Gloomy Prognosis Research Articles

A BODIPY-Naphtholimine-BF2 Dyad for Precision Photodynamic Therapy, Targeting, and Dual Imaging of Endoplasmic Reticulum and Lipid Droplets in Cancer.

Currently, effective therapeutic modalities for pancreatic ductal adenocarcinoma (PDAC) are quite limited, leading to gloomy prognosis and ∼6-months median patient survival. Recent advances showed the promise of photodynamic therapy (PDT) for PDAC patients. Next generation photosensitizers (PS) are based on "organelle-targeted-PDT" and provide new paradigm in the field of precision medicines to address the current challenge for treating PDAC. In this investigation, we have constructed a novel PS, named as N b B, for precise and simultaneous targeting of endoplasmic reticulum (ER) and lipid droplets (LDs) in PDAC, based on the fact that malignant PDAC cells are heavily relying on ER for hormone synthesis. Our live cell imaging and fluorescence recovery after photobleaching (FRAP) experiments revealed that N b B is quickly targeted to ER and subsequently to LDs and shows simultaneous dual fluorescence color due to polar and nonpolar milieu of ER and LDs. Interestingly, the same molecule generates triplet state and singlet oxygen efficiently and causes robust ER stress and cellular lipid peroxidation, leading to apoptosis in two different PDAC cells in the presence of light. Together, we present, for the first time, a potential next generation precision medicine for ER-LD organelle specific imaging and PDT of pancreatic cancer.

Molecular Insight into Iron Homeostasis of Acute Myeloid Leukemia Blasts.

Acute myeloid leukemia (AML) remains a disease of gloomy prognosis despite intense efforts to understand its molecular foundations and to find efficient treatments. In search of new characteristic features of AML blasts, we first examined experimental conditions supporting the amplification of hematological CD34+ progenitors ex vivo. Both AML blasts and healthy progenitors heavily depended on iron availability. However, even if known features, such as easier engagement in the cell cycle and amplification factor by healthy progenitors, were observed, multiplying progenitors in a fully defined medium is not readily obtained without modifying their cellular characteristics. As such, we measured selected molecular data including mRNA, proteins, and activities right after isolation. Leukemic blasts showed clear signs of metabolic and signaling shifts as already known, and we provide unprecedented data emphasizing disturbed cellular iron homeostasis in these blasts. The combined quantitative data relative to the latter pathway allowed us to stratify the studied patients in two sets with different iron status. This categorization is likely to impact the efficiency of several therapeutic strategies targeting cellular iron handling that may be applied to eradicate AML blasts.

Development and validation of a GC-MS method for determination of metformin in normal brain and in glioblastoma tissues

Metformin hydrochloride (MH) has recently been repurposed as an anticancer agent, showing antiproliferative activity in vitro and in vivo. In particular, experimental evidence has suggested its potential clinical efficacy in glioblastoma (GBM), a very aggressive tumor frequently characterized by gloomy prognosis. Unfortunately, the published literature concerning experimental applications of MH in glioblastoma animal models report no data on metformin levels reached in the brain, which, considering the high hydrophilicity of the drug, are likely very low. Therefore, new sensitive analytical methods to be applied on biological tissues are necessary to improve our knowledge of MH in vivo biodistribution and biological effects on tumors. In this research work, a GC-MS method for MH quantification in brain tissues is proposed. MH has been derivatized using N-methyl-bis(trifluoroacetamide), as already described in the literature, but the derivatization conditions have been optimized; moreover, deuterated MH has been selected as the best internal standard, after a comparative evaluation including other internal standards employed in published methods. After ascertaining method linearity, its accuracy, precision, specificity, repeatability, LOD and LOQ (0.373 µM and 1.242 µM, respectively, corresponding to 0.887 and 2.958 pmol/mg of wet tissue) have been evaluated on mouse brain tissue samples, obtained through a straightforward preparation procedure involving methanolic extraction from lyophilized brain homogenates and solid phase purification. The method has been validated on brain samples obtained from mice, either healthy or xenografted with GBM cells, receiving metformin dissolved in the drinking water. This analytical method can be usefully applied in preclinical studies aiming at clarifying MH mechanism of action in brain tumors.

