Sobia Tabassum

Role of nanotechnology and gene delivery systems in TRAIL based therapies

Since its identification as a member of the tumour necrosis factor (TNF) family, TRAIL (TNF-related apoptosis-inducing ligand) has emerged as a new avenue in apoptosis-inducing cancer therapies. Its ability to circumvent the chemoresistance of conventional therapeutics and to interact with cancer stem cells (CSCs) self-renewal pathways, amplified its potential as a cancer apoptotic agent. Many recombinant preparations of this death ligand and monoclonal antibodies targeting its death receptors have been tested in monotherapy and combinational clinical trials. Gene therapy is a new approach for cancer treatment which implies viral or non-viral functional transgene induction of apoptosis in cancer cells or repair of the underlying genetic abnormality on a molecular level. The role of this approach in overcoming the traditional barriers of radiation and chemotherapeutics systemic toxicity, risk of recurrence, and metastasis made it a promising platform for cancer treatment. The recent first Food Drug Administration (FDA) approved oncolytic herpes virus for melanoma treatment brings forth the potency of the cancer gene therapy approach in the future. Many gene delivery systems have been studied for intratumoural TRAIL gene delivery alone or in combination with chemotherapeutic agents to produce synergistic cancer cytotoxicity. However, there still remain many obstacles to be conquered for this different gene delivery systems. Nanomedicine on the other hand offers a new frontier for clinical trials and biomedical research. The FDA approved nanodrugs motivates horizon exploration for other nanoscale designed particles’ implications in gene delivery. In this review we aim to highlight the molecular role of TRAIL in apoptosis and interaction with cancer stem cells (CSCs) self-renewal pathways. Finally, we also aim to discuss the different roles of gene delivery systems, mesenchymal cells, and nanotechnology designs in TRAIL gene delivery.

Prostate Cancer Stem Cells: Viewing Signaling Cascades at a Finer Resolution

It is becoming characteristically more understandable that within tumor cells, there lies a sub-population of tumor cells with “stem cell” like properties and remarkable ability of self-renewal. Many features of these self-renewing cells are comparable with normal stem cells and are termed as “cancer stem cells”. Accumulating experimentally verified data has started to scratch the surface of spatio-temporally dysregulated intracellular signaling cascades in the biology of prostate cancer stem cells. We partition this multicomponent review into how different signaling cascades operate in cancer stem cells and how bioactive ingredients isolated from natural sources may modulate signaling network.

MicroRNA-34a: A Versatile Regulator of Myriads of Targets in Different Cancers

MicroRNA-34a (miR-34a) is a tumor suppressor that has attracted considerable attention in recent years. It modulates cancer cell invasion, metastasis, and drug resistance, and has also been evaluated as a diagnostic and/or prognostic biomarker. A number of targets of miR-34a have been identified, including some other non-coding RNAs, and it is believed that the modulation of these myriads of targets underlines the versatile role of miR-34a in cancer progression and pathogenesis. Seemingly appealing results from preclinical studies have advocated the testing of miR-34a in clinical trials. However, the results obtained are not very encouraging and there is a need to re-interpret how miR-34a behaves in a context dependent manner in different cancers. In this review, we have attempted to summarize the most recent evidence related to the regulation of different genes and non-coding RNAs by miR-34a and the advances in the field of nanotechnology for the targeted delivery of miR-34a-based therapeutics and mimics. With the emergence of data that contradicts miR-34a’s tumor suppressive function, it is important to understand miR-34a’s precise functioning, with the aim to establish its role in personalized medicine and to apply this knowledge for the identification of individual patients that are likely to benefit from miR-34a-based therapy.

Optical Screening of Female Breast Cancer from Whole Blood Using Raman Spectroscopy.

This study is intended to develop a screening method for female breast cancer (BRC) from whole blood using Raman spectroscopy. A multivariate partial least squares (PLS) regression model is developed which is based upon Raman spectra of BRC-positive and healthy participants. It yields coefficients of regression at the corresponding Raman shifts. These coefficients represent the changes in molecular structures which are associated with the progress of disease. The present study pointed out some specific molecules which differentiated BRC-positive and healthy groups. In the BRC-positive group, a rising trend of calcium oxalate, calcium hydroxyapatite, phosphatidylserine and qunoid ring, and a lowering trend of tryptophan, tyrosine, and proline were observed in PLS-based coefficients of regression. The R-square value of the model was found to be 0.987, which is accepted clinically. The model was tested for the prediction of 50 randomly collected samples at a cutoff value of 0.5 with the gray region defined in the range of 0.4–0.6. Goodness of fit was estimated using accuracy, sensitivity, specificity, receiver operating characteristic (ROC) curve, and area under ROC curve. All of these parameters were found to be very promising.

