Comparing weight loss outcomes after conversion to Roux-en-Y gastric bypass versus duodenal switch from sleeve gastrectomy in a community hospital.

BACKGROUND: Recidivism after initial sleeve gastrectomy (SG) remains common. Revisional surgery to convert SG to Roux-en-Y gastric bypass (RYGB) or duodenal switch (DS) for additional weight loss is increasing. This study aims to compare the outcomes after conversion of SG to RYGB or DS. METHODS: A retrospective single-institution review was conducted from 2015 to 2021, identifying 75 patients who underwent conversion from prior SG to either RYGB (40) or DS (35). Mean excess body weight loss (EBWL) at 3, 6, 12, and 24 months was assessed and compared. Secondary measures of length of stay (LOS), procedure length, and 30-day readmission rate were also reviewed. RESULTS: Percentage EBWL for RYGB vs DS was 24.0% vs 18.8% at 3 months (N = 36 vs 26; P < 0.0491), 34.8% vs 29.0% at 6 months (N = 29 vs 17; P < 0.2192), 43.0% vs 40.1% at 12 months (N = 28 vs 12; P < 0.6828), and 36.2% vs 41.7% at 24 months (N = 27 vs 7; P < 0.5553). Average LOS was 2.6 days ± 1.4 for RYGB and 2.8 days ± 1.3 for DS (P < 0.6032). Average procedure length was 134.4 min for RYGB and 189.8 min for DS (P < 0.0001). 30-day readmission rate was 27.5% (N = 11) for RYGB and 14.3% (N = 5) for DS (P < 0.1645). Significant weight loss was observed in both subgroups up to 12 months, with no significant weight loss between 12 and 24 months (RYGB N = 21, P < 0.2961; DS N = 5, P < 0.7233). CONCLUSION: Both revisional RYGB and revisional DS procedures had significant and sustained weight loss in the first 12 months. There was no significant excess body weight loss difference between revisional RYGB and revisional DS patients at 6, 12, and 24 months, with only significant greater weight loss for RYGB patients at 3 months. Additionally, procedure length was significantly longer for DS compared to RYGB, with no significant differences in LOS and 30-day readmission rates.

Pediatric trauma in the rural and low resourced communities.

Death and disability associated with traumatic injury can be significantly decreased with timely and appropriate care. Patients in rural areas tend to have disproportionately decreased access to this care, with the pediatric age group acting as a particularly difficult challenge for pre-hospital and rural hospital settings due to the unfamiliarity of those trauma response teams with pediatric age specific management guidelines as well as a disparity in resource availability. In this review, we attempt to discuss the challenges facing pediatric trauma care in the rural and low resourced communities, as well as initiatives that are being carried out to optimize this kind of care, such as pediatric readiness, rapid transportation to higher levels of care, availability of blood in rural centers as well as in transit, and the utility of telemedicine in improving rural pediatric trauma care.

HOXA5-Mediated Stabilization of IκBα Inhibits the NF-κB Pathway and Suppresses Malignant Transformation of Breast Epithelial Cells.

HOXA5 is a transcription factor and tumor suppressor that promotes differentiation of breast epithelial cells and is frequently lost during malignant transformation. HOXA5 loss alone, however, does not confer tumorigenicity. To determine which molecular alterations combined with loss of HOXA5 expression can transform cells, we examined isogenic derivatives of a nonmalignant breast epithelial cell line containing knock-in or knockout mutations in key breast cancer genes. Knockdown (KD) of HOXA5 in cells harboring double knock-in (DKI) of mutated PIK3CA (E545K) and HER2 (V777L) induced epithelial-mesenchymal transition and migration and promoted invasive tumor outgrowth within mouse mammary ducts. The NF-κB pathway was significantly upregulated in DKI cells following HOXA5 KD. HOXA5 KD upregulated multiple NF-κB target genes, including IL6. IκBα protein, but not RNA, expression was reduced in HOXA5-KD cells. HOXA5 bound and stabilized IκBα, forming a nuclear HOXA5-IκBα complex. Chromatin immunoprecipitation sequencing database queries revealed that HOXA5 and IκBα are co-enriched at 528 genomic loci. In patients with breast cancer, high coexpression of HOXA5 and IκBα conferred a significantly better overall and progression-free survival. Collectively, these data suggest that HOXA5 suppresses malignancy in breast epithelial cells by blunting NF-κB action via stabilization of its inhibitor IκBα. SIGNIFICANCE: Loss of HOXA5 reduces IκBα stability and increases NF-κB signaling to exacerbate breast cancer aggressiveness, providing new insights into the tumor suppressor functions of HOXA5.

