Preference for daily oral pills over long-acting antiretroviral therapy options among people with HIV.

OBJECTIVE: To examine the characteristics of people with HIV (PWH) who prefer remaining on daily oral antiretroviral therapy (ART), rather than switching to long-acting ART (LA-ART). DESIGN: Building upon a discrete choice experiment (DCE), we examined characteristics of individuals who always selected their current daily oral tablet regimen over either of two hypothetical LA-ART options presented in a series of 17 choice tasks. METHODS: We used LASSO to select sociodemographic, HIV-related, and other health-related predictors of preferring current therapy over LA-ART, and logistic regression to measure the associations with those characteristics. RESULTS: Among 700 PWH in Washington State and Atlanta, Georgia, 11% of participants ( n  = 74) chose their current daily treatment over LA-ART in all DCE choice tasks. We found that people with lower educational attainment, good adherence, more aversion to injections, and who participated from Atlanta to be more likely to prefer their current daily regimen over LA-ART. CONCLUSIONS: Gaps in ART uptake and adherence remain, and emerging LA-ART treatments show promise to address these challenges and help a larger portion of PWH to achieve viral suppression, but preferences for these new treatments are understudied. Our results show that certain drawbacks of LA-ART may help to maintain demand for daily oral tablets, especially for PWH with certain characteristics. Some of these characteristics (lower educational attainment and Atlanta participation) were also associated with a lack of viral suppression. Future research should focus on overcoming barriers that impact preferences for LA-ART among those patients who could benefit most from this innovation.

The importance of side branches of glycosylphosphatidylinositol anchors: a molecular dynamics perspective.

Many proteins are anchored to the cell surface of eukaryotes using a unique family of glycolipids called glycosylphosphatidylinositol (GPI) anchors. These glycolipids also exist without a covalently bound protein, in particular on the cell surfaces of protozoan parasites where they are densely populated. GPIs and GPI-anchored proteins participate in multiple cellular processes such as signal transduction, cell adhesion, protein trafficking and pathogenesis of Malaria, Toxoplasmosis, Trypanosomiasis and prion diseases, among others. All GPIs share a common conserved glycan core modified in a cell-dependent manner with additional side glycans or phosphoethanolamine residues. Here, we use atomistic molecular dynamic simulations and perform a systematic study to evaluate the structural properties of GPIs with different side chains inserted in lipid bilayers. Our results show a flop-down orientation of GPIs with respect to the membrane surface and the presentation of the side chain residues to the solvent. This finding agrees well with experiments showing the role of the side residues as active epitopes for recognition of GPIs by macrophages and induction of GPI-glycan-specific immune responses. Protein-GPI interactions were investigated by attaching parasitic GPIs to Green Fluorescent Protein. GPIs are observed to recline on the membrane surface and pull down the attached protein close to the membrane facilitating mutual contacts between protein, GPI and the lipid bilayer. This model is efficient in evaluating the interaction of GPIs and GPI-anchored proteins with membranes and can be extended to study other parasitic GPIs and proteins and develop GPI-based immunoprophylaxis to treat infectious diseases.

Deep care: The COVID-19 pandemic and the work of marginal feminist organizing in India.

In this paper, we adopt a Southern feminist epistemology to critically appraise the ways in which media discourse on gendered organizing during the Indian COVID-19-induced migrant crisis resists or reinforces hegemonic caste hierarchies. To contextualize this work, we briefly historicize scholarship on feminist organizing around land rights, hunger, and violence, while noting the politics of contagion and pollution narratives plaguing the pandemic discourse in India. After conducting a qualitative content analysis (QCA) followed by a critical discourse analysis (CDA) of media discourses across three tiers (international, national, and local), we found that international and national tiers of discourse largely deployed a savarna gaze that worked to 1) Reinforce brahminical and technocratic pandemic narratives and 2) Delegitimize Dalit marginal organizing feminist work and Dalit sensibilities through seven overlapping metrics of erasure. On the other hand, local tier of discourse confronted the savarna gaze, amplified voices of Dalit and Muslim women by centering their narratives of resistance, and tackled the exacerbation of casteist oppression under the pandemic in the service of emancipation. Local discourses also highlight how marginal organizing during the first pandemic lockdown involved provision of essential resources and services (food, medical care, security) for mostly Dalit and Muslim migrant workers, and women intersectionally facing domestic violence and savarna violence. Despite the brahmininal structural oppression, Dalit feminist praxis' emblematic resistance of oppressive structures, during and beyond times of crisis, constitutes what we call the work of deep care.

