An Overview of Selected Bacterial Infections in Cancer, Their Virulence Factors, and Some Aspects of Infection Management.

In cancer development and its clinical course, bacteria can be involved in etiology and secondary infection. Regarding etiology, various epidemiological studies have revealed that Helicobacter pylori can directly impact gastric carcinogenesis. The Helicobacter pylori-associated virulence factor cytotoxin-associated gene A perhaps plays an important role through different mechanisms such as aberrant DNA methylation, activation of nuclear factor kappa B, and modulation of the Wnt/ß-catenin signaling pathway. Many other bacteria, including Salmonella and Pseudomonas, can also affect Wnt/ß-catenin signaling. Although Helicobacter pylori is involved in both gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma, its role in the latter disease is more complicated. Among other bacterial species, Chlamydia is linked with a diverse range of diseases including cancers of different sites. The cellular organizations of Chlamydia are highly complex. Interestingly, Escherichia coli is believed to be associated with colon cancer development. Microorganisms such as Escherichia coli and Pseudomonas aeruginosa are frequently isolated from secondary infections in cancer patients. In these patients, the common sites of infection are the respiratory, gastrointestinal, and urinary tracts. There is an alarming rise in infections with multidrug-resistant bacteria and the scarcity of suitable antimicrobial agents adversely influences prognosis. Therefore, effective implementation of antimicrobial stewardship strategies is important in cancer patients.

Prognostic Significance of the Coagulation and Complement Systems in Critical COVID-19 Infection.

Infection with the SARS-CoV-2 virus (COVID-19 disease) can cause a wide range of clinical situations - from an asymptomatic state to fatal outcomes. In cases of serious clinical manifestations, the underlying mechanisms involve a number of immune cells and stromal cells as well as their products such as pro-inflammatory interleukin-6 and tumour necrosis factor-alpha that ultimately cause the cytokine storm. The situation of overproduction of pro-inflammatory cytokines is somewhat similar to, though in a mild form, health conditions in obesity and related metabolic disorders like type-2 diabetes, which are also considered important risk factors for severe illness in COVID-19. Interestingly, neutrophils perhaps play a significant role in this pathogenesis. On the other hand, it is thought that COVID-19-related critical illness is associated with pathological hyperactivity of the complement system and coagulopathy. Although the precise molecular interactions between the complement and coagulation systems are not clear, we observe an intimate cross-talk between these two systems in critically ill COVID-19 patients. It is believed that both of these biological systems are connected with the cytokine storm in severe COVID-19 disease and actively participate in this vicious cycle. In order to hinder the pathological progression of COVID-19, a number of anticoagulation agents and complement inhibitors have been used with varying success. Among these drugs, low molecular weight heparin enoxaparin, factor Xa inhibitor apixaban, and complement C5 inhibitor eculizumab have been commonly used in patients with COVID-19. Our overall experience might help us in the future to tackle any such conditions.

Infections and immunity: associations with obesity and related metabolic disorders.

About one-fourth of the global population is either overweight or obese, both of which increase the risk of insulin resistance, cardiovascular diseases, and infections. In obesity, both immune cells and adipocytes produce an excess of pro-inflammatory cytokines that may play a significant role in disease progression. In the recent coronavirus disease 2019 (COVID-19) pandemic, important pathological characteristics such as involvement of the renin-angiotensin-aldosterone system, endothelial injury, and pro-inflammatory cytokine release have been shown to be connected with obesity and associated sequelae such as insulin resistance/type 2 diabetes and hypertension. This pathological connection may explain the severity of COVID-19 in patients with metabolic disorders. Many studies have also reported an association between type 2 diabetes and persistent viral infections. Similarly, diabetes favors the growth of various microorganisms including protozoal pathogens as well as opportunistic bacteria and fungi. Furthermore, diabetes is a risk factor for a number of prion-like diseases. There is also an interesting relationship between helminths and type 2 diabetes; helminthiasis may reduce the pro-inflammatory state, but is also associated with type 2 diabetes or even neoplastic processes. Several studies have also documented altered circulating levels of neutrophils, lymphocytes, and monocytes in obesity, which likely modifies vaccine effectiveness. Timely monitoring of inflammatory markers (e.g., C-reactive protein) and energy homeostasis markers (e.g., leptin) could be helpful in preventing many obesity-related diseases.

