Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair (MMR) alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.

Advancements in Laser Therapies for Dermal Hyperpigmentation in Skin of Color: A Comprehensive Literature Review and Experience of Sequential Laser Treatments in a Cohort of 122 Indian Patients.

The heightened awareness of ethnic dermatology aligns with the growing prevalence of skin of color communities globally, where hyperpigmentation disorders pose a common dermatological challenge. Effectively addressing dermal pigmentation is challenging due to its resistance to conventional therapies and its association with impaired quality of life. This underscores the need for effective treatments and a thorough grasp of laser advancements. A relevant literature search spanning the last 7 years across the PubMed database reveals core studies, challenges, and the evolution of laser technologies tailored for various forms of congenital and acquired dermal hyperpigmentation in skin of color. This comprehensive review explores the mechanisms, applications, and recommendations for pigmentary laser technologies, highlighting the key role of Q-switched lasers in their established millisecond/ nanosecond forms and emerging picosecond lasers, fractional non-ablative and ablative lasers, Intense Pulsed Light, etc. The summary of evidence includes studies on dermal melanocytosis (nevus of Ota and Hori's nevus), tattoos, acquired dermal macular hyperpigmentation, etc., and also entities with mixed epidermal-dermal components, such as melasma and post-inflammatory hyperpigmentation. The review offers valuable insights for clinicians to make informed decisions based on diagnosis, skin type, and the latest technologies to optimize results and minimize complications, especially in darker Fitzpatrick skin types. In their five-year study with 122 Indian patients, the authors applied specific laser combinations for diverse dermal melanoses, including tattoos, dermal/mixed melasma, acquired dermal macular hyperpigmentation, and dermal nevi. Substantial pigmentation reduction, subjectively assessed by both physicians and patients, was observed across all groups. A one-way ANOVA indicated a significant difference in mean improvement scores across various pigmentary conditions (F = 3.39, p = 0.02), with melasma patients exhibiting a significantly higher improvement score than tattoos (p = 0.03). The results affirmed the safety and efficacy of sequential laser therapy for dermal pigmentation in skin of color, advocating for flexibility in approach while maintaining the rationale behind the laser sequences. Despite advancements, challenges persist, and gaps in the current literature are identified. In conclusion, this summary highlights the ongoing pursuit of optimal protocols in dermatological laser treatments for dermal melanoses, offering valuable insights for future research and clinical practice.

New pan-ALK inhibitor-resistant EML4::ALK mutations detected by liquid biopsy in lung cancer patients.

ALK and ROS1 fusions are effectively targeted by tyrosine kinase inhibitors (TKIs), however patients inevitably relapse after an initial response, often due to kinase domain mutations. We investigated circulating DNA from TKI-relapsed NSCLC patients by deep-sequencing. New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs.

Studying the use of a proposed three-level grossing protocol in the histopathological diagnosis of COVID-19-associated rhinomaxillary mucormycosis.

Introduction: Mucormycosis is an acute and rapidly progressing opportunistic fungal infection. COVID-19-associated mucormycosis (CAM) had re-emerged as a complication of COVID-19 infection during the second wave of the pandemic in 2021. The rhinomaxillary form is a variant of the rhino-cerebral mucormycosis that presents a diagnostic challenge to the dentist and the oral and maxillofacial pathologist. Gross examination of pathological specimens is the most undermined step even though it plays a vital role in the final diagnosis. No studies have described this post-clinical step for the maxillofacial soft and hard tissue submitted for examination. Material and Methods: A prospective comparative study was carried out on 52 COVID-19-associated rhinomaxillary mucormycosis (CARM) cases to achieve complete, representative, and informative sampling of the submitted tissue and establish a three-level gross macroscopic examination protocol. Complete clinical and radiological histories were recorded after informed, written consent from every patient was received. Details of the number and type of samples received were recorded, grossing procedure was done as per the proposed three-level grossing protocol and were then compared to the presence of fungal hyphae in the soft tissue or decalcified hard tissue. Result: All 100% of the samples consisted of soft tissue (maxillary sinus lining), while 90.4% of the samples contained different hard tissue specimens. Seventy percent of the grossing workload was carried out by first-year oral pathology residents. Sixty-seven point three percent of the total soft tissue samples submitted showed no presence of fungal hyphae, while 69.2% of total decalcified sections of hard tissue were positive for fungal hyphae with a positive correlation. Out of the 29 cases grossed via the three-level grossing protocol, 89.6% of the cases were histopathologically positive for fungal hyphae. Thus a positive association (P < 0.05) between histopathological diagnosis and the proposed three-level grossing protocol was found. Conclusion: It is imperative to recognise that no mucormycosis report is to be signed out without multi-site (three-level grossed) bone decalcified reports. There is an immediate need to realise how vital documentation, correct laboratory practices, and grossing are for accurate histopathological diagnosis.