Coarse-Grained Molecular Model for the Glycosylphosphatidylinositol Anchor with and without Protein.

Glycosylphosphatidylinositol (GPI) anchors are a unique class of complex glycolipids that anchor a great variety of proteins to the extracellular leaflet of plasma membranes of eukaryotic cells. These anchors can exist either with or without an attached protein called GPI-anchored protein (GPI-AP) both in vitro and in vivo. Although GPIs are known to participate in a broad range of cellular functions, it is to a large extent unknown how these are related to GPI structure and composition. Their conformational flexibility and microheterogeneity make it difficult to study them experimentally. Simplified atomistic models are amenable to all-atom computer simulations in small lipid bilayer patches but not suitable for studying their partitioning and trafficking in complex and heterogeneous membranes. Here, we present a coarse-grained model of the GPI anchor constructed with a modified version of the MARTINI force field that is suited for modeling carbohydrates, proteins, and lipids in an aqueous environment using MARTINI's polarizable water. The nonbonded interactions for sugars were reparametrized by calculating their partitioning free energies between polar and apolar phases. In addition, sugar-sugar interactions were optimized by adjusting the second virial coefficients of osmotic pressures for solutions of glucose, sucrose, and trehalose to match with experimental data. With respect to the conformational dynamics of GPI-anchored green fluorescent protein, the accessible time scales are now at least an order of magnitude larger than for the all-atom system. This is particularly important for fine-tuning the mutual interactions of lipids, carbohydrates, and amino acids when comparing to experimental results. We discuss the prospective use of the coarse-grained GPI model for studying protein-sorting and trafficking in membrane models.

Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism.

Glioblastoma multiforme (GBM) is a malignant brain tumor with a poor prognosis resulting from tumor resistance to anticancer therapy and a high recurrence rate. Compelling evidence suggests that this is driven by subpopulations of cancer stem cells (CSCs) with tumor-initiating potential. ABC subfamily B member 5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies. In the current study, we examined the potential role of ABCB5 in growth and chemoresistance of GBM. We found that ABCB5 is expressed in primary GBM tumors, in which its expression was significantly correlated with the CSC marker protein CD133 and with overall poor survival. Moreover, ABCB5 was also expressed by CD133-positive CSCs in the established human U-87 MG, LN-18, and LN-229 GBM cell lines. Antibody- or shRNA-mediated functional ABCB5 blockade inhibited proliferation and survival of GBM cells and sensitized them to temozolomide (TMZ)-induced apoptosis in vitro Likewise, in in vivo human GBM xenograft experiments with immunodeficient mice, mAb treatment inhibited growth of mutant TP53, WT PTEN LN-229 tumors, and sensitized LN-229 tumors to TMZ therapy. Mechanistically, we demonstrate that ABCB5 blockade inhibits TMZ-induced G2/M arrest and augments TMZ-mediated cell death. Our results identify ABCB5 as a GBM chemoresistance marker and point to the potential utility of targeting ABCB5 to improve current GBM therapies.

A molecular dynamics model for glycosylphosphatidyl-inositol anchors: "flop down" or "lollipop"?

We present a computational model of glycosylphosphatidyl-inositol (GPI) anchors for molecular dynamics studies. The model is based on state-of-the-art biomolecular force fields from the AMBER family, employing GLYCAM06 for carbohydrates and Lipid14 to represent fatty acid tails. We construct an adapted glycero-phosphatidyl-inositol unit to establish a seamless transition between the two domains of atom types. This link can readily be extended into a broad variety of GPI variants by applying either domain's building block scheme. As test cases, selected GPI fragments inserted into DMPC and POPC bilayer patches are considered. Our results suggest that the glycan part of the GPI anchor interacts strongly with the lipid head groups, partially embedding the carbohydrate moieties. This behaviour is supported by the conformational preferences of the GPI anchor, which in particular are conveyed by the strong interactions between the proximal amine and phosphate groups. In a similar way we can conclude that the extension of the anchor away from the lipid bilayer surface that could prevent the contact of the membrane with an attached protein ("lollipop picture") is quite unfavorable. Indeed, when attaching green fluorescent protein to the GPI anchor, it is found to reside close to bilayer surface all the time, and the rather flexible phosphoethanolamine linker governs the extent to which the protein directly interacts not only with the head groups, but also with its own GPI core.

ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer.

ABC member B5 (ABCB5) mediates multidrug resistance (MDR) in diverse malignancies and confers clinically relevant 5-fluorouracil resistance to CD133-expressing cancer stem cells in human colorectal cancer (CRC). Because of its recently identified roles in normal stem cell maintenance, we hypothesized that ABCB5 might also serve MDR-independent functions in CRC. Here, in a prospective clinical study of 142 CRC patients, we found that ABCB5 mRNA transcripts previously reported not to be significantly expressed in healthy peripheral blood mononuclear cells are significantly enriched in patient peripheral blood specimens compared with non-CRC controls and correlate with CRC disease progression. In human-to-mouse CRC tumor xenotransplantation models that exhibited circulating tumor mRNA, we observed that cancer-specific ABCB5 knockdown significantly reduced detection of these transcripts, suggesting that the knockdown inhibited tumor invasiveness. Mechanistically, this effect was associated with inhibition of expression and downstream signaling of AXL receptor tyrosine kinase (AXL), a proinvasive molecule herein shown to be produced by ABCB5-positive CRC cells. Importantly, rescue of AXL expression in ABCB5-knockdown CRC tumor cells restored tumor-specific transcript detection in the peripheral blood of xenograft recipients, indicating that ABCB5 regulates CRC invasiveness, at least in part, by enhancing AXL signaling. Our results implicate ABCB5 as a critical determinant of CRC invasiveness and suggest that ABCB5 blockade might represent a strategy in CRC therapy, even independently of ABCB5's function as an MDR mediator.

Coarse-Grained Molecular Dynamics Force-Field for Polyacrylamide in Infinite Dilution Derived from Iterative Boltzmann Inversion and MARTINI Force-Field.

We present a mesoscale model of aqueous polyacrylamide in the infinitely dilute concentration regime, by combining an extant coarse-grained (CG) force-field, MARTINI, and the Iterative Boltzmann Inversion protocol (IBI). MARTINI force-field was used to retain the thermodynamics of solvation of the polymer in water, whereas the structural properties and intrapolymer interactions were optimized by IBI. Atomistic molecular dynamics simulations of polymer in water were performed to benchmark the mesoscale simulations. Our results from the CG model show excellent agreement in structure with the atomistic system. We also studied the dynamical behavior of our CG system by computing the shear viscosity and compared it with the standard IBI model. The viscosity trends of our model were similar to the atomistic system, whereas the standard IBI model was highly dissimilar as expected. In summary, our hybrid CG model sufficiently mimics an infinitely dilute system, and is superior to both MARTINI and IBI in representing the structure and thermodynamics of the atomistic system, respectively. Our hybrid coarse-graining strategy promises applicability in large-scale simulations of polymeric/biological systems where the structure needs to be replicated accurately while preserving the thermodynamics of a smoother surrounding.

Expression of Cell-Surface Marker ABCB5 Causes Characteristic Modifications of Glucose, Amino Acid and Phospholipid Metabolism in the G3361 Melanoma-Initiating Cell Line.

We present a pilot study aimed at determining the effects of expression of ATP-binding cassette member B5 (ABCB5), a previously described marker for melanoma-initiating cells, on cellular metabolism. Metabolic profiles for two groups of human G3361 melanoma cells were compared, i.e. wildtype melanoma cells with intact ABCB5 expression (ABCB5-WT) and corresponding melanoma cell variants with inhibited ABCB5 expression, through shRNA-mediated gene knockdown (ABCB5-KD). A comprehensive metabolomic analysis was performed by using proton and phosphorus NMR spectroscopy of cell extracts to examine water-soluble metabolites and lipids. Parametric and non-parametric statistical analysis of absolute and relative metabolite levels yielded significant differences for compounds involved in glucose, amino acid and phospholipid (PL) metabolism. By contrast, energy metabolism was virtually unaffected by ABCB5 expression. The sum of water-soluble metabolites per total protein was 17% higher in ABCB5-WT vs. ABCB5-KD G3361 variants, but no difference was found for the sum of PLs. Enhanced abundance was particularly pronounced for lactate (+ 23%) and alanine (+ 26%), suggesting an increase in glycolysis and potentially glutaminolysis. Increases in PL degradation products, glycerophosphocholine and glycerophosphoethanolamine (+ 85 and 123%, respectively), and redistributions within the PL pool suggested enhanced membrane PL turnover as a consequence of ABCB5 expression. The possibility of glycolysis modulation by an ABCB5-dependent IL1ß-mediated mechanism was supported by functional studies employing monoclonal antibody (mAb)-dependent ABCB5 protein inhibition in wildtype G3361 melanoma cells. Our metabolomic results suggest that the underlying biochemical pathways may offer targets for melanoma therapy, potentially in combination with other treatment forms.

