AMPK’s double-faced role in advanced stages of prostate cancer

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial–mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors’ expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. (AU)

Effect of vitamin B12 on the symptom severity and psychological profile of fibromyalgia patients; a prospective pre-post study.

BACKGROUND: Fibromyalgia (FM) as a prototypical nociplastic pain condition displays a difficult therapeutic situation in many cases. Given the promising data on the effect of vitamin B12 in improving pain and cognitive functions in various nociplastic pain conditions, we aimed to determine the efficacy of 1000 mcg daily dose of oral vitamin B12 on the symptom severity and psychological profile of FM patients. METHODS: This open-label, pre-post study was performed on FM patients whose diagnoses were confirmed by a rheumatologist based on the 2016 American College of Rheumatology (ACR). Patients were instructed to take a daily dose of 1000mcg vitamin B12 for fifty days. Outcome measures including the Revised Fibromyalgia Impact Questionnaire (FIQR), Hospital Anxiety and Depression Scale (HADS), 12-item Short-Form health survey (SF-12), and pain Visual Analog Scale (pain-VAS) were fulfilled by patients before and after the treatment. RESULTS: Of 30 eligible patients, 28 patients completed the study protocol. Patients were female with a mean age of 47.50 ± 8.47 years. FIQR scores in all domains improved significantly after treatment (total FIQR: 49.8 ± 21.86 vs 40.00 ± 18.36, p value < 0.01; function: 13.17 ± 7.33 vs 10.30 ± 5.84, p value: 0.01; overall: 10.32 ± 6.22 vs 8.25 ± 6.22, p value: 0.03; symptoms: 26.30 ± 10.39 vs 21.44 ± 8.58, p value < 0.01). Vitamin B12 also improved anxiety scores from 9.33 ± 4.30 to 7.70 ± 3.60, p value: 0.01. Depression, pain-VAS, and SF-12 didn't improve following the treatment. The Generalized estimating equations (GEE) analysis showed the improvement in total FIQR score is not cofounded by the improvement of anxiety and patients' baseline characteristics. CONCLUSIONS: This study showed a short course of sublingual vitamin B12, 1000 mcg daily, significantly improves the severity of FM and anxiety score. We postulate that vitamin B12 has a strong potential to consider, at least, as adjunctive therapy of FM. TRIAL REGISTRATION: The study protocol was approved by the ethics committee of Guilan University of Medical Sciences (IR.GUMS.REC.1400.197) in accordance with the World Medical Association's code of ethics (Declaration of Helsinki, revised in Brazil 2013), and registered at an ICMJE and WHO recognized registry of clinical trials ( www.irct.ir ) on 28/08/2021 (registration number: IRCT20200920048782N1).

AMPK's double-faced role in advanced stages of prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. Unfortunately, a very limited number of drugs are available for the relapsed and advanced stages of PCa, adding only a few months to survival; therefore, it is vital to develop new drugs. 5´ AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism. It plays a significant role in the metabolism of PCa; hence, it can serve well as a treatment option for the advanced stages of PCa. However, whether this pathway contributes to cancer cell survival or death remains unknown. The present study reviews the possible pathways by which AMPK plays role in the advanced stages of PCa, drug resistance, and metastasis: (1) AMPK has a contradictory role in promoting glycolysis and the Warburg effect which are correlated with cancer stem cells (CSCs) survival and advanced PCa. It exerts its effect by interacting with hypoxia-induced factor 1 (HIF1) α, pyruvate kinase 2 (PKM2), glucose transporter (GLUT) 1 and pyruvate dehydrogenase complex (PDHC), which are key regulators of glycolysis; however, whether it promotes or discourage glycolysis is not conclusive. It can also exert an anti-CSC effect by negative regulation of NANOG and epithelial-mesenchymal transition (EMT) transcription factors, which are the major drivers of CSC maintenance; (2) the regulatory effect of AMPK on autophagy is also noticeable. Androgen receptors' expression increases AMPK activation through Calcium/calmodulin-dependent protein kinase 2 (CaMKK2) and induces autophagy. In addition, AMPK itself increases autophagy by downregulating the mammalian target of rapamycin complex (mTORC). However, whether increased autophagy inhibits or promotes cell death and drug resistance is contradictory. This study reveals that there are numerous pathways other than cell metabolism by which AMPK exerts its effects in the advanced stages of PCa, making it a priceless treatment target. Finally, we mention some drugs developed to treat the advanced stages of PCa by acting on AMPK.

