text:
Page 1
© 2008 Chen et al.
The Rockefeller University Press $30.00
J. Cell Biol. Vol. 181 No. 7 1129–1139
Correspondence to Kai Chen: firstname.lastname@example.com
Abbreviations used in this paper: EGFR, EGF receptor; ERK, extracellular signal-
regulated kinase; HAEC, human aortic endothelial cell; MEF, mouse embryonic
fi broblast; MSP, mitochondrial signal peptide; NO, nitric oxide; NOS, NO syn-
thase; Nox, NADPH oxidase; PTP, protein tyrosine phosphatase; ROS, reactive
oxygen species; VE, vascular endothelial.
There is now considerable evidence indicating that reactive
oxygen species (ROS) are involved in signal transduction. These
species include the three successive reduction products of molec-
ular oxygen such as superoxide ( • O 2 ? ), hydrogen peroxide
(H 2 O 2 ), and hydroxyl radical ( • OH). Each of these species pos-
sesses chemical properties that potentially impact their signal-
ing function. For example, OH • is the most unstable ROS with
a half-life of 10 ? 9 s ( Pryor, 1986 ), indicating that it will react
with any species within a radius of ? 30 Å , thereby limiting
its ability to transmit signals across any signifi cant distance.
Superoxide carries a negative charge that limits its membrane
permeability to anion channels. In contrast, H 2 O 2 is thought to
be freely permeable and, thus, could react with several intra-
and extracellular targets, limiting its specifi city; however, this
concept has recently been challenged ( Branco et al., 2004 ).
Thus, the chemical properties of ROS suggest signifi cant limi-
tations toward the production of specifi c cellular responses.
The prototypical NADPH oxidase (Nox) family member
is Nox2 (also known as gp91 phox ), which was initially found in
phagocytes and plays a role in host defense by giving an outward
burst of ROS ( Cheng et al., 2001 ). Over the last several years,
Nox2 along with its homologues, including Nox1, Nox3, Nox4,
Nox5, Duox1, and Duox2, have been identifi ed in nonphago-
cytes. It now appears that Noxs in nonphagocytes serve as a major
source of intracellular ROS that play important signaling roles.
However, the complexity of these isoforms in controlling ROS
production is increasingly apparent because each isoform has its
unique expression pattern, subcellular localization, and subunits
requirement. The specifi c mechanisms for specifi c cell signaling
responses are not known; therefore, the goal of this study is to
examine the mechanisms of ROS signaling specifi city.
Exogenous versus endogenous sources of
ROS initiate distinct signaling responses
ROS are known to mediate a variety of cellular signaling path-
ways, and experiments in vitro typically use an exogenous
source of ROS such as H 2 O 2 to directly initiate signaling re-
sponses. However, one must consider that exogenous applica-
tion of H 2 O 2 may not adequately refl ect authentic endogenous
ROS signaling. Indeed, exogenous H 2 O 2 produces broad signal-
ing responses, including the activation of extracellular signal-
regulated kinase (ERK), JNK, p38 MAPKs ( Fig. 1 A ), and Akt
( Thomas et al., 2002 ). In contrast, the EGF-stimulated signaling
response, which is known to be mediated by ROS in epithelial
cells ( Bae et al., 1997 ), was restricted to the mitogenic ERK path-
way ( Fig. 1 B ) in endothelial cells. We found that EGF-induced
diffusible ROS dictate specifi c cellular responses. In this
study, we demonstrate that nicotinamide adenine dinucle-
otide phosphate reduced oxidase 4 (Nox4), a major Nox
isoform expressed in nonphagocytic cells, including vascu-
lar endothelium, is localized to the endoplasmic reticulum
(ER). ER localization of Nox4 is critical for the regulation
of protein tyrosine phosphatase (PTP) 1B, also an ER resi-
eactive oxygen species (ROS) function as intracellu-
lar signaling molecules in a diverse range of bio-
logical processes. However, it is unclear how freely
dent, through redox-mediated signaling. Nox4-mediated
oxidation and inactivation of PTP1B in the ER serves as a
regulatory switch for epidermal growth factor (EGF) re-
ceptor traffi cking and specifi cally acts to terminate EGF
signaling. Consistent with this notion, PTP1B oxidation
could also be modulated by ER targeting of antioxidant
enzymes but not their untargeted counterparts. These data
indicate that the specifi city of intracellular ROS-mediated
signal transduction may be modulated by the localization
of Nox isoforms within specifi c subcellular compartments.
Regulation of ROS signal transduction by NADPH
oxidase 4 localization
Kai Chen , Michael T. Kirber , Hui Xiao , Yu Yang , and John F. Keaney Jr.
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605
Page 2
lation induced by EGF, whereas Nox2 suppression had no mate-
rial impact ( Fig. 1 F ). Together, these data implicate endothelial
Nox4 as an endogenous source of ROS in mediating EGF-
induced signaling responses.
Nox4 is an ER-residing protein
To gain insight into the nature of Nox4, we examined its sub-
cellular localization. The topography of Nox4 was examined in
silico initially using PredictProtein (Columbia University), and
it possesses six putative membrane-spanning regions, predicting
ERK activation was attenuated by catalase overexpression ( Fig. 1,
C and D ), indicating a role for ROS and a distinction between
endogenous and exogenous ROS signaling.
To examine endogenous ROS responses in the endothe-
lium, we suppressed the expression of Nox4 and Nox2, the two
major Nox isoforms present in endothelial cells ( Sorescu et al.,
2002 ), using RNAi. As shown in Fig. 1 E , both Nox4 and Nox2
siRNA substantially reduced their respective mRNA and protein
levels without cross-reactivity by > 75% and 60%, respectively.
We found that suppression of Nox4 attenuated ERK phosphory-
Figure 1. A different source of ROS initiates distinct signaling responses in endothelial cells. (A) HAECs were treated with 100 μ M H 2 O 2 for the indicated
times, and total cell lysates were subjected to antibodies specifi c for pERK, ERK, pcJun, cJun, pp38, or p38. (B) HAECs were treated with 50 ng/ml EGF for the
indicated times followed by immunoblotting with antibodies as in A. (C and D) Cells were treated with control adenovirus (Ad-LacZ) or catalase-overexpressing
adenovirus (Ad-Cat) for 24 h before treatment with EGF followed by immunoblotting as in A. Error bars represent SD. *, P < 0.05. (E and F) HAECs were trans-
fected with siRNA against nontargeting control (NT), Nox4, or Nox2 for 48 h before extraction of total RNA for RT-PCR and Western blotting (E) or treatment with
EGF for 15 min followed by immunoblotting with pERK, ERK, Nox4, and Nox2 antibodies (F). Results are representative of four independent experiments.
Page 3
1131NADPH OXIDASE 4 REGULATES REDOX SIGNALING • Chen et al.
when COS-7 cells were examined after transfection with either
V5- or myc-tagged Nox4, identical results were obtained regard-
less of whether the tag was C or N terminal (unpublished data).
Finally, using immunogold electron microscopy in HAECs trans-
fected with adenoviral V5-tagged Nox4 ( Fig. 2 C ), we observed
gold particles predominantly in the ER membrane. To confi rm
the aforementioned results, a biochemical analysis of sub-
cellular fractionation was performed in Nox4-V5 – overexpressing
cells and revealed that Nox4-V5 was mainly detected in the frac-
tion of membrane/organelle that coincides with the ER marker
GRP78 ( Fig. 2 D ) but not with other intracellular markers, in-
cluding SHP-2 as a cytoplasmic marker, histone H4 as a nuclear
marker, and vimentin as a cytoskeletal marker ( Higashi et al., 2002 ).
Similarly, analysis by nonlinear Nycodenz density gradient
an integral membrane protein similar to Nox2. Further in silico
analysis based on the Nox4 amino acid sequence using the
PSORT II program (Human Genome Center, Tokyo University)
and the k -nearest neighbor algorithm placed the probability of
Nox4 localizing to the ER at 67%, whereas the probability
of localization in plasma membrane, mitochondria, or the Golgi
was only 11% each. Consistent with this prediction, confocal
microscopy revealed a perinuclear distribution of endogenous
Nox4 with colocalization with the ER marker protein GRP78
( Fig. 2 A ). These data were confi rmed using transfection with
V5-tagged Nox4 by adenoviral vector in human aortic endo-
thelial cells (HAECs; Fig. 2 B ). There was no localization to
the plasma membrane, as evident by staining for the plasma
membrane marker vascular endothelial (VE) cadherin. Moreover,
Figure 2. Nox4 is localized to the ER.
(A) HAECs cultured in EBM2 medium were fi xed
and subjected to immunostaining with anti-
Nox4 (AlexaFluor488; green) and anti-GRP78
(AlexaFluor594; red) followed by two-photon
confocal microscopy. (B) HAECs were trans-
fected with adenoviral vector expressing Nox4-V5
(AdNox4-V5). After 24 h, cells were probed
with anti-V5 and VE-cadherin antibodies and
visualized with AlexaFluor594 (red) and Alexa-
Fluor488 (green), respectively. (C) Cells were
transfected with AdNox4-V5 as in B followed
by immunogold staining and were visualized by
electron microscopy. (D and E) Similarly, HAECs
with overexpression of Nox4-V5 were fraction-
ated by biochemical detergent method (D) or
Nycodenz gradient centrifugation (E). The ob-
tained fractions cytosolic (Cyto), membrane/
organelle (MO), nuclear (Nuc), and cytoskeletal/
matrix (CSK/MAT) in D or fractions from top to
bottom in E were subjected to immunoblotting
with antibodies. Bars: (A) 5 μ m; (B) 10 μ m.
