IL-22 regulates MASTL expression in intestinal epithelial cells.

Microtubule-associated serine-threonine kinase-like (MASTL) has recently been identified as a oncogenic kinase given its overexpression in numerous cancers. Our group has shown that MASTL expression is upregulated in mouse models of sporadic CRC and colitis associated cancer (CAC). CAC is one of the most severe complications of chronic IBD, but a limited understanding of the mechanisms governing the switch from normal healing to neoplasia in IBD underscores the need for increased research in this area. However, MASTL expression in IBD patients and its molecular regulation in IBD and CAC have not been studied. This study reveals that MASTL is upregulated by the cytokine interleukin (IL)-22, which promotes proliferation and has important functions in colitis recovery; however, IL-22 can also promote tumorigenesis when chronically elevated. Upon reviewing the publicly available data, we found significantly elevated MASTL and IL-22 levels in the biopsies from late-stage ulcerative colitis patients compared to controls, and that MASTL upregulation was associated with high IL-22 expression. Our subsequent in vitro studies found that IL-22 increases MASTL expression in intestinal epithelial cell lines, facilitating IL-22- mediated cell proliferation and downstream survival signaling. Inhibition of AKT activation abrogated IL-22-induced MASTL upregulation. We further found an increased association of carbonic anhydrase IX (CAIX) with MASTL in IL-22-treated cells, which stabilized MASTL expression. Inhibition of CAIX prevented IL-22-induced MASTL expression and cell survival. Overall, we show that IL-22/AKT signaling increases MASTL expression to promote cell survival and proliferation. Further, CAIX stabilizes MASTL by associating with it in response to IL-22 stimulation.

Albendazole inhibits colon cancer progression and therapy resistance by targeting ubiquitin ligase RNF20.

BACKGROUND: The repurposing of FDA-approved drugs for anti-cancer therapies is appealing due to their established safety profiles and pharmacokinetic properties and can be quickly moved into clinical trials. Cancer progression and resistance to conventional chemotherapy remain the key hurdles in improving the clinical management of colon cancer patients and associated mortality. METHODS: High-throughput screening (HTS) was performed using an annotated library of 1,600 FDA-approved drugs to identify drugs with strong anti-CRC properties. The candidate drug exhibiting most promising inhibitory effects in in-vitro studies was tested for its efficacy using in-vivo models of CRC progression and chemoresistance and patient derived organoids (PTDOs). RESULTS: Albendazole, an anti-helminth drug, demonstrated the strongest inhibitory effects on the tumorigenic potentials of CRC cells, xenograft tumor growth and organoids from mice. Also, albendazole sensitized the chemoresistant CRC cells to 5-fluorouracil (5-FU) and oxaliplatin suggesting potential to treat chemoresistant CRC. Mechanistically, Albendazole treatment modulated the expression of RNF20, to promote apoptosis in CRC cells by delaying the G2/M phase and suppressing anti-apoptotic-Bcl2 family transcription. CONCLUSIONS: Albendazole, an FDA approved drug, carries strong therapeutic potential to treat colon cancers which are aggressive and potentially resistant to conventional chemotherapeutic agents. Our findings also lay the groundwork for further clinical testing.

A preliminary study on the dynamics of serum color in perspective to hemoglobin and bilirubin in indigenous sheep of Pakistan.

The present study is the first of its kind being reported for an indigenous sheep breed of Pakistan with objectives to (a) assess the diagnostic efficacy of a human-based "serum hemolysis reference palette" for sheep serum, (b) deduce normal reference intervals (RIs) for hemoglobin (Hb) and bilirubin, and (c) devise a novel serum color chart for on-field estimation of Hb and bilirubin through color matching of sheep serum. Apparently, healthy Sipli sheep (n = 130) were bled twice attaining whole blood and serum samples (n = 260). The study animals were grouped on the basis of gender, that is, males (n = 51) and females (n = 79) and age, that is, G1 (up till 1 year) (n = 41), G2 (from 1 to 2 years) (n = 46), and G3 (from 2 to 3 years) (n = 43). None of the 260 serum samples of the sheep matched the color given on the human-based "hemolysis reference palette." The G1 animals revealed marked variation in their serum color. Hence, on the basis of RIs, the serum samples (n = 178) of adult sheep (G2 and G3) showing three main color bands were used in devising a novel serum Hb and bilirubin estimation chart for adult sheep serum. In conclusion, the human-based serum hemolysis palette is not valid for sheep serum. The RIs attained in the study could provide a yardstick for assessment of health in indigenous sheep breeds whereas the serum color chart may be of value in estimating Hb and bilirubin in a quick, reliable, and cheaper way for the resource-poor settings of the world.

Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer.

Therapy resistance is the primary problem in treating late-stage colorectal cancer (CRC). Claudins are frequently dysregulated in cancer, and several are being investigated as novel therapeutic targets and biomarkers. We have previously demonstrated that Claudin-1 (CLDN1) expression in CRC promotes epithelial-mesenchymal transition, metastasis, and resistance to anoikis. Here, we hypothesize that CLDN1 promotes cancer stemness and chemoresistance in CRC. We found that high CLDN1 expression in CRC is associated with cancer stemness and chemoresistance signaling pathways in patient datasets, and it promotes chemoresistance both in vitro and in vivo. Using functional stemness assays, proteomics, biophysical binding assays, and patient-derived organoids, we found that CLDN1 promotes properties of cancer stemness including CD44 expression, tumor-initiating potential, and chemoresistance through a direct interaction with ephrin type-A receptor 2 (EPHA2) tyrosine kinase. This interaction is dependent on the CLDN1 PDZ-binding motif, increases EPHA2 protein expression by inhibiting its degradation, and enhances downstream AKT signaling and CD44 expression to promote stemness and chemoresistance. These results suggest CLDN1 is a viable target for pharmacological intervention and/or biomarker development.

Discovery, synthesis and biological evaluation of a series of N-(phenylcarbamothioyl)-2-napthamides as inhibitors of Claudin-1.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide, despite advancements in diagnosis. The main reason for this is that many newly diagnosed CRC patients will suffer from metastasis to other organs. Thus, the development of new therapies is of critical importance. Claudin-1 protein is a component of tight junctions in epithelial cells, including those found in the lining of the colon. It plays a critical role in the formation and maintenance of tight junctions, which are essential for regulating the passage of molecules between cells. In CRC, claudin-1 is often overexpressed, leading to an increase in cell adhesion, which can contribute to the development and progression of the disease. Studies show that high levels of claudin-1 are associated with poor prognosis in CRC patients and targeting claudin-1 may have therapeutic potential for the treatment of CRC. Previously, we have identified a small molecule that inhibits claudin-1 dependent CRC progression. Reported herein are our lead optimization efforts around this scaffold to identify the key SAR components and the discovery of a key new compound that exhibits enhanced potency in SW620 cells.

Synthesis and Characterization of Zinc Oxide Nanoparticles at Different pH Values from Clinopodium vulgare L. and Their Assessment as an Antimicrobial Agent and Biomedical Application.

The current study attempts to evaluate the formation, morphology, and physico-chemical properties of zinc oxide nanoparticles (ZnO NPs) synthesized from Clinopodium vulgare extract at different pH values and to investigate their antimicrobial and biomedical application potential. The reduction of zinc ions to ZnO NPs was determined by UV spectra, which revealed absorption peaks at 390 nm at pH 5 and 348 nm at pH 9, respectively. The spherical morphology of the nanoparticles was observed using scanning electron microscopy (SEM), and the size was 47 nm for pH 5 and 45 nm for pH 9. Fourier-transformed infrared spectroscopy (FTIR) was used to reveal the presence of functional groups on the surface of nanoparticles. The antibacterial activity was examined against Staphylococcus aureus, Streptococcus pyogenes, and Klebsiella pneumonia via the agar-well diffusion method. Comparatively, the highest activities were recorded at pH 9 against all bacterial strains, and among these, biogenic ZnO NPs displayed the maximum inhibition zone (i.e., 20.88 ± 0.79 mm) against S. aureus. ZnO NPs prepared at pH 9 exhibited the highest antifungal activity of 80% at 25 mg/mL and antileishmanial activity of 82% at 400 mg/mL. Altogether, ZnO NPs synthesized at pH 9 show promising antimicrobial potential and could be used for biomedical applications.

Evaluation of potential inhibitory effects on acetylcholinesterase, pancreatic lipase, and cancer cell lines using raw leaves extracts of three fabaceae species.

