Mothers' Awareness of Obesity and Its Complications Among Children in the Western Region of Saudi Arabia: A Cross-Sectional Study.

BACKGROUND: Awareness about obesity, its complications, and an age-appropriate, healthy, active lifestyle are essential to maintaining a healthy life. This study aimed to determine the level of awareness Saudi Arabian caregivers have regarding obesity and regular physical activity. MATERIALS AND METHODS: In this cross-sectional study, a survey was conducted among parents in Saudi Arabia using a structured questionnaire. A convenience and snowball sampling method was employed to recruit participants from various regions of Saudi Arabia. The questionnaire assessed parents' knowledge about obesity, its complications, and healthy, active lifestyle practices. Data were analyzed using descriptive statistics, and associations between variables were examined using chi-squared tests. RESULTS: In this study, responses from 256 moms in various Saudi Arabian locations were included in the analysis. Merely 35.5% of the participants demonstrated good knowledge about obesity and its complications. Regarding the promotion of a healthy, active lifestyle, only 11.3% of the participants were aware that kids should eat five types of vegetables and fruits daily, whereas 85% were aware that kids should have <2 hours a day of screen time, and 75.4% were aware that kids should be engaged in physical activity for at least one hour daily. CONCLUSION: This study highlights a concerning gap in knowledge among caregivers in Saudi Arabia concerning obesity and its consequences, with merely 35.5% of participants demonstrating a good understanding of obesity and its complications. Alarmingly, only a fraction (11.3%) showed awareness of the importance of promoting a healthy, active lifestyle. These findings underscore the urgent need for enhanced awareness initiatives focused on obesity and its prevention to ensure optimal child health development, avert health issues, and strengthen positive dynamics between parents and children.

Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.

BACKGROUND: Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents. METHODS: At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results. RESULTS: A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate. CONCLUSIONS: The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.

Nanoparticles of Thiolated Xanthan Gum for the Oral Delivery of Miconazole Nitrate: In Vitro and In Vivo Evaluation.

The objective of this research was to develop a mucoadhesive delivery system that improves permeation for the administration of poorly absorbed oral medications. Thiolation of xanthan gum (XGM) was carried out by esterification with mercaptobutyric acid. Fourier-transformed infrared spectroscopy was used to confirm thiol-derivatization. Using Ellman's technique, it was revealed that the xanthan-mercaptobutyric acid conjugate had 4.7 mM of thiol groups in 2 mg/mL of polymeric solution. Using mucosa of sheep intestine, the mucoadhesive properties of XGM and thiolated xanthan gum (TXGM) nanoparticles were investigated and we found that TXGM had a longer bioadhesion time than XGM. The disulfide link that forms between mucus and thiolated XGM explains why it has better mucoadhesive properties than XGM. A study on in vitro miconazole (MCZ) release using phosphate buffer (pH 6.8) found that TXGM nanoparticles released MCZ more steadily than MCZ dispersion did. A 1-fold increase in the permeation of MCZ was observed from nanoparticles using albino rat intestine compared to MCZ. Albino rats were used to test the pharmacokinetics of MCZ, and the results showed a 4.5-fold increase in bioavailability. In conclusion, the thiolation of XGM enhances its bioavailability, controlled release of MCZ for a long period of time, and mucoadhesive activity.

Metastatic papillary thyroid carcinoma in pleural effusion: a case report and review of the literature.

