Urinary Metabolomics Identified Metabolic Perturbations Associated with Gutka, a Smokeless Form of Tobacco.

Gutka, a form of smokeless tobacco, is widely used in the Indian subcontinent and in other regions of South Asia. Smokeless tobacco exposure is most likely to increase the incidence of oral cancer in the Indian population, and metabolic changes are a hallmark of cancer. The development of biomarkers for early detection and better prevention measures for smokeless tobacco users at risk of oral cancer can be aided by studying urinary metabolomics and offering insight into altered metabolic profiles. This study aimed to investigate urine metabolic alterations among smokeless tobacco users using targeted LC-ESI-MS/MS metabolomics approaches to better understand the effects of smokeless tobacco on human metabolism. Smokeless tobacco users' specific urinary metabolomics signatures were extracted using univariate, multivariate analysis and machine learning methods. Statistical analysis identified 30 urine metabolites significantly associated with metabolomic alterations in humans who chew smokeless tobacco. Receiver operator characteristic (ROC) curve analysis evidenced the 5 most discriminatory metabolites from each approach that could differentiate between smokeless tobacco users and controls with higher sensitivity and specificity. An analysis of multiple-metabolite machine learning models and single-metabolite ROC curves revealed discriminatory metabolites capable of distinguishing smokeless tobacco users from nonusers more effectively with higher sensitivity and specificity. Furthermore, metabolic pathway analysis depicted several dysregulated pathways in smokeless tobacco users, including arginine biosynthesis, beta-alanine metabolism, TCA cycle, etc. This study devised a novel strategy to identify exposure biomarkers among smokeless tobacco users by combining metabolomics and machine learning algorithms.

Dysbiosis of salivary microbiome and cytokines influence oral squamous cell carcinoma through inflammation.

Advanced combinatorial treatments of surgery, chemotherapy, and radiotherapy do not have any effect on the enhancement of a 5-year survival rate of oral squamous cell carcinoma (OSCC). The discovery of early diagnostic non-invasive biomarkers is required to improve the survival rate of OSCC patients. Recently, it has been reported that oral microbiome has a significant contribution to the development of OSCC. Oral microbiome induces inflammatory response through the production of cytokines and chemokines that enhances tumor cell proliferation and survival. The study aims to develop saliva-based oral microbiome and cytokine biomarker panel that screen OSCC patients based on the level of the microbiome and cytokine differences. We compared the oral microbiome signatures and cytokine level in the saliva of OSCC patients and healthy individuals by 16S rRNA gene sequencing targeting the V3/V4 region using the MiSeq platform and cytokine assay, respectively. The higher abundance of Prevotella melaninogenica, Fusobacterium sp., Veillonella parvula, Porphyromonas endodontalis, Prevotella pallens, Dialister, Streptococcus anginosus, Prevotella nigrescens, Campylobacter ureolyticus, Prevotella nanceiensis, Peptostreptococcus anaerobius and significant elevation of IL-8, IL-6, TNF-α, GM-CSF, and IFN-γ in the saliva of patients having OSCC. Oncobacteria such as S. anginosus, V. parvula, P. endodontalis, and P. anaerobius may contribute to the development of OSCC by increasing inflammation via increased expression of inflammatory cytokines such as IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF. These oncobacteria and cytokines panels could potentially be used as a non-invasive biomarker in clinical practice for more efficient screening and early detection of OSCC patients.

RUNX1T1, a potential prognostic marker in breast cancer, is co-ordinately expressed with ERα, and regulated by estrogen receptor signalling in breast cancer cells.