Both clades of the epidemic KPC-producing Klebsiella pneumoniae clone ST258 share a modified galactan O-antigen type.

Klebsiella pneumoniae ST258 is a globally disseminated, extremely drug resistant, nosocomial clone with limited treatment options. We show that the vast majority of ST258 isolates express modified d-galactan-I lipopolysaccharide O-antigen, termed hereinafter as D-galactan-III. The genetic determinant required for galactan-III synthesis was identified as a distinct operon adjacent to the rfb (wb) locus encoding D-galactan-I synthesis. The three genes within the operon encode predicted glycosyltransferases. Testing an isogenic transformant pair revealed that expression of D-galactan-III, in comparison to D-galactan-I, conferred improved survival in the presence of human serum. Eighty-three percent of the more than 200 ST258 draft genome sequences currently available carries the corresponding operon and hence these isolates are predicted to express galactan-III antigens. A D-galactan-III specific monoclonal antibody (mAb) was shown to bind to extracted LPS from a panel of ST258 isolates. The same mAb confirmed accessibility of galactan-III in surface staining of ST258 irrespective of the distinct capsular antigens expressed by both clades described previously. Based on these data, the galactan-III antigen may represent an attractive target for active and passive immunization approaches against K. pneumoniae ST258.

A 1,3-amino group migration route to form acrylamidines.

A novel 1,3-amino group migration strategy for the synthesis of acrylamidines is presented. Cu(i) catalyzed reaction of N,N-disubstituted propargylamine with tosylazide generates a highly reactive ketenimine intermediate which is trapped by a tethered amino group leading to the rearrangement reaction.

The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways.

Although calcineurin inhibitors (CNIs) are very useful in preventing allograft rejection, they can mediate a rapid progression of post-transplantation malignancies. The CNI cyclosporine A (CsA) can promote renal tumor growth through activation of the proto-oncogene ras and over-expression of the angiogenic cytokine VEGF; the ras activation also induces over-expression of the cytoprotective enzyme HO-1, which promotes survival of renal cancer cells. Here, we show that the natural product honokiol significantly inhibited CsA-induced and Ras-mediated survival of renal cancer cells through the down-regulations of VEGF and HO-1. Thus, honokiol treatment may help to prevent tumor-promoting effects of CsA in transplant patients.

Harnessing clinical psychiatric data with an electronic assessment tool (OPCRIT+): the utility of symptom dimensions.

Progress in personalised psychiatry is dependent on researchers having access to systematic and accurately acquired symptom data across clinical diagnoses. We have developed a structured psychiatric assessment tool, OPCRIT+, that is being introduced into the electronic medical records system of the South London and Maudsley NHS Foundation Trust which can help to achieve this. In this report we examine the utility of the symptom data being collected with the tool. Cross-sectional mental state data from a mixed-diagnostic cohort of 876 inpatients was subjected to a principal components analysis (PCA). Six components, explaining 46% of the variance in recorded symptoms, were extracted. The components represented dimensions of mania, depression, positive symptoms, anxiety, negative symptoms and disorganization. As indicated by component scores, different clinical diagnoses demonstrated distinct symptom profiles characterized by wide-ranging levels of severity. When comparing the predictive value of symptoms against diagnosis for a variety of clinical outcome measures (e.g. 'Overactive, aggressive behaviour'), symptoms proved superior in five instances (R(2) range: 0.06-0.28) whereas diagnosis was best just once (R(2):0.25). This report demonstrates that symptom data being routinely gathered in an NHS trust, when documented on the appropriate tool, have considerable potential for onward use in a variety of clinical and research applications via representation as dimensions of psychopathology.

