The long-term circulation of the PEGylated daunorubicin allows protracted extravasation and underlies this form of handfoot syndrome.

Liposomal daunorubicin is under investigation for the treatment of AIDS-related Kaposi sarcoma, acute myeloblastic leukemia, multiple myeloma, non-Hodgkin lymphoma, and breast cancer.Carbonyl Reductase (CBR) catalyzes the reduction of daunorubicin to its corresponding alcohol, daunorubicinol, which changes the pharmacological properties of this cancer chemotherapeutic drug.

Unlike other common alkylating agents, cyclophosphamide can occasionally induce remission in acute childhood leukemias, and it can be used to prolong remission.

Alopecia caused by cyclophosphamide is common, but usually temporary despite continued administration of the drug.

Cyclophosphamide treatment, which causes a marked and persistent inhibition of Cholinesterase activity, potentiates the effect of succinylcholine chloride.

Cyclophosphamide treatment, which causes a marked and persistent inhibition of Cholinesterase activity, potentiates the effect of succinylcholine chloride.

-Clofarabine triphosphate inhibits Ribonucleotide Reductase, leading to a depletion of the deoxyribonucleotide triphosphate (dNTP) pools.

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.Clofarabine triphosphate inhibits Ribonucleotide Reductase, leading to a depletion of the deoxyribonucleotide triphosphate (dNTP) pools.Clofarabine induces apoptosis through direct and indirect action on mitochondria by releasing Cytochrome c and other pro-apoptotic factors, including AIF (Apoptosis Inducing Factor), APAF-1 (Apoptotic Protease Activating Factor-1), and Caspase-9.The agent received accelerated approval from the U.S. FDA in 2004.

The drug is converted intracellularly to the active metabolites difluorodeoxycytidine di-and triphosphate (dFdCDP and dFdCTP).-dFdCDP inhibits Ribonucleotide Reductase 44 , thereby decreasing the deoxynucleotide pool available for DNA synthesis -dFdCTP is incorporated into DNA, resulting in DNA strand termination and apoptosis.After incorporation into DNA, gemcitabine has a prolonged intracellular half-life.

The agent is lipophilic.Metoprine (DDMP, 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine) (BW 197U) is a diaminopyrimidine folate antagonist that inhibits Dihydrofolate Reductase, resulting in decreased cellular folate metabolism and cell growth.

Rapid infusion of carmustine may produce intensive flushing of the skin and suffusion of the conjunctiva within 2 h, lasting about 4 h.

Drug resistance may be caused by platinum efflux, detoxification through thiols, apoptosis resistance, or enhanced DNA repair.MINOR GROOVE DNA BINDING ANTIBIOTICS (A/T RICH SITES)MINOR GROOVE DNA BINDING ANTIBIOTICS (G/C RICH SITES)) is a methylazirinopyrroloindoledioneFig.

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Steroid-coupled nitrogen mustards Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Steroid-coupled nitrogen mustards Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

Carboplatin causes thrombocytopenia with a nadir of 10–14 days.

Carboplatin also leads to alopecia, fatigue, and abnormal blood electrolyte levels (magnesium, sodium, potassium, calcium).

Carboplatin also leads to alopecia, fatigue, and abnormal blood electrolyte levels (magnesium, sodium, potassium, calcium).

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

Oligomenorrhea or azoospermia can be induced by mechlorethamine and may not recover for years after termination of therapy.

The vasoconstrictor epinephrine in the gel enhances the penetration of methotrexate into the tumor tissue and reduces the dispersion to the surrounding tissues, thereby increasing the local concentration of methotrexate and improving its anti-tumor activity.

Within this subgroup, differences in structure from the parent compound aminopterin are shaded in pink The vasoconstrictor epinephrine in the gel enhances the penetration of methotrexate into the tumor tissue and reduces the dispersion to the surrounding tissues, thereby increasing the local concentration of methotrexate and improving its anti-tumor activity.

In chronic granulocytic leukemia, busulfan can induce remission in 90 % of patients after the initial course of therapy.

The wafers produce high local concentrations of carmustine for several weeks directly into the tumor bed after surgery when the tumor burden is low.Molecularly Targeted Therapy The cells of glioblastomata and anaplastic gliomatas secrete glutamate and also express AMPA Glutamate Receptors, which contribute to proliferation, migration and neurotoxicity.

