STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa

Effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections

AIM: To evaluate the effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections

Bowel Cleansing with Oral Sodium Phosphate is a Risk Factor for Nephropathy in Acromegaly

Because of increased risk of colorectal carcinoma, screening by colonoscopy is recommended in patients with acromegaly. Cleansing should be vigorous in these patients due to increased bowel length and delayed colonic transit time. Recently, cases of phosphate nephropathy associated with a widely preferred purgative oral sodium phosphate (OSP) have been reported. Although main risk factors for phosphate nephropathy have been described, acromegaly has not been included as a risk factor. The present case is a 63-year old male patient, who developed transient renal failure after using three doses of OSP, which increased the serum phosphate level by 8.1 mg/dL. An acromegalic patient may have many risk factors for phosphate nephropathy after OSP administration, including having high basal serum phosphate levels, increased bowel transit time, need for high purgative dosages, increased tubular phosphate reabsorption, advanced age, and concurrent administration of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs). Physicians should be warned against the risks of using OSP in acromegalic patients, and intensive follow-up is necessary in the hospital setting soon after OSP administration. Therefore, we suggest that acromegaly should be included as a risk factor for nephropathy due to OSP in the current guidelines

Investigation of RASSF4 gene in head and neck cancers

Objectives RASSF gene family can inhibit the growth of RAS oncogene. This gene family is suggested to have a role in cell cycle control, apoptosis, cell migration, and mitosis control. This study evaluated RASSF4 gene expression levels, SNPs and serum levels in tissues dissected from both healthy individuals and patients diagnosed with head, and neck cancer. Methods RASSF4 gene expression levels were determined using the RT-PCR. Serum levels of RASSF4 were tested using the Enzyme-Linked Immuno Sorbent Assay technique in study groups. RASSF4 rs7896801 and rs884879 genotypes were identified using by the RT-PCR. Results No statistical difference was observed between study groups according to RASSF4 gene expression levels. According to SNP results, rs7896801 revealed a 2.4 fold increase of G-allele presence in patients (p=0.015). The increase in the presence of AA genotype was statistically significant for the control group (p=0.015). Distribution of genotypes and alleles for rs884879 showed a 2.2 fold increase in CC genotype for healthy group (p=0.031) however, the presence of T allele showed a significant increase in the patients (p=0.048). Conclusions We suggest that this study will play a pioneering role for the next studies on RASSF4 gene, especially on SNPs

Extra-Cochlear Insertion in Cochlear Implantation: A Potentially Disastrous Condition

OBJECTIVES: Cochlear implantation is an increasingly used technique for auditory rehabilitation of pediatric and adult population. Safe implantation is achieved in most cases; however, intraoperative complications and misplacement of the electrode are observed in some. The aim of this presentation was to review the characteristics of patients with extra-cochlear electrode insertion, postoperative diagnostic methods, and considerations in revision surgery

The Investigation of HCV RNA in Tear Fluid and Aqueous Humor in Patients with Anti-HCV Antibody Positive Who Underwent Cataract Surgery

Purpose: To obtain aqueous humor and tear fluid samples during cataract surgery of the hepatitis C virus (HCV)-antibody-positive patients in order to analyze them for HCV RNA and compare these measurements with serum HCV RNA levels

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway.

Acknowledgements: The authors thank Stephanie Ponti, Anna Zacher and Victoria Weissenböck for their skilful help with animal handling as well as biolution GmbH for the support with the graphical abstract.Funder: Christian Doppler Research AssociationFunder: Austrian Federal Ministry of Science, Research and EconomyFunder: National Foundation for Research, Technology and DevelopmentFunder: Siemens HealthineersProstate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Acknowledgements: The authors thank Stephanie Ponti, Anna Zacher and Victoria Weissenböck for their skilful help with animal handling as well as biolution GmbH for the support with the graphical abstract.Funder: Christian Doppler Research AssociationFunder: Austrian Federal Ministry of Science, Research and EconomyFunder: National Foundation for Research, Technology and DevelopmentFunder: Siemens HealthineersProstate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa