Osteochondral fragmentation of the cervical articular process joints; prevalence in horses undergoing CT for investigation of cervical dysfunction.

BACKGROUND: Computed tomography (CT) imaging of the cervical spine of mature horses under general anaesthesia is becoming increasingly accessible. Osteochondral fragmentation (OF) of the cervical articular process joints (APJs) has been identified on CT imaging; the prevalence, clinical features and significance of this finding are currently unknown. OBJECTIVES: To describe the prevalence and clinical features of a population of horses with CT evidence of OF within the cervical APJs. STUDY DESIGN: Retrospective, descriptive case series. METHODS: The study population consisted of all horses undergoing CT imaging of the entire cervical spine between April 2016 and December 2019 at Liphook Equine Hospital for investigation of clinical signs localised to this region. CT scans were examined for evidence of OF within the APJs and additional case features were recorded. RESULTS: A total of 55 horses underwent CT imaging during the study period. OF was identified in 13 horses, giving a CT prevalence of 24% in the study population. OF occurred in a range of ages, breeds and uses of equine, presenting with varied clinical signs. It was identified at every level of the neck. Additional cervical pathology was identified in 11/13 OF cases. MAIN LIMITATIONS: Retrospective analysis of a clinical caseload with a lack of clinically normal controls or post mortem confirmation of imaging findings. Low case numbers. CONCLUSIONS: OF within the cervical APJs is recognised on CT imaging in horses with cervical dysfunction. Fragments are commonly identified in combination with additional cervical pathology. Further investigation is required to confirm their clinical significance and develop potential treatment options where necessary.

Surgical removal of intra-articular loose bodies from the cervical articular process joints in 5 horses.

OBJECTIVE: To describe the surgical removal of intra-articular loose bodies (LBs) from the cervical articular process joints (APJs) in five horses and to describe the outcome of the surgery. STUDY DESIGN: Short case series. ANIMALS: Five client-owned horses with naturally occurring LBs within the cervical APJs. METHODS: Medical records were reviewed of horses that were diagnosed with LBs of the cervical APJs on computed tomography (CT), where the LBs were subsequently removed surgically. Details of case selection and surgical technique were reviewed along with postoperative complications and clinical outcome. Histopathology was performed on LBs in some cases. RESULTS: Surgery was performed on six APJs in five horses. Of the 14 LBs identified with CT, 13 were successfully removed from the C4/C5, C5/C6 and C6/C7 articulations. No surgical complications were encountered, and clinical signs of cervical dysfunction improved in all horses. All clinical cases returned to ridden work by 6 months post surgery. Histopathologic examination revealed the removed structures to be osteochondral or chondral loose bodies consisting of cartilaginous proliferation with or without ossification and central necrosis. CONCLUSIONS: Surgical removal of LBs is achievable from the cervical APJs and can result in the resolution of cervical pain. This procedure offers a new treatment option for management of selected horses with cervical pain, following thorough assessment and CT imaging.

Opioid and Opiate Immunoregulatory Processes.

The discovery of the ability of the nervous system to communicate through "public" circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue. Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes). The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel δ, µ., and κ receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes. In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues, the presence of naturally occurring morphine in plasma and a novel µ3 opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues. In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms. In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules. The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.

Prospective, Randomized Comparison of the Effect of Two Antimicrobial Regimes on Surgical Site Infection Rate in Dogs Undergoing Orthopedic Implant Surgery.

OBJECTIVES: To determine whether extending prophylactic antimicrobial administration into the postoperative period would decrease the surgical site infection (SSI) rate in clean canine orthopedic surgery associated with a metal implant. STUDY DESIGN: Randomized prospective clinical study. SAMPLE POPULATION: Consecutive procedures (n = 400) on dogs that had clean orthopedic surgery using a metal implant. METHODS: Cases were randomly allocated to 1 of 2 groups. Group 1 was only administered perioperative antimicrobial drugs whereas group 2 was administered perioperative and 5 days of postoperative antimicrobial therapy. Owners were questioned or dogs were examined at 2 and 6 weeks after surgery to identify any SSI. Long term follow-up by questionnaire of the referring veterinary surgeon ≥1 year after surgery was obtained. RESULTS: Ten of 191 dogs (5.24%) in group 1 developed SSI within 6 weeks compared with 7 of 198 (3.54%) in group 2; 7.22% of dogs in group 1 and 8.24% in group 2 developed infections more than 6 weeks after surgery. CONCLUSIONS: SSI rates in this population of dogs were similar where antimicrobial prophylaxis was administered perioperatively over 3 hours or as a course continued for 6 days.