Experiences of parents and stakeholders in caring for, and supporting children with special needs in Ghana.

We studied the caring, parenting, and support services for children with special needs in Ghana. Many of the study participants reported re-adjusting their lives in virtually every domain-social, economic, and emotional to deal with and manage the new realities. How parents navigate this space varied considerably from setting to setting. Regardless of individual and interpersonal resources, community, institutional, and policy circumstances seemed to exacerbate notions of disability. In many instances, parents had a low depth of suspicion about the precursors to disabling events in their children. Parents are constantly pursuing health care, including a cure for their children with disabilities. Views about "otherness" were noted, and these tended to undermine medical interpretations/explanations of disability generally, which in turn affected formal education and health-seeking for children. Institutional arrangements exist to encourage parents to invest in their children regardless of their perceived abilities. However, these do not seem to be sufficient, particularly for health and formal education. Programming and policy implications are highlighted.

First detection of endopolyploidy in tapetal cells and chromosomal anomalies in meiocytes of Viola pilosa cytotypes (2n=20) from Pir Panjal (Himalayas).

The nine Viola pilosa Blume populations studied from Pir Panjal contained 20 chromosomes. This count is not reported so far in Indian populations. Currently, comparison of tapetal and meiotic cells revealed the existence of synchrony in different developmental phases. Young tapetal cells at prometaphase co-occurred with the pollen mother cells (PMCs) at diakinesis to metaphase, mature tapetal cells with disintegrated chromatin material co-occurred with tetrads and no tapetal cells were found at mature pollen stage. Cytological studies in young tapetal cells revealed most of these to be endopolyploid, with each having 40 chromosomes. While outnumbering somatic cells contained clear 40 chromosomes which seemed to be the outcome of endomitosis, a sizeable number of cells possessed 40 sticky chromosomes at metaphase. Later chromosomes are likely to form restitution nucleus. Mature tapetal cells, occurring singly/cytomictically connected (3.2-26.31%) or showing coalescence (10.5-22.8%), did not contain recognizable chromosomes. Instead, they were characterized by disintegrated nuclear content. Further, meiotic studies revealed that the present population contained all/outnumbering euploid cells (2n=20); many of which exhibited nearly regular behaviour. However, 6.5-26.9% meiocytes of eight populations and 47% cells of P-Khe population depicted aneuploidy/contained quadri-octavalents, with per cent pollen viabilities of these ranging from 38.6 to 49.9. Going by the normal tapetal development in V. pilosa, existence of various chromosomal anomalies seems to have accounted for the reduction in gametic fertility of this taxon.

Epidemiology for public health practice: The application of spatial epidemiology.

Spatial epidemiology is the description and analysis of geographic patterns and variations in disease risk factors, morbidity and mortality with respect to their distributions associated with demographic, socioeconomic, environmental, health behavior, and genetic risk factors, and time-varying changes. In the Letter to Editor, we had a brief description of the practice for the mortality and the space-time patterns of John Snow's map of cholera epidemic in London, United Kingdom in 1854. This map is one of the earliest public heath practices of developing and applying spatial epidemiology. In the early history, spatial epidemiology was predominantly applied in infectious disease and risk factor studies. However, since the recent decades, noncommunicable diseases have become the leading cause of death in both developing and developed countries, spatial epidemiology has been used in the study of noncommunicable disease. In the Letter, we addressed two examples that applied spatial epidemiology to cluster and identify stroke belt and diabetes belt across the states and counties in the United States. Similar to any other epidemiological study design and analysis approaches, spatial epidemiology has its limitations. We should keep in mind when applying spatial epidemiology in research and in public health practice.