The wafers produce high local concentrations of carmustine for several weeks directly into the tumor bed after surgery when the tumor burden is low.The cells of glioblastomata and anaplastic gliomatas secrete glutamate and also express AMPA Glutamate Receptors, which contribute to proliferation, migration and neurotoxicity.

Like many other genotoxic agents, doxorubicin activates the binding of P53 to DNA, likely inducing apoptosis in this manner.

The combination of doxorubicin with cyclophosphamide causes a dramatic increase in the risk of secondary malignancies, most often acute myelomonocytic leukemia.Idarubicin <Idamycin, Idamycin PFS> is a semi-synthetic anthracycline derived from daunorubicin.

The combination of doxorubicin with cyclophosphamide causes a dramatic increase in the risk of secondary malignancies, most often acute myelomonocytic leukemia.Idamycin PFS> is a semi-synthetic anthracycline derived from daunorubicin.

An elevated activity of PKB associated pathways protects cells from apoptotic death induced by cisplatin.

Nuclear c-ABL activity can be stimulated by cisplatin and acts to transmit DNA damage signals.

Hence the drug efficacy can potentially be enhanced by Helicase inhibitors.Illudins and acylfulvenes alkylate DNA, inhibit DNA synthesis, and deplete thiol anti-oxidant defenses.In 1965, cisplatin was discovered by Barnett Rosenberg, who explored the effects of electric fields on the growth of Escherichia coli bacteria (Rosenberg 1965) .

Because c-ABL tyrosine kinase has a role in cisplatin mediated activation of apoptosis, a reduction in its activity can confer cisplatin resistance.

The metabolite chloroacetaldehyde may lead to the formation of chloroacetic acid and then to S-carboxymethylcysteine (SCMC) after conjugation with the amino acid cysteine.

Interactions between daunorubicin and metallic Cu II ions abundant in skin tissue generate reactive oxygen species, which stimulate Chemokine secretion from keratinocytes and result in inflammation.

The drug is Pregnancy Category D.Concurrent administration of hexamethylmelamine and antidepressants of the MAO inhibitor class can cause severe orthostatic hypotension.

The drug is Pregnancy Category D.Drug Interactions Concurrent administration of hexamethylmelamine and antidepressants of the MAO inhibitor class can cause severe orthostatic hypotension.

It is caused by drug metabolites that agonize AMPA/Kainate Receptors and induce cellular acidification in cortical neurons.

Whereas both cyclophosphamide and ifosfamide are activated by Cytochromes P450 2B1 and 2C6/2C11, only ifosfamide is also activated by Cytochrome P450 3A.N-dechloroethylation of the parent drug yields mono-functional metabolites that have lost their DNA cross-linking activity and therapeutic efficacy.

The drug is Pregnancy Category D.As a natural product, bleomycin may be the cause of anaphylactic reactions, immediate or delayed for several hours.

As a natural product, bleomycin may be the cause of anaphylactic reactions, immediate or delayed for several hours.

Vitamin C supplements can increase the adverse effects of methotrexate.

Iron mediated free radical reactions enable anthracyclines to produce formaldehyde (HCHO) from carbon cellular sources like spermine and lipids.

Because of its higher concentration in the combination, uracil saturates the uracil reducing enzymatic activity of Ddihydropyrimidine Ddehydrogenase, thereby inhibiting first pass hepatic metabolism of 5-fluorouracil and permitting its administration as the orally bioavailable prodrug tetrahydrofuranyl-5-fluorouracil.

ethyl)mitomycin C) (KT6149) is a semi-synthetic, water soluble disulfide derivative of mitomycin C. Activated by blood components and Glutathione, KW-2149 causes inter-strand DNA cross-links and DNA-protein The quinone of mitomycin C is reduced, altering the azinidine group to be opened and set up a conjugated system to a susceptible carbon.

However, it has limited clinical usefulness because of its rapid inactivation by Adenosine Deaminase.A product of the fermentation by Streptomyces antibioticus is 2′-deoxycoformycin (co-vidarabine, dCF) (NSC-218321, CL-825) <Premarin, Pentostatin, Nipent>.

The inhibition of Adenosine Deaminase by deoxycoformycin leads to an intracellular accumulation of deoxy-ATP, which causes apoptosis.

