Outcomes of initially nonoperative management of diverticulitis with abscess formation in immunosuppressed patients. DIPLICAB study COLLABORATIVE group.

AIM: Management of diverticulitis with abscess formation in immunosuppressed patients (IMS) remains unclear. The main objective of the study was to assess short- and long-term outcomes between IMS and immunocompetent patients (IC). The secondary aim was to identify risk factors for emergency surgery. METHODS: A nationwide retrospective cohort study was performed at 29 Spanish referral centres between 2015-2019 including consecutive patients with first episode of diverticulitis classified as modified Hinchey Ib or II. IMS included immunosuppressive therapy, biologic therapy, malignant neoplasm with active chemotherapy and chronic steroid therapy. A multivariate analysis was performed to identify independent risk factors to emergency surgery in IMS. RESULTS: A total of 1395 patients were included; 118 IMS and 1277 IC. There were no significant differences in emergency surgery between IMS and IC (19.5% and 13.5%, p = 0.075) but IMS was associated with higher mortality (15.1% vs. 0.6%, p < 0.001). Similar recurrent episodes were found between IMS and IC (28% vs. 28.2%, p = 0.963). Following multivariate analysis, immunosuppressive treatment, p = 0.002; OR: 3.35 (1.57-7.15), free gas bubbles, p < 0.001; OR: 2.91 (2.01-4.21), Hinchey II, p = 0.002; OR: 1.88 (1.26-2.83), use of morphine, p < 0.001; OR: 3.08 (1.98-4.80), abscess size ≥5 cm, p = 0.001; OR: 1.97 (1.33-2.93) and leucocytosis at third day, p < 0.001; OR: 1.001 (1.001-1.002) were independently associated with emergency surgery in IMS. CONCLUSION: Nonoperative management in IMS has been shown to be safe with similar treatment failure than IC. IMS presented higher mortality in emergency surgery and similar rate of recurrent diverticulitis than IC. Identifying risk factors to emergency surgery may anticipate emergency surgery.

SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities.

Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.

Anastomotic leak in colorectal cancer surgery: Contribution of gut microbiota and prediction approaches.

AIM: To monitor prospectively the occurrence of colorectal anastomotic leakage (CAL) in patients with colon cancer undergoing resectional surgery, characterizing the microbiota in both faeces and mucosal biopsies of anastomosis. In a second stage, we investigated the ability to predict CAL using machine learning models based on clinical data and microbiota composition. METHOD: A total of 111 patients were included, from whom a faecal sample was obtained, as well as biopsy samples from proximal and distal sites in the healthy margins of the tumour piece. The microorganisms present in the samples were investigated using microbial culture and 16S rDNA massive sequencing. Collagenase and protease production was determined, as well as the presence of genes responsible for expressing enzymes with these activities. Machine learning analyses were developed using clinical and microbiological data. RESULTS: The incidence of CAL was 9.0%, and CAL was associated with collagenase/protease-producing Enterococcus. Significant differences were found in the microbiota composition of proximal and distal biopsy samples, but not in faecal samples, among patients who developed CAL. Clinical predictors of CAL were 5-day C-reactive protein and heart disease, whereas 3-day C-reactive protein and diabetes were negative predictors. CONCLUSION: Biopsy samples from surgical margins, rather than faecal samples, are the most appropriate samples for exploring the contribution of the intestinal microbiota to CAL. Enterococci are only enriched in the anastomosis after surgery, and their collagenases and proteases are involved in the degradation of the anastomotic scar.

Fournier's gangrene and fecal diversion. When, in which patients, and what type should I perform?

INTRODUCTION: Fournier's gangrene (FG) is a necrotizing fasciitis affecting the perineum and urogenital tissue. The mortality rate is high although early detection and aggressive debridement can reduce mortality by up to 16%. The prevalence of sequelae is very high and a colostomy is often necessary to control the perineal wound. MATERIAL AND METHODS: A retrospective study was carried out to recruit all patients operated on by the General Surgery and Urology Departments with a diagnosis of GF at the University Hospital over 22 years. Mortality, the Fournier gangrene severity index (FGSI), and fecal diversion (either surgical (colostomy) or straight (Flexi-seal)) are collected. RESULTS: A total of 149 patients met the inclusion criteria. FG's most frequent cause was a perianal abscess (107 patients-72%). Eighteen patients (12%) died of a specific cause of FG. Age (p = 0.014) and patients with an oncological history (p = 0.038) both were the only mortality risk factors for mortality according to logistic regression. Fifty patients required some form of fecal diversion in the postoperative period (32 colostomies and 18 Flexi-seal). Neither the use of postoperative fecal diversion (surgical or Flexi-seal) nor the timing of its use had any effect on postoperative mortality. CONCLUSIONS: One in eight patients died in the immediate postoperative period secondary to FG. Despite improved outcomes, 22% required a colostomy during admission. However, neither the performance of a colostomy nor the timing was associated with decreased FG-associated mortality. Non-invasive methods should be used first and surgical bowel diversion should be postponed as long as possible.

Quality of life and outcomes after rubber band ligation for haemorrhoidal disease.

PURPOSE: The main objective of this study was to assess the impact on quality of life after rubber band ligation (RBL) in patients with symptomatic grade II-III haemorrhoids who did not improve after 6 months of conservative treatment, using quality of life scores. METHODS: This was a prospective cohort observational study where patients with haemorrhoidal disease and indication for RBL were included between December 2019 and December 2020. RBL was offered as first-line treatment in this group. Patient´s quality of life was assessed by scores: HDSS (Hemorrhoidal Disease Symptom Score) and SHS (Short Health Scale).Secondary objectives were: to evaluate the rate of patients requiring one or more RBL procedures, to establish the overall success rate of RBL and to analyse complications. RESULTS: A total of 100 patients were finally included. Regarding the impact on quality of life after RBL, a significant reduction was found in the HDSS and SHS scores (p < 0.001). The main improvement was found in the first month and it was maintained until the sixth month. A high degree of satisfaction with the procedure was reported by 76% of patients. The overall success rate of banding was 89%. A 12% complication rate was detected, the most frequent complication was severe anal pain (58.3%) and self-limiting bleeding (41.7%). CONCLUSION: Rubber band ligation, as a treatment for symptomatic grade II-III haemorrhoids that do not respond to medical treatment, leads to a significant improvement in patients' symptoms and quality of life. It also has a high degree of satisfaction between patients.

2,5-Dimethylfuran Production by Catalytic Hydrogenation of 5-Hydroxymethylfurfural Using Ni Supported on Al2O3-TiO2-ZrO2 Prepared by Sol-Gel Method: The Effect of Hydrogen Donors.

5-Hydroxymethylfurfural (5-HMF) has been described as one of the 12 key platform molecules derived from biomass by the US Department of Energy, and its hydrogenation reaction produces versatile liquid biofuels such as 2,5-dimethylfuran (2,5-DMF). Catalytic hydrogenation from 5-HMF to 2,5-DMF was thoroughly studied on the metal nickel catalysts supported on Al2O3-TiO2-ZrO2 (Ni/ATZ) mixed oxides using isopropanol and formic acid (FA) as hydrogen donors to find the best conditions of the reaction and hydrogen donor. The influence of metal content (wt%), Ni particle size (nm), Nickel Ni0, Ni0/NiO and NiO species, metal active sites and acid-based sites on the catalyst surface, and the effect of the hydrogen donor (isopropanol and formic acid) were systematically studied. The structural characteristics of the materials were studied using different physicochemical methods, including N2 physisorption, XRD, Raman, DRS UV-Vis, FT-IR, SEM, FT-IR Pyad, H2-TPD, CO2-TPD, H2-TPR, TEM and XPS. Second-generation 2,5-DMF biofuel and 5-HMF conversion by-products were analyzed and elucidated using 1H NMR. It was found that the Ni0NiO/ATZ3WI catalyst synthesized by the impregnation method (WI) generated a good synergistic effect between the species, showing the best catalytic hydrogenation of 5-HMF to 2,5-DMF using formic acid as a hydrogen donor for 24 h of reaction and temperature of 210 °C with 20 bar pressure of Argon (Ar).

