Incidence,Risk Factors,and Prognosis of Patients with Hepatocellular Carcinoma and Brain Metastases

Objective Brain metastases significantly impact the clinical course of patients with hepatocellular carcinoma(HCC).This study aimed to examine the age-related incidence,demographics,and survival of patients with HCC and brain metastases.Methods Data of HCC patients from 2010 to 2015 in the Surveillance,Epidemiology,and End Results(SEER)Registry were screened for the presence of brain metastases.They were stratified by age and ethnicity.Multivariable logistic and Cox regression analyses were used to identify factors associated with brain metastases and those with overall survival(OS)and liver cancer-specific survival(CSS),respectively.Results A total of 141 HCC patients presenting with brain metastases were identified,accounting for 0.35% of all HCC patients and 2.37% of patients with metastatic disease.Among all HCC patients,the incidence rate was the highest among patients aged 30-49 years old(0.47%).Ethnicity was not associated with the presence of brain metastases at the time of HCC diagnosis.However,African-American patients presented with a significantly lower disease-specific survival[median time:1 month;interquartile range(IQR):0-3.0 months].Initial lung or bone metastasis was independently associated with an increased risk of the presence of brain metastases[odds ratio(OR):12.62,95% confidence interval(CI):8.40-18.97]but was not associated with a worse OS or CSS among those with brain metastases.Conclusion This study identified the age-related incidence and risk factors of brain metastases in HCC patients.These results may contribute to the consideration of brain screening among patients with initial metastatic HCC with lung or bone metastases,and influence the counseling of this patient population regarding their prognosis.

The Origin of the Flat Rotation Curves in Spiral Galaxies: The Hidden Roles of Glitching SMDEOs and Emission of Gravitational Waves

Supermassive DEOs (SMDEOs) are cosmologically evolved objects made of irreducible incompressible supranuclear dense superfluids: The state we consider to govern the matter inside the cores of massive neutron stars. These cores are practically trapped in false vacua, rendering their detection by outside observers impossible. Based on massive parallel computations and theoretical investigations, we show that SMDEOs at the centres of spiral galaxies that are surrounded by massive rotating torii of normal matter may serve as powerful sources for gravitational waves carrying away roughly 1042 erg/s. Due to the extensive cooling by GWs, the SMDEO-Torus systems undergo glitching, through which both rotational and gravitational energies are abruptly ejected into the ambient media, during which the topologies of the embedding spacetimes change from curved into flatter ones, thereby triggering a burst gravitational energy of order 1059 erg. Also, the effects of glitches found to alter the force balance of objects in the Lagrangian-L1 region between the central SMDEO-Torus system and the bulge, enforcing the enclosed objects to develop violent motions, that may explain the origin of the rotational curve irregularities observed in the innermost part of spiral galaxies. Our study shows that the generated GWs at the centres of galaxies, which traverse billions of objects during their outward propagations throughout the entire galaxy, lose energy due to repeatedly squeezing and stretching the objects. Here, we find that these interactions may serve as damping processes that give rise to the formation of collective forces f∝m(r)/r, that point outward, endowing the objects with the observed flat rotation curves. Our approach predicts a correlation between the baryonic mass and the rotation velocities in galaxies, which is in line with the Tully-Fisher relation. The here-presented self-consistent approach explains nicely the observed rotation curves without invoking dark matter or modifying Newtonian gravitation in the low-field approximation.

Assessment of hindlimb motor recovery affer severe thoracic spinal cord injury in rats: classification of CatWalk XT■ gait analysis parameters

Assessment of locomotion recovery in preclinical studies of experimental spinal cord injury remains challenging. We studied the CatWalk XT■gait analysis for evaluating hindlimb functional recovery in a widely used and clinically relevant thoracic contusion/compression spinal cord injury model in rats. Rats were randomly assigned to either a T9 spinal cord injury or sham laminectomy. Locomotion recovery was assessed using the Basso, Beattie, and Bresnahan open field rating scale and the CatWalk XT■gait analysis. To determine the potential bias from weight changes, corrected hindlimb(H) values(divided by the unaffected forelimb(F) values) were calculated. Six weeks after injury, cyst formation, astrogliosis, and the deposition of chondroitin sulfate glycosaminoglycans were assessed by immunohistochemistry staining. Compared with the baseline, a significant spontaneous recovery could be observed in the CatWalk XT■parameters max intensity, mean intensity, max intensity at%, and max contact mean intensity from 4 weeks after injury onwards. Of note, corrected values(H/F) of CatWalk XT■parameters showed a significantly less vulnerability to the weight changes than absolute values, specifically in static parameters. The corrected CatWalk XT■parameters were positively correlated with the Basso, Beattie, and Bresnahan rating scale scores, cyst formation, the immunointensity of astrogliosis and chondroitin sulfate glycosaminoglycan deposition. The CatWalk XT■gait analysis and especially its static parameters, therefore, seem to be highly useful in assessing spontaneous recovery of hindlimb function after severe thoracic spinal cord injury. Because many CatWalk XT■parameters of the hindlimbs seem to be affected by body weight changes, using their corrected values might be a valuable option to improve this dependency.

