Inversion Concept of the Origin of Life

The essence of the inversion concept of the origin of life can be narrowed down to the following theses: 1) thermodynamic inversion is the key transformation of prebiotic microsystems leading to their transition into primary forms of life; 2) this transformation might occur only in the microsystems oscillating around the bifurcation point under far-from-equilibrium conditions. The transformation consists in the inversion of the balance "free energy contribution / entropy contribution", from negative to positive values. At the inversion moment the microsystem radically reorganizes in accordance with the new negentropy (i.e. biological) way of organization. According to this approach, the origin-of-life process on the early Earth took place in the fluctuating hydrothermal medium. The process occurred in two successive stages: a) spontaneous self-assembly of initial three-dimensional prebiotic microsystems composed mainly of hydrocarbons, lipids and simple amino acids, or their precursors, within the temperature interval of 100-300°C (prebiotic stage); b) non-spontaneous synthesis of sugars, ATP and nucleic acids started at the inversion moment under the temperature 70-100°C (biotic stage). Macro- and microfluctuations of thermodynamic and physico-chemical parameters able to sustain this way of chemical conversion have been detected in several contemporary hydrothermal systems. A minimal self-sufficient unit of life on the early Earth was a community of simplest microorganisms (not a separate microorganism).     

AGR2：一个新的癌症诊断标记

AGR2（anterior gradient．2）是一种分泌蛋白,广泛存在于前列腺、乳腺、肺和胰腺等腺体组织,并在这些腺体的肿瘤组织过量表达,与肿瘤细胞的存活、生长和转移相关。临床上,AGR2的表达与乳腺癌、前列腺癌、胰腺癌等癌症的发展和预后相关,被认为是一个很有前途的早期诊断和判定预后的标志性基因。该文就目前AGR2的研究现状,尤其是肿瘤相关的功能、机制和临床调查上的最新研究进展加以综述。     

Targeted proteomics of solid cancers: from quantification of known biomarkers towards reading the digital proteome maps

The concept of personalized medicine includes novel protein biomarkers that are expected to improve the early detection, diagnosis and therapy monitoring of malignant diseases. Tissues, biofluids, cell lines and xenograft models are the common sources of biomarker candidates that require verification of clinical value in independent patient cohorts. Targeted proteomics – based on selected reaction monitoring, or data extraction from data-independent acquisition based digital maps – now represents a promising mass spectrometry alternative to immunochemical methods. To date, it has been successfully used in a high number of studies answering clinical questions on solid malignancies: breast, colorectal, prostate, ovarian, endometrial, pancreatic, hepatocellular, lung, bladder and others. It plays an important role in functional proteomic experiments that include studying the role of post-translational modifications in cancer progression. This review summarizes verified biomarker candidates successfully quantified by targeted proteomics in this field and directs the readers who plan to design their own hypothesis-driven experiments to appropriate sources of methods and knowledge.     

The tumor suppressor RASSF1A in human carcinogenesis: an update

Loss of heterozygosity of the small arm of chromosome 3 is one of the most common alterations in human cancer. Most notably, a segment in 3p21.3 is frequently lost in lung cancer and several other carcinomas. We and others have identified a novel Ras effector at this segment, which was termed Ras Association Domain family 1 (RASSF1A) gene. RASSF1 consists of two main variants (RASSF1A and RASSF1C), which are transcribed from distinct CpG island promoters. Aberrant methylation of the RASSF1A promoter region is one of the most frequent epigenetic inactivation events detected in human cancer and leads to silencing of RASSF1A. Hypermethylation of RASSF1A was commonly observed in primary tumors including lung, breast, pancreas, kidney, liver, cervix, nasopharyngeal, prostate, thyroid and other cancers. Moreover, RASSF1A methylation was frequently detected in body fluids including blood, urine, nipple aspirates, sputum and bronchial alveolar lavages. Inactivation of RASSF1A was associated with an advanced tumor stage (e.g. bladder, brain, prostate, gastric tumors) and poor prognosis (e.g. lung, sarcoma and breast cancer). Detection of aberrant RASSF1A methylation may serve as a diagnostic and prognostic marker. The functional analyses of RASSF1A reveal an involvement in apoptotic signaling, microtubule stabilization and mitotic progression. The tumor suppressor RASSF1A may act as a negative Ras effector inhibiting cell growth and inducing cell death. Thus, RASSF1A may represent an epigenetically inactivated bona fide tumor suppressor in human carcinogenesis.     