Health in a post-COVID-19 world

In the previous article in this issue (S Afr J Sci. 2022;118(11/12), Art. #13165), the emergence and spread of COVID-19 pari passu with climate change and planetary degradation were interpreted as late manifestations in the trend towards gradual decline into disorder (entropy) in an unstable and ecologically threatened planet. In this article, as we contemplate a post-COVID world, the question is whether new insights could generate courageous, prescient leadership towards new paradigms of health, politics, economics, society, and our relationship with nature. A gloomy prognosis is postulated because of the power of many impediments to such changes, both in an increasingly polarised world and in South Africa as a microcosm. Despite many squandered opportunities and a decline in local and global cooperation between all who have a stake in the future, some hope is retained for innovative shifts towards sustainable futures. Significance: Precarious local and global instabilities are vivid reminders of our interconnectedness with each other and with nature. Insights into local and global threats and opportunities, call for paradigm shifts in thinking about and taking action towards a potentially sustainable future in a country that has its own unique history and problems but is also a microcosm of the world. The impediments to making appropriately constructive paradigm shifts in many countries with their tendencies to authoritarianism that threaten peace and democracy, are even more complex in South Africa, where opportunities for dialogue and cooperation are diminishing. Retaining some hope, with vision and courage for innovative shifts towards a sustainable economic/ecological paradigm locally and globally, is arguably essential.

Cervico-thoracic cellulitis at the Yalgado Ouedraogo University Hospital: About 50 cases

IntroductionCervicofacial cellulitis is mainly due to neglected oral/pharyngeal diseases. Untreated or incorrectly treated, they can be complicated by thoraco-cervical necrosis, which has a gloomy prognosis and is difficult to manage, especially in an under-medicalized environment. The aim of this work was to report the difficulties of management in precarious context by underlining the interest of primary prevention. Patients and methodThis was a descriptive cross-sectional retrospective study from January 2018 to March. ResultsFifty cases of thoracic-cervical necrosis were collected during this period. The man/woman sex ratio was 3.55. Dental etiology was found in 96% of cases. The main complications were: pneumopathy (n = 10), mediastinitis (n = 10), pleurisy (n = 3) and polyseritis (n = 2). The management combined medical and surgical treatment under local or general anesthesia. The mortality rate was 12.8%. The functional results were satisfactory in surviving cases. ConclusionThe management of thoracic-cervical necrosis remains a challenge in precarious conditions. Primary must play a major role in these conditions.

Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition.

Simple SummaryPancreatic cancer remains an incurable cancer with a gloomy prognosis and a median survival of months since the time of diagnosis. Disappointingly, no significant improvement in clinical outcomes has been achieved for the last fifty years. Cancer stem cells (CSCs) are suggested to be critical and responsible for tumor development, drug resistance and cancer relapse, therefore, an effective antitumor therapy against pancreatic cancer should deal with pancreatic CSCs. Here, we found that the alkylphospholipid analog edelfosine induces apoptosis in pancreatic CD44+CD24+EpCAM+ CSCs through its accumulation in the endoplasmic reticulum, leading to sustained endoplasmic reticulum stress and cell death. Edelfosine was effective against primary cultures from pancreatic cancer patients and their corresponding pancreatic CSCs. Autophagy inhibition potentiated the proapoptotic action of edelfosine in pancreatic CSCs. Thus, endoplasmic reticulum targeting and its combination with autophagy inhibitors could open a new framework in pancreatic cancer chemotherapy, directly involving pancreatic CSCs.Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+CD24+EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.

The Crisis of Liberalism and the Western Alliance

Liberalism as the ideology of the Western alliance is in crisis. Having seen off Nazism and communism, it gained influence after the end of the Cold War, which produced optimism about security, human rights and global prosperity. Now liberalism, shaken by the financial crisis and the wars in Afghanistan and Iraq, is in retreat. Illiberal states, notably China and Russia, are reshaping the international system. Liberalism may not be able to continue to bind allies together, or enable them to cooperate effectively in a severe crisis. There are three counters to a gloomy prognosis, however. Firstly, heightened great-power competition has reinforced rather than undermined the alliance. Secondly, Russia and China have no substantial alliances, and are showing that authoritarian governments face serious problems of their own, including entrenched leaderships. Thirdly, liberalism remains better equipped to adapt to new circumstances.

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer.