The present study examined the biological potential and phytochemicals of Sophora mollis, Mucuna pruriens, and Indigofera atropurpurea methanolic leaf extracts. In vitro anti-acetylcholinesterase and anti-lipase assays were performed using different concentrations of plant extracts, and the IC50 values were determined. The cytotoxic potential of the selected plant extracts was assessed against HeLa, PC3, and 3T3 cell lines using an MTT assay. S. mollis leaf extract displayed the highest inhibition percentage (114.60% ± 19.95 at 1000 µg/mL) for the anti-acetylcholinesterase activity with a prominent IC50 value of 75.9 µg/mL. The anti-lipase potential was highest with the M. pruriens leaf extract (355.5 µg/mL IC50), followed by the S. mollis extract (862.7 µg/mL IC50). Among the cell lines tested, the cytotoxic potential of the I. atropurpurea extract (91.1 ppm IC50) against the PC3 cell line was promising. High-performance liquid chromatography revealed gallic acid, chlorogenic acid, caffeic acid, vanillic acid, rutin trihydrate, and quercetin dihydrate in varying concentrations in all plant species. The concentration of chlorogenic acid (69.09 ppm) was highest in M. pruriens, and the caffeic acid concentration (45.20 ppm) was higher in S. mollis. This paper reports the presence of bioactive therapeutic compounds in selected species of the Fabaceae family that could be micro-propagated, isolated, and utilized in pharmaceutical industries.

Biogenic synthesis of silver nanoparticles using Funaria hygrometrica Hedw. and their effects on the growth of Zea mays seedlings.

The biogenic synthesis of silver nanoparticles (AgNPs) is an important step in developing eco-friendly and environmentally stable tools for ameliorating crop growth. In the current study, AgNPs were synthesized using Funaria hygrometrica and characterized using ultraviolet (UV) spectroscopy, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD). The UV spectrum showed an absorption peak at 450 nm. SEM revealed an irregular and spherical morphology, FTIR spectroscopy indicated the presence of various functional groups, while XRD displayed peaks at 45.24°, 38.17°, 44.34°, 64.54°, and 57.48° 2θ. The effects of the F. hygrometrica-mediated AgNPs on maize growth and germination were assessed at 0, 100, 300, and 500 ppm. The germination percentage and relative germination rate were increased to 95% ± 1.83% and 100% ± 2.48% at 100 ppm of synthesized AgNPs and then declined at 300 and 500 ppm. The length, fresh weight, and dry matter of the root, shoot, and seedlings were highest at 100 ppm NPs. The plant height, root length, and dry matter stress tolerance indices were also the highest (112.3%, 118.7%, and 138.20% compared with the control) at 100 ppm AgNPs. Moreover, the growth of three maize varieties, that is, NR-429, NR-449, and Borlog, were assessed at 0, 20, 40, and 60 ppm F. hygrometrica-AgNPs. The results indicated the highest root and shoot length at 20 ppm AgNPs. In conclusion, seed priming with AgNPs enhances the growth and germination of maize and can ameliorate crop production globally. RESEARCH HIGHLIGHTS: Funaria hygrometrica Hedw.-mediated AgNPs were synthesized and characterized. Biogenic AgNPs influenced the growth and germination of maize seedlings. All growth parameters were highest at 100 ppm synthesized NPs.

Functionalization of ampicillin and gentamicin with biogenic copper nanoparticles (CuNPs) remodel antimicrobial and cytotoxic outcome against MDR clinical isolates.

The present study reports the functionalization of antibiotic-conjugated Alternanthera pungens and Trichodesma indicum copper nanoparticles (CuNPs). Initially, antibiotic profiling of multi-drug resistant (MDR) clinical isolates against five antibiotics was verified and then gentamicin and ampicillin conjugates of CuNPs were prepared. Biosynthesized nanostructures were characterized through UV-visible spectroscopy, Fourier-transformed infrared spectroscopy, X-ray diffraction and scanning electron microscope. Biogenic synthesized CuNPs displayed highest antibacterial activity (24.0-31.3 mm inhibition zones) when capped with gentamicin as compared to the ampicillin-conjugated NPs which showed resistance against most of the bacterial species. A. pungens-derived conjugates of gentamicin (CuAp-GNT) along with the vehicle revealed 4.86 ± 0.20% and 4.25 ± 2.96% hemolytic potential and highest MDA production in S. typhimurium (3.18 ± 1.52 µg/mL and 6.31 ± 3.49 µg/mL) and K. pneumoniae (2.99 ± 0.90 µg/mL and 4.06 ± 1.20 µg/mL). Similarly, CuAp-GNT also showed highest DNA protection ability by displaying 1342.99 ± 11.87 band intensity. All-inclusive, CuAp showed more promising effects when conjugated with gentamicin indicating that capping of gentamicin with the active components of the plant-based copper nanostructures increases the antibacterial capacity of the drug. Hence, conjugation of antibiotics with bio-based sources offers great potential for identifying potent drug leads.

Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis.

Colorectal cancer (CRC) is a leading cause of the cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and ß-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in- vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1.

Autonomous schema markups based on intelligent computing for search engine optimization.

With advances in artificial intelligence and semantic technology, search engines are integrating semantics to address complex search queries to improve the results. This requires identification of well-known concepts or entities and their relationship from web page contents. But the increase in complex unstructured data on web pages has made the task of concept identification overly complex. Existing research focuses on entity recognition from the perspective of linguistic structures such as complete sentences and paragraphs, whereas a huge part of the data on web pages exists as unstructured text fragments enclosed in HTML tags. Ontologies provide schemas to structure the data on the web. However, including them in the web pages requires additional resources and expertise from organizations or webmasters and thus becoming a major hindrance in their large-scale adoption. We propose an approach for autonomous identification of entities from short text present in web pages to populate semantic models based on a specific ontology model. The proposed approach has been applied to a public dataset containing academic web pages. We employ a long short-term memory (LSTM) deep learning network and the random forest machine learning algorithm to predict entities. The proposed methodology gives an overall accuracy of 0.94 on the test dataset, indicating a potential for automated prediction even in the case of a limited number of training samples for various entities, thus, significantly reducing the required manual workload in practical applications.

Efficiency of Multiple Extraction Solvents on Antioxidant, Cytotoxic, and Phytotoxic Potential of Taraxacum officinale (L.) Weber ex F.H. Wigg. from Poonch Valley, Azad Kashmir, Pakistan.

Background: Different parts of Taraxacum officinale (L.) were used in traditional medicine in various parts of the world for the treatment of health problems, and they possess significant biological activities. The present study aimed to estimate phytochemical and biological activities of T. officinale using different extraction solvents. Methods: Methanolic, acetone, and n-hexane extracts of selected species were prepared, and ten secondary metabolites were examined using standard protocols. The antioxidant activity was performed using three in vitro methods, namely, DPPH assay, total reducing power (TRP) assay, and total antioxidant capacity (TAC). Toxicological analysis was done using the brine shrimp cytotoxic assay and radish seed phytotoxic assay. Results: The T. officinale methanolic extract showed the highest phenolic (178.27 ± 17.17 mg/GAE/g) and flavonoid (18.50 ± 1.64 mg QE/g) contents. Similarly, the methanolic extract also revealed the highest DPPH activity (32.80 ± 9.66 IC50), reducing potential (0.53 ± 0.02 mg/g), and TAC (19.42 ± 0.97 mg/g) as compared to the acetone and n-hexane extracts. The Pearson correlation analysis confirmed a strong positive correlation (r > 0.9) between total phenolic content (TPC), total flavonoid content (TFC), and all antioxidant assays. Furthermore, a heat map displayed the methanolic extract (red color) as a valuable source of phytochemicals and antioxidant agents. Moreover, the T. officinale methanolic extract also showed the highest (7.12 ppm) cytotoxic potential whereas both methanolic and acetone extracts were revealed as moderate phytotoxic agents when compared with the standard. Conclusion: The T. officinale methanolic extract exhibited comparatively notable phytochemicals that are actively involved in antioxidant activities and possess toxicological properties. This upholds the folkloric use of T. officinale as a possible source to develop natural plant-based drugs. Further investigations to isolate bioactive compounds and elements and on their safety need to be conducted.

University students' mental well-being during COVID-19 pandemic: The mediating role of resilience between meaning in life and mental well-being.