Page 4
tyrosine phosphatases (PTPs). Because PTP1B is an ER-resident
protein and its C-terminal 35 amino acid residues are critical for
ER targeting ( Frangioni et al., 1992 ; Salmeen et al., 2003 ; van
Montfort et al., 2003 ), we fi rst overexpressed PTP1B wild type
(PTP1B) and a mutant lacking the C-terminal 35 amino acids
(PTP1B- ? 35) in COS-7 cells and observed their distinct cellular
localization. Although the wild-type PTP1B shows strong peri-
nuclear colocalization with Nox4, the mutant PTP1B exhibits
diffuse cytoplasmic distribution ( Fig. 3 A ) and predominant
centrifugation revealed that Nox4-V5 is present in fractions that
are enriched with the ER marker GRP78 but not the Golgi marker
GS-28 ( Fig. 2 E ). Collectively, these data establish that Nox4 is
localized to the ER of endothelial cells.
Nox4-dependent redox regulation of
PTP1B requires colocalization
Signaling via ROS is thought to be mediated by regulation of
the redox-sensitive cysteine of target proteins, including protein
Figure 3. PTP1B oxidation by Nox4 is spatially dependent. (A) COS7 cells were transfected with pcDNA3.1/PTP1B wild type or pcDNA3.1/PTP1B- Δ 35
in addition to pcDNA3.1/Nox4-V5. After 24 h, cells were fi xed and immunostained with anti-V5 (green) for Nox4-V5 and anti-PTP1B for PTP1B wild
type and C-terminal deleted PTP1B- Δ 35 (red). (B) Cells transfected as in A were also subjected to detergent fractionation followed by immunoblotting with
anti-PTP1B and anti-GRP78. Fractions include cytosolic (Cyto), membrane/organelle (MO), nuclear (Nuc), and cytoskeletal/matrix (CSK/MAT). (C) COS-7
cells treated as in A were lysed and labeled with biotin polyethylene oxide maleimide. Subsequent immunoprecipitation with avidin followed by immuno-
blotting with anti-PTP1B yields a band that represents the reduced, active form of PTP1B. (D) COS-7 cells were transfected with pcDNA3.1/Nox4-V5 or its
Nox4i-resistant version pcDNA3.1/Nox4-R in combination with/without pQ/Nox4i. PTP1B oxidation was assessed as in C, and the effi ciency of Nox4
knockdown was probed by V5. Total cellular PTP1B is shown in the bottom panel. (E and F) HAECs were transfected with Ad-control siRNA (Ad-Ctli) or
Ad-Nox4i for 48 h before lysis and labeling with biotin polyethylene oxide maleimide. Treatment of cells with H 2 O 2 at 100 μ M for 5 min served as a
positive control. Blots are representative of three independent experiments. Error bars represent SD. *, P < 0.05. Bar, 10 μ m.
Page 5
1133 NADPH OXIDASE 4 REGULATES REDOX SIGNALING • Chen et al.
suggesting an involvement of Nox4 in EGFR signaling at the late
phase. To determine whether the regulation of EGFR phosphory-
lation by Nox4 is mediated by PTP1B, we transfected COS-7
cells with PTP1B in the presence or absence of Nox4. Over-
expression of PTP1B enhanced EGFR dephosphorylation at
30 min after EGF treatment. In contrast, the late component
of EGFR ( Fig. 4 B ) and ERK ( Fig. 4 C ) phosphorylation was
enhanced in cells with Nox4 overexpression compared with
PTP1B alone. Concerning the presence of endogenous PTP1B
in COS-7 cells, we further used immortalized PTP1B ? / ? mouse
embryonic fi broblasts (MEFs) along with PTP1B ? / ? (+WT) MEFs
in which PTP1B has been reconstituted in PTP1B ? / ? MEFs.
Consistent with the fi ndings in COS-7 cells, Nox4 overexpres-
sion prolonged EGFR phosphorylation in PTP1B ? / ? (+WT) MEFs
( Fig. 4 D ). These results suggest Nox4-mediated regulation of
EGFR dephosphorylation via PTP1B.
To address the spatial requirements of Nox4 in regulating
EGFR signaling, we overexpressed PTP1B- Δ 35 ( Frangioni et al.,
1993 ) and observed reduced EGFR phosphorylation ( Fig. 4 B ).
However, Nox4 overexpression did not modify the effect of
PTP1B- Δ 35 on EGFR dephosphorylation and subsequent ERK
activation status ( Fig. 4 C ). Further study with the cotransfec-
tion of Nox4 and PTP1B wild type/PTP1B- Δ 35 in PTP1B ? / ?
MEFs supported PTP1B wild type being the target of Nox4 in
regulation of EGFR dephosphorylation ( Fig. 4 E ). In contrast,
Nox4 was not effective in modulating the effect of PTP1B- Δ 35
( Fig. 4 B ). Thus, these data support the notion that colocalization
of PTP1B and Nox4 in the ER is essential for redox regulation
of EGFR signaling in various cell types, including endothelial
cells ( Fig. 4 F ).
Oxidation of PTP1B trapping mutant
by Nox4 attenuates its substrate-
binding capacity
To gain insight into the mechanism of Nox4-mediated modu-
lation of PTP1B activity, we used substrate-trapping PTP1B
mutant that retains substrate-binding activity but cannot com-
plete the catalytic cycle and release the substrate ( Tonks, 2003 ).
Indeed, COS-7 cell transfection with the PTPT1B trapping mu-
tant (D181A/Q262A) produces an increase in phosphorylation of
the EGFR that is enhanced after treatment with EGF ( Fig. 5 A ).
Because the mutant PTP1B(D181A/Q262A) features disrupted
trapping ability upon oxidation ( Salmeen et al., 2003 ), we then
sought to evaluate the involvement of Nox4-derived ROS in this
setting. Overexpression of Nox4 in this system attenuated EGFR
tyrosine phosphorylation at basal condition and after EGF
stimulation ( Fig. 5 A ). The localization of EGFR visualized by
using an enhanced GFP-EGFR expression vector was consistent
with EGFR mobilization to the ER induced by PTP1B(D181A/
Q262A) as a result of substrate trapping, which was reversed
by Nox4 overexpression ( Fig. 5 B ). In agreement with this
observation, the interaction between EGFR and PTP1B(D181A/
Q262A) was evident but greatly attenuated by the presence of
Nox4 as determined by pull-down assay ( Fig. 5 C ). Thus, these
data suggest that Nox4-derived ROS mediate the oxidation
status/trapping ability of PTP1B(D181A/Q262A) in relation
to EGFR.
relocation to the cytosol by detergent fractionation ( Fig. 3 B ).
Other than the location, PTP1B- ? 35 has retained its enzymatic
activity and indeed has shown a slightly higher activity compared
with wild-type PTP1B ( Frangioni et al., 1992 ). This property
prompted us to determine whether PTP1B is subject to oxida-
tive modifi cation by Nox4 in a spatially dependent manner.
Using the preceding cotransfection system, we assessed the
PTP1B oxidation status with biotin maleimide as a function of co-
overexpressed Nox4 level. Biotin maleimide irreversibly alkylates
SH ? groups on the active cysteine of PTP1B, and, therefore,
its PTP1B incorporation refl ects the amount of reduced PTP1B.
As shown in Fig. 3 C , coexpression of Nox4 with both PTP1B
wild type and PTP1B- ? 35 led to less reduced PTP1B (PTP1B-S ? )
only in wild-type PTP1B, which is consistent with more oxi-
dation. However, there was no material change in PTP1B- ? 35
oxidation with or without Nox4 overexpression ( Fig. 3 C ),
suggesting that cytosolic PTP1B is not subject to oxidation
by Nox4.
To further validate the Nox4-dependent PTP1B oxidation
by rescue experiment, we constructed an RNAi-producing vec-
tor targeting wild-type Nox4 (pQ/Nox4i) and an RNAi-resistant
Nox4 overexpression vector (pcDNA3.1/Nox4-R) containing
silent mutations in the RNAi target region but encoding wild-
type Nox4 protein. Immunoblot analysis verifi ed that Nox4 from
pcDNA3.1/Nox4-V5 could be effi ciently knocked down by
pQ/Nox4i, whereas pcDNA3.1/Nox4-R was indeed resistant to
Nox4i. Further examination of PTP1B wild-type redox status
revealed increased oxidation (less reduced form) in association
with Nox4 overexpression, which was attenuated by the pres-
ence of Nox4i. In contrast, the effect of Nox4-R, the Nox4i-
resistant version of wild-type Nox4, on PTP1B oxidation was
equivalent to that of the wild-type Nox4 but was unaltered by
Nox4i ( Fig. 3 D ), suggesting the specifi city of Nox4i and con-
sistency of Nox4-dependent PTP1B oxidation. To recapitulate
this interaction in HAECs, we used Ad-Nox4i originated from
pQ/Nox4i and found that suppression of Nox4 by RNAi in
HAECs was associated with more of the reduced form of PTP1B
(PTP1B-S ? ), whereas H 2 O 2 treatment attenuated the band inten-
sity ( Fig. 3, E and F ), indicating the Nox4-dependent oxidation
of PTP1B in endothelial cells. Together, these results further
support the notion that colocalization is essential for redox-
dependent regulation.
