Advancing Diversity in Microbiology: A 55-Year Retrospective Analysis.

Background For over 50 years, affirmative action helped advance equity, diversity and inclusion (EDI) in educational institutions in the United States (U.S.). However, the recent U.S. Supreme Court decision to end affirmative action in college admissions threatens the progress toward EDI. Objective This study aimed to assess the progress in promoting gender and racial diversity within the discipline of microbiology over a 55-year period. We sought to analyze the representation of women and minority groups in faculty ranks, tenure positions, and leadership to identify disparities and trends and determine who will likely be impacted most with the end of affirmative action. Materials and methods This longitudinal retrospective study utilized publicly available and non-identifiable Association of American Medical Colleges (AAMC) data on full-time microbiology faculty from 1967 to 2021. Faculty members were categorized based on academic ranks and tenure status, while gender and racial data were also considered. Results The analysis revealed a consistent dominance of white faculty, with over 60% representation across all academic ranks throughout the study period. The Asian and female faculty representation decreased in senior academic ranks. We observed a positive trend in the annual increase of women in faculty positions, academic ranks, chairs, and tenure positions. Furthermore, Asian faculty demonstrated the most robust surge in representation. However, disparities persisted for black, Hispanic, and Native American faculty members, reflecting broader challenges in their representation. Discussion Although efforts to enhance diversity within microbiology have yielded positive results, underrepresented minority groups still face obstacles in attaining leadership positions and senior academic ranks. The diminishing proportion of women at higher academic ranks raises concerns about potential attrition or lack of promotion opportunities. The end of affirmative action poses a risk of perpetuating this trend, leading to a decline in diversity among microbiology faculty.

Detection of high-risk human papillomavirus infected cervical biopsies samples by immunohistochemical expression of the p16 tumor marker.

Cervical cancer is the fourth most common type of cancer in women worldwide. It is widely accepted that the main cause of cervical cancer, especially in underdeveloped countries like Pakistan, is the infection caused by the human papillomavirus (HPV). The current screening and diagnostic methods face several challenges in accurately detecting the various types of lesions caused by HPV. Therefore, the present study was conducted to assess the effectiveness of p16 immunohistochemistry (IHC) analysis as a diagnostic method in samples of cervical biopsies. One hundred cervical biopsy samples were obtained from female patients across various age groups (> 20- ≤ 30, > 31- ≤ 40, > 41- ≤ 50, > 51- ≤ 60 years). These samples were subsequently prepared for subsequent examination. All samples were analyzed using automated tissue processing followed by Hematoxylin and Eosin (H & E) staining, and p16 IHC tumour marker staining. The H & E slides showed changes in normal cervical tissues, while four cervical abnormalities were identified statistically significant using p16 marker including chronic cervicitis, nabothian cyst formation, cervical intraepithelial neoplasia, and cervical cancers (P value 0.014). Furthermore, among females of different age groups (> 31- ≤ 40, > 41- ≤ 50, > 51- ≤ 60 years) were found statistically significant suffering from cervical cancer (P value 0.04), HPV with cervical cancer (P value 0.01), HPV with cervical intraepithelial neoplasia (P value 0.01). Based on the available data, it can be inferred that the incorporation of the p16 tumor marker may be a valuable method for detecting high-risk HPV in cervical biopsies samples.

Modulation of Gut Microbiome Community Mitigates Multiple Sclerosis in a Mouse Model: The Promising Role of Palmaria palmata Alga as a Prebiotic.

BACKGROUND: Red marine algae have shown the potential to reduce inflammation, influence microbiota, and provide neuroprotection. OBJECTIVE: To examine the prebiotic properties of Palmaria palmata aqueous extract (Palmaria p.) and its potential as a neuroprotective agent in multiple sclerosis (MS). METHODS: eighty-eight adult Swiss mice were divided into four male and four female groups, including a control group (distilled water), Palmaria p.-treated group (600 mg/kg b.w.), cuprizone (CPZ)-treated group (mixed chow 0.2%), and a group treated with both CPZ and Palmaria p. The experiment continued for seven weeks. CPZ treatment terminated at the end of the 5th week, with half of the mice sacrificed to assess the demyelination stage. To examine the spontaneous recovery, the rest of the mice continued until the end of week seven. Behavioral (grip strength (GS) and open field tests (OFT)), microbiome, and histological assessments for general morphology of corpus callous (CC) were all conducted at the end of week five and week 7. RESULTS: Palmaria p. can potentially protect against CPZ-induced MS with variable degrees in male and female Swiss mice. This protection was demonstrated through three key findings: (1) increased F/B ratio and expansion of the beneficial Lactobacillus, Proteobacteria, and Bactriodia communities. (2) Protection against the decline in GS induced by CPZ and prevented CPZ-induced anxiety in OFT. (3) Preservation of structural integrity. CONCLUSIONS: Because of its propensity to promote microbiota alterations, its antioxidant activity, and its content of -3 fatty acids, Palmaria p. could be a promising option for MS patients and could be beneficial as a potential probiotic for the at-risk groups as a preventive measure against MS.

Ethnic and Gender Diversity in Pathology: A Dream Deferred.

Background Equity, diversity, and inclusion (EDI) remain an elusive dream in the physician workforce in the United States of America (USA). Many studies have documented the tangible and intangible benefits of EDI, including the caregiver, patients, and healthcare organizations. Objective We aim to examine the ethnic and gender diversity trends of the active residents in pathology in United States residency programs. Methods A retrospective cross-sectional study was conducted on the ethnicity and gender distribution of pathology residency trainees from the academic year 2007-2018. The data was compiled from the American Association of Medical Colleges (AAMC) annual report. Data was entered and analyzed using Microsoft Excel 2013 (Microsoft Corporation, Redmond, WA, USA). Frequencies and percentages were calculated, and bar charts and pie charts were used for graphical representation. Results Almost 35,000 US pathology residents were enrolled according to AAMC during this particular period. The highest trend of enrolling in the field of pathology was observed in 2010 and remained the same for years. This shows that the field of pathology in the USA had some acceptance all these years. The most popular speciality in which most residents were enrolled was anatomic/clinical pathology (80%) in which females were dominant over other fields. Conclusion Over the years, we have failed to overcome gender and ethnicity diversity. Gender and ethnicity have a significant influence on leadership positions, academic ranks, and research productivity among pathology faculty members in the USA.

DNA Methylation and Epigenetic Events Underlying Renal Cell Carcinomas.

Renal cell carcinoma (RCC) refers to a group of tumors that develop from the epithelium of the kidney tubes, including clear cell RCC, papillary RCC, and chromophobe RCC. Most clear cell renal carcinomas have a large histologic subtype, genetic or epigenetic von Hippel-Lindau (VHL). A comprehensive analysis of the genetic modification genome suggested that chromosome 3p loss and chromosome gains 5q and 7 may be significant copy defects in the development of clear RCC. A more potent RCC may develop if chromosome 1p, 4, 9, 13q, or 14q is also lost. Renal carcinogenesis is not associated with chronic inflammation or histological changes. However, if regional hypermethylation of DNA in CpG C-type islands has already accumulated in cancer-free kidney tissue, it implies that the presence of malignant kidney lesions may also be detected by modified DNA methylation. Modification of DNA methylation in cancerous kidney tissue may advance kidney tissue to epigenetic mutations and genes, leading to more serious cancers and even determining a patient's outcome. The genetic and epigenetic profile provides accurate predictors for patients with kidney cancer. New genetic and epigenetic analysis technologies will help to speed up the identification of vital cells for kidney cancer prevention, diagnosis, and treatment.

Immunolocalization of neurokinin 1 receptor in WHO grade 4 astrocytomas, oral squamous cell and urothelial carcinoma.