Assessment of variability among morphological and molecular characters in wild populations of mint [Mentha longifolia (L.) L.] germplasm.

Mentha longifolia is an important medicinal and aromatic perennial herb that exhibits wide distribution range from sub-tropical to temperate regions. In the present study, agro-morphological traits and genetic differences in 19 different populations of M. longifolia were studied to evaluate the level and extent of its diversity. Analysis of variance (ANOVA) showed that the different phenotypic characters show considerable differences among various populations and was significant at p < 0.05. Molecular diversity analysis performed by using arbitrary amplified eleven ISSR primers generated a total of 121 amplicons that range within the size of 200-2500 base pairs (bp). Each primer on average generated 11 amplicons with percentage polymorphism being 100. The analysis of molecular variance (AMOVA) showed more (64%) among population genetic diversity and less (36%) within the populations. Greater genetic differentiation (Gst = 0.6852) among these populations occurs due to low gene flow (Nm = 0.2297) and greater habitat variability. Geographic and genetic distances were positively correlated according to Mantel's test. In order to remove any kind of biases, we used R software to perform cluster and redundancy analysis to analyse the extent of relatedness among studied populations. In terms of morphological and molecular aspects, the populations were grouped into four and five clusters respectively based on hierarchical clustering method. The results demonstrated that M. longifolia displays a great degree of morphological and genetic variation and can be utilized in breeding, genetic improvement, and gene bank conservation programmes in future.

An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone). CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

A Liquid Biopsy Signature for the Detection of Patients With Early-Onset Colorectal Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (EOCRC) is a distinct clinical and molecular entity with poor survival outcomes compared with late-onset CRC. Although the incidence of EOCRC is rising, current CRC screening strategies have several limitations in diagnostic performance for EOCRC. In view of this clinical challenge, novel and robust biomarkers for detection of EOCRC are necessary. The aim of this study was to develop a circulating micro RNA (miRNA) signature for the diagnosis of patients with EOCRC. METHODS: A systematic discovery approach by analyzing a large, publicly available, noncoding RNA expression profiling dataset (GSE115513) was used. A panel of miRNAs was identified, which was subsequently validated in blood samples from patients with EOCRC in 2 independent cohorts (n = 149) compared with controls (n = 110) and pre/postoperative plasma specimens (n = 22) using quantitative reverse-transcription polymerase chain reaction assays. RESULTS: In the discovery phase, 4 miRNAs were found to be expressed in blood samples. A combination signature of these 4 miRNAs (miR-193a-5p, miR-210, miR-513a-5p, and miR-628-3p) yielded an area under the curve of 0.92 (95% confidence interval, 0.85-0.96) for identification of EOCRC in the training cohort. The miRNA panel performance was then confirmed in an independent validation cohort (area under the curve, 0.88; 95% confidence interval, 0.82-0.93). Moreover, the miRNA panel robustly identified patients with early-stage EOCRC (P < .001). The decreased expression of miRNAs in postsurgery plasma specimens indicated their tumor specificity. CONCLUSIONS: Our novel miRNA signature for the diagnosis of EOCRC has the potential to identify patients with EOCRC with high accuracy for clinical application in the noninvasive diagnosis of EOCRC.

Tuning optical properties of zinc oxide and methyl ammonium lead iodide by ultrasound assisted method.

In the last few decades, ultrasound assisted methods have emerged as environmentally friendly and cost-effective technologies for chemical synthesis. It provides higher yields under mild reaction conditions compared to traditional methods. Methyl ammonium lead iodide and zinc oxide have gained importance in academic as well as industrial research due to their unique optoelectronic properties. Ultrasonication induces changes in the material properties due to acoustic cavitation in the solvent based synthetic approach. As a proof of the concept, the present work includes the study of impact of ultrasound treatment on optical and morphological properties of the title compounds. All the products were characterized by using various analytical techniques such as DRUV, PL, FTIR, XRD and FE-SEM-EDS. XRD reveals the formation of pure phase of the products. Optical properties are analyzed using DRUV and PL spectroscopy and Tauc's plot. Surface modification is observed in both the products (ZnO and methyl ammonium lead iodide) synthesized by sono assisted method inducing changes in the optical band gap. Interestingly, ZnO shows increase in particle size because of ultrasound impact leading to decrease in photocatalytic activity.