Folinic acid can enhance the toxicity of 5-fluorouracil; in elderly patients, deaths from severe enterocolitis, diarrhea, and dehydration can result.

Ceramide formation occurs after reactive oxygen activation of Neutral Sphingomyelinase.

Anthracycline-formaldehyde conjugates intercalate into DNA by covalent bonding of the Schiff base with the 2-amino group of a G in the minor groove of the DNA (Taatjes et al. 1997 ).-Ceramide formation occurs after reactive oxygen activation of Neutral Sphingomyelinase.

It depends on binding of a bleomycin/iron complex to DNA, which then reduces molecular oxygen to free oxygen radicals that cause primarily single strand breaks.Bleomycin sulfate <Blenoxane, Teva> is used in the treatment of Hodgkin and non-Hodgkin lymphoma as a component of the ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen, of squamous cell carcinoma, and of testicular cancer.

The metabolic ifosfamide product acrolein can contribute to the hemorrhagic cystitis associated with oxazaphosphorine therapy.

The metabolic ifosfamide product acrolein can contribute to the hemorrhagic cystitis associated with oxazaphosphorine therapy.

However, the polyethylene glycol (PEG) in the formulation may cause hand-foot syndrome as an adverse effect29.Liposomal daunorubicin <DaunoXome> is a liposome encapsulated preparation with a diameter of 45 nm that is free of polyethylene glycol.

glycol (PEG) in the formulation may cause hand-foot syndrome as an adverse effect 29 .

Valrubicin causes DNA damage, inhibits Topoisomerase 2, and leads to cell cycle arrest in G2.

Valrubicin causes DNA damage, inhibits Topoisomerase 2, and leads to cell cycle arrest in G2.

Thereby exatecan inhibits DNA reduplication and triggers apoptotic cell death.

The repair of the irofulven induced DNA damage is dependent on functioning DNA Helicases (the double helical configuration, in which DNA strands naturally reside, requires their separation by Helicases for transcription or reduplication).

50-60 % of the dose administered is excreted in the urine, 5 % in the feces.Adverse Effects Fotemustine may cause retinal atrophy or retinal detachment.

50-60 % of the dose administered is excreted in the urine, 5 % in the feces.Adverse Effects Fotemustine may cause retinal atrophy or retinal detachment.

In America, of course, we don’t have that kind of state coercion. There are currently no laws that shape what academics or journalists can say; there is no government censor, no ruling-party censor. But fear of the internet mob, the office mob, or the peer-group mob is producing some similar outcomes. How many American manuscripts now remain in desk drawers—or unwritten altogether—because their authors fear a similarly arbitrary judgment? How much intellectual life is now stifled because of fear of what a poorly worded comment would look like if taken out of context and spread on Twitter?

Facebook could shift the burden of proof toward people and communities to demonstrate that they’re good actors—and treat reach as a privilege, not a right.

IL-1beta secretion was not affected by treatment with the NLRP3 inhibitor glyburide XREF_BIBR or parthenolide, which has also been shown to inhibit NLRP3 XREF_BIBR.

Glyburide and parthenolide both inhibited NLRP3 activation by LPS and ATP (data not shown).

XREF_BIBR have shown that parthenolide directly inhibits caspase-1 by alkylation of certain cysteine residues.

Water activated by atomic oxygen on Au (111) to oxidize CO at low temperatures.

Neonatal mice deficient in TLR4 have decreased LGR5+ stem cell proliferation and crypt fission compared to wild type mice.

Neonatal mice deficient in TLR4 have markedly diminished LGR5+ stem cell proliferation and diminished crypt fission.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

In contrast, TLR4 activation by LMW-HA requires a TLR4 and MD2 complex but is independent of CD14 and LPS binding protein.

TLR4 activation by LPS requires a TLR4 and MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4 and MD2 complex.

This may be the product of endogenous HAs of different molecular weights binding separately to CD44 and TLR4 or it may be the product of HA binding to a CD44 and TLR4 complex.

Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE 2 production, which transactivates EGFR in LGR5+ crypt epithelial stem cells leading to increased proliferation.

Among the PAMPs are lipoteichoic acid (LTA), a component of gram positive bacteria that binds TLR2, and LPS, a component of gram negative bacteria that binds TLR4.