Nox4-dependent PTP1B oxidation is
involved in EGFR dephosphorylation
One action of PTP1B is the negative regulation of multiple
receptor tyrosine kinases, including the EGF receptor (EGFR;
Flint et al., 1997 ; Liu and Chernoff, 1997 ), in part through re-
ceptor endocytosis to a dephosphorylation compartment within
the ER ( Haj et al., 2002 ). To probe Nox4 involvement in regu-
lating EGFR phosphorylation, we initially transfected COS-7
cells with Nox4 and examined EGF-stimulated EGFR tyrosine
phosphorylation. As shown in Fig. 4 A , EGF treatment pro-
duced early robust EGFR phosphorylation at 5 min, which was
attenuated at 30 min. Overexpression of Nox4 enhanced the
phosphorylation of both EGFR and downstream ERK at 30 min
after EGF treatment with little impact on the early response,


text:
Myths have fuelled much of outside perceptions of the Greek crisis. From the lazy Greeks to the runaway shadow economy, observers have sought explanations for the country's problems in these contrived and skewed observations on life in Greece. Like all fairy tales, though, they make for a good story but are rarely a true reflection of reality.
Scooped by
Luca Baptista
onto Gavagai

subset: commoncrawl


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We know, this week was a busy one: with the Northeast's warm weather and everyone else celebrating St. Patrick's Day—how dare NBC show their comedies on the same night?!—so here's a roundup of everything you may have missed.
Here's a treat from last night's edition of Late Night: Jimmy Fallon performing as Bob Dylan and singing the Charles in Charge theme song. Note that his impression of Dylan is just as good as his impression of Neil Young.
Today Paula Deen filled in for Kathie Lee and shared her personal speculations about her future grandchildren's sonograms: seeing a "big round, rosebud" and "two little balls." The proud Grandma exclaimed, "We gonna have three buttholes and six balls by July!"
Tiger Woods visited Late Night for the first time in a year and a half last night. Immediately, Fallon thanked Woods for having the courage to appear on his show again—and then apologized for a year's worth of jokes about him.
Let me begin by saying that I thought I was "hip" to what the kids were listening to—until I tuned into this college-targeted awards show last night. Regardless, Community's Don Glover provided entertainment for the rest of us.
Can't say we blame Mindy for breaking while filming scenes with Will Ferrell. So what does she channel to fight off the giggles? An awful YouTube video of a woman throwing a cat into a bag and then a river. Sound familiar?
Love her or hate her, Olivia Munn took Kathie Lee's chair today and was just as annoying—or wonderful, if you like her—as she was last time. Watch as she sucks from a wine rack and declares that what she did was Soup-worthy. We'll see, Olivia. We'll see.
It's finally over! Brad Womack's second chance at love has come and gone-and ended in quite a complicated fashion! He proposes to Emily—who accepts—but we discover in the After the Final Rose special that things aren't exactly "peachy" now.
Last night, Jimmy Kimmel Live aired its sequel to the "Hottie Body Hump Club" (the female response to the Handsome Men's Club that had Lindsay Lohan's kind-of comeback.) Here's part two—featuring many more "hotties" and Neil Patrick Harris!
On this morning's Access Hollywood Live, Tyra responded to Kit Hoover's compliment about her outfit by sharing her struggle: "Where do you put them when you have boobs? Over the boob or on the side of the boob?"
On Late Night, Amy Poehler proposed a way that would make the show even more hilarious. Have Bill Murray play the mayor. Since Bill Murray has no representation or accessible contact information, Amy had to ask him on national television.
And we're just getting started! Many, many more of this week's not-to-be-missed TV moments, after the jump...
With all G4TV regulars busy on location, Danny Pudi and Alison Brie from Community usurped the hosting duties on Attack of the Show! yesterday, and it was AWESOME.
Ted Danson appeared on Late Night to promote his new eco-friendly book, so the show went dark and held the interview using only two flashlights. We also got a glimpse of Ted and Mary Steenburgen's farewell tape for Steve Carell.
On Regis and Kelly, Jason Bateman outed himself as a "belieber" after having seen Never Say Never with his daughter. While Kelly similarly had an emotional experience with the film, Regis chides, "You're Jason Bateman, man, pull yourself together!"
Given that Martha had never been on Craig Ferguson's show, she couldn't help but comment on the little man painted in gold or the fake horse named Secretariat that they keep backstage.
Pawnee finally held its Harvest Festival , but not without a few bumps in the road on the way. Leslie is in the unfortunate position of putting on a "cursed" event, and the local news has a Taiwanese animation to prove it!
Not everyone is aware that James Lipton's Inside The Actors Studio is also a class that acting students attend regularly. Last night on the Late Show, Bradley Cooper revealed the time he embarrassed himself in front of Robert De Niro.
On Jimmy Kimmel Live, the host grilled Adam Scott about a slew of magazine appearances: the first, being the Entertainment Weekly cover that he was mysteriously absent from, a new cover featuring just his "family," and his sleek spread for GQ.
Not only is Steve Martin a comedy icon; he's also an accomplished bluegrass musician. On The View, he shared how he keeps his banjo picking fingers in great shape—by getting acryllic nails at the nail salon, of course!
After Jimmy Kimmel called Wiig the "Kobe Bryant of SNL," Kristen humbly spoke about the inspirations of her characters. Yes, Target Lady was real woman who worked at the Burbank Target, but Gilly was a creation all her own.
The Office's Amy Ryan insists that knowing there's a proposal on the way will not spoil anything, saying that it "happens in true Michael Scott fashion" and that it took the show's crew two days to clean up after filming.
Happy St. Patrick's Day ladies and germs! Spring is nigh and Tyra has officially dropped the Banks from her name. It's good to be alive.
On The View, Joy told Marisa Tomei that Lady Gaga had suggested her for the starring role in a future Gaga biopic. Turns out, Marisa's game for the challenge, considering they're both Italian...and they already share the same wardrobe.
Is there a lack of improvisation in your life? Do you miss the days of Whose Line Is It Anyway? Seeing Drew Carey in your primetime lineup? If you said yes to any of these, this is your lucky day.
Howard usually doesn't appear on a talk show unless he meets with his psychiatrist first, which might explain his rant. He goes off about Conan, The Tonight Show, and Late Night after calling himself a "student of late night television."
On last night's Community, Shirley enlisted the help of Jeff to get Chang to hand over his parental rights to his maybe-baby—but ended up inspiring him to become an adult instead.
Walking haircut Billy Ray Cyrus stopped by The View to discuss how fame has destroyed his family. Word of advice, Billy Ray? Things won't get better if you keep giving interviews about your daughter on national television.
Simon Pegg stopped by The Tonight Show to promote his upcoming alien flick, Paul. He discusses America's fascination with the Royal Wedding and how he'd like to Knight himself.
"Check out this boring wicker ball I made. PSYCH. It's actually an adorable armadillo. You're welcome." - Martha Stewart
When Archer goes with Mallory to get her breast cancer test results back, the doctor gives Mallory a clear bill of health-and finds a lump in Archer's chest instead.
Let's take a moment to celebrate everyone's favorite type of drunken spectacle—the kind captured live on television. Here, we've compiled some of the greatest tanked TV news moments, proving that live reporting and alcohol shouldn't mix.
Is it really any surprise that Ashley is the next Bachelorette? She was definitely a fan-favorite from the very first date of this season of The Bachelor, and seemed just a little too excited to be at last week's reunion.
SNL's resident alien Bill "Greg" Hader plays an ET-hunting G-man in Paul, but in reality he's comfortingly nerdy, bonding with the film's cast over comics and re-enacting all of the other iconic movies filmed in Las Vegas, New Mexico.


text:
Helping Single Parents Build a Better Life
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Mom's House is searching for a part-time/substitute teacher beginning August 24, 2015. Hours are Wednesdays from 7:30-3:30 and the flexibility to cover other hours as needed. Please contact Colleen Gawlas, Program Director for more information.
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Release Date:
September 1, 2001
Date Published:
September 1, 2001
"George and Harold have really done it this time--they've created a monster! She's faster, smarter, and more evil than anything the world has seen before--she's Wedgie Woman! With the help of her horrible robots and her horrendous hairdo, Wedgie Woman is on a mission to take over the world, and she'll give a whopping wedgie to anyone who stands in her way--including Captain Underpants."--P. [4] of cover.When Harold and George turn fourth-grade teacher Ms. Ribble into the evil Wedgie Woman, she gives the wedgie of doom to unsuspecting people who stand in her way--including principal-turned-superhero Captain Underpants.
In this fifth book in the Captain Underpants series, George and Harold create a monster--a monster faster, stronger and smarter than anything else in the world, a monster named Wedgie Woman. Now on a mission to take over the world, Wedgie Woman runs wild--giving anyone who crosses her path a wedgie. Will Captain Underpants be able to step in and save the world from the horrible Wedgie Woman? Bw ink drawings accompany the text of this chapter book.
Genre: Juvenile Fiction
Sub-Genre: General, School + Education
- Genre: Juvenile Fiction
- Subgenre: General, School + Education
- Age: 9-12 years
- Language: English
- Author: Dav Pilkey
other Info.
- Online Item #: 11995937
- Store Item Number (DPCI): 248-32-1483
- Item can be gift wrapped.
- Made in the USA or Imported


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Scanning Device not Communicat
ing with the Computer
Can anyone help? I go to launch my Hp Director software to scan a document and an error message appears that says "An error occurred communicating with the scanning device. Please ensure that the scanning device is connected properly and try again." This has happened before but I can't remember the steps performed on the Menu of the scanner. Does anyone know how to get the computer and Laserjet 2840 to communicate?