Applications of endoscopic vacuum therapy in the upper gastrointestinal tract

Endoscopic vacuum therapy(EVT)is an increasingly popular treatment option for wall defects in the upper gastrointestinal tract.After its initial description for the treatment of anastomotic leaks after esophageal and gastric surgery,it was also implemented for a wide range of defects,including acute perforations,duodenal lesions,and postbariatric complications.Apart from the initially proposed handmade sponge inserted using the“piggyback”technique,further devices were used,such as the commercially available EsoSponge and VAC-Stent as well as open-pore film drainage.The reported pressure settings and intervals between the subsequent endoscopic procedures vary greatly,but all available evidence highlights the efficacy of EVT,with high success rates and low morbidity and mortality,so that in many centers it is considered to be a first-line treatment,especially for anastomotic leaks.

Why the Energy Density of the Universe Is Lower and Upper-Bounded? Relaxing the Need for the Cosmological Constant

Recently, it was argued that the energy density of the supranuclear dense matter inside the cores of massive neutron stars must have reached the , beyond which supranuclear dense matter becomes incompressible entropy-free gluon-quark superfluid. As this matter is also confined and embedded in flat spacetime, it is Lorentz invariant and could be treated as vacuum. The lower bound of matter in the universe may be derived using the following observational constraints: 1) The average energy density of the observable universe is erg/cc, 2) The observable universe is remarkably flat, and 3) the Hubble constant is a slowly decreasing function of cosmic time. Based thereon, I argue that the energy density in nature should be bounded from below by the average density of our vast and flat parent universe, , which is, in turn, comparable to the vacuum energy density , and amounts to erg/cc. When the total energy density is measured relative to , then both GR and Newtonian field equations may consistently model the gravitational potential of the parent universe without invoking cosmological constants. Relying on the recently proposed unicentric model of the observable universe, UNIMOUN, the big bang must have warped the initially flat spacetime into a curved one, though the expansion of the fireball doomed the excited energy state to diffuse out and return back to the ground energy state that governs the flat spacetime of our vast parent universe.

Foundation of the Unicentric Model of the Observable Universe—UNIMOUN

In view of the growing difficulties of ΛCDM-cosmologies to compete with recent highly accurate cosmological observations, I propose the alternative model: the Unicentric Model of the Observable UNiverse (UNIMOUN). The model relies on employing a new time-dependent -metric for the GR field equations, which enables reversible phase transitions between normal compressible fluids and incompressible quantum superfluids, necessary for studying the cosmic evolution of the observable universe. The main properties of UNIMOUN read: 1) The observable universe was born in a flat spacetime environment, which is a tiny fraction of our infinitely large and flat parent universe, 2) Our big bang (BB) happened to occur in our neighbourhood, thereby endowing the universe the observed homogeneity and isotropy, 3) The energy density in the universe is upper-bounded by the universal critical density , beyond which matter becomes purely incompressible, rendering formation of physical singulareties, and in particular black holes, impossible, 4) Big bangs are neither singular events nor invoked by external forces, but rather, they are common self-sustaining events in our parent universe, 5) The progenitors of BBs are created through the merger of cosmically dead and inactive neutron stars and/or through “supermassive black holes” that are currently observed at the centres of most massive galaxies, 6) The progenitors are made up of purely incompressible entropy-free superconducting gluon- quark superfluids with (SuSu-matter), which endows these giant objects measurable sizes, 7) Spacetimes embedding SuSu-matter are conformally flat. It is shown that UNIMOUN is capable of dealing with or providing answers to several fundamental open questions in astrophysics and cosmology without invoking inflation, dark matter or dark energy.