Surgical Wound Complications after Colorectal Surgery with Single-Use Negative-Pressure Wound Therapy Versus Surgical Dressing over Closed Incisions: A Randomized Controlled Trial.

BACKGROUND: Global studies indicate that surgical site infections (SSIs) are a major healthcare challenge within hospitals and can have a profound impact on patient quality of life and healthcare costs. Closed-incision negative-pressure therapy (ciNPT) has been reported to provide positive clinical benefits for patients with various incisions, including those following colorectal surgeries. METHODS: Investigators performed a prospective, randomized, multicenter trial to evaluate complications of surgical incisions in patients who received a ciNPT dressing versus a conventional surgical dressing (control) over their closed incision following colorectal surgery. The incidence of SSI was determined at 7, 15, and 30 days postsurgery. RESULTS: A total of 148 patients participated in the study. Results showed that the SSI rate on day 7 was lower in the ciNPT group versus the control group (10/75 [13.3%] vs 17/73 [23.3%]), but this difference was not statistically significant. On day 15, the SSI rate was 12/75 (16.0%) in the ciNPT group versus 21/73 (28.8%) in the control group; however, this difference was only marginally statistically significant (P = .0621). At 1 month, the SSI rate remained lower in the ciNPT group (13/75 [17.3%] vs 21/73 [28.8%], P = .0983) compared with the control group. CONCLUSIONS: Future studies with larger population sizes are necessary to determine the impact of ciNPT on patients' incisions after colorectal surgery.

Personalized monitoring of electrical remodelling during atrial fibrillation progression via remote transmissions from implantable devices.

AIMS: Atrial electrical remodelling (AER) is a transitional period associated with the progression and long-term maintenance of atrial fibrillation (AF). We aimed to study the progression of AER in individual patients with implantable devices and AF episodes. METHODS AND RESULTS: Observational multicentre study (51 centres) including 4618 patients with implantable cardioverter-defibrillator +/-resynchronization therapy (ICD/CRT-D) and 352 patients (2 centres) with pacemakers (median follow-up: 3.4 years). Atrial activation rate (AAR) was quantified as the frequency of the dominant peak in the signal spectrum of AF episodes with atrial bipolar electrograms. Patients with complete progression of AER, from paroxysmal AF episodes to electrically remodelled persistent AF, were used to depict patient-specific AER slopes. A total of 34 712 AF tracings from 830 patients (87 with pacemakers) were suitable for the study. Complete progression of AER was documented in 216 patients (16 with pacemakers). Patients with persistent AF after completion of AER showed ∼30% faster AAR than patients with paroxysmal AF. The slope of AAR changes during AF progression revealed patient-specific patterns that correlated with the time-to-completion of AER (R2 = 0.85). Pacemaker patients were older than patients with ICD/CRT-Ds (78.3 vs. 67.2 year olds, respectively, P < 0.001) and had a shorter median time-to-completion of AER (24.9 vs. 93.5 days, respectively, P = 0.016). Remote transmissions in patients with ICD/CRT-D devices enabled the estimation of the time-to-completion of AER using the predicted slope of AAR changes from initiation to completion of electrical remodelling (R2 = 0.45). CONCLUSION: The AF progression shows patient-specific patterns of AER, which can be estimated using available remote-monitoring technology.

Medullary colorectal carcinoma. Do we really know it?

Medullary carcinoma (MC) is a recently described subtype of mismatch repair deficient (MMRd) colorectal carcinoma (CRC) which, despite being poorly differentiated by traditional morphological criteria, has been reported to have a good prognosis. By the moment, there is a handful reports about its clinical and pathological features, without agreement between results obtained.