Disseminated lipid-rich peritoneal mesothelioma in a horse.

A 9-year-old Haflinger mare presented to the Liphook Equine Hospital with a history of weight loss, azotemia, and repeated episodes of ascites over a period of 10 days. The horse was euthanized after exploratory laparotomy revealed large numbers of variably sized masses distributed throughout the peritoneal cavity. Macroscopically, some masses were papillary, while others were nodular. Histologically, the masses were comprised of large to giant, variably shaped, and occasionally multinucleated neoplastic cells with marked anisokaryosis and anisocytosis and a high mitotic rate. Small to moderate numbers of neoplastic cells were swollen by 1 to several, moderately sized to large, clear, circular or ovoid vacuoles, which stained positive with oil red O. Immunohistochemically, the neoplastic cells co-expressed vimentin and cytokeratin. Electron microscopy demonstrated tumor cells with tight junctions, microvilli, and numerous intracytoplasmic lipid droplets. These findings are consistent with a lipid-rich form of mesothelioma, which should be considered as a differential diagnosis if lipid vacuoles are present in potentially neoplastic cells in equine abdominocentesis samples.

Transpalpebral eye enucleation in 40 standing horses.

OBJECTIVE: To report a technique for eye enucleation in standing sedated horses and to report outcome in 40 horses. STUDY DESIGN: Retrospective study. ANIMALS: Horses (n=40) requiring eye enucleation. METHODS: The eye was enucleated using a transpalpebral technique in 40 horses restrained in stocks and sedated. Anesthesia of orbital structures was provided by local nerve blocks and infiltration of the surgical site with local anesthetic solution. RESULTS: Affected eyes were successfully enucleated with the horse standing. Short-term complications included moderate swelling (5 horses) and wound discharge (1). Long-term complications were not observed. CONCLUSIONS: A diseased eye can be safely enucleated with a horse standing. CLINICAL RELEVANCE: Enucleating an equine eye in the standing position eliminates the risks and costs of general anesthesia.

In vitro evaluation of a single injection technique for diagnostic analgesia of the proximal suspensory ligament of the equine pelvic limb.

OBJECTIVE: To examine the anatomic relationship of the deep branch of the lateral plantar nerve (DBLPN) with structures of the proximal metatarsal region, and to define the anatomic location of a solution injected using a single injection technique for diagnostic analgesia of the proximal suspensory ligament (PSL). STUDY DESIGN: Descriptive study. ANIMALS: Cadaveric equine pelvic limbs (n=29). METHODS: The proximal metatarsal region of both pelvic limbs (n=5 horses, 10 limbs) was dissected and measurements were made of anatomic structures relative to the head of the 4th metatarsal bone (HMT4). A single injection technique was used to inject dye 15 mm distal to the HMT4, axial to the MT4 at a depth of 25 mm in each limb from 10 equine cadavers (19 limbs). Hindlimbs were dissected and the position of the dye was recorded. RESULTS: DBLPN branched from the lateral plantar nerve (LPN) at a mean distance of 30 mm proximal to the HMT4 and entered the PSL at a mean distance of 17 mm distal to the HMT4. A 2nd DBLPN was observed in 1 of 10 dissected limbs. Blue dye surrounded the DBLPN in 18 limbs (95%). CONCLUSIONS: A single injection technique was likely to have resulted in desensitization of the DBLPN in 18 of 19 limbs (95%). CLINICAL RELEVANCE: This technique provides a reliable method using a single needle puncture for perineural analgesia of the DBLPN for diagnosis of proximal suspensory desmitis of the pelvic limb with a minimal risk of inadvertently desensitizing structures within the tarsal sheath and the tarsometatarsal joint.