INTRODUCTION: Neurokinin-1 receptor (NK-1R) induces inflammatory reactions in peripheral tissues but its regulatory effects in target tissues is dependent on receptor signalling. Substance P (SP) has a high affinity for the NK-1R, to which it binds preferentially. We aimed to investigate the expression of NK-1R in World Health Organization (WHO) grade 4 astrocytomas as well as in oral squamous cell carcinoma (OSCC) and urothelial carcinoma, and its association with disease progression. MATERIAL AND METHODS: The study included tissue samples from 19 brain astrocytomas, 40 OSCCs and 10 urothelial carcinomas. NK-1R expression was quantitatively assessed in the tumour cells using immunohistochemistry. The relationship between NK-1R expression in astrocytomas and recurrence-free interval has been explored. RESULTS: The results showed that the NK-1R was intensely expressed in patients with WHO grade 4 astrocytoma, OSCC and urothelial carcinoma. However, cases clinically diagnosed as a low-grade cancer showed reduced NK-1R expression. CONCLUSIONS: NK-1R is overexpressed in all cases of WHO grade 4 astrocytoma, OSCC and urothelial carcinoma. The ubi-quitous presence of SP/NK-1R complex during tumour development and progression suggests a possible therapeutic key strategy to use NK-1R antagonist as an adjuvant therapy in the future.

Work Stress, Dysbiosis, and Immune Dysregulation: The Interconnected Triad in COVID-19 Infection in the Medical Team Staff - A Mini-Review.

The COVID-19 pandemic has hit most of the communities around the globe. Earlier researches have reported the psychological effects of pandemics either on the general populations or on specific communities such as students and health professionals. A scanty number of papers have focused on the interaction among complex factors underlying the pathogenesis of the disease. In this review, we aimed to integrate the accessible data about the possible mechanistic processes predisposing to COVID-19 infection in the health professions. We summarized these factors as "stress, microbiota, and immunity triad." We utilized the PubMed database, Google, and Google Scholar search engines to search the literature related to combinations of these keywords: "pandemics, COVID-19, coronavirus, SARS-CoV2;" "gut microbiota, gut-lung axis, dysbiosis, nutrition;" "work stress, workload, health workers, health professions, and medical team;" and "immunity, cytokine storm, and viral load." We detected no discussions combining the suggested triad concerning the medical team personnel. We cast light, for the first time to our knowledge, on the potential pathogenic role of "stress, microbiota, and immunity triad" in COVID-19-infected health workers.

Prognostic Significance of Substance P/Neurokinin 1 Receptor and Its Association with Hormonal Receptors in Breast Carcinoma.

Expression and immunolocalization of Substance P (SP)/Neurokinin-1 Receptor (NK-1R) in breast carcinoma (BC) patients and its association with routine proliferative markers (ER, PR, HER2/neu, and Ki-67) were evaluated. A cross-sectional study was performed on 34 cases of BC. There were 23 cases of group A (grade III), 8 of group B (grade II), and only 3 cases of group C (grade I). All samples were then processed for SP and NK-1R immunohistochemistry for few cases. 14/23 cases (61%) of group A, 7/8 cases (88%) of group B, and 2/3 (67%) cases of group C were SP positive. Overall, strong staining (≥10% tumor cells), labeled as "+3," was observed in 9/14 (64.2%) cases of group A and 1/8 (12.5%) cases of group B. Moderate staining labelled as "+2" (in ≥10% tumor cells) was observed in 3/14 (21.4%) cases of group A and 4/8 (50%) cases of group B. Weak positive staining "+1" was observed in only 2/14 (14.28%) cases of group A, 2/8 (25%) cases of group B, and all 2/2 (100%) cases of group C. SP and NK-1R are overexpressed in breast carcinomas, and there is significant association between the grade of tumor and their overexpression.

Enhanced Neurokinin-1 Receptor Expression Is Associated with Human Dental Pulp Inflammation and Pain Severity.

Substance P (SP) is a peptide involved in many biological processes, including nociception and inflammation. SP has a high affinity for its receptor neurokinin-1 (NK-1R). SP/NK-1R complex plays a major role in the interactions going on during the onset of dental pain and inflammation. Objective. To identify the expression of NK-1R in healthy and inflamed human dental pulp, as well as to identify any association with severity of dental pain. Methods. This case-control study included ten irreversibly inflamed samples of dental pulp, which were extirpated from patients presenting with chief complaint of dental pain due to caries. Ten healthy pulps, extirpated from those teeth which were indicated for extraction due to orthodontic reasons, were used as the control group. Visual analog scale (VAS) and modified McGill Pain Questionnaire were used to assess the characteristic and severity of pain. Immunohistochemical study was performed using monoclonal antibodies against NK-1R. Results. The results showed that the NK-1R was expressed intensely in patients with higher pain score. The mean pain score in cases was 7.0 ± 2.0. The healthy dental pulps had negative or mild NK-1R staining of +1 intensity. The NK-1R score in cases was 2.4 ± 0.516 and 0.2 ± 0.4216 in controls. There was significant difference in NK-1R score between both groups (p value <0.05). There was a strong positive correlation between the pain score and NK-1R expression score. As the pain increased, the NK-1R expression score was also increased (0.95∗∗, p value 0.000). Conclusions. NK-1R is overexpressed in inflamed dental pulp. SP/NK-1R modulation may provide a novel approach for the treatment of pulpal inflammation and pain.