Evaluation of cancer awareness, cancer education, and prevention intervention techniques among university-level students in the United States and India.

BACKGROUND: Cancer is one of the leading causes of death globally. A considerable number of different cancer types may be preventable, using primary intervention techniques, such as health education, cancer awareness, behaviors and lifestyle modifications. The present study conducted a comparative assessment of cancer awareness among undergraduate students of the United States and India. MATERIALS AND METHODS: Students from an Institution in India (KC) (55 females, 33 males), and an Institution in the United States of America (SHU) (226 female, 58 male) during 2019-2020 participated in this study. Participants (n = 372) across all majors and all years (first through fourth year) completed an online questionnaire and answered the questions on their demographic characteristics (e.g., gender, age, and location), academic status (e.g., year of study, major), multiple-choice questions about cancer knowledge, and opinion questions (e.g., "where would you find info," "should therapies be free"). Student responses were collected using Qualtrics Survey Software. Excel was used to analyze responses. We conducted statistical Χ2 tests for independence to determine whether there is a statistically significant difference between the expected frequencies and the observed frequencies in one or more categories of a contingency table, with a significance of ɑ = 0.01. While small sizes due to the small institutions and the response pool, we note that we achieved the necessary "n" for all tests reported. RESULTS: Our research shows a few important statistically significant differences, including knowledge of cancer and breast lumps is dependent on location, ranking of global cancer deaths is dependent on location, and that cancer knowledge is dependent on the information source. All for Χ2 tests with P < 0.001. CONCLUSIONS: Further encouragement of education for young people in various aspects of cancer and cancer prevention, as well as information facility and sources of reliable data, could be helpful for improving the overall health and primary prevention. A thorough assessment is needed to understand the responsible factors for the observed cancer knowledge variations among students of two different places.

Cancer and comorbidity: The role of leptin in breast cancer and associated pathologies.

Obesity is an important risk factor for postmenopausal breast cancer and also a poor prognostic factor among cancer patients. Moreover, obesity is associated with a number of health disorders such as insulin resistance/type-2 diabetes mellitus, hypertension, and other cardiovascular diseases. Frequently, these health disorders exhibit as components/complications of the metabolic syndrome. Nevertheless, obesity-related diseases may coexist with postmenopausal breast cancer; and these comorbid conditions could be substantial. Therefore, it may be assumed that different diseases including breast cancer could originate from a common pathological background in excessive adipose tissue. Adipocyte-released hormone-like cytokine (or adipokine) leptin behaves differently in a normal healthy state and obesity. A growing body of evidence suggests an important role of leptin in our major obesity-related health issues such as insulin resistance, hypertension, and neoplasia. In this context, this review describes the relationships of the abovementioned pathologies with leptin.

Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway.