INTRODUCTION: Papillary thyroid carcinoma accounts for the most common type of thyroid cancer of well-differentiated type. Papillary thyroid carcinoma is featured by biologically low-grade and less aggressive tumors with a survival rate of 10 years in most of the diagnosed cases. Papillary thyroid carcinoma can be presented with the involvement of cervical lymph nodes in about 50% of the patients, yet distant spread is very uncommon. CASE PRESENTATION: Herein, we discuss a Saudi male patient in his early 50s with a history of papillary thyroid carcinoma who presented to the emergency department complaining of shortness of breath and a radiological finding of hydrothorax. Cytologic examination together with immune-histochemical staining and molecular studies of pleural effusion aspiration concluded the definitive diagnosis of metastatic papillary thyroid carcinoma in the pleural space. CONCLUSIONS: Papillary thyroid carcinoma seldom causes metastatic niches in the pleural space; this is a rare clinical presentation, nevertheless, a differential diagnosis of thyroid metastasis needs to be excluded. A definitive diagnosis of metastatic papillary thyroid carcinoma can be made using clinical presentation, cytologic examination, immunohistochemical investigation, and molecular testing. The most common mutation found in papillary thyroid carcinoma cases is the V600E mutation found in the BRAF gene, yet these patients have a relatively low probability of cancer recurrence. Patients with papillary thyroid carcinoma who have the BRAF mutation frequently experience metastases and relapses of the disease after the cancer has progressed aggressively. To help with therapy planning and the introduction of BRAF inhibitors, genetic testing for BRAF mutation may therefore prove to be a useful tool, especially in cases of aggressive subtypes of TC.

Naringin-Dextrin Nanocomposite Abates Diethylnitrosamine/Acetylaminofluorene-Induced Lung Carcinogenesis by Modulating Oxidative Stress, Inflammation, Apoptosis, and Cell Proliferation.

Nanotechnology has proven advantageous in numerous scientific applications, one being to enhance the delivery of chemotherapeutic agents. This present study aims to evaluate the mechanisms underlying the chemopreventive action of naringin-dextrin nanocomposites (Nar-Dx-NCs) against diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced lung carcinogenesis in male Wistar rats. DEN was administered intraperitoneally (i.p.) (150 mg/kg/week) for two weeks, followed by the oral administration of 2AAF (20 mg/kg) four times a week for three weeks. Rats receiving DEN/2AAF were concurrently treated with naringin or Nar-Dx-NCs orally at a dose of 10 mg/kg every other day for 24 weeks. Naringin and Nar-Dx-NCs treatments prevented the formation of tumorigenic cells within the alveoli of rats exposed to DEN/2AAF. These findings were associated with a significant decrease in lipid peroxidation, upregulation of antioxidant enzyme (glutathione peroxidase and superoxide dismutase) activity, and enhanced glutathione and nuclear factor erythroid 2-related factor 2 expression in the lungs. Naringin and Nar-Dx-NCs exerted anti-inflammatory actions manifested by a decrease in lung protein expression of tumor necrosis factor-α and interleukin-1ß and mRNA expression of interleukin-6, interferon-γ, nuclear factor-κB, and inducible nitric oxide synthase, with a concurrent increase in interleukin-10 expression. The anti-inflammatory effect of Nar-Dx-NCs was more potent than naringin. Regarding the effect on apoptosis, both naringin and Nar-Dx-NCs significantly reduced Bcl-2 and increased Bax and P53 expressions. Moreover, naringin or Nar-Dx-NCs induced a significant decrease in the expression of the proliferator marker, Ki-67, and the effect of Nar-Dx-NCs was more marked. In conclusion, Nar-Dx-NCs improved naringin's preventive action against DEN/2AAF-induced lung cancer and exerted anticarcinogenic effects by suppressing oxidative stress and inflammation and improving apoptotic signal induction and propagation.

Autophagy ablation in skeletal muscles worsens sepsis-induced muscle wasting, impairs whole-body metabolism, and decreases survival.

Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Sepsis triggers sustained induction of autophagy, a key cellular degradative pathway, in skeletal muscles. However, the impact of enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis using the cecal ligation and puncture model. Atg7iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting, hypoglycemia, higher ketone levels, and a decreased in survival as compared to mice with intact Atg7. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced muscle and metabolic dysfunctions and negatively impacts survival.

Knowledge and Attitudes around First Aid and Basic Life Support of Kindergarten and Elementary School Teachers and Parents in Taif City, Saudi Arabia.