Immunohistochemical Expression of the Alpha Nicotinic Acetylcholine Receptor 7 in the Human Normal, Diabetic, and Preeclamptic Placenta and Products of Conception.

Preeclampsia (PE) and gestational diabetes (GD) are complications in advanced pregnancy while miscarriage for early pregnancy. However, the etiological factors are not well understood. Smoking has been associated with these complications as well as the sudden intrauterine deaths, sudden infant death, miscarriages, and still births. However, the immunolocalization of alpha 7 nicotine acetylcholine receptor (α7-nAChR) is not studied. Materials and Methods: α7-nAChR subunit expression was evaluated in 10 paraffin-embedded placental tissues after delivery and 10 tissue samples of products of conception during first trimester by immunohistochemistry. Among the placental tissues, two samples were normal placental tissue, four from PE mother, and four from GD mother. The expression of α7-nAChR was compared between the two groups in general and within the subgroups of placenta as well. Protein expression was evaluated using the nuclear labeling index (%) of villi with positive cells stained, positive cells in the decidua, and intensity of staining in the outer villous trophoblast layer. Results: The expression of α7-nAChR protein was high in all the cases of placenta and products of conception (POCs). α7-nAChR expression showed no notable differences among different cases of miscarriages irrespective of the mother's age and gestational age at which the event occurred. However, there were some changes among the normal, PE, and GD placental groups in the linings of the blood vessels. Changes were restricted to the villi (as opposed to the decidua) lining cells, both cytotrophoblast and syncytiotrophoblast, and were specific to the α7 subunit. PE blood vessel lining was thicker and showed more expression of this receptor in endothelial cells and myofibroblasts in PE and GD groups. In POCs, the strong expression was observed in the decidua myocytes of maternal blood vessels and in syncytiotrophoblast and cytotrophoblast of chronic villi. Conclusion: Nicotine acetyl choline receptors are found to be expressed highly in the placental tissues and in products of conception. They may be associated with the sudden perinatal deaths and miscarriages or complications of pregnancy.

uPAR antibody (huATN-658) and Zometa reduce breast cancer growth and skeletal lesions.

Urokinase plasminogen activator receptor (uPAR) is implicated in tumor growth and metastasis due to its ability to activate latent growth factors, proteases, and different oncogenic signaling pathways upon binding to different ligands. Elevated uPAR expression is correlated with the increased aggressiveness of cancer cells, which led to its credentialing as an attractive diagnostic and therapeutic target in advanced solid cancer. Here, we examine the antitumor effects of a humanized anti-uPAR antibody (huATN-658) alone and in combination with the approved bisphosphonate Zometa (Zoledronic acid) on skeletal lesion through a series of studies in vitro and in vivo. Treatment with huATN-658 or Zometa alone significantly decreased human MDA-MB-231 cell proliferation and invasion in vitro, effects which were more pronounced when huATN-658 was combined with Zometa. In vivo studies demonstrated that huATN-658 treatment significantly reduced MDA-MB-231 primary tumor growth compared with controls. In a model of breast tumor-induced bone disease, huATN-658 and Zometa were equally effective in reducing skeletal lesions. The skeletal lesions were significantly reduced in animals receiving the combination of huATN-658 + Zometa compared with monotherapy treatment. These effects were due to a significant decrease in osteoclastic activity and tumor cell proliferation in the combination treatment group. Transcriptome analysis revealed that combination treatment significantly changes the expression of genes from signaling pathways implicated in tumor progression and bone remodeling. Results from these studies provide a rationale for the continued development of huATN-658 as a monotherapy and in combination with currently approved agents such as Zometa in patients with metastatic breast cancer.

