+ GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1+ or NKG2D+ GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies
Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease
HCV serine protease NS3 represents
an attractive drug target because it is not only essential for viral
replication but also implicated in the viral evasion of the host immune
response pathway through direct cleavage of key proteins in the human
innate immune system. Through structure-based drug design and optimization,
macrocyclic peptidomimetic molecules bearing both a lipophilic P2
isoindoline carbamate and a P1/P1âČ acylsulfonamide/acylsulfamide
carboxylic acid bioisostere were prepared that possessed subnanomolar
potency against the NS3 protease in a subgenomic replicon-based cellular
assay (Huh-7). Danoprevir (compound <b>49</b>) was selected
as the clinical development candidate for its favorable potency profile
across multiple HCV genotypes and key mutant strains and for its good
in vitro ADME profiles and in vivo target tissue (liver) exposures
across multiple animal species. X-ray crystallographic studies elucidated
several key features in the binding of danoprevir to HCV NS3 protease
and proved invaluable to our iterative structure-based design strategy
StructureâActivity Relationship Study of Vitamin K Derivatives Yields Highly Potent Neuroprotective Agents
Introduction STATE OF THE CLIMATE IN 2022
Abstract
âJ. BLUNDEN, T. BOYER, AND E. BARTOW-GILLIES
Earthâs global climate system is vast, complex, and intricately interrelated. Many areas are influenced by global-scale phenomena, including the âtriple dipâ La Niña conditions that prevailed in the eastern Pacific Ocean nearly continuously from mid-2020 through all of 2022; by regional phenomena such as the positive winter and summer North Atlantic Oscillation that impacted weather in parts the Northern Hemisphere and the negative Indian Ocean dipole that impacted weather in parts of the Southern Hemisphere; and by more localized systems such as high-pressure heat domes that caused extreme heat in different areas of the world. Underlying all these natural short-term variabilities are long-term climate trends due to continuous increases since the beginning of the Industrial Revolution in the atmospheric concentrations of Earthâs major greenhouse gases.
In 2022, the annual global average carbon dioxide concentration in the atmosphere rose to 417.1±0.1 ppm, which is 50% greater than the pre-industrial level. Global mean tropospheric methane abundance was 165% higher than its pre-industrial level, and nitrous oxide was 24% higher. All three gases set new record-high atmospheric concentration levels in 2022.
Sea-surface temperature patterns in the tropical Pacific characteristic of La Niña and attendant atmospheric patterns tend to mitigate atmospheric heat gain at the global scale, but the annual global surface temperature across land and oceans was still among the six highest in records dating as far back as the mid-1800s. It was the warmest La Niña year on record. Many areas observed record or near-record heat. Europe as a whole observed its second-warmest year on record, with sixteen individual countries observing record warmth at the national scale. Records were shattered across the continent during the summer months as heatwaves plagued the region. On 18 July, 104 stations in France broke their all-time records. One day later, England recorded a temperature of 40°C for the first time ever. China experienced its second-warmest year and warmest summer on record. In the Southern Hemisphere, the average temperature across New Zealand reached a record high for the second year in a row. While Australiaâs annual temperature was slightly below the 1991â2020 average, Onslow Airport in Western Australia reached 50.7°C on 13 January, equaling Australia's highest temperature on record.
While fewer in number and locations than record-high temperatures, record cold was also observed during the year. Southern Africa had its coldest August on record, with minimum temperatures as much as 5°C below normal over Angola, western Zambia, and northern Namibia. Cold outbreaks in the first half of December led to many record-low daily minimum temperature records in eastern Australia.
The effects of rising temperatures and extreme heat were apparent across the Northern Hemisphere, where snow-cover extent by June 2022 was the third smallest in the 56-year record, and the seasonal duration of lake ice cover was the fourth shortest since 1980. More frequent and intense heatwaves contributed to the second-greatest average mass balance loss for Alpine glaciers around the world since the start of the record in 1970. Glaciers in the Swiss Alps lost a record 6% of their volume. In South America, the combination of drought and heat left many central Andean glaciers snow free by mid-summer in early 2022; glacial ice has a much lower albedo than snow, leading to accelerated heating of the glacier. Across the global cryosphere, permafrost temperatures continued to reach record highs at many high-latitude and mountain locations.