Endoscope-guided, transoral axial division of an entrapping epiglottic fold in fifteen standing horses.

OBJECTIVES: To describe and evaluate the use of a transoral, endoscope-guided technique for transection of an entrapping epiglottic fold in sedated standing horses. STUDY DESIGN: Retrospective study. ANIMALS: Horses (n=16) with epiglottic fold entrapment (EFE). METHODS: Medical records (2005-2006) of 16 horses with EFE were reviewed to determine history, physical and endoscopic examination findings, postoperative complications, and outcome after axial division of EFE using a hooked bistoury, under an endoscopic-guided, transoral approach. RESULTS: EFE was confirmed by endoscopy. Axial division was successfully performed in 15 sedated, standing horses. One horse had to be anesthetized to complete the procedure. None of the horses made abnormal respiratory noise after surgery and all returned to their intended use. After surgery, 1 horse had a short, deformed epiglottis. CONCLUSIONS: EFE can be axially divided safely and effectively using an endoscope-guided, transoral approach, with the horse sedated and standing. CLINICAL RELEVANCE: Endoscopic-guided, transoral axial division of EFE in sedated standing horses is an alternative choice to performing this procedure under general anesthesia.

Interleukin-10 regulated gene expression in cells of hypothalamic-pituitary-adrenal axis origin.

AIM: The hypothalamic-pituitary-adrenal (HPA) axis is a mediator for interactions between the immune and neuroendocrine systems. Pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) have been shown to activate the HPA axis. Recently, interleukin-10, an important anti-inflammatory cytokine in the immune system, has been shown to be expressed in the central nervous system and neuroendocrine system. Little is known, however, about IL-10's functions in the HPA axis. METHODS: The Affymetrix DNA microarray (mouse genome U74Av2 Probe Array) was conducted to determine the gene expression profile regulated by IL-10 in cells of HPA axis origin. RESULTS: In this study, we analyzed gene expression regulated by IL-10 in cells derived from the HPA axis. The results showed that quorums of genes are modulated by IL-10 in these neuroendocrine cells. CONCLUSIONS: These findings will provide a valuable repository to aid in understanding IL-10's functions in the HPA axis at the molecular level.

Serotonin regulation of serotonin uptake in RN46A cells.

AIM: The role of the serotonin transporter (SERT) is to remove serotonin (5-HT) from the synaptic space. In vitro studies have shown that 5-HT uptake via SERT is influenced by the availability of its substrate, 5-HT. We used RN46A cells, a line that expresses SERT, to investigate 5-HT regulation of 5-HT uptake and the intracellular signaling pathways involved. RN46A cells also express mRNAs for 5-HT receptors (5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(2C)) and as cAMP and intracellular Ca(2+) are modulated by different 5-HT receptors, we studied both pathways. METHODS: 5-HT uptake was determined as imipramine-inhibitable uptake of [(3)H]5-HT, intracellular cAMP was measured by RIA and intracellular Ca(2+) changes were determined using the ratiometric method of intracellular Ca(2+) imaging. RESULTS: For uptake experiments, cells were kept for 30 min either with or without 1 microM 5-HT in the medium before measuring uptake. Removal of 5-HT for 30 min significantly decreased [(3)H]5-HT uptake. The absence of 5-HT for 15 min failed to induce any changes in intracellular cAMP levels. Removal of 5-HT from the medium did not change intracellular Ca(2+) levels either; however, adding 1 microM 5-HT after 5 min in 5-HT-free conditions rapidly increased intracellular Ca(2+) levels in 50% of the cells. The remaining cells showed no changes in the intracellular Ca(2+) levels. CONCLUSIONS: We have shown that in RN46A cells, that endogenously express SERT and mRNAs for several 5-HT receptors, changes in 5-HT levels influence 5-HT uptake rate as well as induce changes in intracellular Ca(2+) levels. This suggests that 5-HT may utilize intracellular Ca(2+) to regulate 5-HT uptake.

