Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance : systematic review and meta-analysis

OBJECTIVE To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols. DESIGN Systematic review and meta-analysis. DATA SOURCES Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016. ELIGIBILITY CRITERIA Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months. DATA SYNTHESIS Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I-2 statistics. MAIN OUTCOME MEASURES Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months). RESULTS 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I-2= 77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I-2= 82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I-2= 90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I-2= 0%), 23% (two studies, 226/938 women, 20% to 26%; I-2= 97%), and 11% (three studies, 163/1033 women, 5% to 19%; I-2= 67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%. CONCLUSIONS Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.Peer reviewe

Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts

Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin-eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (chi(2)(2) = 20.61, P <0.001) and T-allele (chi(2)(1) = 21.04, P <0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P <0.001) and A-allele (chi(2)(1) = 25.75, P <0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.Peer reviewe

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis

OBJECTIVETo estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols.DESIGNSystematic review and meta-analysis.DATA SOURCESMedline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016.ELIGIBILITY CRITERIAStudies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months.DATA SYNTHESISTwo reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I-2 statistics.MAIN OUTCOME MEASURESRates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months).RESULTS36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I-2= 77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I-2= 82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I-2= 90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I-2= 0%), 23% (two studies, 226/938 women, 20% to 26%; I-2= 97%), and 11% (three studies, 163/1033 women, 5% to 19%; I-2= 67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%.CONCLUSIONSMost CIN2 lesions, particularly in young women (< 30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.</p

Reaction rate reconstruction from biomass concentration measurement in bioreactors using modified second-order sliding mode algorithms

This paper deals with the estimation of unknown signals in bioreactors using sliding observers. Particular attention is drawn to estimate the specific growth rate of microorganisms from measurement of biomass concentration. In a recent article, notions of high-order sliding modes have been used to derive a growth rate observer for batch processes. In this paper we generalize and refine these preliminary results. We develop a new observer with a different error structure to cope with other types of processes. Furthermore, we show that these observers are equivalent, under coordinate transformations and time scaling, to the classical super-twisting differentiator algorithm, thus inheriting all its distinctive features. The new observers’ family achieves convergence to timevarying unknown signals in finite time, and presents the best attainable estimation error order in the presence of noise. In addition, the observers are robust to modeling and parameter uncertainties since they are based on minimal assumptions on bioprocess dynamics. In addition, they have interesting applications in fault detection and monitoring. The observers performance in batch, fed-batch and continuous bioreactors is assessed by experimental data obtained from the fermentation of Saccharomyces Cerevisiae on glucose.This work was supported by the National University of La Plata (Project 2012-2015), the Agency for the Promotion of Science and Technology ANPCyT (PICT2007-00535) and the National Research Council CONICET (PIP112-200801-01052) of Argentina; the Technical University of Valencia (PAID-02-09), the CICYT (DPI2005-01180) and AECID (A/024186/09) of Spain; and by the project FEDER of the European Union.De Battista, H.; Picó Marco, JA.; Garelli, F.; Navarro Herrero, JL. (2012). Reaction rate reconstruction from biomass concentration measurement in bioreactors using modified second-order sliding mode algorithms. Bioprocess and Biosystems Engineering. 35(9):1-11. https://doi.org/10.1007/s00449-012-0752-yS111359Aborhey S, Williamson D (1978) State amd parameter estimation of microbial growth process. Automatica 14:493–498Bastin G, Dochain D (1986) On-line estimation of microbial specific growth rates. Automatica 22:705–709Bastin G, Dochain D (1990) On-line estimation and adaptive control of bioreactors. Elsevier, AmsterdamBejarano F, Fridman L (2009) Unbounded unknown inputs estimation based on high-order sliding mode differentiator. In: Proceedings of the 48th IEEE conference on decision and control, pp 8393–8398Corless M, Tu J (1998) State and input estimation for a class of uncertain systems. Automatica 34(6):757–764Dabros M, Schler M, Marison I (2010) Simple control of specific growth rate in biotechnological fed-batch processes based on enhanced online measurements of biomass. Bioprocess Biosyst Eng 33:1109–1118Davila A, Moreno J, Fridman L (2010) Variable gains super-twisting algorithm: a lyapunov based design. In: American control conference (ACC), 2010, pp 968–973Dávila J, Fridman L, Levant A (2005) Second-order sliding-mode observer for mechanical systems. IEEE Transact Automatic Control 50(11):1785–1789De Battista H, Picó J, Garelli F, Vignoni A (2011) Specific growth rate estimation in (fed-)batch bioreactors using second-order sliding observers. J Process Control 21:1049–1055Dochain D (2001) Bioprocess control. Wiley, HobokenDochain D (2003) State and parameter estimation in chemical and biochemical processes: a tutorial. J Process Control 13(8):801–818Edwards C, Spurgeon S, Patton R (2000) Sliding mode observers for fault detection and isolation. Automatica 36(2):541–553Evangelista C, Puleston P, Valenciaga F, Fridman L (2012) Lyapunov designed super-twisting sliding mode control for wind energy conversion optimization. Indus Electron IEEE Transact. doi: 10.1109/TIE.2012.2188256Farza M, Busawon K, Hammouri H (1998) Simple nonlinear observers for on-line estimation of kinetic rates in bioreactors. Automatica 34(3):301–318Fridman L, Davila J, Levant A (2008) High-order sliding modes observation. In: International workshop on variable structure systems, pp 203–208Fridman L, Levant A (2002) Sliding mode control in engineering, higher-order sliding modes. Marcel Dekker, Inc., New York, pp 53–101Fridman L, Shtessel Y, Edwards C, Yan X (2008) Higher-order sliding-mode observer for state estimation and input reconstruction in nonlinear systems. Int J Robust Nonlinear Control 18(3–4):399–412Gauthier J, Hammouri H, Othman S (1992) A simple observer for nonlinear systems: applications to bioreactors. IEEE Transact Automatic Control 37(6):875–880Gnoth S, Jenzsch M, Simutis R, Lubbert A (2008) Control of cultivation processes for recombinant protein production: a review. Bioprocess Biosyst Eng 31(1):21–39Hitzmann B, Broxtermann O, Cha Y, Sobieh O, Stärk E, Scheper T (2000) The control of glucose concentration during yeast fed-batch cultivation using a fast measurement complemented by an extended kalman filter. Bioprocess Eng 23(4):337–341Kiviharju K, Salonen K, Moilanen U, Eerikainen T (2008) Biomass measurement online: the performance of in situ measurements and software sensors. J Indus Microbiol Biotechnol 35(7):657–665Levant A (1998) Robust exact differentiation via sliding mode technique. Automatica 34(3):379–384Levant A (2003) Higher-order sliding modes, differentiation and output-feedback control. Int J Control 76(9/10):924–941Lubenova V, Rocha I, Ferreira E (2003) Estimation of multiple biomass growth rates and biomass concentration in a class of bioprocesses. 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Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Triptolide Inhibits the Proliferation of Prostate Cancer Cells and Down-Regulates SUMO-Specific Protease 1 Expression

Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine), have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa) is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1) was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa

HDAC inhibitor confers radiosensitivity to prostate stem-like cells

Background: Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction. Methods: Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2β1integrinhi/CD133+), transit-amplifying (TA, α2β1integrinhi/CD133−) and committed basal (CB, α2β1integrinlo) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser. Results: Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation. Interpretation: Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction