Controlled in vivo intrinsic detrimental effect of d-Limonene channelized by influential proximal interaction through apoptosis and steatosis in embryonic zebrafish (Danio rerio).

Bioaccumulation of d-Limonene in environment due to the aggrandised usage of their natural sources like citrus food wastes and industrial day to day life products has raised concern to their biotoxicity to environment biotic health. Moreover, their after-usage discharge to aquatic system has enhanced the distress of posing threat and needs attention. This study entails mechanistic and molecular evaluation of in-vivo biotoxicity of d-Limonene in zebrafish embryo models. Experimental analysis excavated the controlled concentration-dependent morphological, physiological and cellular in-vivo impact of d-Limonene in zebrafish embryos through significant changes in oxidative stress, steatosis and apoptosis regulated via 6-fold and 5-fold mRNA expression change in p53 and Sod1 genes. Computational evaluation deduced the cellular mechanism of d-limonene biotoxicity as irregularities in oxidative stress, apoptosis and steatosis due of their intrinsic interaction with metabolic proteins like Zhe1a (-4.8 Kcal/mol), Sod1(-5.3 Kcal/mol), p53, caspase3 and apoa1 leading to influential change in structural and functional integrity of the metabolic proteins. The study unravelled the measured in-vivo biotoxicity of d-Limonene at cellular and molecular level to advocate the controlled usage of d-Limonene related natural and industrial product for a sustainable environmental health.

A Study of Association of Insulin Resistance with Pregnancy-induced Hypertension.

BACKGROUND: Preeclampsia is one of the important causes of maternal and fetal mortality and morbidity. One of the important risk factors for the development of diabetes is insulin resistance (IR). AIMS: To evaluate the association of IR with pregnancy-induced hypertension (PIH) and its severity. MATERIALS AND METHODS: Data from 70 pregnant females who had completed 20 weeks of gestation and developed PIH were analyzed and compared with 30 appropriate controls. All females underwent measurement of fasting glucose level, fasting insulin level, and blood pressure. RESULTS: The mean age of the women in the control group was 26.17 years, and in the study group, it was 27.09 years. All females had completed 20 weeks of gestation. Around 86.6% of women in the control group, 54.1% with a variable degree of preeclampsia, and 48.6% of women with eclampsia were at 33-38 weeks of gestation. At the time of sampling, 13.3% of women in the control group, 45.81% of women with preeclampsia, and 51.3% of women with eclampsia were at 26-32 weeks of gestation. The mean IR among the control group was 1.37, in preeclampsia, it was 2.11, and in eclampsia, it was 3.58 with a p-value of 0.000, which is very highly significant. In this study, the severity of the disease was found to be directly proportional to IR. CONCLUSION: Pregnancy complicated with preeclampsia and eclampsia showed more IR in comparison to pregnant women with normal blood pressure, and this relationship is independent of the age of pregnant women.

Biophysical translational paradigm of polymeric nanoparticle: Embarked advancement to brain tumor therapy.

Polymeric nanoparticles have emerged as promising contenders for addressing the intricate challenges encountered in brain tumor therapy due to their distinctive attributes, including adjustable size, biocompatibility, and controlled drug release kinetics. This review comprehensively delves into the latest developments in synthesizing, characterizing, and applying polymeric nanoparticles explicitly tailored for brain tumor therapy. Various synthesis methodologies, such as emulsion polymerization, nanoprecipitation, and template-assisted fabrication, are scrutinized within the context of brain tumor targeting, elucidating their advantages and limitations concerning traversing the blood-brain barrier. Furthermore, strategies pertaining to surface modification and functionalization are expounded upon to augment the stability, biocompatibility, and targeting prowess of polymeric nanoparticles amidst the intricate milieu of the brain microenvironment. Characterization techniques encompassing dynamic light scattering, transmission electron microscopy, and spectroscopic methods are scrutinized to evaluate the physicochemical attributes of polymeric nanoparticles engineered for brain tumor therapy. Moreover, a comprehensive exploration of the manifold applications of polymeric nanoparticles encompassing drug delivery, gene therapy, imaging, and combination therapies for brain tumours is undertaken. Special emphasis is placed on the encapsulation of diverse therapeutics within polymeric nanoparticles, thereby shielding them from degradation and enabling precise targeting within the brain. Additionally, recent advancements in stimuli-responsive and multifunctional polymeric nanoparticles are probed for their potential in personalized medicine and theranostics tailored for brain tumours. In essence, this review furnishes an all-encompassing overview of the recent strides made in tailoring polymeric nanoparticles for brain tumor therapy, illuminating their synthesis, characterization, and multifaceted application.

Addressing the Rising Trend in Early-Age-Onset Cancers in Canada.

A multi-disciplinary symposium on early-age onset cancer (EAOC) was held in October 2023 to explore challenges experienced by this rapidly growing population. A major outcome of the symposium was recognition of the remarkable similarities of EAOC patients' journeys across cancer sites. Prevention and early detection of cancer are hindered by a lack of awareness among patients and family doctors that cancer can and does occur in younger persons. Distinct characteristics of the disease-such as a later stage at diagnosis and more aggressive tumor biology-require more potent treatments, which result in profound physical and psychosocial consequences that are unique to this age group. EAOC patient empowerment emerged as another key theme of the symposium. The development of a greater number of specialized clinics was called for, and patient support groups were recognized for the vital role they play in empowering patients and their families. Leading-edge medical advancements hold tremendous hope across the spectrum of EAOC care. New technologies based on genomic profiling, immunotherapy and microbiome alteration contribute to the development of highly effective, personalized approaches to treatment. All symposium participants expressed their commitment to speak with one resounding voice to advocate for equitable access to leading care practices for EAOC patients; thus, a fourth symposium is planned for November 2024.

Detrimental consequences of micropolymers associated plasticizers on endocrinal disruption.

The prevalence of polymer usage in everyday activities has emerged as a detriment to both human life and the environment. A large number of studies describe severe impacts of micropolymers (MP) and nanopolymers (NP) on various organ systems, including the endocrine system. Additionally, plasticizers utilized as additives have been identified as endocrine-disrupting chemicals (EDCs). MP/NP, along with associated plasticizers, affect principal signalling pathways of endocrine glands such as the pituitary, thyroid, adrenal, and gonads, thereby disrupting hormone function and metabolic processes crucial for maintaining homeostasis, fertility, neural development, and fetal growth. This review delves into the sources, distribution, and effects of micropolymers, nanopolymers, and associated plasticizers acting as EDCs. Furthermore, it provides a detailed review of the mechanisms underlying endocrine disruption in relation to different types of MP/NP.

A common genetic variant in the Neurexin family member CNTNAP2 is related to language but not communication skills in youth with Autism Spectrum Disorder.

One of the candidate genes related to language variability in individuals with Autism Spectrum Disorder (ASD) is the contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin family. However, due to the different assessment tools used, it is unknown whether the polymorphisms of the CNTNAP2 gene are linked to structural language skills or more general communication abilities. A total of 302 youth aged 7 to 18 years participated in the present study: 131 verbal youth with ASD (62 female), 130 typically developing (TD) youth (64 female), and 41 unaffected siblings (US) of youth with ASD (25 female). Blood samples were collected to obtain genomic DNA and processed by the Rutgers University Cell and Data Repository or using standard protocols (Gentra Puregene Blood DNA extraction kit; Qiagen). Language and verbal communication skills were screened with the Clinical Evaluation of Language Fundamental-4 (CELF-4) and Vineland-II Communication domain, subsequently. The results showed that the polymorphism of CNTNAP2 (SNP rs2710102) was related to structural language abilities, such that participants carrying the A-allele had lower language skills in comparison to the G-allele homozygotes. No relationship was found between the polymorphism of CNTNAP2 and more general communication abilities. Although the study revealed genetic mechanisms that are associated with CELF-4 measures but not Vineland-II in youth with ASD, follow-up studies are needed that will include measures of language and communication that are less correlated to each other as well as will include a group of minimally and/or non-verbal individuals with ASD.

Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3ß inhibitors in children and adolescents with cancer.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.

Ocular manifestations and long-term complications of rhabdomyosarcoma in children.