Although both LMW-HA and LPS bind to TLR4, the results of TLR4 activation by LMW-HA and LPS are not identical.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

HA binds to CD44, TLR2, TLR4, the receptor for HA mediated motility (RHAMM), layilin, lymphatic vessel endothelial HA receptor- 1 (LYVE-1), and HA receptor for endocytosis.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

EGFR can activate beta-catenin via the receptor tyrosine kinase-PI3K-Akt pathway.

Although the evidence suggests that EGFR activation in response to TLR4 signaling is mediated by PGE2, it is also possible that TLR4 signaling promotes EGFR activation through the production of amphiregulin, epiregulin or other EGFR ligands.

Administration of exogenous TLR2 or TLR4 agonists activates TLR2 and TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2 expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells.

This suggests that TLR2 and TLR4 signaling driven by PAMPs from commensal bacteria promotes epithelial proliferation during wound repair in the colon.

In contrast to wound repair, where inflammation accompanies enhanced epithelial proliferation driven by TLR2 and TLR4 activation, in intestinal growth TLR4 activation promotes epithelial proliferation in the absence of inflammation.

Administration of exogenous TLR2 or TLR4 agonists activates TLR2 and TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2 expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells.

TLR4 activation by LPS requires a TLR4 and MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4 and MD2 complex.

TLR4 activation by LPS and LMW-HA require different accessory molecules.

Although both LMW-HA and LPS bind to TLR4, the results of TLR4 activation by LMW-HA and LPS are not identical.

In human biliary carcinoma cells in vitro, addition of LPS initiates a positive feedback loop of TLR4 activation, PGE2 production through COX-2 and EGFR activation.

In this pathway, TLR4, which is usually associated with innate immunity, is activated not by the microbial product LPS, but by HA, a host molecule.

TLR4 activation by HA also plays a role in wound repair.

Despite these suggestions there is good evidence that endogenous HA activates TLR4 and promotes growth even though most of the endogenous HA is in the high MW form.

There are suggestions that TLR4 is preferentially activated by the low MW form of HA.

TLR4 activation by HA drives LGR5+ epithelial stem cell proliferation and crypt fission in normal growth in the intestine and colon.

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

In the first pathway (XREF_FIG), intestinal and colonic growth is regulated by endogenous HA activating TLR4 on pericryptal macrophages resulting in the release of PGE2 which promotes LGR5+ stem cell proliferation, crypt fission and intestinal elongation.

A study of pulmonary injury induced by intratracheal bleomycin demonstrates the role of HA activation of TLR4 in sterile injury.

Taken together these studies addressing the cellular location of the TLR4 signaling that drives growth and wound repair and the nature of the relevant TLR4 ligand suggest that HA activation of myeloid TLR4 mediates intestinal and colonic growth and wound repair.

This suggests that TLR4 activation by endogenous HA promotes healing in DSS colitis.

TLR4 activation by HA also affects the immune response in ischemia- reperfusion injury in the kidney and in acute allograft rejection in a skin transplant model.

TLR2 and TLR4 activation by HA mediates wound repair in the bleomycin model of lung injury.

Wound repair mediated by HA activation of TLR2 and TLR4 is also seen in the lung.

In this pathway, TLR4, which is usually associated with innate immunity, is activated not by the microbial product LPS, but by HA, a host molecule.

Based on the growth studies, it is likely that EGFR activation by PGE2 is also the mechanism of the increased epithelial proliferation in the repair phase of DSS colitis.

In growth EGFR activation by PGE2 accounts for about 30% of LGR5+ cell proliferation.

Although the evidence suggests that EGFR activation in response to TLR4 signaling is mediated by PGE2, it is also possible that TLR4 signaling promotes EGFR activation through the production of amphiregulin, epiregulin or other EGFR ligands.

In accordance with our expectation, over-expressed of PIK3CA could restore the expression level of Snail, beta-catenin, Vimentin, and E-cadherin which decreased by CUX1 knockdown (XREF_FIG).

In accordance with our expectation, over-expressed of PIK3CA could restore the expression level of Snail, beta-catenin, Vimentin, and E-cadherin which decreased by CUX1 knockdown (XREF_FIG).

Gain-of-function and loss-of-function studies showed that PIK3CA expression was facilitated by CUX1, leading to activation of epithelial-mesenchymal transition (EMT), accompanied by upregulated expression of Snail, beta-catenin, Vimentin and downregulated expression of E-cadherin in the bladder cancer cell lines.