Simple SummaryPancreatic ductal adenocarcinoma (PDAC), comprising 90–95% of all pancreatic cancers, is one of the deadliest human cancers, with a gloomy prognosis and ~6-month median survival in metastatic tumors. Even patients with resectable tumors show a poor survival rate after surgery. Thus, PDAC represents an unmet therapeutic challenge. The aim of this review was to put into context the conundrum of pancreatic cancer treatment and the advent of a novel therapeutic approach, examining: (a) anatomical factors, demographics, statistics, and therapeutic approaches, affecting tumor detection, treatment, and prognosis; (b) the importance of the endoplasmic reticulum as a major target for pancreatic cancer due to its high abundance and activity in pancreatic cells; (c) the identification of the alkylphospholipid analog edelfosine as a novel drug against pancreatic cancer, showing two outstanding features—selective uptake by tumor tissue, and direct accumulation in the endoplasmic reticulum, leading to persistent endoplasmic reticulum stress and subsequent apoptosis.Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

Epidemiological, Clinical and Therapeutic Aspects of Pancreatic Cancer in the Internal Medicine Department of the Point G Hospital

It’s is primary or secondary malignant neoformations developed at the expense of the structures of the pancreas. Most pancreatic cancers are damage to its exocrine unit: more than 90%against 5 to 10% of islet tumors and they occur twice as often in the head of the pancreas than in the body or of the tail. Cancer is responsible for 9 million deaths each year, the disease is thought to affect 17, 5 million people worldwide. In Mali, Pancreatic cancer accounts for 1, 7 and 0, 8 percent of all cancers in men and women respectively; the five-year survival rate is between1and 10 percent although the diagnosis seems straightforward. However the big one majority of cases are seen at an advanced stage. This gloomy prognosis is to a large extent also linked to the clinical latency not allowing to make the diagnosis at the initial stage of the disease. Ductal adenocarcinoma appears to be the most common 80 percent. Pancreatic endocrine tumors arouse gret interest because of their physiopathological and prognostic characteristics, a heterogeneous evolutionary potential. This condition has been very little studied in Mali.

Refractory Heart Failure of Unknown Etiology May Be Cardiac Amyloid If Preceded by Hereditary Neurological Symptoms.

Transthyretin cardiac amyloidosis results from the deposition of transthyretin amyloid fibrils in the myocardium. This happens because of the misfolding of genetically normal (wild type - ATTR) or mutant (hereditary ATTR) transthyretin. The clinical presentation of hereditary ATTR cardiac amyloidosis is dependent on the exact site of the amino acid substitution. The V122I gene mutation is most common among people of African descent and usually manifests with cardiomyopathy. The mutations are transmitted in an autosomal dominant manner with variable penetrance and associated with clinical features occurring most commonly after the age of 40. The symptoms of heart failure (HF) may be preceded by several years of vague neurological symptoms which is more concerning if there is no clear explanation. A high index of suspicion is therefore crucial in ensuring prompt diagnosis and therapy, as this may favorably alter the gloomy prognosis associated with cardiac amyloidosis.

Prognostic Utility of Troponin I and N Terminal-ProBNP among Patients with Heart Failure due to Non-Ischemic Cardiomyopathy and Important Correlations.

Heart Failure (HF) is accompanied by a high cost of care and gloomy prognosis despite recent advances in its management. Therefore, efforts to minimize HF rehospitalizations is a major focus of several studies. We conducted a retrospective cohort study of 140 patients 18 years and above who had baseline clinical parameters, echocardiography, NT-ProBNP, troponin I and other laboratory parameters following a 3-year electronic medical record review. Patients with coronary artery disease, preserved ejection fraction, pulmonary embolism, cancer, and end-stage renal disease were excluded. Of the 140 patients admitted with HF with reduced Ejection Fraction (HFrEF) secondary to non-ischemic cardiomyopathy, 15 were re-hospitalized within 30 days of discharge while 42 were rehospitalized within 6 months after discharge for decompensated HF. Receiver operating characteristic (ROC) cutoff points were obtained for NT-ProBNP at 5178 pg/ml and serum troponin I at 0.045 ng/ml. After Cox regression analysis, patients with HFrEF who had higher hemoglobin levels had reduced odds of re-hospitalization (p = 0.007) within 30 days after discharge. NT-ProBNP and troponin I were independent predictors of re-hospitalization at 6 months after discharge (p = 0.047 and p = 0.02), respectively, after Cox regression analysis. Troponin I and NT-ProBNP at admission are the best predictors of re-hospitalization 6 months after discharge among patients with HFrEF. Hemoglobin is the only predictor of 30 -day rehospitalization among HFrEF patients in this study. High-risk patients may require aggressive therapy to improve outcomes.