Mutant p53R248Q downregulates oxidative phosphorylation and upregulates glycolysis under normoxia and hypoxia in human cervix cancer cells.

Mutations in p53 are strongly associated with several highly malignant cancer phenotypes but its role in regulating energy metabolism has not been completely elucidated. The effect on glycolysis and oxidative phosphorylation (OxPhos) of mutant p53R248Q overexpression in HeLa cells (HeLa-M) was analyzed and compared with cells overexpressing wild-type p53 (HeLa-H) and nontransfected cells containing negligible p53 levels (HeLa-L). p53 R248Q overexpression induced early cell detachment during in vitro growth; however, detached HeLa-M cells showed high viability, shorter generation time and significant diminution in the adhesion proteins E-cadherin and ß-catenin versus HeLa-H and HeLa-L cells. Under normoxia, a lower growth rate of attached HeLa-M cells correlated with decreased levels of proliferating cell nuclear antigen (PCNA), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), adenosine monophosphate-activated protein kinase (AMPK), mitochondrial proteins (20-80%) and OxPhos flux (69 ± 12%). On the contrary, HeLa-M also showed increased contents of CDKN1A, nuclear factor κB (NF-κB), c-MYC, hypoxia-inducible factor 1-α (HIF-1α; 1-4 times), glycolytic HIF-1α targets (2-4 times), and glycolysis flux (2-fold) versus HeLa-H. In consequence, glycolysis provided ~70% of the cellular adenosine triphosphate (ATP) in HeLa-M cells under normoxia whereas, OxPhos predominated (65-82%) in HeLa-H and HeLa-L cells. Pifithrin-α, a specific p53 inhibitor, did not alter the p53 R248Q target protein contents and OxPhos and glycolytic fluxes, and a poor HIF-1α-p53 R248Q interaction was attained, in HeLa-M cells. These observations suggested that p53 R248Q deficiently interacted with pifithrin-α and HIF-1α. Therefore, lower mitochondrial biogenesis, deficient HIF-1α/mutant p53 interaction, and development of a pseudohypoxic state under normoxia were the apparent biochemical mechanisms underlying glycolysis activation and OxPhos downregulation in HeLa-M cells.

Resveratrol inhibits cancer cell proliferation by impairing oxidative phosphorylation and inducing oxidative stress.

The resveratrol (RSV) efficacy to affect the proliferation of several cancer cell lines was initially examined. RSV showed higher potency to decrease growth of metastatic HeLa and MDA-MB-231 (IC50 = 200-250 µM) cells than of low metastatic MCF-7, SiHa and A549 (IC50 = 400-500 µM) and non-cancer HUVEC and 3T3 (IC50≥600 µM) cells after 48 h exposure. In order to elucidate the biochemical mechanisms underlying RSV anti-cancer effects, the energy metabolic pathways and the oxidative stress metabolism were analyzed in HeLa cells as metastatic-type cell model. RSV (200 µM/48 h) significantly decreased both glycolysis and oxidative phosphorylation (OxPhos) protein contents (30-90%) and fluxes (40-70%) vs. non-treated cells. RSV (100 µM/1-5 min) also decreased at a greater extent OxPhos flux (net ADP-stimulated respiration) of isolated tumor mitochondria (> 50%) than of non-tumor mitochondria (< 50%), particularly with succinate as oxidizable substrate. In addition, RSV promoted an excessive cellular ROS (2-3 times) production corresponding with a significant decrement in the SOD activity (but not in its content) and GSH levels; whereas the catalase, glutahione reductase, glutathione peroxidase and glutathione-S-transferase activities (but not their contents) remained unchanged. RSV (200 µM/48 h) also induced cellular death although not by apoptosis but rather by promoting a strong mitophagy activation (65%). In conclusion, RSV impaired OxPhos by inducing mitophagy and ROS over-production, which in turn halted metastatic HeLa cancer cell growth.