Heme oxygenase-1 promotes survival of renal cancer cells through modulation of apoptosis- and autophagy-regulating molecules.

The cytoprotective enzyme heme oxygenase-1 (HO-1) is often overexpressed in different types of cancers and promotes cancer progression. We have recently shown that the Ras-Raf-ERK pathway induces HO-1 to promote survival of renal cancer cells. Here, we examined the possible mechanisms underlying HO-1-mediated cell survival. Considering the growing evidence about the significance of apoptosis and autophagy in cancer, we tried to investigate how HO-1 controls these events to regulate survival of cancer cells. Rapamycin (RAPA) and sorafenib, two commonly used drugs for renal cancer treatment, were found to induce HO-1 expression in renal cancer cells Caki-1 and 786-O; and the apoptotic effect of these drugs was markedly enhanced upon HO-1 knockdown. Overexpression of HO-1 protected the cells from RAPA- and sorafenib-induced apoptosis and also averted drug-mediated inhibition of cell proliferation. HO-1 induced the expression of anti-apoptotic Bcl-xL and decreased the expression of autophagic proteins Beclin-1 and LC3B-II; while knockdown of HO-1 down-regulated Bcl-xL and markedly increased LC3B-II. Moreover, HO-1 promoted the association of Beclin-1 with Bcl-xL and Rubicon, a novel negative regulator of autophagy. Drug-induced dissociation of Beclin-1 from Rubicon and the induction of autophagy were also inhibited by HO-1. Together, our data signify that HO-1 is up-regulated in renal cancer cells as a survival strategy against chemotherapeutic drugs and promotes growth of tumor cells by inhibiting both apoptosis and autophagy. Thus, application of chemotherapeutic drugs along with HO-1 inhibitor may elevate therapeutic efficiency by reducing the cytoprotective effects of HO-1 and by simultaneous induction of both apoptosis and autophagy.

Effectiveness of a combination therapy using calcineurin inhibitor and mTOR inhibitor in preventing allograft rejection and post-transplantation renal cancer progression.

Calcineurin inhibitors (CNIs) may promote post-transplantation cancer through altered expression of cytokines and chemokines in tumor cells. We found that there is a potential cross-talk among CNI-induced signaling molecules and mTOR. Here, we utilized a murine model of post-transplantation cancer to examine the effect of a combination therapy (CNI + mTOR-inhibitor rapamycin) on allograft survival and renal cancer progression. The therapy prolonged allograft survival; and significantly attenuated CNI-induced post-transplantation cancer progression, with down-regulation of mTOR and S6-kinase phosphorylation. Also, rapamycin inhibited CNI-induced over-expression of the angiogenic cytokine VEGF, and the chemokine receptor CXCR3 and its ligands in post-transplantation tumor tissues.

Hydrochemical analysis to evaluate the seawater ingress in a small coral island of India.

The sustainable development of the limited groundwater resources in the tropical island requires a thorough understanding of detail hydrogeological regime including the hydrochemical behavior of groundwater. Detail analysis of chemical data of groundwater helps in assessing the different groundwater zone affected by formation as well as sea water. Groundwater and saline water interaction is better understood using groundwater major ion chemistry over an island aquifer. Multivariate methods to analyze the geochemical data are used to understand geochemical evolution of groundwater. The methods are successfully used to group the data to evaluate influence of various environs in the study area. Various classification methods such as piper, correlation method, and salinity hazard measurements are also employed to critical study of geochemical characteristics of groundwater to identify vulnerable parts of the aquifer. These approaches have been used to successfully evaluate the aquifer zones of a tiny island off the west coast of India. The most part of island is found to be safe for drinking, however some parts of island are identified that are affected by sea water ingress and dissolution of formation minerals. The analysis has successfully leaded to identification of that part of aquifer on the island which needs immediate attention for restoration and avoids further deterioration.

An unusual presentation of Salmonella typhi bacteriuria in a 10 year old girl from North India.

Enteric fever caused mainly by Salmonella typhi (S. typhi), has a high incidence in India. We report a case of enteric fever in a ten year old patient presenting with clinical history of less than one week. Although blood culture, the most important diagnostic modality in early stage of enteric fever was sterile, S. typhi was isolated from culture of urine sample. Serum antibody titres against S. typhi were unusually raised considering that the infection was still in its early stage. Intravenous ceftriaxone therapy was given leading to complete recovery.