The current study aims to examine (a) the mental well-being of university students, who were taking online classes, and (b) and test whether resilience would mediate the relationship between meaning in life and mental well-being. The sample of 302 university students (Mage = 20.25 years; 36.1% men, 63.9% women) was taken from the universities of Punjab, Pakistan. The participants were recruited online and they completed a cross-sectional survey comprising the scales of meaning in life, resilience, and mental well-being during COVID-19. Findings from the study indicated that participants had a normal to a satisfactory level of overall mental wellbeing during COVID-19. Resilience acted as a mediator for both the presence of meaning in life, the search for meaning in life, and mental well-being. Demographic variables including family size were significantly and positively related to resilience while the availability of personal room showed a significant positive relationship with mental well-being. These findings suggest that meaning in life and resilience supports mental well-being during the COVID-19 pandemic and that effective steps should be taken to make the lives of university students more meaningful and resilient.

Antioxidant, Anticancer, and PXR-Dependent CYP3A4 Attributes of Schweinfurthia papilionacea (Burm.f.) Boiss., Tricholepis glaberrima DC. and Viola stocksii Boiss.

Present study established the biological potential of Schweinfurthia papilionacea, Tricholepis glaberrima and Viola stocksii extracts for their potential applications in drug formulations. Initially, FTIR was performed to ascertain functional groups and then plant extracts were prepared using five solvents depending on the polarity. Total phenolic contents were observed in the range of 36.36 ± 1.08 mg GAE/g to 95.55 ± 2.46 mg GAE/g while flavonoid contents were found in the range of 10.51 ± 0.25 mg QE/g to 22.17 ± 1.79 mg QE/g. Antioxidant activity was determined using TRP, CUPRAC, TAC and DPPH assays and was recorded highest in S. papilionacea followed by T. glaberrima extracts. TPC and TFC were found to be strongly correlated with TRP (r > 0.50), CUPRAC (r > 0.53) and DPPH (r = 0.31 and 0.72) assay while weakly correlated with TAC (r = 0.08 and 0.03) as determined by Pearson correlation analysis. Anticancer activity showed that S. papilionacea chloroform extracts possess highest cell viability (85.04 ± 4.24%) against HepG2 cell lines while T. glaberrima chloroform extracts exhibited highest activity (82.80 ± 2.68%) against HT144 cell lines. Afterwards, highest PXR activation was observed in T. glaberrima (3.49 ± 0.34 µg/mL fold) at 60 µg/mL and was correlated with increase in CYP3A4 activity (15.0 ± 3.00 µg/mL IC50 value). Furthermore, antimalarial activity revealed >47600 IC50 value against P. falciparum D6 and P. falciparum W2 and antimicrobial assay indicated highest activity (32 ± 2.80 mm) in S. papilionacea against C. neoformans. At the end, GC-MS analysis of n-hexane plant extracts showed 99.104% of total identified compounds in T. glaberrima and 94.31% in V. stocksii. In conclusion, present study provides insight about the different biological potentials of S. papilionacea and T. glaberrima extracts that rationalize the applications of these extracts in functional foods and herbal drugs for the management of oxidative-stress related diseases, antimicrobial infections and liver and skin cancer.

Chemical composition of Gastrocotyle hispida (Forssk.) bunge and Heliotropium crispum Desf. and evaluation of their multiple in vitro biological potentials.

Medicinal plants largely serve as a source of bioactive compounds in traditional medicines to cure various diseases. The present study was aimed at chemical composition, antioxidant, antimicrobial, cytotoxic and antihemolytic potential of five different extracts of G. hispida and H. crispum (Boraginaceae). G. hispida methanolic extract displayed highest number (eleven) of polyphenolic compounds by using high performance liquid chromatography (HPLC). Functional groups were identified by Fourier-transformed infrared spectroscopy (FTIR) and elements (Si, Fe, Ba, Mg, Ti, Ca, Mg and Cr) were observed by using laser-induced breakdown spectroscopy (LIBS) which were also highly expressed in G. hispida as compared to H. crispum. Antioxidant activity was determined via six assays and antibacterial activity was observed in decreasing order of methanol > ethanol > chloroform > ethyl acetate > n-Hexane in both species. Cytotoxic potential was investigated against brine shrimps and then liver (HepG2) and skin (HT144) cancer cell lines which was detected highest in the G. hispida ethanolic extract (50.76 % and 72.95 %). However, H. crispum chloroform extract revealed highest (31.869 µg/mL) antihemolytic activity and its methanolic extract indicated highest (13.5 %) alpha-amylase inhibitory potential. Altogether, results suggested that both species could be used effectively in food and drug industries owing to the presence of vital bioactive compounds and elements. In future, we recommend to isolate active compounds and to perform in vivo biological assays to further validate their potential biological applications.

