Targeted Anti-Mitochondrial Therapy: The Future of Oncology.

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells' survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.

Mitochondria determine response to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy: An evidence-based hypothesis.

Immunotherapy based on programmed cell death protein-1 (PD-1) is a promising approach in oncology. However, a significant fraction of patients remain unresponsive. Therefore, it is imperative to clarify the relevant predictive factors. A decrease in cellular adenosine triphosphate (c-ATP) level can predispose to cellular dysfunction. ATP is a prerequisite for proper T cell migration and activation. Therefore, a decrease in the c-ATP level impairs T cell function and promotes cancer progression. This article gives an overview of the potential predictive factors of PD-1 blockade. Besides, it highlights the pivotal role of mitochondria in response to anti-PD-1 therapies.

Convergence Science to Transform Biomedicine: A Narrative Review.

Recently convergence science was proposed and promoted in a large report from US National Science Foundation and Department of Commerce (NSF/DOC). The report was entitled "converging technologies for improving human performance. "It was dealing with converging of four technologies as: Nanotechnology, Biotechnology, Information technology and Cognitive science (NBIC). The report has gained tremendous popularity throughout the academia and scientific world. On Dec 2015 in a monthly meeting of the department of basic science of Iran Academy of Medical Science, the report of NSF/DOC on NBIC has been discussed. A working group has been established for more discussion and application in Iran. Several seminars in this regard have been performed, and presently this technology has been started as pilot in some technical universities in Iran. After US National Research Council (NCR) in the year 2014 and Massachusetts Institute of Technology (MIT) on convergence in biomedicine, the concept opened a new gate to approach solving medical and health care problems; the convergence technology in biomedical sciences has become interested and gained great popularity among the working group of convergence science in academy of medical science. This technology can lead to advances in fighting chronic diseases such as cancer, dementia, psychiatric disorders, disease of aging and others. The following is summary of proposed discussions in several gathered groups of scientists in this field.

Cell Energy: A New Hypothesis in Decoding Cancer Evolution.

The present study deviates from previous approaches as it focuses on the concept of energy to illuminate cancer-related issues. Energy is a prerequisite for any function; cellular function is no exception, and thus, reduced energy in human cells can impair their performance. This hypothesis provides a novel view of cancer formation. It shows that a normal cell transforms into its cancerous counterpart in response to cellular adenosine triphosphate (ATP) depletion. Moreover, it presents a new definition for the origin of cancer stem cells and how they can regenerate cancer. This article regards a distinct aspect of cancer that helps to differentiate various phases of its progression and shed light on some of the uncharted zones of its pathway for the first time that needs further confirmation by empirical studies.

Iran in transition.

Being the second-largest country in the Middle East, Iran has a long history of civilisation during which several dynasties have been overthrown and established and health-related structures have been reorganised. Iran has had the replacement of traditional practices with modern medical treatments, emergence of multiple pioneer scientists and physicians with great contributions to the advancement of science, environmental and ecological changes in addition to large-scale natural disasters, epidemics of multiple communicable diseases, and the shift towards non-communicable diseases in recent decades. Given the lessons learnt from political instabilities in the past centuries and the approaches undertaken to overcome health challenges at the time, Iran has emerged as it is today. Iran is now a country with a population exceeding 80 million, mainly inhabiting urban regions, and has an increasing burden of non-communicable diseases, including cardiovascular diseases, hypertension, diabetes, malignancies, mental disorders, substance abuse, and road injuries.

New Insights into Connection of Nucleolar Functions and Cancer.

The nucleolus is an intranuclear membrane-less organelle. It is involved in ribosome biogenesis and protein synthesis. When the demand for protein synthesis increases in cell growth and proliferation (e.g., tumors), the cell upregulates ribosome biogenesis. Changes in nucleolar size and number have been recognized as known features of many tumor types. Recent evidence suggests that overproduction of ribosome, decreased ribosome biogenesis, and quantitative and qualitative changes in the nucleolus function, may result in oncogenesis. Today, it is clear that the nucleolus is involved in processes other than ribosome biogenesis. Other functions of the nucleolus include detecting and responding to endogenous and exogenous stress, maintaining genome stability, and regulating cell cycle progression, telomere function, cellular senescence, gene expression, and chromatin structure. Alterations in many of these fundamental nucleolar processes may contribute to the formation of cancer cell phenotypes. This phenomenon suggests that normal nucleolar functions are a safeguard against the development of malignancies and have potential therapeutic effects, as reported in non-small-cell lung carcinoma and other malignancies.

Recent Advances on Nucleolar Functions in Health and Disease.