Re: Scanning Device not Communicat
ing with the Computer
Download the HP LaserJet Fix Scan Utility : Fixes errorrs: "Can't Communicate", "Device Not Connected", or "HPImaging Device Could Not Be Initialized" messages when scanning due to the scanner port being set incorrectly or the IP Address being changed in a network environment.
Re: Scanning Device not Communicat
ing with the Computer
Re: Scanning Device not Communicat
ing with the Computer
I also have a communication problem with the "error message" about not communicating on my computer screen. However, the All-in-One (HP 7310) shows a message that scanning software is not installed.
When I try and re-install the software from the CD, the HP software tells me that there is hardware recognition and I don't need to install, but gives me no options to repair.
I downloaded the utility for scanning from HP and run it. It shows that no scanning software is installed. Any suggestions.
Re: Scanning Device not Communicat
[ Edited ]
ing with the Computer
12-31-2010 02:24 PM - last edited on 12-31-2010 03:57 PM by MrMatthew
I have the same problem. However, that "fixit" software is not for my scanner. I have an hp flatbed scanjet 4600. It worked on my old computer. I bought a new computer about a month ago, installed the software from the CD, and when I try to use the scanner, I get that dredded message: "An error occurred communicating with the scanning device. Please ensure that the scanning device is connected properly and try again."
Is there a solution? My computer is a pretty decent, new PC laptop, running Windows 7 Professional.
Thanks for any ideas: [Personal Information Removed]
Re: Scanning Device not Communicat
ing with the Computer
For me, all I had to do was disconnect and reconnect the USB that connected my computer to my printer/scanner. Hope this helps some people, if not all...
Re: Scanning Device not Communicat
ing with the Computer
AlmostThere wrote:If the error message appears on the computer while scanning from a networked product, click this link: http://h10025.www1.hp.com/ewfrf/wc/document?lc=en&
dlc=en&cc=au&product=3204785&docname=c00897542. If with USB, click this link: http://h10025.www1.hp.com/ewfrf/wc/document?docnam e=c00040499&cc=au&lc=en&dlc=en&product=3204785Regards,AlmostThere
your link @ http://h10025.www1.hp.com/ewfrf/wc/document?lc=en&
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text:
Paper Jamz amps and drums bring the noise
We've already found out about Paper Jamz, a range of cardboard electronic guitars that are likely to be one of the top gadget toys come Christmas, but now WowWee, the company behind them, is ready to unleash the fury of Paper Jamz Drums and a range of Amps to share the noise as well.
For those that need a quick refresher, Paper Jamz Guitars (£25) are a range of cardboard guitars that have no strings, but still let you play three tracks a piece as if they were a real guitar. Thanks to sensors behind the paper covers, you can finger and strum your way to a decent tune on three difficult levels by choosing to turn off certain help features.
We grabbed a demo off someone that could play (we can't play for toffee) and it looks like great fun.
All in all, it's designed for kids big and small, and means that you can pretend to be the rock god you should have been and basically have a fun time whilst pretending.
But a guitar, a band doesn't make, and so now WowWee has launched Paper Jamz Drums (£25), a five piece drum kit that lets you either hook up with the guitar of the same design for a band performance, or merely go it alone freestyle.
Combine that with a Paper Jamz Amp (£15) that looks like your good old-fashioned Marshalls amp, including volume knobs that go up to 11 (yes really), and you're ready to do some busking on the cheap with gear that is light enough to carry when running from the fuzz.
Bring on the noise.
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hi my name is miracle and i love to live for god and jesus every minute it is the most wonderful thing i have ever done in my whole life and i hope to keep it that way. Also i love to spend time with family and friends.
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text:
|Publication number
|Publication type
|Publication date
|Sep 8, 1970
|Filing date
|Sep 26, 1968
|Priority date
|Sep 26, 1968
|Also published as
|Publication number
|Boom Clarence O
|Original Assignee
|Gardner Denver Co
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (5), Referenced by (20), Classifications (9)
|External Links: USPTO, USPTO Assignment, Espacenet
Sept. 8, 1970 c. o. BOOM EXHAUST TUBE FOR DOWN-HOLE DRILL 2 Sheets-Sheet l Filed Sept. 26, 1968 INVENTOR.
4 C/arence 0. 500m A geni C. O. BOOM EXHAUST TUBE FOR DOWN-HOLE DRILL Sept. s, 1970 2 Sheets-5heet 2 Filed Sept. 25, 1968 United States Patent O 3,527,239 EXHAUST TUBE FOR DOWN-HOLE DRILL Clarence 0. Boom, Littleton, Colo., assignor to Gardner- Denver Company, Quincy, Ill., a corporation of Delaware Filed Sept. 26, 1968, Ser. No. 762,803 Int. Cl. E21c 7/.00; E21b l/OO U.S. Cl. 173--67 4 Claims ABSTRACT OF THE DISCLOSURE A combination exhaust, lifting air, and auxiliary holecleansing air tube for a down-hole percussion drill. The tube comprises a centrally positioned tubular element divided into parallel exhaust passages both in communication with the drill hammer driving and lifting air expansion chambers. A partition divides the tube into the parallel exhaust passages and also forms elongated conduits for conducting hammer lifting air, and auxiliary hole-cleansing air.
BACKGROUND OF THE INVENTION A class of fluid operated percussion rock drills known commonly as down-hole drills are usually designed to include a iluid operated piston hammer reciprocally disposed in an elongated cylinder to deliver impact blows directly to a drill bit. Exhaust fluid from the drill percussion motor is usually directed through passages in the bit to provide hole cleansing fluid. Due to the fact that down-hole drills follow the drill bit into the hole being drilled, it is accordingly necessary that the drill proper be of compact design since the drill housing must be of a diameter somewhat less than the diameter of the drill bit. It is also desirable that the diameter of the hammer piston be as great as possible to maximize the piston pressure surface area so that greater impact blows can be delivered to the bit by the pressure fluid acting thereon. These design objectives are difficult to realize and yet provide for suitably sized exhaust passages leading from the percussion motor to the drill bit. It has also been a problem in down-hole drill design to make provision for adequate hammer lifting iluid passages and auxiliary hole cleansing fluid passages.
SUMMARY OF THE INVENTION The present invention provides improved means for supplying hammer lifting fluid, auxiliary hole cleansing fluid, and exhaust fluid passages in a down-hole percussion drill. By providing the centrally located multipassage tubular element herein disclosed extending centrally from the drill motive lluid inlet through a coaxial bore in the drill hammer, and into a receiving bore in the drill bit, adequate fluid passage area is provided for all of the aforementioned functions without greatly reducing drill hammer pressure surface area or increasing the drill housing diameter.
The present invention also provides a centrally positioned tube having an auxiliary iluid conduit for conducting pressure fluid directly to the drill bit for improved hole cleansing during deep-hole drilling when exhaust fluid alone is insuiiicient to provide adequate hole cleansing. The auxiliary hole cleansing liuid conduit ad-l vantageously bypasses the distributing valve and the percussion motor and thereby does not adversely affect the operation of the drill. The invention also provides for means to prevent hammer reciprocation when the drill bit is olf the bottom of the hole and concurrently provide for all motive fluid to the drill to be directed to the bit for hole cleansing.
An advantage of the present invention lies in the pro- "ice vision of a multipassage tubular element of unique construction which performs numerous functions in a downhole drill while occupying a minimum of space in the drill proper and being easily removable from the drill.
These and other advantages of the invention will be appreciated upon reading the description of the preferred embodiment.
BRIEF DESCRIPTION O'F THE DRAWING FIG. 1 is a longitudinal section view of a portion of a down-hole drill employing the novel exhaust tube herein disclosed.
FIG. 1a is a continuation of FIG. l from the line a-a illustrating the lower portion of the down-hole drill.
FIG. 2 is an exterior View of the exhaust tube for the down-hole drill shown in FIGS. 1 and la.
FIG. 3 is a transverse section taken along the line 3--3 of FIG. 2.
FIG. 4 is a transverse section taken along the line 4-4 of FIG. 2.
DESCRIPTION OF THE PREFERRED EMBODIMENT Referring to FIG. 1 and FIG. la, a typical down-hole percussion rock drill is illustrated in longitudinal section and generally designated by the numeral 10. The drill 10 is adapted to be suspended from the end of a string of hollow drill pipe 12 in the conventional manner by a threaded connection 14 in the drill backhead 16. The drill 10 basically comprises the backhead 16 threadedly connected to an elongated cylindrical housing 18 having a bore 20 forming with a movable piston hammer 22 a fluid operated percussion motor. The piston hammer 22 includes opposed pressure surfaces 21 and 23 and divides the bore 20 into expansible chambers 24 and 26 which permit the expansion of pressure iluid for driving and lifting the piston hammer 22, respectively. The expansion chamber 26 is closed at its lower end by a chuck member 28 threadedly secured to the drill motor housing 18 and slidably retaining a percussion drill bit 30. The bit 30 is of the integral shank type having an elongated shank portion 32 axially slidably retained in the chuck 28 by means of the lugs 34 and the retainer 36. As can be seen in FIG. 1a the shank portion 32 is adapted to receive percussion blows directly from the piston hammer 22.
