Occult myocardial injury is prevalent amongst elderly patients in the hospital-at-home setting. A retrospective analysis of 213 patients.

Background: Hospital-at-Home (HAH) is a valid alternative for in-hospital stay for a wide variety of clinical indications. Occult myocardial injury, associated with acute illness, mainly occurs in patients with a background of non-obstructive coronary disease. The aim of this study was to describe the prevalence of this phenomenon in our HAH population. Methods: A retrospective description and analysis of data collected for patients admitted to the Sheba beyond's HAH services during 14 months. Results: During a period of 14 months (7/10/21-6/12/22), blood troponin measurements were available for 213 patients (median age 78 years, 52% males) hospitalized mainly for infectious causes. The median HS (highly sensitive) troponin level was 7.7 ng/L (IQR = 13.2 ng/L) (the normal upper limit is 12 ng/L) with 31% of all patients demonstrating an abnormally increased troponin level (68/213). Of all patients, 64% had a background diagnosis of a cardiovascular disease (138/213), of whom, 49% had abnormal HS troponin levels (68/138). No patient suffered from acute cardiac function deterioration and no patient died during their hospital-at-home stay. Conclusion: The prevalence of occult myocardial injury amongst elderly patients admitted to hospital-at-home stay for diagnoses other than myocardial infarction is relatively high but it is not associated with worse short-term clinical outcomes.

Implication of integrin α5ß1 in senescence of SK-Mel-147 human melanoma cells.

Downregulation of α5ß1 integrin in the SK-Mel-147 human melanoma culture model sharply inhibits the phenotypic manifestations of tumor progression: cell proliferation and clonal activity. This was accompanied by a 2-3-fold increase in the content of SA-ß-Gal positive cells thus indicating an increase in the cellular senescence phenotype. These changes were accompanied by a significant increase in the activity of p53 and p21 tumor suppressors and components of the PI3K/Akt/mTOR/p70 signaling pathway. Pharmacological inhibition of mTORC1 reduced the content of SA-ß-Gal positive cells in the population of α5ß1-deficient SK-Mel-147 cells. A similar effect was observed with pharmacological and genetic inhibition of the activity of Akt1, one of the three Akt protein kinase isoenzymes; suppression of other Akt isozymes did not affect melanoma cell senescence. The results presented in this work and previously obtained indicate that α5ß1 shares with other integrins of the ß1 family the function of cell protection from senescence. This function is realized via regulation of the PI3K/Akt1/mTOR signaling pathway, in which Akt1 exhibits a non-canonical activity.

High-content microscopy reveals a morphological signature of bortezomib resistance.

Drug resistance is a challenge in anticancer therapy, particularly with targeted therapeutics and cytotoxic compounds. In many cases, cancers can be resistant to the drug prior to exposure, i.e., possess intrinsic drug resistance. However, we lack target-independent methods to anticipate resistance in cancer cell lines or characterize intrinsic drug resistance without a priori knowledge of its cause. We hypothesized that cell morphology could provide an unbiased readout of drug sensitivity prior to treatment. We therefore isolated clonal cell lines that were either sensitive or resistant to bortezomib, a well-characterized proteasome inhibitor and anticancer drug to which many cancer cells possess intrinsic resistance. We then measured high-dimensional single-cell morphology profiles using Cell Painting, a high-content microscopy assay. Our imaging- and computation-based profiling pipeline identified morphological features typically different between resistant and sensitive clones. These features were compiled to generate a morphological signature of bortezomib resistance, which correctly predicted the bortezomib treatment response in seven of ten cell lines not included in the training dataset. This signature of resistance was specific to bortezomib over other drugs targeting the ubiquitin-proteasome system. Our results provide evidence that intrinsic morphological features of drug resistance exist and establish a framework for their identification.

Analysis of copy number variation in men with non-obstructive azoospermia.