Probabilities of dying from cancer and other causes in French cancer patients based on an unbiased estimator of net survival: A study of five common cancers

BackgroundNet survival is the survival that would be observed if cancer were the only possible cause of death. Although it is an important epidemiological tool allowing temporal or geographical comparisons, it cannot inform on the “crude” probability of death of cancer patients; i.e., when taking into account other possible causes of deaths.MethodsIn this work, we provide estimates of the crude probabilities of death from cancer and from other causes as well as the probability of being alive up to ten years after cancer diagnosis according to the age and year of diagnosis. Based on a flexible excess hazard model providing unbiased estimates of net survival, our methodology avoids the pitfalls associated with the use of the cause of death. We used data from FRANCIM, the French network of cancer registries, and studied five common cancer sites: head and neck, breast, prostate, lung, and colorectal cancers.ResultsFor breast, prostate, and colorectal cancers, the impact of the other causes on the total probability of death increased with the age at diagnosis whereas it remained negligible for lung and head and neck cancers whatever the age. For breast, prostate, and colorectal cancer, the more recently was the cancer diagnosed, the less was the probability of death from cancer.ConclusionThe crude probability of death is an intuitive concept that may prove particularly useful in choosing an appropriate treatment, or refining the indication of a screening strategy by allowing the clinician to estimate the proportion of cancer patients who will die specifically from cancer.     

26 Inversion approach to the origin of life: theoretical notions and experimental data

The essence of the inversion concept of the origin of life can be narrowed down to the following theses: (1) thermodynamic inversion is the key transformation of prebiotic microsystems leading to their transition into primary forms of life; (2) this transformation might occur only in the microsystems oscillating around the bifurcation point under far-from-equilibrium conditions. The transformation consists in the inversion of the balance “free energy contribution entropy contribution” (as well as “information contribution informational entropy contribution”), from negative to positive values. At the inversion moment, the microsystem radically reorganizes in accordance with the new negentropy (i.e. biological) way of organization. According to this concept, the origin-of-life process on the early Earth took place in oscillating hydrothermal medium. The process was taking two successive stages: (1) spontaneous self-assembly of initial three-dimensional prebiotic microsystems composed mainly of hydrocarbons, lipids, and simple amino acids, or their precursors, within the temperature interval of 100–300?°C (prebiotic stage); (2) nonspontaneous synthesis of sugars, ATP, and nucleic acids started at the inversion moment under the temperature 70–100?°C (biotic stage). Macro and microfluctuations of thermodynamic and physicochemical parameters able to sustain this way of chemical conversion have been detected in several contemporary hydrothermal systems (Kompanichenko, 2012). Conditions in potential hydrothermal medium for the origin of life were explored on the examples of several hydrothermal systems in Kamchatka peninsula. Temperature of water in hot springs ranges from?<?60 to 98?°C, in the bore holes water-steam temperature varies from?<?100 to 239?°C, and pressure from?<?1 to 35 bars at the wellheads; pH is within the interval 2.5–9.0. Pressure monitoring at the depth 950?meters in the borehole No. 30 (Mutnovsky field) has revealed high-amplitude (up to 1–2 bars) irregular macrofluctuations and low-amplitude quite regular microoscillations of pressure (amplitudes 0.1–0.3 bars). Hydrocarbons, lipid precursors, and simple amino acids are available in the fluid. The lifeless condensate of water-steam mixture (temperature 108–175?°C) contains aromatic hydrocarbons, n-alkanes, ketons, alcohols, and aldehydes. In addition to those, cycloalkanes, alkenes, dietoxyalkanes, naphtenes, fatty acids, ethyl ethers of fatty acids, and monoglycerides have been detected in hot solutions inhabited by thermophiles and hyperthermophiles (temperature 70–98?°C). According to Mukhin et al. (1979), glycine of probably abiotic origination was detected in lifeless condensate.     