BACKGROUND: The foremost cause of children's (1-19 year) death is inadvertent injuries. While most of these accidental harms occur at home and school, rapid and suitable parental and teacher intervention is required to increase the chances of a child's survival. Therefore, both parents and teachers of the children in kindergarten and elementary school must be knowledgeable in first aid practice and basic life support (BLS) training. OBJECTIVES: In the current study, our ambition is to evaluate the orientation level, knowledge, and attitudes around first aid and BLS training of kindergarten and elementary school teachers and parents in the city of Taif, Makkah region. METHODS: A cross-sectional study in Taif, Saudi Arabia, targeted kindergarten and elementary school teachers and parents of students enrolled at these levels. There were 648 participants included in this study. The researchers assessed teachers' and parents' knowledge and attitudes around first aid and BLS using a validated, self-administered online questionnaire. RESULTS: The study included 648 participants, including 248 (38.3%) teachers and 400 (61.7%) parents. The socio-demographic analysis showed that 412 (63.6%) are females and 233 (36.5%) are between the ages of 36 and 45 years. Approximately 142 (21.9%) participants reported previous training in the cardiopulmonary resuscitation (CPR) program, though more than half of them (53.5%) had outdated certificates (more than 2 years). The mean total knowledge for our study was 4.6 ± 1.4, with 22.4% of the participants being educated about first aid support and expressing a fair level of CPR foundations. Only a small percentage (2.3%) of the participants exposed a good and adequate theoretical level of knowledge around CPR skills and performance, while most of the contributors unveiled a poor level of knowledge (over 75%). There were no statistically significant differences between parents and teachers (p > 0.05). Finally, numerous participants (85%) appreciated training in the CPR program, and the most common motive was a "wish to avoid unnecessary death". CONCLUSIONS: We concluded that a sizable portion of the contributors expressed a lack of proficiency in the fundamental CPR training knowledge and skills, pointing to an alarming public concern. Promisingly, a sizable percentage of participants expressed motivated attitudes toward CPR training. Therefore, additional study and data are required to effectively combat injury, with an emphasis on investigating causes and risk factors, burden and socioeconomic health determinants, community awareness level and desire to contribute, and accessibility for disseminating specific intervention strategies.

MYTHO is a novel regulator of skeletal muscle autophagy and integrity.

Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.

Re-evaluation of the myoepithelial cells roles in the breast cancer progression.

Over the past decades, luminal epithelial cell lineage has gained considerable attraction as the functionally milk-secreting units and as the most fruitful acreage for breast cancer launching. Recognition of the effective involvement of the myoepithelial cells in mammary gland development and in hampering tumorigenesis has renewed the interest in investigating the biological roles of this second main mammary lineage. The human breast is made up of an extensively branching ductal system intervening by copious lobular units. The ductal system is coated by a chain of luminal epithelial cells (LECs) situated on a layer of myoepithelial cells (MECs) and encompassed by a distinguished basement membrane. Ductal contractility during lactation is a well-known function delivered by the MECs however this is not the only assignment mediated by these cellular populations. It has been well appreciated that the MECs exhibit a natural paracrine power in defeating cancer development and advancement. MECs were found to express numerous proteinase inhibitors, anti-angiogenic factors, and tumour suppressors proteins. Additionally, MECs contributed effectively to maintaining the right luminal cells' polarization and further separating them from the adjacent stroma by making an integrated fence. Indeed, disruption of the MECs layer was reported to facilitate the invasion of the cancer cells to the surrounding stroma. Nonetheless, MECs were also found to exhibit cancer-promoting effects and provoke tumour invasion and dissemination by displaying distinct cancer chemokines. Herein in this review, we aimed to address the roles delivered by MECs in breast cancer progression and decipher the molecular mechanisms regulating proper MECs' physiology, integrity, and terminal differentiation.

Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein−protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Camels' biological fluids contained nanobodies: promising avenue in cancer therapy.

Cancer is a major health concern and accounts for one of the main causes of death worldwide. Innovative strategies are needed to aid in the diagnosis and treatment of different types of cancers. Recently, there has been an evolving interest in utilizing nanobodies of camel origin as therapeutic tools against cancer. Nanotechnology uses nanobodies an emerging attractive field that provides promises to researchers in advancing different scientific sectors including medicine and oncology. Nanobodies are characteristically small-sized biologics featured with the ability for deep tissue penetration and dissemination and harbour high stability at high pH and temperatures. The current review highlights the potential use of nanobodies that are naturally secreted in camels' biological fluids, both milk and urine, in the development of nanotechnology-based therapy for treating different typesQuery of cancers and other diseases. Moreover, the role of nano proteomics in the invention of novel therapeutic agents specifically used for cancer intervention is also illustrated.