BACKGROUND: In menopausal women, one of the critical risk factors for breast cancer is obesity/adiposity. It is evident from various studies that leptin, a 16 kDa protein hormone overproduced in obese people, plays the critical role in neovascularization and tumorigenesis in breast and other organs. However, the mechanisms by which obesity influences the breast carcinogenesis remained unclear. In this study, by analyzing different estrogen receptor-α (ER-α)-positive and ER-α-negative BC cell lines, we defined the role of CCN5 in the leptin-mediated regulation of growth and invasive capacity. METHODS: We analyzed the effect of leptin on cell viability of ER-α-positive MCF-7 and ZR-75-1 cell lines and ER-α-negative MDA-MB-231 cell line. Additionally, we also determined the effect of leptin on the epithelial-mesenchymal transition (EMT) bio-markers, in vitro invasion and sphere-formation of MCF-7 and ZR-75-1 cell lines. To understand the mechanism, we determined the impact of leptin on CCN5 expression and the functional role of CCN5 in these cells by the treatment of human recombinant CCN5 protein(hrCCN5). Moreover, we also determined the role of JAK-STAT and AKT in the regulation of leptin-induced suppression of CCN5 in BC cells. RESULTS: Present studies demonstrate that leptin can induce cell viability, EMT, sphere-forming ability and migration of MCF-7 and ZR-75-1 cell lines. Furthermore, these studies found that leptin suppresses the expression of CCN5 at the transcriptional level. Although the CCN5 suppression has no impact on the constitutive proliferation of MCF-7 and ZR-75-1 cells, it is critical for leptin-induced viability and necessary for EMT, induction of in vitro migration and sphere formation, as the hrCCN5 treatment significantly inhibits the leptin-induced viability, EMT, migration and sphere-forming ability of these cells. Mechanistically, CCN5-suppression by leptin is mediated via activating JAK/AKT/STAT-signaling pathways. CONCLUSIONS: These studies suggest that CCN5 serves as a gatekeeper for leptin-dependent growth and progression of luminal-type (ER-positive) BC cells. Leptin may thus need to destroy the CCN5-barrier to promote BC growth and progression via activating JAK/AKT/STAT signaling. Therefore, these observations suggest a therapeutic potency of CCN5 by restoration or treatment in obese-related luminal-type BC growth and progression.

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment.

Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

The potential role of leptin in tumor invasion and metastasis.

The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin's association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-ß signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin's potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

The influence of different calorie restriction protocols on serum pro-inflammatory cytokines, adipokines and IGF-I levels in female C57BL6 mice: short term and long term diet effects.

Calorie restriction (CR) is an effective intervention to prevent chronic diseases including cancer. Although many factors, i.e., sex hormones, IGF-I and mTOR have been studied in response to CR, the molecular mechanisms of CR remain to be identified. Our objective was to determine the short and long-term effects of different CR protocols on pro-inflammatory cytokines. Our hypothesis was that Intermittent CR (ICR) would result in greater inhibition of pro-inflammatory serum cytokines compared to Chronic CR (CCR) as we previously found ICR to be more protective in the prevention of mammary tumor development. From ten weeks of age female C57BL6 mice were maintained on either ad libitum (AL) fed, ICR or CCR protocols (overall CR of ~75% of AL) for up to 74 weeks of age. Blood samples were collected for measurements of serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adiponectin, leptin, IGF-I and insulin at specified ages. For ICR mice samples were collected following 3 weeks of restriction (ICR-R) and after one week of refeeding (ICR-RF). In general, both modes of CR significantly reduced serum IL-6, TNF-α, IGF-I and leptin levels compared to AL with IL-6 levels 24 and 3.5 fold and TNF-α levels t 11 and 1.5 fold lower in ICR and CCR groups, respectively at study termination. There was a trend for adiponectin and insulin to be highest in ICR-RF mice. Body weights were positively correlated with IL-6, TNF-α, insulin and leptin but negatively correlated with adiponectin-to-leptin ratio. Moreover, there was a positive correlation between IL-6 and TNF-α. Beneficial effects of ICR may function through pro-inflammatory cytokine pathways.

Humanized Monoclonal Antibody Alemtuzumab Treatment in Transplant.

Successful attenuation of allograft rejection rate is a major clinical aspect in transplant. The CD52 binding monoclonal antibody CAMPATH1 or alemtuzumab, in this aspect, shows a promise as an effective immunomodifier. This humanized monoclonal antibody efficiently depletes CD52-bearing mature B- and T lymphocytes from circulation and thereby causes transient lymphopenia, a condition for generalized immunosuppression. Alemtuzumab is an approved drug for the treatment of B cell chronic lymphocytic leukemia. However, its implication in transplant as nonsteroidal drug is a growing area of investigation. Here, we provided a brief account on alemtuzumab as an immunomodifier in allotransplant.