New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)-Positive Cancer.

Cancer cells are characterized by high genetic instability, that favors tumor relapse. The identification of the genetic causes of relapse can direct next-line therapeutic choices. As tumor tissue rebiopsy at disease progression is not always feasible, noninvasive alternative methods are being explored. Liquid biopsy is emerging as a non-invasive, easy and repeatable tool to identify specific molecular alterations and monitor disease response during treatment. The dynamic follow-up provided by this analysis can provide useful predictive information and allow prompt therapeutic actions, tailored to the genetic profile of the recurring disease, several months before radiographic relapse. Oncogenic fusion genes are particularly suited for this type of analysis. Anaplastic Lymphoma Kinase (ALK) is the dominant driver oncogene in several tumors, including Anaplastic Large-Cell Lymphoma (ALCL), Non-Small Cell Lung Cancer (NSCLC) and others. Here we review recent findings in liquid biopsy technologies, including ctDNA, CTCs, exosomes, and other markers that can be investigated from plasma samples, in ALK-positive cancers.

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma.

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30-40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

Assessment of C-Reactive Protein Level in Oral Submucous Fibrosis and Oral Squamous Cell Carcinoma Patient.

BACKGROUND: Potentially malignant disorders are highly prevalent in India. In this study, we assessed C-reactive protein (CRP) levels in patients with oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC). METHODOLOGY: Sixty-four patients (OSMF and OSCC) were undertaken and were classified into 3 groups, OSMF patients (Group I, 34), OSCC (Group II, 30), and healthy controls (Group III, 26). Immunoturbidimetry method was used for the estimation of CRP levels. RESULTS: Maximum cases in Group I was seen in the age group 40-60 years (males-10, females-3), Group II in the age group 40-60 years (males-11, females-5) and Group III (males-5, females-6). The mean CRP level in Group I was 6.12 ± 4.5 mg/l, in Group II was 28.4 ± 21.5 mg/l, and in Group III was 3.15 ± 2.19 mg/l. The difference was significant (P < 0.05). CONCLUSION: Authors found that OSMF and oral cancer patients had increased CRP levels as compared to healthy subjects.

Expression of podoplanin in tumor cells and lymphatic vessels in both tumoral and peritumoral areas and correlation with metastatic potential of oral squamous cell carcinoma.

AIM: This study aims to study the expression of podoplanin in tumor cells as well as the lymphatic vessels (LVs) in both tumoral and peritumoral areas and correlate the importance of the lymphatic microvascular density (LMVD) in oral squamous cell carcinoma (OSCC) and its metastatic potential. MATERIALS AND METHODS: D2-40 expression and LV density (LVD) were assessed using antibody D240, in 45 diagnosed cases of all the three grades of OSCC. D2-40 expression was evaluated in both epithelial cells as well as the LVs. RESULTS: D2-40 expression in OSCC showed two different patterns - diffuse and focal. LMVD was calculated and difference in peritumoral and intra tumoral LVs was also assessed. A marked increase was seen we progressed from well-differentiated tumor to poorly differentiated ones, but this difference was found to be statistically nonsignificant. D2-40 immunostaining also highlighted the presence of lymphatic invasion present within the tumors which was detected by the presence of tumor emboli within the LVs. Overall, no significant correlation was found between D240 epithelial positivity and LVD. CONCLUSION: The expression of podoplanin in tumor cells and lymphatics when correlated with histopathological status and clinically with the lymph node status can definitely help in the adjuvant therapies used in OSCC.

Preclinical characterization of dostarlimab, a therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and in vivo animal models.

Inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the treatment landscape for patients with cancer. Clinical activity of anti-PD-(L)1 antibodies has resulted in increased median overall survival and durable responses in patients across selected tumor types. To date, 6 PD-1 and PD-L1, here collectively referred to as PD-(L)1, pathway inhibitors are approved by the US Food and Drug Administration for clinical use. The availability of multiple anti-PD-(L)1 antibodies provides treatment and dosing regimen choice for patients with cancer. Here, we describe the nonclinical characterization of dostarlimab (TSR-042), a humanized anti-PD-1 antibody, which binds with high affinity to human PD-1 and effectively inhibits its interaction with its ligands, PD-L1 and PD-L2. Dostarlimab enhanced effector T-cell functions, including cytokine production, in vitro. Since dostarlimab does not bind mouse PD-1, its single-agent antitumor activity was evaluated using humanized mouse models. In this model system, dostarlimab demonstrated antitumor activity as assessed by tumor growth inhibition, which was associated with increased infiltration of immune cells. Single-dose and 4-week repeat-dose toxicology studies in cynomolgus monkeys indicated that dostarlimab was well tolerated. In a clinical setting, based on data from the GARNET trial, dostarlimab (Jemperli) was approved for the treatment of adult patients with mismatch repair-deficient recurrent or advanced endometrial cancer that had progressed on or following prior treatment with a platinum-containing regimen. Taken together, these data demonstrate that dostarlimab is a potent anti-PD-1 receptor antagonist, with properties that support its continued clinical investigation in patients with cancer.

Using Ultrasound to Screen for Scoliosis to Reduce Unnecessary Radiographic Radiation: A Prospective Diagnostic Accuracy Study on 442 Schoolchildren.

Scoliosis screening is important for timely initiation of brace treatment to mitigate curve progression in skeletally immature children and adolescents. School scoliosis screening programs in Hong Kong follow the protocol of referring children screened positive with a scoliometer and Moiré topography for confirmatory standard radiography. Despite being highly sensitive (88%) in detecting those who require specialist referral, the screening program was found to have a false-positive rate >50%, which could lead to unnecessary X-ray radiation. Radiation-free ultrasound has been reported to be valid and reliable for quantitative assessment of curve severity in scoliosis patients. The aim of this prospective diagnostic accuracy study was to determine the accuracy of ultrasound in determining the threshold of referral that requires X-ray for children screened positive with the scoliometer and Moiré topography. Our study recruited 442 schoolchildren with a mean Cobb angle of 14.0 ± 6.6°. The sensitivity and specificity of ultrasound in predicting the correct referral status, confirmed by X-ray, were 92.3% and 51.6%, with positive and negative predictive values of 29.0% and 96.9%, respectively. Receiver operating characteristic curve analysis revealed area under the curve values of 0.735 for ultrasound alone and 0.832 for ultrasound in combination with measurement of angle of trunk rotation. The finding supports the accuracy of using ultrasound to determine referral status, which could result in a >50% reduction of unnecessary radiation for children undergoing scoliosis screening.

Enhanced anti-cancer activity of andrographis with oligomeric proanthocyanidins through activation of metabolic and ferroptosis pathways in colorectal cancer.

The high degree of morbidity and mortality in colorectal cancer (CRC) patients is largely due to the development of chemoresistance against conventional chemotherapeutic drugs. In view of the accumulating evidence that various dietary botanicals offer a safe, inexpensive and multi-targeted treatment option, herein, we hypothesized that a combination of Andrographis paniculata and Oligomeric Proanthocyanidins (OPCs) might interact together with regard to anti-tumorigenic activity in CRC. As a result, we demonstrated the enhanced anti-cancer activity between these two botanical extracts in terms of their ability to inhibit cancer cell growth, suppress colony formation and induce apoptosis. Furthermore, we validated these findings in subcutaneous xenograft model and in patient derived primary epithelial 3D organoids. Transcriptomic profiling identified involvement of metabolic pathways and ferroptosis-associated genes, including HMOX1, GCLC and GCLM, that may be responsible for the increased anti-tumorigenic activity by the two compounds. Collectively, our study provides novel evidence in support of the combinatorial use of andrographis and OPCs as a potential therapeutic option, perhaps as an adjunctive treatment to classical drugs, in patients with colorectal cancer.

Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.