BACKGROUND: RUNX1T1 is extensively studied in the context of AML1-RUNX1T1 fusion protein in acute myeloid leukemia. Little is known about the function of RUNX1T1 itself, although data on its function and regulation have begun to emerge from clinical, and in vitro studies. It is a putative tumor suppressor, whose expression is altered in a variety of solid tumors. Recently, reduced expression of RUNX1T1 in triple-negative breast tumors, and its influence on prognosis was reported. METHODS AND RESULTS: The Kaplan-Meier Plotter online tool was used to study the relationship between RUNX1T1 expression and survival of breast cancer patients. High RUNX1T1 expression was associated with longer overall survival (OS), relapse-free survival (RFS) and distant metastasis free survival (DMFS). RUNX1T1 expression positively and negatively influenced OS of patients with ERα-positive and ERα-negative breast tumors, respectively. It was also associated with prolonged RFS, and DMFS in tamoxifen-treated patients. Expression of RUNX1T1 and ERα mRNA was analyzed in 40 breast tumor samples, and breast cancer cell lines using RT-PCR. TCGA-BRCA data was mined to study the relationship between RUNX1T1 and ERα mRNA expression. ERα-positive breast tumors showed significantly higher RUNX1T1 mRNA expression compared to ERα-negative tumors. RUNX1T1 mRNA expression was analyzed by qRT-PCR in MCF-7 or T47D cells, which were treated with 17ß-estradiol, or the ERα agonist PPT, alone or in combination with 4-hydroxytamoxifen. Effect of ERα knockdown was also investigated. Results indicate that estrogen downmodulated RUNX1T1 mRNA expression via ERα. CONCLUSION: Higher expression of RUNX1T1 in breast tumors is associated with favourable prognosis. RUNX1T1 and ERα show co-ordinated expression in breast tumors, and breast cancer cell lines. Estrogen-ERα signalling downmodulates the expression of RUNX1T1 mRNA in ERα-positive breast cancer cells. In-depth investigations on the interaction between RUNX1T1 and ERα are warranted to unravel the role and relevance of RUNX1T1 in breast cancer.

Therapeutic nanostructures and nanotoxicity.

Nanotechnology, with its continuous advancement, leads to the development of nanoscale-level therapeutics to mitigate many complex diseases. This results in the emergence of numerous novel nanomaterials and its composite products into the market such as liposome, polymeric nanoparticles, dendrimers, and nanostructured lipid carrier. However, their application is always determined by a high benefit to risk ratio. Very few research have been done on the toxicity assessment of nanoparticles in the biological system; therefore, the limited knowledge regarding the toxicity profile of nanotherapeutics is available leading to the ignorance of its side effects. Nanoparticles can distribute in the whole body through translocating in the bloodstream by crossing membrane barriers efficiently and shows effect in organs and tissues at cellular and molecular levels. The interaction of nanoparticle with cell may consequences into nanotoxicity. The narrow size distribution, large surface area to mass ratio and surface properties of nanoparticle are significantly associated with nanotoxicity. Nanoparticles can enter into the tissue and cell by invading the membranes and cause cellular injury as well as toxicity. Therefore, the exploration of mechanisms of nanotoxicity has prime importance now a day. The toxicity assessment should be an integral part of the development of nanotherapeutics using various toxicity evaluation models. This review has focused on the exploration of different nanostructures for therapeutic delivery system along with its physicochemical characteristics responsible for adverse effects on human biology, various toxicity evaluation models, and environmental and regulatory hurdles.

Alterations of salivary microbial community associated with oropharyngeal and hypopharyngeal squamous cell carcinoma patients.

The highest number (35.1% of global incident cases) of new oropharyngeal (OP) and hypopharyngeal (HP) cancer cases was reported in South-Central Asia. The highest incidence of HP cancer in India was reported in East Khasi Hills District of Meghalaya, Aizawl District of Mizoram, and Kamrup Urban District of Assam. HP and OP cancer showed the highest mortality rate, worst prognoses and the highest rate of nodal metastases and distant metastases. Thus, research is required to detect specific biomarkers for early prevention and diagnosis for these cancers. Oral microbiome signatures in saliva are considered as a potential diagnostic biomarker for OP and HP cancer. Bacterial profile alterations in OP and HP cancer have not been reported in India population, to establish the association of oral bacteria in the progression of OP and HP cancer; we studied bacterial communities in saliva of eight OP and seven HP cancer patients as compared to healthy controls using 16S rRNA V3-V4 region sequencing. The higher abundance of Haemophilus parainfluenzae, Haemophilus influenzae and Prevotella copri and lower abundance of Rothia mucilaginosa, Aggregatibacter segnis, Veillonella dispar, Prevotella nanceiensis, Rothia aeria, Capnocytophaga ochracea, Neisseria bacilliformis, Prevotella nigrescens and Selenomonas noxia in saliva of OP and HP cancer patients may be considered as a non-invasive diagnostic biomarker for OP and HP cancer patients. Streptococcus anginosus may be considered as a non-invasive diagnostic biomarker for OP cancer patients only. Therefore, evaluation of salivary microbial biomarkers may be informative to understand the pathobiology and carcinogenesis of OP and HP cancer.