Effect of vitamin B6 on pain, disease severity, and psychological profile of fibromyalgia patients; a randomized, double-blinded clinical trial.

BACKGROUND: Given the role of vitamin B6 on pronociceptive/antinociceptive neurotransmitters balance, metabolic reactions, and inflammation, it is important to clarify the effect of vitamin B6 on pain and psychological disturbance in fibromyalgia (FM). This study aimed to evaluate whether an 80-mg daily dose of vitamin B6 improves pain, disease severity and psychological symptoms of FM compared to a placebo. METHODS: This randomized, double-blinded, placebo-controlled trial was performed on the FM patients whose diagnosis was confirmed by a rheumatologist based on the 2016 American College of Rheumatology (ACR). 90 Patients were randomized to receive either vitamin B6 (80 mg daily) or placebo in a 1:1 ratio, with a permuted block size of 30 stratified by disease severity. Primary outcomes included the Revised Fibromyalgia Impact Questionnaire (FIQR), Hospital Anxiety and Depression Scale (HADS), 12-item short-form health survey (SF-12), and pain visual analog scale (pain-VAS)). The mean differences in outcomes (before and after treatment) were compared between the vitamin B6 and placebo groups using an independent T-test. An ANCOVA model adjusted for baseline outcome value was also provided to compare the outcomes between the two groups. RESULTS: Of 90 eligible patients, 60 patients (31 patients in vitamin B6 and 29 in the placebo group) completed the trial. Overall, the FIQR, pain-VAS, and HADS-anxiety scores improved after treatment in both vitamin B6 and placebo groups; However, there was no statistically significant intergroup difference regarding primary outcomes. ANCOVA model also showed no difference in the treatment effects. CONCLUSIONS: Our results showed no priority for vitamin B6 over placebo in FM patients. Considering the potential ameliorating role of vitamin B6 on pain and psychological symptoms, acknowledgment of vitamin B6 as a relatively safe adjuvant treatment needs larger future studies. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT20200920048782N2 on 2021/10/04.

Comparison of the serum brain-derived neurotrophic factor (BDNF) between fibromyalgia and nociceptive pain groups; and effect of duloxetine on the BDNF level.

BACKGROUND: The primary objective was to compare the serum brain-derived neurotrophic factor (BDNF) level in the patients with two types of pain: fibromyalgia (FM) and non-FM nociceptive pain (non-FM NP). The secondary objective was to investigate the effect of duloxetine on serum BDNF in FM patients and assess the direction of BDNF changes' relation to clinical parameters' alterations. METHODS: This is a study on 73 patients (50 FM and 23 non-FM chronic non-inflammatory pain patients). Serum BDNF was first compared between both groups. Patients with FM, then prospectively, underwent standardized FM treatment with duloxetine maximized to 60 mg/day. The Revised Fibromyalgia Impact Questionnaire (FIQR), Short-Form Health Survey (SF-12), pain visualized analog scale (pain VAS), Beck Depression Inventory-II (BDI-II), polysymptomatic distress scale (PSD) and serum BDNF were measured and compared at baseline and 4 weeks after treatment in FM group. RESULTS: The mean of adjusted BDNF level in the FM group had no significant difference than the non-FM NP group ((5293.5 ± 2676.3 vs. 6136.3 ± 4037.6; P value = 0.77). Using linear mixed model, we showed that duloxetine reduced BDNF level significantly in FM patients, even after adjusting for depression, pain and severity of the disease (P < 0.01). The FIQR, BDI-II, PSD, and pain VAS improved significantly after duloxetine treatment. CONCLUSIONS: Non-significant BDNF level difference between FM and non-FM nociceptive pain suggested that peripheral BDNF is not a pathophysiological feature of FM. The decreased BDNF level parallel with improvement of PSD/pain scores after duloxetine treatment indicates BDNF alteration in the pain modulation process, regardless of cause and effect.

No effect of approved fibromyalgia drugs on the social pain (invalidation) contrary to physical pain: an open-label short-term randomized clinical trial.