Intraductal administration of transferrin receptor-targeted immunotoxin clears ductal carcinoma in situ in mouse models of breast cancer-a preclinical study.

The human transferrin receptor (TFR) is overexpressed in most breast cancers, including preneoplastic ductal carcinoma in situ (DCIS). HB21(Fv)-PE40 is a single-chain immunotoxin (IT) engineered by fusing the variable region of a monoclonal antibody (HB21) against a TFR with a 40 kDa fragment of Pseudomonas exotoxin (PE). In humans, the administration of other TFR-targeted immunotoxins intrathecally led to inflammation and vascular leakage. We proposed that for treatment of DCIS, intraductal (i.duc) injection of HB21(Fv)-PE40 could avoid systemic toxicity while retaining its potent antitumor effects on visible and occult tumors in the entire ductal tree. Pharmacokinetic studies in mice showed that, in contrast to intravenous injection, IT was undetectable by enzyme-linked immunosorbent assay in blood following i.duc injection of up to 3.0 µg HB21(Fv)-PE40. We demonstrated the antitumor efficacy of HB21(Fv)-PE40 in two mammary-in-duct (MIND) models, MCF7 and SUM225, grown in NOD/SCID/gamma mice. Tumors were undetectable by In Vivo Imaging System (IVIS) imaging in intraductally treated mice within 1 wk of initiation of the regimen (IT once weekly/3 wk, 1.5 µg/teat). MCF7 tumor-bearing mice remained tumor free for up to 60 d of observation with i.duc IT, whereas the HB21 antibody alone or intraperitoneal IT treatment had minimal/no antitumor effects. These and similar findings in the SUM225 MIND model were substantiated by analysis of mammary gland whole mounts, histology, and immunohistochemistry for the proteins Ki67, CD31, CD71 (TFR), and Ku80. This study provides a strong preclinical foundation for conducting feasibility and safety trials in patients with stage 0 breast cancer.

Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer.

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4-/-) CRC mouse model by crossing with Muc4-/- and Apcflox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads to poor survival. Further, the absence of Muc4 was associated with goblet cell dysfunction where the expression of intestinal homeostasis molecules (Muc2 and Fam3D) was downregulated. Next, we also observed that loss of Muc4 showed reduced thickness of mucus layer, leading to infiltration of bacteria, reduction in anti-microbial peptides, and upregulation of pro-inflammatory cytokines. Further, Apc gene mutation results in activation of the Wnt/ß-catenin signaling pathway that corroborated with an increased nuclear accumulation of ß-catenin and activation of its target genes: cyclin D1 and c-Myc in Muc4-/- mice was observed. We conclude that the presence of Muc4 is essential for intestinal homeostasis, reduces tumor burden, and improves overall survival.

Chylolymphatic mesenteric cyst with midgut volvulus in an adolescent: a peculiar presentation.

Mesenteric cysts are rare intra-abdominal masses in the pediatric population, with the chylolymphatic variant comprising only 7.3% of all abdominal cysts. These cysts can have a varied clinical presentation, ranging from asymptomatic cystic masses to intestinal obstruction. We report a 16-year-old female, who presented with acute abdominal pain and vomiting, and was diagnosed with an intra-abdominal cystic mass with midgut volvulus accompanied by the classical "whirlpool sign" on imaging. She underwent laparoscopic abdominal exploration, which revealed a large chylolymphatic mesenteric cyst associated with feeder lymph vessels. This cyst had resulted in volvulus of the small bowel. The bowel was detorsed and found to be viable, and the cyst was removed en bloc after suction evacuation with ligation of the lymphatic feeder vessels. Midgut volvulus in the pediatric population is usually secondary to malrotation, but in this case the patient's small intestine was not found to be malrotated, and hence we present this case and urge physicians to consider a diagnosis of midgut volvulus even in the absence of malrotation in a child with a cystic abdominal mass presenting as intestinal obstruction.

HOX genes and the NF-κB pathway: A convergence of developmental biology, inflammation and cancer biology.