BACKGROUND: Recent findings demonstrate that single nucleotide variants can cause non-obstructive azoospermia (NOA). In contrast, copy number variants (CNVs) were only analysed in few studies in infertile men. Some have reported a higher prevalence of CNVs in infertile versus fertile men. OBJECTIVES: This study aimed to elucidate if CNVs are associated with NOA. MATERIALS AND METHODS: We performed array-based comparative genomic hybridisation (aCGH) in 37 men with meiotic arrest, 194 men with Sertoli cell-only phenotype, and 21 control men. We filtered our data for deletions affecting genes and prioritised the affected genes according to the literature search. Prevalence of CNVs was compared between all groups. Exome data of 2,030 men were screened to detect further genetic variants in prioritised genes. Modelling was performed for the protein encoded by the novel candidate gene TEKT5 and we stained for TEKT5 in human testicular tissue. RESULTS: We determined the cause of infertility in two individuals with homozygous deletions of SYCE1 and in one individual with a heterozygous deletion of SYCE1 combined with a likely pathogenic missense variant on the second allele. We detected heterozygous deletions affecting MLH3, EIF2B2, SLX4, CLPP and TEKT5, in one subject each. CNVs were not detected more frequently in infertile men compared with controls. DISCUSSION: While SYCE1 and MLH3 encode known meiosis-specific proteins, much less is known about the proteins encoded by the other identified candidate genes, warranting further analyses. We were able to identify the cause of infertility in one out of the 231 infertile men by aCGH and in two men by using exome sequencing data. CONCLUSION: As aCGH and exome sequencing are both expensive methods, combining both in a clinical routine is not an effective strategy. Instead, using CNV calling from exome data has recently become more precise, potentially making aCGH dispensable.

[Integrin α3ß1 signaling in regulation of the SK-Mel-147 melanoma cell senescence]. / Signaling integrina α3ß1 v regulirovanii stareniia kletok SK-MEL-147 melanomy cheloveka.

Using a model of the human SK-Mel-147 melanoma cell line, it was shown that blocking the expression of integrin α3ß1 by transduction of cells with α3-specific shRNA did not affect their proliferation, but sharply increased the proportion of SA-ß-Gal-positive cells, a phenotypic feature of cell senescence. These findings were accompanied by a significant increase in the activity of the Akt and mTOR protein kinases and the expression of p53 and p21 oncosupressors. Pharmacological inhibition of mTORC1 reduced the number SA-ß-Gal-positive cells in the SK-Mel-147 cell population depleted of α3ß1. Based on our recent data on a non-canonical function of Akt isomers in the regulation of SK-Mel-147 cell senescence caused by deficiency of α2ß1 receptor, we investigated the role of Akt isomers in senescence induced by the α3ß1 knockdown. It appeared that in the cell population with downregulated α3ß1, inhibition of Akt1 reduced the number SA-ß-Gal positive cells to the level of control cell population, while inhibition of Akt2 had no visible effect. Our results demonstrate that the laminin-specific integrin α3ß1, like the collagen-specific receptor α2ß1, is involved in tumor cell protection from senescence, and senescence induced by α3ß1 depletion, like that caused by α2ß1 deficiency, is based on a signaling mechanism employing a non-canonical function of the Akt1 isoform.

Biomechanical consequences of compromised elastic fiber integrity and matrix cross-linking on abdominal aortic aneurysmal enlargement.

Abdominal aortic aneurysms (AAAs) are characterized histopathologically by compromised elastic fiber integrity, lost smooth muscle cells or their function, and remodeled collagen. We used a recently introduced mouse model of AAAs that combines enzymatic degradation of elastic fibers and blocking of lysyl oxidase, and thus matrix cross-linking, to study progressive dilatation of the infrarenal abdominal aorta, including development of intraluminal thrombus. We quantified changes in biomaterial properties and biomechanical functionality within the aneurysmal segment as a function of time of enlargement and degree of thrombosis. Towards this end, we combined multi-modality imaging with state-of-the art biomechanical testing and histology to quantify regional heterogeneities for the first time and we used a computational model of arterial growth and remodeling to test multiple hypotheses, suggested by the data, regarding the degree of lost elastin, accumulation of glycosaminoglycans, and rates of collagen turnover. We found that standard histopathological findings can be misleading, while combining advanced experimental and computational methods revealed that glycosaminoglycan accumulation is pathologic, not adaptive, and that heightened collagen deposition is ineffective if not cross-linked. In conclusion, loss of elastic fiber integrity can be a strong initiator of aortic aneurysms, but it is the rate and effectiveness of fibrillar collagen remodeling that dictates enlargement. STATEMENT OF SIGNIFICANCE: Precise mechanisms by which abdominal aortic aneurysms enlarge remain unclear, but a recent elastase plus ß-aminopropionitrile mouse model provides new insight into disease progression. As in the human condition, the aortic degeneration and adverse remodeling are highly heterogeneous in this model. Our multi-modality experiments quantify and contrast the heterogeneities in geometry and biomaterial properties, and our computational modeling shows that standard histopathology can be misleading. Neither accumulating glycosaminoglycans nor frustrated collagen synthesis slow disease progression, thus highlighting the importance of stimulating adaptive collagen remodeling to limit lesion enlargement.

Irradiation with 365 nm and 405 nm wavelength shows differences in DNA damage of swine pancreatic islets.

INTRODUCTION: 3D printing is being used more extensively in modern biomedicine. One of the problems is selecting a proper crosslinking method of bioprinted material. Amongst currently used techniques we can distinguish: physical crosslinking (e.g. Ca2+ and Sr2+) and chemical crosslinking-the UV light crosslinking causing the biggest discussion. UV radiation is selectively absorbed by DNA, mainly in the UV-B region but also (to some extent) in UV-A and UV-C regions. DNA excitement results in typical photoproducts. The amount of strand breaks may vary depending on the period of exposition, it can also differ when cells undergo incubation after radiation. AIM: The aim of this study was to show whether and how the time of irradiation with 405 nm and 365 nm wavelengths affect DNA damage in cell lines and micro-organs (pancreatic islets). MATERIALS AND METHODS: The degree of DNA damage caused by different wavelengths of radiation (405 nm and 365 nm) was evaluated by a comet assay. The test was performed on fibroblasts, alpha cells, beta cells and porcine pancreatic islets after 24 hours incubation period. Samples without radiation treatment were selected as a control group. Results analysis consisted of determining the percent of cells with damaged DNA and the tail intensity evaluation. RESULTS: The degree of DNA damage in pancreatic islets after exposure to 405 nm wavelength oscillated between 2% and 6% depending on the tested time period (10 - 300 seconds). However, treating islets using 365 nm wavelength resulted in damage up to 50%. This clearly shows significantly less damage when using 405 nm wavelength. Similar results were obtained for the tested cell lines. CONCLUSIONS: Crosslinking with 405 nm is better for pancreatic islets than crosslinking with 365 nm UV light.

Characterization of novel polydiacetylene gel dosimeter for radiotherapy.

Polymer gel dosimeters are instrumental for clinical and research applications in radiotherapy. These dosimeters possess the unique ability to record dose distribution in three dimensions. A Polymer gel dosimeter is composed of organic molecules in a gel matrix, which upon irradiation polymerize to form a conjugated polymer with optical absorbance proportional to the irradiated dose. Other required characteristics of a radiotherapy clinical dosimeter are soft-tissue equivalency, linear dose-response in a range of clinical treatments, and long term stability for the duration of the analysis. The dosimeter presented in this paper is based on diacetylene bearing fatty acid aggregates embedded in a soft-tissue equivalent gel matrix, Phytagel™, which upon irradiation polymerize to form a blue phase polydiacetylene with a strong optical absorption. Initial characterization showed that PDA-gel irradiated with 160 kV x-ray responded linearly to the irradiated dose, and the calculated diffusion coefficient is [Formula: see text] what is very low. It was also found that the percentage depth dose (PDD) curve of the PDA-gel in a 4 × 4 cm2 field, irradiated with 6 MV x-rays, was with good agreement with the literature. PDA-gel has the potential to detect absorbed dose in a range of clinical radiological irradiation regimes.

Forecasting the general surgery physician workforce deficit in the state of Georgia: a public health perspective.

OBJECTIVES: The aim of the study was to quantify the current shortage of general surgeons in the state of Georgia and to estimate the shortage in 2040. STUDY DESIGN: This is a population-based longitudinal study. METHODS: Data were collected from the US Census Bureau, the Georgia Board for Physician Workforce, and the Accreditation Council for Graduate Medical Education to evaluate changes in the supply of general surgeons from 2000 to 2017 and estimate an expected shortage through 2040. RESULTS: The state of Georgia experienced a net loss of 120 surgeons from 2000 to 2017 and currently faces a shortage of 139 general surgeons. We project a deficit of between 285 and 725 general surgeons in the state of Georgia by 2040. CONCLUSION: Georgia will face a substantial general surgical workforce shortage by 2040. Enhanced efforts at boosting both the output of surgical training programs as well as recruitment and retention of surgeons may help alleviate this deficit.

An overview of heat stress relief with global warming in perspective.