The State-of-the-Art of Gene Editing and its Application to Viral Infections and Diseases Including COVID-19.

Gene therapy delivers a promising hope to cure many diseases and defects. The discovery of gene-editing technology fueled the world with valuable tools that have been employed in various domains of science, medicine, and biotechnology. Multiple means of gene editing have been established, including CRISPR/Cas, ZFNs, and TALENs. These strategies are believed to help understand the biological mechanisms of disease progression. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been designated the causative virus for coronavirus disease 2019 (COVID-19) that emerged at the end of 2019. This viral infection is a highly pathogenic and transmissible disease that caused a public health pandemic. As gene editing tools have shown great success in multiple scientific and medical areas, they could eventually contribute to discovering novel therapeutic and diagnostic strategies to battle the COVID-19 pandemic disease. This review aims to briefly highlight the history and some of the recent advancements of gene editing technologies. After that, we will describe various biological features of the CRISPR-Cas9 system and its diverse implications in treating different infectious diseases, both viral and non-viral. Finally, we will present current and future advancements in combating COVID-19 with a potential contribution of the CRISPR system as an antiviral modality in this battle.

BARD1 mystery: tumor suppressors are cancer susceptibility genes.

The full-length BRCA1-associated RING domain 1 (BARD1) gene encodes a 777-aa protein. BARD1 displays a dual role in cancer development and progression as it acts as a tumor suppressor and an oncogene. Structurally, BARD1 has homologous domains to BRCA1 that aid their heterodimer interaction to inhibit the progression of different cancers such as breast and ovarian cancers following the BRCA1-dependant pathway. In addition, BARD1 was shown to be involved in other pathways that are involved in tumor suppression (BRCA1-independent pathway) such as the TP53-dependent apoptotic signaling pathway. However, there are abundant BARD1 isoforms exist that are different from the full-length BARD1 due to nonsense and frameshift mutations, or deletions were found to be associated with susceptibility to various cancers including neuroblastoma, lung, breast, and cervical cancers. This article reviews the spectrum of BARD1 full-length genes and its different isoforms and their anticipated associated risk. Additionally, the study also highlights the role of BARD1 as an oncogene in breast cancer patients and its potential uses as a prognostic/diagnostic biomarker and as a therapeutic target for cancer susceptibility testing and treatment.

Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.

KEY POINTS: The maintenance of mitochondrial integrity is critical for skeletal muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in the muscle ageing process remains unclear. Here we report that both Drp1 knockdown and Drp1 overexpression late in life in mice is detrimental to skeletal muscle function and mitochondrial health. Drp1 knockdown in 18-month-old mice resulted in severe skeletal muscle atrophy, mitochondrial dysfunction, muscle degeneration/regeneration, oxidative stress and impaired autophagy. Overexpressing Drp1 in 18-month-old mice resulted in mild skeletal muscle atrophy and decreased mitochondrial quality. Our data indicate that silencing or overexpressing Drp1 late in life is detrimental to skeletal muscle integrity. We conclude that modulating Drp1 expression is unlikely to be a viable approach to counter the muscle ageing process. ABSTRACT: Sarcopenia, the ageing-related loss of skeletal muscle mass and function, is a debilitating process negatively impacting the quality of life of afflicted individuals. Although the mechanisms underlying sarcopenia are still only partly understood, impairments in mitochondrial dynamics, and specifically mitochondrial fission, have been proposed as an underlying mechanism. Importantly, conflicting data exist in the field and both excessive and insufficient mitochondrial fission were proposed to contribute to sarcopenia. In Drosophila melanogaster, enhancing mitochondrial fission in midlife through overexpression of dynamin-1-like protein (Drp1) extended lifespan and attenuated several key hallmarks of muscle ageing. Whether a similar outcome of Drp1 overexpression is observed in mammalian muscles remains unknown. In this study, we investigated the impact of knocking down and overexpressing Drp1 protein for 4 months in skeletal muscles of late middle-aged (18 months) mice using intra-muscular injections of adeno-associated viruses expressing shRNA targeting Drp1 or full Drp1 cDNA. We report that knocking down Drp1 expression late in life triggers severe muscle atrophy, mitochondrial dysfunctions, degeneration/regeneration, oxidative stress and impaired autophagy. Drp1 overexpression late in life triggered mild muscle atrophy and decreased mitochondrial quality. Taken altogether, our results indicate that both overexpression and silencing of Drp1 in late middle-aged mice negatively impact skeletal muscle mass and mitochondrial health. These data suggest that Drp1 content must remain within a narrow physiological range to preserve muscle and mitochondrial integrity during ageing. Altering Drp1 expression is therefore unlikely to be a viable target to counter sarcopenia.