Cancer Epidemiology in Lahore, Pakistan - 2010-2015.

OBJECTIVE: To study the cancer incidence rates in Lahore, which has an estimated annual population count of 10.3 million. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Data on new cancer cases diagnosed between 2010 and 2015, among the residents of Lahore district, Pakistan, was reviewed retrospectively in 2015-2017. METHODOLOGY: Nineteen collaborating centres of the population-based Punjab Cancer Registry (PCR), representing both the government and private sectors, reported their cases to the coordinating office located within the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC). The age-standardised incidence rates (ASIR) per 100,000 population, over a six-year period, were computed. Sixteen 5-year age groups were created beginning from 0-4 to 70-74 years, followed by 75+ years. Graphs on the five-year age-specific incidence rates by gender, were also generated. RESULTS: Between 2010 and 2015, 33,028 new malignancies were recorded in Lahore, with the crude average annual incidence rate being 53.1. In adults, the highest ASIRs were noted for cancers of the breast (77.3) among females and of prostate (11.4) in men. Age-specific incidence rates for female breast cancer showed an upward trend at the age of 20 years, reaching a figure of 160 at the age of 55 years. Among males, the rates for prostate cancer started to increase at the age of 55 years and reached a peak of 93 at 75 years. CONCLUSION: These results warrant expanding cancer registration in the region and sharing statistics with policy-makers to establish hospitals accordingly to manage cancer, along with exploring various risk factors within the population.

Elevated Neurokinin-1 Receptor Expression in Uterine Products of Conception Is Associated With First Trimester Miscarriages.

BACKGROUND: Miscarriage is a common complication of early pregnancy, mostly occurring in the first trimester. However, the etiological factors and prognostic and diagnostic biomarkers are not well known. Neurokinin-1 receptor (NK-1R) is a receptor of tachykinin peptide substance P (SP) and has a role in various pathological conditions, cancers, but its association with miscarriages and significance as a clinicopathological parameter are not studied. Accordingly, the present study aimed to clarify the localization and expression for NK-1R in human retained products of conception (POC). The role of NK-1R is not known in miscarriages. MATERIALS AND METHODS: NK-1R expression was assessed in POC and normal placental tissues by immunohistochemistry. Three- to four-micrometer-thin sections of formalin-fixed paraffin-embedded tissues were used for this purpose. Tissues were processed and then immunohistochemically stained with NK-1R antibody. Brain tissue was used as control for antibody. Protein expression was evaluated using the nuclear labeling index (%). Tissues were counterstained with 3,3'-diaminobenzidine (DAB), and microscopy was performed at 10×, 20×, and 40× magnifications. RESULTS: Ten human POC tissues and 10 normal placental tissues were studied by immunohistochemistry to demonstrate the localization of NK-1R. The expression of NK-1R protein was high in all the cases of both groups. NK-1R expression showed no notable differences among different cases of miscarriages as well as normal deliveries at full term regardless of the mother's age and gestational age at which the event occurred. Statistically, no difference was found in both groups, which is in agreement with our hypothesis and previous findings. CONCLUSION: The expression of NK-1R was similar in all the cases, and it was intense. It shows that dysregulation of NK-1R along with its ligand SP might be involved in miscarriages and also involved in normal delivery. Our results provide fundamental data regarding this anti-NK-1R strategy. Thus, the present study recommends that SP/NK-1R system might, therefore, be considered as an emerging and promising diagnostic and therapeutic strategy against miscarriages. Hence, we report for the first time the expression and localization of NK-1R in POC. We suggest NK-1R antagonist in addition to the immunoglobulins and human chorionic gonadotropin to diagnose and treat spontaneous miscarriages.

DNA methylation signatures of breast cancer in peripheral T-cells.