Biological characteristics of CCN proteins in tumor development.

The extracellular membrane (ECM) is no longer regarded as inert, rather it has multiple versatile physiologic functions. Its diverse composition is implicated in each step of cancer progression including inflammation, angiogenesis, tumor invasion and metastasis. In addition to structural proteins, the ECM also contains a family of non-structural proteins called matricellular proteins. The six secreted CCN proteins, which belong to the matricellular protein family, include the following: Cyr61 (CCN1), CTGF (CCN2), Nov (CCN3), WISP- 1 (CCN4), WISP-2 (CCN5) and WISP-3(CCN6). These proteins are capable of modulating a variety of biological processes in health as well as in disease conditions. In tumor development and in tumor microenvironment, CCN proteins can influence multiple facets of pathophysiological processes including cellular proliferation, invasion and metastasis. This review has attempted a cohesive look at the CCN family protein functions in a tumor-specific manner.

Expression of BRCA1 and BRCA2 proteins and their correlation with clinical staging in breast cancer.

OBJECTIVES: The purpose of this study was to evaluate the level of expression of the BRCA1 and BRCA2 proteins in sporadic breast cancer cases to determine the functional role of these genes in breast carcinogenesis. MATERIALS AND METHODS: Paraffin embedded histologically proven invasive breast tissue sections that were obtained from 40 patients and the adjacent normal breast tissue sections used as controls to determine breast carcinoma specific changes in the expression of BRCA1 and BRCA2 by immunohistochemistry (IHC). RESULTS: Majority of the cases express either low or no detectable level of BRCA1 expression in tumor tissues in comparison with control; the decline in BRCA1 expression was found to be more prominent in advanced grade 3 disease. On the other hand, the expression of BRCA2 protein was moderate or low in breast cancer cases and its overall distribution did not show significant difference when compared with controls. Interestingly, those breast cancer cases, which were found to express low or no BRCA1 expression, demonstrated a higher protein level of BRCA2. The inverse correlation of BRCA1 and BRCA2 expression was more prominent in post-menopausal patients. CONCLUSIONS: Our results demonstrate in a subset of cases that decline in BRCA1 expression that may be associated with potentially compensatory increase in BRCA2 protein, which may depend on tumor grade as well as menopausal status.

Extracellular matrix in obesity - cancer interactions.

Obesity or overweight is a risk factor for several health disorders such as type 2 diabetes, hypertension, and certain cancers. Furthermore, obesity affects almost all body systems including the extracellular matrix (ECM) by generating a pro-inflammatory environment, which are associated with abnormal secretions of several cytokines or hormonal substances, for example, insulin-like growth factors (IGFs), leptin, and sex hormones. These chemical mediators most likely have a great impact on the ECM. Accumulating evidence suggests that both obesity and ECM can influence tumor growth and progression through a number of chemical mediators. Conversely, cells in the connective tissue, namely fibroblasts and macrophages, support and aggravate the inflammatory situation in obesity by releasing several cytokines or growth factors such as vascular endothelial growth factor, epidermal growth factor, and transforming growth factor-beta (TGF-ß). A wide range of functions are performed by TGF-ß in normal health and pathological conditions including tumorigenesis. Breast cancer in postmenopausal women is a classic example of obesity-related cancer wherein several of these conditions, for example, higher levels of pro-inflammatory cytokines, impairment in the regulation of estrogen and growth factors, and dysregulation of different ECM components may favor the neoplastic process. Aberrant expressions of ECM components such as matrix metalloproteinases or matricellular proteins in both obesity and cancer have been reported by many studies. Nonstructural matricellular proteins, viz., thrombospondins, secreted protein acidic and rich in cysteine (SPARC), and Cyr61-CTGF-Nov (CCN), which function as modulators of cell-ECM interactions, exhibit protean behavior in cancer. Precise understanding of ECM biology can provide potential therapeutic targets to combat obesity-related pathologies.