Assessment and clinicopathological correlation of matrix metalloproteinase 9 expression in nasopharyngeal carcinoma.

INTRODUCTION: Nasopharyngeal cancer is not a common disease in most parts of the world. In India also, nasopharyngeal carcinoma (NPC) is not a common cancer, except for the Northeastern region of the country. Expression of matrix metalloproteinase 9 (MMP9) in the tumor cells is related to tumor invasion and metastasis. The aim of the present study is to analyze the expression of MMP9 in NPC and evaluate its prognostic implications. MATERIALS AND METHODS: A total of 32 histologically confirmed tissue samples of NPC were examined by immunohistochemical staining to assess the expression of MMP9. Clinicopathological parameters and levels of MMP9 expression in the tumor tissue were analyzed using Chi-square test. Survival analysis was done using the Kaplan-Meier method and was compared using log-rank test. P <0.05 was considered statistically significant. RESULTS: Of the 32 tissue samples of NPC, 23 (71.9%) were male and 9 (28.1%) were female. 7 (21.9%) patients presented in T1 Stage, 8 (25.0%) in T2, 12 (37.5%) in T3, and 5 (15.6%) in T4 Stages, respectively. 29 (90.6%) patients presented with lymph node metastasis. MMP9 expression level was significantly correlated with patient's age (P = 0.033), tumor histology (P = 0.017), tumor stage (P = 0.021), and lymph node metastasis (P = 0.011). The 5-year overall survival is higher for low-level expression as compared to high-level expression of MMP9 (P = 0.046). CONCLUSION: MMP9 is an important prognostic factor for NPC. High expression of MMP9 is associated with cervical lymph nodes metastasis and poor survival outcome.

BSNEU-net: Block Feature Map Distortion and Switchable Normalization-Based Enhanced Union-net for Acute Leukemia Detection on Heterogeneous Dataset.

Acute leukemia is characterized by the swift proliferation of immature white blood cells (WBC) in the blood and bone marrow. It is categorized into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), depending on whether the cell-line origin is lymphoid or myeloid, respectively. Deep learning (DL) and artificial intelligence (AI) are revolutionizing medical sciences by assisting clinicians with rapid illness identification, reducing workload, and enhancing diagnostic accuracy. This paper proposes a DL-based novel BSNEU-net framework to detect acute leukemia. It comprises 4 Union Blocks (UB) and incorporates block feature map distortion (BFMD) with switchable normalization (SN) in each UB. The UB employs union convolution to extract more discriminant features. The BFMD is adapted to acquire more generalized patterns to minimize overfitting, whereas SN layers are appended to improve the model's convergence and generalization capabilities. The uniform utilization of batch normalization across convolution layers is sensitive to the mini-batch dimension changes, which is effectively remedied by incorporating an SN layer. Here, a new dataset comprising 2400 blood smear images of ALL, AML, and healthy cases is proposed, as DL methodologies necessitate a sizeable and well-annotated dataset to combat overfitting issues. Further, a heterogeneous dataset comprising 2700 smear images is created by combining four publicly accessible benchmark datasets of ALL, AML, and healthy cases. The BSNEU-net model achieved excellent performance with 99.37% accuracy on the novel dataset and 99.44% accuracy on the heterogeneous dataset. The comparative analysis signifies the superiority of the proposed methodology with comparing schemes.

Exosome: From biology to drug delivery.

In recent years, different advancements have been observed in nanosized drug delivery systems. Factors such as stability, safety and targeting efficiency cause hindrances in the clinical translation of these synthetic nanocarriers. Therefore, researchers employed endogenous nanocarriers like exosomes as drug delivery vehicles that have an inherent ability to target more efficiently after appropriate functionalization and show higher biocompatibility and less immunogenicity and facilitate penetration through the biological barriers more quickly than the other available carriers. Exosomes are biologically derived lipid bilayer-enclosed nanosized extracellular vesicles (size ranges from 30 to 150 nm) secreted from both prokaryotic and eukaryotic cells and appears significantly in the extracellular space. These EVs (extracellular vesicles) can exist in different sources, including mammals, plants and microorganisms. Different advanced techniques have been introduced for the isolation of exosomes to overcome the existing barriers present with conventional methods. Extensive research on the application of exosomes in therapeutic delivery for treating various diseases related to central nervous system, bone, cancer, skin, etc. has been employed. Several studies are on different stages of clinical trials, and many exosomes patents have been registered.