FruBPase II and ADP-PFK1 are involved in the modulation of carbon flow in the metabolism of carbohydrates in Methanosarcina acetivorans.

To enhance our understanding of the control of archaeal carbon central metabolism, a detailed analysis of the regulation mechanisms of both fructose1,6-bisphosphatase (FruBPase) and ADP-phosphofructokinase-1 (ADP-PFK1) was carried out in the methanogen Methanosarcina acetivorans. No correlations were found among the transcript levels of the MA_1152 and MA_3563 (frubpase type II and pfk1) genes, the FruBPase and ADP-PFK1 activities, and their protein contents. The kinetics of the recombinant FruBPase II and ADP-PFK1 were hyperbolic and showed simple mixed-type inhibition by AMP and ATP, respectively. Under physiological metabolite concentrations, the FruBPase II and ADP-PFK1 activities were strongly modulated by their inhibitors. To assess whether these enzymes were also regulated by a phosphorylation/dephosphorylation process, the recombinant enzymes and cytosolic-enriched fractions were incubated in the presence of commercial protein phosphatase or protein kinase. De-phosphorylation of ADP-PFK1 slightly decreased its activity (i.e. Vmax) and did not change its kinetic parameters and oligomeric state. Thus, the data indicated a predominant metabolic regulation of both FruBPase and ADP-PFK1 activities by adenine nucleotides and suggested high degrees of control on the respective pathway fluxes.

Spontaneous liver rupture secondary to distal right hepatic artery microaneurysms in a patient admitted due to Staphylococcus aureus pneumonia.

Spontaneous liver rupture is an uncommon and life-threatening condition often associated with high mortality rate. The most common causes are preeclampsia and HELLP syndrome during pregnancy, liver tumours and overdosing of anticoagulant therapy, however, hepatic rupture in the absence of underlying pathology is an extremely rare occurrence. Treatment can include observation, embolization, hepatic artery ligation, hepatic lobectomy, hematoma evacuation and packing, and even liver transplantation has been described.

HPI/AMF inhibition halts the development of the aggressive phenotype of breast cancer stem cells.

Cancer stem cells are responsible for tumor recurrence and metastasis. A new highly reproducible procedure for human breast cancer MCF-7 stem cells (BCSC) isolation and selection was developed by using a combination of hypoxia/hypoglycemia plus taxol and adriamycin for 24h. The BCSC enriched fraction (i) expressed (2-15 times) the typical stemness protein markers CD44+, ALDH1A3 and Oct 3/4; (ii) increased its clonogenicity index (20-times), invasiveness profile (>70%), migration capacity (100%) and ability to form mammospheres, compared to its non-metastatic MCF-7 counterpart. This isolation and selection protocol was successful to obtain stem cell enriched fractions from A549, SiHa and medulloblastoma cells. Since the secretion of HPI/AMF cytokine seems involved in metastasis, the effects of erytrose-4-phosphate (E4P) and 6-phosphogluconate (6PG), potent HPI inhibitors, on the acquisition of the breast stem cell-like phenotype were also evaluated. The presence of E4P during the BCSC selection deterred the development of the stemness phenotype, whereas both extracellular E4P (5-250nM) and 6PG (1µM) as well as siRNA HPI/AMF depressed the BCSC invasiveness ability (>90%), clonogenicity index (>90%) and contents (50-96%) of stemness (CD44, ALDH1A), pluripotency (p38 MAPK, Oct3/4, wnt/ß-catenin) and EMT (SNAIL, MMP-1, vimentin) markers. The cytokine inhibitor repertaxin (10nM) or the anti-IL-8 or anti-TGF-ß monoclonal antibodies (10µg/mL) did not significantly affect the BCSC metastatic phenotype. E4P also diminished (75%) the formation and growth of MCF-7 stem cell mammospheres. These results suggested that E4P by directly interacting with extracellular HPI/AMF may be an effective strategy to deter BCSC growth and progression.