BACKGROUND: Immune surveillance acts as a defense mechanism in cancer, and its disruption is involved in cancer progression. DNA methylation reflects the phenotypic identity of cells and recent data suggested that DNA methylation profiles of T cells and peripheral blood mononuclear cells (PBMC) are altered in cancer progression. METHODS: We enrolled 19 females with stage 1 and 2, nine with stage 3 and 4 and 9 age matched healthy women. T cells were isolated from peripheral blood and extracted DNA was subjected to Illumina 450 K DNA methylation array analysis. Raw data was analyzed by BMIQ, ChAMP and ComBat followed by validation of identified genes by pyrosequencing. RESULTS: Analysis of data revealed ~ 10,000 sites that correlated with breast cancer progression and established a list of 89 CG sites that were highly correlated (p < 0.01, r > 0.7, r < - 0.7) with breast cancer progression. The vast majority of these sites were hypomethylated and enriched in genes with functions in the immune system. CONCLUSIONS: The study points to the possibility of using DNA methylation signatures as a noninvasive method for early detection of breast cancer and its progression which need to be tested in clinical studies.

Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasis in vivo; therapeutic and chemopreventive applications.

DNA hypomethylation coordinately targets various signaling pathways involved in tumor growth and metastasis. At present, there are no approved therapeutic modalities that target hypomethylation. In this regard, we examined the therapeutic plausibility of using universal methyl group donor S-adenosylmethionine (SAM) to block breast cancer development, growth, and metastasis through a series of studies in vitro using two different human breast cancer cell lines (MDA-MB-231 and Hs578T) and in vivo using an MDA-MB-231 xenograft model of breast cancer. We found that SAM treatment caused a significant dose-dependent decrease in cell proliferation, invasion, migration, anchorage-independent growth and increased apoptosis in vitro. These results were recapitulated in vivo where oral administration of SAM reduced tumor volume and metastasis in green fluorescent protein (GFP)-tagged MDA-MB-231 xenograft model. Gene expression analyses validated the ability of SAM to decrease the expression of several key genes implicated in cancer progression and metastasis in both cell lines and breast tumor xenografts. SAM was found to be bioavailable in the serum of experimental animals as determined by enzyme-linked immunosorbent assay and no notable adverse side effects were seen including any change in animal behavior. The results of this study provide compelling evidence to evaluate the therapeutic potential of methylating agents like SAM in patients with breast cancer to reduce cancer-associated morbidity and mortality.

Genetic variants in FGFR2 and TNRC9 genes are associated with breast cancer risk in Pakistani women.

Single nucleotide polymorphisms (SNPs) lead to genetic differences in breast cancer (BC) susceptibility among women from different ethnicities. The present study aimed at investigating the involvement of SNPs of three genes, including fibroblast growth factor receptor 2 (FGFR2), trinucleotide-repeat-containing 9 (TNRC9) and mitogen-activated protein kinase kinase kinase 1 (MAP3K1), as risk factors for the development of BC. A case­control study (90­100 cases; 90­100 controls) was performed to evaluate five genetic variants of three genes, including FGFR2 (SNPs: rs1219648, rs2981582), TNRC9 (SNPs: rs8051542, rs3803662) and MAP3K1 (SNP: rs889312) as BC risk factors in Pakistani women. Significant associations were observed between BC risk and two SNPs of FGFR2 [rs2981582 (P=0.005), rs1219648 (P=9.08e­006)] and one SNP of TNRC9 [rs3803662) (P=0.012)] in Pakistani women. On examining the different interactions of these SNPs with various clinicopathological characteristics, all three associated genetic variants, rs2981582 rs1219648 and rs3803662, exhibited a greater predisposition to sporadic, in comparison to familial, BC. Furthermore, there was an increased effect of BC risk between haplotype combinations of the two SNPs of FGFR2 (rs2981582 and rs1219648) in Pakistani women. The results of the present study suggest that variants of FGFR2 and TNRC9 may contribute to the genetic susceptibility of BC in Pakistani women.

A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness.

UNLABELLED: Cancer invasion and metastasis is the most morbid aspect of cancer and is governed by different cellular mechanisms than those driving the deregulated growth of tumors. We addressed here the question of whether a common DNA methylation signature of invasion exists in cancer cells from different origins that differentiates invasive from non-invasive cells. We identified a common DNA methylation signature consisting of hyper- and hypomethylation and determined the overlap of differences in DNA methylation with differences in mRNA expression using expression array analyses. A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways. The relevance of these hypomethylation events in human tumors was validated by identification of the signature in several publicly available databases of human tumor transcriptomes. We shortlisted novel invasion promoting candidates and tested the role of four genes in cellular invasiveness from the list C11orf68, G0S2, SHISA2 and TMEM156 in invasiveness using siRNA depletion. Importantly these genes are upregulated in human cancer specimens as determined by immunostaining of human normal and cancer breast, liver and prostate tissue arrays. Since these genes are activated in cancer they constitute a group of targets for specific pharmacological inhibitors of cancer invasiveness. SUMMARY: Our study provides evidence that common DNA hypomethylation signature exists between cancer cells derived from different tissues, pointing to a common mechanism of cancer invasiveness in cancer cells from different origins that could serve as drug targets.