Quality of Life of Patients With Heart Failure at Teaching Hospitals in Erbil City

Background and objectives: Heart Failure is a common and significant health problem, with an increasing incidence and a gloomy prognosis that is often accompanied by a negative impact on the length and quality of life of patients. This study aimed to assess quality of life among patients with heart failure in Erbil city and to find the association of quality of life domains (physical, level of independence and social relationship) with some socio-demographic data (age, gender, level of education, and marital status)Methods: A quantitative design / a descriptive cross-sectional study was conducted at Hawler and Rizgary Teaching Hospitals in Erbil city Kurdistan region. This study was carried out from November 17th 2014 to November 17th 2015 on non-probability (purposive) samples was selected among 140 heart failure patients who were admitted to coronary care unit and medical ward of both teaching hospitals. Their quality of life was measured by standardized questionnaire of world health organization with some modification.Results: The findings of the study indicated that most patients were Female and Illiterate, their mean age was 68.75. Moreover, significant associations exist between levels of education with physical ability, level of independence, social domains, and marital state with physical domain.Conclusion: The study concluded that the majority of the study sample had moderate level of quality of life while less than one-fourth of them had poor level.

P12.01 Local implantation of thermoresponsive interferon alpha-polypeptide conjugate combined with temozolomide for post-surgical glioblastoma chemoimmunotherapy

Abstract BACKGROUND Glioblastoma(GBM) is associated with gloomy prognosis despite maximal safe resection and following chemoradiation. In recent years, significant progress has been made in cancer immunotherapy except for GBM, which is largerly due to its local immunosuppressive microenvironment. Some research has demonstrated that local immunotherapy may be more efficient than systematic administrators. IFNα has been investigated as antitumor agent for some cancers, including glioma. Nevertheless, the short circulating half-life greatly limits its clinical application. Hence, a thermoresponsive IFNα-elastin-like polypeptide (IFNα-ELP) was genetically engineered for the earliest local intervention post-surgery. MATERIAL AND METHODS Firstly, IFNα-ELP(V) was constructed, expressed and purified, then, its physicochemical characterization was verified. The tumor was resected 10 days after U87MG-mCherry-luc cells orthotopic implantation, and IFNα-ELP(V) was injected into the resection cavity. Two days later, temozolomide(TMZ) was intraperitoneally injected. Using in vivo imaging technique, we could monitor the trends in tumor size. The survival time of mice was counted. Biosafety was evaluated by peripheral blood biochemistry analysis and pathology of the organs. RESULTS In this study, the bioconjugate not only in situ deposited in the resection cavity because of the thermoresponsive characteristic, but also showed zero-order release kinetics from the depot and dramatically improved pharmacokinetics and biodistribution of IFNα. Consequently, it showed the inhibition of tumor relapse in GBM orthotopic resection mice models. When followed by TMZ intraperitoneal injection, IFNα-ELP(V) could significantly prevent the tumor recurrence than itself or TMZ alone. Biosafety results indicated that the systemic toxicity of IFNα-ELP(V) in mice can be reduced to safe levels. CONCLUSION The results reveal that local implantation of thermoresponsive IFNα-ELP(V) combined with TMZ exhibits the synergy of post-surgical GBM chemoimmunotherapy.