Energy Metabolism Drugs Block Triple Negative Breast Metastatic Cancer Cell Phenotype.

To establish alternative targeted therapies against triple negative (TN) breast cancer, the energy metabolism and the sensitivity of cell growth, migration, and invasiveness toward metabolic, canonical, and NSAID inhibitors were analyzed in MDA-MB-231 and MDA-MB-468, two TN metastatic breast cancer cell lines, under both normoxia (21% O2) and hypoxia (0.1% O2). For comparative purposes, the analysis was also carried out in the less-metastatic breast MCF-7 cancer cells. Under normoxia, oxidative phosphorylation (OxPhos) was significantly higher (2-times) in MDA-MB-468 than in MDA-MB-231 and MCF-7, whereas their glycolytic fluxes and OxPhos and glycolytic protein contents were all similar. TN cancer cell lines mainly depended on OxPhos (62-75%), whereas MCF-7 cells equally depended on both pathways for ATP supply. Hypoxia for 24 h promoted a significant increase (>20 times) in the glycolytic transcriptional master factor HIF1-α in its target proteins GLUT-1, HKI and II, and LDH-A (2-4 times) as well as in the glycolytic flux (1.3-2 times) vs normoxia in MDA-MB-468, MDA-MB-231, and MCF-7. On the contrary, hypoxia decreased (15-60%) the contents of COXIV, 2OGDH, ND1, and ATP synthase as well as the OxPhos flux (50-75%), correlating with a high mitophagy level in the three cell lines. Under hypoxia, the three cancer cell lines mainly depended on glycolysis (70-80%). Anti-mitochondrial drugs (oligomycin, casiopeina II-gly, and methoxy-TEA) and celecoxib, at doses used to block OxPhos, significantly decreased TN cancer cell proliferation (IC50 = 2-20 µM), migration capacity (10-90%), and invasiveness (25-65%). The present data support the use of mitochondrially targeted inhibitors for the treatment of TN breast carcinoma.

The long-term recurrence rate and survival of obstructive left-sided colon cancer patients: a stent as a bridge to surgery.

BACKGROUND: a colonic stent as a bridge to elective surgery for left-sided malignant colonic obstruction is an alternative to the classical treatment. The aim of our study was to evaluate the recurrence rate as well as the morbidity and mortality of this treatment. PATIENTS AND METHODS: patients admitted to the Emergency Department with left-sided malignant colonic obstruction between June 2006 and January 2014 were analyzed in a retrospective observational study. Patients who underwent self-expanding metallic stent placement via endoscopy as a bridge to surgery were included. The observation period was performed until May 2017. RESULTS: fifty-three patients were treated with a colonic stent as a bridge to surgery; nine patients died during the postoperative period. The deceased patients were more frequently male (100% in the deceased vs 62% in the non-deceased, p = 0.02), with a more advanced age (81.4 ± 5.1 vs 71.6 ± 10.8, p < 0.001), lower hemoglobin levels on admission (12.9 vs 13.6 p < 0.001), a greater number of leukocytes (12,918 vs 9,437, p < 0.001) and greater coagulopathy (INR 1.6 vs 1, p < 0.001). Eight patients had a distant relapse with a median disease-free survival of 19.1 months. The variables were compared according to the appearance of distant disease and the mean age was lower in patients with a recurrence (65.9 ± 11.3 vs 74.9 ± 9.9, p < 0.001). CONCLUSIONS: the results of the use of a stent as a bridge to curative surgery in patients with obstructive left colon cancer in our hospital is comparable to previous studies.

Hypoglycemia Enhances Epithelial-Mesenchymal Transition and Invasiveness, and Restrains the Warburg Phenotype, in Hypoxic HeLa Cell Cultures and Microspheroids.