Synchronous Anal Squamous Cell Carcinoma and Diffuse Large B Cell Lymphoma of Stomach: the First Report of an Odd Couple.

The unique case study presented here explores an exceptionally rare occurrence in an HIV-positive female-synchronous diagnoses of anal squamous cell carcinoma and diffuse large B cell lymphoma (DLBCL) of the stomach. With limited existing literature on such clinical scenarios, this case serves as an unprecedented insight into the complexities of managing such synchronous malignancies in HIV-positive patients. The article also examines the heightened risk of specific cancer types in individuals living with HIV compared to those without the virus, focusing on AIDS-defining cancers such as Kaposi sarcoma, various lymphomas (including Burkitt lymphoma, immunoblastic lymphoma, and primary central nervous system lymphoma), and invasive cervical cancer. Additionally, it highlights an increased incidence and severity of other cancers amongst HIV-positive individuals, including Hodgkin lymphoma, anal cancer, testicular cancer, melanoma, various skin and superficial eye cancers, and leiomyosarcoma. The article discusses the challenges in the treatment plan, the impact of HIV status on the patient's condition, and the evolving landscape of cancer risk in people living with HIV. Despite significant progress in HIV care, cancer remains a paramount health concern for this population, necessitating tailored approaches and further research to ensure improved outcomes for individuals facing this dual challenge. The case highlights the need for greater inclusivity of PLWH in cancer clinical trials and reinforces the importance of equitable cancer care for this unique patient demographic.

High Risk Human Papillomavirus Prevalence in Patients with Hypopharynx Cancer of Northeast India: A Pilot Study.

Oncogenic viruses such as, Human papillomavirus (HPV) associated head and neck cancers have been considered to represent different etiological and pathological behaviour. This pilot study was conceived to investigate high risk HPV (hr-HPV) infection and its association with life style habits such as tobacco, alcohol consumption in patients with hypopharynx cancer from North -East India. A total of thirty four primary hypopharynx cancer biopsy specimens were collected. These samples were analysed for hr-HPV DNA using nested multiplex PCR (NMPCR). The lifestyle and dietary associated factors were collected through a self- designed questionnaire. The presence of hr-HPV was confirmed in 50% (n = 17) patients with hypopharynx cancer by nested multiplex PCR (NMPCR). Among hr-HPV positive cases, only HPV- 16 genotype was found. Significant association was observed between hr-HPV infections with alcohol consumption (p-0.025), alcohol with tobacco habit (p-0.01). Our study demonstrated that alcohol consumption, tobacco chewing may act as risk factors for hr-HPV infection in a subset of patients with hypopharynx cancer from the North-East region of India.

Concordance of Frozen Section Diagnosis of Epithelial Ovarian Neoplasm and Discussing the Diagnostic Pitfalls: An Institutional Experience.

Background Ovarian neoplasm is the third most common malignancy in Indian women. Intraoperative diagnosis becomes the critical guiding tool for the surgeons to take the decisions on the extent of surgery specially when preserving fertility has to be considered. Aims and Objective The aim of this study is to evaluate the concordance of intraoperative diagnosis of frozen section (IFS) of ovarian epithelial neoplasm at our institute and to review and discuss the diagnostic pitfalls along with the review of literature. Materials and Methods Data were archived from departmental record and the detailed clinical data of the patients were retrieved from hospital record system. The discordant cases were reviewed again in an attempt to address the pitfalls. Statistical Analysis Diagnostic accuracy, sensitivity, specificity, and positive and negative predictive value of IFS of ovarian neoplasm were analyzed. Results The overall frozen section diagnosis was concordant with final histopathology in 36 out of 44 cases (81%). The sensitivity of IFS diagnosis was found to be 100% for benign and borderline tumors, whereas 88.9% for malignant epithelial tumors, but the correctness of diagnosis is high only for benign and malignant tumors (high positive predictive value) in compared with borderline ones. The diagnostic pitfalls were identified individually in discordant cases. Conclusion An accurate interpretation of IFS in ovarian epithelial malignancy can be achieved in benign and malignant cases, but limited in borderline tumors. Awareness of the artifacts and the limitations in mind and the IFS diagnosis can be of great help for proper management of the ovarian neoplasm.

Insight on Cardiac Chronobiology and Latest Developments of Chronotherapeutic Antihypertensive Interventions for Better Clinical Outcomes.