Prolactin receptor-driven combined luminal and epithelial differentiation in breast cancer restricts plasticity, stemness, tumorigenesis and metastasis.

Dedifferentiation increased cellular plasticity and stemness are established derivers of tumor heterogeneity, metastasis and therapeutic failure resulting in incurable cancers. Therefore, it is essential to decipher pro/forward-differentiation mechanisms in cancer that may serve as therapeutic targets. We found that interfering with expression of the receptor for the lactogenic hormone prolactin (PRLR) in breast cancer cells representative of the luminal and epithelial breast cancer subtypes (hormone receptor positive (HR+) and HER2-enriched (HER2-E) resulted in loss of their differentiation state, enriched for stem-like cell subpopulations, and increased their tumorigenic capacity in a subtype-specific manner. Loss of PRLR expression in HR+ breast cancer cells caused their dedifferentiation generating a mesenchymal-basal-like phenotype enriched in CD44+ breast cancer stem-like cells (BCSCs) showing high tumorigenic and metastatic capacities and resistance to anti-hormonal therapy. Whereas loss of PRLR expression in HER2-E breast cancer cells resulted in loss of their luminal differentiation yet enriched for epithelial ALDH+ BCSC population showing elevated HER2-driven tumorigenic, multi-organ metastatic spread, and resistance to anti-HER2 therapy. Collectively, this study defines PRLR as a driver of precise luminal and epithelial differentiation limiting cellular plasticity, stemness, and tumorigenesis and emphasizing the function of pro/forward-differentiation pathways as a foundation for the discovery of anti-cancer therapeutic targets.

A favorable role of prolactin in human breast cancer reveals novel pathway-based gene signatures indicative of tumor differentiation and favorable patient outcome.

Prolactin (PRL) hormone is known to play a key role in mammary gland development allowing for successful lactation. The role of this hormone in breast tumorigenesis is still controversial. Here, we evaluated PRL protein and gene expression levels in human breast cancer using tissue microarray of 100 breast cancer cases, as well as different publically available human breast cancer gene profiling databases. Interestingly, our results showed a significant downregulation of PRL expression in breast cancer compared to normal adjacent tissue. Moreover, expression of PRL was associated with more differentiated tumors, early stage, smaller tumor size and absence of distant metastasis. Importantly, our results indicate that higher PRL mRNA levels are significantly associated with prolonged relapse-free survival (RFS) in breast cancer patients (P=3.7 x 10(-9)). Additionally, examining expression of PRL pathway-based gene signature composed of PRL, PRLR, Jak2 and Stat5a showed a significant association with more differentiated tumors (P<.00001), prolonged RFS (P=1.8 x 10(-6)) as well as overall survival (OS) (P=.0026). As well, our results indicate that PRL-directed differentiation program in mammary epithelial cells offer good prognosis in human breast cancer. Indeed, expression of a gene signature composed of PRL-upregulated genes showed a significant association with well-differentiated tumors (P<.00001). Whereas expression of a gene signature composed of PRL-downregulated genes showed a significant association with shortened distant metastasis-free survival (DMFS) (P=.0086). Altogether our results highlight that PRL hormone and its signaling pathway may play an important role in maintaining tumor differentiation state and in turn better patient outcome.