Evidence for False Vacuum States inside the Cores of Massive Pulsars and the Ramification on the Measurements of Their True Masses

Based on the theory and observations of glitching pulsars, we show that the ultra-cold supranuclear dense matter inside the cores of massive pulsars should condensate in vacua, as predicated by non-perturbative QCD. The trapped matter here forms false vacuums embedded in flat spacetimes and completely disconnected from the outside world. Although the vacuum expectation value here vanishes, the masses and sizes of these incompressible superfluid cores are set to grow with cosmic times, in accord with the Onsager-Feynman superfluidity analysis. We apply our scenario to several well-studied pulsars, namely the Crab, Vela, PSR J0740+6620 and find that the trapped mass-contents in their cores read {0.15,0.55,0.64}, implying that their true masses are {1.55,2.35,2.72} , respectively. Based thereon, we conclude that: 1) The true masses of massive pulsars and neutron stars are much higher than detected by direct observations and, therefore, are unbounded from above, 2) The remnant of the merger event in GW170817 should be a massive NS harbouring a core with 1.66 .

Regulatory T cells in skin regeneration and wound healing

As the body’s integumentary system,the skin is vulnerable to injuries.The subsequent wound healing processes aim to restore dermal and epidermal integrity and functionality.To this end,multiple tissue-resident cells and recruited immune cells cooperate to efficiently repair the injured tissue.Such temporally-and spatially-coordinated interplay necessitates tight regulation to prevent collateral damage such as overshooting immune responses and excessive inflammation.In this context,regulatory T cells(Tregs)hold a key role in balancing immune homeostasis and mediating cutaneous wound healing.A comprehensive understanding of Tregs’multifaceted field of activity may help decipher wound pathologies and,ultimately,establish new treatment modalities.Herein,we review the role of Tregs in orchestrating the regeneration of skin adnexa and catalyzing healthy wound repair.Further,we discuss how Tregs operate during fibrosis,keloidosis,and scarring.

Ageing-related bone and immunity changes:insights into the complex interplay between the skeleton and the immune system

Ageing as a natural irreversible process inherently results in the functional deterioration of numerous organ systems and tissues,including the skeletal and immune systems.Recent studies have elucidated the intricate bidirectional interactions between these two systems.

Why the Central Monster in M87 Should Be a Massive DEO Rather than a SMBH?

In this paper, we show that massive envelopes made of highly compressed normal matter surrounding dark objects (DEOs) can curve the surrounding spacetime and make the systems observationally indistinguishable from their massive black hole counterparts. DEOs are new astrophysical objects that are made up of entropy-free incompressible supranuclear dense superfluid (SuSu-matter), embedded in flat spacetimes and invisible to outside observers, practically trapped in false vacua. Based on highly accurate numerical modelling of the internal structures of pulsars and massive neutron stars, and in combination with using a large variety of EOSs, we show that the mass range of DEOs is practically unbounded from above: it spans those of massive neutron stars, stellar and even supermassive black holes: thanks to the universal maximum density of normal matter, , beyond which normal matter converts into SuSu-matter. We apply the scenario to the Crab and Vela pulsars, the massive magnetar PSR J0740 6620, the presumably massive NS formed in GW170817, and the SMBHs in Sgr A* and M87*. Our numerical results also reveal that DEO-Envelope systems not only mimic massive BHs nicely but also indicate that massive DEOs can hide vast amounts of matter capable of turning our universe into a SuSu-matter-dominated one, essentially trapped in false vacua.

Reactivation of the insulin-like growth factor-Ⅱsignaling pathway in human hepatocellular carcinoma

Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma(HCC).Especially the over- expression of the fetal growth factor IGF-Ⅱ,IGF-Ⅰ receptor(IGF-IR),and cytoplasmic downstream effectors such as insulin-receptor substrates(IRS)contribute to proliferation,anti-apoptosis,and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱsignaling during HCC development and progression.Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies,various experimental strategies have been developed,including neutralizing antibodies and selective receptor kinase inhibitors,with respect to the specific and efficient reduction of oncogenic IGF-Ⅱ/IGF-IR-signaling.

The effect of adenovirus expressing wild-type p53 on 5-fluorouracil chemosensitivity is related to p53 status in pancreatic cancer cell lines