Cardiac circadian rhythms are an important regulator of body functions, including cardiac activities and blood pressure. Disturbance of circadian rhythm is known to trigger and aggravate various cardiovascular diseases. Thus, modulating the circadian rhythm can be used as a therapeutic approach to cardiovascular diseases. Through this work, we intend to discuss the current understanding of cardiac circadian rhythms, in terms of quantifiable parameters like BP and HR. We also elaborate on the molecular regulators and the molecular cascades along with their specific genetic aspects involved in modulating circadian rhythms, with specific reference to cardiovascular health and cardiovascular diseases. Along with this, we also presented the latest pharmacogenomic and metabolomics markers involved in chronobiological control of the cardiovascular system along with their possible utility in cardiovascular disease diagnosis and therapeutics. Finally, we reviewed the current expert opinions on chronotherapeutic approaches for utilizing the conventional as well as the new pharmacological molecules for antihypertensive chronotherapy.

The G-protein-coupled estrogen receptor, a gene co-expressed with ERα in breast tumors, is regulated by estrogen-ERα signalling in ERα positive breast cancer cells.

GPER is a seven transmembrane G-protein-coupled estrogen receptor that mediates rapid estrogen actions. Large volumes of data have revealed its association with clinicopathological variables in breast tumors, role in epidermal growth factor (EGF)-like effects of estrogen, potential as a therapeutic target or a prognostic marker, and involvement in endocrine resistance in the face of tamoxifen agonism. GPER cross-talks with estrogen receptor alpha (ERα) in cell culture models implicating its role in the physiology of normal or transformed mammary epithelial cells. However, discrepancies in the literature have obfuscated the nature of their relationship, its significance, and the underlying mechanism. The purpose of this study was to assess the relationship between GPER, and ERα in breast tumors, to understand the mechanistic basis, and to gauge its clinical significance. We mined The Cancer Genome Atlas (TCGA)-BRCA data to examine the relationship between GPER and ERα expression. GPER mRNA, and protein expression were analyzed in ERα-positive or -negative breast tumors from two independent cohorts using immunohistochemistry, western blotting, or RT-qPCR. The Kaplan-Meier Plotter (KM) was employed for survival analysis. The influence of estrogen in vivo was studied by examining GPER expression levels in estrus or diestrus mouse mammary tissues, and the impact of 17ß-estradiol (E2) administration in juvenile or adult mice. The effect of E2, or propylpyrazoletriol (PPT, an ERα agonist) stimulation on GPER expression was studied in MCF-7 and T47D cells, with or without tamoxifen or ERα knockdown. ERα-binding to the GPER locus was explored by analysing ChIP-seq data (ERP000380), in silico prediction of estrogen response elements, and chromatin immunoprecipitation (ChIP) assay. Clinical data revealed significant positive association between GPER and ERα expression in breast tumors. The median GPER expression in ERα-positive tumors was significantly higher than ERα-negative tumors. High GPER expression was significantly associated with longer overall survival (OS) of patients with ERα-positive tumors. In vivo experiments showed a positive effect of E2 on GPER expression. E2 induced GPER expression in MCF-7 and T47D cells; an effect mimicked by PPT. Tamoxifen or ERα-knockdown blocked the induction of GPER. Estrogen-mediated induction was associated with increased ERα occupancy in the upstream region of GPER. Furthermore, treatment with 17ß-estradiol or PPT significantly reduced the IC50 of the GPER agonist (G1)-mediated loss of MCF-7 or T47D cell viability. In conclusion, GPER is positively associated with ERα in breast tumors, and induced by estrogen-ERα signalling axis. Estrogen-mediated induction of GPER makes the cells more responsive to GPER ligands. More in-depth studies are warranted to establish the significance of GPER-ERα co-expression, and their interplay in breast tumor development, progression, and treatment.

Biological importance and pharmaceutical significance of keratin: A review.

Protein-based biomaterials have emerged as a promising alternative because of their inherent cell-to-cell interaction, structural support, and cellular communications. Over the last century, advances in the extraction, purification, and characterization of keratin proteins from wool, feathers, horns, and other animal sources have created a keratin-based biomaterials platform. Keratins, like many other naturally generated macromolecules, have biological activity and biocompatibility built-in. Furthermore, isolated keratins can self-assemble into structures that control cellular identification and behaviour. As a result, keratin biomaterials with applications in wound healing, drug delivery, tissue engineering, trauma, and medical devices have been developed due to these properties. This review examines the function of keratin in the human body in-depth, focusing on the history of keratin research and a current evaluation of emerging approaches in biomedical fields like tissue engineering, medical science, regenerative medicine, and drug delivery.