Small Circular DNAs in Human Pathology.

In general, human pathogen-related small circular deoxyribonucleic acid (DNA) molecules are bacterial plasmids and a group of viral genomes. Plasmids are extra-chromosomal small circular DNAs that are capable of replicating independently of the host, and are present throughout a variety of different microorganisms, most notably bacteria. While plasmids are not essential components of the host, they can impart an assortment of survival enhancing genes such as for fertility, drug resistance, and toxins. Furthermore, plasmids are of particular interest to molecular biology especially in relation to gene-cloning. Among viruses, genomes of anelloviruses, papillomaviruses, and polyomaviruses consist of small circular DNA. The latter two virus families are known for their potential roles in a number of pathogenic processes. Human papillomaviruses (HPV) are now widely recognised to be associated with a greatly increased risk of cervical cancer, especially oncogenic strains 16 and 18. On the other hand, human cells may contain several types of small circular DNA molecules including mitochondrial DNA (mtDNA). The mitochondrial genome consists of 37 genes that encode for proteins of the oxidation phosphorylation system, transfer ribonucleic acids (tRNAs), and ribosomal RNAs (rRNAs). Though mitochondria can replicate independently of the host; nuclear DNA does encode for several mitochondrial proteins. Mutations in mtDNA contribute to some well characterised diseases; mtDNA is also implicated in several diseases and malignancies with poorly elucidated aetiologies. Furthermore, mtDNA can function as a diagnostic tool. Other extra-chromosomal circular DNAs are usually detected in cancer. This review article is intended to provide an overview of four broad categories of small circular DNAs that are present in non-eukaryotic (plasmids and relevant viral genomes) and eukaryotic (mtDNA and other extra-chromosomal DNAs) systems with reference to human diseases, particularly cancer. For this purpose, a literature search has been carried out mainly from PubMed. Improved understanding of the significance of small circular DNA molecules is expected to have far reaching implications in many fields of medicine.

Immunomodulatory effects of anti-estrogenic drugs.

There are substantial experimental, epidemiological and clinical evidences that show that breast cancer pathology is influenced by endogenous estrogens. This knowledge is the foundation upon which endocrine deprivation therapy has been developed as a major modality for the management of breast cancer. Tamoxifen, which functions as a competitive partial agonist-inhibitor of estrogen at its receptor, has been widely used for more than three decades for adjuvant endocrine treatment in breast cancer. Currently, other effective drugs for endocrine therapy include raloxifene, different aromatase inhibitors (particularly third-generation agents) and luteinizing hormone-releasing hormone agonists. In recent years, a growing body of evidence suggests that these drugs can also act as immune modulators by altering the function of various leukocytes and the release of different cytokines. Moreover, there is evidence that anti-estrogens may prove to be beneficial in the treatment or prevention of some autoimmune diseases due to their effects on immune function. However, their immunopharmacological aspects in the present state of knowledge are not precisely comprehensible. Only a clear pathophysiological understanding could lead to an efficient strategy for breast cancer prevention and decrease in the mortality due to this disease.

Growth and Progression of TRAMP Prostate Tumors in Relationship to Diet and Obesity.

To clarify effects of diet and body weight on prostate cancer development, three studies were undertaken using the TRAMP mouse model of this disease. In the first experiment, obesity was induced by injection of gold thioglucose (GTG). Age of prostate tumor detection (~33 wk) and death (~43 wk) was not significantly different among the groups. In the second study, TRAMP-C2 cells were injected into syngeneic C57BL6 mice and tumor progression was evaluated in mice fed either high-fat or low-fat diets. The high fat fed mice had larger tumors than did the low-fat fed mice. In the third study, tumor development was followed in TRAMP mice fed a high fat diet from 6 weeks of age. There were no significant effects of body weight status or diet on tumor development among the groups. When the tumors were examined for the neuroendocrine marker synaptophysin, there was no correlation with either body weight or diet. However, there was a significant correlation of the expression of synaptophysin with earlier age to tumor detection and death. In summary, TRAMP-C2 cells grew faster when the mice were fed a high-fat diet. Further synaptophysin may be a marker of poor prognosis independent of weight and diet.