Calcineurin inhibitor-induced and Ras-mediated overexpression of VEGF in renal cancer cells involves mTOR through the regulation of PRAS40.

Malignancy is a major problem in patients treated with immunosuppressive agents. We have demonstrated that treatment with calcineurin inhibitors (CNIs) can induce the activation of proto-oncogenic Ras, and may promote a rapid progression of human renal cancer through the overexpression of vascular endothelial growth factor (VEGF). Interestingly, we found that CNI-induced VEGF overexpression and cancer cell proliferation was inhibited by rapamycin treatment, indicating potential involvement of the mammalian target of rapamycin (mTOR) pathway in this tumorigenic process. Here, we examined the role of mTOR pathway in mediating CNI- and Ras-induced overexpression of VEGF in human renal cancer cells (786-0 and Caki-1). We found that the knockdown of raptor (using siRNA) significantly decreased CNI-induced VEGF promoter activity as observed by promoter-luciferase assay, suggesting the role of mTOR complex1 (mTORC1) in CNI-induced VEGF transcription. It is known that mTOR becomes activated following phosphorylation of its negative regulator PRAS40, which is a part of mTORC1. We observed that CNI treatment and activation of H-Ras (through transfection of an active H-Ras plasmid) markedly increased the phosphorylation of PRAS40, and the transfection of cells using a dominant-negative plasmid of Ras, significantly decreased PRAS40 phosphorylation. Protein kinase C (PKC)-ζ and PKC-δ, which are critical intermediary signaling molecules for CNI-induced tumorigenic pathway, formed complex with PRAS40; and we found that the CNI treatment increased the complex formation between PRAS40 and PKC, particularly (PKC)-ζ. Inhibition of PKC activity using pharmacological inhibitor markedly decreased H-Ras-induced phosphorylation of PRAS40. The overexpression of PRAS40 in renal cancer cells significantly down-regulated CNI- and H-Ras-induced VEGF transcriptional activation. Finally, it was observed that CNI treatment increased the expression of phosho-PRAS40 in renal tumor tissues in vivo. Together, the phosphorylation of PRAS40 is critical for the activation of mTOR in CNI-induced VEGF overexpression and renal cancer progression.

The heme oxygenase-1 protein is overexpressed in human renal cancer cells following activation of the Ras-Raf-ERK pathway and mediates anti-apoptotic signal.

The stress-inducible cytoprotective enzyme heme oxygenase-1 (HO-1) may play a critical role in the growth and metastasis of tumors. We demonstrated that overexpressed HO-1 promotes the survival of renal cancer cells by inhibiting cellular apoptosis; we also showed that the proto-oncogene H-Ras becomes activated in these cells under stress following treatment with immunosuppressive agents. However, it is not known if there is an association between Ras activation and HO-1 overexpression. Here, we examined if the activation of H-Ras pathway could induce HO-1, and promote the survival of renal cancer cells (786-0 and Caki-1). In co-transfection assays, using HO-1 promoter-luciferase construct, we found that the activated H-Ras, H-Ras(12V), promoted HO-1 transcriptional activation. The inhibition of endogenous H-Ras by specific dominant-negative mutant/siRNA markedly ablated the HO-1 promoter activity. Active H-Ras increased HO-1 mRNA and protein expression. Moreover, transfection with effector domain mutant constructs of active H-Ras showed that H-Ras-induced HO-1 overexpression was primarily mediated through the Raf signaling pathway. Using pharmacological inhibitor, we observed that ERK is a critical intermediary molecule for Ras-Raf-induced HO-1 expression. Activation of H-Ras and ERK promoted nuclear translocation of the transcription factor Nrf2 for its binding to the specific sequence of HO-1 promoter. The knockdown of Nrf2 significantly inhibited H-Ras-induced HO-1 transcription. Finally, by FACS analysis using Annexin-V staining, we demonstrated that the H-Ras-ERK-induced and HO-1-mediated pathway could protect renal cancer cells from apoptosis. Thus, targeting the Ras-Raf-ERK pathway for HO-1 overexpression may serve as novel therapeutics for the treatment of renal cancer.