Global warming seems more probable, whether as gradual warming or increased frequency of warmer episodes. The productivity of cattle in temperate countries will decline unless counteracting steps are adopted. The probability of pre-emptive breeding for maintaining temperate breed performance coupled with heat stress tolerance is too low to be adopted for counteracting warming. The expected warming will mostly involve temperature increases. These will indirectly affect radiant heat gain in animals owing to reduced radiant heat dissipation from the body by convective heat loss, which results in an increased sensitivity to incoming radiant heat at higher air temperatures. These necessitate an emphasis on increasing convective heat loss by structure design and forced air flow by fans. Convective heat loss diminishes with increasing air temperatures. Evaporative heat loss remains the alternative. Evaporative cooling of the ambient requires partial enclosing of the space surrounding the animals and is limited by the humidity in ambient air. An alternative was developed of coupling forced ventilation with wetting of animal surface. The exchange of ambient air flowing on animal surface makes the evaporation practically independent of air humidity and the loss of heat from animal surface practically independent of the surface to air temperature gradient. The coupling of forced ventilation with wetting combination may be attained in various parts of the dairy farm, the holding area of the milking parlour, the feeding trip and the resting area. Each of these requires differing structural and technological adaptations. Climate and farming systems vary between locations which require specific solutions.

Islet Transplantation - perspective from Poland.

The article describes impact of advanced research in the USA and collaborative approach of US scientists and clinicians on development of the field of islet transplantation in Poland and all over the world. At the same time, it presents negative consequences of islet regulation by FDA as a biological drug leading to decline and extinction of the field in the US, while it is on the rise worldwide.

Implication of Integrin α2ß1 in Proliferation and Invasion of Human Breast Carcinoma and Melanoma Cells: Noncanonical Function of Akt Protein Kinase.

Blocking the expression of integrin α2ß1, which was accomplished by transduction of α2-specific shRNA, resulted in significant inhibition of proliferation and clonal activity in human MCF-7 breast carcinoma and SK-Mel-147 melanoma cells. Along with these changes, deprivation of α2ß1 caused a sharp decrease in melanoma cell invasion in vitro. Analysis of integrin-mediating signal pathways that control cell behavior revealed a significant increase in activity of Akt protein kinase in response to depletion of α2ß1. The increase in Akt activity that accompanies a suppressive effect on cell invasion contradicts well-known Akt function aimed at stimulation of tumor progression. This contradiction could be explained by the "reversed" (noncanonical) role played by Akt in some cells that consists in suppression rather than promotion of invasive phenotype. To test this suggestion, the effects of Akt inhibitors on invasive activity of SK-Mel-147 cells were investigated. If the above suggestion is true, then inhibition of Akt in cells depleted of α2ß1 should result in the restoration of their invasive activity. It appeared that treatment with LY294002, which inhibits all Akt isoforms (Akt1, Akt2, Akt3), not only failed to restore the invasive phenotype of melanoma cells but further attenuated their invasive activity. However, treatment of the cells with an Akt1-specific inhibitor significantly increased their invasion. Thus, the stimulating effect of α2ß1 integrin on invasion of melanoma cells is realized through a mechanism based on inhibition of one of the Akt isoforms, which in these cells exhibits a noncanonical function consisting in suppression of invasion.

Endoscopic Islet Autotransplantation Into Gastric Submucosa-1000-Day Follow-up of Patients.

BACKGROUND: Total pancreatectomy and autologous transplantation of pancreatic islets is a treatment option for patients with severe pain due to chronic pancreatitis. In the standard procedure, pancreatic islets are isolated and subsequently administered into the portal vein. In the case of patients with a history of thrombosis or at risk of thrombosis, this route of administration is not viable. Animal studies conducted in our department led to the development of a technique of endoscopic islets transplantation into the gastric submucosa. In 2013 and 2014, the first human autologous transplant procedures were performed. The objective of this study was to present the results of a 3-year follow-up of these patients. METHODS: Two pancreatectomies were performed in our department, the first in 2013 and another in 2014, along with subsequent autologous transplantation of pancreatic islets into the gastric submucosa. RESULTS: Both patients had been diagnosed previously with diabetes, and both had endogenous islet activity detected. Peptide C concentration after pancreatectomy and before pancreatic cell transplantation was 0.1 ng/mL. After the transplantation, peptide C concentrations for the 2 patients were 0.8 and 0.5 ng/mL on day 7, 1.2 and 0.6 ng/mL on day 30, 1.3 and 0.8 ng/mL on day 180, 1.1 and 0.7 ng/mL on day 360, and 3.0 and 0.6 ng/mL at 3 years, respectively, after transplantation. The pain symptoms resolved in both cases. CONCLUSION: Pancreatic islets may survive in the gastric wall. Endoscopic submucosal transplantation may present an alternative for the management of patients who cannot undergo a classic transplantation procedure.