OBJECTIVES: The social pain or invalidation denoting painful feeling following social conflicts or misunderstanding about illness legitimacy has been proposed as a salient disabling symptom besides physical pain or non-pain symptoms in fibromyalgia (FM). We sought to evaluate the effect of 1-month administration of duloxetine or pregabalin on the invalidation dimensions in FM patients with respect to the comparison of these two drugs on this issue. METHOD: This open-label randomized clinical trial study was performed on FM patients whose diagnoses were confirmed by a rheumatologist based on the 2016 American College of Rheumatology (ACR). Primary outcome measure (Illness Invalidation Inventory (3*I)) and secondary outcome measures (Beck Depression Inventory-II (BDI-II), widespread pain index (WPI), and polysymptomatic distress scale (PSD)) were compared before and after treatment, using paired t test or Wilcoxon signed test. RESULTS: Of 81 eligible FM patients, 44 patients in the duloxetine arm and 27 patients in the pregabalin arm completed the study protocol. Overall, no significant improvement was seen in 3*I scores after treatment with either duloxetine or pregabalin, except in the lack of understanding of medical professionals which improved after treatment with pregabalin (2.43 ± 1.38 to 1.79 ± 0.94, p value: 0.01). There were no intragroup and intergroup differences in the effects of duloxetine and pregabalin on 3*I scores when adjusted with the cofounders. Both duloxetine and pregabalin improved WPI, BDI-II, and PSD scores significantly. CONCLUSIONS: Short-term FM pharmacological treatment had no effect on social pain. This finding was regardless of drug type, improvement of physical pain, and depression.

High cost of illness in fibromyalgia patients in Iran, irrespective of disease severity: A prospective cost study.

AIMS: This study aimed to estimate the economic burden of fibromyalgia (FM) in 6 months, using a cost-diary, and to evaluate its relationship with the disease severity. METHODS: This is a prospective cost-of-illness study on 62 participants with an FM diagnosis within a 6 month period. Patients completed the questionnaires, including FIQR (Revised Fibromyalgia Impact Questionnaire) and SF-12 (12-item short-form survey). The cost-diary method was used to track the cost of the disease. The participants received six cost-diary booklets during the study period to report their FM-related costs, hours, and days of productivity loss. The final costs are reported in US dollars. RESULTS: Most of the participants were women (90.3%) with a mean (±SD) age of 40.80 (±5.50) years and a mean (±SD) FIQR score of 54.38 (±14.13). Moreover, 45.2% of patients fulfilled all six booklets, whereas 24.2% returned only one booklet. The participants showed a mean (±SD) direct healthcare, non-healthcare, and indirect cost of $ 2817.08 (±$ 1860.04), $ 1497.98(±$ 1358.21), and $ 1449.05(±$ 3637.41) per patient for 6 months, respectively. CONCLUSION: Fibromyalgia is associated with high health-related and non-health-related costs in our country, irrespective of its severity. This study warrants urgent consideration in managing the disease burden on both patients and society.

Comparison of three risk scores to predict outcomes in upper gastrointestinal bleeding; modifying Glasgow-Blatchford with albumin.

INTRODUCTION: Management of upper gastrointestinal bleeding (UGIB) is of great importance. In this way, we aimed to evaluate the performance of three well known scoring systems of AIMS65, Glasgow-Blatchford Score (GBS) and Full Rockall Score (FRS) in predicting adverse outcomes in patients with UGIB as well as their ability in identifying low risk patients for outpatient management. We also aimed to assess whether changing albumin cutoff in AIMS65 and addition of albumin to GBS add predictive value to these scores. METHODS: This was a retrospective study on adult patients who were admitted to Razi hospital (Rasht, Iran) with diagnosis of upper gastrointestinal bleeding between March 21, 2013 and March 21, 2017. Patients who didn't undergo endoscopy or had incomplete medical data were excluded. Initially, we calculated three score systems of AIMS65, GBS and FRS for each patient by using initial Vital signs and lab data. Secondary, we modified AIMS65 and GBS by changing albumin threshold from <3.5 to <3.0 in AIMS65 and addition of albumin to GBS, respectively. Primary outcomes were defined as in hospital mortality, 30-day rebleeding, need for blood transfusion and endoscopic therapy. Secondary outcome was defined as composition of primary outcomes excluding need for blood transfusion. We used AUROC to assess predictive accuracy of risk scores in primary and secondary outcomes. For albumin-GBS model, the AUROC was only calculated for predicting mortality and secondary outcome. The negative predictive value for AIMS65, GBS and modified AIMS65 was then calculated. RESULT: Of 563 patients, 3% died in hospital, 69.4% needed blood transfusion, 13.1% needed endoscopic therapy and 3% had 30-day rebleeding. The leading cause of UGIB was erosive disease. In predicting composite of adverse outcomes all scores had statistically significant accuracy with highest AUROC for albumin-GBS. However, in predicting in hospital mortality, only albumin-GBS, modified AIMS65 and AIMS65 had acceptable accuracy. Interestingly, albumin, alone, had higher predictive accuracy than other original risk scores. None of the four scores could predict 30-day rebleeding accurately; on the contrary, their accuracy in predicting need for blood transfusion was high enough. The negative predictive value for GBS was 96.6% in score of ≤2 and 85.7% and 90.2% in score of zero in AIMS65 and modified AIMS65, respectively. CONCLUSION: Neither of risk scores was highly accurate as a prognostic factor in our population; however, modified AIMS65 and albumin-GBS may be optimal choice in evaluating risk of mortality and general assessment. In identifying patient for safe discharge, GBS ≤ 2 seemed to be advisable choice.