Diagnostic Intervals and Its Association with Breast,Prostate, Lung and Colorectal Cancer Survival in England: Historical Cohort Study Using the Clinical Practice Research Datalink

Rapid diagnostic pathways for cancer have been implemented, but evidence whether shorter diagnostic intervals (time from primary care presentation to diagnosis) improves survival is lacking. Using the Clinical Practice Research Datalink, we identified patients diagnosed with female breast (8,639), colorectal (5,912), lung (5,737) and prostate (1,763) cancers between 1998 and 2009, and aged >15 years. Presenting symptoms were classified as alert or non-alert, according to National Institute for Health and Care Excellence guidance. We used relative survival and excess risk modeling to determine associations between diagnostic intervals and five-year survival. The survival of patients with colorectal, lung and prostate cancer was greater in those with alert, compared with non-alert, symptoms, but findings were opposite for breast cancer. Longer diagnostic intervals were associated with lower mortality for colorectal and lung cancer patients with non-alert symptoms, (colorectal cancer: Excess Hazards Ratio, EHR >6 months vs <1 month: 0.85; 95% CI: 0.72-1.00; Lung cancer: EHR 3-6 months vs <1 month: 0.87; 95% CI: 0.80-0.95; EHR >6 months vs <1 month: 0.81; 95% CI: 0.74-0.89). Prostate cancer mortality was lower in patients with longer diagnostic intervals, regardless of type of presenting symptom. The association between diagnostic intervals and cancer survival is complex, and should take into account cancer site, tumour biology and clinical practice. Nevertheless, unnecessary delay causes patient anxiety and general practitioners should continue to refer patients with alert symptoms via the cancer pathways, and actively follow-up patients with non-alert symptoms in the community.     

Expression of insulin-like growth factor (IGF)-II in human prostate, breast, bladder, and paraganglioma tumors

Insulin-like growth factors (IGFs) are potent mitogens for a variety of cancer cells in vitro. A paracrine/autocrine role of IGF-II in the growth of breast and prostate cancer cells has been suggested. Information on cell-type-specific IGF-II expression in vivo in the breast and prostate is, however, limited. Thus, cell types expressing IGF-II mRNA and protein in tumors were identified by in situ hybridization and immunohistochemistry. Of 36 prostate, 17 breast, and 10 bladder cancers, and 9 paraganglioma tissues examined, IGF-II was expressed in more than 50% of prostate, breast, and bladder tumors, and in 100% of paraganglioma tumors. Expression levels of IGF-II were highest in the paraganglioma and bladder followed by prostate and breast tumors. In all the tumors expressing IGF-II, both mRNA and protein were localized to malignant cells, expression in the stroma being minimal. Since previous studies had indicated that an incompletely processed form of 15-kDa IGF-II exhibited higher mitogenic potency than the completely processed 7.5-kDa IGF-II form, the quantity and size of IGF-II proteins expressed in these tumors were analyzed by Western immunoblotting. Greater expression of 15-kDa IGF-II relative to the 7.5-kDa IGF-II form was clearly demonstrated in all six prostate cancers and in half of the two breast and four bladder cancers examined. The results are consistent with the hypothesis that the 15-kDa form of IGF-II expressed in cancerous cells contributes to autocrine cancer cell growth in vivo. Received: 11 June 1997 / Accepted: 22 August 1997     

Trends in stage-specific population-based survival of cancer patients in the Czech Republic in the period 2000–2008

BackgroundThe objective of this study was to assess trends in overall and in stage-specific 5-year relative survival rates of the Czech cancer patients between periods 2000–2004 and 2005–2008.MethodsAll Czech cancer patients diagnosed between 1995 and 2008 were included in the analysis. Period analysis was employed to calculate 5-year relative survival for 21 cancers.ResultsSignificant improvements in crude 5-year relative survival for 14 of 21 assessed types of cancer, including the most frequent diagnoses, such as, colorectal, prostate, breast, lung, kidney, pancreatic, and bladder cancer and melanoma, were identified. Moreover, in case of colorectal, lung, and prostate cancer, improvement in stage-specific 5-year relative survival was confirmed as statistically significant for all clinical stages. No diagnosis showed significant decrease in the 5-year relative survival. However, the 5-year relative survival remained poor in patients with metastatic cancers at diagnosis, particularly in case of liver, pancreatic, lung, and oesophageal cancer.ConclusionsThe cancer-specific outcomes in the Czech Republic are improving. Nevertheless, despite the overall significant improvement in 5-year relative survival of most of the cancer diagnoses, the high proportion of patients primarily diagnosed with metastatic cancer still represents a substantial challenge for prevention and early detection.     