Relationship between loci of control and health-promoting behaviors in Pakistani women with polycystic ovary syndrome: coping strategies as mediators.

BACKGROUND/OBJECTIVES: Understanding the factors that promote healthy lifestyle behaviors in women with polycystic ovary syndrome is of substantial importance. Health-promoting lifestyle behaviors (HPLB) have been observed to be effective in managing various symptoms related to PCOS. This study aimed to examine the relationship between loci of control and health-promoting lifestyle behaviors in Pakistani women with polycystic ovary syndrome and the mediating role of coping strategies. METHOD: A correlational study was carried out with 145 unmarried women with polycystic ovary syndrome diagnosed by a gynecologist using the Rotterdam Criteria of 2003 (M age = 24.75 years). Participants were recruited from public sector hospitals in Lahore, Punjab, Pakistan and a series of hierarchical regression analyses were used to analyze results. RESULTS: Findings suggest that women with internal and powerful others locus of control use more active practical coping strategies and less active distractive coping strategies. These women also get more involved in health-promoting behaviors. On the other hand, those with a high level of chance locus of control use less active practical coping strategies and more active distractive coping strategies. In turn, they engage less in health-promoting behaviors. CONCLUSION: Health professionals should consider the effects of different types of locus of control and coping strategies when planning interventions for women with polycystic ovary syndrome.

MASTL regulates EGFR signaling to impact pancreatic cancer progression.

Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (microtubule-associated serine/threonine-protein kinase-like (MASTL)) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role in PC remains unknown. Based on a comprehensive investigation involving PC patient samples, murine models of PC progression (Kras;PdxCre-KC and Kras;p53;PdxCre-KPC), and loss and gain of function studies, we report a previously undescribed critical role of MASTL in promoting cancer malignancy and therapy resistance. Mechanistically, MASTL promotes PC by modulating the epidermal growth factor receptor protein stability and, thereupon, kinase signaling. We further demonstrate that combinatorial therapy targeting MASTL promotes the efficacy of the cell-killing effects of Gemcitabine using both genetic and pharmacological inhibitions. Taken together, this study identifies a key role of MASTL in promoting PC progression and its utility as a novel target in promoting sensitivity to the anti-PC therapies.

Targeting Wnt Signaling in Endometrial Cancer.

This review presents new findings on Wnt signaling in endometrial carcinoma and implications for possible future treatments. The Wnt proteins are essential mediators in cell signaling during vertebrate embryo development. Recent biochemical and genetic studies have provided significant insight into Wnt signaling, in particular in cell cycle regulation, inflammation, and cancer. The role of Wnt signaling is well established in gastrointestinal and breast cancers, but its function in gynecologic cancers, especially in endometrial cancers, has not been well elucidated. Development of a subset of endometrial carcinomas has been attributed to activation of the APC/ß-catenin signaling pathway (due to ß-catenin mutations) and downregulation of Wnt antagonists by epigenetic silencing. The Wnt pathway also appears to be linked to estrogen and progesterone, and new findings implicate it in mTOR and Hedgehog signaling. Therapeutic interference of Wnt signaling remains a significant challenge. Herein, we discuss the Wnt-activating mechanisms in endometrial cancer and review the current advances and challenges in drug discovery.

Pancreatic Cancer and Therapy: Role and Regulation of Cancer Stem Cells.

Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-ß, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.

Impact of Multifaceted Workplace Bullying on the Relationships between Technology Usage, Organisational Climate and Employee Physical and Emotional Health.

This research article investigates the effect of organisational climate and technology usage on employees' physiological and emotional health damage resulting from face-to-face bullying and cyberbullying at the workplace. Furthermore, we investigated emotional intelligence as a coping strategy to moderate employee physiological and emotional health damage. The research used a quantitative research design. A five-point Likert-scale questionnaire was used to collect data from a multistage sample of 500 officials from Pakistan's four service sectors. Results revealed that organisational climate and technology usage are negatively related to face-to-face bullying and cyberbullying at the workplace. At the same time, workplace bullying adversely affects an employee's emotional and physiological health. However, emotional intelligence can reduce an employee's emotional health damage due to workplace bullying. Thus, we suggest incorporating emotional intelligence training at the workplace to minimise the devastating effects of face-to-face bullying and cyberbullying on employees' physical and emotional health.