The roles of HOX transcription factors as oncogenes and tumor suppressor genes, and the NF-KB pathway in chronic inflammation, both leading to cancer are well-established. HOX transcription factors are members of an evolutionarily conserved family of proteins required for anteroposterior body axis patterning during embryonic development, and are often dysregulated in cancer. The NF-KB pathway aids inflammation and immunity but it is also important during embryonic development. It is frequently activated in both solid and hematological malignancies. NF-KB and HOX proteins can influence each other through mutual transcriptional regulation, protein-protein interactions, and regulation of upstream and downstream interactors. These interactions have important implications both in homeostasis and in disease. In this review, we summarize the role of HOX proteins in regulating inflammation in homeostasis and disease- with a particular emphasis on cancer. We also describe the relationship between HOX genes and the NF-KB pathway, and discuss potential therapeutic strategies.

Multiple roles of HOX proteins in Metastasis: Let me count the ways.

Knowledge of the role of HOX proteins in cancer has been steadily accumulating in the last 25 years. They are encoded by 39 HOX genes arranged in 4 distinct clusters, and have unique and redundant function in all types of cancers. Many HOX genes behave as oncogenic transcriptional factors regulating multiple pathways that are critical to malignant progression in a variety of tumors. Some HOX proteins have dual roles that are tumor-site specific, displaying both oncogenic and tumor suppressor function. The focus of this review is on how HOX proteins contribute to growth or suppression of metastasis. The review will cover HOX protein function in the critical aspects of epithelial-mesenchymal transition, in cancer stem cell sustenance and in therapy resistance, manifested as distant metastasis. The emerging role of adiposity in both initiation and progression of metastasis is described. Defining the role of HOX genes in the metastatic process has identified candidates for targeted cancer therapies that may combat the metastatic process. We will discuss potential therapeutic opportunities, particularly in pathways influenced by HOX proteins.

Mechanistic and Functional Shades of Mucins and Associated Glycans in Colon Cancer.

Mucus serves as the chief protective barrier against pathogenic and mechanical insults in respiratory, gastrointestinal, and urogenital tracts. Altered mucin expression, the major component of mucus, in conjunction with differential glycosylation has been strongly associated with both benign and malignant pathologies of colon. Mucins and their associated glycans arbitrate their impact sterically as well as mechanically by altering molecular and microbial spectrum during pathogenesis. Mucin expression in normal and pathological conditions is regulated by nonspecific (dietary factors and gut microbiota) and specific (epigenetic and transcriptional) modulators. Further, recent studies highlight the impact of altering mucin glycome (cancer-associated carbohydrate antigens including Tn, Sialyl-Tn, Sialyl-Lew A, and Sialyl-Lewis X) on host immunomodulation, antitumor immunity, as well as gut microbiota. In light of emerging literature, the present review article digs into the impact of structural organization and of expressional and glycosylation alteration of mucin family members on benign and malignant pathologies of colorectal cancer.

Intraductal fulvestrant for therapy of ERα-positive ductal carcinoma in situ of the breast: a preclinical study.

Mammographic screening for breast cancer has led to increased detection of ductal carcinoma in situ (DCIS) and a reappraisal of the necessity of aggressive treatment with their attendant toxicities for a preneoplastic lesion. Fulvestrant, a selective estrogen receptor degrader, is very effective in the treatment of estrogen receptor positive (ER+) breast cancer, but delivery by the painful intramuscular (i.m) route is limiting. We hypothesized that intraductal (i.duc) administration of fulvestrant will provide a direct, safe and effective treatment for DCIS. Mice bearing mammary ductal xenografts of ER+, luciferase-tagged MCF-7 breast cancer cells were administered vehicle or fulvestrant i.m or i.duc. I.duc MCF-7-luc tumors in mice treated with fulvestrant i.duc or i.m grew significantly slower than vehicle control. Whole mount analysis and histopathology showed that i.duc fulvestrant achieved significantly larger cancer-free areas. Western blot analysis showed reduced levels of estrogen receptor alpha (ERα) and its downstream targets, c-Myc and Cyclin D1, and increased levels of ERß, which is known to inhibit ERα function. Immunohistochemical analysis of tumor sections showed that Ki67 and ERα protein levels decreased by 3-fold, and neoangiogenesis was inhibited by i.duc fulvestrant treatment. I.duc fulvestrant also reduced outgrowth of ERα+, autochthonous N-methyl-N-nitrosourea-induced mammary tumors in rats. Overall, we have shown that i.duc fulvestrant was significantly more effective than, or equivalent in action to i.m fulvestrant in two preclinical models of breast cancer. These studies provide evidence for a novel and safe route for fulvestrant therapy of DCIS and prevention of breast cancer. This preclinical study provides a strong basis for conducting clinical trials for DCIS and early breast cancer.