Thermodynamic dissection of the binding energetics of proline-rich peptides to the Abl-SH3 domain: implications for rational ligand design

The inhibition of the interactions between SH3 domains and their targets is emerging as a promising therapeutic strategy. To date, rational design of potent ligands for these domains has been hindered by the lack of understanding of the origins of the binding energy. We present here a complete thermodynamic analysis of the binding energetics of the p41 proline-rich decapeptide (APSYSPPPPP) to the SH3 domain of the c-Abl oncogene. Isothermal titration calorimetry experiments have revealed a thermodynamic signature for this interaction (very favourable enthalpic contributions opposed by an unfavourable binding entropy) inconsistent with the highly hydrophobic nature of the p41 ligand and the Abl-SH3 binding site. Our structural and thermodynamic analyses have led us to the conclusion, having once ruled out any possible ionization events or conformational changes coupled to the association, that the establishment of a complex hydrogen-bond network mediated by water molecules buried at the binding interface is responsible for the observed thermodynamic behaviour. The origin of the binding energetics for proline-rich ligands to the Abl-SH3 domain is further investigated by a comparative calorimetric analysis of a set of p41-related ligands. The striking effects upon the enthalpic and entropic contributions provoked by conservative substitutions at solvent-exposed positions in the ligand confirm the complexity of the interaction. The implications of these results for rational ligand design are discussed.     

Pokemon及其在肿瘤中的研究进展

Pokemon基因即POK红系髓性致癌因子,也被称为FBI-1,LRF,OCZF,TIP,它是POK转录抑制物家族成员之一,其编码的产物具有BTB／POZ域和锌指结构,它是第一个被发现的可变阅读框基因ARF（Altemative reading frame,ARF）的特异性转录抑制物,Pokemon通过特异抑制ARF转录来调控细胞周期、诱导肿瘤发生、促进肿瘤的发生发展,在一些人类肿瘤如食管鳞癌、肺癌、结肠癌、人贲门癌、膀胱癌,前列腺癌和乳腺癌等肿瘤组织中具有较高的表达水平。Pokemon的特殊性在于还能与其它癌基因如Bcl-2,MDM2等结合之后发挥作用来促进其他癌基因的活性。因此可以认为Pokemon是肿瘤的总开关,对Pokemon基因的进一步研究有助于为肿瘤的诊断和治疗提供新的途径和方法。     

Cancer therapies: basic and clinical perspectives in brain, prostate, and lung tumors: Naples, September, 24-27, 2000.

A continuous flow of theoretical and practical information among basic research, diagnosis, and therapeutic innovation is a crucial process to achieve a timely and effective progress in defeating human cancer. According to this essential concept, the main objective of the Fourth Joint International Cancer Conference "Cancer Therapies: Basic and Clinical Perspectives in Brain, Prostate and Lung Cancer" has been of gathering together basic scientists and clinicians who represent scientific opinion leaders in their field, to present and discuss the most recent scientific achievements in basic and clinical perspectives, advanced diagnostic and therapeutic strategies, and molecular and cellular therapeutic approaches in brain, prostate, and lung cancer.     

Quality assurance in pathology. Cytologic and histologic correlation.

In this study we used a computerized program to compare the cytologic and histologic diagnoses made in a three-year period with the aim of evaluating the data obtained as an index of the diagnostic accuracy of cytology in a pathology quality assurance program. Concordance between the cytologic and histologic diagnoses was observed in 83.2% of the cases. In 1.2% the cytologic diagnosis was suspected malignancy, and 78.4% of these cases were positive for tumor at histologic examination. Analysis of the data must be performed in accordance with the anatomic site involved, and discordance must be investigated by a pathologist, especially in view of the different modalities of cytologic and histologic sampling. Analytic data on the breast, bladder and lung are presented.     

蛋白酶活化受体1在不同肿瘤中的研究进展

人蛋白酶活化受体1(PAR-1)是蛋白酶活化受体家族的成员之一.它活化方式特殊,生物学功能广泛.已经证实PAR-1在黑色素瘤、乳腺癌、胃癌、鼻咽癌、前列腺癌癌旁间质、肝癌、结肠癌等组织中表达上调,在肿瘤细胞的增殖和转移过程中发挥重要作用,可作为患者临床病理分期及预后的标志物.     

Akt and PTEN: New diagnostic markers of non‐small cell lung cancer?