Gain-of-function and loss-of-function studies showed that PIK3CA expression was facilitated by CUX1, leading to activation of epithelial-mesenchymal transition (EMT), accompanied by upregulated expression of Snail, beta-catenin, Vimentin and downregulated expression of E-cadherin in the bladder cancer cell lines.

In our research, although we found that over-expression of PIK3CA could upregulate the expression of Snail, beta-catenin, and Vimentin, while downregulate the expression of E-cadherin significantly (XREF_FIG).

In EJ cells and T24T cells, over-expression of PIK3CA could upregulate the expression of Snail, beta-catenin and Vimentin, while downregulate the expression of E-cadherin significantly (XREF_FIG) Consistently, knock down of PIK3CA caused downregulation of Snail, beta-catenin, and Vimentin, while E-cadherin was upregulated significantly (XREF_FIG).

Given that PIK3CA has been reported participating in the proceeding of tumor proliferation, migration, and invasion, and in combination with the evidence that the expression of PIK3CA can be directly regulated by CUX1, the effects of CUX1 knockdown and PIK3CA restoration on bladder cancer was further explored.

The Transcription Levels of PIK3CA Was Increased by CUX1 Regulation.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

The Ripka study has demonstrated that CUX1 expression was induced by activation of Akt and protein kinase B signaling, and decreased by PI3K inhibitors in pancreatic cancer.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

Besides, over-expressed CUX1 could restore the expression of downregulated Snail, beta-catenin, Vimentin and E-cadherin which was induced by PIK3CA knockdown.

PIK3CA functions to promote proliferation and metastasis of bladder cancer by activating EMT.

Here, we propose a model of CUX1-PIK3CA-EMT oncoprotein axis, to illustrate how PIK3CA is activated and contributes to bladder cancer progression and metastasis (XREF_FIG).

Overexpression of PIK3CA Restored the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer Cells Through Knockdown of CUX1.

PIK3CA Promoted the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer In Vitro.

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

PIK3CA functions to promote proliferation and metastasis of bladder cancer by activating EMT.

Overexpression of PIK3CA Restored the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer Cells Through Knockdown of CUX1.

PIK3CA Promoted the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer In Vitro.

PIK3CA functions to promote proliferation and metastasis of bladder cancer by activating EMT.

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

Overexpression of PIK3CA Restored the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer Cells Through Knockdown of CUX1.

PIK3CA Promoted the Proliferation, Migration, Invasion, and Angiogenesis of Bladder Cancer In Vitro.

Transwell analysis showed that CUX1 knockdown attenuated invasion ability of EJ and T24T cells (XREF_FIG).

These findings suggest that PIK3CA was targeted by CUX1 and the activation of CUX1 and PIK3CA axis and consequently regulation of EMT pathway may contribute to promote bladder cancer cell progression.

As expected, over-expressed of CUX1 could restore the expression level change of Snail, beta-catenin, Vimentin, and E-cadherin which was induced by PIK3CA knockdown (XREF_SUPPLEMENTARY).

Together, the above results demonstrated that CUX1 stimulated transcription activity via direct interaction with the binding site of PIK3CA promoter.

Our results confirmed a vital regulatory role of CUX1 in PIK3CA induced aggressiveness and angiogenesis of bladder cancer cells PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers -- Snail, E-cadherin, Vimentin, and beta-Catenin.

In accordance with the ability of mutant SPOP to repress the function of endogenous wild type SPOP in a dominant negative manner, the over-expression of mutant SPOP (SPOP-Y87C, -F102C, -W131G, -F133S) phenocopied the effect of SPOP knockdown on ERG mediated invasion in PC3 cells.

In line with these findings, gene ontology analysis of AR-ERG co-bound gene signature in VCaP cells indicated that the most striking transcriptional changes were linked to cellular differentiation and cell cycle arrest that are directly induced by DHT and repressed by ERG (e.g., HOXA genes, CDKN1A and p21, Fig.

In line with these findings, gene ontology analysis of AR-ERG co-bound gene signature in VCaP cells indicated that the most striking transcriptional changes were linked to cellular differentiation and cell cycle arrest that are directly induced by DHT and repressed by ERG (e.g., HOXA genes, CDKN1A and p21, Fig.