The nucleolus is an internuclear organelle without a visible membrane via the light microscope inside the cell nucleus. It is the main site for synthesis of ribosome as a complex machine for coordinating protein production. It forms around a specific chromosomal feature called the nucleolar organizing region (NOR) which possesses numerous ribosomal DNA (rDNA). Although the nucleolus is best known as coordinator of ribosomal biogenesis and protein synthesis, recently, there is exciting awareness both on better understanding of ribosome biogenesis and non-ribosomal nucleolar functions. A great amount of research has clearly indicated that the nucleolus has functional activities in both ribosomal and non-ribosomal conditions such as development, aging, cell cycle, gene stability, lifespan regulation, and progeria. Through recent sophisticated and advanced technologies such as genomics, proteomics, metabolomics, advances of knowledge in RNA species and new approaches in microscopic analysis methods, researchers have shown that perturbation in the nucleolar structure and function (nucleolar stress) have been associated with human diseases including cancer, viral infection, cardiovascular and neurodegenerative diseases. In this review, we discuss the impact of current research providing new information regarding nucleolar roles and functions in some human diseases and aging.

Immunohistochemical findings of the granulomatous reaction associated with tuberculosis.

OBJECTIVE/BACKGROUND: The histological diagnosis of Mycobacterium tuberculosis (MTB) has long been a diagnostic challenge in the anatomical pathology field despite availability of different laboratory methods. Immunohistochemistry (IHC) could not only confirm granulomatous tissue involvement but also demonstrate MTB antigen immunolocalization. This study tries to clarify the details of IHC staining for MTB with pAbBCG. METHODS: A total of 50 patients undergoing simultaneous biopsy and tissue culture with positive tissue culture for MTB during 2005-2009 were selected from the MRC Department at Masih Daneshvari Hospital, Tehran, Iran. Using the archives of the Pathology Department of this hospital, which is a referral center for pathological lung lesions, hematoxylin and eosin slides of the selected patients were evaluated. Twenty-three confirmed TB granulomatous tissue samples with adequate tissue and number of granulomas were chosen and studied by Ziehl-Neelsen and IHC staining with pAbBCG. RESULTS: A total of 23 cases were evaluated, of which 17 (73.9%) were males. The types of tissue obtained from study cases were as follows: pleura (9 cases, 39.1%), lymph node (cervical, axillary, and thoracic [9 cases, 39.1%]), and lung tissues (5 cases, 21.7%). IHC staining was positive in all samples, whereas Ziehl-Neelsen staining was positive in nine cases of 23 (39.1%). IHC showed positive coarse granular cytoplasmic and round, fragmented bacillary staining. In this study, epithelioid cells clearly showed more positive staining at the periphery rather than at the center of granuloma. There is also positive staining in endothelial cells, fibroblasts, plasma cells, macrophages, and lymphocytes outside the granuloma. CONCLUSION: Detection of TB in tissue slides is still based on the histological pattern of the granuloma, which has several differential diagnoses with different treatments. Presence of mycobacterial antigens and tissue morphology can be evaluated using the IHC technique. Considering the criteria of positive IHC staining of TB granulomatous reactions, this stain not only highlights the presence of mycobacterial antigens for tissue diagnosis, but also could morphologically localize their distribution in different cells. Pathologists must be familiar with adequate staining pattern, elimination of background staining, and type of selected antibody. This method is especially important for application in countries with high prevalence of TB as a technique with early diagnostic value in tissue specimens. Early diagnosis using this technique can reduce related morbidity and mortality and decrease the rate of complications due to misdiagnosis and mistreatment of TB.

Telomere Shortening in Blood Leukocytes of Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not completely reversible by administration of inhaled bronchodilators. Many studies propose that telomere length shortening might have occurred in COPD patients. We aimed to determine the telomere length in COPD patients and compare the results of non-smoking and smoking control subjects. MATERIALS AND METHODS: In our case-control study, 84 clinically stable COPD patients were recruited on admission to Masih Daneshvari Hospital. Eighty-five healthy controls were also selected including 45 non-smokers and 40 smokers admitted for diseases other than COPD. Spirometry was done for all subjects. Telomere length was measured by quantitative real time PCR as described by Cawthon. The telomere repeat copy number (T) to single-gene copy number (S) ratio was calculated using the comparative Ct method. RESULTS: The mean ±SD of age was 64.33±10.04 years in patients and 65.06 ±10.02 years in controls (P=0.693). The mean ±SD of FEV1 was 1.62±0.75 L in patients, 2.84±0.54 L in smoker controls and 2.83±0.56 L in non-smoker controls; significant differences were detected in this regard between cases and controls (P<0.001). T/S ratio was significantly lower in COPD patients (0.61±0.08) than in the control subjects (0.69±0.09) (P<0.001). However, telomere length was shorter in the patients than in controls in each age group (P<0.001). Additionally, there were no statistically significant differences in telomere length between the smoker and non-smoker control subjects. Regarding the correlation between BMI and telomere length, there were no significant differences among the patients and control groups. CONCLUSION: In conclusion, we found that telomere length in COPD patients was shorter than that in smoker and non-smoker controls, irrespective of age, sex, spirometric variables, BMI and history of cigarette smoking.