The backhead 16 includes a passage 38 in fluid ow communication with the hollow drill pipe 12 and opening into an area 40 from which a plurality of conduits 42 communicate with the space 44. A check valve 46 is suitably biased in the position shown by a spring 48 retained in a housing 50. Located in a bore 52 in the upper portion of the drill motor housing 18 a platelike member 54 abuts the lower end of the backhead 16 and retains a fluid distributing valve chest 56. The plate 54 includes a series of openings 58 in communication with the space 44 and plural conduits 60 located near the periphery of the valve chest 56. The plate 54 also includes the openings 62 formed at an angle with respect to the longitudinal axis of the drill 10 and opening into the recessed area 64.
The distributing valve chest 56. comprises a housing for an axially shiftable valve element 66 having opposed pressure surfaces 68 and 70. The valve 66 is of a type well `known to those familiar with the art of fluid operated percussion tools and is operable in response to pressure forces acting alternately on the pressure surfaces 68 and 70 to shift to valve pressure yfluid to the expansion chambers 24 and 26, respectively.
A multipassage fluid conducting tube, generally designated by the numeral 72, is retained at the valve chest 56 by a flanged head 74. The tube 72 is substantially coaxial with the longitudinal axis of the drill 10 and extends through the valve chest 56, the piston hammer 22,
and into a central bore 76 in the shank portion 32 of the bit 30. The tube 72 includes an outer cylndrical tube 78 having a bore 80 divided into parallel circular segment shaped passages 81, FIGS. 3 and 4, by a central partition 82 disposed in and extending the length of the tube 78 and having a portion 83, FIG. 2, closing the bore 80 at the flanged head end. The passages 81 are of substantially equal cross sectional area and serve to conduct exhaust pressure uid from the expansion chambers 24 and 26 by means of the longitudinally spaced double exhaust ports 84 and 86, respectively. The exhaust passages 81 open into the bore 76 in the bit 30` from where passages 88 and 90 lead to the exterior of the drill 10.
The central partition 82 includes a longitudinal conduit 92 in communication fwith the area 64 at the head end of the tube 72 and opening into the bore 76 in the bit 30 through the plug 94 having an oriiice 96 therethrough. A parallel conduit 98 extending longitudinally through the partition 82 is in fluid-ow communication with the annular area 100 surrounding the valve element 6'6- by means of the opening 102, and at the lower or bit end of the tube 72 the conduit 98 opens through the aperture 110 into an area 104 formed by an enlarged portion 106 of the bore 76 and a recessed portion 108 of the tube 7.8. As can be seen in FIG. la the area 104 forms a flow passage for conducting pressure Huid to the expansion chamber 26 when the bit 30 is in the position shown. A third opening 112 from the conduit 98 (FIG. 1) is operable to communicate pressure fluid to the expansion chamber 24 in response to the piston hammer 22 being in a certain position to be described below.
The functional aspects of the multipassage tube 72 can best be understood by an explanation of the operation of the drill As previously mentioned, the drill 10 is of the down-hole type whereby it is attached to the end of the drill pipe 12 which is rotated by suitable means, not shown, and which supplies pressure uid such as compressed air from a suitable source to operate the drill percussive motor and provide a cleansing medium for evacuating drill cuttings from the drill hole. In operation, the weight of drill 10 will cause the bit 30 to assume the position shown in FIG. la when the latter is in contact with the bottom of a drill hole. Pressure ilu-id from the drill pipe 12 will ow through the passage 38 in the backhead 16 past the check valve 46, which will be pressure biased open, into the area 40, through the plural conduits 42, into the space 44, and through the passages 58 and 60 to the valve element 66. With the valve element 66 in the position shown in FIG. 1 fluid will -flow past the perimeter of the valve and via the annular area 114 into the expansion chamber 24 to drive the piston hammer 22 downward to strike the bit 30 as shown by the position of the hammer in FIGS. l and la. As the hammer 22 travels downward to the position shown, the exhaust ports 86 for the expansion chamber 26 become closed by the close fitting bore 116 of the hammer 22 thereby resulting in a pressure increase in the expansion chamber 26 due to uid trapped therein. This pressure increase is transmitted via the area 104 and the conduit 98 into the annular area 100 to act on the pressure surface 70 of the valve 66 causing it to shift downward thereby cutting off the communication of pressure fluid to the expansion chamber 24. Also as the hammer 22 travels downward to the position shown, the exhaust ports 84 into the expansion chamber 24 are uncovered permitting exhausting of pressure fluid through i the parallel passages 81 (FIGS. 3 and 4) into the bore 76 and through the passages 88 and 90 to aid in evacuating drill cuttings from the drill hole. With the valve ele ment 66 shifted as described above pressure fluid from the passages 60 will flow into the annular area 100 and down through the conduit 98, the area 104 and between the coacting surfaces of the hammer and bit into the expansion chamber 26 to lift the hammer 22 upward uncovering the exhaust ports `86 and closing off the exhaust ports 84 permitting exhausting of fluid from the expansion chamber 26y through the passages 81, and causing a pressure increase in the expansion chamber 24. The pressure rise in the chamber 24 will accordingly act on the surface 68 of the valve 66 causing the same to shift to the position shown in FIG. 1 whereby pressure iluid will again be communicated to the chamber 24 for providing power to the hammer 22 to strike the bit 30. The aforedescribed cycle is, of course, repeated rapidly in actual operation of the drill 10.
Concurrently with operation of the drill 10, a continuous supply of hole cleansing fluid is supplied to the bore 76 of the bit 30 by way of the passages 62 in the plate 54 into the area 64 and through the elongated conduit 92 and the orifice 96. The orifice 96 is suitably sized to limit the amount of iluid bypassed from the drill percussion motor and the plug 94 is slidably retained in the conduit 92 and thereby is easily removed and replaced with a larger or smaller orice depending on hole cleansing require-ments. For example, as the depth of the drill hole increases greater amounts of high pressure fluid are required to be bypassed around the percussion motor to provide adequate fluid energy for removing drill cuttings from the hole, thus necessitating a large orice. However, in shallow holes or when rst starting the drill hole little or no auxiliary hole cleansing fluid is usually required whereby a small oriiice or a solid plug may be inserted in the conduit 92 and hence exhaust fluid alone substantially meets hole cleaning requirements. Removal of the plug 94 or the entire tube 72 is accomplished by unscrewing the backhead 16 from the housing 18 and lifting the plate 54 out of the bore 52.
'Means are also provided for maximum hole cleansing requirements using all of the fluid supplied to the drill 10 and to prevent operation of the percussion motor when the bit 30 is out of contact with the bottom of the hole being drilled. When the drill 10 is raised oif the bottom of the hole, the bit 30 will drop down until the lugs 34 contact the retainer 36. This position of the bit places the close tting portion 120 of the bore 76 sealingly over the opening 110 into the lifting uid supply conduit 98. Concurrently, the hammer 22 will drop down along with the bit 30 thereby placing the conduit 98 in communication with the expansion chamber 24 by means of the opening 112. The area now |being vented to chamber 24 will cause the valve 66 to remain in the position of FIG. 1 l
to supply pressure fluid through the area 114 to the chamlber 24 and through the exhaust ports y84 and parallel passages y81 to the bore 76 in the bit 30 along with, of course, fluid being bypassed continuously through the auX- iliary conduit 92. Hammer reciprocation is thereby prevented and .all fluid supplied to the drill 10 is used for hole cleansing medium under higher pressure than when the combination of low pressure exhaust fluid and oriced hole cleansing uid is used during normal operation. As can be readily appreciated from the foregoing description and the accompanying illustration, the tube 72 serves a number of functions including providing ample sized exhaust passages, a bypass auxiliary hole cleansing conduit, a lifting uid conduit, means for providing maximum hole cleansing fluid at high pressure, and preventing unwanted hammer reciprocation when the drill 10 is out of contact with the work. All of these functions are provided with a compactly designed tube adapted for ease of assembly and removal from the drill.
In a preferred method of manufacture of the tube 72, the outer cylindrical tube portion 78 and the partition 82 are separately fabricated of steel. The partition '82 is made to have a close sliding or light press t in the bore 80. After assembly, the components are welded at suitably accessible locations and the head end of conduit 98 is plugged as shown in FIG. 1. Separate fabrication of the tube 78 and the partition -82 provide for a tube having maximum ow area for exhaust uid through the circular segment passages 81 thereby formed, as well as providing for conduits 92 and 98, and yielding a structure satisfying performance requirements at low manufacturing cost` What is claimed is:
1. Multipassage fluid conducting means for a down-hole drill, said means comprising an elongated substantially cylindrical tube having a hollow bore therethrough, a partition disposed in said bore and having a portion closing one end of said bore, said partition extending substantially the length of said tube and dividing said tube into parallel passage means, said passage means opening to the exterior of said tube at the end of said bore opposite said closed end, said partition including first conduit means extending longitudinally through said partition and opening axially to both ends of said tube and second conduit means extending longitudially Within said partition and opening to the exterior of said tube through a plurality of spaced radial openings, and longituidnally spaced port means in said tube opening from the exterior of said tube into said parallel passage means.
2. The invention set forth in claim 1 wherein:
said partition is centrally positioned in said bore of said tu'be whereby said parallel passage means are formed of substantially equal cross sectional areas.