Similarly, knockdown of SPOP in VCaP cells reduced cell growth in 3D cell culture and impaired ERG mediated gene transcription.

The oncogenic effect was paralleled by an increase in the expression of the oncogenic transcription factors MYC and HOXB13 and a decrease in the cell cycle inhibitor p21 as seen in an organoid line derived from Spop F133V -mutant transgenic mice 13.

ZMYND11 induces AR signaling pathway and represses ERG activity.

In accordance with the ability of mutant SPOP to repress the function of endogenous wild type SPOP in a dominant negative manner, the over-expression of mutant SPOP (SPOP-Y87C, -F102C, -W131G, -F133S) phenocopied the effect of SPOP knockdown on ERG mediated invasion in PC3 cells.

We found two degron sequences that were required for efficient SPOP mediated ubiquitylation and protein degradation.

Moreover, knockdown of ERG reduced SPOP protein levels in VCaP cells, while forced expression of a DeltaERG led to the upregulation of SPOP mRNA and protein levels in PC3 cells.

Thus, we wondered if ERG itself may directly upregulate SPOP transcription to support its own oncogenic activity.

Indeed, knockdown of TRIM24 by two short-hairpin RNAs partially reverted the growth inhibition mediated by mutant-SPOP in VCaP cells and reduced AR signaling, while over-expression of AR was sufficient to decrease cellular growth.

In agreement with the established repressive function of ZMYND11 on ERG, we found that over-expression of HA-ZMNYD11-DM2 was sufficient to repress ERG induced invasion and established target genes in PC3 cells.

We then asked if the elevated SPOP levels in the context of forced DeltaERG expression have a functional impact on the oncogenic activity of DeltaERG in the androgen independent PC3 cells, in which ERG promotes tumor cell invasion 31.

ZMYND11 induces AR signaling pathway and represses ERG activity.

We postulated that ZMYND11 upregulation could contribute to the synthetic sick relationship by repressing the ERG oncogene 's transcriptional activity or enhancing AR signaling.

Mutant SPOP induced androgen receptor signaling antagonizes ERG activity.

Conversely, we assessed the consequence of ERG overexpression in LNCaP cells under low DHT levels where mutant SPOP triggers AR signaling and tumor growth XREF_BIBR, XREF_BIBR.

Taken together, the data imply a mutual incompatibility of mutant SPOP induced AR signaling and the function of the ERG oncogene.

RPL11 and RPL5 suppressed breast cancer cell growth and induced cell apoptosis.

These findings suggested that RPL11 and RPL5 could inhibit breast cancer cell proliferation and induce apoptosis.

Overexpression of RPL11 and RPL5 significantly suppressed MCF7 and ZR-75-1 cell proliferation, as evidenced by both cell viability and colony formation assays.

Cell viability and colony formation assays showed that downregulation of MeCP2 expression led to suppressed cell proliferation, which was rescued by silencing RPL11 or RPL5.

RPL11 and RPL5 may inhibit cancer cell proliferation and induce apoptosis 40.

Our results indicated that overexpression of RPL11 or RPL5 suppressed breast cancer cell proliferation, blocked G1-S cell-cycle transition, and induced cancer cell apoptosis.

MeCP2 inhibited RPL11 and RPL5 transcription by binding to their promoters.

To further confirm that MeCP2 might promote breast cancer cell proliferation by suppressing RPL11 and RPL5 expression and promoting the E3 ubiquitin ligase activity of MDM2, MeCP2 overexpression vector was co-transfected with RPL11 or RPL5 overexpression vectors or MDM2 inhibitor (Nutlin3) into MCF7 cells.

These results suggested that MeCP2 repressed RPL11 and RPL5 expression by binding to their promoters.

MeCP2 inhibited RPL11 and RPL5 transcription by binding to their promoters.

In addition, silencing MeCP2 remarkably suppressed breast cancer cell migration by inhibiting beta-catenin expression and induced cell apoptosis by downregulating the antiapoptotic gene Bcl-2 and upregulating proapoptotic genes, including Bax, P53, and P21.

To verify that RPL5 and RPL11 promote P53 stability, we treated the breast cancer cells with cycloheximide after transfection with the RPL11 and RPL5 overexpression or control vectors.

The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector transfected cells, indicating that RPL11 and RPL5 could inhibit P53 degradation.