Corticotropin Releasing Factor (CRF) activation of NF-kappaB-directed transcription in leukocytes.

1. The aim of this study was to test whether CRF enhanced nuclear factor kappa B (NF-kappaB)-directed gene transcription in leukocytes and the receptor specificity of the effect. Initially, we examined the ability of CRF to modulate an antigen-specific, in vitro antibody response. Since that could be mediated by NF-kappaB transcription factor activity, we tested CRF in a NF-kappaB driven luciferase gene expression reporter assay. 2. CRF enhanced the antigen-specific antibody production in a dose- and time-dependent manner. RAW 264.7 macrophage cells and splenocytes stained by immunohistochemistry were positive for CRF receptors and CRF. Expression of both was up-regulated by mitogen treatment of the splenocytes. CRF also enhanced the NF-kappaB-regulated reporter assay and this could be blocked by a CRF-R1 receptor antagonist. 3. In light of these findings, it seems likely that CRF enhanced the antigen-specific antibody response through the CRF-R1 receptor by elevation of NF-kappaB activity. This study provides further support for the concept that CRF can act as an immunomodulator mediating neuro-immune interactions.

Regulation of adrenal glucocorticoid synthesis by interleukin-10: a preponderance of IL-10 receptor in the adrenal zona fasciculata.

Several lines of evidence indicate that cytokines can affect adrenal function. To date most of these cytokines have been shown to be pro-inflammatory, such as interleukin (IL)-1, tumor necrosis factor (TNFalpha), and IL-6. However, we have previously shown that IL-10-/- (IL-10 knockout) mice have higher serum corticosterone levels than IL-10+/+ (wild type) mice following acute immune and physiologic stress, implying that IL-10, an anti-inflammatory cytokine, regulates glucocorticoid synthesis in a negative manner. Here, we show that IL-10 knockout mice produce more corticosterone under basal conditions as well (shown by ELISA). We further support this contention by showing that in Y-1 adrenocortical cells IL-10 inhibits steroid production (StAR) (measured by the production of the corticosterone precursor, progesterone), the expression of steroidogenic acute regulatory protein (semi-quantitative RT-PCR), as well as the activity of the proximal steroidogenic enzymes P450scc and/or 3beta-hydroxysteroid dehydrogenase (3beta-HSD) (measured by progesterone production in 22(R)-hydroxycholesterol-treated cells). Interestingly, all of the above-mentioned effects of IL-10 occur through its inhibition of ACTH effects, but not by IL-10 alone. Furthermore, immunocytochemistry data shows that the region of the adrenal gland responsible for the vast majority of corticosterone synthesis, the zona fasciculata, predominantly expresses the IL-10 receptor 1 (IL-10R1), with little expression in the zona glomerulosa and reticularis. These data demonstrate that IL-10 could play an important role in the regulation of glucocorticoid biosynthesis and in maintenance of homeostasis and immunity during periods of stress.

Cytokine regulation of tryptophan metabolism in the hypothalamic-pituitary-adrenal (HPA) axis: implications for protective and toxic consequences in neuroendocrine regulation.

AIM: Indoleamine 2,3-dioxygenase (IDO) catalyzation of tryptophan is the first rate-limiting step of the kynurenine pathway in the majority of tissues. The kynurenine pathway produces neurotoxic metabolites such as 3-hydroxykinurenine and quinolinic acid. IDO is inducible by the cytokine interferon-gamma (IFN-gamma) and has been proposed to mediate the sickness behavior of patients with infectious or other inflammatory diseases.To better understand the neuroendocrine component of cytokine induced sickness behavior we determined the effects of the pro-inflammatory cytokine IFN-gamma and the anti-inflammatory cytokine IL-10 on IDO expression in cells derived from the hypothalamic-pituitary-adrenal axis (HPA): GT1-7 hypothalamic, AtT-20 pituitary, and Y-1 adrenal cells. METHODS: Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to check the IDO expression from IFN-gamma and IL-10 treated cells such as GT1-7, AtT-20 and Y-1 cells. RESULTS: We found that IFN-gamma induces IDO expression after 4 h treatment in GT1-7 and AtT-20 cells. IL-10 was also able to suppress IFN-gamma induced IDO expression in these cells. In Y-1 adrenal cells, IFN-gamma treatment had no effect on IDO expression. CONCLUSIONS: Our results indicate that cytokines such as IFN-gamma and IL-10 are able to regulate IDO expression in cells of hypothalamic and pituitary origin. The ability of IL-10 to suppress IFN-gamma induced IDO expression implies that IL-10 has a putative neuroprotective role in the HPA axis. It can act at two levels, systemically by inhibiting sickness behavior-related Th1 cytokine synthesis and more centrally by inhibiting the kynurenine pathway.