Analysis of Distribution of Expanded- and Standard-Criteria Donors and Complications Among Polish Recipients by Kidney Donor Risk Index Value.

INTRODUCTION: The approach toward transplanting kidneys from expanded-criteria donors (ECDs) in Poland is largely site-dependent. The Kidney Donor Risk Index (KDRI) allows for obtaining a more precise characteristic of ECDs and further stratification into "better" and "worse" quality grafts. METHODS: Comparison of the incidence of delayed graft function (DGF) and biopsy-proven acute rejection (BPAR), median of hospitalization time and median of estimated glomerular filtration rate (eGFR) at 1 year after transplantation among kidney graft recipients (n = 468), divided by donor status (ECD/standard-criteria donor [SCD]) and KDRI value (I: 0.67-1.2, II: 1.21-1.6, III: 1.61-2.0, IV: 2.01-3.48). RESULTS: ECD kidneys have been transplanted to 32.47% of recipients. There were no ECD recipients in KDRI compartment I, 16.55% in compartment II, 79.22% in compartment III, and 100% in IV. In KDRI compartment II, DGF was diagnosed in 34.9% of SCDs and 56% of ECDs (P = .003), BPAR occurred in 7.8% of SCDs and 16% of ECDs (P = .073), median hospital stay was 12 days for SCDs and ECDs (P = 1), and eGFR was 50.7 mL/min for SCDs and 49.4 mL/min for ECDs (P = .734). In KDRI compartment III, DGF was diagnosed in 43.8% of SCDs and 49.2% of ECDs (P = .139), BPAR occurred in 6.3% of SCDs and 31.7% of ECDs (P = .001), median hospital stay was 10 days for SCDs and 12 days for ECDs (P = .634), and eGFR was 49.5 mL/min for SCDs and 45.2 mL/min for ECDs (P = .382). Among ECD recipients, DGF was diagnosed in 56.0%, 49.2%, and 47.7% of patients for KDRI compartments II, III, and IV respectively (P = .776); BPAR occurred in 16% (compartment II), 31.7% (compartment III), and 23.1% (compartment IV) (P = .273); the median hospital stay was 12 days (compartment II), 12 days (compartment III), and 12.5 days (compartment IV) (P = 1); and eGFR was 49.5 mL/min (compartment II), 45.4 mL/min (compartment III), and 36.1 mL/min (compartment IV) (P = .002). CONCLUSION: Assessment using both the ECD and KDRI systems allows for a more precise evaluation of prognosis and predicting complications among recipients.

Islets Allotransplantation Into Gastric Submucosa in a Patient with Portal Hypertension: 4-year Follow-up.

BACKGROUND: Islets transplantation is an established treatment method for patients suffering from brittle diabetes with hypoglycemia unawareness. The standard implantation technique is through the portal vein into the liver. In case of liver diseases or portal hypertension, finding an extra-hepatic site is recommended. There have been attempts to perform islets transplantations into muscles and into the gastric submucosa. OBJECTIVE: The aim of this study is to show a 4-year follow-up of allotransplantation into gastric submucosa in a case of portal hypertension observed during the procedure of islets infusion. PATIENTS AND METHODS: A 36-year-old woman with complicated diabetes for over 30 years was selected to receive simultaneous islets and kidney transplantation. The patient underwent an unsuccessful simultaneous pancreas and kidney transplantation 2 years earlier in another transplantation center. The patient's daily insulin requirement was 60 IU, which corresponded to 1.15 IU/kg of body weight. The HbA1c level was 7.4%. C-peptide levels, both fasting and stimulated, were 0.01 ng/mL. On December 7, 2013, the patient received transplanted kidney and islets procured from the same donor. Only 124,000 islets equivalents (IEQ) were isolated (2400 IEQ/kg body weight). Islets were suspended in 300 mL of Ringer's solution along with albumin, antibiotics, and heparin. After infusing 100 mL of the islets suspension into the portal vein, pressure in portal vein increased from 5 mm Hg to 23 mm Hg. Despite stopping the infusion, pressure did not drop after 30 minutes. The decision was made to transplant the reminder of the islets (200 mL) into the gastric wall. RESULTS: No complications were observed after the procedure. Serum creatinine level was 1.6 mg/dL on day 10 and 1.5 mg/dL 4 years after the transplantation. Fasting C-peptide levels were 1.7, 0.65, 0.55, 0.69, 0.68, and 0.2 ng/mL at 1, 3, 6, 12, 18, and 36 months after the transplantation, respectively. HbA1c levels were 5.2, 6.4, 4.7, 5.2, and 5.9% at 3, 6, 12, 18, and 36 months, respectively. The patient's insulin requirement dropped to 15 U/day immediately after transplantation and equaled 20 and 27 U/day at 18 and 48 months after the simultaneous islet and kidney transplantation, respectively. CONCLUSION: Allotransplantation of islets into the gastric wall may be a safe alternative in cases of contraindications for transplantation into the portal vein.