Histopathological findings in immunohistological staining of the granulomatous tissue reaction associated with tuberculosis.

Purpose. The histological diagnosis of Mycobacterium tuberculosis (MTB) remains a diagnostic challenge despite different methods. Immunohistochemistry (IHC) not only could confirm granulomatous tissue involvement but also can demonstrate MTB antigen immunolocalization. This study tries to clarify the details of immunohistochemical staining for MTB with pAbBCG. Materials/Methods. Twenty-three confirmed TB granulomatous tissue samples were studied by Ziehl-Neelsen and immunohistochemistry (IHC) staining with pAbBCG. Samples were selected from the archive of the Department of Pathology, National Research Institute of Tuberculosis and Lung Disease, Tehran, Iran. Results. IHC staining was positive in all samples, whereas Ziehl-Neelsen was positive in 9 cases out of 23 (39.1%). Tissue types used were pleural tissue, lymph nodes, and lung tissue. IHC showed positive coarse granular cytoplasmic and round, fragmented bacillary staining. In this study, epithelioid cells clearly showed more positive staining at the periphery of the granuloma rather than the center of granuloma. There is also positive staining in endothelial cells, fibroblasts, plasma cells, lymphocytes, and macrophages outside the granuloma. Conclusion. Considering the criteria of positive immunohistochemical staining of TB granulomatous reactions, this stain not only highlights the presence of mycobacterial antigens for tissue diagnosis, but also could morphologically localize its distribution in different cells.

History of cancer in Iran.

The history of human and animal cancers date back to antiquity. The earliest written document on cancer appeared on Egyptian papyrus. For centuries, the theory of "four humors" was the primary hypothesis that explained the cause for cancer.  Finally, in the 19th century a new era began with the detection of the cellular origin of cancer; in due course, the nature of this lethal disease was better recognized and led to further achievements in cancer treatment. During the 20th century researchers investigated several risk factors for cancer such as tobacco smoking and environmental chemicals, in addition to the carcinogenic role of certain viruses, occupational association of cancer, its relationship with certain hormones and dietary habits, and the genetic basis of cancer. These investigations resulted in more efficient cancer management. After the advent of radiotherapy and chemotherapy as two complementary therapeutic modalities to surgery, the campaign against cancer has improved. However, cancer remains a major health challenge that accounts for substantial morbidity and mortality worldwide. The present paper briefly reviews the history of cancer in Iran, particularly during the last decades of the 20th century.

No association between simian virus 40 and diffuse malignant mesothelioma of the pleura in Iranian patients: a molecular and epidemiologic case-control study of 60 patients.

BACKGROUND: Diffuse malignant mesothelioma (DMM) is increasing in incidence on a worldwide basis and is linked to exposure to asbestos. Simian virus 40 (SV40), a DNA virus, was introduced inadvertently to human populations through contaminated polio vaccine during the years 1956-1963. It has been associated with various types of malignancy in animal experiments. There have been suggestions that SV40 might play a role in the pathogenesis of DMM. OBJECTIVE: To evaluate the association between SV40 and DMM in Iranian patients. METHOD: In a case-control study between the years 2007-2008, isolated DNA from 60 paraffin blocks of patients with DMM and 60 controls was assessed to detect three human polyomaviruses (JCV, BKV, and SV40) using three different sets of primers by multiplex nested PCR analysis. We related the patients with diffuse malignant mesothelioma to possible sites of exposure to asbestos. RESULTS: None of the DMMs nor any patient in the control group had SV40 genome on polymerase chain reaction (PCR). All of the cases were SV40 T antigen negative. CONCLUSION: This study suggests that DMM is independent of SV40 infection in Iran.

Use of immunohistochemistry techniques in patients exposed to sulphur mustard gas.