BACKGROUND/OBJECTIVES: The purpose of the study was to describe the ocular manifestations of rhabdomyosarcoma in a large cohort of children. SUBJECT/METHODS: This was a retrospective observational cohort study. The medical records of all pediatric patients with head and neck rhabdomyosarcoma diagnosed between 1997 and 2021 at a tertiary-care pediatric hospital were analyzed. The main outcome measures were the incidence and prognostic role of ocular findings at presentation and long-term ocular complications. RESULTS: There were 77 children with head and neck rhabdomyosarcoma in the study cohort with 38 patients showing ocular manifestations at presentation. Median age at diagnosis was 6.0 years, the median follow-up was 5.7 years and 54.5% were male. At last follow-up, 70.1% had no evidence of progression, 26.0% were deceased, and 2.6% were on palliative treatment. Orbital signs were common (44.2%). The most common ocular findings were proptosis (18.2%), restriction of extraocular motility (28.6%), strabismus/diplopia (22.1%) and ptosis (16.9%). The most common long-term complications were bony hypoplasia/facial asymmetry (40.3%) and keratopathy/dry eye (31.2%). Poor visual acuity (≤20/200) was noted in 13 (16.9%) patients with 5 (6.5%) patients requiring an exenteration. Survival was 100% in primary orbital RMS (p = 0.02), whereas any or a combination of cranial nerve palsies carried a poor prognosis (42% survival, p = 0.008). CONCLUSIONS: In our cohort, half of children with rhabdomyosarcoma had ocular manifestations at presentation with about one-third showing orbital tumor involvement. Cranial nerve involvement carried a significantly worse prognosis for survival.

Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.

BACKGROUND: The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. OBJECTIVE: The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. PATIENTS AND METHODS: Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. RESULTS: Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥ 10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). CONCLUSIONS: Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.

Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. METHODS: ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete. FINDINGS: Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified. INTERPRETATION: Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population. FUNDING: The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).

The relationship between gamma-band neural oscillations and language skills in youth with Autism Spectrum Disorder and their first-degree relatives.

BACKGROUND: Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairments and some of these autism-specific language difficulties are also present in their non-autistic first-degree relatives. One of the possible neural mechanisms associated with variability in language functioning is alterations in cortical gamma-band oscillations, hypothesized to be related to neural excitation and inhibition balance. METHODS: We used a high-density 128-channel electroencephalography (EEG) to register brain response to speech stimuli in a large sex-balanced sample of participants: 125 youth with ASD, 121 typically developing (TD) youth, and 40 unaffected siblings (US) of youth with ASD. Language skills were assessed with Clinical Evaluation of Language Fundamentals. RESULTS: First, during speech processing, we identified significantly elevated gamma power in ASD participants compared to TD controls. Second, across all youth, higher gamma power was associated with lower language skills. Finally, the US group demonstrated an intermediate profile in both language and gamma power, with nonverbal IQ mediating the relationship between gamma power and language skills. LIMITATIONS: We only focused on one of the possible neural contributors to variability in language functioning. Also, the US group consisted of a smaller number of participants in comparison to the ASD or TD groups. Finally, due to the timing issue in EEG system we have provided only non-phase-locked analysis. CONCLUSIONS: Autistic youth showed elevated gamma power, suggesting higher excitation in the brain in response to speech stimuli and elevated gamma power was related to lower language skills. The US group showed an intermediate pattern of gamma activity, suggesting that the broader autism phenotype extends to neural profiles.

Perilous paradigm of graphene oxide and its derivatives in biomedical applications: Insight to immunocompatibility.

With advancements in nanotechnology and innovative materials, Graphene Oxide nanoparticles (GONP) have attracted lots of attention among the diverse types of nanomaterials owing to their distinctive physicochemical characteristics. However, the usage at scientific and industrial level has also raised concern to their toxicological interaction with biological system. Understanding these interactions is crucial for developing guidelines and recommendations for applications of GONP in various sectors, like biomedicine and environmental technologies. This review offers crucial insights and an in-depth analysis to the biological processes associated with GONP immunotoxicity with multiple cell lines including human whole blood cultures, dendritic cells, macrophages, and multiple cancer cell lines. The complicated interactions between graphene oxide nanoparticles and the immune system, are highlighted in this work, which reveals a range of immunotoxic consequences like inflammation, immunosuppression, immunostimulation, hypersensitivity, autoimmunity, and cellular malfunction. Moreover, the immunotoxic effects are also highlighted with respect to in vivo models like mice and zebrafish, insighting GO Nanoparticles' cytotoxicity. The study provides invaluable review for researchers, policymakers, and industrialist to understand and exploit the beneficial applications of GONP with a controlled measure to human health and the environment.

Real-word experience of pazopanib and sorafenib in patients with desmoid tumors: A CanSaRCC multi-center study.

BACKGROUND: Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. METHODS: Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. RESULTS: 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. CONCLUSION: This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.