We are particularly interested in testing the principles of cell proliferation and apoptosis in the microenvironment of human lung cancers with respect to the cell survival protein Akt¹ and PTEN². Akt is a cytosolic protein which promotes cell survival by phosphorylative inactivation of targets in apoptotic pathways. Akt has been found to play a role in the survival of experimental cancer cell lines in breast, prostate, ovary, lung and brain tissue. PTEN is a tumor suppressor gene whose protein product is expressed in inverse proportion to phosphorylated Akt in endometrial and breast cancer cell lines. No studies of the diagnostic significance of Akt and PTEN in human lung cancers have been reported.     

Decreasing waiting time for treatment before and during implementation of cancer patient pathways in Norway

Background: In 2015, Norway implemented cancer patient pathways to reduce waiting times for treatment. The aims of this paper were to describe patterns in waiting time and their association with patient characteristics for colorectal, lung, breast and prostate cancers.Methods: National, population-based data from 2007 to 2016 were used. A multivariable quantile regression examined the association between treatment period, age, stage, sex, place of residence, and median waiting times.Results: Reduction in median waiting times for radiotherapy among colorectal, lung and prostate cancer patients ranged from 14 to 50 days. Median waiting time for surgery remained approximately 21 days for both colorectal and breast cancers, while it decreased by 7 and 36 days for lung and prostate cancers, respectively. The proportion of lung and prostate cancer patients with metastatic disease at the time of diagnosis decreased, while the proportion of colorectal patients with localised disease and patients with stage I breast cancer increased (p < 0.001). After adjusting for case-mix, a patient’s place of residence was significantly associated with waiting time for treatment (p < 0.001), however, differences in waiting time to treatment decreased over the study period.Conclusions: Between 2007 and 2016, Norway experienced improved stage distributions and consistently decreasing waiting times for treatment. While these improvements occurred gradually, no significant change was observed from the time of cancer patient pathway implementation.     

The emerging role of miR-653 in human cancer

MicroRNAs (miRNAs) refer to a family of non-coding RNA with ~22 nucleotides in length. A high number of studies show evidence that deregulation in miRNAs expression could be implicated in the processes of many pathologies such as cancer, hypoxia, and stroke. Herein, we aimed to summarize the miR-653 expression level and molecular mechanisms through which it functions in human cancer. It was found that variations in miR-653 expression are linked to tumor aggressiveness and unfavorable prognosis in human cancer, and it plays an inhibitory effect in some types of cancer, such as breast, cervical, liver, renal, and lung cancers. In contrast, it plays an acceleratory impact in some other cancers, such as bladder and prostate cancers. In gastric cancer, the role played by miR-653 is still controversial and will need to be elucidated in future studies. Future studies could definitely establish targeting miR-653 as a novel strategy in human cancer, from diagnosis to effective treatment.     

骨唾液酸蛋白在乳腺癌骨转移中的研究进展

骨唾液酸蛋白（Bonesialoprotein,BSP）是细胞外基质中一种高度磷酸化和糖基化分泌性蛋白,它是多种癌症（乳腺癌,前列腺癌和肺癌等）进程中的重要参与者。乳腺癌细胞转染实验和裸鼠移植模型证明过表达BSP可以促进乳腺癌细胞骨转移。BSP抗体和反义核酸均可有效抑制乳腺癌细胞骨转移的发生,故BSP有可能成为一种新的诊断和治疗乳腺癌骨转移的靶蛋白。     

The STEAP protein family: Versatile oxidoreductases and targets for cancer immunotherapy with overlapping and distinct cellular functions

The human six‐transmembrane epithelial antigen of the prostate (STEAP) protein family contains at least five homologous members. The necessity of multiple homologous STEAP proteins is still unclear, but their peculiar and tissue‐specific expression suggests that they are assigned to distinct functional tasks. This concept is supported by the fact that especially STEAP1, and to a lesser extent STEAP2 and ‐4, are highly over‐expressed in many different cancer entities, while being only minimally expressed in a few normal tissues. Despite their very similar domain organisation, STEAP3 seems to act as a potent metalloreductase essential for physiological iron uptake and turnover, while in particular STEAP4 appears to be rather involved in responses to nutrients and inflammatory stress, fatty acid and glucose metabolism. Moreover, individual STEAP proteins possess overlapping functions important for growth and survival of cancer cells. Due to their membrane‐bound localisation and their high expression in many different cancers such as prostate, breast and bladder carcinoma as well as Ewing's sarcoma, STEAP proteins have been recognised and utilised as promising targets for cell‐ and antibody‐based immunotherapy. This review summarises our present knowledge of the individual members of the human STEAP family and highlights the functional differences between them.