3. Fluid conducting means for a pressure fluid operated percussion drill, said drill including:
a pressure tiuid percussion motor having a piston hammer reciprocably disposed in a cylinder and forming therewith opposed expansion chambers for driving and lifting said hammer respectively;
pressure Huid inlet means and fluid distributing means in communication with said inlet and operable to distribute pressure uid alternately to said opposed expansion chambers;
blow receiving means disposed in one end of said percussion motor including a bore in communication with the exterior of said drill, and said Huid conducting means comprising:
an elongated substantially cylindrical walled hollow tube located in said motor cylinder and extending from said fluid inlet means to said bore in said blow receiving means;
a longitudinal partition disposed within said hollow tube forming a pair of elongated parallel passages between said tube wall and said partition, said tube including exhaust port means opening into said parallel passages from said opposed expansion chambers;
first conduit means extending longitudinally through said partition from said uid inlet means to said bore in said blow receiving means for conducting pressure fluid directly to said bore in said blow receiving means; and,
second conduit means extending longitudinally within said partition for conducting pressure uid from said fluid distributing means to said hammer lifting expansion chamber.
4. The invention set forth in claim 3 wherein:
said first conduit means includes variable orifice means for limiting the amount of pressure fluid conducted by said rst conduit means to said bore in said blow receiving means.
References Cited UNITED STATES PATENTS FOREIGN PATENTS 8/ 1964 England.
JAMES A. LEPPINK, Primary Examiner
|Cited Patent
|Filing date
|Publication date
|Jan 20, 1960
|Dec 12, 1961
|Pan American Petroleum Corporation
|Percussion drilling apparatus
|Jul 14, 1958
|Jul 24, 1962
|Gardner Denver Co
|Fluid operated percussion drill
|Apr 16, 1962
|Apr 9, 1963
|St Joseph Lead Co
|Down-hole drill
|Mar 11, 1963
|Jan 18, 1966
|Mission Mfg Co
|Impact drilling tool
|Title not available
|Citing Patent
|Filing date
|Publication date
|Feb 19, 1970
|Nov 2, 1971
|Kostylev Alexandr Dmitrievich
|Pneumatic percussion device for making holes in the ground by packing the latter
|Sep 20, 1974
|Jun 22, 1976
|Reed Tool Company
|Pneumatic impact drilling tool
|Dec 6, 1976
|Jul 18, 1978
|Reed Tool Co.
|Pneumatic impact drilling tool
|Jul 25, 1977
|Jan 9, 1979
|Compair Construction And Mining Limited
|Down-the-hole percussion drills
|Apr 17, 1979
|Jul 28, 1981
|Walter Hans Philipp
|Drill hammer
|Jul 10, 1980
|Nov 10, 1981
|Boart International Limited
|Down-the-hole drilling
|Jun 11, 1979
|May 8, 1984
|Dresser Industries, Inc.
|Fluid operated rock drill hammer
|Oct 26, 1987
|Mar 27, 1990
|William Lister
|Pneumatic percussion hammer
|Dec 18, 1990
|Jul 21, 1992
|Percussion Drilling, Inc.
|Down hole percussion drill apparatus
|Apr 26, 1991
|Oct 13, 1992
|D.T.A. Pty Ltd
|Transmission sleeve for a down hole hammer
|Feb 24, 1993
|Jan 11, 1994
|Ranck Gerald L
|Air hammer
|Feb 17, 1994
|Apr 4, 1995
|Ingersoll-Rand Company
|Fluid distributor for a debris flushing system in a percussive, fluid-activated apparatus
|Aug 11, 2003
|Feb 7, 2006
|Wassara Ab
|Hydraulic drill string
|Nov 4, 2005
|May 27, 2008
|Grey Bassinger
|Downhole percussion tool
|Aug 5, 2009
|Jan 15, 2013
|Atlas Copco Secoroc, LLC
|Percussion assisted rotary earth bit and method of operating the same
|Dec 20, 2010
|Jul 1, 2014
|Atlas Copco Secoroc, LLC
|Percussion assisted rotary earth bit and method of operating the same
|Aug 11, 2003
|Sep 30, 2004
|Fredrik Egerstrom
|Hydraulic drill string
|Aug 22, 1996
|Dec 22, 1998
|Sds Digger Tools Pty, Ltd.
|Transmission sleeve for a down hole hammer
|Sep 29, 2011
|Apr 18, 2012
|Injector, drill bit combination structure and combination drilling tool
|Sep 29, 2011
|Feb 19, 2014
|Injector, drill bit combination structure and combination drilling tool
|U.S. Classification
|173/64, 173/137, 175/92, 173/17, 173/67
|International Classification
|Cooperative Classification
|European Classification


text:
« You Don't See Many Names Starting with "Tellura-" |
| How Not to Do It: Acetylene Cylinders »
Posted by Derek
In early 2007 there was quite a stir caused by reports of dichloroacetate (DCA) salts as possible cancer therapies. I didn't cover it as well as I should have here, partly because I was in the final stages of getting laid off from my previous job at the time, but here's a good roundup from Orac while the story was going on. It appeared that dichloroacetate was quite active in a number of cancer cell lines, where it worked by some sort of metabolic disruption pathway, quite possibly involving the Warburg effect through inhibition of mitochondrial PDHK. In short form, what that means is that some of these tumors stop using glucose exclusively as an energy source, and divert more of it into other pathways where it's used as a feedstock for the synthesis of other biomolecules. That allows the cells to get by on less oxygen (since the traditional glucose pathways use up a fair amount), which is particularly important in a solid tumor. This is also tied with with a resistance to apoptosis (programmed cell death), so it makes a pretty good package, if you're a tumor cell. But it does leave them metabolically vulnerable, and there have been attempts over the years to target this. (The latest idea in the area is a kinase called PKM2, a good candidate for the key switch that turns on the whole Warburg effect).
The news sent a lot of people searching for their own sources of dichloroacetic acid, and also was the occasion for a lot of "Unpatentable Cancer Wonder Drug Ignored By Big Pharma" commentary, which is always enjoyable. A new paper is now out in Science Translational Medicine looking at DCA in glioblastoma. That's a good place to look, because aggressive solid tumors of that sort are probably the most vulnerable to a Warburg-effect strategy. The authors found that mitochondia from glioblastoma tissue isolated from a number of patients do indeed show the signs of altered metabolism, which DCA reversed in cell culture. And they present the results of treating 5 patients over a period of months with oral DCA therapy.
How'd it work? They were able to compare pre- and post-therapy tissue samples in only three of the patients, but all three showed signs that more cells were undergoing apoptosis, slowing the growth of the tumors. So this wasn't an amazing cancer-disappears result, but it definitely keeps the story going. Three patients is not enough to draw robust conclusions from, of course, and they did see some (reversible) neuropathy as a side effect, but I'd say that DCA is still worth looking into on a larger scale.
Should cancer patients just up and take it themselves? It's really hard to recommend that, since we still don't know a lot about what's going on with the stuff. But it's also hard to tell someone with a refractory solid tumor not to try whatever they can get their hands on.
Update: more from Orac, including details of all five patients treated in this study.
Comments (43)
+ TrackBacks (0) | Category: Cancer | Clinical Trials
1. blah on May 14, 2010 11:17 AM writes...
excellent post Derek. If someone were to think of the best uses of blogs, this type of post should be a prime example of how blogs can have some wonderful impact on those with bio/chem background AND the average reader.
I agree that someone who has refractory solid tumor should be given the chance to try anything possible even if it's not FDA approved.
2. David Young on May 14, 2010 11:33 AM writes...
Stephen Lippard and Shanta Dhar, at MIT took an ingenious approach by combinging DCA with cisplatin to make Mitaplatin, two molecules of DCA covalently bound to one molecule of cisplatin. Supposedly the agent dissociates in the cancer cell to a reactive platinum species and two molecules of DCA and act synergistically (or perhaps additively) to kill the cancer cell. Early studies in progress.
3. Andy Advani on May 14, 2010 11:57 AM writes...
I began to use DCA recently but unfortunately the source I was getting it from has been closed probably for political reasons>Can you recommend a source I can get DCA in pure form?I am running out of DCA and I would really appreciate any information you can provide me.I wish to thank you in advance and look forward to hearing from you ASAP--Andy Advani
4. alig on May 14, 2010 12:01 PM writes...
I would be wary of buying DCA for personal use from a questionable supplier. The mono-chloroacetic acid is quite toxic and the monofluoroacetic acid is one of the common rat poisons.
5. Hap on May 14, 2010 12:13 PM writes...
I didn't think it was common any more (sodium fluoroacetate is 1080) - rat poisons with high toxicities and no antidotes are ungood.
6. Sili on May 14, 2010 12:14 PM writes...
At least this sounds like it might be working - unlike so many of the other woo woo alternatives out there.
I'll not be holding my breath, though.
7. blah on May 14, 2010 12:18 PM writes...
Rat poison is not unlike many other anti-cancer agents
8. Harry on May 14, 2010 12:32 PM writes...
As far as fluoroacetate rat poisons are concerned, I believe that all the EPA registrations for that have been cancelled. The was some use for coyote poison a long while back, but I think that's gone as well.
Back when I was involved in making and selling the stuff, the biggest pesticide use was for rabbits and opossums in New Zealand.
The ethyl fluoroacetate was used in manufacturing 5-fluorouracil, but I believe that's been superceded as well. The last US manufacturer of SFA (1080) was Tull Chemicals in Alabama, and they may be out of business as well.
9. Luke Weston on May 14, 2010 12:33 PM writes...
If we start to see people self-medicating with things like DCA from Dawkins-only-knows-where, I fear we might see something similar to the 2006 case where a guy did a bit of reading of various "alternative health" resources on the Web and self-administered ~10g of sodium selenite, which quite rapidly killed him.
10. blah on May 14, 2010 2:16 PM writes...
Your fear is not someone else's problem. If somebody chooses to take something that they feel will make them live, then who are you to say that they don't have that right. Sure, this guy died from this. But in the case of refractory solid tumor, won't the person die anyway? Not to be cliche, but at least they can die trying.