ACTH enhancement of T-lymphocyte cytotoxic responses.

1. Corticotropin (ACTH) was one of the first neuropeptides shown to bind to receptors on leukocytes and modulate immune responses. Generally ACTH inhibits immune responses, but certain functions can be enhanced. The present study was performed to determine the effects of ACTH on cytotoxic T-lymphocyte responses, the components, and the major phenotypes of the participating cells. 2. The action of ACTH on cytotoxicity was measured in vitro, in assays utilizing T-lymphocytes that had been previously sensitized in vivo. The cells were then cultured with ACTH and target cells bearing the appropriate stimulatory major histocompatiblity antigens. 3. ACTH did not significantly affect a primary mixed lymphocyte reaction whereas it enhanced a secondary (memory) cytotoxic response up to 100% following 2 days of ACTH treatment. The effect was a shift in the kinetics of effector cell generation so that ACTH-treated cultures demonstrated an augmented cytotoxic activity on day 2, that was not as pronounced on day 3 as cytotoxic activity in control cultures became maximal. ACTH also inhibited Concanavalin A-stimulated T-lymphocyte mitogenesis. Immature thymocyte mitogenesis was inhibited more than that of mature thymocytes. 4. The finding that IFN-gamma was elevated in the cultures suggested that ACTH may enhance memory cytotoxic responses through a combination of mechanisms such as direct cell alterations or synergy with regulatory cytokines. While corticosteroids are probably the most recognized neuroendocrine, stress hormone to affect immune functions, our study illustrates that other neuroendocrine factors such as ACTH, also directly affect immune functions.

Colostrinin-driven neurite outgrowth requires p53 activation in PC12 cells.

1. Colostrinin (CLN) induces maturation and differentiation of murine thymocytes, promotes proliferation of peripheral blood leukocytes, induces immunomodulator cytokines, and ameliorates oxidative stress-mediated activation of c-Jun NH2-terminal kinases. 2. Here we report that upon treatment with CLN, medullary pheochromocytoma (PC12) cells ceased to proliferate and extend neurites. 3. The arrest of CLN-treated PC12 cells in the G1 phase of the cell cycle was due to an increase in the phosphorylation of p53 at serine(15) (p53ser15) and expression of p21WAF1. PC12 cells treated with inhibitory oligonucleotides to p53 lacked p53ser15 and p21WAF1 expression, and did not show morphological changes after CLN exposure. Transfection with inhibitory oligonucleotides to p21WAF1 had no effect on p53 activation; however, cells failed to arrest or extend neurites. An oligonucleotide inhibiting luciferase expression had no effect on CLN-mediated p53 activation, p21WAF1 expression, growth arrest, or neurite outgrowth. 4. We conclude that CLN induces delicate cassettes of signaling pathways common to cell proliferation and differentiation, and mediates activities that are similar to those of hormones and neurotrophins, leading to neurite outgrowth.

Nested PCR with the PGMY09/11 and GP5(+)/6(+) primer sets improves detection of HPV DNA in cervical samples.