In this study, we observed that RPL11 and RPL5 suppressed ubiquitination mediated P53 degradation by directly binding to MDM2.

The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector transfected cells, indicating that RPL11 and RPL5 could inhibit P53 degradation.

To verify that RPL5 and RPL11 promote P53 stability, we treated the breast cancer cells with cycloheximide after transfection with the RPL11 and RPL5 overexpression or control vectors.

In this study, we observed that RPL11 and RPL5 suppressed ubiquitination mediated P53 degradation by directly binding to MDM2.

These findings suggested that RPL11 and RPL5 could inhibit breast cancer cell proliferation and induce apoptosis.

RPL11 and RPL5 suppressed breast cancer cell growth and induced cell apoptosis.

RPL11 and RPL5 may inhibit cancer cell proliferation and induce apoptosis 40.

Our results indicated that overexpression of RPL11 or RPL5 suppressed breast cancer cell proliferation, blocked G1-S cell-cycle transition, and induced cancer cell apoptosis.

MDM2 is an E3 ubiquitin ligase that targets P53 protein for proteasomal degradation XREF_BIBR, XREF_BIBR.

TCGA data revealed significantly lower RPL11 and RPL5 expression in breast cancer tissues; additionally, overexpression of RPL11 and RPL5 significantly suppressed breast cancer cell proliferation and G1-S cell cycle transition and induced apoptosis in vitro.

Investigation of the molecular mechanism showed that MeCP2 repressed RPL11 and RPL5 transcription by binding to their promoter regions.

Investigation of the molecular mechanism showed that MeCP2 repressed RPL11 and RPL5 transcription by binding to their promoter regions.

TCGA data revealed significantly lower RPL11 and RPL5 expression in breast cancer tissues; additionally, overexpression of RPL11 and RPL5 significantly suppressed breast cancer cell proliferation and G1-S cell cycle transition and induced apoptosis in vitro.

Moreover, Rb1 activated the PI3K and AKT pathway, down-regulated Cleaved caspase-3 and Bax, and up-regulated Bcl-2 expression.

Moreover, Rb1 activated the PI3K and AKT pathway, down-regulated Cleaved caspase-3 and Bax, and up-regulated Bcl-2 expression.

The low nutrient concentrations and high oxygen concentrations measured in these samples support the influence of the Polar Surface Water or the Polar Intermediate water from the EGC.

Parthenolide has previously been shown to inhibit NLRC4 dependent caspase-1 activation 15, although it did not do so in these experiments (XREF_FIG).

MCC950 blocks NLRP3 induced ASC oligomerization.

Water fluxes through pressurized root systems treated with nitrogen and low oxygen (< 2% O (2)), elevated CO (2) (20% CO (2)), and low O (2) with elevated CO (2) concentrations were reduced to 40, 51 and 58%, respectively, of J (v) of plants aerated with ambient air.

The probability for the occurrence of sulphur plumes is enhanced in years with a lower annual mean of upwelling intensity, decreased oxygen supply associated with decreased lateral ventilation of bottom waters, more southern position of the Angola Benguela Frontal Zone, increased mass fraction of South Atlantic Central Water and stronger downwelling coastal trapped waves.

Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive 53.

One study showed that Nuclear Receptor Binding SET Domain Protein 2 (NSD2)-mediated dimethylation of PTEN promotes 53BP1 interactions and subsequent recruitment to sites of DNA-damage sites 75.

By using specific mutants of PTEN lacking lipid phosphatase function, an early study concluded that PTEN may block cell migration through a protein phosphatase mediated function on focal adhesion kinase (FAK) protein 14.

PTEN and PDHK1 were observed to have a synthetic-lethal relationship, as loss of PTEN and upregulation of PDHK1 in cells induced glycolysis and a dependency on PDHK1 100.

This PTEN/ARID4B/PI3K signalling axis identifies a novel player in the PTEN mediated suppression of the PI3K pathway and provides a new opportunity to design novel therapeutics to target this axis to promote the tumour suppressive functions of PTEN.

In one of these studies, Baker et al. reported that Notch1 can mediate transcriptional suppression of PTEN, resulting in the derepression of PI3K signalling and development of trastuzumab resistance 91.

This study was the first to link the Ras-MAPK and PI3K pathways through Notch1 transcriptional suppression of PTEN 91.