Crocetin: an agent derived from saffron for prevention and therapy for cancer.

Cancer is one of the leading causes of death in the United States and accounts for approximately 8 million deaths per year worldwide. Although there is an increasing number of therapeutic options available for patients with cancer, their efficacy is time-limited and non-curative. Approximately 50-60% cancer patients in the United States utilize agents derived from different parts of plants or nutrients (complementary and alternative medicine), exclusively or concurrently with traditional therapeutic regime such as chemotherapy and/or radiation therapy. The need for new drugs has prompted studies evaluating possible anti-cancer agents in fruits, vegetables, herbs and spices. Saffron, a spice and a food colorant present in the dry stigmas of the plant Crocus sativus L., has been used as an herbal remedy for various ailments including cancer by the ancient Arabian, Indian and Chinese cultures. Crocetin, an important carotenoid constituent of saffron, has shown significant potential as an anti-tumor agent in animal models and cell culture systems. Crocetin affects the growth of cancer cells by inhibiting nucleic acid synthesis, enhancing anti-oxidative system, inducing apoptosis and hindering growth factor signaling pathways. This review discusses the studies on cancer preventive potential of crocetin and its future use as an anticancer agent.

Obesity and breast cancer: a clinical biochemistry perspective.

OBJECTIVES: To evaluate the laboratory diagnosis aspects of obesity-related health problems with special reference to postmenopausal breast cancer. DESIGN AND METHODS: We conducted a systemic search of the literature primarily from the PubMed to obtain the relevant data. RESULTS: Obesity is associated with the dysregulations of a number of body components such as blood constituents, extracellular matrix, and hormones/growth factors axes, which could be utilized for early diagnosis. CONCLUSIONS: Obesity-related disorders including breast cancer have emerged as major health problems in almost all the nations. There is a need to elucidate different biochemical markers that are being used in the clinics or have the potential for such use. A precise understanding of the complex pathologies related with obesity is useful in prevention, early diagnosis and overall clinical management.

Epidermal growth factor receptor expression in urinary bladder cancer.

OBJECTIVE: To evaluate the expression pattern of epidermal growth factor receptor (EGFR) in urinary bladder cancer and its association with human epidermal growth factor receptor 2 (HER2), epidermal growth factor (EGF), interleukin-6 (IL-6), and high risk human papilloma virus (HPV) types 16 and 18. MATERIALS AND METHODS: Thirty cases of urothelial carcinoma were analyzed. EGFR, HER2, EGF, and IL-6 expressions in the tissue were evaluated by immunohistochemical staining. For HPV, DNA from tissue samples was extracted and detection of HPV was done by PCR technique. Furthermore, evaluation of different intracellular molecules associated with EGFR signaling pathways was performed by the western blot method using lysates from various cells and tissues. RESULTS: In this study, the frequencies of immunopositivity for EGFR, HER2, EGF, and IL-6 were 23%, 60%, 47%, and 80%, respectively. No cases were positive for HPV-18, whereas HPV-16 was detected in 10% cases. Overall, expression of EGFR did not show any statistically significant association with the studied parameters. However, among male patients, a significant association was found only between EGFR and HER2. CONCLUSIONS: Overexpression of EGFR and/or HER2, two important members of the same family of growth factor receptors, was observed in a considerable proportion of cases. Precise knowledge in this subject would be helpful to formulate a rational treatment strategy in patients with urinary bladder cancer.