11. Design Monkey on May 14, 2010 2:17 PM writes...
took an ingenious approach by combinging DCA with cisplatin to make Mitaplatin, two molecules of DCA covalently bound to one molecule of cisplatin.
Uuuh. "me too" cisplatin and quite probably not really better one than original cisplatin, or original cisplatin plus optimally dosed DCA not in one molecule.
The usual activity problem - doses for DCA seems to be quite a bit higher than that of cisplatin, so trying to stuff both of them in one molecule, results in incomplete level of DCA activity, if staying at doses where cisplatin toxicity is acceptable.
12. CMCguy on May 14, 2010 2:31 PM writes...
#4 alig and a couple others bring up good point that there needs to be a "pharmaceutical" grade to monitor and define acceptable limits of impurities in pursuit of DCA treatments. I have seen side reaction from chloral in TFA and suspect DCA could have similar species present (in fact doubtful but could such an impurity be the active involved?). Even simply things can get very complicated when attempt to use in people especially when FDA gets involved.
13. Anonymous on May 14, 2010 2:33 PM writes...
Check out the route to funding this installment of the DCA/cancer story:
14. blah on May 14, 2010 3:19 PM writes...
thanks for the link Anonymous...
after reading a few of the comments on the website, you can see why cancer patients should be the one who decide what they try or don't try as their treatment. here's a sampling:
"My mother died at the age of 49 in 1995 of glioblastoma multiforme. Two surgeries, chemo, and radiation only slowed it long enough for her to have 10 good months, and 2 months of absolute unadulterated hell.
She would have volunteered for this study in a heartbeat, human testing ethics be damned. The infinitisimal chance of survival would have been only a minor reason....to further human knowledge and maybe facilitate a better outcome for other patients would have been motivation enough.
This cancer eats your brain, strips you of your memories and cognitive function, and forces you to endure obscene pain. My mother, in the quiet of the night, used to beg us to kill her. Beg us."
15. David Young on May 14, 2010 3:28 PM writes...
There is a problem with the Edmonton News Report. It reads.... In four of the glioblastoma patients, researchers saw no further brain cancer growth 15 months after initial treatment. Does that mean initial chemotherapy and radiation or initial treatment with DCA. Probably the former. Almost all patients get treated with surgery (often suboptimal) followed by radiation with Temodar chemotherapy. They are then likely to stay in remission for a number of months, sometimes quite a long number of months and often it is difficult to know exactly when they have progression of disease. So, taking DCA during that period of time could give the impression of holding the disease in check whereas the patient just had a good response to surgery/radiation/chemotherapy. All of us would be much more impressed if a patient had definite progression of disease and then put on DCA and then noticing demonstrable regression of tumor.
16. Rob on May 14, 2010 7:32 PM writes...
I have been using DCA since last May 21st for metastatic colon cancer. No other chemo. The first two CT scans after May 21st showed significant reductions in tumor size and the last four have shown no change. A year after discovering a rapid growing set of large tumors I remain symptom free and have raised my dosage back to my initial dosage to see if I can get another tumor reduction. I think the DCA is working and the latest oncologist I saw agrees.
17. Hanna on May 15, 2010 6:16 AM writes...
Hi Rob,
Would you please share the dosage of DCA that you used? Did you take other medicine? My father also has mCRC and we decided to let him try CDA.
Thank you so much!!
18. Rob on May 15, 2010 12:01 PM writes...
I started out at one gram per day, I weigh around 190. I have been at 2 grams a day and now have upped it to 3 grams a day. That is for five days and them two weeks off. I don't have any rationale for this other than to avoid peripheral neuropathy which I have. And after stopping DCA the neuropathy continues to increase for a week. I take 300 to 500 mg of B-l plus a B Complex to counter this also.
Look at theDCAsite for far better dosage info than from me.
While I give all the credit for my stable cancer to DCA because that is all I took in the beginning when I had the actual reductions in tumor size and also when I took it for the longest periods, 20 days without a break and when I developed PN, I now take a lot of other things.
Metformin 200 mg
Artemisinin one gram
Artesunate 100 mg
Fish Oil 7 grams
Vit D3 4000 iu
EGCG for its caffeine
Again no symptoms, feel fine, ride my bike. My oncologist hear nothing in my lungs. It is a bit unreal since on average I am supposed to be dead having had no standard chemo.
Resection in 12/06
Diagnosed with metastatic colon cancer 4/09
Six CT scans since but no treatment since at leading, number one or two, cancer hospital.
Accepted for Phase One clinical trial last month but am waiting for later, higher dose, cohort in Oct or Dec.
Being considered for another Phase One trial.
Have been seen by four oncologist at three major hospitals and a medical group.
No doctor has agreed to work with me and DCA but there are doctors who will. Check it out.
19. David Young on May 15, 2010 7:18 PM writes...
Well, Rob, it is stories like that that make one want to take a closer look at DCA. The most compelling information, if I have it right, is that your tumors regressed while on DCA and while on nothing but DCA. I presume that this happened over a course of a few months, and then the regression slowed down, but you continued to have stable disease. In other words there was never any progression of disease while on DCA.
A little more information would be helpful. Where were the tumor nodules seen that you indicate have regressed? If there were clear cut nodules in the liver, generally more than one, and one consistently noted that all of these regressed (perhaps to different degrees) on serial CT scans, I would be impressed that something (in this case, the DCA) had caused this regression. and presumable with limited and tolerable side effects (you indicate that peripheral neuropathy is a troublesome side effect at times.)
Was your CEA blood test initially elevated? And did it lessen while on DCA? ... and consistently lessen? (perhaps to a lesser degree later on). And did it stay low and stable after that? (Not all metastatic colon cancer produces CEA, but many do.)
As an oncologist, I would be impressed and excited by DCA if I noticed such responses in one of my patients. I would think that almost all oncologists would be impressed if they saw regression of cancer with DCA being the only treatment. (And somewhat impressed if one could maintain a remission with DCA, if that remission was for, say,... 4, or 5 months or more.
You are not on any maintenance Avastin, or Xeloda pills (you didn't mention anything else.
20. Roland Perry on May 17, 2010 9:56 PM writes...
Tuesday , December 08, 2009 13:29ET
By Fain Hughes, firstname.lastname@example.com
Viral Genetics (VRAL) has entered into an exclusive license agreement with the University of Colorado to develop cancer therapies based on the work of M. Karen Newell, Ph. D., a professor of biology at the University of Colorado at Colorado Springs. This new line of research into a means of killing drug-resistant cancer cells will be pursued by scientists at MetaCytolytics, Inc., a wholly owned subsidiary of Viral Genetics.
Newell has discovered a process called "metabolic disruption technology" (MDT) that blocks invasive cells' ability to generate energy from sugars or fatty acids. In essence, MDT "starves" cancer cells, causing them to die. As proof of principle, Newell's team at the University of Colorado has performed over 400 metabolic disruption technology experiments in vitro and in animal models.
According to Newell, MDT is expected to be combined with traditional chemotherapy and radiation treatments.
21. rob on May 23, 2010 3:41 AM writes...
Nothing but DCA and what I listed. No progression last 8 months, two regressions in the first four months. total now approaching 13 months. No weight loss, good appetite.
Hylar tumor originally 4x3.6 cm now 3x2 something cm. Nodule in right upper lung always at 2x2 cm but looks broken up to me in last CT scan.
Here is a recent UK study of colon cancer and DCA that looks promising.
22. rob on May 23, 2010 4:21 AM writes...
CEA level was originally 13 reduced to 6 and stayed stable on DCA till CT scan before last at 8. Last CT scan I don't know.
23. PBS on June 3, 2010 10:45 PM writes...
Hi Rob,
Have just started DCA this week having been diagnosed with lung cancer 3 weeks ago. Primary tumour is 10x10x6 cm and hilar mets 7x8. Still awaiting pathology after two biopsies but my onc refuses to treat with chemo unless I drop the DCA. Am considering this, but am disapointed in her lack of open mindedness.
In the meantime, can you tell me if you're taking capsules or powder? I'm currently breaking open the capsules my chemist put together and mixing in water before drinking, but if this is a step I can avoid, I certainly will...
24. Hanna on June 7, 2010 12:21 PM writes...
Rob---thank you so much for your very detailed information! It took us a while to get DCA and my father just started with it. I am keeping my fingers crossed...
25. Dave on June 10, 2010 10:03 AM writes...
I read this post and then read the update at the end of the post "More From Orac". The thing that blows my mind here ("thing" being that the FDA is holding back DCA until proper trials) is that what we are talking about here is cancer - and in many cases terminal cancer. We are not talking about some illness which we might already have a workable solution like diabetes or bad breath. We're talking about something that will kill you, and kill you rather quickly and painfully. So, so what if someone who is going to die takes a shot in the dark on a hope and prayer to try and cure themselves. So what if the drug they take kills them, because afterall they're going to die anyways and it may as well be a result of their own doing. So what if a drug hasn't gone thru medical trials. Lets just consider these people a phase 0, 1,2,3, whatever subject. These pencil necks in the powers that be cannot think beyond their happy little bureaucratic model. Its called "thinking out of the box". My cousin swallowed a bottle of sleeping pills because there was no hope for his cancer. So if instead he experimented on himself with DCA, would that have been any worse????
26. Rob on June 10, 2010 12:41 PM writes...
I am taking a powder. Don't think it makes a difference though, could be wrong.