Anemia and chronic heart failure (CHF): Prevalence and prognosis: About 3000 cases

Anemia is common in patients with heart failure (HF) and it is one of many factors whose presence allows us to draw a gloomy prognosis. The aim of the study was to determine the prevalence of anemia, its potential prognostic impact and its physio-pathological mechanism in patients suffering of heart failure. Retrospective study of all CHF patients registered in the therapeutic Unit of Chronic Heart failure over a period of 8 years, between June 2006 and March 2015. Anemia is defined as a hemoglobin level less than 11 g/dl. During this period 3000 patients were studied and divided into two groups: Group 1 with anemia (58.5%) and group 2 without anemia (41.5%). The mean age is 66 years in the group 1 and 65 in the group 2. A male predominance in both groups was notified. Ischemic heart disease was the most common etiology in both groups. The average heart rate of group 1 was higher than the group 2. It was found that the group 1 was more symptomatic than the group 2 and these patients had more cardiac decompensation. The atrial fibrillation in group 1 and group 2 was respectively 6.9% and 10.9%. Renal failure was significantly more frequent in group 1 (34.3%) than the group 2 (10.3%). There was not much difference concerning therapeutic classes used in both groups. The presence of anemia increases the risk of re-hospitalization and mortality rate at 4 years. In the context of heart failure, anemia is a common complication as shown in our study. It is an important and common factor for predicting unfortunate evolution in patients with HF. An early and appropriate management of anemia would improve the symptoms of these patients and reduce the frequency of re-hospitalization.

Arrhythmia Risk in Patients with ChronicHepatic Disease

Cardiac affectation is one of the leading causes of death in the world. Rhythmic disorders such as ventricular extrasystoles, atrial extrasysoles, atrial fibrillation, atrial flutter represent a major risk factor with a gloomy progression and prognosis. Our goal was to analyze the existing arrhythmia risk in patients with chronic hepatic disease. Being known the alteration of the somatic status of the patient with liver cirrhosis or other chronic liver disease in the presence of comorbid cardiac symptoms, we consider vital to prevent arrhythmia risk in hepatic pathology.

From Rebellion to Opposition: UNITA’s Social Engagement in Post-War Angola

AbstractThe endurance and indeed the growing electoral support manifested by the Angolan opposition party UNITA since its defeat as an armed movement in 2002 defies generally gloomy prognoses both for opposition parties in dominant party systems and for defeated rebel movements that recast themselves as political parties. This article examines social service and training projects implemented by UNITA in the Angolan Central Highlands. I argue that the case of UNITA illustrates the need to take into account the importance of resources that accrue outside of the space of formal politics, including historical narratives and social relationships, which UNITA has mobilized and built upon in order to expand its vote share and consolidate its place within electoral politics.

Telewizyjne gry z Pirandellem

Televisions Play with PirandelloAbstractIn the beginning of 1960s, the Polish press witnessed a discussion on Pirandello’s rightfor innovation, which was started by Zygmunt Greń who harshly attacked the writer for„pseudointellectualism” and using the metaphor of a mask as an empty stage effect. At thesame time, however, in Polish theatres, the author witnessed great prosperity. This includedalso Teatr Telewizji (Television Theatre) which in the course of 30 years showed his mostimportant plays, i.e.: Six Characters in Search of an Author, Henry IV, Right You Are (If You Think So), and comedies The Man, the Beast and the Virtue, Cecè, Il berretto a sonagli, The Manwith the Flower In His Mouth, and Tutto per bene.When analyzing two of them – Right You Are (If You Think So) from 1967 directed by IreneuszKanicki and Henry IV directed by Maciej Prus and shown as late as 1989 – it should be notedthat in both plays political undertones could be noticed. A characteristic interpretativefeature of adaptations of Pirandello in Polish theatres was the manifestation of the “role”his characters are doomed for, which happens at the price of their internal truth. Society,often using the institutions of power, tries to trespass the intimate space in order to conformit to predictable stereotypes uncovered by – real or pretend – “madness” of Pirandello’scharacters. Both Right You Are (If You Think So) and Henry IV gave us two different faces ofresistance of an individual in the context of pressure of collectivity, regardless of whether it isgoverned by institutions or stereotypes of worldview.Even though in the contemporary (almost non-existent) Teatr Telewizji it is difficult toimagine new adaptations of the author’s plays, in spite of gloomy prognosis of criticism, Polishtheatres are still interested in the author. Six Characters in Search of an Author treating abouta destruction of subjective structure and attempts of rebuilding it is especially constantlypresent in theatre programme. The play was even used in an experiment with theatre therapyin Lublin – a disabled group prepared the production.Therefore, maybe the Italian Nobelist still has a lot to offer to contemporary theatre?Keywords: innovation, myth, reception, truth, illusion, mask, theatricality, collectivity,stereotype, power, madness