The accelerated growth of solid tumors leads to episodes of both hypoxia and hypoglycemia (HH) affecting their intermediary metabolism, signal transduction, and transcriptional activity. A previous study showed that normoxia (20% O2 ) plus 24 h hypoglycemia (2.5 mM glucose) increased glycolytic flux whereas oxidative phosphorylation (OxPhos) was unchanged versus normoglycemia in HeLa cells. However, the simultaneous effect of HH on energy metabolism has not been yet examined. Therefore, the effect of hypoxia (0.1-1% O2 ) plus hypoglycemia on the energy metabolism of HeLa cells was analyzed by evaluating protein content and activity, along with fluxes of both glycolysis and OxPhos. Under hypoxia, in which cell growth ceased and OxPhos enzyme activities, ΔΨm and flux were depressed, hypoglycemia did not stimulate glycolytic flux despite increasing H-RAS, p-AMPK, GLUT1, GLUT3, and HKI levels, and further decreasing mitochondrial enzyme content. The impaired mitochondrial function in HH cells correlated with mitophagy activation. The depressed OxPhos and unchanged glycolysis pattern was also observed in quiescent cells from mature multicellular tumor spheroids, suggesting that these inner cell layers are similarly subjected to HH. The principal ATP supplier was glycolysis for HH 2D monolayer and 3D quiescent spheroid cells. Accordingly, the glycolytic inhibitors iodoacetate and gossypol were more effective than mitochondrial inhibitors in decreasing HH-cancer cell viability. Under HH, stem cell-, angiogenic-, and EMT-biomarkers, as well as glycoprotein-P content and invasiveness, were also enhanced. These observations indicate that HH cancer cells develop an attenuated Warburg and pronounced EMT- and invasive-phenotype. J. Cell. Physiol. 232: 1346-1359, 2017. © 2016 Wiley Periodicals, Inc.

Superior mesenteric artery syndrome: an uncommon cause of intestinal obstruction.

Superior mesenteric artery syndrome, also Wilkie's syndrome, is an uncommon cause of upper intestinal obstruction. It includes compression of the third duodenal portion by the aorta and the overlying superior mesenteric artery when the angle formed by these two structures becomes smaller. It may result from significant weight loss or abdominal trauma, or may have a congenital origin. Treatment for most cases is conservative.

Dual regulation of energy metabolism by p53 in human cervix and breast cancer cells.

The role of p53 as modulator of OxPhos and glycolysis was analyzed in HeLa-L (cells containing negligible p53 protein levels) and HeLa-H (p53-overexpressing) human cervix cancer cells under normoxia and hypoxia. In normoxia, functional p53, mitochondrial enzyme contents, mitochondrial electrical potential (ΔΨm) and OxPhos flux increased in HeLa-H vs. HeLa-L cells; whereas their glycolytic enzyme contents and glycolysis flux were unchanged. OxPhos provided more than 70% of the cellular ATP and proliferation was abolished by anti-mitochondrial drugs in HeLa-H cells. In hypoxia, both cell proliferations were suppressed, but HeLa-H cells exhibited a significant decrease in OxPhos protein contents, ΔΨm and OxPhos flux. Although glycolytic function was also diminished vs. HeLa-L cells in hypoxia, glycolysis provided more than 60% of cellular ATP in HeLa-H cells. The energy metabolism phenotype of HeLa-H cells was reverted to that of HeLa-L cells by incubating with pifithrin-α, a p53-inhibitor. In normoxia, the energy metabolism phenotype of breast cancer MCF-7 cells was similar to that of HeLa-H cells, whereas p53shRNAMCF-7 cells resembled the HeLa-L cell phenotype. In hypoxia, autophagy proteins and lysosomes contents increased 2-5 times in HeLa-H cells suggesting mitophagy activation. These results indicated that under normoxia p53 up-regulated OxPhos without affecting glycolysis, whereas under hypoxia, p53 down-regulated both OxPhos (severely) and glycolysis (weakly). These p53 effects appeared mediated by the formation of p53-HIF-1α complexes. Therefore, p53 exerts a dual and contrasting regulatory role on cancer energy metabolism, depending on the O2level.