Therapeutic approach of Cancer stem cells (CSCs) in gastric adenocarcinoma; DNA methyltransferases enzymes in cancer targeted therapy.

Cancer stem cells (CSCs) show a remarkable sub class of cancer cells population which have a potential to organize and regulate stemness properties which possess a main particular responsibility for uncontrolled growth in carcinogenesis, production of different cancers in differentiated situation and also resistancy to radiotherapy and chemotherapy. Correspondingly, gastric cancer (GC) as a very serious type in cancer mortality in the world, has received a deep attention in molecular therapy recently. Besides the main characteristics of CSCs like differentiation, epithelial mesenchymal transition, self-renewal and metastasis, they are so effective in expression of stemness genes resistancy in radiotherapy and chemotherapy. In this way, the regulation of epigenetic elements including DNA methylation and the performance of DNA methyltransferase (DNMT) which is a notable epigenetic trait in GC, is of great importance. Inhibitors of DNA methylation are the first epigenetic drugs in cancer therapy. Considerably, recent studies indicate that low doses of DNMT inhibitors have a high potential in sustaining reduced DNA methylation and related with re-expression of silenced genes in tumorigenesis. Importantly, these certain doses have the ability to decrease the carcinogenesis and tumorigenesis in CSC populations within GC. Meaningly, the inhibition of DNMTs are able to reduce the accumulation of tumorigenic ability of GC CSCs. Furthermore, many epigenetic drugs have a great potential in cancer therapy, including histone methyltransferases, lysine demethylases, histone deacetylasesand, bromodomain and extra-terminal domain proteins and DNA methyltransferases inhibitors. In this review article, we try to focus on the therapeutic mechanism of DNMTs alongside with their impact on CSCs in GC.

Inflammatory Myofibroblastic Tumors in a Case with Hypogastric Discomfort.

BACKGROUND Inflammatory myofibroblastic tumors (IMTs) are scarce tumors with discrete immunohistochemical and molecular attributes which are not related to a particular location. There are different reports about the intrinsic nature of these tumors as benign to possibly malignant. CASE REPORT Here we report the case of a 68-year-old man referred to the Internal Medicine Department of Razi Hospital in Rasht (a city in the north of Iran) due to right lower quadrant (RLQ) discomfort with no specific symptoms. Colonoscopy revealed a mass-like lesion. Polymorphonuclear cells (PMNCs) admixed by some eosinophils were demonstrated histopathologically. Immunohistochemical evaluation was positive for vimentin, CD34, smooth muscle actin, and ALK, and negative for CD117 and desmin. The tumor was successfully removed by surgery with no chemotherapy. No recurrence was reported. CONCLUSIONS We have performed surgical excision of the mass with no chemotherapy and no recurrence. Although recurrence is reported to be low, we recommend long-term follow-up after surgery.

Innumerable Liver Masses in a Patient with Autoimmune Hepatitis and Primary Sclerosing Cholangitis Overlap Syndrome.

BACKGROUND In patients with the diagnosis of autoimmune hepatitis (AIH), the presence of cholestatic features raise the possibility of an overlap syndrome with primary sclerosing cholangitis (PSC). Here, we present a unique case with AIH-PSC overlap syndrome and innumerable liver masses. CASE REPORT A 26-year-old man presented with generalized icterus. Based on the serological findings of hypergamainmunoglobulinemia and positive anti-nuclear antibody tests, together with an abnormal cholangiogram, he was diagnosed with overlap syndrome (AIH-PSC). Liver imaging revealed innumerable liver masses with a benign appearance in the pathological evaluation. To rule out the colon abnormalities that usually coexist with such liver masses, colonoscopy was performed and showed no significant changes. The liver masses were nonmalignant and were resolved after immunosuppressant therapy. CONCLUSIONS Because AIH-PSC overlap syndrome is rare, it is suggested that radiological evaluation of the biliary tree should be performed routinely in adults diagnosed with AIH to reduce the missed diagnosis of overlap syndrome and liver masses.