Neddylation, a novel paradigm in liver cancer

Liver cancer is the sixth most prevailing cancer worldwide. Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, has a rather heterogeneous pathogenesis making it highly refractive to current therapeutic approaches. Hence, HCC patients have a poor and gloomy prognosis making liver cancer the second leading cause of global cancer-related deaths. On this basis, a more global mechanism, such as post-translational modifications (PTMs) of proteins, may provide a valuable therapeutic approach for HCC clinical management by simultaneously regulating multiple disrupted signaling pathways. In the last years, the ubiquitin-like molecule NEDD8 (Neural precursor cell-expressed developmentally downregulated-8) conjugation pathway, neddylation, was shown to be aberrant in HCC patients with a significant positive correlation found among global levels of neddylation and poorer prognosis. Even though the best-established role for NEDD8 is the activation of ubiquitin E3 ligase family of cullin-RING ligases, the putative role for other NEDD8 substrates has been explored in recent years leading to the identification of novel neddylation targets in HCC. Importantly, treatment with the small pharmacological inhibitor Pevonedistat (MLN4924) (Millennium Pharmaceuticals, Takeda Pharmaceutical), currently in clinical trials for the treatment of some types of leukemias and other advanced solid tumors, was shown to suppress the outgrowth of hepatoma cells and liver cancer in pre-clinical mouse models. Overall, considering that the neddylation inhibitor Pevonedistat was well-tolerated and displayed a significant antitumor effect in pre-clinical models, combinatory pharmacological treatment based on Pevonedistat are highly recommended to enter clinical trials targeting advanced HCC.

Anemia and chronic heart failure (CHF): Prevalence and prognosis: About 3048 cases

Anemia is common inpatients with heart failure (HF) and it is one of many factors whose presence allows us to draw a gloomy prognosis. The aim of the study was to determine the prevalence of anemia, its potential prognostic impact and its physiopathological mechanism inpatients suffering of heart failure. Retrospective study of all CHF patients registered in the therapeutic Unit of Chronic Heart failure over a period of 8 years, between June 2006 and March 2015. Anemia is defined as a hemoglobin level less than 11 g/dL. During this period? 3000 patients were studied and divided into two groups: group 1 with anemia (58.5%) and group 2 without anemia (41.5%). The mean age is 66 years in the group 1 and 65 in the group 2. A male predominance in both groups was notified. Ischemic heart disease was the most common etiology in both groups. The average heart rate of group 1 was higher than the group 2. It was found that the group 1 was more symptomatic than the group 2 and these patients had more cardiac decompensation. The atrial fibrillation in group 1 and group 2 was respectively 6.9% and 10.9%. Renal failure was significantly more frequent in group 1 (34.3%) than the group 2 (10.3%). There was not much difference concerning therapeutic classes used in both groups. The presence of anemia increases the risk of rehospitalization and mortality rate at 4 years. In the context of heart failure, anemia is a common complication as shown in our study. It is an important and common factor for predicting unfortunate evolution inpatients with HF. An early and appropriate management of anemia would improve the symptoms of these patients and reduce the frequency of rehospitalization.

Low SIRT3 expression contributes to tumor progression, development and poor prognosis in human pancreatic carcinoma

SIRT3, an important mitochondrial protein, may act as either an oncogene or tumor suppressor depending on the tumor-type. The aim of this study was to investigate the expression of SIRT3 in pancreatic carcinoma (PC) and its clinical association in PC patients. Immunohistochemistry was adopted to investigate the expression of SIRT3 in cancer and corrresponding adjacent non-cancer tissues across 79 patients with PC. The log-rank test and Cox hazard model were used to estimate the relationship between SIRT3 expression and prognosis. The staining results revealed that SIRT3 negative expression was more common in cancer tissues than in adjacent non-cancer tissues (P<0.001). Chi-square tests indicated that the expression of SIRT3 correlated with T status (p<0.001) and tumor stage (p=0.013). Kaplan-Meier analysis showed that negative SIRT3 expression is linked to a poor prognosis in PC patients. Multivariate analysis identified SIRT3 expression as an independent predictor for PC outcome both in the whole cohort and several subgroups of PC patients. Our results indicate that down-regulated SIRT3 may contribute to tumor progression and gloomy prognosis in PC patients and may sever as a novel prognostic marker.