We performed a pathologic study with further using an immunohistochemical technique (using anti-p63 and anti-CK5) on tissues obtained by open lung biopsy from 18 patients with previous exposure to sulphur mustard (SM) as case group and 8 unexposed patients (control group). The most frequent pathologic diagnosis was constrictive bronchiolitis (44.4%), followed by respiratory (22.2%) and chronic cellular bronchiolitis (16.7%) in the case group, and hypersensitivity bronchiolitis (50%) in the control group. The pathologic diagnoses were significantly different in the case and control groups (P = 0.042). In slides stained by anti-p63 and anti-CK5, the percent of stained cells and the mean number of epithelial cells were lower in the case group in comparison to the control group. This difference was significant for the mean number of cells stained by anti-CK5 (P = 0.042). Furthermore, there was a significant correlation between pathologic diagnosis and total number of cells and mean number of cells stained with anti-p63 and anti-CK5 (P value = 0.002, <0.001, 0.044). These results suggest that constrictive bronchiolitis may be the major pathologic consequence of exposure to SM. Moreover, decrease of p63 in respiratory tissues affected by SM may suggest the lack of regenerative capacity in these patients.

Cerebral tuberculoma in pregnancy: overview of the literature and report of a case.

Tubercle bacilli infect about one third of the world's population and over the past decade resurgence of tuberculosis has been a major health threat mainly due to increasing frequencies of immunosuppressive states and drug-resistant organisms. Although tuberculosis is essentially a lung disease, intracranial elements become involved in 5-10% of cases either as meningitis or tumour-like masses (tuberculoma). Tuberculoma is common in endemic areas but its occurrence during pregnancy is occasional and of particular interest is its intriguing clinical picture mimicking toxemia of pregnancy and brain tumor. In addition, the effects of pregnancy on tuberculosis or vice versa have been controversial. We present here a review of the recent literature and discuss a case coming to medical attention with manifestations of intracranial hypertension during 2 consecutive pregnancies; 4 years apart. On operation a dura-attached mass was detected that proved to be a tuberculoma. After 18 months of close observation and under drug therapy she obviously improved with no ensuing complication. Immunodeficiency state associated with pregnancy is likely to play a role in activation of infection. Tuberculoma should be considered in differential diagnosis of eclampsia and brain mass particularly in women coming from endemic areas for this infection even in the absence of pulmonary involvement.

Practical application of angiogenesis and vasculogenic mimicry in prostatic adenocarcinoma.

BACKGROUND: Tumor growth depends on vascular blood supply. The novel discovery of non-endothelialized vessel-like channels in malignant tumors called vasculogenic mimicry has provided new insights about tumor behavior and also serves as a potential target for drug therapy. Although the association between vasculogenic mimicry and poor prognosis has been established in some tumors, there are only a few studies concerning prostatic carcinoma. METHODS: Using a histochemical and immunohistochemical dual staining method for PAS-CD34 and special immunohistochemical staining for laminin, we studied the presence and pattern of non-endothelialized channels known as vasculogenic mimicry as well as the quantity of endothelialized vessels designated as microvessel density in usual paraffin sections of 20 low-grade and 20 high-grade prostatic adenocarcinomas by routine light microscopy. RESULTS: We found a direct positive relationship between higher microvessel density and tumor grade (P<0.001), presence of vascular invasion (P<0.001) and percent of involved tissue (P<0.001); however, no such relationship was found with vasculogenic mimicry and only a weak correlation was noted between vasculogenic mimicry and perineurial invasion (P=0.03). CONCLUSION: Unlike other cancers and despite the results of in vitro studies on prostatic adenocarcinoma, we were not able to demonstrate a significant relationship between vasculogenic mimicry channels and histologic grading as one of the most important prognostic factors; however, this may be due to an inherent limitation of prostatic tissue imposed by abundant smooth muscle fibers stained by this method. On the other hand, microvessel density scoring appears to be an important, simple, and applicable histologic tool for prostatic cancer evaluation in daily practice.

Environmental risk factors for lung cancer in Iran: a case-control study.

BACKGROUND: Lung cancer remains the leading cause of cancer death in the world. In Iran, lung cancer is one of the five leading tumours and its incidence has been increasing steadily in both men and women. There is a paucity of data from Iran on risk factors for lung cancer. We evaluated environmental risk factors for lung cancer in a case-control study in five hospitals of Tehran. METHODS: Between October 2002 and October 2005, 242 (178 male, 64 female) patients with histologically confirmed lung cancer and two controls for each patient (242 hospital controls and 242 visiting healthy controls) matched for age, sex and place of residence were interviewed using a structured questionnaire on potential risk factors for lung cancer, including environmental and occupational exposures. Associations between risk factors and lung cancer were assessed using conditional logistic regression. RESULTS: Smokers were 66.5% of all cases (85.4% of men and 14.1% of women) and smoking was the strongest correlate of lung cancer in multivariate analysis [odds ratio (OR) 5.4, 95% confidence interval (CI) 3.2-8.9]. Occupational exposures to inorganic dusts (OR 4.2, 95% CI 2.8-6.7), chemical compounds (OR = 3.4, 95% CI 2.1-5.6) and heavy metals (OR 3.0, 95% CI 1.3-7.0) were also independent risk factors for lung cancer. CONCLUSIONS: In our study, smoking was the principal risk factor for lung cancer. However, preventable exposures in the environment, including occupational settings, should not be ignored.