Based on epidemiological and research evidence, HPV has a causal role in cervical carcinogenesis. Several HPV detection methods exist to date; the most commonly used method for detection of genital HPVs consists of nested PCR using the MY09/11 and GP5(+)/6(+) primer sets (MY/GP(+)). Recently, the PGMY09/11 primer set, a modified version of the MY09/11 primer set, was introduced for single PCR and was found to detect a wider range of HPV types. The next logical step was taken and the efficacy of nested PCR using the PGMY09/11 and GP5(+)/6(+) primer sets (PGMY/GP(+)) to detect HPV in cervical samples was evaluated. In this comparative study, nested PCR using the novel PGMY/GP(+) primer set combination was found to be more type sensitive than the nested PCR with the MY/GP(+) primer sets, detecting a wider range of HPV types, low copy HPVs, and better characterizing samples infected with multiple strains of HPV. Standardization and use of the PGMY/GP(+) PCR system could aid physicians in providing more efficient HPV screening and better treatment for patients.

Comprehensive analysis of genetic polymorphisms in the interleukin-10 promoter: implications for immune regulation in specific ethnic populations.

The association of interleukin-10 (IL-10) promoter single-nucleotide polymorphisms (SNPs) as risk factors for certain inflammatory diseases, viral infections, cancers, and transplant rejection have been the subject of recent studies. The SNPs -1082 G --> A, -819 C --> T, and -592 C --> A, which have been associated with differential IL-10 production, are strongly linked with ethnicity. In this study, we determined the ethnic distribution of IL-10 promoter SNPs and their haplotype rates among Hispanics, African Americans, and Caucasians from Texas and Ashkenazi Jews from New York. Significant differences in prevalence rates of IL-10 SNPs (and their haplotype distribution) were found. African Americans and Hispanics have a lower rate of putative high-producer SNPs and a higher rate of low IL-10 producers when compared to Caucasians or Ashkenazi Jews. No statistically significant differences in allelic frequencies and haplotype rates were observed between Caucasians and Ashkenazi Jews. This study provides critical new information on the ethnic distribution of IL-10 promoter SNPs in a regional U. S. population and is the first to analyze the rate of SNPs in an unstudied ethnic population, Ashkenazi Jews. Knowledge of IL-10 promoter polymorphisms may prove useful in prediction of immunization responses, disease severity, and in the intelligent design of customized immunotherapy.

Association of p53 arginine polymorphism with skin cancer.

BACKGROUND: The presence of arginine at codon 72 in p53 protein is proposed to be a genetic risk factor in human papillomavirus (HPV)-related carcinogenesis. OBJECTIVE: To study the prevalence of p53 polymorphism at codon 72 in skin biopsies of epidermodysplasia verruciformis (EV) patients compared to DNA samples from healthy individuals. PATIENTS AND METHODS: DNA samples extracted from normal skin and tumor biopsies of 22 Brazilian patients with EV and blood samples from 27 healthy Brazilian individuals were studied for p53 codon 72 polymorphisms using restriction fragment length polymorphism (RFLP) analysis. RESULTS: All EV patients with the malignant form of EV were homozygous for arginine (Arg/Arg) at codon 72 of the p53 gene, in contrast to none with the benign form (P < 0.0001). CONCLUSIONS: p53 arginine polymorphism is likely to be associated with the development of skin malignancies in EV patients from Brazil.

HPV typing in Brazilian patients with epidermodysplasia verruciformis: high prevalence of EV-HPV 25.

BACKGROUND: Epidermodysplasia verruciformis is a rare genetic disorder characterized by development of lesions associated with HPV#5 or HPV#8 in early childhood; malignant transformation occurs in approximately half of individuals during adulthood. OBJECTIVE: Our goal was to study the presence and spectrum of EV-HPV types in Brazilian EV patients, a population that had never been studied in this regard. PATIENTS AND METHODS: Forty-one biopsies from different lesions (benign and skin tumors) and one biopsy from clinically normal skin from each of 20 Brazilian patients with EV were studied for HPV typing using nested PCR. RESULTS: EV-HPV DNA was detected in all 41 skin lesions of the patients and was also identified in specimens considered as normal skin from 8 patients (40%). In this study HPV-EV 25 was the most prevalent (70%), and HPV 14d (67%) was highly associated with malignant lesions. CONCLUSION: EV-HPV 25 was the most prevalent in our study. The noteworthy association of EV-HPV type 14d with skin cancers suggests its possible oncogenic role in malignant transformation in this population.