S-adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: therapeutic and diagnostic clinical applications.

Osteosarcoma (OS) is an aggressive and highly metastatic form of primary bone cancer affecting young children and adults. Previous studies have shown that hypomethylation of critical genes is driving metastasis. Here, we examine whether hypermethylation treatment can block OS growth and pulmonary metastasis. Human OS cells LM-7 and MG-63 were treated with the ubiquitous methyl donor S-adenosylmethionine (SAM) or its inactive analog S-adenosylhomocystine (SAH) as control. Treatment with SAM resulted in a dose-dependent inhibition of tumor cell proliferation, invasion, cell migration, and cell cycle characteristics. Inoculation of cells treated with 150 µmol/L SAM for 6 days into tibia or via intravenous route into Fox Chase severe combined immune deficient (SCID) mice resulted in the development of significantly smaller skeletal lesions and a marked reduction in pulmonary metastasis as compared to control groups. Epigenome wide association studies (EWAS) showed differential methylation of several genes involved in OS progression and prominent signaling pathways implicated in bone formation, wound healing, and tumor progression in SAM-treated LM-7 cells. Real-time polymerase chain reaction (qPCR) analysis confirmed that SAM treatment blocked the expression of several prometastatic genes and additional genes identified by EWAS analysis. Immunohistochemical analysis of normal human bone and tissue array from OS patients showed significantly high levels of expression of one of the identified gene platelet-derived growth factor alpha (PDGFA). These studies provide a possible mechanism for the role of DNA demethylation in the development and metastasis of OS to provide a rationale for the use of hypermethylation therapy for OS patients and identify new targets for monitoring OS development and progression.

Role of neurotransmitter Substance P in progression of oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most frequent type of head and neck cancers. OBJECTIVES: In the present study, we evaluated the expression and distribution of Substance P (SP) in different grades of OSCC and role of SP in its proliferation and progression. SUBJECTS AND METHODS: Forty OSCC biopsies were immunohistochemically analyzed by using SP antibody, including 29 male and 11 female cases. 35% were well differentiated, 35% moderately differentiated and 30% poorly differentiated OSCC. The majority of patients were in the age range of 41-80 years. 62% of the cases were positive for SP. SP positivity was expressed in the cytoplasm of the tumor cells. Most of the positive cases were from the tongue region. RESULTS: 93% of moderately differentiated, 92% of poorly differentiated and 8% of well-differentiated carcinomas were SP-positive, but SP expression intensity was highest in poorly differentiated cases (+3). More positive patients were males (68.96% of all male patients) with moderately and poorly differentiated OSCC. Among all positive cases, 48% were poorly differentiated, 48% moderately differentiated and 4% well differentiated. CONCLUSION: Strong expression of SP in poorly and moderately differentiated cases suggests a role of SP in the progression and development of tumor. Expression of SP in the current study increased as the proliferation of cells increased. Prevalence of oral cancer in males may be due to the fact that they smoke and use pan, chewing gum, beetle nut etc. in this region. SP antagonists can help in the reduction and inhibition of oral cancer. SP has a diagnostic value with sensitivity of 92.5% and specificity of 93.7%. The positive predictive value is 96.2% and the negative predictive value 88.2%.

Pulmonary renal syndrome in a patient with vasculitis: Case report and review of literature.

Granulomatosis with polyangiitis (GPA) previously known as Wegner's granulomatosis, is a small vessel vasculitis that preferentially involves capillaries, arterioles and venules, presenting as multisystemic disease classically with alveolar haemorrhage and renal insufficiency. We report a case of GPA diagnosed on history, clinical findings and supported by imaging and very high levels of C-ANCA. Renal biopsy confirmed the typical histopathological findings. We discuss herein the management of the case and review of literature.