Human papillomavirus infection in females with normal cervical cytology: Genotyping and phylogenetic analysis among women in Punjab, Pakistan

BACKGROUND Globally, cervical cancer is the fourth most common cancer in women and the seventh most common cancer overall, accounting for an estimated 300 000 annual deaths. Human papillomavirus (HPV) is the second most common cause of cervical cancer worldwide. HPV screening is not a common practice in Pakistan. The aim of this study was to determine the prevalence of HPV and HPV types in women with a normal cytology of the cervix living in the upper and lower regions of Punjab, Pakistan, and to analyze the risk factors for HPV in this region. METHODS PCR analysis was performed for 1011 female patients with a normal cytology of the cervix from various districts of Punjab Province, Pakistan. Risk factors for the acquisition of HPV were studied. High-risk HPV types (HPV16 and HPV18) were detected using the Abbott Real Time HR HPV test. To determine the genotype, partial L1 region sequences of HPV-positive samples were subjected to sequencing using MY/09/MY11 primers, and a phylogenetic tree was constructed using CLC software. RESULTS The study found a 4.74% prevalence of HPV, with the most frequent HPV type found being the low-risk HPV6 (in 25% of infected individuals), followed by HPV55 (22.9%), HPV11 (20.8%), and high-risk types HPV45 (12.5%), HPV33 (8.33%), HPV18 (6.25%), and HPV16 (4.16%). Phylogenetic analysis of all HPV types in this study showed 80-99% nucleotide identity with types related to the same species. The sequences were clustered with China, India, Mexico, Iran, Slovenia, and Germany, showing the diversity in origin of the various genotypes prevalent in Pakistan. CONCLUSIONS In this population with a normal cervical cytology, the prevalence of high-risk HPV types was very low. The major prevalent HPV genotype in Punjab Province of Pakistan was the low-risk HPV type 6, followed by HPV type 55. Sequencing of the partial L1 region suggested that the region was highly conserved in all reported sequences. This study highlights the need to conduct robust epidemiological studies in the region and to develop regular HPV screening so that the situation does not reach an alarming stage resulting in cervical cancer.

Natural Agents-Mediated Targeting of Histone Deacetylases

In the past few years, basic and clinical scientists have witnessed landmark achievements in many research projects, such as those conducted by the US National Institutes of Health Roadmap Epigenomics Mapping Consortium, the International Human Epigenome Consortium, The Cancer Genome Atlas Network and the International Cancer Genome Consortium, which have provided near-complete resolution of epigenetic landscape in different diseases. Furthermore, genome sequencing of tumors has provided compelling evidence related to frequent existence of mutations in readers, erasers and writers of epigenome in different cancers. Histone acetylation is an intricate mechanism modulated by two opposing sets of enzymes and deeply studied as a key biological phenomenon in 1964 by Vincent Allfrey and colleagues. The research group suggested that this protein modification contributed substantially in transcriptional regulation. Subsequently, histone deacetylases (HDACs), histone acetyltransferases and acetyl-Lys-binding proteins were identified as transcriptional mediators, which further deepened our comprehension regarding biochemical modifications. Overwhelmingly increasing high-impact research is improving our understanding of this molecularly controlled mechanism; moreover, quantification and identification of lysine acetylation by mass spectrometry has added new layers of information. We partition this multi-component review into how both activity and expression of HDAC are targeted using natural agents. We also set spotlight on how oncogenic fusion proteins tactfully utilize HDAC-associated nano-machinery to modulate expression of different genes and how HDAC inhibitors regulate TRAIL-induced apoptosis in cancer cells. HDAC inhibitors have been reported to upregulate expression of TRAIL receptors and protect TRAIL from proteasomal degradation. Deeper understanding of HDAC biology will be useful for stratification and selection of patients who are responders, non-responders and poor-responders for HDACi therapy, and for the rational design of combination studies using HDACi.