AIM:There are conflicting data about p53 function on cellular sensitivity to the cytotoxic action of 5-fluorouracil (5-FU). Therefore the objective of this study was to determine the combined effects of adenovirus-mediated wild-type (wt) p53 gene transfer and 5-FU chemotherapy on pancreatic cancer cells with different p53 gene status. METHODS:Human pancreatic cancer cell lines Capan-1^(p53mut), Capan-2^(p53wt),FAMPAC^(p53mut),PANC1^(p53mut),and rat pancreatic cancer cell lines AS^(p53wt) and DSL6A^(p53null) were used for in vitro studies.Following infection with different ratios of Ad- p53-particles (MOI) in combination with 5-FU,proliferation of tumor cells and apoptosis were quantified by cell proliferation assay (WST-1) and FACS (PI-staining).In addition,DSL6A syngeneic pancreatic tumor cells were inoculated subcutaneously in to Lewis rats for in vivo studies. Tumor size,apoptosis (TUNEL) and survival were determined. RESULTS:Ad-p53 gene transfer combined with 5-FU significantly inhibited tumor cell proliferation and substantially enhanced apoptosis in all four cell lines with an alteration in the p53 gene compared to those two cell lines containing wt-p53.In vivo experiments showed the most effective tumor regression in animals treated with Ad-p53 plus 5-FU.Both in vitro and in vivo analyses revealed that a sublethal dose of Ad-p53 augmented the apoptotic response induced by 5-FU. CONCLUSION:Our results suggest that Ad-p53 may synergistically enhance 5-FU-chemosensitivity most strikingly in pancreatic cancer cells lacking p53 function.These findings illustrate that the anticancer efficacy of this combination treatment is dependent on the p53 gene status of the target tumor cells.

Non-invasive diagnosis of alcoholic liver disease

Alcoholic liver disease(ALD)is the most common liver disease in the Western world.For many reasons,it isunderestimated and underdiagnosed.An early diagnosis is absolutely essential since it(1)helps to identify patients at genetic risk for ALD;(2)can trigger efficient abstinence namely in non-addicted patients;and(3)initiate screening programs to prevent life-threateningcomplications such as bleeding from varices,spontaneous bacterial peritonitis or hepatocellular cancer.The two major end points of ALD are alcoholic liver cirrhosis and the rare and clinically-defined alcoholic hepatitis(AH).The prediction and early diagnosis of both entities is still insufficiently solved and usually relies on acombination of laboratory,clinical and imaging findings.It is not widely conceived that conventional screeningtools for ALD such as ultrasound imaging or routine laboratory testing can easily overlook ca.40%of manifest alcoholic liver cirrhosis.Non-invasive methods such as transient elastography(Fibroscan),acoustic radiation force impulse imaging or shear wave elastography have significantly improved the early diagnosis of alcoholiccirrhosis.Present algorithms allow either the exclusion or the exact definition of advanced fibrosis stages in ca.95%of patients.The correct interpretation of liver stiffness requires a timely abdominal ultrasound and actual transaminase levels.Other non-invasive methods such as controlled attenuation parameter,serum levels of M30 or M65,susceptometry or breath tests are under current evaluation to assess the degree of steatosis,apoptosis and iron overload in these patients.Liver biopsy still remains an important option to rule out comorbidities and to confirm the prognosis namely for patients with AH.

Value of three-dimensional reconstructions in pancreatic carcinoma using multidetector CT:Initial results

AIM:To evaluate the use of three-dimensional imaging of pancreatic carcinoma using multidetector computed tomography(CT)in a prospective study.METHODS:Ten patients with suspected pancreatic tumors were examined prospectively using multidetec-tor CT(Somatom Sensation 16,Siemens,Erlangen,Germany).The images were evaluated for the pres-ence of a pancreatic carcinoma and invasion of the peripancreatic vessels and surrounding organs.Using the isotropic CT data sets,a three-dimensional image was created with automatic vascular analysis and semi-automatic segmentation of the organs and pancreatic tumor by a radiologist.The CT examinations and the three-dimensional images were presented to the sur-geon directly before and during the patient's operation using the Medical Imaging Interaction Toolkit-based software "ReLiver".Immediately after surgery,the value of the two images was judged by the surgeon.The operation and the histological results served as the gold standard.RESULTS:Nine patients had a pancreatic carcinoma(all pT3),and one patient had a serous cystadenoma.One tumor inf iltrated the superior mesenteric vein.The inf iltration was correctly evaluated.All carcinomas were resectable.In comparison to the CT image with axial and coronal reconstructions,the three-dimensional image was judged by the surgeons as better for operation planning and consistently described as useful.CONCLUSION:A 3D-image of the pancreas repre-sents an invaluable aid to the surgeon.However,the 3D-software must be further developed in order to be integrated into daily clinical routine.

Entecavir as treatment for reactivation of hepatitis B in immunosuppressed patients

AIM: To study the efficacy and safety of entecavir (ETV) as first-line therapy for hepatitis B virus (HBV) reactivation due to immunosuppression. METHODS: Four patients that were treated with different immunosuppressive regimens for hematological malignancies, who presented with HBV reactivation were treated with ETV. Clinical outcome, biochemical and virological factors, including quantitative hepatitis B surface antigen (HBsAg) were studied. RESULTS: In all patients, ETV induced suppression of HBV, and rapid clinical improvement without side effects. In one patient with an alanine aminotransferase (ALT) flare, tenofovir was added after 3 mo of treatment. Until death from disease progression at 6 mo after treatment initiation, this patient did not clear HBV infection. Retrospectively, it is highly probable that thepatient had been non-adherent. In the other three patients, the virological responses were associated with an expeditious decrease in quantitative HBsAg titers with negativity after 2 mo, and all three had HBsAg seroconversion. In one patient, HBV DNA reached a plateau after 3 mo, before becoming undetectable after 1 year, despite early ALT normalization and undetectable quantitative HBsAg. CONCLUSION: ETV seems to be effective and safe treatment for HBV reactivation. Monitoring of quantitative HBsAg might be an additional useful tool to monitor treatment response.