Mucins and associated O-glycans based immunoprofile for stratification of colorectal polyps: clinical implication for improved colon surveillance.

Sessile serrated adenoma/polyps (SSA/P) are premalignant lesions of colorectal cancer that are difficult to distinguish histologically from hyperplastic polyps (HP) of minimal to no malignant potential. Specific markers for differentiating SSA/P from HP can aid clinicians for optimizing colon surveillance intervals. The present study investigates the potential of mucins and associated O-glycans to distinguish SSA/P from HP. Expression of colonic mucins (MUC1, MUC4, MUC17, MUC2, and MUC5AC) and O-glycans [Sialyl LewisA (CA19-9) and Tn/Sialyl-Tn on MUC1] were analyzed in HP (n=33), SSA/P (n=39), and tubular adenoma (TA) (n=36) samples by immunohistochemistry. A significantly reduced expression of MUC4 (p=0.0066), elevated expression of MUC17 (p=0.0002), and MUC5AC (p<0.0001) was observed in SSA/P cases in comparison to HP cases. Interestingly, significantly higher number of SSA/P cases (p<0.0001) exhibited MUC5AC expression in the goblet cells as well as filled the crypt lumen compared to only goblet cells in majority of the HP cases. Improved diagnostic potential was revealed by multivariate logistic regression analysis where combinatorial panel of MUC5AC/MUC17 discriminated SSA/P from HP (SN/SP=85/82%). Finally, the decision tree model based marker panel (CA19-9/MUC17/MUC5AC) predicted HP, SSA/P and TA with SN/SP of 58%/95%, 79%/90% and 97%/83%, respectively. Overall, the mucin and associated O-glycan based panel defined in the present study could aid in discriminating SSA/P from HP to devise better colon surveillance strategies.

MUC4 is negatively regulated through the Wnt/ß-catenin pathway via the Notch effector Hath1 in colorectal cancer.

MUC4 is a transmembrane mucin lining the normal colonic epithelium. The aberrant/de novo over-expression of MUC4 is well documented in malignancies of the pancreas, ovary and breast. However, studies have reported the loss of MUC4 expression in the majority of colorectal cancers (CRCs). A MUC4 promoter analysis showed the presence of three putative TCF/LEF sites, implying a possible regulation by the Wnt/ß-catenin pathway, which has been shown to drive CRC progression. Thus, the objective of our study was to determine whether MUC4 is regulated by ß-catenin in CRC. We first knocked down (KD) ß-catenin in three CRC cell lines; LS180, HCT-8 and HCT116, which resulted in increased MUC4 transcript and MUC4 protein. Additionally, the overexpression of stabilized mutant ß-catenin in LS180 and HCT-8 resulted in a decrease in MUC4 expression. Immunohistochemistry (IHC) of mouse colon tissue harboring tubular adenomas and high grade dysplasia showed dramatically reduced Muc4 in lesions relative to adjacent normal tissue, with increased cytosolic/nuclear ß-catenin. Luciferase assays with the complete MUC4 promoter construct p3778 showed increased MUC4 promoter luciferase activity in the absence of ß-catenin (KD). Mutation of all three putative TCF/LEF sites showed that MUC4 promoter luciferase activity was increased relative to the un-mutated promoter. Interestingly, it was observed that MUC4 expressing CRC cell lines also expressed high levels of Hath1, a transcription factor repressed by both active Wnt/ß-catenin and Notch signaling. The KD of ß-catenin and/or treatment with a Notch γ-secretase inhibitor, Dibenzazepine (DBZ) resulted in increased Hath1 and MUC4 in LS180, HCT-8 and HCT116. Furthermore, overexpression of Hath1 in HCT-8 and LS180 caused increased MUC4 transcript and MUC4 protein. Taken together, our results indicate that the Wnt/ß-catenin pathway suppresses the Notch pathway effector Hath1, resulting in reduced MUC4 in CRC.

Mucins and Wnt/ß-catenin signaling in gastrointestinal cancers: an unholy nexus.