Perspectives of Health Care Providers on Peer Support for Adolescents with Cancer in Pediatrics.

Health care providers (HCPs) play a key role in psychosocial care of adolescents with cancer (AWC) and present a unique perspective. This prospective study included a brief survey followed by an interview, seeking to understand HCPs' viewpoints on peer support needs of AWC. Participants were 10 multidisciplinary HCPs with 5-30 years of experience. Three key themes found were: observations made and relationships with AWC; challenges to providing support; and potential peer support interventions. HCPs want to provide peer support resources but lack adequate information. Next steps: interventions should include information dissemination to all HCPs caring for AWC.

Adapting an Adolescent and Young Adult Program Housed in a Quaternary Cancer Centre to a Regional Cancer Centre: Creating Equitable Access to Developmentally Tailored Support.

Adolescents and young adults (AYAs) with cancer, representing those between 15 and 39 years of age, face distinctive challenges balancing their life stage with the physical, emotional, and social impacts of a cancer diagnosis. These challenges include fertility concerns, disruptions to educational and occupational pursuits, issues related to body image and sexual health, and the need for age-appropriate psychosocial support within their communities. The Princess Margaret Cancer Centre (PM), a quaternary care center, established a specialized AYA program in 2014, offering holistic and developmentally tailored psychosocial support and currently, efforts are underway to expand this to other regions in the province to address the need for equitable access. The establishment process involves securing funding, conducting an environmental scan, identifying service gaps, developing clinical pathways, and implementing AYA supportive care. An accessible AYA program should also consider social determinants of health, social location, intersectionality, and an interdisciplinary health approach in understanding health inequities in AYA oncology care. This paper describes the processes implemented and challenges faced in creating a community-based AYA program beyond major resource-rich cities and efforts to address intersectionality.

Proximal discrepancies in intrinsic atomic interaction determines comparative in vivo biotoxicity of Chlorpyrifos and 3,5,6-trichloro-2-pyridinol in embryonic zebrafish.

Bioaccumulation of Chlorpyrifos (CP) as pesticides due to their aggrandized use in agriculture has raised serious concern on the health of ecosystem and human beings. Moreover, their degraded products like 3,5,6-trichloro-2-pyridinol (TCP) has enhanced the distress due to their unpredictable biotoxicity. This study evaluates and deduce the comparative in vivo mechanistic biotoxicity of CP and TCP with zebrafish embryos through experimental and computational approach. Experimental cellular and molecular analysis showed higher induction of morphological abnormalities, oxidative stress and apoptosis in TCP exposed embryos compared to CP exposure due to upregulation of metabolic enzymes like Zhe1a, Sod1 and p53. Computational analysis excavated the differential discrepancies in intrinsic atomic interaction as a reason of disparity in biotoxicity of CP and TCP. The mechanistic differences were deduced due to the differential accumulation and internalisation leading to variable interaction with metabolic enzymes for oxidative stress and apoptosis causing physiological and morphological abnormalities. The study unravelled the information of in vivo toxicity at cellular and molecular level to advocate the attention of taking measures for management of CP as well as TCP for environmental and human health.

Prospects and challenges of noncoding-RNA-mediated inhibition of heat shock protein 90 for cancer therapy.

Heat Shock Protein 90 (HSP90) is a potential drug target for cancer therapy as it is often dysregulated in several cancers, including lung, breast, pancreatic, and prostate cancers. In cancer, HSP90 fails to maintain the structural and functional integrity of its several client proteins which are involved in the hallmarks of cancer such as cell proliferation, invasion, migration, angiogenesis, and apoptosis. Several small molecule inhibitors of HSP90 have been shown to exhibit anticancer effects in vitro and in vivo animal models. However, a few of them are currently under clinical studies. The status and potential limitations of these inhibitors are discussed here. Studies demonstrate that several noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) regulate HSP90 and its client proteins to modulate cellular processes to exhibit oncogenic or tumor suppressing properties. Over the last decade, miRNAs and lncRNAs have drawn significant interest from the scientific community as therapeutic agents or targets for clinical applications. Here, we discuss the detailed mechanistic regulation of HSP90 and its client proteins by ncRNAs. Moreover, we highlight the significance of these ncRNAs as potential therapeutic agents/targets, and the challenges associated with ncRNA-based therapies. This article aims to provide a holistic view on HSP90-regulating ncRNAs for the development of novel therapeutic strategies to combat cancer.