The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) framework: protocol to determine a core outcome set for efficacy and effectiveness trials of alcohol screening and brief intervention.

BACKGROUND: The evidence base to assess the efficacy and effectiveness of alcohol brief interventions (ABI) is weakened by variation in the outcomes measured and by inconsistent reporting. The 'Outcome Reporting in Brief Intervention Trials: Alcohol' (ORBITAL) project aims to develop a core outcome set (COS) and reporting guidance for its use in future trials of ABI in a range of settings. METHODS/DESIGN: An international Special Interest Group was convened through INEBRIA (International Network on Brief Interventions for Alcohol and Other Drugs) to inform the development of a COS for trials of ABI. ORBITAL will incorporate a systematic review to map outcomes used in efficacy and effectiveness trials of ABI and their measurement properties, using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. This will support a multi-round Delphi study to prioritise outcomes. Delphi panellists will be drawn from a range of settings and stakeholder groups, and the Delphi study will also be used to determine if a single COS is relevant for all settings. A consensus meeting with key stakeholder representation will determine the final COS and associated guidance for its use in trials of ABI. DISCUSSION: ORBITAL will develop a COS for alcohol screening and brief intervention trials, with outcomes stratified into domains and guidance on outcome measurement instruments. The standardisation of ABI outcomes and their measurement will support the ongoing development of ABI studies and a systematic synthesis of emerging research findings. We will track the extent to which the COS delivers on this promise through an exploration of the use of the guidance in the decade following COS publication.

Hyperexpression of Integrin α5ß1 Promotes Resistance of MCF-7 Human Breast Carcinoma Cells to Doxorubicin via ERK Protein Kinase Down-regulation.

In MCF-7 human breast carcinoma cells, α5ß1 integrin hyperexpression, which was accomplished by transduction of a full-length α5 integrin cDNA, increased by about 50-70% the number of cells, survived during 48-72 h cell treatment with doxorubicin. Up-regulation of α5ß1 reduced the level of the apoptogenic p53 protein and p21 cell cycle inhibitor, but enhanced the activity of Akt and mTOR protein kinases. In addition to these findings, we observed a significant decrease in the activity of both isoforms of phosphokinase Erk1/2, which is known to play a key role in cell viability pathways, including pathways alleviating stress damages caused by distinct antitumor drugs. Diminished Erk activity accompanying the rise of drug resistance can be explained by an "atypical" function of this kinase, which, in the cells studied, promotes an enhanced rather than reduced sensitivity to doxorubicin. To verify this suggestion, the effect of a specific Erk inhibitor, PD98059, on the resistance to doxorubicin of control and α5 cDNA-transduced MCF-7 cells was investigated. The data showed that suppression of Erk activity increased the resistance of control cells (transduced with an "empty" vector) to a level higher than that demonstrated by the α5 cDNA-transduced cells. The highest level of resistance was observed in α5ß1-trancduced cells treated with PD98059. Akt and mTOR kinase inhibitors had little if any effect on doxorubicin resistance of α5 cDNA-transduced MCF-7 cells. The data show for the first time that integrin α5ß1 can stimulate drug resistance of tumor cells through a mechanism based on the inhibition of protein kinase Erk. From a more general view, the results of this investigation suggest that signal protein kinases can perform in tumor cells "non-canonical" functions, opposite to those, which are the basis for using kinase inhibitors in targeted cancer therapy. It follows that if a protein kinase is supposed to be used as a target for such therapy, it is important to explore its features in the particular tumor prior to the onset of treatment.