Variant influenza: connecting the missing dots.

BACKGROUND: In June 2009, the World Health Organization declared a new pandemic, the 2009 swine influenza pandemic (swine flu). The symptoms of the swine flu pandemic causing strain were comparable to most of the symptoms noted by seasonal influenza. AREA COVERED: Zoonotic viruses that caused the swine flu pandemic and its preventive measures. EXPERT OPINION: As per Centers for Disease Control and Prevention (CDC), the clinical manifestations in humans produced by the 2009 H1N1 'swine flu' virus were equivalent to the manifestations caused by related flu strains. The H1N1 vaccination was the most successful prophylactic measure since it prevented the virus from spreading and reduced the intensity and consequences of the pandemic. Despite the availability of therapeutics, the ongoing evolution and appearance of new strains have made it difficult to develop effective vaccines and therapies. Currently, the CDC recommends yearly flu immunization for those aged 6 months and above. The lessons learned from the A/2009/H1N1 pandemic in 2009 indicated that readiness of mankind toward new illnesses caused by mutant viral subtypes that leap from animals to people must be maintained.

Salivary microbial dysbiosis may predict lung adenocarcinoma: A pilot study.

BACKGROUND: Adenocarcinoma is a more common type of Non-small cell lung cancer (NSCLC). Lung cancer showed a statistically significant increment in the Kamrup Urban district of Assam, Tripura, Sikkim, and Manipur of India. The goal of our pilot study is to identify non-invasive microbial biomarkers to detect lung adenocarcinoma (LAC). MATERIAL AND METHODS: DNA extraction from saliva samples of five LAC patients and five healthy controls was performed by Qiagen DNeasy blood and tissue kit using Lysozyme (3mg/ml) treatment. 16S rRNA genes of distinct regions (V3-V4) were amplified from saliva DNA by PCR. Paired-end sequencing targeting the V3-V4 region of the 16S rRNA gene has been performed on the Illumina MiSeq platform. Raw sequences were analyzed using the QIIME(Quantitative Insights Into Microbial Ecology) software package. RESULTS: Our preliminary results showed that Rothia mucilaginosa, Veillonella dispar, Prevotella melaninogenica, Prevotella pallens, Prevotella copri, Haemophilus parainfluenzae, Neisseria bacilliformis and Aggregatibacter segnis were significantly elevated in saliva of LAC which may serve as potential non-invasive biomarkers for LAC detection. Functional prediction analysis showed that bacterial genes involved in glycosyltransferase, peptidases, amino sugar, and nucleotide sugar metabolism, starch and sucrose metabolism were significantly enriched in LAC. CONCLUSION: These salivary bacteria may contribute to the development of LAC by increasing expression of glycosyltransferase and peptidases. However to understand their role in pathobiology, studies are required to perform in large cohort.

BMP4 enhances anoikis resistance and chemoresistance of breast cancer cells through canonical BMP signaling.

Bone morphogenetic proteins (BMPs) regulate cell fate during development and mediate cancer progression. In this study, we investigated the role of BMP4 in proliferation, anoikis resistance, metastatic migration, and drug resistance of breast cancer cells. We utilized breast cancer cell lines and clinical samples representing different subtypes to understand the functional effect of BMP4 on breast cancer. The BMP pathway was inhibited with the small molecule inhibitor LDN193189 hydrochloride (LDN). BMP4 signaling enhanced the expression of stem cell genes CD44, ALDH1A3, anti-apoptotic gene BCL2 and promoted anoikis resistance in MDA-MB-231 breast cancer cells. BMP4 enhanced self-renewal and chemoresistance in MDA-MB-231 by upregulating Notch signaling while LDN treatment abrogated anoikis resistance and proliferation of anoikis resistant breast cancer cells in the osteogenic microenvironment. Conversely, BMP4 downregulated proliferation, colony-forming ability, and suppressed anoikis resistance in MCF7 and SkBR3 cells, while LDN treatment promoted tumor spheroid formation and growth. These findings indicate that BMP4 has a context-dependent role in breast cancer. Further, our data with MDA-MB-231 cells representing triple-negative breast cancer suggest that BMP inhibition might impair its metastatic spread and colonization.