Cancer registry in Iran: a brief overview.

Cancer registry is an important tool for any successful cancer control program. The first formal cancer related data from Iran were published in 1956. In 1969, observations documenting a high incidence of esophageal cancer in the Caspian Littoral, urged researchers to set up the first population-based cancer registry in this region. This cancer registry was established jointly by University of Tehran and the International Agency for Research on Cancer (IARC). In 1976, another cancer registry started its activities in Fars Province. In 1984, the Parliament passed a bill mandating the report of all tissues "diagnosed or suspected as cancer tissue" to the Ministry of Health. While only 187percnt; of all estimated cancer cases were reported in first reports, this rate increased to 81% in 2005 In 1998, Tehran Population-Based Cancer Registry started to collect data from cases of cancer referred to the treatment and diagnostic facilities throughout the Tehran metropolis. Digestive Disease Research Center, Tehran University of Medical Sciences, established four new population-based cancer registries in Northern Iran and another in Kerman Province in the south. These five provinces have a total population of about 9.5 million, and constitute about 16% of the total population of Iran. While the pathology-based cancer registration is in place, we hope that the addition of the population-based cancer registries, and establishment of new registries in poorly-covered areas, will improve cancer reporting in the country.

New Advances in RNAs.

Since the discovery of the first microRNA gene, lin-4, in Caenorhabditis elegans in 1993, many of this small regulatory genes have been reported in plants, viruses, and various kinds of animals. This announced a new world of RNA molecules, which subverted our traditional thinking about RNA. In this review, I summarized the main findings from researchers at different laboratories on microRNAs importance, functionality, production, and different aspects of their biologic activities.A narrative literature overview of relevant papers known to the author and that were retrieved from PubMed is presented.MicroRNA, a nonprotein-coding small RNA with almost 21 - 23 nucleotides in length, is an essential regulatory apparatus in the cells and their environment. They are crucial molecules for development, evolution, cellular differentiation, proliferation, embryogenesis, and cell death. Two classes of microRNAs exist: small temporal RNA--stRNA (miRNAs) and small interfering RNA--siRNAs (RNAi). The latter is a useful tool for the diagnosis, treatment, and prevention of diseases particularly cancer and viral diseases.There have been tremendous research regarding various aspects of these genes silencing and regulatory molecules which are preserved in all kinds of creatures. Currently, about 1% of the known human genes encode microRNAs.

The diagnostic value of Ki-67 and repp86 in distinguishing between benign and malignant mesothelial proliferations.

CONTEXT: The differentiation of benign mesothelial proliferations from malignant mesotheliomas may be difficult, especially when evaluating small specimens from pleural biopsies. OBJECTIVE: To explore the potential value of 2 proliferative cell markers, Ki-67 and restrictedly expressed proliferation-associated protein 86 kDa (repp86), in distinguishing between malignant mesothelioma (MM) and benign reactive mesothelial hyperplasia (MH). DESIGN: Thirty-six cases of MM from 26 men and 10 women with a mean age of 62.9 years (range, 36-80 years) and 22 cases of benign reactive MH from 14 male and 8 female patients with a mean age of 51.5 years (range, 15- 88 years) were included in this study. The proliferative status of the lesions was assessed by immunohistochemistry using monoclonal antibodies to Ki-S2 (repp86) and Ki-S5 (Ki-67). The labeling indices were quantified. RESULTS: The mean labeling indexes for Ki-67 in MM and benign reactive MH were 24.6% (range, 1%-66%) and 6.23% (range, 0%-25%), respectively. The mean labeling indexes for repp86 in MM and benign reactive MH were 26.3% (range, 0%-50%) and 3.26% (range, 0%- 21%), respectively. The average proliferative cell count was significantly higher in MM compared with benign reactive MH (P < .001). Furthermore, both markers showed a significant correlation in their expression in MM and benign reactive MH (r = 77.5, P < .001). Sensitivities of 88% and 92% and specificities of 92% and 94% were obtained at a cutoff point of 9% for Ki-67 and repp86, respectively. CONCLUSIONS: Used in combination, Ki-67 and repp86 appear to be useful markers in differentiating MM from benign reactive MH.