It has been almost 13 months now and I can accurately say that I have taken 140 grams of DCA so far at a cost of $125.
And Medicare has not been paying for DCA or any of the supplements I am taking. They do pay for the CT scans at around $4000 a pop.
Went on Medicare June 1st last year, one month after being diagnosed with metastatic colon cancer.
27. Alison on June 22, 2010 5:17 AM writes...
hi Rob and others
Can you tell me where you are sourcing your DCA? My husband has a v aggressive brain tumour which has progressed in spite of surgery and radiotherapy. He's currently on TMZ (2nd cycle just started) and we want to use DCA as well.
It seems v confusing as to whether you could buy from a chemical co (Sigma Aldrich sell it with the proviso that it's for lab use, not human consumption - but they do point out that what they sell is what was used at the Uni of Alberta!), or whether this has to be refined in some way.
And it's a bit scary just buying at random off the internet!
Any advice would be deeply appreciated.
28. Alison on June 22, 2010 5:19 AM writes...
PS we're in the UK.
29. ellen s on July 12, 2010 6:02 PM writes...
Hi everyone we live in Sydney
Husband diagnosed with thalamic tumor in January waiting to see iif progressed to do a biopsy because biopsy in the thalamic area can cause many more problems. MRI at the end of June shown progression to left temp. lobe and possible spread to right and frontal . He is in hospital awaiting results from biopsy ( in temp. lobe) in order to start radio and chemo ASAP. Does anyone know the results from phase 1 trials on DCA ? anyone with similar problems?
Hard to obtain DCA in Sydney. Doctors are as close minded as in any other western country.
30. Pat on July 28, 2010 6:21 PM writes...
I started in DCA for Stage I breast cancer on July 16th, and purchase it from the UK (I live in the U.S.). A Naturopathic Doctor in Spain who runs the Budwig Center suggested this as a reliable source:
Took about 11 calendar days to get to me, which I didn't think was bad.
I probably won't be back to this site so if anyone has a question, send it direct to me:
31. dustin on September 14, 2010 7:52 PM writes...
I've been doing a lot of reading about DCA and the possible benefits on brain tumours and I can tell you all this.....my wife was diagnosed with a tumour on her cerebellum and because we are lucky enough to be living in Alberta AND because she met all the requirements, she was included in the U of A trials. With that said, she had NO surgery and NO chemo or radiation....she was only given DCA and some vitamines and after two months her scan revealed that it shrunk by 20% and two weeks later it revealed that that little piece of hell in her head was stopped in its tracks!She is too continue this treatment until November and than we will see whats next....
32. dustin on September 14, 2010 8:57 PM writes...
I would also like to add this...
We are the RICHEST city in Canada and yet these reserchers at the U of A are funding most of this research ON THEIR OWN!!!!!!!!!
We like too roll around in our big gas gullping pick-ups, bragging about big oil money and pissing away money arguing over "should we get rid of our secod airport" AND the CURE FOR CANCER IS IN OUR OWN BACK YARD!?!?!?!?!
Help put us in the history books as the red necks who cured cancer!
Maybe sell the oilers?! They aren't doing much for us anyway!!
33. 1lunker on November 12, 2010 1:58 PM writes...
Or someone else, please illuminate the following?
DCA taken through GI/oral consumption presents some unanswered questions. FIrst, what becomes of dca upon introduction to hydrochloric acid? That should be pretty easy to answer, although I don't have the answer. My intuition here is this; by consuming vinegar with salt, you'll provide your body with the same building blocks, to influence these pathways you speak of, as the powder, "DCA - sodium salt of 2 chlorine and 1 acetic acid". Salt with vinegar = acetic acid+chlorine+vinegar. COuld it be that simple. Cut salt from other parts of diet and simply do some salt, vinegar shots. Any thoughts here? Last summer, there was a movie out called ____? In the Divinci Code, the cypher is Apple, so as to not break the casing and expose the scroll to vinegar.
Anyone thoughts on DCM - dichloromalate?
34. 1lunker on November 12, 2010 6:51 PM writes...
35. LRT on June 22, 2011 1:15 AM writes...
I have been taking DCA for my Aggressive Fibromatosis, a cancer like invasive affliction that is caused by trauma , also known as Desmoid tumors. It had grown through my sternum and infiltrated my ribs, and was causing complications with my esophagus, and vagas nerve. I elected NOT to allow western medicine doctors to cut me up and poison and irradiate me. My lesions and tumors are dissolving and have all reduced in size by 40% in 7 months of treatment of only 20 mg every other day. It does cause mild pain in the lesions and tumors as they vascularize prior to dissolution, but compared to what my recommended course of treatment was (wide resection of affected tissue, along with chemotherapy and radiation) I don't mind a little pain. I got mine at the dca store dot com. Anyone who speaks out against DCA or anything else that works for desperate people who are dying anyway, obviously aren't faced with the hopeless feeling of anyone with cancer- otherwise they would have an open mind and be willing to try something outside the parameters of Holy Western Medicine's accepted Dogma regarding oncological treatment. Good Luck. I am posting because DCA is saving me as I write this. I feel compelled to share-especially since it might save someone from suffering horrible death or barbaric treatments or surgeries. What if there were a miracle cure for some types of cancer.?Should we keep it a secret?
36. Merran on December 2, 2011 7:23 PM writes...
Can anyone tell me if DCA is Ok to use concurrently with Chemotherapy. I am currently on Doxyrubicin after further spreading of metastatic breast cancer.
I am keen to try DCA and have a friend in South Australia who is using it now with some rather promising results.
Thank you
37. Mary on March 31, 2012 7:00 PM writes...
I have an aggressive, rare kidney cancer. The cancer progressed while on Cisplatin/Gemzar. My oncologist has me starting Sutent in a couple of days, which at best, might slow the cancer. I am considering DCA and must decide soon. Does anyone know if you can use it with this drug?
38. Danilo on April 21, 2012 3:11 PM writes...
I think we need an urgent research about the four PDK isoenzymes: which Laboratory or University is doing that?
"We hypothesized that DCA may have differential effects on hypoxic versus normoxic colorectal cancer cells, and found that while some cell lines are refractory to DCA's effects, most colorectal cancer cells examined actually displayed enhanced survival under hypoxic conditions in the presence of DCA. Consistent with this, DCA treated xenografts showed no anti-tumor effect but instead there was enhanced growth of treated tumors. Our findings suggest that DCA may have differential effects on cancer cell survival depending on the regional microenvironment within treated tumors, which may complicate its usefulness as an adjuvant anti-cancer therapy." (Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia, http://www.sciencedirect.com/science/article/pii/S030438351000251X ).
"Thus, although DCA inhibits growth of a variety of cancer cells, the effect and the underlying mechanisms seem to be cell-type dependent. A likely explanation for these differential effects could be the difference in expression of the PDK isoenzymes in the cancer cells examined. Dichloroacetate is a non-specific inhibitor of PDK (Whitehouse and Randle, 1973), and has a different Ki for each of the four PDK isoenzymes (Bowker-Kinley et al, 1998). In addition, the four PDK isoenzymes are known to be differentially expressed in various tissues. Thus, there is a need to develop inhibitors to the individual PDK isoenzymes that should allow cancer cell-type-specific metabolic manipulation." (Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. , http://www.nature.com/bjc/journal/v102/n12/full/6605701a.html )
39. jacqueline on October 15, 2012 12:30 AM writes...
need DCA, information my mom has stage 1v pancreatic cancer... will this meds word...need help me soon!!!!!
40. Navin on November 20, 2013 9:54 AM writes...
If you think FDA and MEDICALGUYS ARE WORKING FOR YOU THEN WATCH THIS DOCUMENTARY. CURE FOR CANCER HAS BEEN INTENTIONALLY DESTROYED BY FDA AND ROCKFELLERS JUST RELAX AND WATCH
41. Eve on March 31, 2014 4:55 PM writes...
We are uk based. My mum has stage 4 lung cancer. We are thinking if buying dca but are afraid if the source as can only get it via the net??? Help please!!!!
42. Eve on March 31, 2014 4:57 PM writes...
We are uk based. My mum has stage 4 lung cancer. We are thinking of buying dca but are afraid of the source as can only get it via the net??? Help please!!!!
43. Eve on March 31, 2014 4:57 PM writes...
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Tower Bridge looks so small and positively dwarfed from your view point - super detail Lin
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Wonderful city scape Lin, excellent composition,, London really has changed since I was last up there
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Fab cityscape - excellent composition! Love it!
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Good time for this image
Where were you?
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full of detail Lin would not realise it was through glass so well done
Happy New Week
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A stunning view Lin,
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Cool shot of my favourite city. Great view!
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An excellent cityscape Lin, this is a wonderful rooftop view of London, I half expected you to include Mary Poppins on her broomstick!
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text:
10 Bike-Fix Essentials
Cable Cutter
10 / 10
This bike-specific tool has meshing triangular jaws to ensure a clean cut without causing frayed ends on cables or leaving sharp burrs on housing.
Use it: To snip cables, cut housing, and crimp caps.
10 / 10
Copyright © 2015 Rodale Inc.


text:
Twenty Valley Nature Primer – Volume 1
The Niagara Escarpment is the most diverse ecosystem in the province. It is a life force that protects thousands of acres of trees and sustains species of birds, flowers, amphibians, and reptiles that are rare in Southern Ontario. Considering that Southern Ontario is the most urbanized and intensive agricultural area of Canada, it is a blessing that the escarpment has been protected as much as it has been.