The Wnt/ß-catenin signaling pathway is indispensable for embryonic development, maintenance of adult tissue homeostasis and repair of epithelial injury. Unsurprisingly, aberrations in this pathway occur frequently in many cancers and often result in increased nuclear ß-catenin. While mutations in key pathway members, such as ß-catenin and adenomatous polyposis coli, are early and frequent occurrences in most colorectal cancers (CRC), mutations in canonical pathway members are rare in pancreatic ductal adenocarcinoma (PDAC). Instead, in the majority of PDACs, indirect mechanisms such as promoter methylation, increased ligand secretion and decreased pathway inhibitor secretion work in concert to promote aberrant cytosolic/nuclear localization of ß-catenin. Concomitant with alterations in ß-catenin localization, changes in mucin expression and localization have been documented in multiple malignancies. Indeed, numerous studies over the years suggest an intricate and mutually regulatory relationship between mucins (MUCs) and ß-catenin. In the current review, we summarize several studies that describe the relationship between mucins and ß-catenin in gastrointestinal malignancies, with particular emphasis upon colorectal and pancreatic cancer.

The canonical Wnt pathway regulates the metastasis-promoting mucin MUC4 in pancreatic ductal adenocarcinoma.

Aberrant Wnt signaling frequently occurs in pancreatic cancer (PC) and contributes to disease progression/metastases. Likewise, the transmembrane-mucin MUC4 is expressed de novo in early pancreatic intraepithelial neoplasia (PanINs) and incrementally increases with PC progression, contributing to metastasis. To determine the mechanism of MUC4 upregulation in PC, we examined factors deregulated in early PC progression, such as Wnt/ß-catenin signaling. MUC4 promoter analysis revealed the presence of three putative TCF/LEF-binding sites, leading us to hypothesize that MUC4 can be regulated by ß-catenin. Immunohistochemical (IHC) analysis of rapid autopsy PC tissues showed a correlation between MUC4 and cytosolic/nuclear ß-catenin expression. Knock down (KD) of ß-catenin in CD18/HPAF and T3M4 cell lines resulted in decreased MUC4 transcript and protein. Three MUC4 promoter luciferase constructs, p3778, p3000, and p2700, were generated. The construct p3778, encompassing the entire MUC4 promoter, elicited increased luciferase activity in the presence of stabilized ß-catenin. Mutation of the TCF/LEF site closest to the transcription start site (i.e., -2629/-2612) and furthest from the start site (i.e., -3425/-3408) reduced MUC4 promoter luciferase activity. Transfection with dominant negative TCF4 decreased MUC4 transcript and protein levels. Chromatin immunoprecipitation confirmed enrichment of ß-catenin on -2629/-2612 and -3425/-3408 of the MUC4 promoter in CD18/HPAF. Functionally, CD18/HPAF and T3M4 ß-catenin KD cells showed decreased migration and decreased Vimentin, N-cadherin, and pERK1/2 expression. Tumorigenicity studies in athymic nude mice showed CD18/HPAF ß-catenin KD cells significantly reduced primary tumor sizes and metastases compared to scrambled control cells. We show for the first time that ß-catenin directly governs MUC4 in PC.

Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.

Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets.

MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers.

Gastrointestinal (GI) cancers remain one of the most common malignancies and are the second common cause of cancer deaths worldwide. The limited effectiveness of therapy for patients with advanced stage and recurrent disease is a reflection of an incomplete understanding of the molecular basis of GI carcinogenesis. Major advancements have improved our understanding of pathology and pathogenesis of GI cancers, but high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate new sensitive and specific diagnostic and prognostic markers for GI cancers. MicroRNAs (miRNAs) are short (19-24 nucleotides) noncoding RNA molecules that regulate gene expression at the posttranscriptional level thus playing an important role in modulating various biological processes including, but not limited to developmental processes, proliferation, apoptosis, metabolism, differentiation, epithelial-mechenchymal transition and are involved in the initiation and progression of various human cancers. Unique miRNA expression profiles have been observed in various cancer types at different stages, suggesting their potential as diagnostic and prognostic biomarkers. Due to their tumor-specific and tissue-specific expression profiles, stability, robust clinical assays for detection in serum as well as in formalin-fixed tissue samples, miRNAs have emerged as attractive candidates for diagnostic and prognostic applications. This review summarizes recent research supporting the utility of miRNAs as novel diagnostic and prognostic tools for GI cancers.

Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling.