Geometry encoded functional programming of tumor homing peptides for targeted drug delivery.

Poly-peptide molecules have shown promising applications in drug delivery and tumor targeting. A series of tumor homing peptides were designed by exhaustively sampling low energy geometrical basins of amino acids at specific sites of a peptide molecule to induce a conformational lock. This peptide library was pruned to a limited set of eight molecules, employing electrostatic interactions, docking, and molecular dynamics simulations. These designed and optimized peptides were synthesized and tested on various cell lines, including breast cancer (MDA-MB-231), cervical cancer (HeLa), osteosarcoma (U2-OS), and non-cancerous mammary epithelial cells (MCF-10A) using confocal microscopy and flow cytometry. Peptides show differential uptake in cancerous MDA-MB-231, HeLa, U2-OS, and non-cancerous MCF-10A cells. Confocal imaging verified their ability to penetrate even in 3D tumorospheres of MDA-MB-231 cells. Further, experiments of mitochondrial membrane potential depolarization and Caspase-3 activation confirmed that their cytotoxic effects are by apoptosis. Homing ability of the designed peptides in in vivo system and fluorescence imaging with clinical samples of human origin have further confirmed that the in vitro studies are qualitatively identical and quantitatively comparable in their ability to selectively recognize tumor cells. Overall, we present a roadmap for the functional programming of peptide-based homing and penetrating molecules that can perform selective tumor targeting.

Nose to brain delivery of antiretroviral drugs in the treatment of neuroAIDS.

NeuroAIDS (Neuro Acquired Immunodeficiency Syndrome) or HIV (Human Immunodeficiency Virus) associated neuronal abnormality is continuing to be a significant health issue among AIDS patients even under the treatment of combined antiretroviral therapy (cART). Injury and damage to neurons of the brain are the prime causes of neuroAIDS, which happens due to the ingress of HIV by direct permeation across the blood-brain barrier (BBB) or else via peripherally infected macrophage into the central nervous system (CNS). The BBB performs as a stringent barricade for the delivery of therapeutics drugs. The intranasal route of drug administration exhibits as a non-invasive technique to bypass the BBB for the delivery of antiretroviral drugs and other active pharmaceutical ingredients inside the brain and CNS. This method is fruitful for the drugs that are unable to invade the BBB to show its action in the CNS and thus erase the demand of systemic delivery and thereby shrink systemic side effects. Drug delivery from the nose to the brain/CNS takes very less time through both olfactory and trigeminal nerves. Intranasal delivery does not require the involvement of any receptor as it occurs by an extracellular route. Nose to brain delivery also involves nasal associated lymphatic tissues (NALT) and deep cervical lymph nodes. However, very little research has been done to explore the utility of nose to brain delivery of antiretroviral drugs in the treatment of neuroAIDS. This review focuses on the potential of nasal route for the effective delivery of antiretroviral nanoformulations directly from nose to the brain.

Fungal profile and antifungal susceptibility pattern of candidiasis in esophageal cancer patients.

AIM: This study was carried out to determine the fungal profile and antifungal susceptibility pattern in the brushing samples of candidiasis in patients with carcinoma of esophagus. MATERIALS AND METHODS: The study was carried out in the Departments of Microbiology and Surgical Oncology of a regional cancer center from January 2017 to December 2017. Samples were collected under all aseptic precaution and Clinical Laboratory Standards Institute guidelines 2017 was followed for antifungal susceptibility testing. RESULTS: A total of 132 endoscopy brushing samples were collected from histological proven esophageal cancer patients and processed for fungal culture. Of which, 75 (56.81%) samples showed culture positivity and were recruited. Candida albicans in 40 (53.33%), Candida krusei in 25 (33.33%), Candida tropicalis in 7 (9.33%), and Candida glabrata in 3 (4%) patients were seen. Among the 40 C. albicans isolates, all were sensitive to caspofungin - 40 (100%), 34 (85%) showed sensitivity to fluconazole, and 32 (80%) showed sensitivity to flucytosine. C. krusei and C. tropicalis showed 100% sensitivity to caspofungin, and C. glabrata isolates showed 100% resistance to caspofungin and 80% resistance to Amphotericin B. CONCLUSION: The present study revealed the emergence of multidrug-resistant, nonalbicans Candida isolates in cancer esophagus patients with candidiasis in northeast India.