In the high northern latitudes, the annual surface-air temperature across the Arctic was the fifth highest in the 123-year record. The seasonal Arctic minimum sea-ice extent, typically reached in September, was the 11th-smallest in the 43-year record; however, the amount of multiyear iceâice that survives at least one summer melt seasonâremaining in the Arctic continued to decline. Since 2012, the Arctic has been nearly devoid of ice more than four years old.
In Antarctica, an unusually large amount of snow and ice fell over the continent in 2022 due to several landfalling atmospheric rivers, which contributed to the highest annual surface mass balance, 15% to 16% above the 1991â2020 normal, since the start of two reanalyses records dating to 1980. It was the second-warmest year on record for all five of the long-term staffed weather stations on the Antarctic Peninsula. In East Antarctica, a heatwave event led to a new all-time record-high temperature of â9.4°Câ44°C above the March averageâon 18 March at Dome C. This was followed by the collapse of the critically unstable Conger Ice Shelf. More than 100 daily low sea-ice extent and sea-ice area records were set in 2022, including two new all-time annual record lows in net sea-ice extent and area in February.
Across the worldâs oceans, global mean sea level was record high for the 11th consecutive year, reaching 101.2 mm above the 1993 average when satellite altimetry measurements began, an increase of 3.3±0.7 over 2021. Globally-averaged ocean heat content was also record high in 2022, while the global sea-surface temperature was the sixth highest on record, equal with 2018. Approximately 58% of the ocean surface experienced at least one marine heatwave in 2022. In the Bay of Plenty, New Zealandâs longest continuous marine heatwave was recorded.
A total of 85 named tropical storms were observed during the Northern and Southern Hemisphere storm seasons, close to the 1991â2020 average of 87. There were three Category 5 tropical cyclones across the globeâtwo in the western North Pacific and one in the North Atlantic. This was the fewest Category 5 storms globally since 2017. Globally, the accumulated cyclone energy was the lowest since reliable records began in 1981. Regardless, some storms caused massive damage. In the North Atlantic, Hurricane Fiona became the most intense and most destructive tropical or post-tropical cyclone in Atlantic Canadaâs history, while major Hurricane Ian killed more than 100 people and became the third costliest disaster in the United States, causing damage estimated at $113 billion U.S. dollars. In the South Indian Ocean, Tropical Cyclone Batsirai dropped 2044 mm of rain at Commerson Crater in RĂ©union. The storm also impacted Madagascar, where 121 fatalities were reported.
As is typical, some areas around the world were notably dry in 2022 and some were notably wet. In August, record high areas of land across the globe (6.2%) were experiencing extreme drought. Overall, 29% of land experienced moderate or worse categories of drought during the year. The largest drought footprint in the contiguous United States since 2012 (63%) was observed in late October. The record-breaking megadrought of central Chile continued in its 13th consecutive year, and 80-year record-low river levels in northern Argentina and Paraguay disrupted fluvial transport. In China, the Yangtze River reached record-low values. Much of equatorial eastern Africa had five consecutive below-normal rainy seasons by the end of 2022, with some areas receiving record-low precipitation totals for the year. This ongoing 2.5-year drought is the most extensive and persistent drought event in decades, and led to crop failure, millions of livestock deaths, water scarcity, and inflated prices for staple food items.
In South Asia, Pakistan received around three times its normal volume of monsoon precipitation in August, with some regions receiving up to eight times their expected monthly totals. Resulting floods affected over 30 million people, caused over 1700 fatalities, led to major crop and property losses, and was recorded as one of the worldâs costliest natural disasters of all time. Near Rio de Janeiro, Brazil, PetrĂłpolis received 530 mm in 24 hours on 15 February, about 2.5 times the monthly February average, leading to the worst disaster in the city since 1931 with over 230 fatalities.
On 14â15 January, the Hunga Tonga-Hunga Ha'apai submarine volcano in the South Pacific erupted multiple times. The injection of water into the atmosphere was unprecedented in both magnitudeâfar exceeding any previous values in the 17-year satellite recordâand altitude as it penetrated into the mesosphere. The amount of water injected into the stratosphere is estimated to be 146±5 Terragrams, or âŒ10% of the total amount in the stratosphere. It may take several years for the water plume to dissipate, and it is currently unknown whether this eruption will have any long-term climate effect.</jats:p