Signaling cascades in thyroid cancer: Increasing the armory of archers to hit bullseye

Thyroid cancer is a multifaceted and therapeutically challenging disease and rapidly accumulating experimentally verified findings have considerably improve our understanding of the molecular mechanisms which underlie its development. Substantial fraction of information has been added into existing landscape of molecular oncology and we have started to develop a sharper understanding of the underlying mechanisms of thyroid cancer. Wealth of information demystified different intracellular signaling cascades which are frequently deregulated in thyroid cancer. In vitro assays and xenografted mice based studies have helped us to identify drug targets and different synthetic and natural products are currently being tested to effectively treat thyroid cancer. Cabozantinib and vandetanib have been approved to treat medullary thyroid cancer (MTC) and two agents (lenvatinib and sorafenib) are also being used to treat radioactive‐iodine refractory differentiated thyroid cancer. This review comprehensively summarizes most recent advancements in our knowledge related to dysregulated intracellular signaling cascades in thyroid cancer and how different proteins can be therapeutically exploited. (1) We discuss how loss of TRAIL mediated apoptosis occurred in thyroid cancer cells and how different strategies can be used to restore apoptosis in resistant cancer cells; (2) We provide detailed account of seemingly opposite roles of NOTCH signaling in thyroid cancers; (3) TGF/SMAD mediated signaling also needs detailed research because of context dependent role in thyroid cancer. Researchers have only begun to scratch the surface of how TGF signaling works in thyroid cancer and metastasis; and (4) Role of SHH signaling in thyroid cancer stem cells is also well appreciated and targeting of SHH pathway will be an important aspect in treatment of thyroid cancer. Better concepts and improved knowledge will be helpful for clinicians in getting a step closer to individualized medicine.

CDKN2A/P16INK4A variants association with breast cancer and their in-silico analysis

CDKN2A was first identified as melanoma predisposition tumour suppressor gene and has been successively studied. The previous researches have not established any noteworthy association with breast cancer. Therefore, through extensive literature search and in-silico analysis, we have tried to focus on the role of CDKN2A in breast cancer. CDKN2A variants in breast cancer were collected from different databases. The overall percentage of variants (approximately 5.8%) and their incidence frequency in breast cancer cases were found to be very low as compared to the number of samples screened in different studies. Exon 2 was identified as the major region of alternations. Approximately 42.8% were entire gene deletions, while 24.2% were missense mutations. These variants cannot be ignored because of their pathogenic effects as interpreted by the bioinformatics tools used in the present study. Earlier studies have shown that CDKN2A excludes the predisposition of germline variants, but interestingly shares common breast cancer germline variants with other carcinomas. Most of the data have revealed this gene as rarely mutated or deleted in breast cancer. However, few association studies have shown that in addition to being a ‘multiple’ tumour suppressor gene, it is mutated/deleted more in breast cancer cell lines as compared to breast cancer tissues or blood samples; thus, this gene cannot be neglected as a breast cancer candidate gene. The deletion/malfunctioning of CDKN2A in different tumours including breast cancer has recently led to the discovery of many clinical CDK inhibitors. Furthermore, these collected genetic variants will also be helpful in developing diagnostic, preventive, and treatment approaches for patients.

Effect of Hexane and Ethanol Extracts of Ten Basil Genotypes on the Growth of Selected Bacterial Strains

Bacterial infections are a nuisance to mankind from prehistoric times and still alive particularly in third world countries, where medicinal plants are extensively used as a treatment to pathogens since the known human history. In the current investigation, we used the crude extracts of an annual Holy Basil plant (Ocimum basilicum L. Family: Lamiaceae) enriched with a variety of aromatics, against the virulence of five pathogenic bacteria i.e., Staphylococcus aureus, Pseudomonas aeruginosa, Escheria coli, Proteus mirabilis and Klebsiella pneumoni. Among the crude ethanolic and hexane extracts, the latter showed much higher antibacterial activity than the former. Phytochemical profiling confirmed the presence of certain organic compounds (terpenoids, flavonoids, phenolics, tannins and coumarines) in the crude basil extracts, bearing strong antibacterial properties. Antibacterial chemistry was studied through thin layer chromatography (TLC) analyses with selected Pakistani varieties of basil, and it was confirmed the presence of bioactive compounds like alkaloids and terpenoids (15% sulphuric acid and Dragedroff’s reagent) in hexane extracts. The study sets further need for exploration of structure of these bioactive compounds with biological effect for pharmaceutical industry and future studies.