Inadequate efficacy, high toxicity and drug resistance associated with existing chemotherapeutic agents mandate a need for novel therapeutic strategies for highly aggressive Pancreatic Cancer (PC). Guggulsterone (GS) exhibits potent anti-proliferative effects against various cancer cells and has emerged as an attractive candidate for use in complementary or preventive cancer therapies. However, the knowledge regarding the therapeutic potential of GS in PC is still limited and needs to be explored. We studied the effect of GS on PC cell growth, motility and invasion and elucidated the molecular mechanisms associated with its anti-tumor effects. Treatment of Capan1 and CD18/HPAF PC cells with GS resulted in dose- and time-dependent growth inhibition and decreased colony formation. Further, GS treatment induced apoptosis and cell cycle arrest as assessed by Annexin-V assay and FACS analysis. Increased apoptosis following GS treatment was accompanied with Bad dephosphorylation and its translocation to the mitochondria, increased Caspase-3 activation, decreased Cyclin D1, Bcl-2 and xIAP expression. Additionally, GS treatment decreased motility and invasion of PC cells by disrupting cytoskeletal organization, inhibiting activation of FAK and Src signaling and decreased MMP9 expression. More importantly, GS treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway. In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC.

Prospects of miRNA-based therapy for pancreatic cancer.

Pancreatic cancer (PC) is the fourth leading cause of cancer related deaths in the U.S., with a less than 6% five-year survival rate. Treatment is confounded by advanced stage of disease at presentation, frequent metastasis to distant organs at the time of diagnosis and resistance to conventional chemotherapy. In addition, the molecular pathogenesis of the disease is unclear. The extensive study of miRNAs over the past several years has revealed that miRNAs are frequently de-regulated in pancreatic cancer and contribute to the pathogenesis and aggressiveness of the disease. Several studies have tackled the practical difficulties in the application of miRNAs as viable therapeutic and diagnostic tools. Given that a single miRNA can affect a myriad of cellular processes, successful targeting of miRNAs as therapeutic agents could likely yield dramatic results. The current review attempts to summarize the advances in the field and assesses the prospects for miRNA profiling and targeting in aiding PC treatment.

MUC4 overexpression augments cell migration and metastasis through EGFR family proteins in triple negative breast cancer cells.

INTRODUCTION: Current studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs. METHOD: In the present study, we investigated the functional and mechanistic roles of MUC4 in potentiating pathogenic signals including EGFR family proteins to promote TNBC aggressiveness using in vitro and in vivo studies. Further, we studied the expression of MUC4 in invasive TNBC tissue and normal breast tissue by immunostaining. RESULTS: MUC4 promotes proliferation, anchorage-dependent and-independent growth of TNBC cells, augments TNBC cell migratory and invasive potential in vitro, and enhances tumorigenicity and metastasis in vivo. In addition, our studies demonstrated that MUC4 up-regulates the EGFR family of proteins, and augments downstream Erk1/2, PKC-γ, and FAK mediated oncogenic signaling. Moreover, our studies also showed that knockdown of MUC4 in TNBC cells induced molecular changes suggestive of mesenchymal to epithelial transition. We also demonstrated in this study, for the first time, that knockdown of MUC4 was associated with reduced expression of EGFR and ErbB3 (EGFR family proteins) in TNBC cells, suggesting that MUC4 uses an alternative to ErbB2 mechanism to promote aggressiveness. We further demonstrate that MUC4 is differentially over-expressed in invasive TNBC tissues compared to normal breast tissue. CONCLUSIONS: MUC4 mucin expression is associated with TNBC pathobiology, and its knockdown reduced aggressiveness in vitro, and tumorigenesis and metastasis in vivo. Overall, our findings suggest that MUC4 mucin promotes invasive activities of TNBC cells by altering the expression of EGFR, ErbB2, and ErbB3 molecules and their downstream signaling.

Altered biochemical parameters in saliva of pediatric attention deficit hyperactivity disorder.

Oxidative stress is one of the common causes in etiopathogenesis of attention deficit hyperactivity disorder (ADHD). Hence, the salivary levels of protein thiols, ceruloplasmin, magnesium and pseudocholinesterase were estimated in children with ADHD. The symptoms of ADHD were identified using Conner's rating and DSM IV criteria. Saliva was collected and assessed for the levels of protein thiols, ceruloplasmin, magnesium and pseudocholinesterase, spectrophotometrically. It was also checked for pH and the flow rate was noted down. There was a significant increase (P < 0.001) in the salivary protein thiols and pseudocholinesterase levels in ADHD children when compared to controls. Ceruloplasmin levels did not show any significant change. Magnesium levels were significantly decreased (P < 0.001) in cases when compared to controls. Further, a receiver operating characteristic curve for validity of the biochemical parameters in saliva of ADHD children indicated a sensitivity and specificity above 90% for protein thiols and magnesium values. Our study shows that protein thiols, magnesium, and pseudocholinesterase might have a role in the pathogenesis of ADHD and saliva can be effectively used as a non-invasive tool for evaluation of such children.