Heme oxygenase-1 as a therapeutic target in inflammatory disorders of the gastrointestinal tract

Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because ofits potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic po- tential for the treatment ofinflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatorybowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.

Pain sensation in pancreatic diseases is not uniform: The different facets of pancreatic pain

AIM: To systematically characterize specific pain patterns in the most frequent pancreatic diseases.

Serum levels of soluble Fas, nitric oxide and cytokines in acute decompensated cirrhotic patients

AIM： To evaluate plasma levels of nitrite/nitrate （NOx）, soluble Pas （spas） antigen, tumor necrosis factor alpha （TNF-α） and interleukin-6 （IL-6） in patients with compensated and acute decompensated cirrhosis and to evaluate mediators causing acute decompensation in liver cirrhosis, METHODS： This prospective study was conducted in the medical intensive care unit of an academic tertiary center, Fifty-five patients with acute decompensation （gastrointestinal hemorrhage, encephalopathy, hydropic decompensation） and twenty-five patients with compensated liver drrhosis were included, Blood samples were taken for analyses of spas, Nox, IL-6, TNF-α, Liver enzymes and kidney functions were also tested, RESULTS： In patients with acute decompensation, plasma spas levels were higher than in non-decompensated patients （15305 ± 4646 vs 12458± 4322 pg/mL, P 〈 0.05）. This was also true for the subgroup of patients with alcoholic liver cirrhosis （P 〈 0.05）. The other mediators were not different and none of the parameters predicted survival, except for ALT （alanine-aminotransferase）. In patients with portal-hypertension-induced acute hemorrhage, NOx levels were significantly lower than in patients with other forms of decompensation （70.8 ± 48.3 vs 112.9 ± 74.9 pg/mL, P 〈 0.05）. When NOx levels were normalized to creatinine levels, the difference disappeared. IL-6, TNF-α and spas were not different between bleeders and non-bleeders. In decompensated patients spas, IL-6 and NOx levels correlated positively with creatinine levels, while IL-6 levels were dependent on Child class. CONCLUSION： In acute decompensated cirrhotic patients sPas is increased, suggesting a role of apoptosis in this process and patients with acute bleeding have lower NOx levels, However, in this acute complex clinical situation, kidney function seems to have a predominant influence on mediator levels,

Are heat stroke and physical exhaustion underestimated causes of acute hepatic failure?

While cardiopulmonary symptoms are common in patients undergoing dassical or, due to physical exercise, exertional heat stroke, the failure of other organs is a rarely described phenomenon. Here we present two cases of acute hepatic failure, one due to classic heat shock, while the other occurred while the patient was doing a marathon-type running. Both cases presented with very high transaminases and significantly elevated international normalized ratio （INR）. No other causes for liver failure could be identified but physical exhaustion and hyperthermia.

Aquaporin-8 expression is reduced in ileum and induced in colon of patients with ulcerative colitis

AIM： To study susceptibility genes which may play a potential role in the pathogenesis and etiology of inflammatory bowel disease （IBD）. METHODS： To identify potential susceptibility genes we performed global gene expression profiling in patients with IBD and control specimens. For determination of an intrinsic gene expression profile in ulcerative colitis （UC） and Crohn＇s disease （CD） compared to normal subjects, mucosal biopsies of non-inflamed regions of the colon and the terminal ileum were subjected to DNA microarray analysis. Real-time RT-PCR and immunohistochemistry were used for verification of selected regulated candidate genes and a genetic analysis was performed. RESULTS： We could show that aquaporin-8 （AQP8） mRNA and protein levels were significantly increased in the colon of UC patients compared to controls. Genetic analysis of the six exons and the promoter region of AQPS, however, revealed no mutations or polymorphisms in IBD patients. CONCLUSION： Our results suggest that upregulation of AQP8 in the colon of UC patients represents a secondary phenomenon which may, due to altered water exchange of the distal intestinal mucosa, disturb the physiologic colonic mucus barrier and thus lead to chronic inflao mmation and ulceration.